In their article in this issue of the Cleveland Clinic Journal of Medicine, Kabach et al answer no to the question of whether stenting of severe renal artery stenosis improves outcomes compared with medical therapy alone.¹ They review the findings of four key studies^2–5 published between 2003 and 2014 and conclude that, in patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting with medical therapy can improve blood pressure control but has no significant impact on cardiovascular or mortality outcomes.¹

See related article

Furthermore, the authors state that in view of the risk of complications associated with stenting, medical management should continue to be the first-line therapy.¹ Indeed, the ASTRAL study (Angioplasty and Stenting for Renal Artery Lesions) investigators found substantial risks without evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.³

Nevertheless, I believe that this procedure may benefit certain patients.

MAYO CLINIC COHORT STUDY

In 2008, our group at Mayo Clinic Health system in Eau Claire, Wisconsin, published the results of a prospective cohort study in 26 patients with renal artery stenosis and chronic kidney disease who presented with rapidly worsening renal failure (defined as an increase in serum creatinine of ≥ 25%) while receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).^6,7

These drugs—inhibitors of the renin-angiotensin-aldosterone system—slow the progression of chronic kidney disease but can acutely worsen renal function, especially in patients with renal artery stenosis, and withdrawing them in this situation was the focus of our study.

The patients (10 men and 16 women) ranged in age from 63 to 87 (mean age 75.3).

At enrollment, the ACE inhibitors and ARBs were discontinued, standard nephrologic care was applied, and the glomerular filtration rate (estimated by the Modification of Diet in Renal Disease Study equation) was monitored. After at least 2 weeks, percutaneous renal angioplasty with stent placement was considered if the patient met any of the following criteria:

• Persistence of renal failure
• Flash pulmonary edema
• Uncontrolled hypertension despite the use of at least three antihypertensive medications.

Nine patients underwent percutaneous angioplasty and stenting and 17 did not. The procedure was done on one renal artery in 8 patients and both renal arteries in 1. Indications for the procedure were recent worsening of renal failure in 8 patients and recent worsening renal failure together with symptomatic flash pulmonary edema in 1 patient. (Flash pulmonary edema is the only class I recommendation for percutaneous renal angioplasty in the 2006 joint guidelines of the American College of Cardiology and the American Heart Association.⁸) As noted above, all the patients were experiencing acute exacerbation of chronic kidney disease at the time.

We found clear evidence of additional improved and sustained renal function in the patients who underwent percutaneous renal angioplasty and stenting compared with the patients who did not (Figures 1 and 2).^6,7

In an editorial⁹ following publication of the ASTRAL study, our group reported a subsequent 82-month analysis of our 26-patient cohort completed in June 2009. In the 7 surviving patients who had undergone percutaneous renal angioplasty and stenting, the estimated glomerular filtration rate had increased from 27.4 mL/min/1.73 m² (± 12.7, range 11–47) at baseline to 50.3 (± 21.7, range 23–68) (P = .018) after 46.9 months.

PATIENT NUMBER 13

To illustrate how percutaneous renal angioplasty and stenting can reverse recently worsening renal failure in renal artery stenosis, I would like to discuss in greater detail a patient from our two previous reports.^6,7

Patient 13, a 67-year-old woman with hypertension, was referred to our nephrology service in September 2004 to consider starting hemodialysis for symptomatic renal failure. Her serum creatinine had increased to 3.4 mg/dL from a previous baseline level of 2.0 mg/dL, and she also had worsening anemia and hyperkalemia. She had been taking lisinopril 10 mg/day for the last 12 months. Magnetic resonance angiography revealed high-grade (> 95%) bilateral renal artery stenosis with an atrophic left kidney.

Lisinopril was promptly discontinued, and within 2 weeks her serum creatinine level had decreased by more than 0.5 mg/dL. In mid-November 2004, she underwent right renal artery angioplasty with stent placement. After that, her serum creatinine decreased further, and 3 months later it had dropped to 1.6 mg/dL. The value continued to improve, with the lowest measurement of 1.1 mg/dL, equivalent to an estimated glomerular filtration rate of 51 mL/min/1.73 m². This was in May 2006, 19 months after stopping lisinopril and 17 months after angioplasty and stenting. The last available serum creatinine level (August 2006) was 1.2 mg/dL, equivalent to an estimated glomerular filtration rate of 45 mL/min/1.73 m² (Figure 1). Unfortunately, the patient died of metastatic lung cancer in December of that year.

Also of note, the patient who underwent angioplasty because of recurrent flash pulmonary edema had no recurrences of it afterward.

We concluded that, in patients with hemodynamically significant renal artery stenosis presenting with acutely worsening renal failure, renal angioplasty with stenting has the potential to reverse renal failure, improve blood pressure control, and stop flash pulmonary edema.^6–8

In severe renal artery stenosis, no one treatment fits all

Notably, all patients in our study who underwent renal angioplasty with stenting had new-onset acute renal injury as defined by an increase in the baseline serum creatinine of more than 25% during the 3 months before stent placement.^6–8 Patients in the STAR,² HERCULES,⁴ and CORAL⁵ studies had renal artery stenosis but otherwise stable chronic kidney disease at the time of enrollment. In the ASTRAL study,³ 12% of the patients had acute kidney injury on study enrollment, defined as an increase in the serum creatinine level of more than 20% or of more than 1.13 mg/dL.³

While we strongly agree with aggressive yet monitored medical therapy for patients with hemodynamically significant renal artery stenosis, I posit that selected patients do indeed derive significant clinical benefits from renal angioplasty and stenting. Our group’s prospective individual-patient-level data support the paradigm that angioplasty with stenting is useful in patients with renal artery stenosis who experience “acute-on-chronic” kidney disease.

The pathophysiology of renal artery stenosis and the progression of chronic kidney disease are complex, and many factors affect patient outcomes and response to treatment. Thus, the message is that treatment of severe renal artery stenosis must be individualized.^9–11 No one treatment fits all.^10,11

In their article in this issue of the Cleveland Clinic Journal of Medicine, Kabach et al answer no to the question of whether stenting of severe renal artery stenosis improves outcomes compared with medical therapy alone.¹ They review the findings of four key studies^2–5 published between 2003 and 2014 and conclude that, in patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting with medical therapy can improve blood pressure control but has no significant impact on cardiovascular or mortality outcomes.¹

See related article

Furthermore, the authors state that in view of the risk of complications associated with stenting, medical management should continue to be the first-line therapy.¹ Indeed, the ASTRAL study (Angioplasty and Stenting for Renal Artery Lesions) investigators found substantial risks without evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.³

Nevertheless, I believe that this procedure may benefit certain patients.

MAYO CLINIC COHORT STUDY

In 2008, our group at Mayo Clinic Health system in Eau Claire, Wisconsin, published the results of a prospective cohort study in 26 patients with renal artery stenosis and chronic kidney disease who presented with rapidly worsening renal failure (defined as an increase in serum creatinine of ≥ 25%) while receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).^6,7

These drugs—inhibitors of the renin-angiotensin-aldosterone system—slow the progression of chronic kidney disease but can acutely worsen renal function, especially in patients with renal artery stenosis, and withdrawing them in this situation was the focus of our study.

The patients (10 men and 16 women) ranged in age from 63 to 87 (mean age 75.3).

At enrollment, the ACE inhibitors and ARBs were discontinued, standard nephrologic care was applied, and the glomerular filtration rate (estimated by the Modification of Diet in Renal Disease Study equation) was monitored. After at least 2 weeks, percutaneous renal angioplasty with stent placement was considered if the patient met any of the following criteria:

• Persistence of renal failure
• Flash pulmonary edema
• Uncontrolled hypertension despite the use of at least three antihypertensive medications.

Nine patients underwent percutaneous angioplasty and stenting and 17 did not. The procedure was done on one renal artery in 8 patients and both renal arteries in 1. Indications for the procedure were recent worsening of renal failure in 8 patients and recent worsening renal failure together with symptomatic flash pulmonary edema in 1 patient. (Flash pulmonary edema is the only class I recommendation for percutaneous renal angioplasty in the 2006 joint guidelines of the American College of Cardiology and the American Heart Association.⁸) As noted above, all the patients were experiencing acute exacerbation of chronic kidney disease at the time.

We found clear evidence of additional improved and sustained renal function in the patients who underwent percutaneous renal angioplasty and stenting compared with the patients who did not (Figures 1 and 2).^6,7

In an editorial⁹ following publication of the ASTRAL study, our group reported a subsequent 82-month analysis of our 26-patient cohort completed in June 2009. In the 7 surviving patients who had undergone percutaneous renal angioplasty and stenting, the estimated glomerular filtration rate had increased from 27.4 mL/min/1.73 m² (± 12.7, range 11–47) at baseline to 50.3 (± 21.7, range 23–68) (P = .018) after 46.9 months.

PATIENT NUMBER 13

To illustrate how percutaneous renal angioplasty and stenting can reverse recently worsening renal failure in renal artery stenosis, I would like to discuss in greater detail a patient from our two previous reports.^6,7

Patient 13, a 67-year-old woman with hypertension, was referred to our nephrology service in September 2004 to consider starting hemodialysis for symptomatic renal failure. Her serum creatinine had increased to 3.4 mg/dL from a previous baseline level of 2.0 mg/dL, and she also had worsening anemia and hyperkalemia. She had been taking lisinopril 10 mg/day for the last 12 months. Magnetic resonance angiography revealed high-grade (> 95%) bilateral renal artery stenosis with an atrophic left kidney.

Lisinopril was promptly discontinued, and within 2 weeks her serum creatinine level had decreased by more than 0.5 mg/dL. In mid-November 2004, she underwent right renal artery angioplasty with stent placement. After that, her serum creatinine decreased further, and 3 months later it had dropped to 1.6 mg/dL. The value continued to improve, with the lowest measurement of 1.1 mg/dL, equivalent to an estimated glomerular filtration rate of 51 mL/min/1.73 m². This was in May 2006, 19 months after stopping lisinopril and 17 months after angioplasty and stenting. The last available serum creatinine level (August 2006) was 1.2 mg/dL, equivalent to an estimated glomerular filtration rate of 45 mL/min/1.73 m² (Figure 1). Unfortunately, the patient died of metastatic lung cancer in December of that year.

Also of note, the patient who underwent angioplasty because of recurrent flash pulmonary edema had no recurrences of it afterward.

We concluded that, in patients with hemodynamically significant renal artery stenosis presenting with acutely worsening renal failure, renal angioplasty with stenting has the potential to reverse renal failure, improve blood pressure control, and stop flash pulmonary edema.^6–8

In severe renal artery stenosis, no one treatment fits all

Notably, all patients in our study who underwent renal angioplasty with stenting had new-onset acute renal injury as defined by an increase in the baseline serum creatinine of more than 25% during the 3 months before stent placement.^6–8 Patients in the STAR,² HERCULES,⁴ and CORAL⁵ studies had renal artery stenosis but otherwise stable chronic kidney disease at the time of enrollment. In the ASTRAL study,³ 12% of the patients had acute kidney injury on study enrollment, defined as an increase in the serum creatinine level of more than 20% or of more than 1.13 mg/dL.³

While we strongly agree with aggressive yet monitored medical therapy for patients with hemodynamically significant renal artery stenosis, I posit that selected patients do indeed derive significant clinical benefits from renal angioplasty and stenting. Our group’s prospective individual-patient-level data support the paradigm that angioplasty with stenting is useful in patients with renal artery stenosis who experience “acute-on-chronic” kidney disease.

The pathophysiology of renal artery stenosis and the progression of chronic kidney disease are complex, and many factors affect patient outcomes and response to treatment. Thus, the message is that treatment of severe renal artery stenosis must be individualized.^9–11 No one treatment fits all.^10,11

In their article in this issue of the Cleveland Clinic Journal of Medicine, Kabach et al answer no to the question of whether stenting of severe renal artery stenosis improves outcomes compared with medical therapy alone.¹ They review the findings of four key studies^2–5 published between 2003 and 2014 and conclude that, in patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting with medical therapy can improve blood pressure control but has no significant impact on cardiovascular or mortality outcomes.¹

See related article

Furthermore, the authors state that in view of the risk of complications associated with stenting, medical management should continue to be the first-line therapy.¹ Indeed, the ASTRAL study (Angioplasty and Stenting for Renal Artery Lesions) investigators found substantial risks without evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease.³

Nevertheless, I believe that this procedure may benefit certain patients.

MAYO CLINIC COHORT STUDY

In 2008, our group at Mayo Clinic Health system in Eau Claire, Wisconsin, published the results of a prospective cohort study in 26 patients with renal artery stenosis and chronic kidney disease who presented with rapidly worsening renal failure (defined as an increase in serum creatinine of ≥ 25%) while receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).^6,7

These drugs—inhibitors of the renin-angiotensin-aldosterone system—slow the progression of chronic kidney disease but can acutely worsen renal function, especially in patients with renal artery stenosis, and withdrawing them in this situation was the focus of our study.

