Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

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.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 50-year-old woman presents for a new patient visit. She underwent vaginal hysterectomy for menorrhagia 4 years ago, with removal of the uterus and cervix. Tissue studies at that time were negative for dysplasia. Her previous physician performed routine Papanicolaou (Pap) tests, and she asks you to continue this screening. How do you counsel her about Pap testing after hysterectomy for benign disease?

SCREENING GUIDELINES

Introduced in 1941, the Pap test is an example of a successful screening tool, improving detection of early cervical cancer and reducing rates of morbidity and death due to cervical cancer. Early stages of cervical cancer are the most curable.¹

Screening in women who have a cervix

In 2012, the US Preventive Services Task Force (USPSTF) updated its 2003 recommendations for cervical cancer screening.¹ In the same year, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology published a consensus guideline.² This was followed by publication of a guideline from the American College of Obstetricians and Gynecologists.³ These guidelines all recommend Pap testing for cervical cancer every 3 years in women ages 21 to 65. In women ages 30 to 65, the screening interval can be lengthened to every 5 years if the patient undergoes cotesting for human papillomavirus (HPV). These recommendations apply only to women with a cervix.

No screening after hysterectomy for benign indications

Women who undergo hysterectomy with complete removal of the cervix for benign indications, ie, for reasons other than malignancy, are no longer at risk of cervical cancer. Pap testing could still detect vaginal cancer, but vaginal cancer is rare and screening for it is not indicated. The USPSTF 2003 and 2012 guidelines recommend not performing Pap testing in women who had had a hysterectomy for benign indications.¹

Vaginal cancer is rare

Although cervical and vaginal cancers share risk factors, vaginal cancer accounts for only 0.3% of all invasive cancers and 1% to 2% of all gynecologic malignancies in the United States.⁴

A review of 39 population-based cancer registries from 1998 to 2003 found the incidence rate for in situ vaginal cancer to be 0.18 per 100,000 women, and the incidence rate for invasive vaginal cancer was 0.69 per 100,000. Rates were higher in older women and in certain ethnic and racial groups, including black and Hispanic women.⁴

When the cervix is removed during hysterectomy for a benign indication, the patient’s risk of vaginal cancer or its precursors is extremely low. Pearce et al⁵ reviewed Pap tests obtained from the vaginal cuff in 6,265 women who had undergone hysterectomy for benign disease. Their 2-year study reviewed 9,610 vaginal Pap tests, and in only 5 women was vaginal intraepithelial neoplasia type I or II found, and none of the 5 had biopsy-proven vaginal cancer. Only 1.1% of all Pap tests were abnormal. The authors concluded that the positive predictive value for detecting vaginal cancer was 0%.⁵

A retrospective study by Piscitelli et al⁶ in 1995 looked back 10 years and found an extremely low incidence of vaginal dysplasia in women who had undergone hysterectomy for a benign indication. Their findings, coupled with the high rate of false-positive tests, do not support cytologic screening of the vagina after hysterectomy for a benign indication. The data also suggested that 633 tests would need to be performed to diagnose 1 case of vaginal dysplasia.⁶ Other studies have also reported a low yield of vaginal cuff cytologic testing after hysterectomy for benign disease.

Therefore, given the low prevalence of disease and the lack of evidence of benefit of screening after hysterectomy for benign indications, Pap testing of the vaginal cuff is not recommended in these patients.⁷

For women with a history of grade 2 or 3 cervical intraepithelial neoplasia who have undergone hysterectomy, there are only limited data on subsequent disease risk.

Wiener et al⁸ followed 193 post-hysterectomy patients who had a history of cervical intraepithelial neoplasia with Pap testing annually for more than 10 years for a total of 2,800 years of follow-up. The estimated incidence of abnormal cytology (0.7/1,000) was higher than in the general population.⁸

Thus, for these women and for others at high risk who have undergone hysterectomy and have a previous diagnosis of cervical cancer, who had been exposed to diethylstilbestrol, or who are immunocompromised, Pap testing to screen for cancer in the vaginal cuff is recommended, as they are at higher risk of dysplasia at the vaginal cuff.²

PRACTICE TRENDS, AREAS FOR IMPROVEMENT

Despite recommendations against screening, many providers continue this non-evidence-based practice.⁴

The 2000–2013 National Health Interview Survey of women age 20 or older who had undergone hysterectomy asked about their most recent Pap test by self-report. Women were excluded if they had a history of cervical cancer, if they had had a Pap test for another health problem, or if the result of the recent Pap test was not known. In 2000, nearly half (49.1%) of the respondents said they had received a Pap test in the previous year; in 2013, the percentage undergoing testing was down to 32.1%, but testing was unnecessary in 22.1%. Screening was largely due to clinician recommendations, but it was initiated by patients without clinician recommendations in about one-fourth of cases.⁹ Lack of knowledge of the revised 2012 guidelines was cited as the primary reason for unnecessary screening.¹⁰

A study of provider attitudes toward the cancer screening guidelines cited several reasons for nonadherence: patient concern about the guidelines; quality metrics that are incongruent with the guidelines; provider disagreement with the guidelines; risk of malpractice litigation; and lack of time to discuss the guidelines with patients.¹¹

As the healthcare landscape changes to team-based care, the clinician and the entire healthcare team should educate patients about the role of vaginal cancer screening after hysterectomy for benign reasons. Given the limited time clinicians have with patients during an office visit, innovative tools and systems outside the office are needed to educate patients about the risks and benefits of screening.¹¹ And notices in the electronic medical record may help busy clinicians keep up with current guidelines.¹⁰

THE CLINICAL BOTTOM LINE

Pap testing to screen for vaginal cancer in women who have undergone hysterectomy for a benign indication is an example of more testing, not better care. Evidence is lacking to justify this test in women who are not at high risk of cervical cancer. To reduce the overuse of cytology screening tests, providers need to stay informed about evidence-based best practices and and to pass this information along to patients.

We should focus our resources on HPV vaccination and outreach to increase screening efforts in geographic areas with low rates of Pap testing rather than provide unnecessary Pap testing for women who have undergone hysterectomy for a benign indication.

A 50-year-old woman presents for a new patient visit. She underwent vaginal hysterectomy for menorrhagia 4 years ago, with removal of the uterus and cervix. Tissue studies at that time were negative for dysplasia. Her previous physician performed routine Papanicolaou (Pap) tests, and she asks you to continue this screening. How do you counsel her about Pap testing after hysterectomy for benign disease?

SCREENING GUIDELINES

Introduced in 1941, the Pap test is an example of a successful screening tool, improving detection of early cervical cancer and reducing rates of morbidity and death due to cervical cancer. Early stages of cervical cancer are the most curable.¹

Screening in women who have a cervix

In 2012, the US Preventive Services Task Force (USPSTF) updated its 2003 recommendations for cervical cancer screening.¹ In the same year, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology published a consensus guideline.² This was followed by publication of a guideline from the American College of Obstetricians and Gynecologists.³ These guidelines all recommend Pap testing for cervical cancer every 3 years in women ages 21 to 65. In women ages 30 to 65, the screening interval can be lengthened to every 5 years if the patient undergoes cotesting for human papillomavirus (HPV). These recommendations apply only to women with a cervix.

No screening after hysterectomy for benign indications

Women who undergo hysterectomy with complete removal of the cervix for benign indications, ie, for reasons other than malignancy, are no longer at risk of cervical cancer. Pap testing could still detect vaginal cancer, but vaginal cancer is rare and screening for it is not indicated. The USPSTF 2003 and 2012 guidelines recommend not performing Pap testing in women who had had a hysterectomy for benign indications.¹

Vaginal cancer is rare

Although cervical and vaginal cancers share risk factors, vaginal cancer accounts for only 0.3% of all invasive cancers and 1% to 2% of all gynecologic malignancies in the United States.⁴

A review of 39 population-based cancer registries from 1998 to 2003 found the incidence rate for in situ vaginal cancer to be 0.18 per 100,000 women, and the incidence rate for invasive vaginal cancer was 0.69 per 100,000. Rates were higher in older women and in certain ethnic and racial groups, including black and Hispanic women.⁴

When the cervix is removed during hysterectomy for a benign indication, the patient’s risk of vaginal cancer or its precursors is extremely low. Pearce et al⁵ reviewed Pap tests obtained from the vaginal cuff in 6,265 women who had undergone hysterectomy for benign disease. Their 2-year study reviewed 9,610 vaginal Pap tests, and in only 5 women was vaginal intraepithelial neoplasia type I or II found, and none of the 5 had biopsy-proven vaginal cancer. Only 1.1% of all Pap tests were abnormal. The authors concluded that the positive predictive value for detecting vaginal cancer was 0%.⁵

A retrospective study by Piscitelli et al⁶ in 1995 looked back 10 years and found an extremely low incidence of vaginal dysplasia in women who had undergone hysterectomy for a benign indication. Their findings, coupled with the high rate of false-positive tests, do not support cytologic screening of the vagina after hysterectomy for a benign indication. The data also suggested that 633 tests would need to be performed to diagnose 1 case of vaginal dysplasia.⁶ Other studies have also reported a low yield of vaginal cuff cytologic testing after hysterectomy for benign disease.

Therefore, given the low prevalence of disease and the lack of evidence of benefit of screening after hysterectomy for benign indications, Pap testing of the vaginal cuff is not recommended in these patients.⁷

For women with a history of grade 2 or 3 cervical intraepithelial neoplasia who have undergone hysterectomy, there are only limited data on subsequent disease risk.

Wiener et al⁸ followed 193 post-hysterectomy patients who had a history of cervical intraepithelial neoplasia with Pap testing annually for more than 10 years for a total of 2,800 years of follow-up. The estimated incidence of abnormal cytology (0.7/1,000) was higher than in the general population.⁸

Thus, for these women and for others at high risk who have undergone hysterectomy and have a previous diagnosis of cervical cancer, who had been exposed to diethylstilbestrol, or who are immunocompromised, Pap testing to screen for cancer in the vaginal cuff is recommended, as they are at higher risk of dysplasia at the vaginal cuff.²

PRACTICE TRENDS, AREAS FOR IMPROVEMENT

Despite recommendations against screening, many providers continue this non-evidence-based practice.⁴

The 2000–2013 National Health Interview Survey of women age 20 or older who had undergone hysterectomy asked about their most recent Pap test by self-report. Women were excluded if they had a history of cervical cancer, if they had had a Pap test for another health problem, or if the result of the recent Pap test was not known. In 2000, nearly half (49.1%) of the respondents said they had received a Pap test in the previous year; in 2013, the percentage undergoing testing was down to 32.1%, but testing was unnecessary in 22.1%. Screening was largely due to clinician recommendations, but it was initiated by patients without clinician recommendations in about one-fourth of cases.⁹ Lack of knowledge of the revised 2012 guidelines was cited as the primary reason for unnecessary screening.¹⁰

A study of provider attitudes toward the cancer screening guidelines cited several reasons for nonadherence: patient concern about the guidelines; quality metrics that are incongruent with the guidelines; provider disagreement with the guidelines; risk of malpractice litigation; and lack of time to discuss the guidelines with patients.¹¹

As the healthcare landscape changes to team-based care, the clinician and the entire healthcare team should educate patients about the role of vaginal cancer screening after hysterectomy for benign reasons. Given the limited time clinicians have with patients during an office visit, innovative tools and systems outside the office are needed to educate patients about the risks and benefits of screening.¹¹ And notices in the electronic medical record may help busy clinicians keep up with current guidelines.¹⁰

THE CLINICAL BOTTOM LINE

Pap testing to screen for vaginal cancer in women who have undergone hysterectomy for a benign indication is an example of more testing, not better care. Evidence is lacking to justify this test in women who are not at high risk of cervical cancer. To reduce the overuse of cytology screening tests, providers need to stay informed about evidence-based best practices and and to pass this information along to patients.

