CHAPTER 52
Primary biliary cholangitis

Marlyn J. Mayo

University of Texas Southwestern Medical Center, Dallas, TX, USA

This chapter illustrates the clinical manifestations, histopathology, clinical course, and management of primary biliary cholangitis (PBC). PBC is a chronic liver disease that is defined by slowly progressive, nonnecrotizing inflammatory destruction of the biliary epithelial cells lining the small to medium‐sized interlobular ducts. The vast majority of patients are female and have antimitochondrial antibodies in the serum. Loss of normal biliary drainage leads to chronic cholestasis and its potential complications, including cirrhosis. However, therapy may delay or prevent disease progression, and other complications of cholestasis may be medically managed.

Clinical manifestations

Xanthomas

Xanthomas are more often seen in PBC patients with prolonged cholestasis but can also be seen before the onset of cirrhosis. Xanthomas are frequently seen around the eyes (xanthelasma), but may also develop over tendons, in palmar‐digital creases, and even in unusual areas such as the ear or gums.

Hyperpigmentation

Hyperpigmentation, which results from increased melanin deposition, is also more often seen with prolonged cholestasis but may occur before cirrhosis. Hyperpigmentation is most often found on the trunk and arms. Skin may also darken in areas that are repetitively scratched, which may result in a butterfly pattern of sparing in the middle of the back.

Limited scleroderma (CREST)

CREST (Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias) syndrome is seen in 5–7% of PBC patients. Telangiectasias are most commonly found on the lips and the fingertips.

Pruritus

Itching (pruritus) characteristically, although not universally, involves the palms and soles. It follows a circadian rhythm and is more severe in the evenings. There is no primary rash, but secondary changes from scratching such as excoriations and red crusted papules may be seen on exam.

Histopathology

Progression of histological stages

Primary biliary cholangitis progresses through four histological stages. The typical findings are patchy in distribution and may be missed on a liver biopsy, particularly a small sample.

Stage I is characterized by a mononuclear cell portal infiltrate that does not extend beyond the limiting plate. The inflammatory infiltrate consists predominantly of T lymphocytes, but it may also contain plasma cells and eosinophils. The inflammation may involve the bile duct.

Stage II is characterized by inflammation that extends beyond the limiting plate. Interface hepatitis, foci of lobular hepatitis, florid duct lesions (granulomatous involvement of bile duct), and pseudoductular (cholangiolar) proliferation occur. Pseudoducts or cholangioles arise from hepatic cell plates or putative stem cells under conditions of chronic cholestasis and are found at the periphery of the portal tract (as opposed to the native bile ducts, which are located adjacent to the portal arteriole); they frequently have poorly defined basement membranes and lumens. Nonsuppurative cholangitis, portal granulomas, and granulomatous cholangitis are present in about 50% of stage II PBC biopsies. Septal fibrosis and/or ductopenia may also be present.

Stage III is defined by the presence of bridging fibrosis. All the features seen in stage II PBC may be present, but ductopenia is more common in later stages of the disease. The diagnosis of ductopenia is often difficult to make because of lack of sufficient diagnostic material. A minimum sample of four portal tracts (with all four tracts containing arterioles but no ducts) or ideally 20 portal tracts (with >10 tracts containing arterioles but no ducts) is needed to make a diagnosis of ductopenia.

Stage IV is defined by the presence of cirrhosis. Although any of the characteristic histological features of PBC may be present, they may also be absent if much of the liver has been replaced by fibrous tissue. Ductopenia is usually evident in stage IV PBC.

Other histological features

A florid duct lesion with granulomatous involvement of the bile duct is the most specific histological finding suggestive of the diagnosis of PBC. The granulomas in PBC are often poorly defined. Portal granulomas without bile duct involvement are also seen in PBC, but lobular granulomas are much less common.

Severe or prolonged cholestasis may lead to biliary piecemeal necrosis, Mallory bodies, and copper granules. In biliary piecemeal necrosis, there is death of periportal hepatocytes associated with an inflammatory infiltrate. The injured hepatocytes appear swollen (feathery degeneration) as a result of cholate stasis. Copper accumulates in the periportal hepatocytes as cholestasis progresses. It is frequently accompanied by Mallory hyaline in areas of cholate stasis.