Genetics

To the Editor: The review of thoracic aortic aneurysm by Cikach et al¹ was excellent. However, we noted that referral for clinical genetic counseling and testing is suggested only if 1 or more first-degree relatives have aneurysmal disease.

Absence of a family history does not rule out syndromic aortopathy, which can occur de novo. In addition, a clinical diagnosis of syndromic aortopathy can be made on the basis of physical features that can be very subtle, such as pectus deformities, scoliosis, dolichostenomelia, joint hypermobility or contractures, craniofacial features, or skin fragility.²

Genetic counseling is paramount even if molecular testing is negative or inconclusive, which can occur in more than 50% of patients referred.³ Clinical genetic evaluation would also facilitate testing for other family members who may be affected, and would help to coordinate care for nonvascular conditions that may be associated with the syndrome.

To the Editor: The review of thoracic aortic aneurysm by Cikach et al¹ was excellent. However, we noted that referral for clinical genetic counseling and testing is suggested only if 1 or more first-degree relatives have aneurysmal disease.

Absence of a family history does not rule out syndromic aortopathy, which can occur de novo. In addition, a clinical diagnosis of syndromic aortopathy can be made on the basis of physical features that can be very subtle, such as pectus deformities, scoliosis, dolichostenomelia, joint hypermobility or contractures, craniofacial features, or skin fragility.²

Genetic counseling is paramount even if molecular testing is negative or inconclusive, which can occur in more than 50% of patients referred.³ Clinical genetic evaluation would also facilitate testing for other family members who may be affected, and would help to coordinate care for nonvascular conditions that may be associated with the syndrome.

To the Editor: The review of thoracic aortic aneurysm by Cikach et al¹ was excellent. However, we noted that referral for clinical genetic counseling and testing is suggested only if 1 or more first-degree relatives have aneurysmal disease.

Absence of a family history does not rule out syndromic aortopathy, which can occur de novo. In addition, a clinical diagnosis of syndromic aortopathy can be made on the basis of physical features that can be very subtle, such as pectus deformities, scoliosis, dolichostenomelia, joint hypermobility or contractures, craniofacial features, or skin fragility.²

Genetic counseling is paramount even if molecular testing is negative or inconclusive, which can occur in more than 50% of patients referred.³ Clinical genetic evaluation would also facilitate testing for other family members who may be affected, and would help to coordinate care for nonvascular conditions that may be associated with the syndrome.

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the University of Arizona Cancer Center, Tucson, AZ (Dr. Ehsani), and University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, WI (Dr. Wisinski).

Abstract

• Objectives: To describe common genomic tests being used clinically to assess prognosis and guide adjuvant chemotherapy and endocrine therapy decisions for early-stage breast cancer.
• Methods: Case presentation and review of the literature.
• Results: Hormone receptor–positive (HR-positive) breast cancers, which express the estrogen and/or progesterone receptor, account for the majority of breast cancers. Endocrine therapy can be highly effective for patients with these HR-positive tumors, and identification of HR-positive breast cancers that do not require the addition of chemotherapy is critical. Clinicopathological features of the breast cancer, including tumor size, nodal involvement, grading, and HR status, are insufficient in predicting the risk for recurrence or the need for chemotherapy. Furthermore, a portion of HR-positive breast cancers have an ongoing risk for late recurrence, and longer durations of endocrine therapy are being used to reduce this risk.
• Conclusion: There is sufficient evidence for use of genomic testing in early-stage HR-positive breast cancer to aid in chemotherapy recommendations. Further confirmation of genomic assays for prediction of benefit from prolonged endocrine therapy is needed.

Key words: molecular testing; decision aids; HR-positive cancer; recurrence risk; adjuvant chemotherapy; endocrine therapy.

Despite the increase in incidence of breast cancer, breast cancer mortality has decreased over the past several decades. This is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns regarding potential overdiagnosis of cancer [1]. One key challenge is that breast cancer is a heterogeneous disease. Thus, improved tools for determining breast cancer biology can help physicians individualize treatments, with low-risk cancers approached with less aggressive treatments, thus preventing unnecessary toxicities, and higher-risk cancers treated appropriately.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment recommendations, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, there are individuals with low-risk HR-positive, HER2-negative breast cancers who could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given for extended durations. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34% [2]. However, the overall survival was similar between the 2 groups and the results were not confirmed in other studies [3–5]. Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2 negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy rec-ommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. Hormone receptor (HR)–positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for HR-positive breast cancer [6], the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B [7]. These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors [8]. Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Tests for Guiding Adjuvant Chemotherapy Decisions

Ki-67 Assays, Including IHC4 and PEPI

Chronic proliferation is a hallmark of cancer cells [9]. Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation [10]. Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates [11,12]. Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang et al determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors [13]. However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This IHC4 score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy [14]. The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology, and intraobserver variability in interpreting the Ki-67 results [15]. Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point [16]. These issues continue to impact the clinical utility of Ki-67 for decision making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease [17]. The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial [18] to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. This was subsequently validated in an independent data set from the IMPACT trial [19]. Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors which are at higher risk for early relapse [20]. The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Oncotype DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer-related genes and 5 reference genes using quantitative polymerase chain reaction. The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling [21]. Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy [22]. Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival [21]. Inferior breast cancer survival with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease [23–25].

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores [26]. However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low- or intermediate-risk did not have an improved freedom from distant recurrence with chemotherapy [27]. Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores [24].

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive and HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard of care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to hemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low-recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98% [28]. Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score [24], due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like [7,29]. Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive, early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials [30,31]. In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy [30]. The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5 %, indicating lack of benefit from additional chemotherapy [31]. A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis [32]. Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy [33]. Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results [34]. In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue [35].

Summary

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemo-therapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole [36]. She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer [37]. Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease [38]. Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care [39]. AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen [40].

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66; P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference [2]. Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years [3]. Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

Tests for Assessing Risk for Late Recurrence

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group [44]. Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse [45].

EndoPredict

EndoPredict (EP) is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EP low- and EP high-risk groups. EP has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive, HER2-negative early breast cancer [46]. More important, EP has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy [47]. Recently, EP and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EP and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events [48]. EndoPredict is the first multigene expression assay that could be routinely performed in decentral molecular pathological laboratories with a short turnaround time [49].

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial [50]. In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%) [50].

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease [51,52]. The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence [53]. BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence [54].

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety [55].

