Abstract
Purpose
This study describes the clinical, histological, and genetic profile of AMA-M2 positive liver disease in north India.
Methods
Over 13.5 years, 11,221 patients suspected of AiLD (autoimmune liver disease) and negative for viral markers were screened for autoantibodies, ANA, ASMA, AMA, and LKM, by indirect immunofluorescence. Of these patients, 135 were AMA positive and 132 AMA-M2 positive. Clinical presentation of most of these patients was neither typical of AIH nor PBC. Sera of these patients were further tested for gp 210 and Sp 100. Fifty consecutive consenting patients were typed for HLA class II alleles DR and DQ and their clinical, biochemical, histology and genetic profiles were reviewed to characterize the disease spectrum in north India.
Results
Only 22 of 50 patients had liver histology reports, and could be categorized on the basis of the criteria by Chazouillers et al. Of these 22, 13 had overlap syndrome, eight had classical PBC, whereas one had probable PBC. The remaining 28 could not be suitably categorized due to lack of liver histology. HLA DRB1*03 was found to be significantly associated with the disease in North Indian population.
Conclusion
This 13.5-year study demonstrates a definite rising annual incidence of AMA-M2-positive liver disease in north India. Complete evaluation of 50 patients indicated that a hepatitic variant of PBC (PBC-AIH), which is significantly associated with DRB1*03, predominates in north India.
Similar content being viewed by others
References
Invernizzi P, Lleo A, Podda M. Interpreting serological tests in diagnosing autoimmune liver diseases. Semin Liver Dis 2007;27:161–172
Ishibashi H, Shimoda S, Gershwin ME. The immune response to mitochondrial autoantigens. Semin Liver Dis 2002;22:291–302
Nishio A, Keeffe EB, Gershwin ME. Immunopathogenesis of primary biliary cirrohosis. Semin Liver Dis 2002;22:291–302
Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OFW. Natural history of early primary biliary cirrohosis. Lancet 1996;348:1399–1402
Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol 2001;34:366–372
Charatcharoenwittaya P, Lindor KD. Current concepts in the pathogenesis of primary biliary cirrhosis. Ann Hepatol 2005;4:161–175
Lleo A, Invernizzi P, Mackay IR, Prince H, Zhong RQ, Gershwin ME. Etiopathogenesis of primary biliary cirrhosis. World J Gasteroenterol 2008;14:3328–3337
Crosignani A, Battezatti PM, Invernizzi P, Selmi C, Prina E, Podda M. Clinical management of primary biliary cirrhosis. World J Gasteroenterol 2008;14:3313–3327
Bensen GD, Kikuchi K, Miyakawa H, Tanaka A, Watnik MR, Gershwin ME. Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol 2004;11:129–33
Innervizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J. Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis 2005;25:298–310
Nakamura M, Kondo H, Mori T, Komori A, Matsuyana M, Ito M, et al. Anti GP 210 and anticentromeric antibodies are different risk factors for progression of primary biliary cirrhosis. Hepatology 2007;45:118–127
Mackay IR. Historical reflections on autoimmune hepatitis. World J Gastroenterol 2008;14:3292–3300
Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354:54–66
Manns MP, Strassburg CP. Autoimmune hepatitis: clinical challenges. Gasteroenterology 2001;120:1502–1517
Silveira MG, Talwalker JA, Angulo P, Lindor K. Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes. Am J Gasteroenterol 2007;102:1244–1250
Invernizzi P, Mackay IR. Overlap syndrome among autoimmune liver diseases. World J Gasteroenterol 2008;14:3368–3373
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcoate EJ. Primary biliary cirrhosis. AASLD practice guidelines. Hepatology 2009;50:291–308
Czaja AJ. Frequency and nature of the variant forms of autoimmune liver disease. Hepatology 1998;28:360–365
O’Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcoate EJ. Long-term follow up of antimitochondrial antibody positive autoimmune hepatitis. Hepatology 2008;48:550–556