The patients (10 men and 16 women) ranged in age from 63 to 87 (mean age 75.3).

At enrollment, the ACE inhibitors and ARBs were discontinued, standard nephrologic care was applied, and the glomerular filtration rate (estimated by the Modification of Diet in Renal Disease Study equation) was monitored. After at least 2 weeks, percutaneous renal angioplasty with stent placement was considered if the patient met any of the following criteria:

• Persistence of renal failure
• Flash pulmonary edema
• Uncontrolled hypertension despite the use of at least three antihypertensive medications.

Nine patients underwent percutaneous angioplasty and stenting and 17 did not. The procedure was done on one renal artery in 8 patients and both renal arteries in 1. Indications for the procedure were recent worsening of renal failure in 8 patients and recent worsening renal failure together with symptomatic flash pulmonary edema in 1 patient. (Flash pulmonary edema is the only class I recommendation for percutaneous renal angioplasty in the 2006 joint guidelines of the American College of Cardiology and the American Heart Association.⁸) As noted above, all the patients were experiencing acute exacerbation of chronic kidney disease at the time.

We found clear evidence of additional improved and sustained renal function in the patients who underwent percutaneous renal angioplasty and stenting compared with the patients who did not (Figures 1 and 2).^6,7

In an editorial⁹ following publication of the ASTRAL study, our group reported a subsequent 82-month analysis of our 26-patient cohort completed in June 2009. In the 7 surviving patients who had undergone percutaneous renal angioplasty and stenting, the estimated glomerular filtration rate had increased from 27.4 mL/min/1.73 m² (± 12.7, range 11–47) at baseline to 50.3 (± 21.7, range 23–68) (P = .018) after 46.9 months.

PATIENT NUMBER 13

To illustrate how percutaneous renal angioplasty and stenting can reverse recently worsening renal failure in renal artery stenosis, I would like to discuss in greater detail a patient from our two previous reports.^6,7

Patient 13, a 67-year-old woman with hypertension, was referred to our nephrology service in September 2004 to consider starting hemodialysis for symptomatic renal failure. Her serum creatinine had increased to 3.4 mg/dL from a previous baseline level of 2.0 mg/dL, and she also had worsening anemia and hyperkalemia. She had been taking lisinopril 10 mg/day for the last 12 months. Magnetic resonance angiography revealed high-grade (> 95%) bilateral renal artery stenosis with an atrophic left kidney.

Lisinopril was promptly discontinued, and within 2 weeks her serum creatinine level had decreased by more than 0.5 mg/dL. In mid-November 2004, she underwent right renal artery angioplasty with stent placement. After that, her serum creatinine decreased further, and 3 months later it had dropped to 1.6 mg/dL. The value continued to improve, with the lowest measurement of 1.1 mg/dL, equivalent to an estimated glomerular filtration rate of 51 mL/min/1.73 m². This was in May 2006, 19 months after stopping lisinopril and 17 months after angioplasty and stenting. The last available serum creatinine level (August 2006) was 1.2 mg/dL, equivalent to an estimated glomerular filtration rate of 45 mL/min/1.73 m² (Figure 1). Unfortunately, the patient died of metastatic lung cancer in December of that year.

Also of note, the patient who underwent angioplasty because of recurrent flash pulmonary edema had no recurrences of it afterward.

We concluded that, in patients with hemodynamically significant renal artery stenosis presenting with acutely worsening renal failure, renal angioplasty with stenting has the potential to reverse renal failure, improve blood pressure control, and stop flash pulmonary edema.^6–8

In severe renal artery stenosis, no one treatment fits all

Notably, all patients in our study who underwent renal angioplasty with stenting had new-onset acute renal injury as defined by an increase in the baseline serum creatinine of more than 25% during the 3 months before stent placement.^6–8 Patients in the STAR,² HERCULES,⁴ and CORAL⁵ studies had renal artery stenosis but otherwise stable chronic kidney disease at the time of enrollment. In the ASTRAL study,³ 12% of the patients had acute kidney injury on study enrollment, defined as an increase in the serum creatinine level of more than 20% or of more than 1.13 mg/dL.³

While we strongly agree with aggressive yet monitored medical therapy for patients with hemodynamically significant renal artery stenosis, I posit that selected patients do indeed derive significant clinical benefits from renal angioplasty and stenting. Our group’s prospective individual-patient-level data support the paradigm that angioplasty with stenting is useful in patients with renal artery stenosis who experience “acute-on-chronic” kidney disease.

The pathophysiology of renal artery stenosis and the progression of chronic kidney disease are complex, and many factors affect patient outcomes and response to treatment. Thus, the message is that treatment of severe renal artery stenosis must be individualized.^9–11 No one treatment fits all.^10,11

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

Losing weight through lifestyle changes can significantly improve several measures of nonalcoholic fatty liver disease, particularly if patients lose at least 10% of their body weight, and bariatric surgery is a valid alternative if diet and exercise fail, according to two studies reported in the August issue of Gastroenterology (2015 Apr. 9 [doi:10.1053/j.gastro.2015.04.005]).

Global rates of nonalcoholic fatty liver disease (NAFLD) are up because of the “parallel epidemics” of obesity and type 2 diabetes mellitus, said Dr. Eduardo Vilar-Gomez of the National Institute of Hepatology in Havana, Cuba, who authored the study of lifestyle changes. There are no approved therapies for the more aggressive form of NAFLD, steatohepatitis, he and his associates said. In past studies, patients who lost about 7%-10% of their body weight substantially improved their NAFLD activity score and had reductions in steatosis, lobular inflammation, and ballooning, but the results did not extend to fibrosis, and prospective studies of the effect of lifestyle changes on histology are lacking, the researchers added .

To fill the gap, they followed 293 adults with histologically confirmed nonalcoholic steatohepatitis who completed a 52-week lifestyle intervention program that included keeping a food diary, restricting saturated fats to less than 10% of total intake, and walking at least 200 minutes a week. Patients had not received hypolipidemic treatment in the preceding 3 months and were not allowed to take insulin sensitizers or vitamin E, both of which are potentially beneficial for nonalcoholic steatohepatitis, the investigators said.

At the end of the yearlong program, steatohepatitis had resolved in 25% of patients, 47% had lower NAFLD activity scores, and 19% had regression of fibrosis, the researchers reported. Although only 30% of participants lost at least 5% of their body weight, weight loss correlated positively with resolution of steatohepatitis and with 2-point reductions in histologic activity scores (P <.001). Among patients who lost at least 10% of their body weight, 90% had resolution of steatohepatitis, 45% had regression of fibrosis, and all had improved histologic activity scores, even if they had negative risk factors such as female sex, a baseline body mass index of at least 35 kg/m², and a baseline fasting glucose level of at least 5.5 mmol/L, the investigators added. “Our findings support the current recommendation for weight loss using lifestyle modification as the first step in the management of patients with nonalcoholic steatohepatitis,” they wrote.

But what if lifestyle changes fail? The impact of bariatric surgery on nonalcoholic steatohepatitis has not been well studied, said Dr. Guillaume Lassailly at CHRU Lille (France). He and his associates therefore followed 109 morbidly obese patients (BMI ≥40 kg/m²) with biopsy-confirmed nonalcoholic steatohepatitis who underwent bariatric surgery at a single tertiary hospital (Gastroenterology 2015 Apr. 25 [doi:10.1053/j.gastro.2015.04.014]) .

One year after surgery, 85% of patients had achieved disease resolution (95% confidence interval, 75.8%-92.2%), the investigators reported. Stratifying patients by baseline Brunt scores showed that those with milder presurgical disease were more likely to have complete resolution than were patients whose disease was severe (94% vs. 70%; P <.05), the researchers added. Histologic analyses supported the findings, revealing steatosis in 60% of presurgical tissue samples, compared with 10% of samples taken a year after surgery. In addition, average NAFLD disease scores dropped from 5 to 1 (P <.001), hepatocyte ballooning decreased in 84% of samples, lobular inflammation decreased in 67%, and Metavir fibrosis scores dropped in one-third of specimens.

Notably, BMI scores for patients with persistent postsurgical disease dropped by an average of only 9.1, compared with 12.3 for patients whose disease resolved (P = .005), said the researchers. Gastric bypass surgery achieved greater weight loss and improvements in disease status, compared with laparoscopic banding, they added. “The encouraging results of the present study suggest that bariatric surgery should be tested in multicenter, randomized controlled trials in morbidly or severely obese patients with nonalcoholic steatohepatitis who did not respond to lifestyle therapy,” they wrote.

The Cuban National Institute of Gastroenterology and Ministry of Health partially funded the study by Dr. Vilar-Gomez and his associates. The French Ministry of Health and the Conseil Regional Nord-Pas de Calais supported the work by Dr. Lassailly and his colleagues. All investigators declared having no relevant financial conflicts of interest.

Losing weight through lifestyle changes can significantly improve several measures of nonalcoholic fatty liver disease, particularly if patients lose at least 10% of their body weight, and bariatric surgery is a valid alternative if diet and exercise fail, according to two studies reported in the August issue of Gastroenterology (2015 Apr. 9 [doi:10.1053/j.gastro.2015.04.005]).

Global rates of nonalcoholic fatty liver disease (NAFLD) are up because of the “parallel epidemics” of obesity and type 2 diabetes mellitus, said Dr. Eduardo Vilar-Gomez of the National Institute of Hepatology in Havana, Cuba, who authored the study of lifestyle changes. There are no approved therapies for the more aggressive form of NAFLD, steatohepatitis, he and his associates said. In past studies, patients who lost about 7%-10% of their body weight substantially improved their NAFLD activity score and had reductions in steatosis, lobular inflammation, and ballooning, but the results did not extend to fibrosis, and prospective studies of the effect of lifestyle changes on histology are lacking, the researchers added .

To fill the gap, they followed 293 adults with histologically confirmed nonalcoholic steatohepatitis who completed a 52-week lifestyle intervention program that included keeping a food diary, restricting saturated fats to less than 10% of total intake, and walking at least 200 minutes a week. Patients had not received hypolipidemic treatment in the preceding 3 months and were not allowed to take insulin sensitizers or vitamin E, both of which are potentially beneficial for nonalcoholic steatohepatitis, the investigators said.

At the end of the yearlong program, steatohepatitis had resolved in 25% of patients, 47% had lower NAFLD activity scores, and 19% had regression of fibrosis, the researchers reported. Although only 30% of participants lost at least 5% of their body weight, weight loss correlated positively with resolution of steatohepatitis and with 2-point reductions in histologic activity scores (P <.001). Among patients who lost at least 10% of their body weight, 90% had resolution of steatohepatitis, 45% had regression of fibrosis, and all had improved histologic activity scores, even if they had negative risk factors such as female sex, a baseline body mass index of at least 35 kg/m², and a baseline fasting glucose level of at least 5.5 mmol/L, the investigators added. “Our findings support the current recommendation for weight loss using lifestyle modification as the first step in the management of patients with nonalcoholic steatohepatitis,” they wrote.

But what if lifestyle changes fail? The impact of bariatric surgery on nonalcoholic steatohepatitis has not been well studied, said Dr. Guillaume Lassailly at CHRU Lille (France). He and his associates therefore followed 109 morbidly obese patients (BMI ≥40 kg/m²) with biopsy-confirmed nonalcoholic steatohepatitis who underwent bariatric surgery at a single tertiary hospital (Gastroenterology 2015 Apr. 25 [doi:10.1053/j.gastro.2015.04.014]) .

One year after surgery, 85% of patients had achieved disease resolution (95% confidence interval, 75.8%-92.2%), the investigators reported. Stratifying patients by baseline Brunt scores showed that those with milder presurgical disease were more likely to have complete resolution than were patients whose disease was severe (94% vs. 70%; P <.05), the researchers added. Histologic analyses supported the findings, revealing steatosis in 60% of presurgical tissue samples, compared with 10% of samples taken a year after surgery. In addition, average NAFLD disease scores dropped from 5 to 1 (P <.001), hepatocyte ballooning decreased in 84% of samples, lobular inflammation decreased in 67%, and Metavir fibrosis scores dropped in one-third of specimens.

Notably, BMI scores for patients with persistent postsurgical disease dropped by an average of only 9.1, compared with 12.3 for patients whose disease resolved (P = .005), said the researchers. Gastric bypass surgery achieved greater weight loss and improvements in disease status, compared with laparoscopic banding, they added. “The encouraging results of the present study suggest that bariatric surgery should be tested in multicenter, randomized controlled trials in morbidly or severely obese patients with nonalcoholic steatohepatitis who did not respond to lifestyle therapy,” they wrote.

The Cuban National Institute of Gastroenterology and Ministry of Health partially funded the study by Dr. Vilar-Gomez and his associates. The French Ministry of Health and the Conseil Regional Nord-Pas de Calais supported the work by Dr. Lassailly and his colleagues. All investigators declared having no relevant financial conflicts of interest.