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays have been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10; low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patient’s compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Corresponding author: Kari Braun Wisinski, MD, 1111 Highland Avenue, 6033 Wisconsin Institute for Medical Research, Madison, WI 53705-2275, [email protected].

Financial disclosures: This work was supported by the NCI Cancer Center Support Grant P30 CA014520.

From the University of Arizona Cancer Center, Tucson, AZ (Dr. Ehsani), and University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, WI (Dr. Wisinski).

Abstract

• Objectives: To describe common genomic tests being used clinically to assess prognosis and guide adjuvant chemotherapy and endocrine therapy decisions for early-stage breast cancer.
• Methods: Case presentation and review of the literature.
• Results: Hormone receptor–positive (HR-positive) breast cancers, which express the estrogen and/or progesterone receptor, account for the majority of breast cancers. Endocrine therapy can be highly effective for patients with these HR-positive tumors, and identification of HR-positive breast cancers that do not require the addition of chemotherapy is critical. Clinicopathological features of the breast cancer, including tumor size, nodal involvement, grading, and HR status, are insufficient in predicting the risk for recurrence or the need for chemotherapy. Furthermore, a portion of HR-positive breast cancers have an ongoing risk for late recurrence, and longer durations of endocrine therapy are being used to reduce this risk.
• Conclusion: There is sufficient evidence for use of genomic testing in early-stage HR-positive breast cancer to aid in chemotherapy recommendations. Further confirmation of genomic assays for prediction of benefit from prolonged endocrine therapy is needed.

Key words: molecular testing; decision aids; HR-positive cancer; recurrence risk; adjuvant chemotherapy; endocrine therapy.

Despite the increase in incidence of breast cancer, breast cancer mortality has decreased over the past several decades. This is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns regarding potential overdiagnosis of cancer [1]. One key challenge is that breast cancer is a heterogeneous disease. Thus, improved tools for determining breast cancer biology can help physicians individualize treatments, with low-risk cancers approached with less aggressive treatments, thus preventing unnecessary toxicities, and higher-risk cancers treated appropriately.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment recommendations, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, there are individuals with low-risk HR-positive, HER2-negative breast cancers who could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given for extended durations. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34% [2]. However, the overall survival was similar between the 2 groups and the results were not confirmed in other studies [3–5]. Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2 negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy rec-ommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. Hormone receptor (HR)–positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for HR-positive breast cancer [6], the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B [7]. These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors [8]. Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Tests for Guiding Adjuvant Chemotherapy Decisions

Ki-67 Assays, Including IHC4 and PEPI

Chronic proliferation is a hallmark of cancer cells [9]. Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation [10]. Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates [11,12]. Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang et al determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors [13]. However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This IHC4 score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy [14]. The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology, and intraobserver variability in interpreting the Ki-67 results [15]. Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point [16]. These issues continue to impact the clinical utility of Ki-67 for decision making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease [17]. The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial [18] to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. This was subsequently validated in an independent data set from the IMPACT trial [19]. Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors which are at higher risk for early relapse [20]. The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Oncotype DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer-related genes and 5 reference genes using quantitative polymerase chain reaction. The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling [21]. Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy [22]. Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival [21]. Inferior breast cancer survival with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease [23–25].

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores [26]. However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low- or intermediate-risk did not have an improved freedom from distant recurrence with chemotherapy [27]. Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores [24].

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive and HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard of care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to hemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low-recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98% [28]. Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score [24], due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like [7,29]. Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive, early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials [30,31]. In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy [30]. The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5 %, indicating lack of benefit from additional chemotherapy [31]. A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis [32]. Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy [33]. Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results [34]. In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue [35].

Summary

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemo-therapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole [36]. She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer [37]. Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease [38]. Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care [39]. AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen [40].

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66; P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference [2]. Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years [3]. Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

Tests for Assessing Risk for Late Recurrence

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group [44]. Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse [45].

EndoPredict

EndoPredict (EP) is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EP low- and EP high-risk groups. EP has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive, HER2-negative early breast cancer [46]. More important, EP has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy [47]. Recently, EP and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EP and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events [48]. EndoPredict is the first multigene expression assay that could be routinely performed in decentral molecular pathological laboratories with a short turnaround time [49].

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial [50]. In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%) [50].

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease [51,52]. The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence [53]. BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence [54].

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety [55].

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays have been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10; low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patient’s compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Corresponding author: Kari Braun Wisinski, MD, 1111 Highland Avenue, 6033 Wisconsin Institute for Medical Research, Madison, WI 53705-2275, [email protected].

Financial disclosures: This work was supported by the NCI Cancer Center Support Grant P30 CA014520.

From the University of Arizona Cancer Center, Tucson, AZ (Dr. Ehsani), and University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, WI (Dr. Wisinski).

Abstract

• Objectives: To describe common genomic tests being used clinically to assess prognosis and guide adjuvant chemotherapy and endocrine therapy decisions for early-stage breast cancer.
• Methods: Case presentation and review of the literature.
• Results: Hormone receptor–positive (HR-positive) breast cancers, which express the estrogen and/or progesterone receptor, account for the majority of breast cancers. Endocrine therapy can be highly effective for patients with these HR-positive tumors, and identification of HR-positive breast cancers that do not require the addition of chemotherapy is critical. Clinicopathological features of the breast cancer, including tumor size, nodal involvement, grading, and HR status, are insufficient in predicting the risk for recurrence or the need for chemotherapy. Furthermore, a portion of HR-positive breast cancers have an ongoing risk for late recurrence, and longer durations of endocrine therapy are being used to reduce this risk.
• Conclusion: There is sufficient evidence for use of genomic testing in early-stage HR-positive breast cancer to aid in chemotherapy recommendations. Further confirmation of genomic assays for prediction of benefit from prolonged endocrine therapy is needed.

Key words: molecular testing; decision aids; HR-positive cancer; recurrence risk; adjuvant chemotherapy; endocrine therapy.

