Variants of Primary Biliary Cholangitis: An Updated Mini-Review
DOI:
https://doi.org/10.12970/2310-9874.2018.06.04Keywords:
Primary biliary cholangitis, Antimitochondrial antibodies, Autoimmune hepatitis, Autoimmune liver diseases, Variant syndromes, Overlap syndromes.Abstract
Primary biliary cirrhosis (PBC) is an autoimmune cholestatic disease of the liver which affects mainly middle-aged women characterized by progressive destruction and loss of the small intrahepatic bile ducts which in turn, may lead to end-stage liver disease. The typical clinical phenotype is characterized by a middle-aged female with elevated cholestatic enzymes and positive antimitochondrial antibodies (AMA). However, apart from this typical presentation, there are important variants in everyday clinical practice. These variants include the AMA-negative PBC, the isolated AMA positivity, the AMA-positivity in patients with well-established autoimmune hepatitis (AIH), the premature ductopenic PBC variant and the PBC variant with characteristics of AIH (PBC-AIH variant). In this mini-review, we summarize and discuss the literature data and our own experience on the PBC variants highlighting also the uncertainties and a potential new era of the research agenda.
References
EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67: 145-72. https://doi.org/10.1016/j.jhep.2017.03.022
Hirschfield GM, Dyson JK, Alexander GJM, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67: 1568-94. https://doi.org/10.1136/gutjnl-2017-315259
Rigopoulou EI, Dalekos GN. Molecular diagnostics of primary biliary cirrhosis. Expert Opin Med Diagn 2008; 2: 621-34. https://doi.org/10.1517/17530059.2.6.621
Gatselis NK, Dalekos GN. Molecular diagnostic testing for primary biliary cholangitis. Expert Rev Mol Diagn. 2016; 16: 1001-10. https://doi.org/10.1080/14737159.2016.1217159
Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386: 1565-75. https://doi.org/10.1016/S0140-6736(15)00154-3
Gatselis NK, Zachou K, Lygoura V, et al. Geoepidemiology, clinical manifestations and outcome of primary biliary cholangitis in Greece. Eur J Intern Med 2017; 42: 81-8. https://doi.org/10.1016/j.ejim.2017.05.006
Floreani A, Caroli D, Variola A et al. A 35-year follow-up of a large cohort of patients with primary biliary cirrhosis seen at a single centre. Liver Int 2011; 31: 361-8. https://doi.org/10.1111/j.1478-3231.2010.02366.x
Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholicacid therapy. Gastroenterology 2015; 149: 1804-12. https://doi.org/10.1053/j.gastro.2015.07.061
Murillo Perez CF, Goet JC, Lammers WJ, et al. Milder disease stage in patients with primary biliary cholangitis over a 44-year period: A changing natural history. Hepatology 2018; 67: 1920-30. https://doi.org/10.1002/hep.29717
Harms MH, Lammers WJ, Thorburn D, et al. Major hepatic complications in ursodeoxycholicacid-treated patients with primary biliary cholangitis: risk factors and time trends in inci-dence and outcome. Am J Gastroenterol 2018; 113: 254-64. https://doi.org/10.1038/ajg.2017.440
Rigopoulou EI, Davies ET, Pares A, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut 2005; 54: 528-32. https://doi.org/10.1136/gut.2003.036558
Gatselis NK, Zachou K, Norman GL, et al. Clinical significance of the fluctuation of primary biliary cirrhosis-related autoantibodies during the course of the disease. Autoimmunity 2013; 46: 471-9. https://doi.org/10.3109/08916934.2013.801461
Granito A, Muratori P, Quarneti C, et al. Antinuclear antibodies as ancillary markers in primary biliary cirrhosis. Expert Rev Mol Diagn 2012; 12: 65-74. https://doi.org/10.1586/erm.11.82
Zachou K, Muratori P, Koukoulis GK, et al. Review article: autoimmune hepatitis - current management and challenges. Aliment Pharmacol Ther 2013; 38: 887-913. https://doi.org/10.1111/apt.12470
EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol 2015; 63: 971-1004. https://doi.org/10.1016/j.jhep.2015.06.030
Dalekos GN, Koskinas J, Papatheodoridis GV. HASL Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019 (in press). https://doi.org/10.20524/aog.2018.0330
Gatselis NK, Zachou K, Koukoulis GK, et al. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21: 60-83. https://doi.org/10.3748/wjg.v21.i1.60