We should focus our resources on HPV vaccination and outreach to increase screening efforts in geographic areas with low rates of Pap testing rather than provide unnecessary Pap testing for women who have undergone hysterectomy for a benign indication.

A 50-year-old woman presents for a new patient visit. She underwent vaginal hysterectomy for menorrhagia 4 years ago, with removal of the uterus and cervix. Tissue studies at that time were negative for dysplasia. Her previous physician performed routine Papanicolaou (Pap) tests, and she asks you to continue this screening. How do you counsel her about Pap testing after hysterectomy for benign disease?

SCREENING GUIDELINES

Introduced in 1941, the Pap test is an example of a successful screening tool, improving detection of early cervical cancer and reducing rates of morbidity and death due to cervical cancer. Early stages of cervical cancer are the most curable.¹

Screening in women who have a cervix

In 2012, the US Preventive Services Task Force (USPSTF) updated its 2003 recommendations for cervical cancer screening.¹ In the same year, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology published a consensus guideline.² This was followed by publication of a guideline from the American College of Obstetricians and Gynecologists.³ These guidelines all recommend Pap testing for cervical cancer every 3 years in women ages 21 to 65. In women ages 30 to 65, the screening interval can be lengthened to every 5 years if the patient undergoes cotesting for human papillomavirus (HPV). These recommendations apply only to women with a cervix.

No screening after hysterectomy for benign indications

Women who undergo hysterectomy with complete removal of the cervix for benign indications, ie, for reasons other than malignancy, are no longer at risk of cervical cancer. Pap testing could still detect vaginal cancer, but vaginal cancer is rare and screening for it is not indicated. The USPSTF 2003 and 2012 guidelines recommend not performing Pap testing in women who had had a hysterectomy for benign indications.¹

Vaginal cancer is rare

Although cervical and vaginal cancers share risk factors, vaginal cancer accounts for only 0.3% of all invasive cancers and 1% to 2% of all gynecologic malignancies in the United States.⁴

A review of 39 population-based cancer registries from 1998 to 2003 found the incidence rate for in situ vaginal cancer to be 0.18 per 100,000 women, and the incidence rate for invasive vaginal cancer was 0.69 per 100,000. Rates were higher in older women and in certain ethnic and racial groups, including black and Hispanic women.⁴

When the cervix is removed during hysterectomy for a benign indication, the patient’s risk of vaginal cancer or its precursors is extremely low. Pearce et al⁵ reviewed Pap tests obtained from the vaginal cuff in 6,265 women who had undergone hysterectomy for benign disease. Their 2-year study reviewed 9,610 vaginal Pap tests, and in only 5 women was vaginal intraepithelial neoplasia type I or II found, and none of the 5 had biopsy-proven vaginal cancer. Only 1.1% of all Pap tests were abnormal. The authors concluded that the positive predictive value for detecting vaginal cancer was 0%.⁵

A retrospective study by Piscitelli et al⁶ in 1995 looked back 10 years and found an extremely low incidence of vaginal dysplasia in women who had undergone hysterectomy for a benign indication. Their findings, coupled with the high rate of false-positive tests, do not support cytologic screening of the vagina after hysterectomy for a benign indication. The data also suggested that 633 tests would need to be performed to diagnose 1 case of vaginal dysplasia.⁶ Other studies have also reported a low yield of vaginal cuff cytologic testing after hysterectomy for benign disease.

Therefore, given the low prevalence of disease and the lack of evidence of benefit of screening after hysterectomy for benign indications, Pap testing of the vaginal cuff is not recommended in these patients.⁷

For women with a history of grade 2 or 3 cervical intraepithelial neoplasia who have undergone hysterectomy, there are only limited data on subsequent disease risk.

Wiener et al⁸ followed 193 post-hysterectomy patients who had a history of cervical intraepithelial neoplasia with Pap testing annually for more than 10 years for a total of 2,800 years of follow-up. The estimated incidence of abnormal cytology (0.7/1,000) was higher than in the general population.⁸

Thus, for these women and for others at high risk who have undergone hysterectomy and have a previous diagnosis of cervical cancer, who had been exposed to diethylstilbestrol, or who are immunocompromised, Pap testing to screen for cancer in the vaginal cuff is recommended, as they are at higher risk of dysplasia at the vaginal cuff.²

PRACTICE TRENDS, AREAS FOR IMPROVEMENT

Despite recommendations against screening, many providers continue this non-evidence-based practice.⁴

The 2000–2013 National Health Interview Survey of women age 20 or older who had undergone hysterectomy asked about their most recent Pap test by self-report. Women were excluded if they had a history of cervical cancer, if they had had a Pap test for another health problem, or if the result of the recent Pap test was not known. In 2000, nearly half (49.1%) of the respondents said they had received a Pap test in the previous year; in 2013, the percentage undergoing testing was down to 32.1%, but testing was unnecessary in 22.1%. Screening was largely due to clinician recommendations, but it was initiated by patients without clinician recommendations in about one-fourth of cases.⁹ Lack of knowledge of the revised 2012 guidelines was cited as the primary reason for unnecessary screening.¹⁰

A study of provider attitudes toward the cancer screening guidelines cited several reasons for nonadherence: patient concern about the guidelines; quality metrics that are incongruent with the guidelines; provider disagreement with the guidelines; risk of malpractice litigation; and lack of time to discuss the guidelines with patients.¹¹

As the healthcare landscape changes to team-based care, the clinician and the entire healthcare team should educate patients about the role of vaginal cancer screening after hysterectomy for benign reasons. Given the limited time clinicians have with patients during an office visit, innovative tools and systems outside the office are needed to educate patients about the risks and benefits of screening.¹¹ And notices in the electronic medical record may help busy clinicians keep up with current guidelines.¹⁰

THE CLINICAL BOTTOM LINE

Pap testing to screen for vaginal cancer in women who have undergone hysterectomy for a benign indication is an example of more testing, not better care. Evidence is lacking to justify this test in women who are not at high risk of cervical cancer. To reduce the overuse of cytology screening tests, providers need to stay informed about evidence-based best practices and and to pass this information along to patients.

We should focus our resources on HPV vaccination and outreach to increase screening efforts in geographic areas with low rates of Pap testing rather than provide unnecessary Pap testing for women who have undergone hysterectomy for a benign indication.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

A 57-year-old man was transferred to our  hospital with leg pain and confusion. His family reported that he had injured his leg while launching a motorized personal watercraft at the North Carolina seashore 2 days before. He had a history of cirrhosis secondary to hepatitis C and alcohol abuse.

Blood and wound cultures eventually grew V vulnificus, and surgical pathology confirmed the diagnosis of necrotizing fasciitis (Figure 2).

RISE IN V VULNIFICUS INFECTIONS IS ATTRIBUTED TO GLOBAL WARMING

V vulnificus infection occurs most commonly from consuming raw shellfish, especially oysters, but it also occurs after exposure of an open wound to contaminated salt water. The pathogen is a gram-negative bacterium that resides in coastal waters worldwide, but in the United States it is usually seen on the Pacific and Gulf coasts¹ during the summer.²

Although only 58 cases of V vulnificus infection were reported to the US Centers for Disease Control and Prevention in 1997, the number more than doubled to 124 in 2014.¹ This rise is suspected to be due in part to warmer coastal waters associated with global warming.²

Various marine pathogens can cause wound infections, but V vulnificus is most commonly implicated in deaths and hospitalizations.² Immunocompromised patients and those with liver disease are at particularly high risk of rapid progression to septic shock.

First-line antibiotics are doxycycline plus a third-generation cephalosporin.³ Studies have shown a direct correlation between delay of antibiotics and death,⁴ and early surgery is critical.⁵

Given the rising incidence of V vulnificus infection, it is increasingly important for providers across the United States to be aware of this infection.

A 57-year-old man was transferred to our  hospital with leg pain and confusion. His family reported that he had injured his leg while launching a motorized personal watercraft at the North Carolina seashore 2 days before. He had a history of cirrhosis secondary to hepatitis C and alcohol abuse.

Blood and wound cultures eventually grew V vulnificus, and surgical pathology confirmed the diagnosis of necrotizing fasciitis (Figure 2).

RISE IN V VULNIFICUS INFECTIONS IS ATTRIBUTED TO GLOBAL WARMING

V vulnificus infection occurs most commonly from consuming raw shellfish, especially oysters, but it also occurs after exposure of an open wound to contaminated salt water. The pathogen is a gram-negative bacterium that resides in coastal waters worldwide, but in the United States it is usually seen on the Pacific and Gulf coasts¹ during the summer.²

Although only 58 cases of V vulnificus infection were reported to the US Centers for Disease Control and Prevention in 1997, the number more than doubled to 124 in 2014.¹ This rise is suspected to be due in part to warmer coastal waters associated with global warming.²

Various marine pathogens can cause wound infections, but V vulnificus is most commonly implicated in deaths and hospitalizations.² Immunocompromised patients and those with liver disease are at particularly high risk of rapid progression to septic shock.

First-line antibiotics are doxycycline plus a third-generation cephalosporin.³ Studies have shown a direct correlation between delay of antibiotics and death,⁴ and early surgery is critical.⁵

Given the rising incidence of V vulnificus infection, it is increasingly important for providers across the United States to be aware of this infection.

A 57-year-old man was transferred to our  hospital with leg pain and confusion. His family reported that he had injured his leg while launching a motorized personal watercraft at the North Carolina seashore 2 days before. He had a history of cirrhosis secondary to hepatitis C and alcohol abuse.

Blood and wound cultures eventually grew V vulnificus, and surgical pathology confirmed the diagnosis of necrotizing fasciitis (Figure 2).

RISE IN V VULNIFICUS INFECTIONS IS ATTRIBUTED TO GLOBAL WARMING

V vulnificus infection occurs most commonly from consuming raw shellfish, especially oysters, but it also occurs after exposure of an open wound to contaminated salt water. The pathogen is a gram-negative bacterium that resides in coastal waters worldwide, but in the United States it is usually seen on the Pacific and Gulf coasts¹ during the summer.²

Although only 58 cases of V vulnificus infection were reported to the US Centers for Disease Control and Prevention in 1997, the number more than doubled to 124 in 2014.¹ This rise is suspected to be due in part to warmer coastal waters associated with global warming.²

Various marine pathogens can cause wound infections, but V vulnificus is most commonly implicated in deaths and hospitalizations.² Immunocompromised patients and those with liver disease are at particularly high risk of rapid progression to septic shock.

