Primary biliary cholangitis (PBC)

Primary biliary cholangitis (PBC) is a chronic disease of the liver characterized by autoimmune destruction of small intrahepatic bile ducts and cholestasis. The designation “primary biliary cholangitis” has replaced “primary biliary cirrhosis” because many patients do not have cirrhosis.

The disease is insidious in onset, occurs usually in women aged 40–60 years, and is often detected by the chance finding of elevated alkaline phosphatase levels. Estimated incidence and prevalence rates in the United States are 4.5 and 65.4 per 100,000, respectively, in women, and 0.7 and 12.1 per 100,000, respectively, in men.

These rates may be increas­ing. The frequency of the disease among first-degree rela­tives of affected persons is 1.3–6%, and the concordance rate in identical twins is high. PBC is associated with HLA DRB1*08 and DQB1. The disease may be associated with Sjögren syndrome, autoimmune thyroid disease, Raynaud syndrome, scleroderma, hypothyroidism, and celiac disease. Infection with Novosphingobium aromaticivorans or Chla­mydophila pneumoniae may trigger or cause PBC.

A history of urinary tract infections (caused by E coli or Lactobacillus delbrueckii) and smoking, and possibly use of hormone replacement therapy and hair dye, are risk factors, and clustering of cases in time and space argues for a causative role of environmental agents.

Signs and symptoms

Many patients are asymptomatic for years. The onset of clinical illness is insidious and is heralded by fatigue (excessive daytime somnolence) and pruritus.

With pro­gression, physical examination reveals hepatosplenomeg­aly.

Xanthomatous lesions may occur in the skin and tendons and around the eyelids.

Jaundice, steatorrhea, and signs of portal hypertension are late findings, although occasional patients have esophageal varices despite an early histologic stage.

Autonomic dysfunction, including ortho­static hypotension and associated fatigue and cognitive dysfunction, appear to be common.

The risk of low bone density, osteoporosis, and fractures is increased in patients with PBC (who tend to be older women) possibly due in part to polymorphisms of the vitamin D receptor.

Diagnosis

The diagnosis of PBC is based on the detection of choles­tatic liver chemistries (often initially an isolated elevation of the alkaline phosphatase) and antimitochondrial anti­bodies in serum. Liver biopsy is not necessary for diagnosis unless antimitochondrial antibodies are absent but permits histologic staging: I, portal inflammation with granulo­mas; II, bile duct proliferation, periportal inflammation; III, interlobular fibrous septa; and IV, cirrhosis. Estimation of histologic stage by an “enhanced liver fibrosis (ELF) assay,” which incorporates serum levels of hyaluronic acid, tissue inhibitor of metalloproteinase-1, and procollagen III ami­nopeptide, has shown promise.

Differential Diagnosis

The disease must be differentiated from chronic biliary tract obstruction (stone or stricture), carcinoma of the bile ducts, primary sclerosing cholangitis, sarcoidosis, choles­tatic drug toxicity (eg, chlorpromazine), and in some cases chronic hepatitis. Patients with a clinical and histologic picture of PBC but no antimitochondrial antibodies are said to have antimitochondrial antibody-negative PBC (previously termed “autoimmune cholangitis”), which has been associated with lower serum IgM levels and a greater frequency of smooth muscle antibodies and ANA. Many such patients are found to have antimitochondrial antibod­ies by immunoblot against recombinant proteins (rather than standard immunofluorescence). Some patients have overlapping features of PBC and autoimmune hepatitis.

Treatment

Cholestyramine (4 g) in water or juice three times daily may be beneficial for pruritus; colestipol and colesevelam may be better tolerated but have not been shown to reduce pruritus.

Rifampin, 150–300 mg orally twice daily, is incon­sistently beneficial.

Opioid antagonists (eg, naloxone, 0.2 mcg/kg/min by intravenous infusion, or naltrexone, starting at 12.5 mg/day by mouth) show promise in the treatment of pruritus but may cause opioid withdrawal symptoms.

The 5-hydroxytryptamine (5-HT3) serotonin receptor antagonist ondansetron, 4 mg orally three times a day as needed, and the selective serotonin reuptake inhibi­tor sertraline, 75–100 mg/day orally, may also provide some benefit.

For refractory pruritus, plasmapheresis or extracorporeal albumin dialysis may be needed.

Modafinil, 100–200 mg/day orally, may improve daytime somnolence but is poorly tolerated.

Deficiencies of vitamins A, D, and K may occur if steatorrhea is present and are aggravated when cholestyramine is administered.

Ursodeoxycholic acid (13–15 mg/kg/day in one or two doses) is the preferred medical treatment for PBC. It has been shown to slow the progression of disease (particularly in early-stage disease), stabilize histology, improve long-term survival, reduce the risk of developing esophageal varices, and delay (and possibly prevent) the need for liver transplantation, even in the absence of liver biochemical improvement. Complete normalization of liver biochemi­cal tests occurs in 20% of treated patients within 2 years and 40% within 5 years, and survival is similar to that of healthy controls when the drug is given to patients with stage 1 or 2 PBC.

Response rates have been reported to be lower in men than women (72% vs 80%) and higher in women diagnosed after age 70 than before age 30 (90% vs 50%). Ursodeoxycholic acid has also been reported to reduce the risk of recurrent colorectal adenomas in patients with PBC. Side effects include weight gain and rarely loose stools. The drug can be continued during pregnancy.

Obeticholic acid, a farsenoid-X receptor agonist, was approved by the FDA in 2016 for the treatment of PBC in patients with an incomplete response or intolerance to ursodeoxycholic acid. Obeticholic acid is begun in a dose of 5 mg orally daily and increased to 10 mg daily if neces­sary, based on the decline in serum alkaline phosphatase and bilirubin levels. In patients with Child-Pugh class B or C cirrhosis, the initial dose is 5 mg weekly. The principal side effect is pruritus. Given the expensesiveness of the drug, it may not be cost-effective.

Colchicine (0.6 mg orally twice daily) and methotrexate (15 mg/wk orally) have had some reported benefit in improving symptoms and serum levels of alkaline phos­phatase and bilirubin.

Methotrexate may also improve liver histology in some patients, but overall response rates have been disappointing.

For patients with advanced disease, liver transplantation is the treatment of choice.