Despite the increase in incidence of breast cancer, breast cancer mortality has decreased over the past several decades. This is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns regarding potential overdiagnosis of cancer [1]. One key challenge is that breast cancer is a heterogeneous disease. Thus, improved tools for determining breast cancer biology can help physicians individualize treatments, with low-risk cancers approached with less aggressive treatments, thus preventing unnecessary toxicities, and higher-risk cancers treated appropriately.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment recommendations, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, there are individuals with low-risk HR-positive, HER2-negative breast cancers who could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given for extended durations. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34% [2]. However, the overall survival was similar between the 2 groups and the results were not confirmed in other studies [3–5]. Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2 negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy rec-ommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. Hormone receptor (HR)–positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for HR-positive breast cancer [6], the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B [7]. These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors [8]. Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Tests for Guiding Adjuvant Chemotherapy Decisions

Ki-67 Assays, Including IHC4 and PEPI

Chronic proliferation is a hallmark of cancer cells [9]. Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation [10]. Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates [11,12]. Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang et al determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors [13]. However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This IHC4 score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy [14]. The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology, and intraobserver variability in interpreting the Ki-67 results [15]. Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point [16]. These issues continue to impact the clinical utility of Ki-67 for decision making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease [17]. The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial [18] to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. This was subsequently validated in an independent data set from the IMPACT trial [19]. Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors which are at higher risk for early relapse [20]. The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Oncotype DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer-related genes and 5 reference genes using quantitative polymerase chain reaction. The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling [21]. Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy [22]. Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival [21]. Inferior breast cancer survival with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease [23–25].

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores [26]. However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low- or intermediate-risk did not have an improved freedom from distant recurrence with chemotherapy [27]. Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores [24].

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive and HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard of care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to hemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low-recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98% [28]. Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score [24], due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like [7,29]. Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive, early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials [30,31]. In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy [30]. The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5 %, indicating lack of benefit from additional chemotherapy [31]. A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis [32]. Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy [33]. Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results [34]. In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue [35].

Summary

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemo-therapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole [36]. She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer [37]. Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease [38]. Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care [39]. AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen [40].

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66; P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference [2]. Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years [3]. Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

Tests for Assessing Risk for Late Recurrence

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group [44]. Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse [45].

EndoPredict

EndoPredict (EP) is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EP low- and EP high-risk groups. EP has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive, HER2-negative early breast cancer [46]. More important, EP has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy [47]. Recently, EP and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EP and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events [48]. EndoPredict is the first multigene expression assay that could be routinely performed in decentral molecular pathological laboratories with a short turnaround time [49].

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial [50]. In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%) [50].

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease [51,52]. The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence [53]. BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence [54].

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety [55].

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays have been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10; low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patient’s compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Corresponding author: Kari Braun Wisinski, MD, 1111 Highland Avenue, 6033 Wisconsin Institute for Medical Research, Madison, WI 53705-2275, [email protected].

Financial disclosures: This work was supported by the NCI Cancer Center Support Grant P30 CA014520.

A 30-year-old man presented with multiple asymptomatic skin-colored and yellowish papules and nodules over the elbows, wrists, feet, buttocks, hands, and forearms (Figure 1) that had appeared suddenly 2 weeks before.

His medical history included diabetes mellitus, Hansen disease diagnosed 6 years earlier and treated with a multibacillary regimen for 1 year, and pancreatitis diagnosed 6 months earlier.

Laboratory testing. When a serum sample was centrifuged at 1,500 rpm for 15 minutes, a large lipid layer formed at the top (Figure 2). Other results:

• Triglycerides 5,742 mg/dL (reference range < 160)
• Total cholesterol 293 mg/dL (< 240 mg/dL)
• Fasting blood glucose 473 mg/dL
• Low-density and high-density lipoprotein cholesterol levels normal
• Complete blood cell count within normal limits.

Other testing. The electrocardiogram was normal. Retinal examination showed evidence of lipemia retinalis. Histologic study of a biopsy specimen from one of the lesions showed foamy macrophages in the superficial dermis with lymphocytic infiltrate, confirming the diagnosis of eruptive xanthoma.

An urgent medical referral was sought. The patient was started on statins and fibrates, and the treatment resulted in remarkable improvement.

ERUPTIVE XANTHOMA

Cutaneous manifestations can be warning signs of systemic disease, and physicians should be aware of the dermatologic presentations of common medical conditions.

Eruptive xanthoma is a sign of severe hypertriglyceridemia and is almost always due to an acquired cause such as hyperchylomicro­nemia or an inherited lipoprotein disorder (eg, lipoprotein lipase deficiency in children, common familial hypertriglyceridemia type 5 in adults).¹

Chylomicronemia syndrome is characterized by triglyceride levels greater than 1,000 mg/dL in a patient with eruptive xanthoma, lipemia retinalis, or abdominal pain or pancreatitis. The syndrome has a prevalence of 1.7 out of 10,000 patients.² Treatment is a strict low-fat diet, with a minimal role for fibrates and nicotinic acid.

Eruptive xanthoma is seen at the time of presentation in 8.5% of patients with severe hypertriglyceridemia (serum level > 1,772 mg/dL).³ In patients with serum triglyceride levels greater than 1,000 mg/dL, the risk of acute pancreatitis is 5%, and at levels above 2,000 mg/dL, the risk is 10% to 20%.⁴

In our patient, the diagnosis of chylomicronemia was based on the appearance of the skin lesions, his history of pancreatitis and diabetes mellitus, and the results of the initial workup, which revealed severe hypertriglyceridemia and lipemia retinalis. The presence of eruptive xanthomas should raise suspicion for a grossly elevated triglyceride level. Therefore, in view of the increased risk of acute pancreatitis and pancreatic necrosis associated with chylomicronemic syndrome,² recognizing the cutaneous signs is mandatory.

A 30-year-old man presented with multiple asymptomatic skin-colored and yellowish papules and nodules over the elbows, wrists, feet, buttocks, hands, and forearms (Figure 1) that had appeared suddenly 2 weeks before.

His medical history included diabetes mellitus, Hansen disease diagnosed 6 years earlier and treated with a multibacillary regimen for 1 year, and pancreatitis diagnosed 6 months earlier.

Laboratory testing. When a serum sample was centrifuged at 1,500 rpm for 15 minutes, a large lipid layer formed at the top (Figure 2). Other results:

• Triglycerides 5,742 mg/dL (reference range < 160)
• Total cholesterol 293 mg/dL (< 240 mg/dL)
• Fasting blood glucose 473 mg/dL
• Low-density and high-density lipoprotein cholesterol levels normal
• Complete blood cell count within normal limits.

Other testing. The electrocardiogram was normal. Retinal examination showed evidence of lipemia retinalis. Histologic study of a biopsy specimen from one of the lesions showed foamy macrophages in the superficial dermis with lymphocytic infiltrate, confirming the diagnosis of eruptive xanthoma.

An urgent medical referral was sought. The patient was started on statins and fibrates, and the treatment resulted in remarkable improvement.

