Hepatitis: Bittencourt PL

Goldberg AC, Bittencourt PL, Oliveira LC, Ramasawmy R, Marin ML, Palacios SA, Kalil J, Porta G. · Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil. · Scand J Immunol. · Pubmed #17635798 No free full text.

Abstract: Autoimmune hepatitis is an immune cell-mediated chronic liver disease of unknown cause that leads, when untreated, to cirrhosis and liver failure. Importantly, this disease affects not only adults but children as well. Genetic susceptibility is clearly important and the major susceptibility factor identified up to now is the HLA-DRB1 locus, but other genes may play a role as well. HLA-DRB1 alleles present in South American patients differ from those found in patients in other parts of the world. In addition, we have recently identified two chromosomal regions where additional susceptibility factors may be found in Brazilian patients, namely, the class III MHC region and the 5q31 region where the IL-4 and IL-13 genes are located. This review discusses the current knowledge of the pathogenesis of this autoimmune disease occurring in the setting of an immune-privileged organ, the liver, and compares the data on gene polymorphisms studied in Brazil and in other parts of the world.

Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW, Anonymous00035. · Department of Medicine, University Medical Centre Hamburg Eppendorf, Germany. · Hepatology. · Pubmed #18537184 No free full text.

Abstract: Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff > or =6) and 81% sensitivity and 99% specificity (cutoff > or =7) in the validation set. CONCLUSION: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher.

Bittencourt PL, Farias AQ, Porta G, Cançado EL, Miura I, Pugliese R, Kalil J, Goldberg AC, Carrilho FJ. · Portuguese Hospital of Salvador, Bahia, Brazil. · J Clin Gastroenterol. · Pubmed #18223493 No free full text.

Abstract: 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 alpha gene promoter and exon 1 cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms were determined by polymerase chain reaction-based techniques. 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 alpha 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 associated 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.

Bittencourt PL, Silva Rde C, Pessoa MG, Marroni CA, Anonymous00097. · Hospital Português, Salvador, BA. · Arq Gastroenterol. · Pubmed #17639189 links to  free full text

Abstract: BACKGROUND: Recurrence of hepatitis C after orthotopic liver transplantation is one of the major clinical challenges faced by the liver transplantation community. Treatment of hepatitis C recurrence with peguilated interferon and ribavirin has been associated with sustained virological response in 21% to 45% of treated patients. Furthermore, it has been shown to halt disease progression after orthotopic liver transplantation and to prevent graft failure and the need for retransplantation at least in those subjects with sustained virological response. However, treatment of hepatitis C recurrence after orthotopic liver transplantation in Brazil was not recommended according to ministerial Law number 863. AIMS: To assess the management and treatment options of hepatitis C recurrence after orthotopic liver transplantation in different liver transplantation centers in Brazil. METHODS: Inquiries were sent to active liver transplantation centers throughout the country. RESULTS: Nineteen centers accepted to participate and answered the questionnaire. Altogether they transplanted around 2,800 subjects, half of them with hepatitis C. Immunosuppressive regimen is comprised by tacrolimus and short-term prednisone in 53% of the centers. One third of them claim to use different schedules for hepatitis C patients. Protocol biopsies for diagnosis of recurrence are employed by 13 centers. Different histological criteria are used for the either diagnosis or decision for treatment in most of the centers. Approximately half of them (42%) indicate treatment in subjects with less severe stages of fibrosis (less than F2 according to METAVIR classification). All centers are referring patients for treatment with peguilated interferon and ribavirin, for 1 year, for 6 months or 1 year based on the genotype, or a la carte based on response, respectively, in 32%, 21% and 47% of the centers. Most of them (84%) do not stop treatment in early non-responders at the 12th week. CONCLUSIONS: Even in the absence of national guidelines and federal support, most of the liver transplantation centers in Brazil are treating patients with hepatitis C recurrence after orthotopic liver transplantation.

Farias AQ, Gonçalves LL, Bittencourt PL, De Melo ES, Abrantes-Lemos CP, Porta G, Nakhle MC, Carrilho FJ, Cancado EL. · Department of Gastroenterology, Institute of Tropical Medicine, Division of Pathology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil. · J Gastroenterol Hepatol. · Pubmed #16704541 No free full text.