First-line antibiotics are doxycycline plus a third-generation cephalosporin.³ Studies have shown a direct correlation between delay of antibiotics and death,⁴ and early surgery is critical.⁵

Given the rising incidence of V vulnificus infection, it is increasingly important for providers across the United States to be aware of this infection.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

A 29-year-old African American woman presents with a photosensitive malar rash, fatigue, morning stiffness, and swelling in her hands. She is found to have elevated anti­nuclear antibody at a titer of 1:320. A complete blood cell count demonstrates leukopenia and thrombocytopenia. Results of renal function testing and urinalysis are within normal limits. She has no other medical problems and no history of blood clots or pregnancy loss.

Her arthritis and rash suggest systemic lupus erythematosus. She is counseled to avoid sun exposure, and treatment with hydroxychloroquine is considered.

WHAT IS HYDROXYCHLOROQUINE?

Hydroxychloroquine was developed to treat malaria but was later found to have immunomodulatory properties. It is now approved by the US Food and Drug Administration for treatment of discoid lupus, systemic lupus ery­thematosus, and rheumatoid arthritis. It is also approved to treat malaria; however, of the several malarial parasites, only Plasmodium falciparum can still be cured by hydroxychloroquine, and growing resistance limits the geographic locations where this drug can be used effectively.^1,2

HISTORICAL BACKGROUND

Antimalarial drugs were discovered shortly before World War II. Their production was industrialized during the war because malaria was a leading cause of disease among soldiers, especially those deployed to the South Pacific.³

Atabrine (quinacrine), the first antimalarial widely used, had numerous side effects including yellowing of the skin. Aggressive research efforts to develop an alternative led to field testing of one of its derivative compounds, chloroquine, by the US Army in 1943. Continued chemical modification would create hydroxychloroquine, introduced in 1955.

A serendipitous consequence of the mass use of antimalarials during World War II was the discovery that they could be used to treat inflammatory arthritis and lupus. Eight years after the war ended, Shee⁴ reported that chloroquine had a beneficial effect on lupus and rheumatoid arthritis in US soldiers. Hydroxychloroquine is now the most commonly prescribed antimalarial for treatment of autoimmune disease.

HOW HYDROXYCHLOROQUINE WORKS

The primary mechanism by which hydroxychloroquine modulates systemic lupus erythematosus is by suppressing activation of Toll-like receptors, which exist on the surface of endosomes and play a significant role in the innate immune response and in autoimmune disease. Their activation is necessary for the expression of interferon-regulated genes and production of tumor necrosis factor alpha, which are key in the cell-mediated inflammatory response.

Antimalarial drugs such as hydroxychlor­oquine prevent Toll-like receptor activation by binding directly to nucleic acids in the activation pathway.⁵ In vitro studies show that blocking this pathway blunts the body’s primary cell-mediated inflammatory response; in vivo studies show that use of hydroxychloroquine is strongly correlated with a reduction in interferon alpha levels.⁶ The powerful effect of hydroxychloroquine on the cell-mediated pattern of inflammation found in lupus is consistent with this theory.

It was previously hypothesized that the immune-modulating effects of hydroxychloroquine were associated with a more general dysregulation of cellular lysosomes through inhibition of proteolysis or changes in cellular pH.⁷ This theory has since been displaced by the more specific and elegant mechanism described above.⁵

HOW WELL DOES IT WORK?

Benefit in systemic lupus erythematosus

Hydroxychloroquine has consistently demonstrated significant and multifaceted benefit in patients with systemic lupus erythematosus.

A systematic review of 95 articles⁸ concluded that this drug decreases lupus flares and decreases mortality rates in lupus patients by at least 50%, with a high level of evidence. Beneficial effects that had a moderate level of evidence were an increase in bone mineral density, fewer thrombotic events, and fewer cases of irreversible organ damage.

The preventive effect of hydroxychlor­oquine on thrombosis in lupus patients has been consistently demonstrated and is one of the key reasons the drug is considered a cornerstone of therapy in this disease.⁹ A nested case-control study of patients with lupus and thromboembolism demonstrated an odds ratio of 0.31 and relative risk reduction of 68% for those using antimalarials.¹⁰

Benefit in antiphospholipid antibody syndrome

Hydroxychloroquine prevents thrombosis in other diseases as well. For example, it has been shown to reduce the incidence of thrombotic events in patients with primary antiphospholipid syndrome.

In a retrospective cohort study in 114 patients with this disease, hydroxychloroquine significantly reduced the incidence of arterial thrombotic events over 10 years of follow-up (recurrence incidence 0 in those treated with hydroxychloroquine vs 1.14% in those not treated).¹¹ The study also tracked levels of antiphospholipid antibodies and reported that hydroxychloroquine significantly reduced the levels of antibodies to cardiolipin and beta-2 glycoprotein 1, both implicated in the pathology of thrombosis.¹¹

In vitro studies have also demonstrated that hydroxychloroquine can modulate a dysregulated inflammatory system to reduce thrombosis. For example, it has been shown that hydroxychloroquine can reverse platelet activation by antiphospholipid antibodies, prevent linking of antibody complexes to cell membranes, and promote proper membrane protein expression, thereby reducing the thrombotic qualities of antiphospholipid antibodies and even improving clearance times of antiphospholipid-related thrombi.¹²

Though there is less evidence, hydroxychloroquine has also shown benefit in rheumatoid arthritis, where it can be used by itself in mild disease or as part of combination therapy with active arthritis. Compared with biologic therapy in patients with early aggressive rheumatoid arthritis, triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine was nearly as effective in terms of quality of life, and it cost only one-third as much, saving $20,000 per year of therapy per patient.¹³

Hydroxychloroquine has also been compared directly with chloroquine, its closest relation, in a large study incorporating patients with rheumatoid arthritis and patients with systemic lupus erythematosus. Patients using chloroquine experienced significantly more side effects, though it did prove marginally more effective.¹⁴

No benefit shown in Sjögren syndrome

Unfortunately, despite widespread use, hydroxychloroquine has not demonstrated positive clinical effects when used to treat primary Sjögren syndrome. Most notably, a 2014 randomized controlled trial of hydroxychloroquine vs placebo in 120 Sjögren patients found no significant improvement in primary symptoms of dryness, pain, or fatigue after 6 months of therapy.¹⁵

Metabolic benefits

Unexpectedly, hydroxychloroquine is associated with multiple metabolic benefits including improved lipid profiles and lower blood glucose levels. These findings, in addition to a reduced incidence of thrombosis, were initially reported in the Baltimore Lupus Cohort in 1996.¹⁶ Specifically, longitudinal evaluation of a cohort of lupus patients showed that hydroxychloroquine use was associated with a 7.6% reduction in total cholesterol and a 13.7% reduction in low-density lipoprotein cholesterol (LDL-C) over 3 months of therapy.¹⁷

Similar findings, including a reduction in LDL-C and an increase in high-density lipoprotein cholesterol, were strongly associated with the addition of hydroxychloroquine to methotrexate or to methotrexate and etanercept in a large cohort of rheumatoid arthritis patients followed over 2 years of therapy.¹⁸

In nondiabetic women with systemic lupus erythematosus or rheumatoid arthritis, average blood glucose was significantly lower in those taking hydroxychloroquine than in nonusers. The incidence of insulin resistance was also lower, but the difference was not statistically significant.¹⁹

Some have suggested that hydroxychloroquine may prevent diabetes mellitus. In a retrospective case series, compared with rheumatoid arthritis patients not taking the drug, patients treated with hydroxychloroquine for more than 4 years had a 25% lower risk of developing diabetes mellitus.²⁰

In view of these metabolic benefits, especially regarding lipid regulation, and the above described antithrombotic properties of hydroxychloroquine, some researchers have recently hypothesized that hydroxychloroquine may be of benefit in patients with coronary artery disease.²¹ They suggested that the inflammatory contribution to the mechanism of coronary artery disease could be lessened by hydroxychloroquine even in patients without lupus erythematosus or rheumatoid arthritis.

PHARMACOLOGIC PROPERTIES

Understanding the pharmacologic properties of hydroxychloroquine is key to using it appropriately in clinical practice.

The half-life of elimination of hydroxychloroquine is 40 to 50 days, with half of the drug excreted renally in a concentration-dependent fashion.^22,23 The drug reaches 95% of its steady-state concentration by about 6 months of therapy. Shorter durations of therapy do not provide adequate time for the drug to achieve steady-state concentration and may not allow patients and providers time to see its full clinical results. Therefore, its manufacturers recommend a 6-month trial of therapy to adequately determine if the drug improves symptoms.¹

The oral bioavailability of hydroxychloroquine is about 75%, but pharmacokinetics vary among individuals.^22,23 It has been suggested that this variability affects the efficacy of hydroxychloroquine. In a study of 300 patients with cutaneous lupus erythematosus, those whose treatment failed had significantly lower blood concentrations of hydroxychloroquine, while those who achieved complete remission had significantly higher concentrations.²⁴

Another study found that titrating doses to target therapeutic blood concentrations can reduce disease activity in cutaneous lupus erythematosus.²⁵ Measuring the blood concentration of hydroxychloroquine is not common in clinical practice but may have a role in select patients in whom initial therapy using a standard dosing regimen does not produce the desired results.

HOW SAFE IS HYDROXYCHLOROQUINE?

Hydroxychloroquine has numerous adverse effects, necessitating vigilance on the part of the prescriber. Most commonly reported are retinopathy, hyperpigmentation, myopathy, and skin reactions.¹

Retinopathy

Retinopathy’s irreversibility—the threat of permanent vision loss—and its substantial prevalence in patients with a large drug exposure history, have marked retinopathy as the most concerning potential toxicity. The risk of ocular toxicity increases with the cumulative hydroxychloroquine dose. The prevalence of retinopathy in those using the drug less than 10 years is less than 2%; in contrast, the prevalence in patients with more than 20 years of exposure is reported to be as high as 20%.²⁶

The American Academy of Ophthalmology has long stated that retinopathy is a significant risk of hydroxychloroquine therapy and that patients taking hydroxychloroquine should therefore undergo routine retinal and visual field screening by an ophthalmologist.

Currently, initial screening followed by yearly screening beginning 5 years thereafter is recommended for patients at low risk of toxicity (Table 1).²⁷ Patients determined by an ophthalmologist to be at higher risk of retinopathy should be screened yearly. As identified by the American Academy of Ophthalmology, major risk factors for retinopathy include duration of use, concomitant tamoxifen exposure, significant renal disease, and preexisting retinal and macular disease.^26,28

Recommendations for hydroxychloroquine dosing and screening were recently revised, for 2 reasons. Initially, its manufacturers recommended that hydroxychloroquine dosage be no higher than 6.5 mg/kg of ideal body weight to prevent retinopathy.^1,29,30 However, it has recently been demonstrated that real body weight is a better predictor of risk of retinopathy than ideal body weight when dosing hydroxychloroquine, perhaps because of the increasing variance of real body weight in our patient population.²⁶

Further, an atypical pattern of retinopathy called pericentral retinopathy is more common in Asians. A study of about 200 patients with a history of hydroxychloroquine retinopathy, including 36 Asian patients, found that the pericentral pattern occurred in half the Asian patients but only 2% of the white patients.³¹ The mechanism for this finding is unclear, but because pericentral retinopathy spares the macula, it can be missed using standard screening methods. Therefore, the American Academy of Ophthalmology now recommends that the dose limit be reduced from 6.5 mg/kg of ideal body weight to no more than 5.0 mg/kg of real body weight (Table 2).²⁸

It is also recommended that screening methods such as automated visual fields and optical coherence tomography extend their fields beyond the macula in Asian patients to ensure that pericentral retinopathy is not missed.²⁸

Optical coherence tomography is a particularly useful tool in the ocular evaluation of patients taking hydroxychloroquine. It can detect subtle changes such as thinning of the foveal photoreceptor outer segment, thickening of the retinal pigment epithelium, and loss of the macular ganglion cell–inner plexiform layer before there are visible signs of retinopathy and before symptoms arise.³²

Currently, these guidelines are underutilized in clinical practice. Physician adherence to ophthalmologic guidelines is reported at about 50%.³³ This statistic is jarring, given the potential for permanent loss of vision in those with hydroxychloroquine-mediated retinopathy, and demonstrates the importance of reinforcing proper understanding of the use of hydroxychloroquine in clinical practice.

