Genetics

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

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

Case 2: Marfan syndrome in a young woman

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

LIKELY UNDERDETECTED

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

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

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

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

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

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

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

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

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

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

Imaging tests

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

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

Bicuspid aortic valve aortopathy

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

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

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

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

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

Control blood pressure with beta-blockers

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

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

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

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

Activity restriction

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

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

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

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

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

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

To a cardiologist at the time of diagnosis

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

To a surgeon relatively early

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

To a clinical geneticist

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

WHEN SHOULD TAA BE REPAIRED?

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

Size and other factors

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

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

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

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

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

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

Ratio of aortic cross-sectional area to height

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

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

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

Initial screening and follow-up

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

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

Screening of family members

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

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

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

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

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

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

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

BACK TO OUR PATIENT WITH MARFAN SYNDROME

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

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

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

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

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

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

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

Case 2: Marfan syndrome in a young woman

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

LIKELY UNDERDETECTED

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

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

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

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

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

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

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

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

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

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

Imaging tests

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

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

Bicuspid aortic valve aortopathy

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

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

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

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

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

Control blood pressure with beta-blockers

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

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

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

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

Activity restriction

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

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

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

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

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

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

To a cardiologist at the time of diagnosis

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

To a surgeon relatively early

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

To a clinical geneticist

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

WHEN SHOULD TAA BE REPAIRED?

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

Size and other factors

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

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

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

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

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

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

Ratio of aortic cross-sectional area to height

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

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

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

Initial screening and follow-up

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

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

Screening of family members

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

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

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

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

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

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

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

BACK TO OUR PATIENT WITH MARFAN SYNDROME

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

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

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

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

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

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

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

Case 2: Marfan syndrome in a young woman

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

LIKELY UNDERDETECTED

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

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

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

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

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

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

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

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

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

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

Imaging tests

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

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

Bicuspid aortic valve aortopathy

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

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

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

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

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

Control blood pressure with beta-blockers

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

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

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

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

Activity restriction

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

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

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

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

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

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

To a cardiologist at the time of diagnosis

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

To a surgeon relatively early

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

To a clinical geneticist

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

WHEN SHOULD TAA BE REPAIRED?

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

Size and other factors

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

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

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

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

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

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

Ratio of aortic cross-sectional area to height

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

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

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

Initial screening and follow-up

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

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

Screening of family members

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

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

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

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

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

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

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

BACK TO OUR PATIENT WITH MARFAN SYNDROME

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

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

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