ERUPTIVE XANTHOMA

Cutaneous manifestations can be warning signs of systemic disease, and physicians should be aware of the dermatologic presentations of common medical conditions.

Eruptive xanthoma is a sign of severe hypertriglyceridemia and is almost always due to an acquired cause such as hyperchylomicro­nemia or an inherited lipoprotein disorder (eg, lipoprotein lipase deficiency in children, common familial hypertriglyceridemia type 5 in adults).¹

Chylomicronemia syndrome is characterized by triglyceride levels greater than 1,000 mg/dL in a patient with eruptive xanthoma, lipemia retinalis, or abdominal pain or pancreatitis. The syndrome has a prevalence of 1.7 out of 10,000 patients.² Treatment is a strict low-fat diet, with a minimal role for fibrates and nicotinic acid.

Eruptive xanthoma is seen at the time of presentation in 8.5% of patients with severe hypertriglyceridemia (serum level > 1,772 mg/dL).³ In patients with serum triglyceride levels greater than 1,000 mg/dL, the risk of acute pancreatitis is 5%, and at levels above 2,000 mg/dL, the risk is 10% to 20%.⁴

In our patient, the diagnosis of chylomicronemia was based on the appearance of the skin lesions, his history of pancreatitis and diabetes mellitus, and the results of the initial workup, which revealed severe hypertriglyceridemia and lipemia retinalis. The presence of eruptive xanthomas should raise suspicion for a grossly elevated triglyceride level. Therefore, in view of the increased risk of acute pancreatitis and pancreatic necrosis associated with chylomicronemic syndrome,² recognizing the cutaneous signs is mandatory.

A 30-year-old man presented with multiple asymptomatic skin-colored and yellowish papules and nodules over the elbows, wrists, feet, buttocks, hands, and forearms (Figure 1) that had appeared suddenly 2 weeks before.

His medical history included diabetes mellitus, Hansen disease diagnosed 6 years earlier and treated with a multibacillary regimen for 1 year, and pancreatitis diagnosed 6 months earlier.

Laboratory testing. When a serum sample was centrifuged at 1,500 rpm for 15 minutes, a large lipid layer formed at the top (Figure 2). Other results:

• Triglycerides 5,742 mg/dL (reference range < 160)
• Total cholesterol 293 mg/dL (< 240 mg/dL)
• Fasting blood glucose 473 mg/dL
• Low-density and high-density lipoprotein cholesterol levels normal
• Complete blood cell count within normal limits.

Other testing. The electrocardiogram was normal. Retinal examination showed evidence of lipemia retinalis. Histologic study of a biopsy specimen from one of the lesions showed foamy macrophages in the superficial dermis with lymphocytic infiltrate, confirming the diagnosis of eruptive xanthoma.

An urgent medical referral was sought. The patient was started on statins and fibrates, and the treatment resulted in remarkable improvement.

ERUPTIVE XANTHOMA

Cutaneous manifestations can be warning signs of systemic disease, and physicians should be aware of the dermatologic presentations of common medical conditions.

Eruptive xanthoma is a sign of severe hypertriglyceridemia and is almost always due to an acquired cause such as hyperchylomicro­nemia or an inherited lipoprotein disorder (eg, lipoprotein lipase deficiency in children, common familial hypertriglyceridemia type 5 in adults).¹

Chylomicronemia syndrome is characterized by triglyceride levels greater than 1,000 mg/dL in a patient with eruptive xanthoma, lipemia retinalis, or abdominal pain or pancreatitis. The syndrome has a prevalence of 1.7 out of 10,000 patients.² Treatment is a strict low-fat diet, with a minimal role for fibrates and nicotinic acid.

Eruptive xanthoma is seen at the time of presentation in 8.5% of patients with severe hypertriglyceridemia (serum level > 1,772 mg/dL).³ In patients with serum triglyceride levels greater than 1,000 mg/dL, the risk of acute pancreatitis is 5%, and at levels above 2,000 mg/dL, the risk is 10% to 20%.⁴

In our patient, the diagnosis of chylomicronemia was based on the appearance of the skin lesions, his history of pancreatitis and diabetes mellitus, and the results of the initial workup, which revealed severe hypertriglyceridemia and lipemia retinalis. The presence of eruptive xanthomas should raise suspicion for a grossly elevated triglyceride level. Therefore, in view of the increased risk of acute pancreatitis and pancreatic necrosis associated with chylomicronemic syndrome,² recognizing the cutaneous signs is mandatory.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Primary care providers can play a critical role in detecting it and managing patients who have it.

RECOGNIZED CASES ARE THE TIP OF THE ICEBERG

First described in 1963,¹ alpha-1 antitrypsin deficiency is estimated to affect 100,000 Americans, fewer than 15,000 of whom have received a clinical diagnosis. As further evidence of its underrecognition,^2–7 many patients experience long delays between their first symptoms and the diagnosis. Early studies indicated that the average diagnostic delay was 7.2 years,4 and the latest studies, as recent as 2013, indicate a similar diagnostic delay.⁷

Furthermore, many patients see multiple healthcare providers before receiving the correct diagnosis. A 1994 survey by this author⁴ found that 43.7% of patients who had severe deficiency of alpha-1 antitrypsin saw at least three physicians before the correct diagnosis was made.

Why is the disease underrecognized?

Several reasons may account for underrecognition of this disease. Many clinicians—including, unfortunately, many pulmonologists—do not know much about it,^7,8 do not adhere to clinical guidelines,^9,10 or harbor the misperception that there is no therapy available and, therefore, no compelling reason to make a diagnosis.⁷

Regarding inadequate knowledge, in a study by Taliercio, Chatburn, and this author,⁸ internal medicine residents scored only 63% correct on a 10-question quiz on diagnostic features of alpha-1 antitrypsin deficiency. There was no evidence of a training effect—senior residents scored no higher than interns.

Similarly, when Greulich et al⁷ surveyed German and Italian internists, general practitioners, and pulmonologists, one-fourth to one-half of them (depending on specialty and country) stated that they knew either very little or nothing at all about alpha-1 antitrypsin deficiency. In addition, 7% to 8% agreed with the statement, “There is no treatment available for this disease.”⁷

Nonadoption of clinical guidelines has been widely recognized in medicine and is evident in the failure to implement various recommended practices,^9,10 such as low-stretch ventilation for acute respiratory distress syndrome and prophylaxis against deep vein thrombosis.