Cutaneous hyperpigmentation can occur with hydroxychloroquine use (Figure 1). The hyperpigmentation appears to be due to local bruising following deposition of iron in the soft tissue.

While the pigmentation may persist permanently and cause an undesirable cosmetic effect, it has not been associated with other adverse outcomes.

Myopathy is a rare adverse effect. In one case series, 3 of 214 patients treated with hydroxychloroquine developed hydroxychloroquine-induced myopathy.³⁵ Over the duration of their therapy, this was equivalent to an incidence of 1 case of myopathy in 100 patient-years of therapy. Myopathy improves with discontinuation of therapy, though it can persist for weeks, likely because of hydroxychloroquine’s prolonged elimination half-life.

Cardiomyopathy, specifically neurocardio­myopathy, is also an extremely rare adverse effect of hydroxychloroquine use. The mechanism is believed to be associated with the effect of hydroxychloroquine on lysosomal action, leading to an acquired lysosomal storage disorder with the typical cardiac hypertrophy and conduction abnormalities associated with this family of diseases.³⁶

Acute generalized exanthematous pustulosis is another rare complication of hydroxychloroquine therapy. The appearance of the reaction is similar to that of pustular psoriasis, with pustules overlying flaking and scaling skin. It usually resolves within 2 weeks after cessation of hydroxychloroquine therapy. In a select few cases, the reaction persists or waxes and wanes over a period of weeks to months, and longer durations of recovery are thought to be due to hydroxychloroquine’s long half-life, as in hydroxychloroquine-induced myopathy.³⁷

In view of this rare reaction, manufacturers of hydroxychloroquine recommend caution when using the drug in patients with psoriasis.¹

Hematologic abnormalities. In very rare cases, hydroxychloroquine is associated with hematologic abnormalities including agranulocytosis, anemia, aplastic anemia, leukopenia, and thrombocytopenia.¹

While no specific guidelines exist, caution is warranted when using hydroxychloroquine in patients with porphyria. Additionally, hydroxychloroquine and other antimalarials including primaquine have been associated with hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The risk of hemolysis is generally considered low except at high hydroxychloroquine doses in patients with severe G6PD deficiency.³⁸

For the above reasons, manufacturers recommended baseline and routine blood counts, and some providers screen patients for G6PD deficiency when prescribing hydroxychloroquine (Table 3).

PREGNANCY

Hydroxychloroquine is in pregnancy category C. Information is limited, and in view of the risks, the manufacturer says that it should be avoided in pregnancy.¹ Nevertheless, it is generally considered safe during pregnancy, and its benefits may make it acceptable to continue in a patient who becomes pregnant, in spite of the possible risks.

We favor continuing hydroxychloroquine. This drug has been associated with improved maternal and fetal outcomes in lupus patients. Its use during pregnancy has not been associated with congenital malformations. The adverse visual effects of long-term hydroxychloroquine use, namely retinopathy, have never been reported in children as a consequence of exposure in utero.

In addition, hydroxychloroquine is transmitted only in minute quantities in breast milk.³⁹ In pregnant women with systemic lupus erythematosus, hydroxychloroquine was associated with a lower risk of adverse outcomes, including preterm delivery and intrauterine growth restriction.⁴⁰ However, hydroxychloroquine is far more toxic when ingested directly by infants than in adults.¹

Maternal outcomes are also improved with the use of hydroxychloroquine. Stopping hydroxychloroquine during pregnancy in women with systemic lupus erythematosus is associated with significantly higher disease activity—fully twice as high as in those who continue hydroxychloroquine.⁴¹ These study results were corroborated in a small randomized trial in which pregnant women with lupus on placebo had significantly higher lupus disease activity scores than those pregnant women who were given hydroxychloroquine.⁴² The women taking hydroxychloroquine experienced no severe lupus flares for the duration of their pregnancies.

These findings suggest not only that hydroxychloroquine is safe in pregnancy, but also that it should be continued in lupus patients during pregnancy to prevent disease flares and adverse fetal outcomes.

Benefit in preclinical lupus?

Hydroxychloroquine has a consistently profound effect on outcomes in systemic lupus erythematosus. These findings, in addition to the more widespread use of antibody screening, have led to suggestions that hydroxychloroquine could be of benefit even before systemic lupus erythematosus is diagnosed.

A study in US military personnel found that patients taking hydroxychloroquine experienced a significantly longer lag time between first reported clinical symptoms of lupus and official diagnosis compared with  matched controls who also went on to develop the disease, averaging 1.08 vs 0.29 years to disease classification.⁴³ Those who used hydroxychloroquine also had lower rates of autoantibody accumulation. Therefore, hydroxychloroquine could be of benefit in carefully selected candidates at high risk of developing systemic lupus erythematosus.

The beneficial effects of hydroxychloroquine on patients with lupus and rheumatoid arthritis, in terms of primary measures of disease activity and secondary outcomes, were discovered fortuitously and were not the original intended targets of the drug. Because of its versatility, there are numerous other disease states in which hydroxychloroquine has shown a degree of benefit or has shown a potential for benefit.

Antiviral activity?

It has been suggested that antimalarial drugs could serve as adjunctive therapies against filoviruses such as Marburg and Ebola. There is a small body of in vitro and in vivo evidence that hydroxychloroquine could temper severe systemic inflammatory responses to filoviruses both through dysregulation of lysosomes and lysosomal pH (filoviruses have a pH-dependent mechanism of action) and through decreased production of tumor necrosis factor alpha and interferons. Heavy burdens of interferons and tumor necrosis factor alpha are associated with increased mortality rates in those infected with filoviruses.⁴⁴

Antineoplastic activity?

Hydroxychloroquine has undergone in vitro testing as an adjunct to cancer therapies. There are several mechanisms by which it is theorized that hydroxychloroquine could target malignant cells, including inhibition of multidrug resistance pumps or autophagy, improvement of chemotherapy cell penetration, potentiation of presentation of major histocompatibility complexes, or even intercalation directly into DNA.^45,46 However, it can also impair natural anticancer immunity and may allow cancer cells better nutrient supply through vascular effects.

In vitro studies have shown tumoricidal effects in lymphoma and melanoma, and inhibition of growth in lung, colon, breast, cervix, larynx, liver, and prostate cancers. In vivo studies have shown that hydroxychloroquine in high doses can prolong survival in glioblastoma.⁴⁵

Unfortunately, all of these theorized or observed effects are dose-dependent and likely require doses that exceed currently recommended maximums.

Negative chronotropic effect?

Hydroxychloroquine has been found to decrease the resting heart rate in a cumulative dose-dependent fashion.⁴⁷ Further, hydroxychloroquine has been known to increase digoxin levels, and the medications should not be used in combination.¹

Whether the decrease in resting heart rate is associated with harm or benefit and whether the effect is significant enough to be considered when implementing therapy remain unanswered and deserve further investigation, as does the primary use of hydroxychloroquine for beneficial lipid and glucose reduction in patients who are otherwise healthy.

CASE CONCLUSION

The patient described at the beginning of this article was provided with information on the risks and benefits of hydroxychloroquine for treatment of her arthritis and rash suggestive of mild systemic lupus, and she opted to begin therapy. Her baseline eye screening was within normal limits. Based on her weight of 62 kg, she was started on 300 mg of hydroxychloroquine daily.

She had no significant adverse effects from the medication and reported slow improvement in her rash and joint complaints over the next 2 months. She remained on hydroxychloroquine over the next year without adverse effects or new evidence of autoimmune disease.

A 29-year-old African American woman presents with a photosensitive malar rash, fatigue, morning stiffness, and swelling in her hands. She is found to have elevated anti­nuclear antibody at a titer of 1:320. A complete blood cell count demonstrates leukopenia and thrombocytopenia. Results of renal function testing and urinalysis are within normal limits. She has no other medical problems and no history of blood clots or pregnancy loss.

Her arthritis and rash suggest systemic lupus erythematosus. She is counseled to avoid sun exposure, and treatment with hydroxychloroquine is considered.

WHAT IS HYDROXYCHLOROQUINE?

Hydroxychloroquine was developed to treat malaria but was later found to have immunomodulatory properties. It is now approved by the US Food and Drug Administration for treatment of discoid lupus, systemic lupus ery­thematosus, and rheumatoid arthritis. It is also approved to treat malaria; however, of the several malarial parasites, only Plasmodium falciparum can still be cured by hydroxychloroquine, and growing resistance limits the geographic locations where this drug can be used effectively.^1,2

HISTORICAL BACKGROUND

Antimalarial drugs were discovered shortly before World War II. Their production was industrialized during the war because malaria was a leading cause of disease among soldiers, especially those deployed to the South Pacific.³

Atabrine (quinacrine), the first antimalarial widely used, had numerous side effects including yellowing of the skin. Aggressive research efforts to develop an alternative led to field testing of one of its derivative compounds, chloroquine, by the US Army in 1943. Continued chemical modification would create hydroxychloroquine, introduced in 1955.

A serendipitous consequence of the mass use of antimalarials during World War II was the discovery that they could be used to treat inflammatory arthritis and lupus. Eight years after the war ended, Shee⁴ reported that chloroquine had a beneficial effect on lupus and rheumatoid arthritis in US soldiers. Hydroxychloroquine is now the most commonly prescribed antimalarial for treatment of autoimmune disease.

HOW HYDROXYCHLOROQUINE WORKS

The primary mechanism by which hydroxychloroquine modulates systemic lupus erythematosus is by suppressing activation of Toll-like receptors, which exist on the surface of endosomes and play a significant role in the innate immune response and in autoimmune disease. Their activation is necessary for the expression of interferon-regulated genes and production of tumor necrosis factor alpha, which are key in the cell-mediated inflammatory response.

Antimalarial drugs such as hydroxychlor­oquine prevent Toll-like receptor activation by binding directly to nucleic acids in the activation pathway.⁵ In vitro studies show that blocking this pathway blunts the body’s primary cell-mediated inflammatory response; in vivo studies show that use of hydroxychloroquine is strongly correlated with a reduction in interferon alpha levels.⁶ The powerful effect of hydroxychloroquine on the cell-mediated pattern of inflammation found in lupus is consistent with this theory.

It was previously hypothesized that the immune-modulating effects of hydroxychloroquine were associated with a more general dysregulation of cellular lysosomes through inhibition of proteolysis or changes in cellular pH.⁷ This theory has since been displaced by the more specific and elegant mechanism described above.⁵

HOW WELL DOES IT WORK?

Benefit in systemic lupus erythematosus

Hydroxychloroquine has consistently demonstrated significant and multifaceted benefit in patients with systemic lupus erythematosus.