Sarin SK, Monga R, Sandhu BS, Sharma BC, Sakhuja P, Malhotra V. Primary biliary cirrhosis in India. Hepatobiliary Pancreat Dis Int 2006;5:105–109
Minz RW, Anand S, Bhasin DK, Sood S, Das A, Bhansali A, Dhiman RK, Chawla YK. Rising annual detection of antimitochondrial antibody (AMA) in liver disease in north India. Indian J Gastroenterol 2004;23:A50
Minz RW, Chhabra S, Aggarwal R, Das A, Saikia B, Chawla YK. Incipient primary biliary cirrhosis/autoimmune hepatitis overlap or hepatitic form of primary biliary cirrohosis: a case report. Cases J 2009;2:7491
Papamichalis PA, Zachou K, Koukkoulis GK, Veloni A, Karacosta EG, Kypri L, et al. The revised international autoimmune hepatitis score in chronic liver diseases including autoimmune hepatitis/overlap syndrome and autoimmune hepatitis with concurrent other liver disorders. J Autoimmun Dis 2007;4:3
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
Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–176
Samanta AKS, Bhagwat AG, Mukherjee M, Gupta NM, Sehgal S, Datta DV. Primary biliary cirrhosis in India: a case report. Gut 1973;14:448–450
Czaja AJ. The variant forms of autoimmune hepatitis. Ann Intern Med 1996;125:588–598
Lohse AW, Meyer zum Buschenfelde KH MZ, Franz B, Kanzler S, Gerken G, Dienes HP. Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence of it being a hepatitic form of primary biliary cirrhosis in generally susceptible individuals. Hepatology 1999;29:1078–1084
Invernizzi P, Battezzati PM, Crosignani A, Perego F, Poli F, Morabito A, et al. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis. J Hepatol 2003;38:401–406
Juran BD, Lazaridis KN. Genetics and genomics of primary biliary cirrhosis. Clin Liver Dis 2008;12:349–365
Donaldson PT, Baragiotta A, Heneghan MA, Floreani A, Venturi C, Underhill JA, et al. HLA class II alleles, genotypes, haplotypes and amino acids in primary biliary cirrhosis: a large scale study. Hepatology 2006;44:667–74
Stone J, Wade JA, Cauch-Dudek K, Ng C, Lindor KD, Heathcoate EJ. Human leucocyte antigen class II associations in serum antimitochondrial antibodies (AMAs)-positive and AMA negative primary biliary cirrhosis. J Hepatol 2002;36:8–13
Mullarkey ME, Stevens AM, Mc Donnell WM, Loubiere LS, Brackensick JA, Pang JM, et al. Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis. Tissue Antigens 2005;65:199–205
Begovich AB, Klitz W, Moonsamy PV, Van de Water J, Peltz G, Gershwin ME. Genes within HLA class II region confer both predisposition and resistance to primary biliary cirrhosis. Tissue Antigens 1994;43:71–77
Wassmuth R, Depner F, Danielson A, Hultcrantz R, Loof L, Olson R, et al. HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis. J Hepatol 1994;21:1053–1060
Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatology Research 2010;40:494–504
Seki T, Kiyosawa K, Ota M, Furuta S, Fukushima H, Tanaka E, et al. Association of primary biliary cirrhosis with human leucocyte antigen DPB1*0501 in Japanese patients. Hepatology 1993;18:73–78
Liu HY, Deng AM, Zhou Y, Yao DK, Xu DX, Zhong RQ. Analysis of HLA alleles polymorphism in Chinese patients with primary biliary cirrhosis. Hepatobiliary Pancreat Dis Int 2006;5:129–132
Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, et al. Primary Biliary Cirrhosis associated with HLA, ILI2A, and IL12RB2 variants. N Engl J Med 2009;360:2544–55.
Indian genome consortium. Genetic landscape of the people of India: A canvas for disease gene exploration. J Genet 2008;87:3–20
Acknowledgement
The authors acknowledge Mrs. Ranjit Sharma for her substantial contribution toward autoimmune screening of the patients. This work was supported by a research grant from Indian Council of Medical Research, New Delhi, India.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Minz, R.W., Kaur, N., Anand, S. et al. Complete spectrum of AMA-M2 positive liver disease in north India. Hepatol Int 6, 790–795 (2012). https://doi.org/10.1007/s12072-011-9326-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12072-011-9326-3