eMedicine Specialties > Gastroenterology > Liver

Primary Biliary Cirrhosis

Author: Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Coauthor(s): K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Dec 23, 2009

Introduction

Background

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic disease of the liver. The etiology is unknown, although it is presumed to be autoimmune in nature. The major pathology of this disease is a destruction of the small-to-medium bile ducts, which leads to progressive cholestasis and often end-stage liver disease.

In 1851, Addison and Gull described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. In 1950, Ahrens and colleagues named this disease primary biliary cirrhosis.1 The term is controversial because cirrhosis only develops late in the course of the disease.

Primary biliary cirrhosis is most frequently a disease of women and occurs between the fourth and sixth decades of life. The symptoms may strongly affect patients' quality of life and may induce incapacitation. Various therapeutic approaches have been implemented with variable results; in selected candidates, liver transplantation is the only treatment option for the terminal stages of the disease. After the procedure, the disease has a relatively high recurrence rate despite immunosuppressive therapy.

The image below demonstrates the histologic appearance of stage 2 primary biliary cirrhosis.

This histologic picture is compatible with stage ...

This histologic picture is compatible with stage 2 primary biliary cirrhosis.

[ CLOSE WINDOW ]
This histologic picture is compatible with stage ...

This histologic picture is compatible with stage 2 primary biliary cirrhosis.


Pathophysiology

The exact mechanism of the liver damage is unknown, although evidence indicates that it can be of autoimmune origin. The data supporting this hypothesis are as follows: (1) abnormalities of the humoral and cellular immune systems (ie, elevated serum levels of immunoglobulins, mainly immunoglobulin M [IgM]), (2) multiple circulating autoantibodies, (3) granulomas in the liver and regional lymph nodes, (4) impaired regulation of both B and T lymphocytes, and (5) the association of this disease with a variety of autoimmune-mediated diseases (eg, autoimmune thyroiditis; keratoconjunctivitis sicca; scleroderma; calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia [CREST] syndrome).2

A continuous destruction of small and medium bile ducts occurs, which is mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding. Once destroyed, it is well established that regeneration of bile ducts is either not possible or inefficient.

Subsequent to the loss of the intrahepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and the hepatocytes. In addition, increased expression of the HLA class II antigens in the liver occurs, rendering hepatocytes and bile duct epithelial cells more susceptible to activated T lymphocytes and perhaps exacerbating immunologically mediated cytotoxicity. An association has been suggested between primary biliary cirrhosis and haplotype HLA-DR8 and, for some populations, HLA-DPB1.

In a controlled, interview-based study of 1032 patients, Gershwin et al noted that in genetically susceptible persons, environmental factors, including chemicals found in cigarette smoke and infectious agents introduced through urinary tract infections, may induce primary biliary cirrhosis. The authors stated that exogenous estrogens may also contribute to the disease's development and that this may help to explain why the disease occurs more frequently in females than in males.3,4

Frequency

United States

Although the epidemiology of primary biliary cirrhosis has not been studied systematically, the published prevalence is 65.4 cases for women and 12.1 cases for men (40.2 cases overall) per 100,000 population. The incidence of the disease has been estimated as 4.5 cases for women and 0.7 cases for men (2.7 cases overall) per 100,000 population.

International

Primary biliary cirrhosis is reported to be more prevalent in the United Kingdom and Scandinavia. The prevalence of the disease has been estimated as 24 cases per 100,000 population in Newcastle, United Kingdom; 12.9 cases per 100,000 population in Northeast England; 1.9 cases per 100,000 population in Victoria, Australia; 2.2 cases per 100,000 population in Ontario, Canada; 2.7 cases per 100,000 population in Estonia; 9.2 cases per 100,000 in Malmö, Sweden; and 15.1 cases per 100,000 population in Umea, Sweden.

Mortality/Morbidity

For asymptomatic patients with antimitochondrial antibody (AMA)–positive findings, a normal biochemical liver profile, and histologic features that are compatible with primary biliary cirrhosis, the progression of the disease is relatively slow; however, the patient life expectancy is not identical to that of the general population. Of these patients, 40-67% develop symptomatic disease in approximately 5-7 years. Once they develop symptoms (mainly cholestasis) and remain untreated, the median patient survival duration ranges from 5.5-12 years. Generally, the median survival duration from the time of diagnosis is 7.5 years for patients who are symptomatic and 16 years for patients who are asymptomatic.