A systematic review of 95 articles⁸ concluded that this drug decreases lupus flares and decreases mortality rates in lupus patients by at least 50%, with a high level of evidence. Beneficial effects that had a moderate level of evidence were an increase in bone mineral density, fewer thrombotic events, and fewer cases of irreversible organ damage.

The preventive effect of hydroxychlor­oquine on thrombosis in lupus patients has been consistently demonstrated and is one of the key reasons the drug is considered a cornerstone of therapy in this disease.⁹ A nested case-control study of patients with lupus and thromboembolism demonstrated an odds ratio of 0.31 and relative risk reduction of 68% for those using antimalarials.¹⁰

Benefit in antiphospholipid antibody syndrome

Hydroxychloroquine prevents thrombosis in other diseases as well. For example, it has been shown to reduce the incidence of thrombotic events in patients with primary antiphospholipid syndrome.

In a retrospective cohort study in 114 patients with this disease, hydroxychloroquine significantly reduced the incidence of arterial thrombotic events over 10 years of follow-up (recurrence incidence 0 in those treated with hydroxychloroquine vs 1.14% in those not treated).¹¹ The study also tracked levels of antiphospholipid antibodies and reported that hydroxychloroquine significantly reduced the levels of antibodies to cardiolipin and beta-2 glycoprotein 1, both implicated in the pathology of thrombosis.¹¹

In vitro studies have also demonstrated that hydroxychloroquine can modulate a dysregulated inflammatory system to reduce thrombosis. For example, it has been shown that hydroxychloroquine can reverse platelet activation by antiphospholipid antibodies, prevent linking of antibody complexes to cell membranes, and promote proper membrane protein expression, thereby reducing the thrombotic qualities of antiphospholipid antibodies and even improving clearance times of antiphospholipid-related thrombi.¹²

Though there is less evidence, hydroxychloroquine has also shown benefit in rheumatoid arthritis, where it can be used by itself in mild disease or as part of combination therapy with active arthritis. Compared with biologic therapy in patients with early aggressive rheumatoid arthritis, triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine was nearly as effective in terms of quality of life, and it cost only one-third as much, saving $20,000 per year of therapy per patient.¹³

Hydroxychloroquine has also been compared directly with chloroquine, its closest relation, in a large study incorporating patients with rheumatoid arthritis and patients with systemic lupus erythematosus. Patients using chloroquine experienced significantly more side effects, though it did prove marginally more effective.¹⁴

No benefit shown in Sjögren syndrome

Unfortunately, despite widespread use, hydroxychloroquine has not demonstrated positive clinical effects when used to treat primary Sjögren syndrome. Most notably, a 2014 randomized controlled trial of hydroxychloroquine vs placebo in 120 Sjögren patients found no significant improvement in primary symptoms of dryness, pain, or fatigue after 6 months of therapy.¹⁵

Metabolic benefits

Unexpectedly, hydroxychloroquine is associated with multiple metabolic benefits including improved lipid profiles and lower blood glucose levels. These findings, in addition to a reduced incidence of thrombosis, were initially reported in the Baltimore Lupus Cohort in 1996.¹⁶ Specifically, longitudinal evaluation of a cohort of lupus patients showed that hydroxychloroquine use was associated with a 7.6% reduction in total cholesterol and a 13.7% reduction in low-density lipoprotein cholesterol (LDL-C) over 3 months of therapy.¹⁷

Similar findings, including a reduction in LDL-C and an increase in high-density lipoprotein cholesterol, were strongly associated with the addition of hydroxychloroquine to methotrexate or to methotrexate and etanercept in a large cohort of rheumatoid arthritis patients followed over 2 years of therapy.¹⁸

In nondiabetic women with systemic lupus erythematosus or rheumatoid arthritis, average blood glucose was significantly lower in those taking hydroxychloroquine than in nonusers. The incidence of insulin resistance was also lower, but the difference was not statistically significant.¹⁹

Some have suggested that hydroxychloroquine may prevent diabetes mellitus. In a retrospective case series, compared with rheumatoid arthritis patients not taking the drug, patients treated with hydroxychloroquine for more than 4 years had a 25% lower risk of developing diabetes mellitus.²⁰

In view of these metabolic benefits, especially regarding lipid regulation, and the above described antithrombotic properties of hydroxychloroquine, some researchers have recently hypothesized that hydroxychloroquine may be of benefit in patients with coronary artery disease.²¹ They suggested that the inflammatory contribution to the mechanism of coronary artery disease could be lessened by hydroxychloroquine even in patients without lupus erythematosus or rheumatoid arthritis.

PHARMACOLOGIC PROPERTIES

Understanding the pharmacologic properties of hydroxychloroquine is key to using it appropriately in clinical practice.

The half-life of elimination of hydroxychloroquine is 40 to 50 days, with half of the drug excreted renally in a concentration-dependent fashion.^22,23 The drug reaches 95% of its steady-state concentration by about 6 months of therapy. Shorter durations of therapy do not provide adequate time for the drug to achieve steady-state concentration and may not allow patients and providers time to see its full clinical results. Therefore, its manufacturers recommend a 6-month trial of therapy to adequately determine if the drug improves symptoms.¹

The oral bioavailability of hydroxychloroquine is about 75%, but pharmacokinetics vary among individuals.^22,23 It has been suggested that this variability affects the efficacy of hydroxychloroquine. In a study of 300 patients with cutaneous lupus erythematosus, those whose treatment failed had significantly lower blood concentrations of hydroxychloroquine, while those who achieved complete remission had significantly higher concentrations.²⁴

Another study found that titrating doses to target therapeutic blood concentrations can reduce disease activity in cutaneous lupus erythematosus.²⁵ Measuring the blood concentration of hydroxychloroquine is not common in clinical practice but may have a role in select patients in whom initial therapy using a standard dosing regimen does not produce the desired results.

HOW SAFE IS HYDROXYCHLOROQUINE?

Hydroxychloroquine has numerous adverse effects, necessitating vigilance on the part of the prescriber. Most commonly reported are retinopathy, hyperpigmentation, myopathy, and skin reactions.¹

Retinopathy

Retinopathy’s irreversibility—the threat of permanent vision loss—and its substantial prevalence in patients with a large drug exposure history, have marked retinopathy as the most concerning potential toxicity. The risk of ocular toxicity increases with the cumulative hydroxychloroquine dose. The prevalence of retinopathy in those using the drug less than 10 years is less than 2%; in contrast, the prevalence in patients with more than 20 years of exposure is reported to be as high as 20%.²⁶

The American Academy of Ophthalmology has long stated that retinopathy is a significant risk of hydroxychloroquine therapy and that patients taking hydroxychloroquine should therefore undergo routine retinal and visual field screening by an ophthalmologist.

Currently, initial screening followed by yearly screening beginning 5 years thereafter is recommended for patients at low risk of toxicity (Table 1).²⁷ Patients determined by an ophthalmologist to be at higher risk of retinopathy should be screened yearly. As identified by the American Academy of Ophthalmology, major risk factors for retinopathy include duration of use, concomitant tamoxifen exposure, significant renal disease, and preexisting retinal and macular disease.^26,28

Recommendations for hydroxychloroquine dosing and screening were recently revised, for 2 reasons. Initially, its manufacturers recommended that hydroxychloroquine dosage be no higher than 6.5 mg/kg of ideal body weight to prevent retinopathy.^1,29,30 However, it has recently been demonstrated that real body weight is a better predictor of risk of retinopathy than ideal body weight when dosing hydroxychloroquine, perhaps because of the increasing variance of real body weight in our patient population.²⁶

Further, an atypical pattern of retinopathy called pericentral retinopathy is more common in Asians. A study of about 200 patients with a history of hydroxychloroquine retinopathy, including 36 Asian patients, found that the pericentral pattern occurred in half the Asian patients but only 2% of the white patients.³¹ The mechanism for this finding is unclear, but because pericentral retinopathy spares the macula, it can be missed using standard screening methods. Therefore, the American Academy of Ophthalmology now recommends that the dose limit be reduced from 6.5 mg/kg of ideal body weight to no more than 5.0 mg/kg of real body weight (Table 2).²⁸

It is also recommended that screening methods such as automated visual fields and optical coherence tomography extend their fields beyond the macula in Asian patients to ensure that pericentral retinopathy is not missed.²⁸

Optical coherence tomography is a particularly useful tool in the ocular evaluation of patients taking hydroxychloroquine. It can detect subtle changes such as thinning of the foveal photoreceptor outer segment, thickening of the retinal pigment epithelium, and loss of the macular ganglion cell–inner plexiform layer before there are visible signs of retinopathy and before symptoms arise.³²

Currently, these guidelines are underutilized in clinical practice. Physician adherence to ophthalmologic guidelines is reported at about 50%.³³ This statistic is jarring, given the potential for permanent loss of vision in those with hydroxychloroquine-mediated retinopathy, and demonstrates the importance of reinforcing proper understanding of the use of hydroxychloroquine in clinical practice.

Cutaneous hyperpigmentation can occur with hydroxychloroquine use (Figure 1). The hyperpigmentation appears to be due to local bruising following deposition of iron in the soft tissue.

While the pigmentation may persist permanently and cause an undesirable cosmetic effect, it has not been associated with other adverse outcomes.

Myopathy is a rare adverse effect. In one case series, 3 of 214 patients treated with hydroxychloroquine developed hydroxychloroquine-induced myopathy.³⁵ Over the duration of their therapy, this was equivalent to an incidence of 1 case of myopathy in 100 patient-years of therapy. Myopathy improves with discontinuation of therapy, though it can persist for weeks, likely because of hydroxychloroquine’s prolonged elimination half-life.

Cardiomyopathy, specifically neurocardio­myopathy, is also an extremely rare adverse effect of hydroxychloroquine use. The mechanism is believed to be associated with the effect of hydroxychloroquine on lysosomal action, leading to an acquired lysosomal storage disorder with the typical cardiac hypertrophy and conduction abnormalities associated with this family of diseases.³⁶

Acute generalized exanthematous pustulosis is another rare complication of hydroxychloroquine therapy. The appearance of the reaction is similar to that of pustular psoriasis, with pustules overlying flaking and scaling skin. It usually resolves within 2 weeks after cessation of hydroxychloroquine therapy. In a select few cases, the reaction persists or waxes and wanes over a period of weeks to months, and longer durations of recovery are thought to be due to hydroxychloroquine’s long half-life, as in hydroxychloroquine-induced myopathy.³⁷

In view of this rare reaction, manufacturers of hydroxychloroquine recommend caution when using the drug in patients with psoriasis.¹

Hematologic abnormalities. In very rare cases, hydroxychloroquine is associated with hematologic abnormalities including agranulocytosis, anemia, aplastic anemia, leukopenia, and thrombocytopenia.¹

While no specific guidelines exist, caution is warranted when using hydroxychloroquine in patients with porphyria. Additionally, hydroxychloroquine and other antimalarials including primaquine have been associated with hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The risk of hemolysis is generally considered low except at high hydroxychloroquine doses in patients with severe G6PD deficiency.³⁸

For the above reasons, manufacturers recommended baseline and routine blood counts, and some providers screen patients for G6PD deficiency when prescribing hydroxychloroquine (Table 3).