Losing weight through lifestyle changes can significantly improve several measures of nonalcoholic fatty liver disease, particularly if patients lose at least 10% of their body weight, and bariatric surgery is a valid alternative if diet and exercise fail, according to two studies reported in the August issue of Gastroenterology (2015 Apr. 9 [doi:10.1053/j.gastro.2015.04.005]).

Global rates of nonalcoholic fatty liver disease (NAFLD) are up because of the “parallel epidemics” of obesity and type 2 diabetes mellitus, said Dr. Eduardo Vilar-Gomez of the National Institute of Hepatology in Havana, Cuba, who authored the study of lifestyle changes. There are no approved therapies for the more aggressive form of NAFLD, steatohepatitis, he and his associates said. In past studies, patients who lost about 7%-10% of their body weight substantially improved their NAFLD activity score and had reductions in steatosis, lobular inflammation, and ballooning, but the results did not extend to fibrosis, and prospective studies of the effect of lifestyle changes on histology are lacking, the researchers added .

To fill the gap, they followed 293 adults with histologically confirmed nonalcoholic steatohepatitis who completed a 52-week lifestyle intervention program that included keeping a food diary, restricting saturated fats to less than 10% of total intake, and walking at least 200 minutes a week. Patients had not received hypolipidemic treatment in the preceding 3 months and were not allowed to take insulin sensitizers or vitamin E, both of which are potentially beneficial for nonalcoholic steatohepatitis, the investigators said.

At the end of the yearlong program, steatohepatitis had resolved in 25% of patients, 47% had lower NAFLD activity scores, and 19% had regression of fibrosis, the researchers reported. Although only 30% of participants lost at least 5% of their body weight, weight loss correlated positively with resolution of steatohepatitis and with 2-point reductions in histologic activity scores (P <.001). Among patients who lost at least 10% of their body weight, 90% had resolution of steatohepatitis, 45% had regression of fibrosis, and all had improved histologic activity scores, even if they had negative risk factors such as female sex, a baseline body mass index of at least 35 kg/m², and a baseline fasting glucose level of at least 5.5 mmol/L, the investigators added. “Our findings support the current recommendation for weight loss using lifestyle modification as the first step in the management of patients with nonalcoholic steatohepatitis,” they wrote.

But what if lifestyle changes fail? The impact of bariatric surgery on nonalcoholic steatohepatitis has not been well studied, said Dr. Guillaume Lassailly at CHRU Lille (France). He and his associates therefore followed 109 morbidly obese patients (BMI ≥40 kg/m²) with biopsy-confirmed nonalcoholic steatohepatitis who underwent bariatric surgery at a single tertiary hospital (Gastroenterology 2015 Apr. 25 [doi:10.1053/j.gastro.2015.04.014]) .

One year after surgery, 85% of patients had achieved disease resolution (95% confidence interval, 75.8%-92.2%), the investigators reported. Stratifying patients by baseline Brunt scores showed that those with milder presurgical disease were more likely to have complete resolution than were patients whose disease was severe (94% vs. 70%; P <.05), the researchers added. Histologic analyses supported the findings, revealing steatosis in 60% of presurgical tissue samples, compared with 10% of samples taken a year after surgery. In addition, average NAFLD disease scores dropped from 5 to 1 (P <.001), hepatocyte ballooning decreased in 84% of samples, lobular inflammation decreased in 67%, and Metavir fibrosis scores dropped in one-third of specimens.

Notably, BMI scores for patients with persistent postsurgical disease dropped by an average of only 9.1, compared with 12.3 for patients whose disease resolved (P = .005), said the researchers. Gastric bypass surgery achieved greater weight loss and improvements in disease status, compared with laparoscopic banding, they added. “The encouraging results of the present study suggest that bariatric surgery should be tested in multicenter, randomized controlled trials in morbidly or severely obese patients with nonalcoholic steatohepatitis who did not respond to lifestyle therapy,” they wrote.

The Cuban National Institute of Gastroenterology and Ministry of Health partially funded the study by Dr. Vilar-Gomez and his associates. The French Ministry of Health and the Conseil Regional Nord-Pas de Calais supported the work by Dr. Lassailly and his colleagues. All investigators declared having no relevant financial conflicts of interest.

A foam formulation of azelaic acid has been approved for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea, the manufacturer announced July 31.

Azelaic acid foam, 15%, was compared with a vehicle foam, applied twice a day for 12 weeks, in two studies with a total of 1,362 people with papulopustular rosacea (mean age 50.6 years) and a mean of about 21 inflammatory papules and pustules at baseline. The success rate was defined as a score of clear or minimal with at least a two-step reduction from baseline on the Investigator’s Global Assessment scale.

At 12 weeks, the success rate in the two studies, respectively, was 32% and 43% among those treated with azelaic foam vs. 23% and 32% among controls, according to the Bayer HealthCare press release announcing the approval.

The most common adverse events associated with treatment were pain at the application site in about 6%, pruritus (2.5%), dryness (0.7%), and erythema (0.7%). Warnings in the prescribing information note that treatment has been associated with “isolated” cases of hypopigmentation and can cause eye irritation, and that the contents are flammable. Patients are instructed to avoid “fire, flame, and smoking during and immediately following application.”

Azelaic acid foam is marketed as Finacea Foam by Bayer; it is the first foam formulation of azelaic acid to be approved, and it will be available in September, according to the company. A gel formulation of azelaic acid, 15%, was approved by the FDA in 2002 for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.

Serious adverse events associated with azelaic acid should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

A foam formulation of azelaic acid has been approved for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea, the manufacturer announced July 31.

Azelaic acid foam, 15%, was compared with a vehicle foam, applied twice a day for 12 weeks, in two studies with a total of 1,362 people with papulopustular rosacea (mean age 50.6 years) and a mean of about 21 inflammatory papules and pustules at baseline. The success rate was defined as a score of clear or minimal with at least a two-step reduction from baseline on the Investigator’s Global Assessment scale.

At 12 weeks, the success rate in the two studies, respectively, was 32% and 43% among those treated with azelaic foam vs. 23% and 32% among controls, according to the Bayer HealthCare press release announcing the approval.

The most common adverse events associated with treatment were pain at the application site in about 6%, pruritus (2.5%), dryness (0.7%), and erythema (0.7%). Warnings in the prescribing information note that treatment has been associated with “isolated” cases of hypopigmentation and can cause eye irritation, and that the contents are flammable. Patients are instructed to avoid “fire, flame, and smoking during and immediately following application.”

Azelaic acid foam is marketed as Finacea Foam by Bayer; it is the first foam formulation of azelaic acid to be approved, and it will be available in September, according to the company. A gel formulation of azelaic acid, 15%, was approved by the FDA in 2002 for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.

Serious adverse events associated with azelaic acid should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

A foam formulation of azelaic acid has been approved for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea, the manufacturer announced July 31.

Azelaic acid foam, 15%, was compared with a vehicle foam, applied twice a day for 12 weeks, in two studies with a total of 1,362 people with papulopustular rosacea (mean age 50.6 years) and a mean of about 21 inflammatory papules and pustules at baseline. The success rate was defined as a score of clear or minimal with at least a two-step reduction from baseline on the Investigator’s Global Assessment scale.

At 12 weeks, the success rate in the two studies, respectively, was 32% and 43% among those treated with azelaic foam vs. 23% and 32% among controls, according to the Bayer HealthCare press release announcing the approval.

The most common adverse events associated with treatment were pain at the application site in about 6%, pruritus (2.5%), dryness (0.7%), and erythema (0.7%). Warnings in the prescribing information note that treatment has been associated with “isolated” cases of hypopigmentation and can cause eye irritation, and that the contents are flammable. Patients are instructed to avoid “fire, flame, and smoking during and immediately following application.”

Azelaic acid foam is marketed as Finacea Foam by Bayer; it is the first foam formulation of azelaic acid to be approved, and it will be available in September, according to the company. A gel formulation of azelaic acid, 15%, was approved by the FDA in 2002 for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.

Serious adverse events associated with azelaic acid should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

Clinicians and researchers must get better at identifying Lynch syndrome because the diagnosis is so often missed, according to new AGA clinical guidelines for diagnosing and managing the disorder, published in the September issue of Gastroenterology.

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is the most common heritable cause of colorectal cancer and also is associated with cancers of the endometrium, stomach, small intestine, pancreas, biliary tract, ovary, urinary tract, and brain. Lynch syndrome accounts for 2%-3% of all colorectal cancers in the United States, and the estimated prevalence is 1 in 440 in the general population. People with the syndrome are estimated to have a lifetime cumulative incidence of colorectal cancer approaching 80%, and affected women have an estimated 60% lifetime cumulative incidence of endometrial cancer.

The new AGA guidelines focus on identifying Lynch syndrome, both in patients without cancer who have a family history suggestive of the disorder and in all patients who develop colorectal cancer, said Dr. Joel H. Rubenstein and his associates on the clinical guidelines committee (Gastroenterology 2015 Jul. 28 [doi: 10.1053/j.gastro.2015.07.036]).

The guidelines strongly recommend that all colorectal cancers now be tested using immunohistochemistry or assessment of microsatellite instability to identify potential cases of Lynch syndrome. Given the high incidence of colorectal cancer in the United States, this recommendation in particular “may be ripe for consideration as a process measure of quality of care,” they noted.

Until now, older patients with colorectal cancer have not undergone such testing because the yield of positive results was lower than in younger patients, but now there is new appreciation that these results have a significant impact on younger family members, not just the patients themselves. From the perspective of preventing cancer in these relatives, such testing is actually cost effective, said Dr. Rubenstein of the Veterans Affairs Center for Clinical Management Research and the gastroenterology division at the University of Michigan, both in Ann Arbor, and his associates.

At present, the evidence is insufficient to recommend either of these tests above the other for identifying Lynch syndrome. The two have comparable sensitivities and specificities.

The guidelines also recommend that, in people who have no personal history of colorectal or other cancer but who have a family history that suggests Lynch syndrome, risk prediction should be performed, “rather than doing nothing.” If a first-degree relative is known to have a Lynch mutation, people should be offered germline genetic testing for that mutation. Alternatively, “if tumor tissue from an affected relative is available, the screening process should begin with testing on that tumor.”

If none of this information is available, online risk prediction models or free downloadable software incorporating such models can be used to quickly and easily estimate the probability of carrying a Lynch syndrome mutation. This approach is “imperative” to improve case finding, since it is likely that most Lynch syndrome kindreds are undiagnosed, Dr. Rubenstein and his associates said.

Such patients should be offered risk-prediction models rather than proceeding directly to germline genetic testing because of the currently high costs of genetic testing. People without cancer who have a family history suggestive of Lynch syndrome should proceed straight to germline testing if they are considered to be at high risk – for example, if they meet the highly specific Amsterdam criteria.

The AGA guidelines strongly recommend that patients identified as having Lynch syndrome undergo surveillance colonoscopy, as opposed to no surveillance. Good-quality evidence shows that this strategy decreases the overall burden of colorectal cancer and reduces disease-specific mortality. People who carry Lynch syndrome genetic mutations increase their life expectancy by 7 years if they undergo surveillance colonoscopy, and cost-effectiveness analyses indicate that the expense of such screening is lower than the expense of no screening.

The optimal screening interval for such patients has not been determined, but low-quality evidence suggests that undergoing colonoscopy every 1-2 years is the “most prudent” course and is better than doing so at longer intervals.

The guidelines also include a conditional recommendation that people found to have Lynch syndrome should be offered aspirin therapy as cancer prophylaxis. The optimal dose and frequency of aspirin use is not yet known, and there is no evidence that the treatment improves mortality, but some low-quality evidence suggests that aspirin therapy reduces the risk of colorectal and other cancers, and the risk of adverse events is quite low.

Clinicians and researchers must get better at identifying Lynch syndrome because the diagnosis is so often missed, according to new AGA clinical guidelines for diagnosing and managing the disorder, published in the September issue of Gastroenterology.

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is the most common heritable cause of colorectal cancer and also is associated with cancers of the endometrium, stomach, small intestine, pancreas, biliary tract, ovary, urinary tract, and brain. Lynch syndrome accounts for 2%-3% of all colorectal cancers in the United States, and the estimated prevalence is 1 in 440 in the general population. People with the syndrome are estimated to have a lifetime cumulative incidence of colorectal cancer approaching 80%, and affected women have an estimated 60% lifetime cumulative incidence of endometrial cancer.

The new AGA guidelines focus on identifying Lynch syndrome, both in patients without cancer who have a family history suggestive of the disorder and in all patients who develop colorectal cancer, said Dr. Joel H. Rubenstein and his associates on the clinical guidelines committee (Gastroenterology 2015 Jul. 28 [doi: 10.1053/j.gastro.2015.07.036]).

The guidelines strongly recommend that all colorectal cancers now be tested using immunohistochemistry or assessment of microsatellite instability to identify potential cases of Lynch syndrome. Given the high incidence of colorectal cancer in the United States, this recommendation in particular “may be ripe for consideration as a process measure of quality of care,” they noted.

