Sclerosing cholangitis
Hepatocellular disease
    Viral hepatitis
    Alcoholic hepatitis
    Medications
Intrahepatic cholestasis of pregnancy
Systemic infection
Total parenteral nutrition-associated cholestasis
Postoperative cholestasis

Liver injury results from the nonsuppurative destruction of small bile ducts in the lobule. Reduced biliary excretion leads to cholestasis and toxic hepatocyte injury from the accumulation of bile acids and copper. The disease evolves through four histologically described stages. In stage I, the portal tracts are expanded by chronic inflammatory cells and noncaseating granulomas adjacent to the damaged bile ducts, including the classic “florid duct lesion.” Stage II is characterized by expansion of the inflammatory infiltrate into the hepatic parenchyma and proliferation of the bile ductules. In stage III, interlobular fibrous septa and ductopenia are present. Stage IV represents cirrhosis.

Clinical presentation

Forty percent to 50% of persons with PBC are asymptomatic at presentation. The disease is detected in most of these individuals from elevated serum alkaline phosphatase or γ-glutamyltransferase levels. About 50–60% of patients have presenting symptoms, usually fatigue and pruritus, and in some, upper right quadrant discomfort. Less than 25% present with jaundice. The pruritus may be relentless and profound, prompting the patient to seek advice from a dermatologist before it is recognized as a complication of cholestasis. The skin may become excoriated and hyperpigmented from incessant scratching. Other physical findings include hepatomegaly, splenomegaly, palmar erythema, spider angiomata, xanthomas, and xanthelasma. The last finding correlates with the hypercholesterolemia (particularly of high-density lipoprotein) which is observed in PBC. The defect in bile acid secretion leads to impaired fat digestion with resultant steatorrhea, weight loss, and fat-soluble vitamin deficiencies. Long-standing cholestasis can also result in bone resorption and osteoporosis, which often lead to vertebral compression fractures and long bone fractures. A rare patient may have hepatic failure or a complication of portal hypertension (e.g. variceal bleeding) as the initial manifestation of PBC.

Table 39.2 Extrahepatic manifestations of primary biliary cirrhosis

Extrahepatic disease	Prevalence (%)
Sjögren syndrome	30–58
Gallstones	30–50
Decreased pulmonary diffusion capacity	40–50
Renal tubular acidosis	20–33
Osteoporosis	15–40
Bacteriuria	11–35
Arthropathy	4–38
Rheumatoid arthritis	3–26
Hypothyroidism	11–32
Raynaud phenomenon	7–14
CREST^* syndrome	3–6
Autoimmune thyroiditis	3–6
Autoimmune anemias	1–2
Psoriasis	1–13
Lichen planus	0.5–6
Ulcerative colitis	0.5–1

*CREST: syndrome of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.

Most patients with PBC have associated autoimmune diseases. These diseases, of which Sjögren syndrome is by far the most common, usually are mild and survival is dictated by the severity of hepatic dysfunction. Autoimmune thyroiditis with hypothyroidism and CREST syndrome also often occur with PBC and may predate the diagnosis of liver disease. Other diseases associated with PBC include rheumatoid arthritis, gallstones, decreased pulmonary diffusion capacity, psoriasis, Raynaud phenomenon, and distal renal tubular acidosis (Table 39.2).

Diagnostic investigation

Laboratory studies

Patients with PBC typically have elevated serum alkaline phosphatase levels. Similar elevations in levels of 5′-nucleotidase and γ-glutamyltransferase help confirm the hepatic origin of the elevated alkaline phosphatase level. Serum bilirubin levels usually are normal at diagnosis. As the disease progresses, more than 50% of patients develop hyperbilirubinemia, a poor prognostic indicator. As with other cholestatic syndromes, levels of aminotransferases usually are only slightly elevated. Other nonspecific surrogate markers of cholestasis include increased levels of serum bile acids, cholesterol, triglycerides, elevated serum and hepatic copper levels, and decreased levels of fat-soluble vitamins A, D, E, and K.

Serological testing

The immunological abnormalities observed in PBC provide useful diagnostic information. Antimitochondrial antibodies (AMAs) are present in 90–95% of patients with PBC. Although other autoantibodies are present in a large number of cholestatic syndromes, elevated titers of AMAs rarely occur in other diseases and therefore are quite specific for PBC. Similarly, the finding of elevated IgM levels on serum protein electrophoresis, often in the absence of hyperglobulinemia, has high predictive value for PBC. Other serological abnormalities include increased titers of antinuclear antibodies (ANAs) in 25–70% of patients and other autoantibodies but these findings are not specific to PBC and are of limited diagnostic value.