PREGNANCY

Hydroxychloroquine is in pregnancy category C. Information is limited, and in view of the risks, the manufacturer says that it should be avoided in pregnancy.¹ Nevertheless, it is generally considered safe during pregnancy, and its benefits may make it acceptable to continue in a patient who becomes pregnant, in spite of the possible risks.

We favor continuing hydroxychloroquine. This drug has been associated with improved maternal and fetal outcomes in lupus patients. Its use during pregnancy has not been associated with congenital malformations. The adverse visual effects of long-term hydroxychloroquine use, namely retinopathy, have never been reported in children as a consequence of exposure in utero.

In addition, hydroxychloroquine is transmitted only in minute quantities in breast milk.³⁹ In pregnant women with systemic lupus erythematosus, hydroxychloroquine was associated with a lower risk of adverse outcomes, including preterm delivery and intrauterine growth restriction.⁴⁰ However, hydroxychloroquine is far more toxic when ingested directly by infants than in adults.¹

Maternal outcomes are also improved with the use of hydroxychloroquine. Stopping hydroxychloroquine during pregnancy in women with systemic lupus erythematosus is associated with significantly higher disease activity—fully twice as high as in those who continue hydroxychloroquine.⁴¹ These study results were corroborated in a small randomized trial in which pregnant women with lupus on placebo had significantly higher lupus disease activity scores than those pregnant women who were given hydroxychloroquine.⁴² The women taking hydroxychloroquine experienced no severe lupus flares for the duration of their pregnancies.

These findings suggest not only that hydroxychloroquine is safe in pregnancy, but also that it should be continued in lupus patients during pregnancy to prevent disease flares and adverse fetal outcomes.

Benefit in preclinical lupus?

Hydroxychloroquine has a consistently profound effect on outcomes in systemic lupus erythematosus. These findings, in addition to the more widespread use of antibody screening, have led to suggestions that hydroxychloroquine could be of benefit even before systemic lupus erythematosus is diagnosed.

A study in US military personnel found that patients taking hydroxychloroquine experienced a significantly longer lag time between first reported clinical symptoms of lupus and official diagnosis compared with  matched controls who also went on to develop the disease, averaging 1.08 vs 0.29 years to disease classification.⁴³ Those who used hydroxychloroquine also had lower rates of autoantibody accumulation. Therefore, hydroxychloroquine could be of benefit in carefully selected candidates at high risk of developing systemic lupus erythematosus.

The beneficial effects of hydroxychloroquine on patients with lupus and rheumatoid arthritis, in terms of primary measures of disease activity and secondary outcomes, were discovered fortuitously and were not the original intended targets of the drug. Because of its versatility, there are numerous other disease states in which hydroxychloroquine has shown a degree of benefit or has shown a potential for benefit.

Antiviral activity?

It has been suggested that antimalarial drugs could serve as adjunctive therapies against filoviruses such as Marburg and Ebola. There is a small body of in vitro and in vivo evidence that hydroxychloroquine could temper severe systemic inflammatory responses to filoviruses both through dysregulation of lysosomes and lysosomal pH (filoviruses have a pH-dependent mechanism of action) and through decreased production of tumor necrosis factor alpha and interferons. Heavy burdens of interferons and tumor necrosis factor alpha are associated with increased mortality rates in those infected with filoviruses.⁴⁴

Antineoplastic activity?

Hydroxychloroquine has undergone in vitro testing as an adjunct to cancer therapies. There are several mechanisms by which it is theorized that hydroxychloroquine could target malignant cells, including inhibition of multidrug resistance pumps or autophagy, improvement of chemotherapy cell penetration, potentiation of presentation of major histocompatibility complexes, or even intercalation directly into DNA.^45,46 However, it can also impair natural anticancer immunity and may allow cancer cells better nutrient supply through vascular effects.

In vitro studies have shown tumoricidal effects in lymphoma and melanoma, and inhibition of growth in lung, colon, breast, cervix, larynx, liver, and prostate cancers. In vivo studies have shown that hydroxychloroquine in high doses can prolong survival in glioblastoma.⁴⁵

Unfortunately, all of these theorized or observed effects are dose-dependent and likely require doses that exceed currently recommended maximums.

Negative chronotropic effect?

Hydroxychloroquine has been found to decrease the resting heart rate in a cumulative dose-dependent fashion.⁴⁷ Further, hydroxychloroquine has been known to increase digoxin levels, and the medications should not be used in combination.¹

Whether the decrease in resting heart rate is associated with harm or benefit and whether the effect is significant enough to be considered when implementing therapy remain unanswered and deserve further investigation, as does the primary use of hydroxychloroquine for beneficial lipid and glucose reduction in patients who are otherwise healthy.

CASE CONCLUSION

The patient described at the beginning of this article was provided with information on the risks and benefits of hydroxychloroquine for treatment of her arthritis and rash suggestive of mild systemic lupus, and she opted to begin therapy. Her baseline eye screening was within normal limits. Based on her weight of 62 kg, she was started on 300 mg of hydroxychloroquine daily.

She had no significant adverse effects from the medication and reported slow improvement in her rash and joint complaints over the next 2 months. She remained on hydroxychloroquine over the next year without adverse effects or new evidence of autoimmune disease.

A 29-year-old African American woman presents with a photosensitive malar rash, fatigue, morning stiffness, and swelling in her hands. She is found to have elevated anti­nuclear antibody at a titer of 1:320. A complete blood cell count demonstrates leukopenia and thrombocytopenia. Results of renal function testing and urinalysis are within normal limits. She has no other medical problems and no history of blood clots or pregnancy loss.

Her arthritis and rash suggest systemic lupus erythematosus. She is counseled to avoid sun exposure, and treatment with hydroxychloroquine is considered.

WHAT IS HYDROXYCHLOROQUINE?

Hydroxychloroquine was developed to treat malaria but was later found to have immunomodulatory properties. It is now approved by the US Food and Drug Administration for treatment of discoid lupus, systemic lupus ery­thematosus, and rheumatoid arthritis. It is also approved to treat malaria; however, of the several malarial parasites, only Plasmodium falciparum can still be cured by hydroxychloroquine, and growing resistance limits the geographic locations where this drug can be used effectively.^1,2

HISTORICAL BACKGROUND

Antimalarial drugs were discovered shortly before World War II. Their production was industrialized during the war because malaria was a leading cause of disease among soldiers, especially those deployed to the South Pacific.³

Atabrine (quinacrine), the first antimalarial widely used, had numerous side effects including yellowing of the skin. Aggressive research efforts to develop an alternative led to field testing of one of its derivative compounds, chloroquine, by the US Army in 1943. Continued chemical modification would create hydroxychloroquine, introduced in 1955.

A serendipitous consequence of the mass use of antimalarials during World War II was the discovery that they could be used to treat inflammatory arthritis and lupus. Eight years after the war ended, Shee⁴ reported that chloroquine had a beneficial effect on lupus and rheumatoid arthritis in US soldiers. Hydroxychloroquine is now the most commonly prescribed antimalarial for treatment of autoimmune disease.

HOW HYDROXYCHLOROQUINE WORKS

The primary mechanism by which hydroxychloroquine modulates systemic lupus erythematosus is by suppressing activation of Toll-like receptors, which exist on the surface of endosomes and play a significant role in the innate immune response and in autoimmune disease. Their activation is necessary for the expression of interferon-regulated genes and production of tumor necrosis factor alpha, which are key in the cell-mediated inflammatory response.

Antimalarial drugs such as hydroxychlor­oquine prevent Toll-like receptor activation by binding directly to nucleic acids in the activation pathway.⁵ In vitro studies show that blocking this pathway blunts the body’s primary cell-mediated inflammatory response; in vivo studies show that use of hydroxychloroquine is strongly correlated with a reduction in interferon alpha levels.⁶ The powerful effect of hydroxychloroquine on the cell-mediated pattern of inflammation found in lupus is consistent with this theory.

It was previously hypothesized that the immune-modulating effects of hydroxychloroquine were associated with a more general dysregulation of cellular lysosomes through inhibition of proteolysis or changes in cellular pH.⁷ This theory has since been displaced by the more specific and elegant mechanism described above.⁵

HOW WELL DOES IT WORK?

Benefit in systemic lupus erythematosus

Hydroxychloroquine has consistently demonstrated significant and multifaceted benefit in patients with systemic lupus erythematosus.

A systematic review of 95 articles⁸ concluded that this drug decreases lupus flares and decreases mortality rates in lupus patients by at least 50%, with a high level of evidence. Beneficial effects that had a moderate level of evidence were an increase in bone mineral density, fewer thrombotic events, and fewer cases of irreversible organ damage.

The preventive effect of hydroxychlor­oquine on thrombosis in lupus patients has been consistently demonstrated and is one of the key reasons the drug is considered a cornerstone of therapy in this disease.⁹ A nested case-control study of patients with lupus and thromboembolism demonstrated an odds ratio of 0.31 and relative risk reduction of 68% for those using antimalarials.¹⁰

Benefit in antiphospholipid antibody syndrome

Hydroxychloroquine prevents thrombosis in other diseases as well. For example, it has been shown to reduce the incidence of thrombotic events in patients with primary antiphospholipid syndrome.

In a retrospective cohort study in 114 patients with this disease, hydroxychloroquine significantly reduced the incidence of arterial thrombotic events over 10 years of follow-up (recurrence incidence 0 in those treated with hydroxychloroquine vs 1.14% in those not treated).¹¹ The study also tracked levels of antiphospholipid antibodies and reported that hydroxychloroquine significantly reduced the levels of antibodies to cardiolipin and beta-2 glycoprotein 1, both implicated in the pathology of thrombosis.¹¹

In vitro studies have also demonstrated that hydroxychloroquine can modulate a dysregulated inflammatory system to reduce thrombosis. For example, it has been shown that hydroxychloroquine can reverse platelet activation by antiphospholipid antibodies, prevent linking of antibody complexes to cell membranes, and promote proper membrane protein expression, thereby reducing the thrombotic qualities of antiphospholipid antibodies and even improving clearance times of antiphospholipid-related thrombi.¹²

Though there is less evidence, hydroxychloroquine has also shown benefit in rheumatoid arthritis, where it can be used by itself in mild disease or as part of combination therapy with active arthritis. Compared with biologic therapy in patients with early aggressive rheumatoid arthritis, triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine was nearly as effective in terms of quality of life, and it cost only one-third as much, saving $20,000 per year of therapy per patient.¹³

Hydroxychloroquine has also been compared directly with chloroquine, its closest relation, in a large study incorporating patients with rheumatoid arthritis and patients with systemic lupus erythematosus. Patients using chloroquine experienced significantly more side effects, though it did prove marginally more effective.¹⁴

No benefit shown in Sjögren syndrome

Unfortunately, despite widespread use, hydroxychloroquine has not demonstrated positive clinical effects when used to treat primary Sjögren syndrome. Most notably, a 2014 randomized controlled trial of hydroxychloroquine vs placebo in 120 Sjögren patients found no significant improvement in primary symptoms of dryness, pain, or fatigue after 6 months of therapy.¹⁵

Metabolic benefits

Unexpectedly, hydroxychloroquine is associated with multiple metabolic benefits including improved lipid profiles and lower blood glucose levels. These findings, in addition to a reduced incidence of thrombosis, were initially reported in the Baltimore Lupus Cohort in 1996.¹⁶ Specifically, longitudinal evaluation of a cohort of lupus patients showed that hydroxychloroquine use was associated with a 7.6% reduction in total cholesterol and a 13.7% reduction in low-density lipoprotein cholesterol (LDL-C) over 3 months of therapy.¹⁷

Similar findings, including a reduction in LDL-C and an increase in high-density lipoprotein cholesterol, were strongly associated with the addition of hydroxychloroquine to methotrexate or to methotrexate and etanercept in a large cohort of rheumatoid arthritis patients followed over 2 years of therapy.¹⁸

In nondiabetic women with systemic lupus erythematosus or rheumatoid arthritis, average blood glucose was significantly lower in those taking hydroxychloroquine than in nonusers. The incidence of insulin resistance was also lower, but the difference was not statistically significant.¹⁹

Some have suggested that hydroxychloroquine may prevent diabetes mellitus. In a retrospective case series, compared with rheumatoid arthritis patients not taking the drug, patients treated with hydroxychloroquine for more than 4 years had a 25% lower risk of developing diabetes mellitus.²⁰

In view of these metabolic benefits, especially regarding lipid regulation, and the above described antithrombotic properties of hydroxychloroquine, some researchers have recently hypothesized that hydroxychloroquine may be of benefit in patients with coronary artery disease.²¹ They suggested that the inflammatory contribution to the mechanism of coronary artery disease could be lessened by hydroxychloroquine even in patients without lupus erythematosus or rheumatoid arthritis.