Until now, older patients with colorectal cancer have not undergone such testing because the yield of positive results was lower than in younger patients, but now there is new appreciation that these results have a significant impact on younger family members, not just the patients themselves. From the perspective of preventing cancer in these relatives, such testing is actually cost effective, said Dr. Rubenstein of the Veterans Affairs Center for Clinical Management Research and the gastroenterology division at the University of Michigan, both in Ann Arbor, and his associates.

At present, the evidence is insufficient to recommend either of these tests above the other for identifying Lynch syndrome. The two have comparable sensitivities and specificities.

The guidelines also recommend that, in people who have no personal history of colorectal or other cancer but who have a family history that suggests Lynch syndrome, risk prediction should be performed, “rather than doing nothing.” If a first-degree relative is known to have a Lynch mutation, people should be offered germline genetic testing for that mutation. Alternatively, “if tumor tissue from an affected relative is available, the screening process should begin with testing on that tumor.”

If none of this information is available, online risk prediction models or free downloadable software incorporating such models can be used to quickly and easily estimate the probability of carrying a Lynch syndrome mutation. This approach is “imperative” to improve case finding, since it is likely that most Lynch syndrome kindreds are undiagnosed, Dr. Rubenstein and his associates said.

Such patients should be offered risk-prediction models rather than proceeding directly to germline genetic testing because of the currently high costs of genetic testing. People without cancer who have a family history suggestive of Lynch syndrome should proceed straight to germline testing if they are considered to be at high risk – for example, if they meet the highly specific Amsterdam criteria.

The AGA guidelines strongly recommend that patients identified as having Lynch syndrome undergo surveillance colonoscopy, as opposed to no surveillance. Good-quality evidence shows that this strategy decreases the overall burden of colorectal cancer and reduces disease-specific mortality. People who carry Lynch syndrome genetic mutations increase their life expectancy by 7 years if they undergo surveillance colonoscopy, and cost-effectiveness analyses indicate that the expense of such screening is lower than the expense of no screening.

The optimal screening interval for such patients has not been determined, but low-quality evidence suggests that undergoing colonoscopy every 1-2 years is the “most prudent” course and is better than doing so at longer intervals.

The guidelines also include a conditional recommendation that people found to have Lynch syndrome should be offered aspirin therapy as cancer prophylaxis. The optimal dose and frequency of aspirin use is not yet known, and there is no evidence that the treatment improves mortality, but some low-quality evidence suggests that aspirin therapy reduces the risk of colorectal and other cancers, and the risk of adverse events is quite low.

Clinicians and researchers must get better at identifying Lynch syndrome because the diagnosis is so often missed, according to new AGA clinical guidelines for diagnosing and managing the disorder, published in the September issue of Gastroenterology.

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is the most common heritable cause of colorectal cancer and also is associated with cancers of the endometrium, stomach, small intestine, pancreas, biliary tract, ovary, urinary tract, and brain. Lynch syndrome accounts for 2%-3% of all colorectal cancers in the United States, and the estimated prevalence is 1 in 440 in the general population. People with the syndrome are estimated to have a lifetime cumulative incidence of colorectal cancer approaching 80%, and affected women have an estimated 60% lifetime cumulative incidence of endometrial cancer.

The new AGA guidelines focus on identifying Lynch syndrome, both in patients without cancer who have a family history suggestive of the disorder and in all patients who develop colorectal cancer, said Dr. Joel H. Rubenstein and his associates on the clinical guidelines committee (Gastroenterology 2015 Jul. 28 [doi: 10.1053/j.gastro.2015.07.036]).

The guidelines strongly recommend that all colorectal cancers now be tested using immunohistochemistry or assessment of microsatellite instability to identify potential cases of Lynch syndrome. Given the high incidence of colorectal cancer in the United States, this recommendation in particular “may be ripe for consideration as a process measure of quality of care,” they noted.

Until now, older patients with colorectal cancer have not undergone such testing because the yield of positive results was lower than in younger patients, but now there is new appreciation that these results have a significant impact on younger family members, not just the patients themselves. From the perspective of preventing cancer in these relatives, such testing is actually cost effective, said Dr. Rubenstein of the Veterans Affairs Center for Clinical Management Research and the gastroenterology division at the University of Michigan, both in Ann Arbor, and his associates.

At present, the evidence is insufficient to recommend either of these tests above the other for identifying Lynch syndrome. The two have comparable sensitivities and specificities.

The guidelines also recommend that, in people who have no personal history of colorectal or other cancer but who have a family history that suggests Lynch syndrome, risk prediction should be performed, “rather than doing nothing.” If a first-degree relative is known to have a Lynch mutation, people should be offered germline genetic testing for that mutation. Alternatively, “if tumor tissue from an affected relative is available, the screening process should begin with testing on that tumor.”

If none of this information is available, online risk prediction models or free downloadable software incorporating such models can be used to quickly and easily estimate the probability of carrying a Lynch syndrome mutation. This approach is “imperative” to improve case finding, since it is likely that most Lynch syndrome kindreds are undiagnosed, Dr. Rubenstein and his associates said.

Such patients should be offered risk-prediction models rather than proceeding directly to germline genetic testing because of the currently high costs of genetic testing. People without cancer who have a family history suggestive of Lynch syndrome should proceed straight to germline testing if they are considered to be at high risk – for example, if they meet the highly specific Amsterdam criteria.

The AGA guidelines strongly recommend that patients identified as having Lynch syndrome undergo surveillance colonoscopy, as opposed to no surveillance. Good-quality evidence shows that this strategy decreases the overall burden of colorectal cancer and reduces disease-specific mortality. People who carry Lynch syndrome genetic mutations increase their life expectancy by 7 years if they undergo surveillance colonoscopy, and cost-effectiveness analyses indicate that the expense of such screening is lower than the expense of no screening.

The optimal screening interval for such patients has not been determined, but low-quality evidence suggests that undergoing colonoscopy every 1-2 years is the “most prudent” course and is better than doing so at longer intervals.

The guidelines also include a conditional recommendation that people found to have Lynch syndrome should be offered aspirin therapy as cancer prophylaxis. The optimal dose and frequency of aspirin use is not yet known, and there is no evidence that the treatment improves mortality, but some low-quality evidence suggests that aspirin therapy reduces the risk of colorectal and other cancers, and the risk of adverse events is quite low.

Question: Which of the following statements regarding the doctrine of informed consent is best?

A. All jurisdictions now require disclosure geared toward the reasonable patient rather than the reasonable doctor.

B. Disclosures are less important and sometimes unnecessary in global clinical research protocols.

C. The trend is toward the use of simplified and personalized consent forms.

D. A and C.

Answer: C. An important development in the doctrine of informed consent deals with the typical consent form, which is lengthy (going on 14 pages in one report), largely incomprehensible, and densely legalistic. Worse, the physician may misconstrue the form as a proxy for risk disclosure, whereas in fact the duly signed form merely purports to indicate that meaningful discussion of risks, benefits, and alternatives had taken place – if indeed that has been the case.

A review of more than 500 separate informed consent forms revealed these documents have limited educational value, go mostly unread, and are frequently misunderstood by patients (Arch. Surg. 2000;135:26-33).Thus, there is much to recommend the recent move toward shorter forms that use simpler language, bigger type fonts, and even graphics to improve patient and family understanding.

For example, a novel personalized approach currently being tested offers evidence-based benefits and risks to patients undergoing elective percutaneous coronary intervention. The consent document draws on the American College of Cardiology’s National Cardiovascular Data Registry to offer individualized risk estimates, and lists the experience of the health care team and the anticipated financial costs (JAMA 2010;303:1190-1).

Such approaches are consonant with the notion of patient-centered care, which the Institute of Medicine has identified as a core attribute of high-quality health care systems.

One of the continuing controversies in informed consent is the requisite standard of disclosure.

Historically, what needed to be disclosed was judged by what was ordinarily expected of the reasonable physician in the community. However, in 1972, Canterbury v. Spence (464 F.2d 772 [D.C. Cir. 1972]) persuasively argued for replacing such a professional standard (what doctors customarily would disclose) with a patient-oriented standard, i.e., what a reasonable patient would want to know.

California quickly followed, and an increasing number of jurisdictions such as Alaska, Hawaii, Massachusetts, Minnesota, Texas, West Virginia, and Wisconsin have since embraced this patient-centered standard. However, a number of other jurisdictions, including Arkansas, Indiana, Michigan, Montana, Nebraska, Nevada, and Wyoming, continue to adhere to the professional or physician-centered standard.

The momentum toward patient-centered disclosure appears to be growing, and has spread to other common-law jurisdictions abroad such as Canada and Australia. The United Kingdom was a steadfast opponent of patient-centric consent since Sidaway v. Board of Governors of the Bethlem Royal Hospital and the Maudsley Hospital ([1985] AC 871), its seminal House of Lords decision in the 1980s.

However, it finally abandoned its opposition on March 11, 2015, when its Supreme Court decided the case of a baby boy who sustained brain injury and arm paralysis at birth as a result of shoulder dystocia (Montgomery v. Lanarkshire Health Board [2015] UKSC 11).

The plaintiff alleged that being a diabetic mother, she should have been warned of the risks of shoulder dystocia and offered the alternative of a cesarean section. The obstetrician said she did not warn because the risks of a serious problem were very small. The court sided with the plaintiff, overturned Sidaway’s professional standard, and adopted the patient standard of disclosure as the new law.

What needs to be disclosed continues to plague the practitioner. The term “material risks” merely begs the question of the definition of “material.” It has been said that the crucial factor is the patient’s need.

The vexing issue surrounding the scope of risk disclosure is compounded by court decisions allowing inquiry outside the medical condition itself, such as a physician’s alcoholism or HIV status, and financial incentives amounting to a breach of fiduciary responsibility. However, courts have tended to reject requiring disclosure of practitioner experience or patient prognosis.

Novel issues continue to surface. For example, a recent Wisconsin Supreme Court case dealt with whether it was necessary for a physician to disclose the availability of a collateral test not directly linked to a patient’s diagnosis.

In Jandre v. Wis. Injured Patients & Families Comp. Fund (813 N.W.2d 627 [Wis. 2012]), a doctor diagnosed Bell’s palsy as the cause of a patient’s neurologic symptoms, because she heard no carotid bruits and the head CT scan was normal. Shortly thereafter, the patient developed a stroke. Although the doctor was found not negligent for the misdiagnosis, the plaintiff then proceeded on a lack of informed consent theory, asserting that the doctor should have advised him of the availability of a carotid ultrasound test to rule out a TIA.

In a momentous decision, the Wisconsin Supreme Court affirmed the lower court’s judgment in finding the physician liable for failing to disclose the availability of the ultrasound procedure.

Another area where informed consent is under renewed scrutiny is in research. Doctors in practice are increasingly participating as coinvestigators in industry-sponsored drug trials, and should be familiar with what is expected in the research context.

Augmented rules regarding informed consent govern all clinical research, with patient safety and free meaningful choice being paramount considerations. Federal and state regulations, implemented and monitored by institutional review boards, serve to enforce compliance and safeguard the safety of experimental subjects.

Still, as predicted nearly 50 years ago by Dr. Henry K. Beecher, “In any precise sense, statements regarding consent are meaningless unless one knows how fully the patient was informed of all risks, and if these are not known, that fact should also be made clear. A far more dependable safeguard than consent is the presence of a truly responsible investigator” (N. Engl. J. Med. 1966;274:1354-60).

Scandals in human research led by or in collaboration with U.S. investigators in foreign countries have been in the news. Global clinical trials are supposed to be carried out in compliance with the Nuremberg Code and the Declaration of Helsinki, but there may be occasional lapses or disregard for such international laws. A recent example is the trial using the antibiotic trovafloxacin, administered orally, versus FDA-approved parenteral ceftriaxone, during a meningitis outbreak in Nigeria (N. Engl. J. Med. 2009;360:2050-3).

Finally, the politics of abortion and first amendment rights have managed to insinuate themselves into the informed consent debate. Can states mandate disclosure in the name of securing meaningful informed consent, e.g., requiring physicians to provide information that might encourage a woman to reconsider her decision to have an abortion?

In 1992, the U.S. Supreme Court decided that this passes constitutional muster, because it did not place an undue burden on the woman. However, the Fourth Circuit Appellate Court recently ruled unconstitutional a North Carolina statute called Display of Real-Time View Requirement. The statute requires physicians to display ultrasound images of the unborn child to a mother contemplating an abortion, which the court ruled violated the First Amendment’s prohibition on state-compelled speech (N. Engl. J. Med. 2015;372:1285-7).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].

Question: Which of the following statements regarding the doctrine of informed consent is best?

A. All jurisdictions now require disclosure geared toward the reasonable patient rather than the reasonable doctor.

B. Disclosures are less important and sometimes unnecessary in global clinical research protocols.

C. The trend is toward the use of simplified and personalized consent forms.

D. A and C.

Answer: C. An important development in the doctrine of informed consent deals with the typical consent form, which is lengthy (going on 14 pages in one report), largely incomprehensible, and densely legalistic. Worse, the physician may misconstrue the form as a proxy for risk disclosure, whereas in fact the duly signed form merely purports to indicate that meaningful discussion of risks, benefits, and alternatives had taken place – if indeed that has been the case.

