16-12: Primary Biliary Cholangitis

GENERAL CONSIDERATIONS

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%, the risk is increased in second- and third-degree relatives, and the concordance rate in identical twins is high. PBC is associated with HLA DRB1*08 and DQB1 as well as the IL12A and IL12RB2 genes, which encode interleukin-12alpha and interleukin 12 receptor beta2, respectively, and IRF5-TNPO3, which encodes interferon regulatory factor 5-transportin 3. The disease may be associated with Sjögren syndrome, autoimmune thyroid disease, Raynaud syndrome, systemic sclerosis (scleroderma), hypothyroidism, and celiac disease; all patients with PBC should be screened for these conditions. Infection with Novosphingobium aromaticivorans or Chlamydophila pneumoniae may trigger or cause PBC. Other triggers, including viruses (such as human betaretrovirus), lactobacillus vaccination to prevent recurrent vaginitis, and xenobiotics, are also suspected. X-chromosome monosomy may be a predisposing factor. 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.

CLINICAL FINDINGS

A. Symptoms and Signs

Many patients are asymptomatic for years. The onset of clinical illness is insidious and is heralded by fatigue (excessive daytime somnolence) and pruritus, which appears to correlate with elevated serum levels of the enzyme autotaxin and its product lysophosphatidic acid. With progression, physical examination reveals hepatosplenomegaly. Xanthomatous lesions may occur in the skin (eFigure 16–35) 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.