Finding the rest of the iceberg

Efforts to enhance compliance with guidelines on testing for alpha-1 antitrypsin deficiency have included using the electronic medical record to prompt physicians to test appropriate candidates.^11–13

Jain et al¹³ examined the effect of installing such a prompting system to remind physicians to test for alpha-1 antitrypsin deficiency in patients with airflow obstruction that does not reverse with a bronchodilator—a recognized indication for testing for this disease according to standards endorsed by the American Thoracic Society and European Respiratory Society.¹⁴ At baseline, only 4.7% of appropriate candidates were being tested; after a prompt was installed in the electronic medical record, the rate rose to 15.1%, still a minority of candidates.

Another strategy is to empower respiratory therapists who perform pulmonary function tests to invite patients to be tested if their pulmonary function tests show postbronchodilator airflow obstruction. Rahaghi et al¹⁵ showed that using this strategy, 20 (0.63%) of 3,152 patients who were found to have fixed airflow obstruction when they underwent pulmonary function testing were newly diagnosed with severe deficiency of alpha-1 antitrypsin. Other targeted detection studies in patients with COPD estimated the prevalence of alpha-1 antitrypsin deficiency at up to 12%.³

PHYSIOLOGY AND PATHOPHYSIOLOGY OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Alpha-1 antitrypsin is a single-chain, 394-amino acid glycoprotein with three carbohydrate side chains found at asparagine residues along the primary structure.¹⁶

A major physiologic function of this molecule is to bind neutrophil elastase, which it does avidly. In a “mousetrap-like” mechanism,¹⁶ an active site on the alpha-1 antitrypsin molecule captures the neutrophil elastase and is cleaved, releasing steric energy in the molecule, catapulting the neutrophil elastase to the opposite side of the alpha-1 antitrypsin molecule, and inactivating it (Figure 1).

MM is normal, ZZ is not

Alpha-1 antitrypsin deficiency is inherited as an autosomal-codominant condition.¹⁷

The SERPINA1 gene, which codes for alpha-1 antitrypsin, is located on the long arm of the 14th chromosome, and more than 150 alleles of this gene have been identified to date. The normal allele is denoted M, and the allele most commonly associated with severe deficiency is denoted Z. People who are homozygous for the M allele (ie, normal) are called PI*MM (PI stands for “protease inhibitor”), and those who are homozygous for the Z allele are PI*ZZ. More than 90% of patients with severe alpha-1 antitrypsin deficiency are PI*ZZ.¹⁸

The Z allele has a single amino acid substitution (glutamic acid-to-lysine at position 342), which results in abnormal folding and formation of polymers of the Z molecule within hepatocytes.^19,20 These polymers are recognized on liver biopsy as periodic acid-Schiff diastase-resistant eosinophilic inclusion bodies on histologic staining (Figure 2).

With alpha-1 antitrypsin trapped as Z-molecule polymers in the liver, the amount in the bloodstream falls, and there is a consequent decrease in the amount available in the lung to oppose the proteolytic burden of neutrophil elastase, especially in people who smoke or work in dusty environments.²¹

Tan et al²² have shown that some of the polymerized Z protein can escape the liver and circulate in the blood and that alveolar macrophages may also produce Z polymers. These Z polymers are chemotactic for neutrophils,²³ so that their presence in the lung fuels the inflammatory cascade by recruiting more neutrophils to the lung, thereby increasing the proteolytic burden to the lung and increasing the risk of emphysema. Z monomers that do circulate can bind neutrophil elastase, but their binding avidity to neutrophil elastase is substantially lower than that of M-type alpha-1 antitrypsin.

CLINICAL MANIFESTATIONS

Alpha-1 antitrypsin deficiency of the PI*ZZ type is associated with two major clinical manifestations:

• Emphysema, resulting from the loss of proteolytic protection of the lung by alpha-1 antitrypsin (a toxic loss of function), and
• Liver diseases such as cirrhosis and chronic hepatitis, which result from abnormal accumulation of alpha-1 antitrypsin within hepatocytes (a toxic gain of function), and hepatoma.¹⁷

Other clinical manifestations of PI*ZZ alpha-1 antitrypsin deficiency include panniculitis and an association with cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis.¹⁷

Some uncertainty exists regarding the risk associated with the PI*MZ heterozygous state because there has been no systematic longitudinal study of people with this genotype. However, the weight of available experience suggests that PI*MZ individuals who have never smoked are not at increased risk of developing emphysema.²⁴

Findings from a national registry: PI*ZZ COPD resembles ‘usual’ COPD

Distinguishing patients with alpha-1 antitrypsin deficiency from those with “usual” COPD (ie, without alpha-1 antitrypsin deficiency) can be difficult, as shown in data from the National Heart, Lung, and Blood Institute’s   Alpha-1 Antitrypsin Deficiency Registry study.¹⁸ This multicenter, longitudinal, observational study contains the largest well-characterized cohort with severe deficiency of alpha-1 antitrypsin (PI*ZZ, PI*ZNull, etc), with 1,129 patients. 

Pulmonary function test results were consistent with emphysema in most of the patients in the registry. Mean postbronchodilator pulmonary function values (± standard error of the mean) were:

• Forced expiratory volume in 1 second (FEV₁) 46.7% of predicted (± 30%)
• Ratio of FEV₁ to forced vital capacity 42.9% (± 20.4% )
• Mean diffusing capacity for carbon monoxide 50.3% of predicted (± 22.5%).

Like many patients with usual COPD, 60% of the registry patients demonstrated a component of airway reactivity, with significant reversal of airflow obstruction over three spirometries after receiving a dose of an inhaled bronchodilator (characterized by a 12% and 200-mL postbronchodilator rise in FEV₁). Moreover, 78 patients had normal lung function.

Symptoms also resembled those in patients with usual emphysema, chronic bronchitis, or both. On enrollment in the registry, 83.9% of the patients had shortness of breath on exertion, 75.5% had wheezing with upper respiratory infections, 65.3% had wheezing without upper respiratory infection, 67.6% had recent debilitating chest illness, 42.4% had “usual” cough, and 49.6% had annual cough and phlegm episodes.

Imaging findings. Although the classic teaching is that emphysema due to alpha-1 antitrypsin deficiency produces lower-lobe hyperlucency on plain films, relying on this sign would lead to underrecognition, as 36% of PI*ZZ patients have apical-predominant emphysema on chest computed tomography,²⁴ which resembles the usual centriacinar emphysema pattern. Figure 3 shows axial computed tomographic scans through the apices and the bases of the lungs of a patient with alpha-1 antitrypsin deficiency.  