Significant changes in the mortality rate have been noticed since the early 1980s with an increase in the age of death. This might be a consequence of treatment.5

Race

Primary biliary cirrhosis is more common in Northern Europeans and is less common in populations of African descent.

Sex

Women account for 75-90% of patients with primary biliary cirrhosis. Males who are affected have a disease course similar to that of females; however, men appear to be more likely to develop hepatocellular carcinoma.

Age

Primary biliary cirrhosis mostly affects middle-aged women, with a mean age of 39 years. Onset usually occurs in persons aged 30-65 years. However, patients as young as 22 years and as old as 93 years at the time of diagnosis have been reported.

Clinical

History

Of patients with primary biliary cirrhosis, 25% are incidentally diagnosed during a routine blood evaluation.

  • Fatigue (65%)
    • Fatigue is the first reported symptom. It can cause disability in some patients and has been associated with depression and obsessive-compulsive behavior. The etiology is unknown; however, a sleep abnormality, particularly excessive daytime somnolence, has been identified in a significant proportion of patients and has been associated with the degree of fatigue.
    • No correlation exists between this symptom and the stage of the liver disease, the height of the levels of liver enzymes, the Mayo model score, or the duration of therapy.
    • The etiology of fatigue is unclear; although some evidence suggests that abnormalities of the hypothalamic-pituitary-adrenal axis, decreased release of serotonin, and increased production of proinflammatory cytokines (ie, interleukin-1 [IL-1], interleukin-6 [IL-6], tumor necrosis factor-a [TNF-a ]) may be responsible.6
  • Pruritus (55%)
    • According to estimates, 10% of patients experience severe pruritus.
    • The cause of this symptom is not known.
    • Pruritus appears unrelated to the deposition of bile acids in the skin.
    • Increased opioidergic tone (ie, increased production of endogenous opioid peptides, up-regulation of endogenous opioid receptors) appears to be the major mechanism. The height of the bilirubin level is proportionally related to the production of these peptides.
  • Right upper quadrant discomfort occurs in 8-17% of patients.

Physical

Physical examination findings depend on the stage of the disease. In the early stages, examination findings are normal. As the disease advances, excoriations of the skin, xanthelasmata, or findings of cirrhosis may be present.

  • Hepatomegaly (25%)
  • Hyperpigmentation (25%)
  • Splenomegaly (15%)
  • Jaundice (10%)
  • Xanthelasmata (10%) - In late stages of the disease
  • Sicca syndrome (50-75%) - Xerophthalmia (ie, dry eyes), xerostomia (ie, dry mouth)
  • Kayser-Fleischer rings (extremely rare)
  • Stigmata of advanced liver disease (ie, cirrhosis), such as spider nevi, palmar erythema, ascites, temporal and proximal muscle wasting, and peripheral edema

Causes

Primary biliary cirrhosis is a disease of unknown etiology, but various factors have been implicated as the causes of this illness.

  • Genetic factors: First-degree relatives have a 570- to 1000-fold increased chance of developing primary biliary cirrhosis. The presence of an inherited abnormality of immune regulation has been proposed.
  • Infection with organisms of the family Enterobacteriaceae: Cross-reactivity between antigens on the bacterial wall and the mitochondria has been postulated. Patients with primary biliary cirrhosis present with an increased incidence of gram-negative urinary tract infections.

More on Primary Biliary Cirrhosis

Overview: Primary Biliary Cirrhosis
Differential Diagnoses & Workup: Primary Biliary Cirrhosis
Treatment & Medication: Primary Biliary Cirrhosis
Follow-up: Primary Biliary Cirrhosis
Multimedia: Primary Biliary Cirrhosis
References
Further Reading
[ CLOSE WINDOW ]

References

  1. Ahrens EH Jr, Payne MA, Kunkel HG, et al. Primary biliary cirrhosis. 1950. Medicine (Baltimore). Sep 1994;73(5):264-78; discussion 278-80. [Medline].

  2. Solis Herruzo JA, Solis Munoz P, Munoz Yague T. The pathogenesis of primary biliary cirrhosis. Rev Esp Enferm Dig. Jun 2009;101(6):413-23. [Medline].

  3. McNally RJ, Ducker S, James OF. Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis. Hepatology. Jun 24 2009;[Medline].