A review of more than 500 separate informed consent forms revealed these documents have limited educational value, go mostly unread, and are frequently misunderstood by patients (Arch. Surg. 2000;135:26-33).Thus, there is much to recommend the recent move toward shorter forms that use simpler language, bigger type fonts, and even graphics to improve patient and family understanding.

For example, a novel personalized approach currently being tested offers evidence-based benefits and risks to patients undergoing elective percutaneous coronary intervention. The consent document draws on the American College of Cardiology’s National Cardiovascular Data Registry to offer individualized risk estimates, and lists the experience of the health care team and the anticipated financial costs (JAMA 2010;303:1190-1).

Such approaches are consonant with the notion of patient-centered care, which the Institute of Medicine has identified as a core attribute of high-quality health care systems.

One of the continuing controversies in informed consent is the requisite standard of disclosure.

Historically, what needed to be disclosed was judged by what was ordinarily expected of the reasonable physician in the community. However, in 1972, Canterbury v. Spence (464 F.2d 772 [D.C. Cir. 1972]) persuasively argued for replacing such a professional standard (what doctors customarily would disclose) with a patient-oriented standard, i.e., what a reasonable patient would want to know.

California quickly followed, and an increasing number of jurisdictions such as Alaska, Hawaii, Massachusetts, Minnesota, Texas, West Virginia, and Wisconsin have since embraced this patient-centered standard. However, a number of other jurisdictions, including Arkansas, Indiana, Michigan, Montana, Nebraska, Nevada, and Wyoming, continue to adhere to the professional or physician-centered standard.

The momentum toward patient-centered disclosure appears to be growing, and has spread to other common-law jurisdictions abroad such as Canada and Australia. The United Kingdom was a steadfast opponent of patient-centric consent since Sidaway v. Board of Governors of the Bethlem Royal Hospital and the Maudsley Hospital ([1985] AC 871), its seminal House of Lords decision in the 1980s.

However, it finally abandoned its opposition on March 11, 2015, when its Supreme Court decided the case of a baby boy who sustained brain injury and arm paralysis at birth as a result of shoulder dystocia (Montgomery v. Lanarkshire Health Board [2015] UKSC 11).

The plaintiff alleged that being a diabetic mother, she should have been warned of the risks of shoulder dystocia and offered the alternative of a cesarean section. The obstetrician said she did not warn because the risks of a serious problem were very small. The court sided with the plaintiff, overturned Sidaway’s professional standard, and adopted the patient standard of disclosure as the new law.

What needs to be disclosed continues to plague the practitioner. The term “material risks” merely begs the question of the definition of “material.” It has been said that the crucial factor is the patient’s need.

The vexing issue surrounding the scope of risk disclosure is compounded by court decisions allowing inquiry outside the medical condition itself, such as a physician’s alcoholism or HIV status, and financial incentives amounting to a breach of fiduciary responsibility. However, courts have tended to reject requiring disclosure of practitioner experience or patient prognosis.

Novel issues continue to surface. For example, a recent Wisconsin Supreme Court case dealt with whether it was necessary for a physician to disclose the availability of a collateral test not directly linked to a patient’s diagnosis.

In Jandre v. Wis. Injured Patients & Families Comp. Fund (813 N.W.2d 627 [Wis. 2012]), a doctor diagnosed Bell’s palsy as the cause of a patient’s neurologic symptoms, because she heard no carotid bruits and the head CT scan was normal. Shortly thereafter, the patient developed a stroke. Although the doctor was found not negligent for the misdiagnosis, the plaintiff then proceeded on a lack of informed consent theory, asserting that the doctor should have advised him of the availability of a carotid ultrasound test to rule out a TIA.

In a momentous decision, the Wisconsin Supreme Court affirmed the lower court’s judgment in finding the physician liable for failing to disclose the availability of the ultrasound procedure.

Another area where informed consent is under renewed scrutiny is in research. Doctors in practice are increasingly participating as coinvestigators in industry-sponsored drug trials, and should be familiar with what is expected in the research context.

Augmented rules regarding informed consent govern all clinical research, with patient safety and free meaningful choice being paramount considerations. Federal and state regulations, implemented and monitored by institutional review boards, serve to enforce compliance and safeguard the safety of experimental subjects.

Still, as predicted nearly 50 years ago by Dr. Henry K. Beecher, “In any precise sense, statements regarding consent are meaningless unless one knows how fully the patient was informed of all risks, and if these are not known, that fact should also be made clear. A far more dependable safeguard than consent is the presence of a truly responsible investigator” (N. Engl. J. Med. 1966;274:1354-60).

Scandals in human research led by or in collaboration with U.S. investigators in foreign countries have been in the news. Global clinical trials are supposed to be carried out in compliance with the Nuremberg Code and the Declaration of Helsinki, but there may be occasional lapses or disregard for such international laws. A recent example is the trial using the antibiotic trovafloxacin, administered orally, versus FDA-approved parenteral ceftriaxone, during a meningitis outbreak in Nigeria (N. Engl. J. Med. 2009;360:2050-3).

Finally, the politics of abortion and first amendment rights have managed to insinuate themselves into the informed consent debate. Can states mandate disclosure in the name of securing meaningful informed consent, e.g., requiring physicians to provide information that might encourage a woman to reconsider her decision to have an abortion?

In 1992, the U.S. Supreme Court decided that this passes constitutional muster, because it did not place an undue burden on the woman. However, the Fourth Circuit Appellate Court recently ruled unconstitutional a North Carolina statute called Display of Real-Time View Requirement. The statute requires physicians to display ultrasound images of the unborn child to a mother contemplating an abortion, which the court ruled violated the First Amendment’s prohibition on state-compelled speech (N. Engl. J. Med. 2015;372:1285-7).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].

Question: Which of the following statements regarding the doctrine of informed consent is best?

A. All jurisdictions now require disclosure geared toward the reasonable patient rather than the reasonable doctor.

B. Disclosures are less important and sometimes unnecessary in global clinical research protocols.

C. The trend is toward the use of simplified and personalized consent forms.

D. A and C.

Answer: C. An important development in the doctrine of informed consent deals with the typical consent form, which is lengthy (going on 14 pages in one report), largely incomprehensible, and densely legalistic. Worse, the physician may misconstrue the form as a proxy for risk disclosure, whereas in fact the duly signed form merely purports to indicate that meaningful discussion of risks, benefits, and alternatives had taken place – if indeed that has been the case.

A review of more than 500 separate informed consent forms revealed these documents have limited educational value, go mostly unread, and are frequently misunderstood by patients (Arch. Surg. 2000;135:26-33).Thus, there is much to recommend the recent move toward shorter forms that use simpler language, bigger type fonts, and even graphics to improve patient and family understanding.

For example, a novel personalized approach currently being tested offers evidence-based benefits and risks to patients undergoing elective percutaneous coronary intervention. The consent document draws on the American College of Cardiology’s National Cardiovascular Data Registry to offer individualized risk estimates, and lists the experience of the health care team and the anticipated financial costs (JAMA 2010;303:1190-1).

Such approaches are consonant with the notion of patient-centered care, which the Institute of Medicine has identified as a core attribute of high-quality health care systems.

One of the continuing controversies in informed consent is the requisite standard of disclosure.

Historically, what needed to be disclosed was judged by what was ordinarily expected of the reasonable physician in the community. However, in 1972, Canterbury v. Spence (464 F.2d 772 [D.C. Cir. 1972]) persuasively argued for replacing such a professional standard (what doctors customarily would disclose) with a patient-oriented standard, i.e., what a reasonable patient would want to know.

California quickly followed, and an increasing number of jurisdictions such as Alaska, Hawaii, Massachusetts, Minnesota, Texas, West Virginia, and Wisconsin have since embraced this patient-centered standard. However, a number of other jurisdictions, including Arkansas, Indiana, Michigan, Montana, Nebraska, Nevada, and Wyoming, continue to adhere to the professional or physician-centered standard.

The momentum toward patient-centered disclosure appears to be growing, and has spread to other common-law jurisdictions abroad such as Canada and Australia. The United Kingdom was a steadfast opponent of patient-centric consent since Sidaway v. Board of Governors of the Bethlem Royal Hospital and the Maudsley Hospital ([1985] AC 871), its seminal House of Lords decision in the 1980s.

However, it finally abandoned its opposition on March 11, 2015, when its Supreme Court decided the case of a baby boy who sustained brain injury and arm paralysis at birth as a result of shoulder dystocia (Montgomery v. Lanarkshire Health Board [2015] UKSC 11).

The plaintiff alleged that being a diabetic mother, she should have been warned of the risks of shoulder dystocia and offered the alternative of a cesarean section. The obstetrician said she did not warn because the risks of a serious problem were very small. The court sided with the plaintiff, overturned Sidaway’s professional standard, and adopted the patient standard of disclosure as the new law.

What needs to be disclosed continues to plague the practitioner. The term “material risks” merely begs the question of the definition of “material.” It has been said that the crucial factor is the patient’s need.

The vexing issue surrounding the scope of risk disclosure is compounded by court decisions allowing inquiry outside the medical condition itself, such as a physician’s alcoholism or HIV status, and financial incentives amounting to a breach of fiduciary responsibility. However, courts have tended to reject requiring disclosure of practitioner experience or patient prognosis.

Novel issues continue to surface. For example, a recent Wisconsin Supreme Court case dealt with whether it was necessary for a physician to disclose the availability of a collateral test not directly linked to a patient’s diagnosis.

In Jandre v. Wis. Injured Patients & Families Comp. Fund (813 N.W.2d 627 [Wis. 2012]), a doctor diagnosed Bell’s palsy as the cause of a patient’s neurologic symptoms, because she heard no carotid bruits and the head CT scan was normal. Shortly thereafter, the patient developed a stroke. Although the doctor was found not negligent for the misdiagnosis, the plaintiff then proceeded on a lack of informed consent theory, asserting that the doctor should have advised him of the availability of a carotid ultrasound test to rule out a TIA.

In a momentous decision, the Wisconsin Supreme Court affirmed the lower court’s judgment in finding the physician liable for failing to disclose the availability of the ultrasound procedure.

Another area where informed consent is under renewed scrutiny is in research. Doctors in practice are increasingly participating as coinvestigators in industry-sponsored drug trials, and should be familiar with what is expected in the research context.

Augmented rules regarding informed consent govern all clinical research, with patient safety and free meaningful choice being paramount considerations. Federal and state regulations, implemented and monitored by institutional review boards, serve to enforce compliance and safeguard the safety of experimental subjects.

Still, as predicted nearly 50 years ago by Dr. Henry K. Beecher, “In any precise sense, statements regarding consent are meaningless unless one knows how fully the patient was informed of all risks, and if these are not known, that fact should also be made clear. A far more dependable safeguard than consent is the presence of a truly responsible investigator” (N. Engl. J. Med. 1966;274:1354-60).

Scandals in human research led by or in collaboration with U.S. investigators in foreign countries have been in the news. Global clinical trials are supposed to be carried out in compliance with the Nuremberg Code and the Declaration of Helsinki, but there may be occasional lapses or disregard for such international laws. A recent example is the trial using the antibiotic trovafloxacin, administered orally, versus FDA-approved parenteral ceftriaxone, during a meningitis outbreak in Nigeria (N. Engl. J. Med. 2009;360:2050-3).

Finally, the politics of abortion and first amendment rights have managed to insinuate themselves into the informed consent debate. Can states mandate disclosure in the name of securing meaningful informed consent, e.g., requiring physicians to provide information that might encourage a woman to reconsider her decision to have an abortion?

In 1992, the U.S. Supreme Court decided that this passes constitutional muster, because it did not place an undue burden on the woman. However, the Fourth Circuit Appellate Court recently ruled unconstitutional a North Carolina statute called Display of Real-Time View Requirement. The statute requires physicians to display ultrasound images of the unborn child to a mother contemplating an abortion, which the court ruled violated the First Amendment’s prohibition on state-compelled speech (N. Engl. J. Med. 2015;372:1285-7).

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].

Witch hunt: An intensive effort to discover and expose disloyalty, subversion, dishonesty or the like, usually based on slight, doubtful or irrelevant evidence, and to punish accordingly.
 - Merriam-Webster Dictionary

Over the years, several excellent vascular surgeons have either lost their jobs or been pressured to resign for reasons that are unclear – although in some instances a few particular cases with bad outcomes have been cited as a reason.

Vascular Surgery is a difficult specialty. If one takes on challenging cases that need treatment – patients with large complex AAAs, extensive foot gangrene, or high-risk symptomatic carotid disease, an occasional poor outcome can be expected even if everything the vascular surgeon does is correct. One, two, or three bad outcomes per year in a busy vascular practice are inevitable, and should not be a reason for a vascular surgeon’s termination. Something more must be involved. Likely it is a hidden agenda.