In view of these difficulties, guidelines from the American Thoracic Society and European Respiratory Society¹⁴ endorse testing for alpha-1 antitrypsin deficiency in all adults who have symptoms and fixed airflow obstruction (Table 1).

CONSEQUENCES OF ALPHA-1 ANTITRYPSIN DEFICIENCY

Two large screening studies^2,3,25,26 followed people who were identified at birth as having alpha-1 antitrypsin deficiency to examine the natural course of the disease.

The larger of the two studies²⁷ tested 200,000 Swedish newborns. Follow-up of this cohort to age 35 indicated that 35-year-old never-smoking PI*ZZ individuals have normal lung function and no excess emphysema on computed tomography compared with normal peers matched for age and sex.²⁷ In contrast, the few PI*ZZ ever-smokers demonstrated a lower level of transfer factor and significantly more emphysema on computed tomography than normal (PI*MM) never-smokers.

Faster decline in lung function

Data from the National Heart, Lung, and Blood Institute registry indicate that, on average, people with severe alpha-1 antitrypsin deficiency lose lung function faster than people without the disease.²⁸ Specifically, in never-smokers in the registry, the average rate of FEV₁ decline was 67 mL/year, and among ex-smokers, it was 54 mL/year. Both of these values exceed the general age-related rate of FEV₁ decline of approximately 20 to 25 mL/year in never-smoking, normal adults. Among current smokers in the registry with severe alpha-1 antitrypsin deficiency, the rate of FEV₁ decline was 109 mL/year.

Rates of FEV₁ decline over time vary among groups with differing degrees of airflow obstruction. For example, PI*ZZ patients with moderate COPD (stage II of the four-stage Global Initiative for Chronic Obstructive Lung Disease classification system) lose lung function faster than patients with either milder or more severe degrees of airflow obstruction.²⁹

As with COPD in general, exacerbations of COPD in people with severe deficiency of alpha-1 antitrypsin are associated with worsened clinical status. In one series,³⁰ 54% of 265 PI*ZZ patients experienced an exacerbation in the first year of follow-up, and 18% experienced at least three. Such exacerbations occurred in December and January in 32% of these individuals, likely due to a viral precipitant.

Increased mortality

Severe deficiency of alpha-1 antitrypsin is associated not only with severe morbidity but also death. In the national registry, the overall rate of death was 18.6% at 5 years of follow-up, or approximately 3% per year.²⁸

A low FEV₁ at entry was a bad sign. Patients entering the registry with FEV₁ values below 15% of predicted had a 36% mortality rate at 3 years, compared with 2.6% in those whose baseline FEV₁ exceeded 50% of predicted.

Underlying causes of death in registry participants included emphysema (accounting for 72% of deaths) and cirrhosis (10%),³¹ which were the only causes of death more frequent than in age- and sex-matched controls. In a series of never-smokers who had PI*ZZ alpha-1 antitrypsin deficiency,³² death was less frequently attributed to emphysema than in the national registry (46%) and more often attributed to cirrhosis (28%), indicating that never-smokers may more frequently escape the ravages of emphysema but experience a higher rate of developing cirrhosis later in life.³³

DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY

Available blood tests for alpha-1 antitrypsin deficiency include:

The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.

Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.

Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.¹⁷

Gene sequencing is occasionally necessary to achieve an accurate, definitive  diagnosis.

Free, confidential testing is available

Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.

The Alpha-1 Foundation (www.alpha1.org)³⁴ also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina ([email protected]) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.

The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.¹⁵

TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY

The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.

Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,³⁵ specifically because the magnitude of FEV₁ increase and the duration of such a rise are lower than in usual COPD patients.

Augmentation therapy

Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:

• Prolastin-C (Grifols, Barcelona, Spain)
• Aralast NP (Baxalta, Bonneckborn, IL)
• Zemaira (CSL Behring, King of Prussia, PA)
• Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).

All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).

Randomized controlled trials^36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,³⁷ augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.

On the basis of the available evidence, the American Thoracic Society and European Respiratory Society¹⁴ have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”¹⁴ Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV₁ 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”

The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),³⁸ it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.

Novel therapies

In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.

Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.¹

See related editorial

The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,² and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.^3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.⁵

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.⁴ The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.⁶ Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).⁷

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.^8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.^10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,¹⁴ as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,¹⁵ more recent studies have not confirmed these benefits.^16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.^18,19

Abdominal pain and weight loss are also common.²⁰

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.^21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.^21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.²³ A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.²⁴ If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.²⁴

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,²⁵ type 1 diabetes mellitus,²⁶ primary biliary cirrhosis,²⁷ primary sclerosing cholangitis,²⁸ and Addison disease.²⁹

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.³⁰

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks³¹ (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa³² or purpura on the palms and soles.^33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.³⁶ In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.^37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.⁴⁰ Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.⁴¹

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.^42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.⁴⁶

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.⁴⁷ Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.^48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.⁵⁰ T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.⁵¹

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.⁵²

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.^53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.⁵⁵

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).⁵⁶ The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

Biopsy for confirmation

If testing for IgA to tissue transglutaminase is positive, upper endoscopy with biopsy is needed. Ideally, one to two samples should be taken from the duodenal bulb and at least four samples from the rest of the duodenum, preferably from two different locations.⁵⁶

Celiac disease has a broad spectrum of pathologic expressions, from mild distortion of crypt architecture to total villous atrophy and infiltration of lamina propria by lymphocytes⁵⁷ (Figures 5 and 6). Because these changes can be seen in a variety of diarrheal diseases, their reversal after adherence to a gluten-free diet is part of the current diagnostic criteria for the diagnosis of celiac disease.⁵⁶

Genetic testing

Photomicrograph courtesy of Homer Wiland MD, Department of Pathology, Cleveland Clinic.

Although the combination of positive serologic tests and pathologic changes confirms the diagnosis of celiac disease, in some cases one type of test is positive and the other is negative. In this situation, genetic testing for HLA-DQ2 and HLA-DQ8 can help rule out the diagnosis, as a negative genetic test rules out celiac disease in more than 99% of cases.⁵⁸

Genetic testing is also useful in patients who are already adhering to a gluten-free diet at the time of presentation to the clinic and who have had no testing done for celiac disease in the past. Here again, a negative test for both HLA-DQ2 and HLA-DQ8 makes a diagnosis of celiac disease highly unlikely.