  4. Selmi C, Gershwin ME. The role of environmental factors in primary biliary cirrhosis. Trends Immunol. Aug 2009;30(8):415-20. [Medline].

  5. Mendes FD, Kim WR, Pedersen R, et al. Mortality attributable to cholestatic liver disease in the United States. Hepatology. Apr 2008;47(4):1241-7. [Medline].

  6. Niro GA, Poli F, Andriulli A, Bianchi I, Bernuzzi F, Caliari L, et al. TNF-alpha polymorphisms in primary biliary cirrhosis: a northern and southern Italian experience. Ann N Y Acad Sci. Sep 2009;1173:557-63. [Medline].

  7. Drebber U, Mueller JJ, Klein E, Kasper HU, Schulze F, Schardt K, et al. Liver biopsy in primary biliary cirrhosis: clinicopathological data and stage. Pathol Int. Aug 2009;59(8):546-54. [Medline].

  8. Scheuer P. Primary biliary cirrhosis. Proc R Soc Med. Dec 1967;60(12):1257-60. [Medline]. [Full Text].

  9. Charatcharoenwitthaya P, Pimentel S, Talwalkar JA, et al. Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl. Sep 2007;13(9):1236-45. [Medline].

  10. Bjornsson E, Kalaitzakis E, Neuhauser M, et al. Fatigue measurements in patients with primary biliary cirrhosis and the risk of mortality during follow-up. Liver Int. Nov 17 2009;[Medline].

  11. Balasubramaniam K, Grambsch PM, Wiesner RH, et al. Diminished survival in asymptomatic primary biliary cirrhosis. A prospective study. Gastroenterology. Jun 1990;98(6):1567-71. [Medline].

  12. Ballardini G, Mirakian R, Bianchi FB, et al. Aberrant expression of HLA-DR antigens on bileduct epithelium in primary biliary cirrhosis: relevance to pathogenesis. Lancet. Nov 3 1984;2(8410):1009-13. [Medline].

  13. Burroughs AK, Rosenstein IJ, Epstein O, et al. Bacteriuria and primary biliary cirrhosis. Gut. Feb 1984;25(2):133-7. [Medline].

  14. Bush A, Mitchison H, Walt R, et al. Primary biliary cirrhosis and ulcerative colitis. Gastroenterology. Jun 1987;92(6):2009-13. [Medline].

  15. Calmus Y, Gane P, Rouger P, et al. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology. Jan 1990;11(1):12-5. [Medline].

  16. Christensen E, Crowe J, Doniach D, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients. Gastroenterology. Feb 1980;78(2):236-46. [Medline].

  17. Culp KS, Fleming CR, Duffy J, et al. Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc. Jun 1982;57(6):365-70. [Medline].

  18. Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology. Jul 1989;10(1):1-7. [Medline].

  19. Elta GH, Sepersky RA, Goldberg MJ, et al. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci. Nov 1983;28(11):971-5. [Medline].

  20. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. Nov 2005;42(5):1194-202. [Medline].

  21. Hoffmann RM, Pape GR, Spengler U, et al. Clonal analysis of liver-derived T cells of patients with primary biliary cirrhosis. Clin Exp Immunol. May 1989;76(2):210-5. [Medline].

  22. Janes CH, Dickson ER, Okazaki R, et al. Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice. J Clin Invest. Jun 1995;95(6):2581-6. [Medline].

  23. Jones DE, Metcalf JV, Collier JD, et al. Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology. Nov 1997;26(5):1138-42. [Medline].

  24. Kaplan MM, Elta GH, Furie B, et al. Fat-soluble vitamin nutriture in primary biliary cirrhosis. Gastroenterology. Sep 1988;95(3):787-92. [Medline].

  25. Kim WR, Lindor KD, Locke GR 3rd, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. Dec 2000;119(6):1631-6. [Medline].

  26. Klein R, Huizenga JR, Gips CH, et al. Antimitochondrial antibody profiles in patients with primary biliary cirrhosis before orthotopic liver transplantation and titres of antimitochondrial antibody-subtypes after transplantation. J Hepatol. Feb 1994;20(2):181-9. [Medline].

  27. Lacerda MA, Ludwig J, Dickson ER, et al. Antimitochondrial antibody-negative primary biliary cirrhosis. Am J Gastroenterol. Feb 1995;90(2):247-9. [Medline].

