Primary biliary cirrhosis

Summary

Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.

Introduction

In 1950, Ahrens and colleagues¹ defined primary biliary cirrhosis in a compilation of 25 cases of diagnosed chronic intrahepatic biliary obstruction with xanthomatosis, reported between 1851 and 1950. The first case of primary biliary cirrhosis had been described almost 100 years earlier by Addison and Gull.² Ahrens and colleagues noted the female preponderance, hyperpigmentation, jaundice, pruritus, hepatomegaly, hyperlipidaemia, and xanthomatosis that are now known to be characteristic of the disease. In 1959, Sherlock³ reported an exhaustive description of 42 patients followed up for up to 15 years. It is now known that primary biliary cirrhosis is a progressive disease characterised by the destruction of small intrahepatic bile ducts, leading to periportal inflammation, fibrosis, and potential cirrhosis. However, many patients with primary biliary cirrhosis do not have cirrhosis and this misnomer has led to concern that patients are unfairly stigmatised for a disorder that they do not have. Patient advocacy groups are working with the medical community to choose a new name that more accurately describes the disease.

Primary biliary cirrhosis is deemed a model autoimmune disease because of the serological findings, detection of antimitochondrial antibody (AMA), and specific bile duct pathological changes that occur in the disorder.⁴ Primary biliary cirrhosis is most often diagnosed when routine laboratory studies reveal an increase in alkaline phosphatase. AMA, the serological hallmark of primary biliary cirrhosis, is present in about 95% of patients with the disorder, but in less than 1% of healthy adults.5, 6, 7 High alkaline phosphatase in conjunction with presence of AMA is sufficient to diagnose the disorder. Liver biopsy is not necessary for diagnosis but can be useful in the absence of AMA or in the presence of overlap syndromes. Primary biliary cirrhosis predominantly affects women, and usually presents in the fifth or sixth decade of life.

Fatigue and pruritus are the most common symptoms of primary biliary cirrhosis, and both can be debilitating in some patients. The only accepted therapy is ursodeoxycholic acid (UDCA), which has been shown to extend transplant-free survival, especially when started early in the course of disease. However, UDCA does not cure the disease and about 40% of patients with primary biliary cirrhosis do not have a biochemical response to UDCA. Recent years have brought exciting new insights into the mechanisms that contribute to the disorder, including advances that are leading to novel treatments.