Gabeta S, Norman GL, Liaskos C et al. Diagnostic relevance and clinical significance of the new enhanced performance M2 (MIT3) ELISA for the detection of IgA and IgG antimitochondrial antibodies in primary biliary cirrhosis. J Clin Immunol 2007; 27: 378-87. https://doi.org/10.1007/s10875-007-9092-0
Liu H, Norman GL, Shums Z, et al. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun 2010; 35: 436-42. https://doi.org/10.1016/j.jaut.2010.09.005
Bizzaro N, Covini G, Rosina F et al. Overcoming a "probable" diagnosis in antimitochondrial antibody negative primary biliary cirrhosis: study of 100 sera and review of the literature. Clin Rev Allergy Immunol 2012; 42: 288-97. https://doi.org/10.1007/s12016-010-8234-y
Hirschfield GM, Heathcote EJ. Antimitochondrial antibody-negative primary biliary cirrhosis. Clin Liver Dis 2008; 12: 323-31. https://doi.org/10.1016/j.cld.2008.02.003
Mendes F, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Gastroenterol Clin North Am 2008; 37: 479-84, viii. https://doi.org/10.1016/j.gtc.2008.02.006
Invernizzi P, Podda M, Battezzati PM et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol 2001; 34: 366-72. https://doi.org/10.1016/S0168-8278(00)00040-4
Nakamura M, Kondo H, Mori T, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 2007; 45: 118-27. https://doi.org/10.1002/hep.21472
Bogdanos DP, Liaskos C, Pares A et al. Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis. Hepatology 2007; 45: 1583-4. https://doi.org/10.1002/hep.21678
Rigopoulou EI, Dalekos GN. Anti-sp100 antibodies in primary biliary cirrhosis.Scand J Gastroenterol 2004; 39: 406-7. https://doi.org/10.1080/00365520310008746
Mattalia A, Quaranta S, Leung PS, et al. Characterization of antimitochondrial antibodies in health adults. Hepatology 1998; 27: 656-61. https://doi.org/10.1002/hep.510270303
Shibata M, Onozuka Y, Morizane T, et al. Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture. J Gastroenterol 2004; 39: 255-59. https://doi.org/10.1007/s00535-003-1285-6
Turchany JM, Uibo R, Kivik T, et al. A study of antimitochondrial antibodies in a random population in Estonia. Am J Gastroenterol 1997; 92: 124-6.
Mitchison HC, Bassendine MF, Hendrick A, et al. Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology1986; 6: 1279-84. https://doi.org/10.1002/hep.1840060609
Metcalf J, Mitchinson H, Palmer J, et al. Natural history of early primary biliary cirrhosis. Lancet 1996; 348: 1399-402. https://doi.org/10.1016/S0140-6736(96)04410-8
Dahlqvist G, Gaouar F, Carrat F, et al. Large-scale characterization study of patients with antimitochondrial antibodies but non established primary biliary cholangitis. Hepatology 2017; 65: 152-63. https://doi.org/10.1002/hep.28859
Montano-Loza AJ, Carpenter HA, Czaja AJ. Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis. J Clin Gastroenterol 2008; 42: 1047-53. https://doi.org/10.1097/MCG.0b013e3181587d18
Liaskos C, Bogdanos DP, Rigopoulou EI, Dalekos GN. Development of anti-mitochondrial antibodies in patients with autoimmune hepatitis: an art of facts or an artifact? J Gastroenterol Hepatol 2007; 22: 454-5. https://doi.org/10.1111/j.1440-1746.2006.04751.x
O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology 2008; 48: 550-6. https://doi.org/10.1002/hep.22380
Dinani AM, Fischer SE, Mosko J, Guindi M, Hirschfield GM. Patients with autoimmune hepatitis who have antimitochondrial antibodies need long-term follow-up to detect late development of primary biliary cirrhosis. Clin Gastroenterol Hepatol 2012; 10: 682-4. https://doi.org/10.1016/j.cgh.2012.02.010
Muratori P, Efe C, Muratori L, et al. Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis: a multicentre study. Eur J Gastroenterol Hepatol 2017; 29: 777-80. https://doi.org/10.1097/MEG.0000000000000870
Nakanuma Y, Hoso M, Mizuno Y, et al. Pathologic study of primary biliary cirrhosis of early histologic stages presenting cholestatic jaundice. Liver 1988; 8: 319-24. https://doi.org/10.1111/j.1600-0676.1988.tb01010.x
Vleggaar FP, van Buuren HR, Zondervan PE, ten Kate FJ, Hop WC; Dutch Multicentre PBC study group. Jaundice in non-cirrhotic primary bilairy cirrhosis: the premature ductopenic variant. Gut 2001; 49: 276-81. https://doi.org/10.1136/gut.49.2.276
Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54: 374-85. https://doi.org/10.1016/j.jhep.2010.09.002
Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36: 517-33. https://doi.org/10.1111/j.1365-2036.2012.05223.x
Haldar D, Hirschfield GM. Overlap syndrome: a real syndrome? Clin Liver Dis2014; 3: 43-7. https://doi.org/10.1002/cld.317
Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998; 28: 296-301. https://doi.org/10.1002/hep.510280203
Wang Q, Selmi C, Zhou X, et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. J Autoimmun 2013; 41: 140-5. https://doi.org/10.1016/j.jaut.2012.10.004
Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol1999; 31: 929-38. https://doi.org/10.1016/S0168-8278(99)80297-9
Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48: 169-76. https://doi.org/10.1002/hep.22322
Papamichalis PA, Zachou K, Koukoulis GK, et al. The revised international autoimmune hepatitis score in chronic liver diseases including autoimmune hepatitis/overlap syndromes and autoimmune hepatitis with concurrent other liver disorders. J Autoimmune Dis 2007; 4: 3. https://doi.org/10.1186/1740-2557-4-3
Gatselis NK, Zachou K, Papamichalis P, et al. Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score? Dig Liver Dis 2010; 42: 807-12. https://doi.org/10.1016/j.dld.2010.03.005
Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Significance of antibodies to soluble liver antigen/liver pancreas: a large French study. Liver Int 2009; 29: 857-64. https://doi.org/10.1111/j.1478-3231.2009.01986.x
Kanzler S, Bozkurt S, Herkel J, Galle PR, Dienes HP, Lohse AW. Presence of SLA/LP autoantibodies in patients with primary biliary cirrhosis as a marker for secondary autoimmune hepatitis (overlap syndrome). Dtsch Med Wochenschr 2001; 126: 450-6. https://doi.org/10.1055/s-2001-12906
Muratori P, Granito A, Pappas G, et al. The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Am J Gastroenterol 2009; 104: 1420-5. https://doi.org/10.1038/ajg.2009.126
Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology 2006; 44: 85-90. https://doi.org/10.1002/hep.21229
Chazouilleres O, Wendum D, Serfaty L, et al. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44: 400-6. https://doi.org/10.1016/j.jhep.2005.10.017
Silveira MG, Talwalkar JA, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes. Am J Gastroenterol 2007; 102: 1244-50. https://doi.org/10.1111/j.1572-0241.2007.01136.x
Heurgue A, Vitry F, Diebold MD, et al. Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Clin Biol 2007; 31: 17-25. https://doi.org/10.1016/S0399-8320(07)89323-7
Al-Chalabi T, Portmann BC, Bernal W, et al. Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival. Aliment Pharmacol Ther 2008; 28: 209-20. https://doi.org/10.1111/j.1365-2036.2008.03722.x
Levy C, Naik J, Giordano C, et al. Hispanics with primary biliary cirrhosis are more likely to have features of autoimmune hepatitis and reduced response to ursodeoxycholic acid than non-Hispanics. Clin Gastroenterol Hepatol 2014; 12: 1398-405. https://doi.org/10.1016/j.cgh.2013.12.010
Ozaslan E, Efe C, Heurgue-Berlot A, et al. Factors associated with response to therapy and outcome of patients with primary biliary cirrhosis with features of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12: 863-9. https://doi.org/10.1016/j.cgh.2013.09.021
Yang F, Wang Q, Wang Z, et al. The natural history and prognosis of primary biliary cirrhosis with clinical features of autoimmune hepatitis. Clin Rev Allergy Immunol 2016; 50: 114-23. https://doi.org/10.1007/s12016-015-8516-5
Zhang H, Li S, Yang J, et al. A meta-analysis of ursodeoxycholic acid therapy versus combination therapy with corticosteroids for PBC-AIH-overlap syndrome: evidence from 97 monotherapy and 117 combinations. Prz Gastroenterol 2015; 10: 148-55. https://doi.org/10.5114/pg.2015.51187
Zachou K, Gatselis NK, Papadamou G, et al. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naive patients. J Hepatol 2011; 55: 636-46. https://doi.org/10.1016/j.jhep.2010.12.032
Zachou K, Gatselis NK, Arvaniti P, et al. A real-world study focused on the long-term efficacy of mycophenolatemofetil as first-line treatment of autoimmune hepatitis. Aliment Pharmacol Ther 2016; 43: 1035-47. https://doi.org/10.1111/apt.13584
