Abstract
To determine if shared genetic risk factors for autoimmune liver disease affect clinical manifestations, we evaluated 271 patients and 92 normal subjects by DNA-based techniques. Genetic risk factors were intermixed in all conditions, and frequency varied according to disease type. DR4 distinguished autoimmune hepatitis (P = 0.0002) and primary biliary cirrhosis (P = 0.004) from primary sclerosing cholangitis. DR52 distinguished primary sclerosing cholangitis from autoimmune hepatitis (P = 0.0007) and primary biliary cirrhosis (P = 0.00007) and DR3 distinguished autoimmune hepatitis (P = 0.002) and primary sclerosing cholangitis (P = 0.0005) from primary biliary cirrhosis. Only the occurrence of DR4 in primary sclerosing cholangitis was lower than in normal subjects (P = 0.02). Patients with mixed genetic risk factors did not have distinctive features or manifestations of hybrid conditions. We conclude that patients with shared genetic risk factors do not have characteristic features nor do they have overlap syndromes. DR4 may be protective against primary sclerosing cholangitis.
Similar content being viewed by others
REFERENCES
Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R: Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 13:701–706, 1991
Strettell MDJ, Donaldson PT, Thomson LJ, Santrach PJ, Moore SB, Czaja AJ, Williams R: Allelic basis for HLAencoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 112:2028–2035, 1997
Sanchez-Urdazpal L, Czaja AJ, van Hoek B, Krom RAF, Wiesner RH: Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis. Hepatology 15:215–221, 1992
Czaja AJ, Strettell MDJ, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, Williams R: Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 25:317–323, 1997
Czaja AJ, Carpenter HA, Santrach PJ, Moore SB: Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 105:1502–1507, 1993
Czaja AJ, Donaldson PT: Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 174:250–259, 2000
Gores GJ, Moore SB, Fisher LD, Powell FC, Dickson ER: Primary biliary cirrhosis: associations with class II major histocompability complex antigens. Hepatology 7:889–892, 1987
Manns MP, Bremm A, Schneider PM, Notghi A, Gerken G, Prager-Eberle M, Stradmann-Bellinghausen B, Meyer zum Buschenfelde K-H, Rittner C: HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis. Gastroenterology 101:1367–1373, 1991
Mehal WZ, Gregory WL, Lo Y-MD, Cross SJ, Fleming KA, Bassendine MF, James OFW, Campbell RD, Chapman RW, Rosenberg WMC: Defining the immunogenetic susceptibility to primary biliary cirrhosis. Hepatology 20:1213–1219, 1994
Onishi S, Sakamaki T, Maeda T, Iwamura S, Tomita A, Saibara T, Yamamoto Y: DNA typing of HLA class II genes: DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis. J Hepatol 21:1053–1060, 1994
Prochazka EJ, Terasaki PI, Park MS, Golstein LI, Busuttil RW: Association of primary sclerosing cholangitis with HLADRw52a. N Engl J Med 322:1842–1844, 1990
Farrant JM, Doherty DG, Donaldson PT, Vaughan RW, Hayllar KM, Welsh KI, Eddleston ALWF, Williams R: Amino acid substitutions at position 38 of the DRb polypeptide confer susceptibility to and protection from primary sclerosing cholangitis. Hepatology 16:390–395, 1992
Czaja AJ: Chronic active hepatitis: The challenge for a new nomenclature. Ann Intern Med 119:510–517, 1993
Czaja AJ: The variant forms of autoimmune hepatitis. Ann Intern Med 125:588–598, 1996
Czaja AJ: Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 28:360–365, 1998
Czaja AJ, Carpenter HA, Santrach PJ, Moore SB: Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology 31:1231–1238, 2000
Chazouilleres O, Wendum D, Serfaty L, Montebault S, Rosmorduc O, Poupon R: Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: Clinical features and response to therapy. Hepatology 28:296–301, 1998
McNair AN, Moloney M, Portmann BC, Williams R, McFarlane IG: Autoimmune hepatitis overlapping with primary sclerosing cholangitis in 5 cases. Am J Gastroenterol 93:777–784, 1998
Johnson PJ, McFarlane IG, Alvarez F, Bianchi FB, Bianchi L, Burroughs A, Chapman RW, Czaja AJ, Desmet V, Edleston ALWF, Gerber MA, Hoofnagle JH, Kakumu S, MacSween RNM, Maddrey WC, Manns MP, Meyer zum Buschenfelde K-H, Mieli-Vergani G, Portmann BC, Reed WD, Schalm SW, Scheuer PJ, Toda G, Tsuji T, Tygstrup N, Vergani D, Zeniya M: Meeting report. International Autoimmune Hepatitis Group. Hepatology 18:998–1005, 1993
Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WGE, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston ALWF, Fainboim L, Heathcote J, Homberg J-C, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RNM, Maddrey WC, Manns MP, Mc-Farlane IG, Meyer zum Buschenfelde K-H, Mieli-Vergani G, Nakanuma Y, Nishioka M, Penner E, Porta G, Portmann BC, Reed WD, Rodes J, Schalm SW, Scheuer PJ, Schrumpf E, Seki T, Toda G, Tsuji T, Tygstrup N, Vergani D, Zeniya M. International Autoimmune Hepatitis Group report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31: 929–938, 1999
Czaja AJ, Manns MP: The validity and importance of subtypes of autoimmune hepatitis: A point of view. Am J Gastroenterol 90:1206–1211, 1995
Wiesner RH, LaRusso NF, Ludwig J, Dickson ER: Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 88:108–114, 1985
Wiesner RH, LaRusso NF: Clinicopathologic features of the syndrome of primary sclerosing cholangitis. Gastroenterology 79:200–206, 1980
Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB: Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 24:1068–1073, 1996
Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB: Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis. Dig Dis Sci 42:1688–1696, 1997
Czaja AJ, Carpenter HA, Manns MP: Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 105:1522–1528, 1993
Czaja AJ, Manns MP, Homburger HA: Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology 103:1290–1295, 1992
Czaja AJ, Carpenter HA, Santrach PJ, Moore SB: Genetic predispositions for the immunological features of chronic active hepatitis. Hepatology 18:816–822, 1993
Czaja AJ, Dos Santos RM, Porto A, Santrach PJ, Moore SB: Immune phenotype of chronic liver disease. Dig Dis Sci 43:2149–2155, 1998
Czaja AJ, Manns MP, McFarlane IG, Hoofnagle JH: Autoimmune hepatitis: The investigational and clinical challenges. Hepatology 31:1194–1200, 2000
Mieli-Vergani G, Lobo-Yeo A, McFarlane BM, McFarlane IG, Mowat AP, Vergani D: Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood. Hepatology 9:198–203, 1989
Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, Donaldson PT: Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 30:851–856, 1999
Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT: Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 117:645–652, 1999
Agarwal K, Czaja AJ, Jones DEJ, Donaldson PT: CTLA-4 gene polymorphism and susceptibility to type 1 autoimmune hepatitis. Hepatology 31:49–53, 2000.
Czaja AJ, Sievers C, Zein NN: Nature and behavior of serum cytokines in type 1 autoimmune hepatitis. Dig Dis Sci 45: 1028–1035, 2000
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Czaja, A.J., Santrach, P.J. & Moore, S.B. Shared Genetic Risk Factors in Autoimmune Liver Disease. Dig Dis Sci 46, 140–147 (2001). https://doi.org/10.1023/A:1005670111068
Issue Date:
DOI: https://doi.org/10.1023/A:1005670111068