Primary biliary cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]


Primary biliary cirrhosis also known as primary biliary cholangitis is an autoimmune cholestatic disease. The disease is chronic and slowly progressive. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Overexpression of Bcl-2 in small apoptotic biliary epithelial cells and cell lineage-specific lack of glutathione prevents loss of immunogenicity of the PDC-E2 component after apoptosis of biliary epithelial cells which finally results in autoimmunity. Primary biliary cirrhosis may be familial and is related to factors inherited maternally. Primary biliary cirrhosis is strongly associated with a variety of rheumatologic conditions, most commonly Sjogren's syndrome. On gross pathology, characteristic findings of primary biliary cirrhosis include hepatomegaly, splenomegaly, and cirrhosis (in late stage). On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.



Algorithm showing postulated hypothesis of pathogenesis of primary biliary cirrhosis[2][3][4][5]

Biliary epithelial cells (BEC)
Overexpression of Bcl-2 in small apoptotic BEC
Cell lineage specific lack of glutathione
Inhibition of PDC-E2 glutathiolation
Prevents loss of immunogenicity after apoptosis of BEC
PDC-E2 component remains intact and antigenic in apoptotic blebs of BEC
Antigenic PDC-E2 are engulfed by intrahepatic dendritic cells
Dendritic cells transfer antigenic PDC-E2 to regional lymph nodes
Antigenic PDC-E2 is recognized by MHC class I restricted CD8+ T cells
Initiates autoimmunity
Primary biliary cirrhosis


  • Primary biliary cirrhosis may be familial and is related to factors inherited maternally.[6]
  • Primary biliary cirrhosis tends to present at an earlier age in the second generation.

Associated Conditions

Conditions associated with primary biliary cirrhosis include:[7][8][9]

Gross Pathology

Microscopic Pathology

  • On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.
  • Primary biliary cirrhosis can be classified into four stages according to histological classification of Ludwig. According to Ludwig classification, all four stages may be present on a single liver biopsy.[10][11]
  • It can also be classified into four stages according to the histological classification of P. Scheuer.[12]

Classification of Primary biliary cirrhosis on the basis of histology
Stage Histologic appearance
Ludwig classification Scheuer's classification
Stage 1 Portal inflammation Florid duct lesion or chronic non-suppurative destructive cholangitis
Stage 2 Extension of inflammation beyond portal tracts into surrounding parenchyma with or without ductal loss Proliferation of the small bile ductules
Stage 3 Presence of fibrous septa linking adjacent portal tracts Fibrosis or scarring
Stage 4 Cirrhosis Cirrhosis


  1. Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ; et al. (2004). "Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis". Hepatology. 39 (5): 1415–22. doi:10.1002/hep.20175. PMID 15122771.
  2. Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR; et al. (2009). "Apotopes and the biliary specificity of primary biliary cirrhosis". Hepatology. 49 (3): 871–9. doi:10.1002/hep.22736. PMC 2665925. PMID 19185000.
  3. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A (2001). "Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis". J Clin Invest. 108 (2): 223–32. doi:10.1172/JCI10716. PMC 203018. PMID 11457875.
  4. Charlotte F, L'Herminé A, Martin N, Geleyn Y, Nollet M, Gaulard P; et al. (1994). "Immunohistochemical detection of bcl-2 protein in normal and pathological human liver". Am J Pathol. 144 (3): 460–5. PMC 1887102. PMID 8129031.
  5. Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A; et al. (2008). "Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells". Hepatology. 47 (3): 958–65. doi:10.1002/hep.22102. PMID 18181218.
  6. Brind AM, Bray GP, Portmann BC, Williams R (1995). "Prevalence and pattern of familial disease in primary biliary cirrhosis". Gut. 36 (4): 615–7. PMC 1382507. PMID 7737573.
  7. 7.0 7.1 Kumagi T, Heathcote EJ (2008). "Primary biliary cirrhosis". Orphanet J Rare Dis. 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315.
  8. Watt FE, James OF, Jones DE (2004). "Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study". QJM. 97 (7): 397–406. PMID 15208427.
  9. Tsianos EV, Hoofnagle JH, Fox PC, Alspaugh M, Jones EA, Schafer DF; et al. (1990). "Sjögren's syndrome in patients with primary biliary cirrhosis". Hepatology. 11 (5): 730–4. PMID 2347546.
  10. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; et al. (2009). "Primary biliary cirrhosis". Hepatology. 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543.
  11. Ludwig J, Dickson ER, McDonald GS (1978). "Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)". Virchows Arch A Pathol Anat Histol. 379 (2): 103–12. PMID 150690.
  12. Scheuer P (1967). "Primary biliary cirrhosis". Proc R Soc Med. 60 (12): 1257–60. PMC 1901478. PMID 6066569.

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