PHARMACOLOGIC PROPERTIES

Understanding the pharmacologic properties of hydroxychloroquine is key to using it appropriately in clinical practice.

The half-life of elimination of hydroxychloroquine is 40 to 50 days, with half of the drug excreted renally in a concentration-dependent fashion.^22,23 The drug reaches 95% of its steady-state concentration by about 6 months of therapy. Shorter durations of therapy do not provide adequate time for the drug to achieve steady-state concentration and may not allow patients and providers time to see its full clinical results. Therefore, its manufacturers recommend a 6-month trial of therapy to adequately determine if the drug improves symptoms.¹

The oral bioavailability of hydroxychloroquine is about 75%, but pharmacokinetics vary among individuals.^22,23 It has been suggested that this variability affects the efficacy of hydroxychloroquine. In a study of 300 patients with cutaneous lupus erythematosus, those whose treatment failed had significantly lower blood concentrations of hydroxychloroquine, while those who achieved complete remission had significantly higher concentrations.²⁴

Another study found that titrating doses to target therapeutic blood concentrations can reduce disease activity in cutaneous lupus erythematosus.²⁵ Measuring the blood concentration of hydroxychloroquine is not common in clinical practice but may have a role in select patients in whom initial therapy using a standard dosing regimen does not produce the desired results.

HOW SAFE IS HYDROXYCHLOROQUINE?

Hydroxychloroquine has numerous adverse effects, necessitating vigilance on the part of the prescriber. Most commonly reported are retinopathy, hyperpigmentation, myopathy, and skin reactions.¹

Retinopathy

Retinopathy’s irreversibility—the threat of permanent vision loss—and its substantial prevalence in patients with a large drug exposure history, have marked retinopathy as the most concerning potential toxicity. The risk of ocular toxicity increases with the cumulative hydroxychloroquine dose. The prevalence of retinopathy in those using the drug less than 10 years is less than 2%; in contrast, the prevalence in patients with more than 20 years of exposure is reported to be as high as 20%.²⁶

The American Academy of Ophthalmology has long stated that retinopathy is a significant risk of hydroxychloroquine therapy and that patients taking hydroxychloroquine should therefore undergo routine retinal and visual field screening by an ophthalmologist.

Currently, initial screening followed by yearly screening beginning 5 years thereafter is recommended for patients at low risk of toxicity (Table 1).²⁷ Patients determined by an ophthalmologist to be at higher risk of retinopathy should be screened yearly. As identified by the American Academy of Ophthalmology, major risk factors for retinopathy include duration of use, concomitant tamoxifen exposure, significant renal disease, and preexisting retinal and macular disease.^26,28

Recommendations for hydroxychloroquine dosing and screening were recently revised, for 2 reasons. Initially, its manufacturers recommended that hydroxychloroquine dosage be no higher than 6.5 mg/kg of ideal body weight to prevent retinopathy.^1,29,30 However, it has recently been demonstrated that real body weight is a better predictor of risk of retinopathy than ideal body weight when dosing hydroxychloroquine, perhaps because of the increasing variance of real body weight in our patient population.²⁶

Further, an atypical pattern of retinopathy called pericentral retinopathy is more common in Asians. A study of about 200 patients with a history of hydroxychloroquine retinopathy, including 36 Asian patients, found that the pericentral pattern occurred in half the Asian patients but only 2% of the white patients.³¹ The mechanism for this finding is unclear, but because pericentral retinopathy spares the macula, it can be missed using standard screening methods. Therefore, the American Academy of Ophthalmology now recommends that the dose limit be reduced from 6.5 mg/kg of ideal body weight to no more than 5.0 mg/kg of real body weight (Table 2).²⁸

It is also recommended that screening methods such as automated visual fields and optical coherence tomography extend their fields beyond the macula in Asian patients to ensure that pericentral retinopathy is not missed.²⁸

Optical coherence tomography is a particularly useful tool in the ocular evaluation of patients taking hydroxychloroquine. It can detect subtle changes such as thinning of the foveal photoreceptor outer segment, thickening of the retinal pigment epithelium, and loss of the macular ganglion cell–inner plexiform layer before there are visible signs of retinopathy and before symptoms arise.³²

Currently, these guidelines are underutilized in clinical practice. Physician adherence to ophthalmologic guidelines is reported at about 50%.³³ This statistic is jarring, given the potential for permanent loss of vision in those with hydroxychloroquine-mediated retinopathy, and demonstrates the importance of reinforcing proper understanding of the use of hydroxychloroquine in clinical practice.

Cutaneous hyperpigmentation can occur with hydroxychloroquine use (Figure 1). The hyperpigmentation appears to be due to local bruising following deposition of iron in the soft tissue.

While the pigmentation may persist permanently and cause an undesirable cosmetic effect, it has not been associated with other adverse outcomes.

Myopathy is a rare adverse effect. In one case series, 3 of 214 patients treated with hydroxychloroquine developed hydroxychloroquine-induced myopathy.³⁵ Over the duration of their therapy, this was equivalent to an incidence of 1 case of myopathy in 100 patient-years of therapy. Myopathy improves with discontinuation of therapy, though it can persist for weeks, likely because of hydroxychloroquine’s prolonged elimination half-life.

Cardiomyopathy, specifically neurocardio­myopathy, is also an extremely rare adverse effect of hydroxychloroquine use. The mechanism is believed to be associated with the effect of hydroxychloroquine on lysosomal action, leading to an acquired lysosomal storage disorder with the typical cardiac hypertrophy and conduction abnormalities associated with this family of diseases.³⁶

Acute generalized exanthematous pustulosis is another rare complication of hydroxychloroquine therapy. The appearance of the reaction is similar to that of pustular psoriasis, with pustules overlying flaking and scaling skin. It usually resolves within 2 weeks after cessation of hydroxychloroquine therapy. In a select few cases, the reaction persists or waxes and wanes over a period of weeks to months, and longer durations of recovery are thought to be due to hydroxychloroquine’s long half-life, as in hydroxychloroquine-induced myopathy.³⁷

In view of this rare reaction, manufacturers of hydroxychloroquine recommend caution when using the drug in patients with psoriasis.¹

Hematologic abnormalities. In very rare cases, hydroxychloroquine is associated with hematologic abnormalities including agranulocytosis, anemia, aplastic anemia, leukopenia, and thrombocytopenia.¹

While no specific guidelines exist, caution is warranted when using hydroxychloroquine in patients with porphyria. Additionally, hydroxychloroquine and other antimalarials including primaquine have been associated with hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The risk of hemolysis is generally considered low except at high hydroxychloroquine doses in patients with severe G6PD deficiency.³⁸

For the above reasons, manufacturers recommended baseline and routine blood counts, and some providers screen patients for G6PD deficiency when prescribing hydroxychloroquine (Table 3).

PREGNANCY

Hydroxychloroquine is in pregnancy category C. Information is limited, and in view of the risks, the manufacturer says that it should be avoided in pregnancy.¹ Nevertheless, it is generally considered safe during pregnancy, and its benefits may make it acceptable to continue in a patient who becomes pregnant, in spite of the possible risks.

We favor continuing hydroxychloroquine. This drug has been associated with improved maternal and fetal outcomes in lupus patients. Its use during pregnancy has not been associated with congenital malformations. The adverse visual effects of long-term hydroxychloroquine use, namely retinopathy, have never been reported in children as a consequence of exposure in utero.

In addition, hydroxychloroquine is transmitted only in minute quantities in breast milk.³⁹ In pregnant women with systemic lupus erythematosus, hydroxychloroquine was associated with a lower risk of adverse outcomes, including preterm delivery and intrauterine growth restriction.⁴⁰ However, hydroxychloroquine is far more toxic when ingested directly by infants than in adults.¹

Maternal outcomes are also improved with the use of hydroxychloroquine. Stopping hydroxychloroquine during pregnancy in women with systemic lupus erythematosus is associated with significantly higher disease activity—fully twice as high as in those who continue hydroxychloroquine.⁴¹ These study results were corroborated in a small randomized trial in which pregnant women with lupus on placebo had significantly higher lupus disease activity scores than those pregnant women who were given hydroxychloroquine.⁴² The women taking hydroxychloroquine experienced no severe lupus flares for the duration of their pregnancies.

These findings suggest not only that hydroxychloroquine is safe in pregnancy, but also that it should be continued in lupus patients during pregnancy to prevent disease flares and adverse fetal outcomes.

Benefit in preclinical lupus?

Hydroxychloroquine has a consistently profound effect on outcomes in systemic lupus erythematosus. These findings, in addition to the more widespread use of antibody screening, have led to suggestions that hydroxychloroquine could be of benefit even before systemic lupus erythematosus is diagnosed.

A study in US military personnel found that patients taking hydroxychloroquine experienced a significantly longer lag time between first reported clinical symptoms of lupus and official diagnosis compared with  matched controls who also went on to develop the disease, averaging 1.08 vs 0.29 years to disease classification.⁴³ Those who used hydroxychloroquine also had lower rates of autoantibody accumulation. Therefore, hydroxychloroquine could be of benefit in carefully selected candidates at high risk of developing systemic lupus erythematosus.

The beneficial effects of hydroxychloroquine on patients with lupus and rheumatoid arthritis, in terms of primary measures of disease activity and secondary outcomes, were discovered fortuitously and were not the original intended targets of the drug. Because of its versatility, there are numerous other disease states in which hydroxychloroquine has shown a degree of benefit or has shown a potential for benefit.

Antiviral activity?

It has been suggested that antimalarial drugs could serve as adjunctive therapies against filoviruses such as Marburg and Ebola. There is a small body of in vitro and in vivo evidence that hydroxychloroquine could temper severe systemic inflammatory responses to filoviruses both through dysregulation of lysosomes and lysosomal pH (filoviruses have a pH-dependent mechanism of action) and through decreased production of tumor necrosis factor alpha and interferons. Heavy burdens of interferons and tumor necrosis factor alpha are associated with increased mortality rates in those infected with filoviruses.⁴⁴

Antineoplastic activity?

