Elsevier

The Lancet

Volume 377, Issue 9777, 7–13 May 2011, Pages 1600-1609
The Lancet

Seminar
Primary biliary cirrhosis

https://doi.org/10.1016/S0140-6736(10)61965-4Get rights and content

Summary

Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and, in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.

Introduction

Primary biliary cirrhosis is an autoimmune liver disease characterised by the presence in serum of highly specific antimitochondrial antibodies (AMAs) and progressive destruction of intrahepatic bile ducts, resulting in chronic cholestasis, portal inflammation, and fibrosis that can lead to cirrhosis and, ultimately, liver failure. The disease predominantly affects women, who are diagnosed typically in their fifth and sixth decade, although younger patients have been described, including children, albeit rarely.1 Loss of bile ducts leads to intrahepatic retention of detergent bile acids, resulting in liver damage through interaction with cell membranes and organelles. Disruption of enterohepatic bile acid circulation is probably the cause of other pathophysiological changes, which contribute to extrahepatic manifestations of this disease.

In 1761, the Italian pathologist Giovanni Battista Morgagni described biliary cirrhosis, and the earliest report of non-obstructive biliary cirrhosis was made by Addison and Gull in 1851.2 The term primary biliary cirrhosis was coined more than 50 years later.3 Presence of AMAs in serum samples of patients with primary biliary cirrhosis was recognised in 1965 by Walker and colleagues,4 and in 1987, antigens to these antibodies were cloned and identified as subunits of the pyruvate dehydrogenase complex, located on the inner mitochondrial membrane.5, 6

Clinical features and natural history of primary biliary cirrhosis vary greatly between affected individuals, ranging from either asymptomatic and stable or only slowly progressive to symptomatic and rapidly progressive. The typical clinical presentation has changed over the past few decades because the natural history has been modified by early recognition of more indolent cases and use of ursodeoxycholic acid.

Section snippets

Epidemiology

Data about incidence and prevalence of primary biliary cirrhosis have generally been obtained passively and might not indicate true rates in the general population; regional differences could vary on the basis of medical awareness and expertise. Indeed, a population-based approach to case detection has little feasibility for primary biliary cirrhosis because of its rarity. As a result, reported prevalence ranges between 19 and 402 cases per million.7, 8 By contrast, findings of serological

Cause and pathogenesis

Three important observations must be taken into account for us to understand the pathogenic basis of primary biliary cirrhosis (figure 1). First, appearance of AMAs before liver disease suggests that loss of tolerance to the mitochondrial autoantigen is an early event and could be independent of the development of liver disease. Second, although the autoantigen is present ubiquitously in all nucleated cells, the immune response is restricted to epithelial cells of intrahepatic bile ducts and,

Clinical features

The clinical features and natural history of primary biliary cirrhosis vary greatly between patients, ranging from asymptomatic and slowly progressive to symptomatic and rapidly evolving. The frequency of asymptomatic disease seems to be increasing, probably because of raised awareness of the disease together with broad use of routine testing of liver biochemistry. Many asymptomatic patients will, however, develop symptomatic liver disease within 5 years of diagnosis, although a third could

Diagnosis and liver histology

The diagnosis of primary biliary cirrhosis should be suspected in anyone with findings of chronic cholestasis after liver tests, particularly with raised concentrations of alkaline phosphatase. Furthermore, patients with primary biliary cirrhosis generally have increased amounts of aminotransferases and immunoglobulins (mainly IgM). Diagnosis can be established if two of three objective criteria are present: a concentration in serum of AMAs at titres of 1:40 or higher; an unexplained rise in

Treatment and natural history

The natural history and prognosis of primary biliary cirrhosis has become notably more benign, with substantial improvements in disease outcome reported in studies. Although these observations could be secondary to early diagnosis and a consequent lead-time bias,109 falling rates of liver transplantation for primary biliary cirrhosis in Europe and North America since widespread use of ursodeoxycholic acid was introduced suggest a true change in natural history.110, 111 Figure 2 presents a

Management guidelines

On the basis of guidelines from the American Association for the Study of Liver Diseases47 and the European Association for the Study of the Liver46 for management of primary biliary cirrhosis, we propose a pragmatic approach to patients with this disorder. Irrespective of the presence of symptoms or signs of liver cirrhosis, individuals with primary biliary cirrhosis should be treated with ursodeoxycholic acid (13–15 mg/kg per day).139 Monitoring of biochemical response is helpful for

Future perspectives

Several important steps towards better understanding of the causes and pathogenesis of primary biliary cirrhosis have been taken in recent years, yet important knowledge gaps remain with respect to genetic and immunological aberrancies that lead to the disorder. Data for epigenetic changes in primary biliary cirrhosis are sparse, which is perhaps surprising in view of the regularity with which such studies are reported for other complex conditions. Despite improvements in outcomes with

Search strategy and selection criteria

We searched Medline with the terms “primary biliary cirrhosis” and “autoimmune cholangitis” for original research published in peer-reviewed journals between 1970 and 2010. We focused on publications from the past 5 years, but we did not exclude commonly cited and highly regarded older publications. We also searched the reference lists of reports identified by this search strategy and selected articles we judged relevant. Reviews obtained by the same Medline search were included when they

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