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
SeminarPrimary biliary cirrhosis
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
References (139)
- et al.
Pediatric-onset primary biliary cirrhosis
Gastroenterology
(2003) - et al.
Serological tests in diagnosis of primary biliary cirrhosis
Lancet
(1965) - et al.
Epidemiology and natural history of primary biliary cirrhosis in a US community
Gastroenterology
(2000) - et al.
Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations
Gastroenterology
(2004) - et al.
Is autoimmunity a matter of sex?
Autoimmun Rev
(2008) - et al.
Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis
J Autoimmun
(2005) - et al.
Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment
Gastroenterology
(2004) - et al.
Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis
Gastroenterology
(2003) - et al.
Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium
Hepatology
(2003) - et al.
Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis
Gastroenterology
(2004)
Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis
Gastroenterology
Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis
J Autoimmun
Defining criteria for autoimmune diseases (Witebsky's postulates revisited)
Immunol Today
Detection of antimitochondrial autoantibodies in immunofluorescent AMA-negative patients with primary biliary cirrhosis using recombinant autoantigens
Hepatology
CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis
J Autoimmun
Natural history of early primary biliary cirrhosis
Lancet
Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies
Hepatology
Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis
Am J Gastroenterol
Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis
J Hepatol
Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis
Hepatology
Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis
Gastroenterology
Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis
J Autoimmun
Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer
Gastroenterology
The consequences of apoptosis in autoimmunity
J Autoimmun
Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC
Hepatology
The X and why of xenobiotics in primary biliary cirrhosis
J Autoimmun
The true impact of fatigue in primary biliary cirrhosis: a population study
Gastroenterology
Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis
Clin Gastroenterol Hepatol
Patients with primary biliary cirrhosis do not show post-exercise depression of cortical excitability
Clin Neurophysiol
The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: results of a 9 year follow-up
J Hepatol
Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis
Gastroenterology
Endogenous opioid peptides and chronic liver disease: from bedside to bench
J Hepatol
Pruritus in primary biliary cirrhosis: pathogenesis and therapy
Clin Liver Dis
AGA technical review on osteoporosis in hepatic disorders
Gastroenterology
Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis
J Hepatol
Clustering and commonalities among autoimmune diseases
J Autoimmun
The serology of the Addison-Gull syndrome
Hepatology
Primary biliary cirrhosis
Medicine (Baltimore)
Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis
J Immunol
Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis
Proc Natl Acad Sci USA
Characterization of antimitochondrial antibodies in health adults
Hepatology
Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology
Semin Liver Dis
Incidence, prevalence and clinical course of primary biliary cirrhosis in a Spanish community
Eur J Gastroenterol Hepatol
Primary biliary cirrhosis: an epidemiological study
BMJ
Epidemiology of PBC in Sheffield updated: demographics and relation to water supply
Gut
The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease?
Q J Med
Primary biliary cirrhosis once rare, now common in the United Kingdom?
Hepatology
Bacteriuria and primary biliary cirrhosis
Gut
Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations
Gut
Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation
Liver Transpl
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