If the test is positive, further testing needs to be done, as a positive genetic test cannot differentiate celiac disease from nonceliac gluten sensitivity. In this case, a gluten challenge needs to be done, ideally for 8 weeks, but for at least 2 weeks if the patient cannot tolerate gluten-containing food for a longer period of time. The gluten challenge is to be followed by testing for antibodies to tissue transglutaminase or obtaining duodenal biopsies to confirm the presence or absence of celiac disease.

Standard laboratory tests

Standard laboratory tests do not help much in diagnosing celiac disease, but they should include a complete blood chemistry along with a complete metabolic panel. Usually, serum albumin levels are normal.

Due to malabsorption of iron, patients may have iron deficiency anemia,⁵⁹ but anemia can also be due to a deficiency of folate or vitamin B₁₂. In patients undergoing endoscopic evaluation of iron deficiency anemia of unknown cause, celiac disease was discovered in approximately 15%.⁶⁰ Therefore, some experts believe that any patient presenting with unexplained iron deficiency anemia should be screened for celiac disease.

Because of malabsorption of vitamin D, levels of vitamin D can be low.

Elevations in levels of aminotransferases are also fairly common and usually resolve after the start of a gluten-free diet. If they persist despite adherence to a gluten-free diet, then an alternate cause of liver disease should be sought.⁶¹

Diagnosis of dermatitis herpetiformis

When trying to diagnose dermatitis herpetiformis, antibodies against epidermal transglutaminase can also be checked if testing for antibody against tissue transglutaminase is negative. A significant number of patients with biopsy-confirmed dermatitis herpetiformis are positive for epidermal transglutaminase antibodies but not for tissue transglutaminase antibodies.⁶²

The confirmatory test for dermatitis herpetiformis remains skin biopsy. Ideally, the sample should be taken while the patient is on a gluten-containing diet and from an area of normal-appearing skin around the lesions.⁶³ On histopathologic study, neutrophilic infiltrates are seen in dermal papillae and a perivascular lymphocytic infiltrate can also be seen in the superficial zones.⁶⁴ This presentation can also be seen in other bullous disorders, however. To differentiate dermatitis herpetiformis from other disorders, direct immunofluorescence is needed, which will detect granular IgA deposits in the dermal papillae or along the basement membrane, a finding pathognomic of dermatitis herpetiformis.⁶³

A GLUTEN-FREE DIET IS THE MAINSTAY OF TREATMENT

The mainstay of treatment is lifelong adherence to a gluten-free diet. Most patients report improvement in abdominal pain within days of starting this diet and improvement of diarrhea within 4 weeks.⁶⁵

The maximum amount of gluten that can be tolerated is debatable. A study established that intake of less than 10 mg a day is associated with fewer histologic abnormalities,⁶⁶ and an earlier study noted that intake of less than 50 mg a day was clinically well tolerated.⁶⁷ But patients differ in their tolerance for gluten, and it is hard to predict what the threshold of tolerance for gluten will be for a particular individual. Thus, it is better to avoid gluten completely.

Gluten-free if it is inherently gluten-free. If the food has a gluten-containing grain, then it should be processed to remove the gluten, and the resultant food product should not contain more than 20 parts per million of gluten. Gluten-free products that have gluten-containing grain that has been processed usually have a label indicating the gluten content in the food in parts per million.

Patients who understand the need to adhere to a gluten-free diet and the implications of not adhering to it are generally more compliant. Thus, patients need to be strongly educated that they need to adhere to a gluten-free diet and that nonadherence can cause further damage to the gut and can pose a higher risk of malignancy. Even though patients are usually concerned about the cost of gluten-free food and worry about adherence to the diet, these factors do not generally limit diet adherence.⁶⁸ All patients diagnosed with celiac disease should meet with a registered dietitian to discuss diet options based on their food preferences and to better address all their concerns.

With increasing awareness of celiac disease and with increasing numbers of patients being diagnosed with it, the food industry has recognized the need to produce gluten-free items. There are now plenty of food products available for these patients, who no longer have to forgo cakes, cookies, and other such items. Table 2 lists some common foods that patients with celiac disease can consume.

Nutritional supplements for some

If anemia is due purely to iron deficiency, it may resolve after starting a gluten-free diet, and no additional supplementation may be needed. However, if it is due to a combination of iron plus folate or vitamin B₁₂ deficiency, then folate, vitamin B₁₂, or both should be given.

In addition, if the patient is found to have a deficiency of vitamin D, then a vitamin D supplement should be given.⁶⁹ At the time of diagnosis, all patients with celiac disease should be screened for deficiencies of vitamins A, B₁₂, D, E, and K, as well as copper, zinc, folic acid, and iron.

Follow-up at 3 to 6 months

A follow-up visit should be scheduled for 3 to 6 months after the diagnosis and after that on an annual basis, and many of the abnormal laboratory tests will need to be repeated.

If intestinal or extraintestinal symptoms or nutrient deficiencies persist, then the patient’s adherence to the gluten-free diet needs to be checked. Adherence to a gluten-free diet can be assessed by checking for serologic markers of celiac disease. A decrease in baseline values can be seen within a few months of starting the diet.⁷⁰ Failure of serologic markers to decrease by the end of 1 year of a gluten-free diet usually indicates gluten contamination.⁷¹ If adherence is confirmed (ie, if baseline values fall) but symptoms persist, then further workup needs to be done to find the cause of refractory disease.

Skin lesions should also respond to a gluten-free diet

The first and foremost therapy for the skin lesions in dermatitis herpetiformis is the same as that for the intestinal manifestations in celiac disease, ie, adherence to a gluten-free diet. Soon after patients begin a gluten-free diet, the itching around the skin lesions goes away, and over time, most patients have complete resolution of the skin manifestations.

Dapsone is also frequently used to treat dermatitis herpetiformis if there is an incomplete response to a gluten-free diet or as an adjunct to diet to treat the pruritus. Patients often have a good response to dapsone.⁷²

The recommended starting dosage is 100 to 200 mg a day, and a response is usually seen within a few days. If the symptoms do not improve, the dose can be increased. Once the lesions resolve, the dose can be tapered and patients may not require any further medication. In some cases, patients may need to be chronically maintained on the lowest dose possible, due to the side effects of the drug.³

Dapsone is associated with significant adverse effects. Methemoglobinemia is the most common and is seen particularly in dosages exceeding 200 mg a day. Hemolytic anemia, another common adverse effect, is seen with dosages of more than 100 mg a day. Patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) are at increased risk of hemolysis, and screening for G6PD deficiency is usually done before starting dapsone. Other rare adverse effects of dapsone include agranulocytosis, peripheral neuropathy, psychosis,⁷³ pancreatitis, cholestatic jaundice, bullous and exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, nephrotic syndrome, and renal papillary necrosis.