  28. Liermann Garcia RF, Evangelista Garcia C, et al. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology. Jan 2001;33(1):22-7. [Medline].

  29. Lindor K, Dickson R. Primary biliary cirrhosis. In: Schiff's Diseases of the Liver. Vol 1. 8th ed. Lippincott-Raven: 1999:679-92.

  30. Mahl TC, Shockcor W, Boyer JL. Primary biliary cirrhosis: survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years. J Hepatol. Jun 1994;20(6):707-13. [Medline].

  31. Mang FW, Michieletti P, O'Rourke K, et al. Primary biliary cirrhosis, sicca complex, and dysphagia. Dysphagia. Summer 1997;12(3):167-70. [Medline].

  32. Marx WJ, O'Connell DJ. Arthritis of primary biliary cirrhosis. Arch Intern Med. Feb 1979;139(2):213-6. [Medline].

  33. Nakanuma Y, Tsuneyama K, Kono N, et al. Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis: an immunohistochemical and immunoelectron microscopic study. Hum Pathol. Jan 1995;26(1):92-8. [Medline].

  34. Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology. Jul 2006;44(1):91-8. [Medline].

  35. Pares A, Rimola A, Bruguera M, et al. Renal tubular acidosis in primary biliary cirrhosis. Gastroenterology. Apr 1981;80(4):681-6. [Medline].

  36. Parikh-Patel A, Gold E, Mackay IR, et al. The geoepidemiology of primary biliary cirrhosis: contrasts and comparisons with the spectrum of autoimmune diseases. Clin Immunol. May 1999;91(2):206-18. [Medline].

  37. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. Mar 2006;130(3):715-20. [Medline].

  38. Reynolds TB, Denison EK, Frankl HD, Lieberman FL, Peters RL. Primary biliary cirrhosis with scleroderma, Raynaud's phenomenon and telangiectasia. New syndrome. Am J Med. Mar 1971;50(3):302-12. [Medline].

  39. Ricci P, Therneau TM, Malinchoc M, et al. A prognostic model for the outcome of liver transplantation in patients with cholestatic liver disease. Hepatology. Mar 1997;25(3):672-7. [Medline].

  40. Roll J, Boyer JL, Barry D, et al. The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med. Jan 6 1983;308(1):1-7. [Medline].

  41. Ros E, Garcia-Puges A, Reixach M, et al. Fat digestion and exocrine pancreatic function in primary biliary cirrhosis. Gastroenterology. Jul 1984;87(1):180-7. [Medline].

  42. Rutan G, Martinez AJ, Fieshko JT, et al. Primary biliary cirrhosis, Sjogren's syndrome, and transverse myelitis. Gastroenterology. Jan 1986;90(1):206-10. [Medline].

  43. Selinger S, Tsai J, Pulini M, et al. Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. A case report. Ann Intern Med. Nov 1987;107(5):686-8. [Medline].

  44. Shapiro JM, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut. Feb 1979;20(2):137-40. [Medline].

  45. Thomas PK, Walker JG. Xanthomatous neuropathy in primary biliary cirrhosis. Brain. Dec 1965;88(5):1079-88. [Medline].

  46. Yamada G, Hyodo I, Tobe K, et al. Ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelia in primary biliary cirrhosis. Hepatology. May-Jun 1986;6(3):385-91. [Medline].

[ CLOSE WINDOW ]

Keywords

primary biliary cirrhosis, cirrhosis, PBC, liver cirrhosis, cirrhosis of the liver, antinuclear antibody, antinuclear antibodies, chronic nonsuppurative destructive cholangitis, autoimmune liver disease, ductopenia, liver granulomas, progressive cholestasis, end-stage liver disease, progressive obstructive jaundice

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Nikolaos T Pyrsopoulos, MD, PhD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Liver Foundation, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Transplantation, International Liver Transplantation Society, and Transplantation Society
Disclosure: Gilead Sciences Honoraria Speaking and teaching; Schering-Plough Honoraria Speaking and teaching; Roche Honoraria Speaking and teaching

Coauthor(s)

K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
K Rajender Reddy, MD, FACP, FACG is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and Florida Medical Association
Disclosure: Nothing to disclose.

Medical Editor

George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians
Disclosure: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

James L Achord, MD, Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine
James L Achord, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, American Society for Gastrointestinal Endoscopy, Mississippi State Medical Association, New York Academy of Sciences, Sigma Xi, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.