eMedicine Specialties > Gastroenterology > Liver

Primary Biliary Cirrhosis: Differential Diagnoses & Workup

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

Differential Diagnoses

Autoimmune Hepatitis
Biliary Obstruction
Graft Versus Host Disease
Primary Sclerosing Cholangitis
Sarcoidosis

Other Problems to Be Considered

Drug-induced hepatotoxicity
Idiopathic adulthood ductopenia

Workup

Laboratory Studies

  • An elevation of the aminotransferases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be identified in most patients with primary biliary cirrhosis, but significant elevations of the alkaline phosphatase (ALP), g -glutamyl transpeptidase (GGTP), and immunoglobulin levels (mainly immunoglobulin M [IgM]) are usually the most prominent findings.
  • Lipid levels and cholesterol levels may be increased, with an increased high-density lipoprotein (HDL) fraction. The latter finding explains why these patients do not have an increased risk for atherosclerosis.
  • An increased erythrocyte sedimentation rate is another finding.
  • As the disease progresses to cirrhosis, an elevated bilirubin level, a prolonged prothrombin time, and a decreased albumin level can be found. The increased bilirubin level is an ominous sign of disease progression, and liver transplantation must be considered.
  • Thrombocytopenia is indicative of portal hypertension. Additionally, but not as commonly, abnormalities include elevated levels of ceruloplasmin, bile acids, and serum hyaluronate.
  • The hallmark of this disease is the presence of antimitochondrial antibodies (AMAs) in the sera.
    • AMAs can be found in 90-95% of patients with primary biliary cirrhosis, and they have a specificity of 98% for this disease.
    • These antibodies target different components, mainly enzymes, in the mitochondria.
    • The presence of anti-M2, anti-M4, anti-M8, and anti-M9 has been associated with the severity of primary biliary cirrhosis. Patients with profile A (ie, only anti-M9) or profile B (ie, anti-M9 and/or anti-M2–positive by enzyme-linked immunosorbent assay [ELISA]) have a better disease course than patients with profile C (ie, anti-M2, anti-M4, and/or anti-M8–positive by ELISA) and profile D (ie, anti-M2, anti-M4, and/or anti-M8–positive by ELISA and complement-fixation test).
    • Antinuclear antibodies (ANAs) can be identified in 20-50% of patients with primary biliary cirrhosis.
    • Some patients have clinical, biochemical, and histologic features of primary biliary cirrhosis, but their sera are negative for AMA. The diagnosis of autoimmune cholangitis has been used for these patients, but whether these patients represent the AMA-negative primary biliary cirrhosis group is a matter of debate. In terms of autoimmune markers, their profile is compatible with this type of autoimmune hepatitis (ie, high-titer ANA and/or SMA).
    • The natural history and associated autoimmune conditions in AMA-positive and AMA-negative primary biliary cirrhosis appear to be identical. A careful review of the liver biochemical pattern reveals cholestasis (ie, ALP and GGTP are elevated), and the liver biopsy findings are compatible with bile duct injury, ductopenia, cholestasis, and granulomas.7

Imaging Studies

  • Abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) are important to exclude biliary obstruction.
    • Nonspecific findings include increased echogenicity of the liver parenchyma and findings compatible with portal hypertension.
    • Portal lymphadenopathy can be recognized in approximately 15% of these patients.
    • Once patients are cirrhotic, findings compatible with portal hypertension (eg, nodular appearance of the liver, splenomegaly, intra-abdominal varices, ascites) can be observed. At this stage, follow-up imaging every 6 months with abdominal ultrasonography is suggested for early detection of hepatic malignancy.

Procedures

  • The diagnosis of primary biliary cirrhosis should be established or confirmed by performing a percutaneous or laparoscopic liver biopsy. This procedure also provides additional information about the stage of the disease and the patient's prognosis.
  • In the late stages of the disease (ie, cirrhosis), an upper endoscopy study should be performed. If the patient has developed esophageal varices, prophylactic treatment (eg, beta-blockers, nitrates) can be initiated in an attempt to prevent variceal bleeding.

Histologic Findings

Primary biliary cirrhosis is characterized by chronic, nonsuppurative, destructive cholangitis of the small interlobular bile ducts with a diameter of 40-80 mm. Early lesions signal damage of the basement membrane of the bile ducts and reactive hyperplasia of the epithelial lining. Lymphocytic and plasma cell infiltration, with eosinophilic condensation in the portal tracts, is another feature. Epithelioid aggregates or granulomas may be found around the bile ducts. Fibrosis and cirrhosis develop later.

Staging

Various staging systems have been developed, but the most prominent are those proposed by Ludwig et al and Scheuer.8

  • Stage 1 (portal stage of Ludwig): Portal inflammation, bile duct abnormalities, or both are present.
  • Stage 2 (periportal stage): Periportal fibrosis is present, with or without periportal inflammation or prominent enlargement of the portal tracts with seemingly intact, newly formed limiting plates.

    • 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.

  • Stage 3 (septal stage): Septal fibrosis with active inflammatory, passive paucicellular septa, or both are present.
  • Stage 4 (cirrhosis): Nodules with various degrees of inflammation are present.

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.