SeminarPrimary biliary cirrhosis
Section snippets
Epidemiology
Primary biliary cirrhosis affects all races, yet seems to cluster within specific geographical areas.1 Women are mainly affected, with a female/male ratio of 9/1. The median age of disease onset is 50 years, but varies between 20 and 90 years. Estimates of annual incidence2, 3 and prevalence3, 4 range from 2 to 24 cases per million and 19 to 240 cases per million population, respectively. Data from Olmsted County, Minnesota, USA,4 suggest a stable incidence rate over the past 25 years but a
Genetics
Genetic predisposition to autoimmunity in primary biliary cirrhosis has been associated with alleles from MHC loci. However, class 2 MHC loci, including DR8, DQA1*0102, and DQ/β1*0402, have only been reported in selected patients with the disorder.11, 12, 13 The haplotypes DR3, DR8, and DR4 are more frequent in white populations by contrast with DR2 and DR8 haplotypes in Japanese patients.11 Conflicting results, however, are noted for the observation between the DQA1*0102 haplotype and disease
Immune-mediated mechanisms
Present evidence lends support to the notion of primary biliary cirrhosis as an immune-mediated disease. Cellular and humoral abnormalities have both been noted. Immunohistochemical staining of T lymphocytes in portal and periportal areas shows CD4–positive and CD8–positive T cells.17 Furthermore, abnormal suppressor T-cell activity has been reported in asymptomatic first-degree relatives of people with the disease.18 Intracellular adhesion molecules (eg, ICAM-1), which are expressed in areas
Asymptomatic primary biliary cirrhosis
Individuals with asymptomatic disease consist of 20·60% of all first-time diagnoses, based largely on increased use of screening liver-biochemistry profiles.35 Asymptomatic patients tend to be older than symptomatic counterparts at diagnosis.6 However, most asymptomatic patients, over time, will develop symptoms and hepatic disease will progress.2 No specific features to predict development of symptomatic disease have been identified.36
Symptomatic primary biliary cirrhosis
The most common symptoms reported in this disorder include
Biochemical features
Rises in serum alkaline phosphatase (2–10 times upper limit of normal) are frequently seen at diagnosis of primary biliary cirrhosis; normal values (41–133 IU/L) are rarely noted.39 No association exists between the amount of the rise in serum alkaline phosphatase and outlook in untreated patients. Modestly raised values for alanine aminotransferase and aspartate aminotransferase are typical. Serum total bilirubin concentrations are generally normal at diagnosis yet rise with histological
Fatigue
Frequency of fatigue in people with primary biliary cirrhosis is reported to be between 65% and 85%. Alterations in central neurotransmission55 and impaired corticotropin-releasing hormone response56 have been postulated as putative causes. Results of investigations with validated methods that measure fatigue severity show it to be independent of severity of hepatic disease,57 sleep disturbance, or depression.58 However, a lower than expected frequency of reported fatigue in cases versus
Disease-modifying therapies
Ursodeoxycholic acid is the only medical treatment for primary biliary cirrhosis that has received US Food and Drug Administration approval.
Immunosuppressive drugs
Corticosteroids,88, 89 azathioprine,90, 91 ciclosporin,92, 93 and methotrexate94, 95 have not been shown to be effective treatments for primary biliary cirrhosis.
Antifibrotic agents
Penicillamine, a potential antifibrotic drug studied in 312 patients,96 was ineffective and associated with drug-related toxic effects in primary biliary cirrhosis. Although a rise in liver-related survival from colchicine treatment was reported in one investigation after all placebo-treated patients were crossed over to colchicine, no effect was seen on overall survival.97
Ursodeoxycholic acid
The mechanism of action for ursodeoxycholic acid treatment in primary biliary cirrhosis is multifactorial. In addition to promotion of endogenous bile-acid secretion, evidence suggests that this compound is associated with membrane stabilisation,98 reduced aberrant HLA type 1 expression on hepatocytes,99 and a fall in cytokine production.100 Inhibition of apoptosis and mitochondrial dysfunction caused by exposure to hydrophobic bile acids are also prevented by ursodeoxycholic acid.101
Responders to treatment
Five randomised controlled trials of adequate size and duration have provided extensive information about the effectiveness of ursodeoxycholic acid in primary biliary cirrhosis.102, 103, 104, 105, 106 Three studies used daily doses of 13–15 mg/kg,102, 103, 104 one used daily doses of 14–16 mg/kg,105 and the remaining investigation used 10–12 mg/kg per day.106 Improvements in symptoms and concentrations of hepatic enzymes were shown in all five studies. Results of one investigation showed
Combination treatments
Adjunctive treatments have also been studied in patients with primary biliary cirrhosis with an incomplete response to ursodeoxycholic acid alone. Corticosteroids,116, 117, 118, 119 azathioprine,117 colchicine,120, 121 and methotrexate122, 123 have all been used with this drug. No significant histological or survival benefit has been reported. In an investigation of ursodeoxycholic acid with colchicine (compared with monotherapy), however, reductions in the number of treatment failures, slow
Asymptomatic primary biliary cirrhosis
The natural history of asymptomatic disease has not been extensively reported. In a study, 29 patients with antimitochondrial antibody titres of 1/40 or greater and normal serum hepatic enzyme concentrations were followed up for a median of 17·8 years.39 Initial liver histological findings at study entry were diagnostic for or accorded with primary biliary cirrhosis in 24 patients (83%). 22 (76%) developed symptoms associated with the disorder, including fatigue, pruritus, and right upper
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