That something can best be summarized by the term “medical politics.” This term may sound benign. In fact, medical politics are anything but benign. In the case of vascular surgeons, they are often subject to the governance and direction of administrators or senior surgical leaders who have little understanding of the risks of complex vascular surgery, and are interested only in the money generated by vascular admissions and procedures. Quantity and dollars trumps quality most times in the eyes of these administrative leaders.

Moreover, these leaders are not immune from the frailties of bias and jealousy which motivate much of human behavior. Throughout my career I have seen many instances when such administrative leaders resented a vascular surgeon because he or she used many hospital resources for a large practice, was successful academically, but behaved “too independently” from the larger department or its leader. It was one reason, vascular surgery needed to be its own independent specialty rather than a part of general surgery.

In the case of the vascular surgeons facing termination for reasons that they cannot understand, there is usually an administrative superior who is involved. Perhaps the vascular surgeon has questioned the authority or judgment of the superior on the grounds that they do not understand a particular vascular surgery issue. The resulting anger of the superior prompts him to want to eliminate the vascular surgeon who is under his administrative control. The witch hunt begins and may be inflamed by other unjustified motives such as jealousy or other hidden agendas which may never be known.

Once the witch hunt has begun, if the vascular surgeon has one or a few cases with bad outcomes, they make him or her vulnerable to the unjustified attack leading to termination by those who do not understand the nature of vascular surgery. Other factors, e.g., a disgruntled or jealous competitor in vascular surgery, can exacerbate the situation and accelerate the termination. The few bad-outcome cases, however, are the excuse or smoking gun which is used as the reason for termination. What goes unrecognized is the fact that every competent vascular surgeon who treats sick patients has such cases which can be used if uninformed enemies wish to focus on them.

How can a vascular surgeon protect him or herself from such witch hunts? First, they must be aware that the nature of vascular surgery and its requirement for treating challenging patients makes them vulnerable if one or another superior dislikes them or is “out to get them.” Second, if one is dealing with a case likely to have a bad outcome, it should be discussed beforehand with superiors, and it is wise to get help from a colleague who can share responsibility if things go poorly.

Third, try not to make enemies of important administrative leaders by challenging their authority or judgment.

Share successes with them, rather than taking all the glory. It will help to neutralize their jealousy. If possible, be humble. Make as many friends in other specialties as possible. They can sometimes diffuse the intensity of a witch hunt. And lastly be aware that any vascular surgeon, particularly a good one, can be the subject of a damaging witch hunt in the imperfect world in which we function.

Dr. Veith is professor of surgery at New York University Medical Center and the Cleveland Clinic and an associate medical editor for Vascular Specialist.

The ideas and opinions expressed in Vascsular Specialist do not necessarily reflect those of the Society or publisher.

Witch hunt: An intensive effort to discover and expose disloyalty, subversion, dishonesty or the like, usually based on slight, doubtful or irrelevant evidence, and to punish accordingly.
 - Merriam-Webster Dictionary

Over the years, several excellent vascular surgeons have either lost their jobs or been pressured to resign for reasons that are unclear – although in some instances a few particular cases with bad outcomes have been cited as a reason.

Vascular Surgery is a difficult specialty. If one takes on challenging cases that need treatment – patients with large complex AAAs, extensive foot gangrene, or high-risk symptomatic carotid disease, an occasional poor outcome can be expected even if everything the vascular surgeon does is correct. One, two, or three bad outcomes per year in a busy vascular practice are inevitable, and should not be a reason for a vascular surgeon’s termination. Something more must be involved. Likely it is a hidden agenda.

That something can best be summarized by the term “medical politics.” This term may sound benign. In fact, medical politics are anything but benign. In the case of vascular surgeons, they are often subject to the governance and direction of administrators or senior surgical leaders who have little understanding of the risks of complex vascular surgery, and are interested only in the money generated by vascular admissions and procedures. Quantity and dollars trumps quality most times in the eyes of these administrative leaders.

Moreover, these leaders are not immune from the frailties of bias and jealousy which motivate much of human behavior. Throughout my career I have seen many instances when such administrative leaders resented a vascular surgeon because he or she used many hospital resources for a large practice, was successful academically, but behaved “too independently” from the larger department or its leader. It was one reason, vascular surgery needed to be its own independent specialty rather than a part of general surgery.

In the case of the vascular surgeons facing termination for reasons that they cannot understand, there is usually an administrative superior who is involved. Perhaps the vascular surgeon has questioned the authority or judgment of the superior on the grounds that they do not understand a particular vascular surgery issue. The resulting anger of the superior prompts him to want to eliminate the vascular surgeon who is under his administrative control. The witch hunt begins and may be inflamed by other unjustified motives such as jealousy or other hidden agendas which may never be known.

Once the witch hunt has begun, if the vascular surgeon has one or a few cases with bad outcomes, they make him or her vulnerable to the unjustified attack leading to termination by those who do not understand the nature of vascular surgery. Other factors, e.g., a disgruntled or jealous competitor in vascular surgery, can exacerbate the situation and accelerate the termination. The few bad-outcome cases, however, are the excuse or smoking gun which is used as the reason for termination. What goes unrecognized is the fact that every competent vascular surgeon who treats sick patients has such cases which can be used if uninformed enemies wish to focus on them.

How can a vascular surgeon protect him or herself from such witch hunts? First, they must be aware that the nature of vascular surgery and its requirement for treating challenging patients makes them vulnerable if one or another superior dislikes them or is “out to get them.” Second, if one is dealing with a case likely to have a bad outcome, it should be discussed beforehand with superiors, and it is wise to get help from a colleague who can share responsibility if things go poorly.

Third, try not to make enemies of important administrative leaders by challenging their authority or judgment.

Share successes with them, rather than taking all the glory. It will help to neutralize their jealousy. If possible, be humble. Make as many friends in other specialties as possible. They can sometimes diffuse the intensity of a witch hunt. And lastly be aware that any vascular surgeon, particularly a good one, can be the subject of a damaging witch hunt in the imperfect world in which we function.

Dr. Veith is professor of surgery at New York University Medical Center and the Cleveland Clinic and an associate medical editor for Vascular Specialist.

The ideas and opinions expressed in Vascsular Specialist do not necessarily reflect those of the Society or publisher.

Witch hunt: An intensive effort to discover and expose disloyalty, subversion, dishonesty or the like, usually based on slight, doubtful or irrelevant evidence, and to punish accordingly.
 - Merriam-Webster Dictionary

Over the years, several excellent vascular surgeons have either lost their jobs or been pressured to resign for reasons that are unclear – although in some instances a few particular cases with bad outcomes have been cited as a reason.

Vascular Surgery is a difficult specialty. If one takes on challenging cases that need treatment – patients with large complex AAAs, extensive foot gangrene, or high-risk symptomatic carotid disease, an occasional poor outcome can be expected even if everything the vascular surgeon does is correct. One, two, or three bad outcomes per year in a busy vascular practice are inevitable, and should not be a reason for a vascular surgeon’s termination. Something more must be involved. Likely it is a hidden agenda.

That something can best be summarized by the term “medical politics.” This term may sound benign. In fact, medical politics are anything but benign. In the case of vascular surgeons, they are often subject to the governance and direction of administrators or senior surgical leaders who have little understanding of the risks of complex vascular surgery, and are interested only in the money generated by vascular admissions and procedures. Quantity and dollars trumps quality most times in the eyes of these administrative leaders.

Moreover, these leaders are not immune from the frailties of bias and jealousy which motivate much of human behavior. Throughout my career I have seen many instances when such administrative leaders resented a vascular surgeon because he or she used many hospital resources for a large practice, was successful academically, but behaved “too independently” from the larger department or its leader. It was one reason, vascular surgery needed to be its own independent specialty rather than a part of general surgery.

In the case of the vascular surgeons facing termination for reasons that they cannot understand, there is usually an administrative superior who is involved. Perhaps the vascular surgeon has questioned the authority or judgment of the superior on the grounds that they do not understand a particular vascular surgery issue. The resulting anger of the superior prompts him to want to eliminate the vascular surgeon who is under his administrative control. The witch hunt begins and may be inflamed by other unjustified motives such as jealousy or other hidden agendas which may never be known.

Once the witch hunt has begun, if the vascular surgeon has one or a few cases with bad outcomes, they make him or her vulnerable to the unjustified attack leading to termination by those who do not understand the nature of vascular surgery. Other factors, e.g., a disgruntled or jealous competitor in vascular surgery, can exacerbate the situation and accelerate the termination. The few bad-outcome cases, however, are the excuse or smoking gun which is used as the reason for termination. What goes unrecognized is the fact that every competent vascular surgeon who treats sick patients has such cases which can be used if uninformed enemies wish to focus on them.

How can a vascular surgeon protect him or herself from such witch hunts? First, they must be aware that the nature of vascular surgery and its requirement for treating challenging patients makes them vulnerable if one or another superior dislikes them or is “out to get them.” Second, if one is dealing with a case likely to have a bad outcome, it should be discussed beforehand with superiors, and it is wise to get help from a colleague who can share responsibility if things go poorly.

Third, try not to make enemies of important administrative leaders by challenging their authority or judgment.

Share successes with them, rather than taking all the glory. It will help to neutralize their jealousy. If possible, be humble. Make as many friends in other specialties as possible. They can sometimes diffuse the intensity of a witch hunt. And lastly be aware that any vascular surgeon, particularly a good one, can be the subject of a damaging witch hunt in the imperfect world in which we function.

Dr. Veith is professor of surgery at New York University Medical Center and the Cleveland Clinic and an associate medical editor for Vascular Specialist.

The ideas and opinions expressed in Vascsular Specialist do not necessarily reflect those of the Society or publisher.

Familial hypercholesterolemia (FH) poses a “silent” threat to patients with the condition, putting them at great risk of a coronary event. This genetic disorder, in which one or more mutations cause extremely high low-density lipoprotein (LDL) cholesterol levels, goes undiagnosed in approximately 80% of patients who have it.¹ As a result, men with FH have a >50% risk of coronary heart disease (CHD) by age 50 and women with FH have a 30% risk of CHD by age 60.² Patients with FH face a much higher risk of dying from a coronary event than those in the general population.³ For example, women between the ages of 20 and 39 who have this disorder are 125 times more likely to die of a coronary event than those who don’t.³

Unfortunately, FH can be difficult to diagnose. Some patients have physical findings, but these features can be subtle and easily missed. Typically, however, FH is diagnosed based on a patient’s cholesterol level and family history. By implementing screening and early treatment for FH, you may be able to initiate treatment that can temper the development of atherosclerosis and possibly extend a patient’s life.⁴

Two forms of the disorder, although one is more common

There are 2 types of FH:

Heterozygous FH (HeFH) occurs in about 1 in 300 to 500 people, which makes it more common than Down syndrome.⁵ More than a half a million people in the United States have HeFH.⁶

Homozygous FH (HoFH) is more serious than HeFH, and less common, affecting one in 1 million people. Homozygous carriers suffer from CHD much earlier than those with HeFH; some die within the first few years of life.⁷

Regardless of whether an affected individual inherited FH from one or both parents, more than one thousand mutations are known to cause inadequate clearance of LDL from the bloodstream.⁸ One of the most common mutations is a defective LDL receptor gene. Other abnormalities are known to occur with the proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B genes.⁹

Start with screening

Suspect FH in patients who have a family history of premature heart disease. Also consider the patient’s ethnic background. The prevalence of FH is as high as one in 100 among certain groups, including French Canadians, Christian Lebanese, and 3 populations in South Africa (Ashkenazi Jews, Dutch Afrikaners, and Asian Indians).¹⁰

When there is high suspicion of FH based on a patient’s family history or ethnicity, additional screening is warranted for any patient older than age 2.¹¹ If a patient’s family history is incomplete (eg, adoption, single-parent family), a lower threshold for screening is appropriate.

Lipid screening includes measuring serum total, LDL, and high-density lipoprotein cholesterol in either fasting or non-fasting samples. The United States Preventive Services Task Force (USPSTF) offers gender-specific recommendations for lipid disorder screening in the general population. For men, universal screening is recommended starting at age 35, and screening for those at increased risk of CHD should start at age 20.¹²

For women, the USPSTF recommends lipid screening only for those over age 20 who are at increased risk for CHD; such screening is strongly recommended for high-risk women ages 45 and older. In light of the serious consequences associated with FH, the National Lipid Association recommends lipid screening for all adults starting at age 20 (TABLE 1).¹³

What about kids? The recommendations for lipid screening in children and adolescents are mixed. Both the USPSTF and the American Academy of Family Physicians indicate that there is insufficient evidence to screen for lipid disorders in asymptomatic children and adolescents.^14,15 However, in a set of recommendations based on expert opinion, the National Heart, Lung, and Blood Institute (NHLBI) suggests universal screening for younger patients with a non-fasting lipid profile once between ages 9 to 11 and again between ages 17 to 21.¹⁶ The American Academy of Pediatrics has adopted the NHLBI recommendations.¹⁷

FIGURE
Physical exam findings that suggest familial hypercholesterolemia

Tendon xanthomas (A), a thickening of the soft tissue as a result of infiltration by lipid-rich cells, most commonly occur at the Achilles and metacarpal tendons, but also can be seen at the patellar and triceps tendons.