Abstract: BACKGROUND AND AIMS: According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH. METHODS: Eighteen patients with AMA-AIH were enrolled and compared with 206 classical AIH and 85 primary biliary cirrhosis (PBC) controls. Human leukocyte antigen (HLA) class II alleles were determined by polymerase chain reaction (PCR) amplification with sequence-specific primers, and biopsies were blindly reevaluated. RESULTS: The patients with AMA-AIH were, on average, older than patients with classical AIH and had an hepatocellular pattern of elevated liver enzymes, hypergammaglobulinemia and lower levels of cholesterol, when compared with PBC controls. There were no histological signs of PBC or overlapping forms in any AMA-AIH biopsies. The majority of patients with AMA-AIH carried HLA antigens associated with classical AIH (DRB1*03, n = 5; DRB1*04, n = 7, and DRB1*13, n = 6). Pretreatment scores classified all AMA-AIH patients with probable (n = 17) or improbable (n = 1) AIH. After treatment, only 28% of AMA-AIH patients reached scores for definite diagnosis, compared with 90.1% of AIH-1 and 96.4 AIH-2. In the AMA-AIH group, only patients who relapsed after immunosuppressive drug withdrawal could be classified with definite AIH. CONCLUSIONS: AMA-AIH shares common features with classical AIH. The diagnosis of AMA-AIH may be swayed by the IAIHG criteria, rendering questionable the applicability of the revised scoring system to this variant form of AIH.

Bittencourt PL, Palácios SA, Cançado EL, Porta G, Carrilho FJ, Laudanna AA, Kalil J, Goldberg AC. · University of São Paulo School of Medicine, São Paulo, Brazil. · Am J Gastroenterol. · Pubmed #12873588 No free full text.

Abstract: OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) has been linked to different HLA-DR antigens in distinct populations. Recently, an A-G polymorphism in exon 1 of the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene was associated with predisposition to AIH type 1 (AIH-1) in white individuals in North America. This polymorphism has been associated with several other autoimmune diseases, presumably because of its effect in the expression of CTLA-4, an adhesion molecule that downregulates peripheral T cell responses. The aims of this study were to assess the frequency of CTLA-4 genotypes in Brazilian patients with AIH-1 and AIH type 2 (AIH-1), as well as to investigate the influence of these genotypes in disease expression. METHODS: Determination of CTLA-4 genotypes was carried out in 106 patients with AIH-1, 26 subjects with AIH-2, and 67 healthy control subjects by polymerase chain reaction (PCR)-based techniques. RESULTS: No difference in the distribution of CTLA-4 genotypes was observed in subjects with AIH-1 and AIH-2 as compared to healthy controls. Patients with AIH-1 and AIH-2 with the GG genotype exhibited lower gamma-globulin and ALT levels, respectively. CONCLUSIONS: Susceptibility to AIH-1 and AIH-2 in Brazilian patients is not influenced by exon 1 CTLA-4 gene polymorphisms at position 49.

Czaja AJ, Souto EO, Bittencourt PL, Cancado EL, Porta G, Goldberg AC, Donaldson PT. · Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA. · J Hepatol. · Pubmed #12175624 No free full text.

Abstract: BACKGROUND/AIMS: Type 1 autoimmune hepatitis has a strong genetic predisposition that varies among different ethnic groups. Our aims were to determine if the clinical manifestations differed between patients with type 1 autoimmune hepatitis from Brazil and the United States and if classical disease could be associated with region-specific susceptibility markers. METHODS: The clinical manifestations and genetic risk factors of 161 patients from the United States were compared to those of 115 patients from Brazil. RESULTS: The patients from Brazil had earlier disease onset, lower frequency of concurrent immune diseases, higher serum levels of aspartate aminotransferase and gamma-globulin, greater occurrence of smooth muscle antibodies, and lower frequency of antinuclear antibodies than the patients from the United States. Human leukocyte antigen (HLA) DR13 and DRB1*1301 occurred more commonly in the Brazilian patients and HLA DR4 less often. Normal subjects from each country had similar frequencies of HLA DR13 and DR3. CONCLUSIONS: Type 1 autoimmune hepatitis in Brazil has different features at presentation than the disease in Caucasoid patients from the United States, and it is associated with HLA DR13. Background populations in each country have similar frequencies of HLA DR13 and DR3, and region-specific etiologic factors may determine the HLA association.

da Silva ME, Porta G, Goldberg AC, Bittencourt PL, Fukui RT, Correia MR, Miura IK, Pugliese RS, Baggio VL, Cançado EL, Kalil J, Santos RF, Rochal DM, Wajchenberg BL, Ursich MJ, Rosenbloom AL, Golberg AC. · Laboratory of Medical Investigation, São Paulo Medical School, Brazil. · J Pediatr Endocrinol Metab. · Pubmed #12099394 No free full text.

