Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)

INTRODUCTION AND PREVALENCE — Hypercholesterolemia is a common feature of primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) and other forms of cholestatic liver disease. The mechanism of hyperlipidemia in cholestatic disorders is different from that in other conditions because unusual lipoprotein particles, such as lipoprotein-X, may accumulate and levels of high-density lipoprotein cholesterol are typically elevated.

Hypercholesterolemia (ie, cholesterol values above 200 mg/dL [5.2 mmol/L]) affects approximately 75 percent of patients with primary biliary cholangitis at presentation, but is not associated with an increased risk of atherosclerosis [1-4]. However, patients with primary biliary cholangitis may have other independent risk factors for cardiovascular disease that require attention in the setting of normal life expectancy with ursodeoxycholic acid treatment.

This topic will review hypercholesterolemia in patients with primary biliary cholangitis. The pathogenesis and management of hypercholesterolemia and its role in the development of atherosclerosis are discussed separately.

●(See "Screening for lipid disorders in adults".)

●(See "Overview of established risk factors for cardiovascular disease".)

●(See "Pathogenesis of atherosclerosis".)

●(See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

CHOLESTEROL METABOLISM IN PBC — Hypercholesterolemia in primary biliary cholangitis is related to an increase in lipoprotein–X and a decrease in functional low-density lipoprotein (LDL) receptors.

Lipoprotein-X — Lipoprotein-X, an abnormal lipoprotein particle within the LDL region that is rich in free cholesterol and phospholipids, is increased in patients with cholestatic liver disease, including those with primary biliary cholangitis [5-7]. Lipoprotein-X reduces the atherogenicity of LDL cholesterol by preventing LDL oxidation [6]. Prolonged LDL oxidation has been demonstrated in patients with primary biliary cholangitis, and normalizes following liver transplantation [5].

Low-density lipoprotein receptors — Functional LDL receptors are decreased in injured hepatocytes, which leads to elevated serum cholesterol levels in patients with cholestatic liver disease, despite decreased cholesterol synthesis [7]. Cholestasis leads to reduced bile acid secretion, which results in diminished synthesis of both bile acids and hepatic cholesterol, but this does not result in reduced serum cholesterol levels because of the decline in LDL receptors.

CLINICAL FEATURES

Signs and symptoms — Patients with primary biliary cholangitis and hypercholesterolemia may present with plane xanthomas, which are soft, yellow, thin plaques found most commonly around the eyelids (xanthelasma), neck, trunk, shoulders, and axillae (picture 1). Xanthoma can also occur on the palms, soles, tendon sheaths, bony prominences, and peripheral nerves [8]. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)

Affected patients may complain about the appearance of these lesions, which are usually asymptomatic. (See 'Treatment for xanthomas' below and "Cutaneous xanthomas", section on 'Plane xanthomas'.)

Laboratory findings — Serum cholesterol levels may exceed 1000 mg/dL (26 mmol/L) in patients with xanthomas [7]. Xanthomas, but not xanthelasmas, correlate with total plasma cholesterol levels.

Patients in the early stages of primary biliary cholangitis often have mild elevations of low-density and very-low-density lipoproteins and striking elevations of high-density lipoproteins (HDL) [9]. HDL levels tend to decrease in the later stages of the disease, while triglyceride levels are often elevated [7]. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis", section on 'Diagnosis'.)

RISK OF CARDIOVASCULAR DISEASE — The risk of cardiovascular disease in patients with primary biliary cholangitis and hypercholesterolemia is generally not increased [2,3,7,10]. In a large study which included 930 patients with primary biliary cholangitis, the risk of myocardial infarction, stroke, or transient ischemic attack was not increased compared with an age- and sex-matched control group (HRs in patients with primary biliary cholangitis compared with controls were for myocardial infarction HR 1.04 [95% CI 0.67-1.62], stroke HR 0.98 [95% CI 0.73-1.31], and transient ischemia attack HR 0.66 [95% CI 0.38-1.16]) [2].

However, these patients may have other, independent risk factors for cardiovascular disease (eg, family history of coronary artery disease, diabetes mellitus, hypertension, or metabolic syndrome). Patients with primary biliary cholangitis should be screened for risk factors for cardiovascular disease, and patients with both primary biliary cholangitis and metabolic syndrome are at increased risk of cardiovascular disease. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Clinical evaluation and implications of diagnosis' and 'Clinical and laboratory monitoring' below.)

In a study of 171 patients with primary biliary cholangitis who responded to treatment with ursodeoxycholic acid with follow-up of over 10 years, the risk of cardiovascular disease was higher in patients who fulfilled criteria for metabolic syndrome (ie, any three of five possible risk factors: hyperglycemia, low HDL cholesterol, elevated triglycerides, obesity, hypertension) (table 1) compared with patients who did not have metabolic syndrome (29 versus 5 percent) [11].

MANAGEMENT

Clinical and laboratory monitoring — We routinely screen patients with primary biliary cholangitis for metabolic syndrome by measuring blood pressure, waist circumference, fasting lipid profile, and fasting glucose.

We obtain a fasting lipid profile in all patients with primary biliary cholangitis at presentation and every two years thereafter. If the patient meets criteria for metabolic syndrome as defined by the National Cholesterol Education Program’s Adult Treatment Panel III report (table 1), we obtain a fasting lipid profile annually. The overall approach for monitoring patients with primary biliary cholangitis is discussed elsewhere. (See "Overview of the management of primary biliary cholangitis".)