Tuberous xanthomas or xanthelasmas (B) are waxy-appearing growths that appear to be pasted on the skin in areas around the face, commonly the eyelids.

Arcus corneae (C) is an opaque ring around the outer edge of the cornea.

Use validated criteria to make the diagnosis

Include FH in your differential diagnosis when evaluating patients with very high LDL levels. However, rule out possible secondary causes of elevated LDL before rendering a conclusion. Hypothyroidism, nephrotic syndrome, diabetes, and liver disease are among the most common secondary causes of high LDL cholesterol.¹³

Several validated criteria sets can be used to establish an FH diagnosis. No single criteria set is more valid or more widely adopted around the world. All 3 of the most commonly used criteria sets take into account family history and a patient’s LDL level, and 2 of the 3 factor in physical findings (TABLE 2).⁹

Physical exam findings that suggest FH can be subtle (FIGURE). Tendon xanthomas are a thickening of the soft tissue as a result of infiltration by lipid-rich cells. They most commonly occur at the Achilles and metacarpal tendons, but can also be seen at the patellar and triceps tendons. Xanthomas may not be readily visible, so it’s important to run your fingers over these areas to detect nodularity or thickening. While the presence of a tendon xanthoma makes FH highly likely, they are present in less than half of patients with FH.¹⁷

Tuberous xanthomas or xanthelasmas are waxy-appearing growths that may look yellow or orange and appear to be pasted on the skin in areas around the face, commonly the eyelids. The presence of xanthelasmas in a patient younger than age 25 suggests FH.

Finally, arcus corneae is an opaque ring around the outer edge of the cornea. When this is seen in patients younger than age 45, it’s suggestive of FH.¹³ If you note tendon xanthomas, xanthelasmas, or arcus corneae while examining any of your patients, be sure to order an LDL level if it hasn’t already been done.

Is genetic testing necessary?

The only way to make a definitive diagnosis of FH is to find a mutation in a gene known to affect LDL metabolism. However, because genetic testing is expensive—and because more than one thousand different genetic defects can contribute to FH—it’s not practical to test every patient. Furthermore, since an estimated 20% of the mutations that contribute to FH have not yet been clearly delineated, a “normal” result on a genetic test might be misleading.⁵ Therefore, the diagnosis of FH usually is a clinical one. After clinically diagnosing a patient with FH, it’s imperative to screen first-degree family members by measuring their LDL cholesterol levels.

Lifestyle changes, statins can ward off CHD

Lifestyle modifications (ie, improved diet and exercise) and statins are the treatments of choice for patients with FH. Before starting pharmacotherapy, patients should undergo 3 months of lifestyle modification to assess how well this approach improves their lipid levels, assuming the patient doesn’t have additional risk factors such as hypertension or tobacco use, in which case he or she might require immediate pharmacotherapy. Statins can be initiated simultaneously with lifestyle choices in patients with an LDL >190 mg/dL.¹⁸

Lifestyle modification. Although FH is a genetic problem, patients should be encouraged to make healthy choices regarding diet and exercise. While the best choices may not get FH patients to their LDL goal, better choices may mean that patients can take fewer medications, or lower doses of them. Healthy lifestyle choices can also have other positive effects on cardiovascular risk (eg, lowering blood pressure).

Patients can’t be expected to navigate their food choices alone, and several visits with a dietician will likely be needed. It’s important to emphasize the family influence on diet and get the entire family involved with making healthy food choices.

In addition to addressing diet and exercise, be sure to encourage patients to abstain from tobacco and manage stress as part of their overall effort to reduce the likelihood of a cardiovascular event.

Statins. Early treatment of FH with statins can delay initial coronary events and prolong life.¹⁹ In a 12.5-year study of 2146 patients with FH, approximately 80% of patients treated with statins survived without experiencing CHD, compared to slightly less than 40% of those who were not treated with statins.¹⁹ Patients treated with statins had a 76% reduction in risk of CHD compared to those who didn’t receive statins.¹⁹ Even low doses of statins started early have been shown to help avoid myocardial infarction in adults with FH.²⁰

The goal of treatment for FH is to reduced LDL levels by 50%.²¹ In pediatric patients, treating to an LDL level of 130 mg/dL is an alternative goal.²¹ Because it’s challenging to achieve this goal with improved diet and exercise alone, treatment with a statin is often necessary.²²

In one study, about 80% of patients with familial hypercholesterolemia who received a statin did not develop CHD, compared to slightly less than 40% of those who didn't get a statin.

Statins can be used in children as young as age 8, or even earlier in homozygous FH.⁶ While a physician might be hesitant to start a chronic medication in a young patient, research shows that earlier intervention results in additional years of life.²³ To date, no significant adverse effects of statins in pediatric patients have been identified, and statins have not been shown to impair growth.^24,25 Young female patients should be counseled about the adverse effects statins can have on a fetus if the patient becomes pregnant while taking the medication.

Navigating the waters of statin treatment

Musculoskeletal symptoms are the most common adverse effect reported by patients taking statins. A thorough assessment of a patient’s muscle complaints is necessary to avoid prematurely concluding that he or she cannot tolerate statins.

A study in which “statin-intolerant” patients were re-challenged found that more than 90% of patients could tolerate statins through the course of the one-year study and that it was likely that the patients’ initial muscle complaints were not due to statin use.²³ (To read more about potential adverse events of statins, see “Statin adverse effects: Sorting out the evidence,” J Fam Pract. 2014;63:497-506.).

The goal of treatment for familial hypercholesterolemia is to reduce LDL levels by 50%.

If LDL levels in a patient with HeFH remain at or above 160 mg/dL, intensifying treatment by adding another lipid-lowering medication might be warranted.²² For patients with HoFH, in whom the condition is more quickly life-threatening, there are additional choices, including LDL apheresis and medications such as mipomersen and lomitapide. Both of these medications can cause hepatotoxicity, and are available only through a Risk Evaluation and Mitigation Strategy program, which means they can only be prescribed by certified physicians. PCSK9 inhibitors are in the pipeline and may one day help patients with HoFH by addressing one of the genetic causes of this disorder.

CORRESPONDENCE 
Richard Safeer, MD, 6704 Curtis Court, Glen Burnie, MD 21060; [email protected]

Familial hypercholesterolemia (FH) poses a “silent” threat to patients with the condition, putting them at great risk of a coronary event. This genetic disorder, in which one or more mutations cause extremely high low-density lipoprotein (LDL) cholesterol levels, goes undiagnosed in approximately 80% of patients who have it.¹ As a result, men with FH have a >50% risk of coronary heart disease (CHD) by age 50 and women with FH have a 30% risk of CHD by age 60.² Patients with FH face a much higher risk of dying from a coronary event than those in the general population.³ For example, women between the ages of 20 and 39 who have this disorder are 125 times more likely to die of a coronary event than those who don’t.³

Unfortunately, FH can be difficult to diagnose. Some patients have physical findings, but these features can be subtle and easily missed. Typically, however, FH is diagnosed based on a patient’s cholesterol level and family history. By implementing screening and early treatment for FH, you may be able to initiate treatment that can temper the development of atherosclerosis and possibly extend a patient’s life.⁴

Two forms of the disorder, although one is more common

There are 2 types of FH:

Heterozygous FH (HeFH) occurs in about 1 in 300 to 500 people, which makes it more common than Down syndrome.⁵ More than a half a million people in the United States have HeFH.⁶

Homozygous FH (HoFH) is more serious than HeFH, and less common, affecting one in 1 million people. Homozygous carriers suffer from CHD much earlier than those with HeFH; some die within the first few years of life.⁷

Regardless of whether an affected individual inherited FH from one or both parents, more than one thousand mutations are known to cause inadequate clearance of LDL from the bloodstream.⁸ One of the most common mutations is a defective LDL receptor gene. Other abnormalities are known to occur with the proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B genes.⁹

Start with screening

Suspect FH in patients who have a family history of premature heart disease. Also consider the patient’s ethnic background. The prevalence of FH is as high as one in 100 among certain groups, including French Canadians, Christian Lebanese, and 3 populations in South Africa (Ashkenazi Jews, Dutch Afrikaners, and Asian Indians).¹⁰

When there is high suspicion of FH based on a patient’s family history or ethnicity, additional screening is warranted for any patient older than age 2.¹¹ If a patient’s family history is incomplete (eg, adoption, single-parent family), a lower threshold for screening is appropriate.

Lipid screening includes measuring serum total, LDL, and high-density lipoprotein cholesterol in either fasting or non-fasting samples. The United States Preventive Services Task Force (USPSTF) offers gender-specific recommendations for lipid disorder screening in the general population. For men, universal screening is recommended starting at age 35, and screening for those at increased risk of CHD should start at age 20.¹²

For women, the USPSTF recommends lipid screening only for those over age 20 who are at increased risk for CHD; such screening is strongly recommended for high-risk women ages 45 and older. In light of the serious consequences associated with FH, the National Lipid Association recommends lipid screening for all adults starting at age 20 (TABLE 1).¹³

What about kids? The recommendations for lipid screening in children and adolescents are mixed. Both the USPSTF and the American Academy of Family Physicians indicate that there is insufficient evidence to screen for lipid disorders in asymptomatic children and adolescents.^14,15 However, in a set of recommendations based on expert opinion, the National Heart, Lung, and Blood Institute (NHLBI) suggests universal screening for younger patients with a non-fasting lipid profile once between ages 9 to 11 and again between ages 17 to 21.¹⁶ The American Academy of Pediatrics has adopted the NHLBI recommendations.¹⁷

FIGURE
Physical exam findings that suggest familial hypercholesterolemia

Tendon xanthomas (A), a thickening of the soft tissue as a result of infiltration by lipid-rich cells, most commonly occur at the Achilles and metacarpal tendons, but also can be seen at the patellar and triceps tendons.

Tuberous xanthomas or xanthelasmas (B) are waxy-appearing growths that appear to be pasted on the skin in areas around the face, commonly the eyelids.

Arcus corneae (C) is an opaque ring around the outer edge of the cornea.

Use validated criteria to make the diagnosis

Include FH in your differential diagnosis when evaluating patients with very high LDL levels. However, rule out possible secondary causes of elevated LDL before rendering a conclusion. Hypothyroidism, nephrotic syndrome, diabetes, and liver disease are among the most common secondary causes of high LDL cholesterol.¹³

Several validated criteria sets can be used to establish an FH diagnosis. No single criteria set is more valid or more widely adopted around the world. All 3 of the most commonly used criteria sets take into account family history and a patient’s LDL level, and 2 of the 3 factor in physical findings (TABLE 2).⁹

Physical exam findings that suggest FH can be subtle (FIGURE). Tendon xanthomas are a thickening of the soft tissue as a result of infiltration by lipid-rich cells. They most commonly occur at the Achilles and metacarpal tendons, but can also be seen at the patellar and triceps tendons. Xanthomas may not be readily visible, so it’s important to run your fingers over these areas to detect nodularity or thickening. While the presence of a tendon xanthoma makes FH highly likely, they are present in less than half of patients with FH.¹⁷

Tuberous xanthomas or xanthelasmas are waxy-appearing growths that may look yellow or orange and appear to be pasted on the skin in areas around the face, commonly the eyelids. The presence of xanthelasmas in a patient younger than age 25 suggests FH.

Finally, arcus corneae is an opaque ring around the outer edge of the cornea. When this is seen in patients younger than age 45, it’s suggestive of FH.¹³ If you note tendon xanthomas, xanthelasmas, or arcus corneae while examining any of your patients, be sure to order an LDL level if it hasn’t already been done.

Is genetic testing necessary?

The only way to make a definitive diagnosis of FH is to find a mutation in a gene known to affect LDL metabolism. However, because genetic testing is expensive—and because more than one thousand different genetic defects can contribute to FH—it’s not practical to test every patient. Furthermore, since an estimated 20% of the mutations that contribute to FH have not yet been clearly delineated, a “normal” result on a genetic test might be misleading.⁵ Therefore, the diagnosis of FH usually is a clinical one. After clinically diagnosing a patient with FH, it’s imperative to screen first-degree family members by measuring their LDL cholesterol levels.

Lifestyle changes, statins can ward off CHD

Lifestyle modifications (ie, improved diet and exercise) and statins are the treatments of choice for patients with FH. Before starting pharmacotherapy, patients should undergo 3 months of lifestyle modification to assess how well this approach improves their lipid levels, assuming the patient doesn’t have additional risk factors such as hypertension or tobacco use, in which case he or she might require immediate pharmacotherapy. Statins can be initiated simultaneously with lifestyle choices in patients with an LDL >190 mg/dL.¹⁸

Lifestyle modification. Although FH is a genetic problem, patients should be encouraged to make healthy choices regarding diet and exercise. While the best choices may not get FH patients to their LDL goal, better choices may mean that patients can take fewer medications, or lower doses of them. Healthy lifestyle choices can also have other positive effects on cardiovascular risk (eg, lowering blood pressure).

