Elsevier

The Lancet

Volume 362, Issue 9377, 5 July 2003, Pages 53-61
The Lancet

Seminar
Primary biliary cirrhosis

https://doi.org/10.1016/S0140-6736(03)13808-1Get rights and content

Summary

Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications—including fatigue and metabolic bone disease—remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide.

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

References (140)

  • P Angulo et al.

    Primary biliary cirrhosis and primary sclerosing cholangitis

    Clin Liv Dis

    (1999)
  • T Sadamoto et al.

    Expression of pyruvate-dehydrogenase complex PDC-E2 on biliary epithelial cells induced by lymph nodes from primary biliary cirrhosis

    Lancet

    (1998)
  • J Springer et al.

    Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis

    Am J Gastroenterol

    (1999)
  • JG Walker et al.

    Serological tests in diagnosis of primary biliary cirrhosis

    Lancet

    (1965)
  • SC Gordon et al.

    Antibodies to carbonic anhydrase in patients with immune cholangiopathies

    Gastroenterology

    (1995)
  • WR Kim et al.

    Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation

    Hepatology

    (1997)
  • JA Talwalkar et al.

    Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system

    Am J Gastroenterol

    (2002)
  • J Ludwig

    Pathology of PBC and autoimmune cholangitis

    Bailleres Best Pract Res

    (2000)
  • A Pares et al.

    Renal tubular acidosis in primary biliary cirrhosis

    Gastroenterology

    (1981)
  • EA Jones et al.

    Is fatigue associated with cholestasis mediated by altered central neurotransmission

    Hepatology

    (1997)
  • MG Swain et al.

    Defective corticotrophin-releasing hormone mediated neuroendocrine and behavioural responses in cholestatic rats: implications for cholestatic liver disease-related sickness behaviors

    Hepatology

    (1995)
  • MI Prince et al.

    Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use

    J Hepatol

    (2000)
  • J Goldblatt et al.

    The true impact of fatigue in primary biliary cirrhosis: a population study

    Gastroenterology

    (2002)
  • NV Bergasa et al.

    Pruritus and fatigue in primary biliary cirrhosis

    Best Prac Res Clin Gastro

    (2000)
  • DV Datta et al.

    Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis

    Gastroenterology

    (1966)
  • WL Gregory et al.

    Reduced serum lipoprotein (a) levels in patients with primary biliary cirrhosis

    Atherosclerosis

    (1994)
  • V Balan et al.

    Effects of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis

    Mayo Clin Proc

    (1994)
  • JE Springer et al.

    Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis

    Gastroenterology

    (2000)
  • KV Menon et al.

    Bone disease in primary biliary cirrhosis: independent indicators and rate of progression

    J Hepatol

    (2001)
  • JR Phillips et al.

    Fat-soluble vitamin levels in patients with primary biliary cirrhosis

    Am J Gastroenterol

    (2001)
  • N Guanabens et al.

    Sodium fluoride prevents bone loss in primary biliary cirrhosis

    J Hepatol

    (1992)
  • KD Lindor et al.

    Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

    J Hepatol

    (2000)
  • AM Arria et al.

    Vitamin E deficiency and psychomotor dysfunction in adults with primary biliary cirrhosis

    Am J Clin Nutr

    (1990)
  • HC Mitchison et al.

    A controlled trial of prednisolone treatment in primary biliary cirrhosis: three-year results

    J Hepatol

    (1992)
  • J Crowe et al.

    Azathioprine in primary biliary cirrhosis: a preliminary report of an international trial

    Gastroenterology

    (1980)
  • E Christensen et al.

    Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis: final results of an international trial

    Gastroenterology

    (1985)
  • M Lombard et al.

    Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial

    Gastroenterology

    (1993)
  • MM Kaplan et al.

    Treatment of primary biliary cirrhosis with low-dose weekly methotrexate

    Gastroenterology

    (1991)
  • MT Hendrickse et al.

    Low-dose of methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial

    Gastroenterology

    (1999)
  • DM Heuman et al.

    Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts

    Gastroenterology

    (1994)
  • S Hillaire et al.

    Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes

    Gastroenterology

    (1994)
  • JV Metcalf et al.

    Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England

    Int J Epidemiol

    (1997)
  • RG Watson et al.

    Low prevalence of primary biliary cirrhosis in Victoria Australia

    Gut

    (1995)
  • H Witt-Sullivan et al.

    The demography of primary biliary cirrhosis in Ontario, Canada

    Hepatology

    (1990)
  • D Howel et al.

    An exploratory population-based case-control study of primary biliary cirrhosis

    Hepatology

    (2000)
  • GH Haydon et al.

    PBC: an infectious disease?

    Gut

    (2000)
  • JA Talwalkar et al.

    Impact of primary biliary cirrhosis on outcomes of pregnancy and socioeconomic position

    Hepatology

    (2001)
  • ME Gershwin et al.

    Primary biliary cirrhosis: an orchestrated immune response against biliary epithelial cells

    Immunol Rev

    (2000)
  • GJ Gores et al.

    Primary biliary cirrhosis: association with class II major histocompatibility antigens

    Hepatology

    (1987)
  • J Underhill et al.

    Susceptibility to primary biliary cirrhosis is associated with HLA-DR8–DQB1*0402 haplotype

    Hepatology

    (1992)
  • Cited by (304)

    • Challenges for diagnosis and treatment of primary biliary cholangitis

      2022, Translational Autoimmunity: Challenges for Autoimmune Diseases: Volume 5
    • S-adenosyl-L-methionine (SAMe) halts the autoimmune response in patients with primary biliary cholangitis (PBC) via antioxidant and S-glutathionylation processes in cholangiocytes

      2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
      Citation Excerpt :

      Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune destruction of small and medium-size intrahepatic bile ducts, mostly affecting middle-aged women [1,2].

    • Quantile based dimension reduction in censored regression

      2020, Computational Statistics and Data Analysis
    View all citing articles on Scopus
    View full text