Candidates for lipid lowering agents — For patients with primary biliary cholangitis (PBC), the efficacy of drug therapy for PBC in lowering cardiovascular morbidity and mortality is uncertain [3,7].

Ursodeoxycholic acid and obeticholic acid are used in the management of PBC, and these drugs also reduce lipid levels. Ursodeoxycholic acid, the mainstay of treatment for primary biliary cholangitis, results in decreased levels of total and low density lipoprotein (LDL) cholesterol in patients with primary biliary cholangitis [12,13]. This effect is mediated through increased catabolism of cholesterol into primary bile acids and reduced intestinal absorption of cholesterol [14]. (See "Overview of the management of primary biliary cholangitis", section on 'Initial therapy'.)

Treatment with obeticholic acid decreases total and high-density lipoprotein (HDL) cholesterol [15]. In a three month trial of 165 patients with primary biliary cholangitis, total cholesterol and HDL cholesterol levels decreased in a dose-dependent fashion in patients treated with obeticholic acid compared with those given placebo (eg, decrease in total cholesterol of 3, 5, and 13 percent in patients on obeticholic acid 10-mg, 25 mg or 50 mg, respectively). The mean HDL at the end of the trial was 56 mg/dL, and the lower limit of the range was above 40 mg/dL. (See "Overview of the management of primary biliary cholangitis", section on 'Subsequent therapy'.)

Use of statins or fibrates — Lipid-lowering agents result in mild to moderate reductions in cholesterol levels in patients with primary biliary cholangitis. Our approach is the following:

●For patients with persistent cholestasis despite treatment with ursodeoxycholic acid (ie, total bilirubin level >1.75 mg/dL or 30 microm/L), we use fibrates (eg, bezafibrate 400 mg once daily [not available in the United States] or fenofibrate) in combination with ursodeoxycholic acid (UDCA). We typically target a daily dose in the range of 100 to 150 mg of micronized fenofibrate, but specific dosing depends on the formulation as there are several preparations with different bioavailability [16,17]. Detailed recommendations are available separately in the fenofibrate drug information monograph.

Fibrate therapy has been associated with reductions total serum cholesterol, non-high density lipoprotein cholesterol, and triglycerides but without increases in serum alanine aminotransferase or alkaline phosphatase [17-20]. In a trial including 100 patients with PBC and incomplete biochemical response to UDCA, bezafibrate plus UDCA resulted in a greater reduction in total cholesterol level after 24 months compared with placebo plus UDCA (difference in median percent change from baseline cholesterol: -16 percentage points, 95% CI -23 to -9 percentage points) [17].

●For patients who have elevated total and/or LDL cholesterol associated with metabolic syndrome and who have normal liver enzymes, statins may be used. We have no preference for a particular statin, and we monitor the liver enzymes annually in these patients. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

Because many of the statins (eg, lovastatin, simvastatin, atorvastatin, and rosuvastatin) are excreted into bile, levels may accumulate in patients with primary biliary cholangitis and may lead to toxicity. Thus, statins should be avoided in patients with significant cholestasis (ie, total bilirubin level >1.75 mg/dL [30 microm/L]) [7].

Data for most statins in patients with primary biliary cholangitis are limited to case series [14,21,22]. In a four-week study including 15 patients with primary biliary cholangitis, atorvastatin was associated with reductions in serum cholesterol and low-density lipoprotein cholesterol levels by 35 and 49 percent, respectively [23]. However, 3 of 15 patients (20 percent) had increases in serum alanine aminotransferase levels by two to three times the upper limit of normal.

Treatment for xanthomas — Cutaneous xanthomas associated with hypercholesterolemia are usually asymptomatic, although treatment may be desired for cosmetic reasons. Pharmacologic treatment of dyslipidemia often leads to improvement in xanthomas caused by hyperlipidemia. The treatment of cutaneous xanthomas is discussed separately. (See "Cutaneous xanthomas", section on 'Treatment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary biliary cholangitis".)

SUMMARY AND RECOMMENDATIONS

●Background – Hypercholesterolemia (cholesterol values above 200 mg/dL [5.2 mmol/L]) affects approximately 75 percent of patients with primary biliary cholangitis at presentation, but it is not associated with an increased risk of atherosclerosis in these patients. (See 'Introduction and prevalence' above and 'Risk of cardiovascular disease' above.)

●Clinical features – Patients with primary biliary cholangitis and hypercholesterolemia may present with xanthomas, which are soft, yellow plaques found most commonly around the eyelids (xanthelasma), neck, trunk, shoulders, and axillae (picture 1). Affected patients may complain about the appearance of these lesions, which are usually asymptomatic. (See 'Clinical features' above.)

●Clinical and laboratory monitoring – For all patients with primary biliary cholangitis, we obtain a fasting lipid profile at presentation and every two years thereafter, and we screen patients for features of metabolic syndrome.

For patients with primary biliary cholangitis who meet criteria for metabolic syndrome, we obtain lipid profiles annually. (See 'Clinical and laboratory monitoring' above.)

●Use of lipid lowering agents – For patients with primary biliary cholangitis who have elevated total and/or low density lipoprotein cholesterol associated with metabolic syndrome and who have normal liver enzymes, statins may be used. We monitor liver enzymes annually in these patients. (See 'Use of statins or fibrates' above.)

Patients with primary biliary cholangitis and independent risk factors for cardiovascular disease are managed with a standard approach that is discussed separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)