Besides testing for G6PD deficiency, a complete blood cell count, a reticulocyte count, a hepatic function panel, renal function tests, and urinalysis should be done before starting dapsone therapy and repeated while on therapy. The complete blood cell count and reticulocyte count should be checked weekly for the first month, twice a month for the next 2 months, and then once every 3 months. Liver and renal function tests are to be done once every 3 months.⁷⁴

NOVEL THERAPIES BEING TESTED

Research is under way for other treatments for celiac disease besides a gluten-free diet.

Larazotide (Alba Therapeutics, Baltimore, MD) is being tested in a randomized, placebo-controlled trial. Early results indicate that it is effective in controlling both gastrointestinal and nongastrointestinal symptoms of celiac disease, but it still has to undergo phase 3 clinical trials.

Sorghum is a grain commonly used in Asia and Africa. The gluten in sorghum is different from that in wheat and is not immunogenic. In a small case series in patients with known celiac disease, sorghum did not induce diarrhea or change in levels of antibodies to tissue transglutaminase.⁷⁵

Nonimmunogenic wheat that does not contain the immunogenic gluten is being developed.

Oral enzyme supplements called glutenases are being developed. Glutenases can cleave gluten, particularly the proline and glutamine residues that make gluten resistant to degradation by gastric, pancreatic, and intestinal brush border proteases. A phase 2 trial of one of these oral enzyme supplements showed that it appeared to attenuate mucosal injury in patients with biopsy-proven celiac disease.⁷⁶

These novel therapies look promising, but for now the best treatment is lifelong adherence to the gluten-free diet.

NONRESPONSIVE AND REFRACTORY CELIAC DISEASE

Celiac disease is considered nonresponsive if its symptoms or laboratory abnormalities persist after the patient is on a gluten-free diet for 6 to 12 months. It is considered refractory if symptoms persist or recur along with villous atrophy despite adherence to the diet for more than 12 months in the absence of other causes of the symptoms. Refractory celiac disease can be further classified either as type 1 if there are typical intraepithelial lymphocytes, or as type 2 if there are atypical intraepithelial lymphocytes.

Celiac disease is nonresponsive in about 10% to 19% of cases,⁷⁶ and it is refractory in 1% to 2%.⁷⁷

Managing nonresponsive celiac disease

The first step in managing a patient with nonresponsive celiac disease is to confirm the diagnosis by reviewing the serologic tests and the biopsy samples from the time of diagnosis. If celiac disease is confirmed, then one should re-evaluate for gluten ingestion, the most common cause of nonresponsiveness.⁷⁸ If strict adherence is confirmed, then check for other causes of symptoms such as lactose or fructose intolerance. If no other cause is found, then repeat the duodenal biopsies with flow cytometry to look for CD3 and CD8 expression in T cells in the small-bowel mucosa.⁷⁹ Presence or absence of villous atrophy can point to possible other causes of malabsorption including pancreatic insufficiency, small intestinal bowel overgrowth, and microscopic colitis.

Managing refractory celiac disease

Traditionally, corticosteroids have been shown to be beneficial in alleviating symptoms in patients with refractory celiac disease but do not improve the histologic findings.⁸⁰ Because of the adverse effects associated with long-term corticosteroid use, azathioprine has been successfully used to maintain remission of the disease after induction with corticosteroids in patients with type 1 refractory celiac disease.⁸¹

Cladribine, a chemotherapeutic agent used to treat hairy cell leukemia, has shown some benefit in treating type 2 refractory celiac disease.⁸²

In type 2 refractory celiac disease, use of an immunomodulator agent carries an increased risk of transformation to lymphoma.

Because of the lack of a satisfactory response to the agents available so far to treat refractory celiac disease, more treatment options acting at the molecular level are being explored.

NONCELIAC GLUTEN SENSITIVITY DISORDER

Nonceliac gluten sensitivity disorder is an evolving concept. The clinical presentation of this disorder is similar to celiac disease in that patients may have diarrhea or other extra­intestinal symptoms when on a regular diet and have resolution of symptoms on a gluten-free diet. But unlike celiac disease, there is no serologic or histologic evidence of celiac disease even when patients are on a regular diet.

One of every 17 patients who presents with clinical features suggestive of celiac disease is found to have nonceliac gluten sensitivity disorder, not celiac disease.⁸³ In contrast to celiac disease, in which the adaptive immune system is thought to contribute to the disease process, in nonceliac gluten sensitivity disorder the innate immune system is believed to play the dominant role,⁸⁴ but the exact pathogenesis of the disease is still unclear.

The diagnosis of nonceliac gluten sensitivity disorder is one of exclusion. Celiac disease needs to be ruled out by serologic testing and by duodenal biopsy while the patient is on a regular diet, and then a trial of a gluten-free diet needs to be done to confirm resolution of symptoms before the diagnosis of nonceliac gluten sensitivity disorder can be established.

As with celiac disease, the treatment involves adhering to a gluten-free diet, but it is still not known if patients need to stay on it for the rest of their life, or if they will be able to tolerate gluten-containing products after a few years.

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.¹

See related editorial

The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,² and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.^3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.⁵

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.⁴ The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.⁶ Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).⁷

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.^8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.^10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,¹⁴ as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,¹⁵ more recent studies have not confirmed these benefits.^16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.^18,19

Abdominal pain and weight loss are also common.²⁰

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.^21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.^21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.²³ A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.²⁴ If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.²⁴

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,²⁵ type 1 diabetes mellitus,²⁶ primary biliary cirrhosis,²⁷ primary sclerosing cholangitis,²⁸ and Addison disease.²⁹

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.³⁰

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks³¹ (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa³² or purpura on the palms and soles.^33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.³⁶ In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.^37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.⁴⁰ Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.⁴¹

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.^42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.⁴⁶

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.⁴⁷ Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.^48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.⁵⁰ T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.⁵¹

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.⁵²

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.^53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.⁵⁵

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).⁵⁶ The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

Biopsy for confirmation

If testing for IgA to tissue transglutaminase is positive, upper endoscopy with biopsy is needed. Ideally, one to two samples should be taken from the duodenal bulb and at least four samples from the rest of the duodenum, preferably from two different locations.⁵⁶