The underlying pathophysiology of primary biliary cholangitis (PBC) remains unresolved but may involve a combination of autoimmune-mediated mechanisms as well as genetic and environmental factors1-3


The majority of patients with PBC have antimitochondrial antibodies (AMAs) that target the E2 component of pyruvate dehydrogenase complex (PDC-E2), which is expressed in the inner membrane of mitochondria.4,5

  • A combination of host susceptibility and environmental factors that trigger loss of immune tolerance provide a possible mechanism for the pathogenesis of autoimmunity in PBC6-8
  • Almost all patients with PBC (90%-100%) have detectable AMAs and their detection in sera can precede liver damage by several years4,9,10
  • Lymphocytes selectively infiltrate and destroy biliary epithelial cells (ie, cholangiocytes) that line the small ducts of the hepatobiliary system11
    • This selectivity may be due, in part, to the unique properties of apoptosis in these cells (generally, not just in PBC) and their retention of intact PDC-E2 in apoptotic blebs11
  • The chronic immune-mediated destruction of small bile ducts and associated inflammation leads to cholestasis, followed by fibrosis12-14
    • Bile acid accumulation due to cholestasis contributes to progressive liver damage, leading to fibrosis and cirrhosis12

Certain genetic factors may render patients susceptible to developing PBC.3

  • Several loci (many associated with immune processes) have been implicated in PBC, including3
    • Major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1)
    • Interleukin 12A (IL12A)
    • Interleukin 12 receptor, beta 2 (IL12RB2)
    • Signal transducer and activator of transcription 4 (STAT4)
  • Unknown heritable factors likely contribute to a predisposition for PBC3
    • Highlighted by the striking concordance of PBC among monozygotic twins (~60%) but not dizygotic twins6

Exposure to environmental factors may trigger loss of immune tolerance.15

  • Certain microorganisms and xenobiotics can modify or mimic self-antigens (known as molecular mimicry) respectively that can trigger a cross-species immune response, leading to the loss of immune tolerance15,16
  • Some bacteria (eg, Escherichia coli and Novosphingobium aromaticivorans) express proteins with epitopes that have a high homology with PDC-E215
    • This may explain the increased risk for PBC among patients with frequent urinary tract infections17
  • Xenobiotics such as 2-octynoic acid—commonly found in many cosmetics and detergents—can stimulate the production of AMAs and induce autoimmune cholangitis in rodent models16,18,19

References:  1. Chuang Y-H, Lian Z-X, Tsuneyama K, et al. Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun. 2006;26(4):232-240. doi:10.1016/j.jaut.2006.04.001.  2. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011;377(9777):1600-1609. doi:10.1016/S0140-6736(10)61965-4.  3. Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360(24):2544-2555. doi:10.1056/NEJMoa0810440.  4. Fussey SPM, Guest JR, James OFW, Bassendine MF, Yeaman SJ. Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci U S A. 1988;85(22):8654-8658. doi:10.1073/pnas.85.22.8654.  5. Yeaman SJ, Fussey SPM, Danner DJ, James OFW, Mutimer DJ, Bassendine MF. Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet. 1988;1(8594):1067-1070. doi:10.1016/S0140-6736(88)91894-6.  6. Long SA, Quan C, Van de Water J, et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol. 2001;167(5):2956-2963. doi:10.4049/jimmunol.167.5.2956.  7. Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127(2):485-492. doi:10.1053/S0016-5085(04)00841-8.  8. Padgett KA, Selmi C, Kenny TP, et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun. 2005;24(3):209-219. doi:10.1016/j.jaut.2005.01.012.  9. Irie J, Wu Y, Wicker LS, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med. 2006;203(5):1209-1219. doi:10.1084/jem.20051911.  10. Munoz LE, Thomas HC, Scheuer PJ, Doniach D, Sherlock S. Is mitochondrial antibody diagnostic of primary biliary cirrhosis? Gut. 1981;22(2):136-140. doi:10.1136/gut.22.2.136.  11. Lleo A, Selmi C, Invernizzi P, et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology. 2009;49(3):871-879. doi:10.1002/hep.22736.  12. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-758. doi:10.1016/j.jhep.2009.11.027.  13. Washington MK. Autoimmune liver disease: overlap and outliers. Mod Pathol. 2007;20(suppl 1):S15-S30. doi:10.1038/modpathol.3800684.  14. Zimmermann HW, Seidler S, Gassler N, et al. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One. 2011;6(6):e21381. doi:10.1371/journal.pone.0021381.  15. Selmi C, Balkwill DL, Invernizzi P, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38(5):1250-1257. doi:10.1053/jhep.2003.50446.  16. Wakabayashi K, Lian Z-X, Leung PSC, et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology. 2008;48(2):531-540. doi:10.1002/hep.22390.  17. Burroughs AK, Rosenstein IJ, Epstein O, Hamilton-Miller JMT, Brumfitt W, Sherlock S. Bacteriuria and primary biliary cirrhosis. Gut. 1984;25(2):133-137. doi:10.1136/gut.25.2.133.  18. Rieger R, Leung PSC, Jeddeloh MR, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun. 2006;27(1):7-16. doi:10.1016/j.jaut.2006.06.002.  19. Wakabayashi K, Yoshida K, Leung PSC, et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol. 2009;155(3):577-586. doi:10.1111/j.1365-2249.2008.03837.x.