Patients can’t be expected to navigate their food choices alone, and several visits with a dietician will likely be needed. It’s important to emphasize the family influence on diet and get the entire family involved with making healthy food choices.

In addition to addressing diet and exercise, be sure to encourage patients to abstain from tobacco and manage stress as part of their overall effort to reduce the likelihood of a cardiovascular event.

Statins. Early treatment of FH with statins can delay initial coronary events and prolong life.¹⁹ In a 12.5-year study of 2146 patients with FH, approximately 80% of patients treated with statins survived without experiencing CHD, compared to slightly less than 40% of those who were not treated with statins.¹⁹ Patients treated with statins had a 76% reduction in risk of CHD compared to those who didn’t receive statins.¹⁹ Even low doses of statins started early have been shown to help avoid myocardial infarction in adults with FH.²⁰

The goal of treatment for FH is to reduced LDL levels by 50%.²¹ In pediatric patients, treating to an LDL level of 130 mg/dL is an alternative goal.²¹ Because it’s challenging to achieve this goal with improved diet and exercise alone, treatment with a statin is often necessary.²²

In one study, about 80% of patients with familial hypercholesterolemia who received a statin did not develop CHD, compared to slightly less than 40% of those who didn't get a statin.

Statins can be used in children as young as age 8, or even earlier in homozygous FH.⁶ While a physician might be hesitant to start a chronic medication in a young patient, research shows that earlier intervention results in additional years of life.²³ To date, no significant adverse effects of statins in pediatric patients have been identified, and statins have not been shown to impair growth.^24,25 Young female patients should be counseled about the adverse effects statins can have on a fetus if the patient becomes pregnant while taking the medication.

Navigating the waters of statin treatment

Musculoskeletal symptoms are the most common adverse effect reported by patients taking statins. A thorough assessment of a patient’s muscle complaints is necessary to avoid prematurely concluding that he or she cannot tolerate statins.

A study in which “statin-intolerant” patients were re-challenged found that more than 90% of patients could tolerate statins through the course of the one-year study and that it was likely that the patients’ initial muscle complaints were not due to statin use.²³ (To read more about potential adverse events of statins, see “Statin adverse effects: Sorting out the evidence,” J Fam Pract. 2014;63:497-506.).

The goal of treatment for familial hypercholesterolemia is to reduce LDL levels by 50%.

If LDL levels in a patient with HeFH remain at or above 160 mg/dL, intensifying treatment by adding another lipid-lowering medication might be warranted.²² For patients with HoFH, in whom the condition is more quickly life-threatening, there are additional choices, including LDL apheresis and medications such as mipomersen and lomitapide. Both of these medications can cause hepatotoxicity, and are available only through a Risk Evaluation and Mitigation Strategy program, which means they can only be prescribed by certified physicians. PCSK9 inhibitors are in the pipeline and may one day help patients with HoFH by addressing one of the genetic causes of this disorder.

CORRESPONDENCE 
Richard Safeer, MD, 6704 Curtis Court, Glen Burnie, MD 21060; [email protected]

Familial hypercholesterolemia (FH) poses a “silent” threat to patients with the condition, putting them at great risk of a coronary event. This genetic disorder, in which one or more mutations cause extremely high low-density lipoprotein (LDL) cholesterol levels, goes undiagnosed in approximately 80% of patients who have it.¹ As a result, men with FH have a >50% risk of coronary heart disease (CHD) by age 50 and women with FH have a 30% risk of CHD by age 60.² Patients with FH face a much higher risk of dying from a coronary event than those in the general population.³ For example, women between the ages of 20 and 39 who have this disorder are 125 times more likely to die of a coronary event than those who don’t.³

Unfortunately, FH can be difficult to diagnose. Some patients have physical findings, but these features can be subtle and easily missed. Typically, however, FH is diagnosed based on a patient’s cholesterol level and family history. By implementing screening and early treatment for FH, you may be able to initiate treatment that can temper the development of atherosclerosis and possibly extend a patient’s life.⁴

Two forms of the disorder, although one is more common

There are 2 types of FH:

Heterozygous FH (HeFH) occurs in about 1 in 300 to 500 people, which makes it more common than Down syndrome.⁵ More than a half a million people in the United States have HeFH.⁶

Homozygous FH (HoFH) is more serious than HeFH, and less common, affecting one in 1 million people. Homozygous carriers suffer from CHD much earlier than those with HeFH; some die within the first few years of life.⁷

Regardless of whether an affected individual inherited FH from one or both parents, more than one thousand mutations are known to cause inadequate clearance of LDL from the bloodstream.⁸ One of the most common mutations is a defective LDL receptor gene. Other abnormalities are known to occur with the proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B genes.⁹

Start with screening

Suspect FH in patients who have a family history of premature heart disease. Also consider the patient’s ethnic background. The prevalence of FH is as high as one in 100 among certain groups, including French Canadians, Christian Lebanese, and 3 populations in South Africa (Ashkenazi Jews, Dutch Afrikaners, and Asian Indians).¹⁰

When there is high suspicion of FH based on a patient’s family history or ethnicity, additional screening is warranted for any patient older than age 2.¹¹ If a patient’s family history is incomplete (eg, adoption, single-parent family), a lower threshold for screening is appropriate.

Lipid screening includes measuring serum total, LDL, and high-density lipoprotein cholesterol in either fasting or non-fasting samples. The United States Preventive Services Task Force (USPSTF) offers gender-specific recommendations for lipid disorder screening in the general population. For men, universal screening is recommended starting at age 35, and screening for those at increased risk of CHD should start at age 20.¹²

For women, the USPSTF recommends lipid screening only for those over age 20 who are at increased risk for CHD; such screening is strongly recommended for high-risk women ages 45 and older. In light of the serious consequences associated with FH, the National Lipid Association recommends lipid screening for all adults starting at age 20 (TABLE 1).¹³

What about kids? The recommendations for lipid screening in children and adolescents are mixed. Both the USPSTF and the American Academy of Family Physicians indicate that there is insufficient evidence to screen for lipid disorders in asymptomatic children and adolescents.^14,15 However, in a set of recommendations based on expert opinion, the National Heart, Lung, and Blood Institute (NHLBI) suggests universal screening for younger patients with a non-fasting lipid profile once between ages 9 to 11 and again between ages 17 to 21.¹⁶ The American Academy of Pediatrics has adopted the NHLBI recommendations.¹⁷

FIGURE
Physical exam findings that suggest familial hypercholesterolemia

Tendon xanthomas (A), a thickening of the soft tissue as a result of infiltration by lipid-rich cells, most commonly occur at the Achilles and metacarpal tendons, but also can be seen at the patellar and triceps tendons.

Tuberous xanthomas or xanthelasmas (B) are waxy-appearing growths that appear to be pasted on the skin in areas around the face, commonly the eyelids.

Arcus corneae (C) is an opaque ring around the outer edge of the cornea.

Use validated criteria to make the diagnosis

Include FH in your differential diagnosis when evaluating patients with very high LDL levels. However, rule out possible secondary causes of elevated LDL before rendering a conclusion. Hypothyroidism, nephrotic syndrome, diabetes, and liver disease are among the most common secondary causes of high LDL cholesterol.¹³

Several validated criteria sets can be used to establish an FH diagnosis. No single criteria set is more valid or more widely adopted around the world. All 3 of the most commonly used criteria sets take into account family history and a patient’s LDL level, and 2 of the 3 factor in physical findings (TABLE 2).⁹

Physical exam findings that suggest FH can be subtle (FIGURE). Tendon xanthomas are a thickening of the soft tissue as a result of infiltration by lipid-rich cells. They most commonly occur at the Achilles and metacarpal tendons, but can also be seen at the patellar and triceps tendons. Xanthomas may not be readily visible, so it’s important to run your fingers over these areas to detect nodularity or thickening. While the presence of a tendon xanthoma makes FH highly likely, they are present in less than half of patients with FH.¹⁷

Tuberous xanthomas or xanthelasmas are waxy-appearing growths that may look yellow or orange and appear to be pasted on the skin in areas around the face, commonly the eyelids. The presence of xanthelasmas in a patient younger than age 25 suggests FH.

Finally, arcus corneae is an opaque ring around the outer edge of the cornea. When this is seen in patients younger than age 45, it’s suggestive of FH.¹³ If you note tendon xanthomas, xanthelasmas, or arcus corneae while examining any of your patients, be sure to order an LDL level if it hasn’t already been done.

Is genetic testing necessary?

The only way to make a definitive diagnosis of FH is to find a mutation in a gene known to affect LDL metabolism. However, because genetic testing is expensive—and because more than one thousand different genetic defects can contribute to FH—it’s not practical to test every patient. Furthermore, since an estimated 20% of the mutations that contribute to FH have not yet been clearly delineated, a “normal” result on a genetic test might be misleading.⁵ Therefore, the diagnosis of FH usually is a clinical one. After clinically diagnosing a patient with FH, it’s imperative to screen first-degree family members by measuring their LDL cholesterol levels.

Lifestyle changes, statins can ward off CHD

Lifestyle modifications (ie, improved diet and exercise) and statins are the treatments of choice for patients with FH. Before starting pharmacotherapy, patients should undergo 3 months of lifestyle modification to assess how well this approach improves their lipid levels, assuming the patient doesn’t have additional risk factors such as hypertension or tobacco use, in which case he or she might require immediate pharmacotherapy. Statins can be initiated simultaneously with lifestyle choices in patients with an LDL >190 mg/dL.¹⁸

Lifestyle modification. Although FH is a genetic problem, patients should be encouraged to make healthy choices regarding diet and exercise. While the best choices may not get FH patients to their LDL goal, better choices may mean that patients can take fewer medications, or lower doses of them. Healthy lifestyle choices can also have other positive effects on cardiovascular risk (eg, lowering blood pressure).

Patients can’t be expected to navigate their food choices alone, and several visits with a dietician will likely be needed. It’s important to emphasize the family influence on diet and get the entire family involved with making healthy food choices.

In addition to addressing diet and exercise, be sure to encourage patients to abstain from tobacco and manage stress as part of their overall effort to reduce the likelihood of a cardiovascular event.

Statins. Early treatment of FH with statins can delay initial coronary events and prolong life.¹⁹ In a 12.5-year study of 2146 patients with FH, approximately 80% of patients treated with statins survived without experiencing CHD, compared to slightly less than 40% of those who were not treated with statins.¹⁹ Patients treated with statins had a 76% reduction in risk of CHD compared to those who didn’t receive statins.¹⁹ Even low doses of statins started early have been shown to help avoid myocardial infarction in adults with FH.²⁰

The goal of treatment for FH is to reduced LDL levels by 50%.²¹ In pediatric patients, treating to an LDL level of 130 mg/dL is an alternative goal.²¹ Because it’s challenging to achieve this goal with improved diet and exercise alone, treatment with a statin is often necessary.²²

In one study, about 80% of patients with familial hypercholesterolemia who received a statin did not develop CHD, compared to slightly less than 40% of those who didn't get a statin.

Statins can be used in children as young as age 8, or even earlier in homozygous FH.⁶ While a physician might be hesitant to start a chronic medication in a young patient, research shows that earlier intervention results in additional years of life.²³ To date, no significant adverse effects of statins in pediatric patients have been identified, and statins have not been shown to impair growth.^24,25 Young female patients should be counseled about the adverse effects statins can have on a fetus if the patient becomes pregnant while taking the medication.

Navigating the waters of statin treatment

Musculoskeletal symptoms are the most common adverse effect reported by patients taking statins. A thorough assessment of a patient’s muscle complaints is necessary to avoid prematurely concluding that he or she cannot tolerate statins.

A study in which “statin-intolerant” patients were re-challenged found that more than 90% of patients could tolerate statins through the course of the one-year study and that it was likely that the patients’ initial muscle complaints were not due to statin use.²³ (To read more about potential adverse events of statins, see “Statin adverse effects: Sorting out the evidence,” J Fam Pract. 2014;63:497-506.).

The goal of treatment for familial hypercholesterolemia is to reduce LDL levels by 50%.

If LDL levels in a patient with HeFH remain at or above 160 mg/dL, intensifying treatment by adding another lipid-lowering medication might be warranted.²² For patients with HoFH, in whom the condition is more quickly life-threatening, there are additional choices, including LDL apheresis and medications such as mipomersen and lomitapide. Both of these medications can cause hepatotoxicity, and are available only through a Risk Evaluation and Mitigation Strategy program, which means they can only be prescribed by certified physicians. PCSK9 inhibitors are in the pipeline and may one day help patients with HoFH by addressing one of the genetic causes of this disorder.

CORRESPONDENCE 
Richard Safeer, MD, 6704 Curtis Court, Glen Burnie, MD 21060; [email protected]