Hydroxychloroquine has undergone in vitro testing as an adjunct to cancer therapies. There are several mechanisms by which it is theorized that hydroxychloroquine could target malignant cells, including inhibition of multidrug resistance pumps or autophagy, improvement of chemotherapy cell penetration, potentiation of presentation of major histocompatibility complexes, or even intercalation directly into DNA.^45,46 However, it can also impair natural anticancer immunity and may allow cancer cells better nutrient supply through vascular effects.

In vitro studies have shown tumoricidal effects in lymphoma and melanoma, and inhibition of growth in lung, colon, breast, cervix, larynx, liver, and prostate cancers. In vivo studies have shown that hydroxychloroquine in high doses can prolong survival in glioblastoma.⁴⁵

Unfortunately, all of these theorized or observed effects are dose-dependent and likely require doses that exceed currently recommended maximums.

Negative chronotropic effect?

Hydroxychloroquine has been found to decrease the resting heart rate in a cumulative dose-dependent fashion.⁴⁷ Further, hydroxychloroquine has been known to increase digoxin levels, and the medications should not be used in combination.¹

Whether the decrease in resting heart rate is associated with harm or benefit and whether the effect is significant enough to be considered when implementing therapy remain unanswered and deserve further investigation, as does the primary use of hydroxychloroquine for beneficial lipid and glucose reduction in patients who are otherwise healthy.

CASE CONCLUSION

The patient described at the beginning of this article was provided with information on the risks and benefits of hydroxychloroquine for treatment of her arthritis and rash suggestive of mild systemic lupus, and she opted to begin therapy. Her baseline eye screening was within normal limits. Based on her weight of 62 kg, she was started on 300 mg of hydroxychloroquine daily.

She had no significant adverse effects from the medication and reported slow improvement in her rash and joint complaints over the next 2 months. She remained on hydroxychloroquine over the next year without adverse effects or new evidence of autoimmune disease.

Lerman and Jameson¹ recently called for expanding formal leadership development of physicians and increasing the reach of effective physician leaders. From the perspective of physicians, these are certainly good goals. We should have leaders in white coats who understand the joy of practicing medicine and can rally for our missions, challenges, and passions as doctors, clinical educators, and researchers.

But the rationale for most of their argument seems to stem from the perceived need to train physician leaders to promote the survival of increasingly complex health systems and strategically guide individual institutions. This seems also to be the focus of many health systems as they search for and hire physicians for various system leadership positions. But only in the final sentence of their thoughtful essay do Lerman and Jameson mention “patient and physician satisfaction and improved clinical outcomes,” and then only as a byproduct of achieving “organizational efficiency.”¹

The financial success (ie, survival) of a health system and the emotional well-being and clinical skills of its physicians are clearly interrelated and cannot be completely dichotomized, and I am not implying that Lerman and Jameson have done so. But trying to promote both can create potential for mission malalignment. Achieving an appropriate balance between these two goals, which at a tactical level are not always congruent, is critical. Training leaders in the skills to achieve alignment with the organization’s culture and priorities may make it easier to administer and guide the course of a medical system with apparent physician leadership, but it still may not well represent the human constituents. The recent trend for health systems to establish new committees charged with improving physician wellness is a statement of problem recognition, but whether their existence can accomplish “mission alignment” remains to be seen.

Swensen et al² from the Mayo Clinic have highlighted the need to focus on the needs of the physician, and not primarily on those of the institution, to reduce the epidemic of physician burnout. A physician leader who is wonderfully trained in organizational psychology, communication skills, and performance metrics analysis, but who lacks a deep and authentic understanding of the joys of practicing medicine and delivering care to the sick, of the need to stoke the individual physician’s intellectual curiosity and provide time for reflection to clinicians working in their institutions, is a unidirectional institutional leader, and thus a leader in name alone. We need to be careful about grooming young physician leaders at too early a stage. Having the book knowledge of a physician is not the same as having the heart of one.

We have appropriately morphed away from the academic curriculum vitae as the only ticket to titled organizational leadership. But we need to look closely at our choice of physician leaders and be careful that the physician component of that terminology is not defined by degree alone. Just as the number of first-authored publications and surgical procedures performed should not suffice for selection to leadership positions, nor should participation in leadership courses or the ability to respond as desired in a behavioral interview be viewed as adequate for selection as a leader of physicians. Administrators with a tailored MBA degree, extensive and real job experience in a clinical center, and participation in a seminar on physician behavior can also be successful supervisors and (maybe) leaders in a medical center.

But if we really care about our clinical staff, organizational leadership must include physicians in positions of influence who are true advocates for clinicians and patients, and not primarily caretakers of the health system and enforcers of performance metrics. Although (some of) the latter are absolutely necessary, we need more than that from our physician leaders. We need them to reflect and support our perspective as well as the institution’s needs. We need them to understand and defend the need to maintain the joy of practicing medicine. How can we as physicians really take care of others if there is no one to take care of us?³ 

Note: this discussion is not new. We had a dialogue on this topic in the Journal almost 10 years ago!⁴

Lerman and Jameson¹ recently called for expanding formal leadership development of physicians and increasing the reach of effective physician leaders. From the perspective of physicians, these are certainly good goals. We should have leaders in white coats who understand the joy of practicing medicine and can rally for our missions, challenges, and passions as doctors, clinical educators, and researchers.

But the rationale for most of their argument seems to stem from the perceived need to train physician leaders to promote the survival of increasingly complex health systems and strategically guide individual institutions. This seems also to be the focus of many health systems as they search for and hire physicians for various system leadership positions. But only in the final sentence of their thoughtful essay do Lerman and Jameson mention “patient and physician satisfaction and improved clinical outcomes,” and then only as a byproduct of achieving “organizational efficiency.”¹

The financial success (ie, survival) of a health system and the emotional well-being and clinical skills of its physicians are clearly interrelated and cannot be completely dichotomized, and I am not implying that Lerman and Jameson have done so. But trying to promote both can create potential for mission malalignment. Achieving an appropriate balance between these two goals, which at a tactical level are not always congruent, is critical. Training leaders in the skills to achieve alignment with the organization’s culture and priorities may make it easier to administer and guide the course of a medical system with apparent physician leadership, but it still may not well represent the human constituents. The recent trend for health systems to establish new committees charged with improving physician wellness is a statement of problem recognition, but whether their existence can accomplish “mission alignment” remains to be seen.

Swensen et al² from the Mayo Clinic have highlighted the need to focus on the needs of the physician, and not primarily on those of the institution, to reduce the epidemic of physician burnout. A physician leader who is wonderfully trained in organizational psychology, communication skills, and performance metrics analysis, but who lacks a deep and authentic understanding of the joys of practicing medicine and delivering care to the sick, of the need to stoke the individual physician’s intellectual curiosity and provide time for reflection to clinicians working in their institutions, is a unidirectional institutional leader, and thus a leader in name alone. We need to be careful about grooming young physician leaders at too early a stage. Having the book knowledge of a physician is not the same as having the heart of one.

We have appropriately morphed away from the academic curriculum vitae as the only ticket to titled organizational leadership. But we need to look closely at our choice of physician leaders and be careful that the physician component of that terminology is not defined by degree alone. Just as the number of first-authored publications and surgical procedures performed should not suffice for selection to leadership positions, nor should participation in leadership courses or the ability to respond as desired in a behavioral interview be viewed as adequate for selection as a leader of physicians. Administrators with a tailored MBA degree, extensive and real job experience in a clinical center, and participation in a seminar on physician behavior can also be successful supervisors and (maybe) leaders in a medical center.

But if we really care about our clinical staff, organizational leadership must include physicians in positions of influence who are true advocates for clinicians and patients, and not primarily caretakers of the health system and enforcers of performance metrics. Although (some of) the latter are absolutely necessary, we need more than that from our physician leaders. We need them to reflect and support our perspective as well as the institution’s needs. We need them to understand and defend the need to maintain the joy of practicing medicine. How can we as physicians really take care of others if there is no one to take care of us?³ 

Note: this discussion is not new. We had a dialogue on this topic in the Journal almost 10 years ago!⁴

Lerman and Jameson¹ recently called for expanding formal leadership development of physicians and increasing the reach of effective physician leaders. From the perspective of physicians, these are certainly good goals. We should have leaders in white coats who understand the joy of practicing medicine and can rally for our missions, challenges, and passions as doctors, clinical educators, and researchers.

But the rationale for most of their argument seems to stem from the perceived need to train physician leaders to promote the survival of increasingly complex health systems and strategically guide individual institutions. This seems also to be the focus of many health systems as they search for and hire physicians for various system leadership positions. But only in the final sentence of their thoughtful essay do Lerman and Jameson mention “patient and physician satisfaction and improved clinical outcomes,” and then only as a byproduct of achieving “organizational efficiency.”¹

The financial success (ie, survival) of a health system and the emotional well-being and clinical skills of its physicians are clearly interrelated and cannot be completely dichotomized, and I am not implying that Lerman and Jameson have done so. But trying to promote both can create potential for mission malalignment. Achieving an appropriate balance between these two goals, which at a tactical level are not always congruent, is critical. Training leaders in the skills to achieve alignment with the organization’s culture and priorities may make it easier to administer and guide the course of a medical system with apparent physician leadership, but it still may not well represent the human constituents. The recent trend for health systems to establish new committees charged with improving physician wellness is a statement of problem recognition, but whether their existence can accomplish “mission alignment” remains to be seen.

Swensen et al² from the Mayo Clinic have highlighted the need to focus on the needs of the physician, and not primarily on those of the institution, to reduce the epidemic of physician burnout. A physician leader who is wonderfully trained in organizational psychology, communication skills, and performance metrics analysis, but who lacks a deep and authentic understanding of the joys of practicing medicine and delivering care to the sick, of the need to stoke the individual physician’s intellectual curiosity and provide time for reflection to clinicians working in their institutions, is a unidirectional institutional leader, and thus a leader in name alone. We need to be careful about grooming young physician leaders at too early a stage. Having the book knowledge of a physician is not the same as having the heart of one.

We have appropriately morphed away from the academic curriculum vitae as the only ticket to titled organizational leadership. But we need to look closely at our choice of physician leaders and be careful that the physician component of that terminology is not defined by degree alone. Just as the number of first-authored publications and surgical procedures performed should not suffice for selection to leadership positions, nor should participation in leadership courses or the ability to respond as desired in a behavioral interview be viewed as adequate for selection as a leader of physicians. Administrators with a tailored MBA degree, extensive and real job experience in a clinical center, and participation in a seminar on physician behavior can also be successful supervisors and (maybe) leaders in a medical center.

But if we really care about our clinical staff, organizational leadership must include physicians in positions of influence who are true advocates for clinicians and patients, and not primarily caretakers of the health system and enforcers of performance metrics. Although (some of) the latter are absolutely necessary, we need more than that from our physician leaders. We need them to reflect and support our perspective as well as the institution’s needs. We need them to understand and defend the need to maintain the joy of practicing medicine. How can we as physicians really take care of others if there is no one to take care of us?³ 

Note: this discussion is not new. We had a dialogue on this topic in the Journal almost 10 years ago!⁴