Frequency of Concurrent Autoimmune Disorders in Patients With Autoimmune Hepatitis Effect of Age, Gender, and Genetic Background Paulo Lisboa Bittencourt, MD, PhD, Alberto Queiroz Farias, MD, PhD, Gilda Porta, MD, PhD, Eduardo L. R. Canc¸ado, MD, PhD, Irene Miura, MD, PhD, Renata Pugliese, MD, Jorge Kalil, MD, PhD, Anna C. Goldberg, PhD, and Flair J. Carrilho, MD, PhD Background: Concurrent autoimmune disorders (CAIDs) have been shown to occur in 22% to 34% of the patients with autoimmune hepatitis (AIH). Their presence has been linked to female gender, older age, and to certain HLA antigens, namely HLA-A11, DRB1*04, and DRB4*01. Aims: To assess the frequency and nature of CAID in Brazilian patients with AIH types 1 (AIH-1) and 2 (AIH-2) and to investigate the influence of age, gender, and genetic background in their occurrence. Patients and Methods: The presence and nature of CAID was studied in 143 patients [117 females, median age 11 (1.3 to 69)] with AIH-1 (n = 125) and AIH-2 (n = 28). HLA typing and tumor necrosis factor a gene promoter and exon 1 cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms were determined by polymerase chain reaction-based techni- ques. Results: The frequency of CAID was similar in patients with AIH-1 (14%) and AIH-2 (18%), but their nature was shown to vary. Arthritis was seen in half of the patients (n = 8) with CAID and AIH-1 and in none of those with AIH-2. Subjects with AIH-1 and CAID were shown to be older [24 (1.3 to 61) vs. 11 (1.3 to 69) y, P = 0.02] and to have more often circulating antinuclear antibody (76% vs. 40%, P = 0.008) and less frequently antiactin antibodies (33% vs. 75%, P = 0.008) when compared with their counterparts without CAID. No particular HLA-DR and DQ alleles, as well as tumor necrosis factor a and CTLA-4 genotypes, were associated with CAID. Conclusions: The nature, but not the frequency, of CAID was shown to vary in AIH-1 and AIH-2. In subjects with AIH-1, CAID was linked to older subjects and to the presence of antinuclear antibody. No predisposition to CAID was asso- ciated to HLA-DRB1*04 or DDB4*01 alleles. The observed lower frequency of CAID could be attributed to the lower age of disease onset in Brazilians and to differences in HLA-encoded susceptibility to AIH-1 observed in South America. Key Words: autoimmune hepatitis, autoimmune diseases, autoantibodies, HLA antigens, CTLA-4, TNF-a (J Clin Gastroenterol 2008;42:300–305) A utoimmune hepatitis (AIH) is a chronic liver disorder of unknown cause that leads to cirrhosis and liver failure when untreated. 1–3 The disease usually affects females and is characterized by the presence of circulating autoantibodies and by severe interface hepatitis on liver biopsy. The disease is classified into at least 2 distinct types according to the nature of autoantibodies. 1,4 The presence of anti-smooth muscle antibody with F-actin specificity and/or antinuclear antibody (ANA) defines AIH type 1 (AIH-1), whereas, reactivity for antiliver kidney micro- some type 1 (anti-LKM1) and/or antiliver cytosol type 1 (anti-LC1) characterizes AIH type 2 (AIH-2). Susceptibility to AIH is linked to distinct HLA- DRB1 alleles in different populations. 5,6 In this respect, AIH-1 has been associated with DRB1*0301 and DRB1*0401 in United Kingdom and North America, 6,7 HLA-DRB1*0404 in Mexico, 8 HLA-DRB1*0405 in Argentina, 9 China, 10 and Japan, 11 and HLA- DRB1*1301 in Brazil 12,13 and Argentina. 9 On the other hand, predisposition to AIH-2 has been linked to either HLA-DRB1*0701 or DQB1*0201. 12,14,15 Type 1 AIH has been additionally related to tumor necrosis factor a (TNFA) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene polymorphisms in some 16,17 but not in all 18,19 reports. Extrahepatic immune-mediated or autoimmune disorders, currently designated as concurrent autoim- mune disorders (CAIDs), were shown to occur in around 22% to 46% of the patients with AIH-1 8,20–23 and in 20% to 34% of the subjects with AIH-2. 20,24 In those subjects Copyright r 2008 by Lippincott Williams & Wilkins Received for Publication August 24, 2006; accepted November 1, 2006. From the Portuguese Hospital of Salvador, Bahia, Department of Gastroenterology, Children’s Institute, Liver Unit, Laboratory of Immunology, Heart Institute, University of Sa˜o Paulo School of Medicine, Chemistry Institute, University of Sa˜o Paulo, Sa˜o Paulo, Brazil. The authors declare no conflict of interest. The Research Council of Brazil and the Alves de Queiroz Family Research Fund for financial support. Reprints: Paulo Lisboa Bittencourt, MD, PhD, Rua Clementino Fraga 220, apto 1901, Ondina, Salvador, BA, Brasil, CEP 40170050 (e-mail: plbbr@uol.com.br). ORIGINAL ARTICLE 300 J Clin Gastroenterol  Volume 42, Number 3, March 2008