Abstract: OBJECTIVE: To determine the frequency and significance of diabetes mellitus (DM)-related autoantibodies in children with autoimmune hepatitis (AIH). RESEARCH DESIGN AND METHODS: Anti-islet cell antibodies (ICA), insulin autoantibodies (IAA), and anti-glutamic acid decarboxylase (GAD65) antibodies were assessed in 28 children (25 female) with AIH before and after 3-9 years of therapy with azathioprine and prednisone. RESULTS: There was biochemical and clinical remission of AIH activity in 76% of the children after 1 year of immunosuppressive therapy. Positive ICA and IAA were found in 60.7% and 18.5% of the patients, decreasing to 38.5% and 12% after 3-9 years of therapy. Anti-GAD autoantibodies were present in only one patient who had Graves' disease, high ICA titer, and developed type 1 DM after 3 years. After 3-9 years of follow up, all had normal fasting glycemia, glycosylated hemoglobin (HbA1c), and, with a single exception, normal responses to oral glucose tolerance testing. No increase in the frequencies of HLA antigens was observed in ICA- and IAA-positive patients compared to antibody-negative patients or a control population. The majority of the patients with HLA-DRB1*03 or DRB1*04, however, were positive for ICA (7/10), and three of them had IAA. The frequency of high risk HLA DQB1*0302 or DQB1*02 alleles was low and similar to control frequencies, indicating low-risk for DM despite the presence of DM-related autoimmunity markers. CONCLUSIONS: AIH in childhood is associated with high frequency of ICA and IAA, with less than expected rates of progression to DM. Immunosuppression reduced ICA and IAA frequency and titers.

Couto CA, Bittencourt PL, Farias AQ, Lallee MP, Cançado EL, Massarollo PC, Mies S. · Liver Unit, School of Medicine, University of São Paulo, Brazil. · Rev Inst Med Trop Sao Paulo. · Pubmed #11781604 links to  free full text

Abstract: BACKGROUND: Use of polyclonal anti-hepatitis B surface antigen immunoglobulin (HBIg) has been shown to reduce hepatitis B virus (HBV) recurrence after liver transplantation (LT) and to decrease the frequency of acute cellular rejection (ACR). However, the protective role of HBIg against ACR remains controversial, since HBV infection has been also associated with a lower incidence of ACR. AIM: To assess the relationship between HBIg immunoprophylaxis and the incidence of rejection after LT. METHODS: 260 patients (158 males, 43 +/- 14 years old) submitted to LT were retrospectively evaluated and divided into three groups, according to the presence of HBsAg and the use of HBIg. Group I was comprised of HBsAg-positive patients (n = 12) that received HBIg for more than 6 months. Group II was comprised of HBsAg-positive patients that historically have not received HBIg or have been treated irregularly for less than 3 months (n = 10). Group III was composed of 238 HBsAg-negative subjects that have not received HBIg. RESULTS: HBIg-treated patients (group I) had significantly less ACR episodes, when compared to group II and III. No differences between groups II and III were observed. CONCLUSIONS: Long-term HBIg administration contributes independently to reduce the number of ACR episodes after LT.

Bittencourt PL, Palácios SA, Cançado EL, Porta G, Drigo S, Carrilho FJ, Laudanna AA, Kalil J, Goldberg AC. · Department of Gastroenterology, University of São Paulo School of Medicine, Brazil. · J Hepatol. · Pubmed #11495038 No free full text.

Abstract: BACKGROUND/AIMS: Susceptibility to autoimmune hepatitis (AIH) has been linked to different HLA-DR antigens. Recently, AIH type 1 was associated with polymorphisms in the tumor necrosis factor alpha gene promoter (TNFA) at position -308. In this respect, the frequency of the TNFA*2 allele, in linkage disequilibrium with HLA-DRB1*0301, was shown to be significantly increased in whites with AIH type 1. The aim of this study was to assess the role of TNFA alleles in conferring susceptibility to AIH, studying a population where the disease is not primarily associated with HLA-DRB1*03. METHODS: The determination of HLA-DRB1 and TNFA alleles was performed in 92 patients with AIH type 1, 29 subjects with AIH type 2 and 83 healthy controls by polymerase chain reaction-based techniques. RESULTS: The distribution of TNFA alleles was similar in patients with AIH types 1 and 2, when compared with controls. In addition, the TNFA*2 allele was identified in patients carrying HLA-DR antigens other than HLA-DRB1*03. Interestingly, higher gammaglobulin levels were observed in TNFA*2 positive patients. CONCLUSIONS: Our data indicate that susceptibility to AIH remains primarily linked to the HLA-DRB1 locus, and suggest that the association of AIH with TNFA*2 previously observed in whites might be secondary to a linkage disequilibrium with HLA-DRB1*0301.

Goldberg AC, Bittencourt PL, Mougin B, Cançado EL, Porta G, Carrilho F, Kalil J. · Heart Institute, Faculty of Medicine, São Paulo University, Brazil. · Hum Immunol. · Pubmed #11182227 No free full text.

Abstract: Susceptibility to autoimmune hepatitis type I (AIH-1) has been associated with HLA-DR3, DR52, and DR4 antigens in Caucasian and Oriental patients. However, in Brazil, disease susceptibility is primarily linked to DR13 and DR52. In this highly admixed population, we find different DR13-associated haplotypes, presenting a unique opportunity to discriminate relevant genes within a tightly linked genomic region. To identify the primary susceptibility locus, we sequenced DR13 alleles of 39 patients with AIH-1 and 22 controls. Patients were almost exclusively DRB1*1301, but half of controls typed DRB1*1302. HLA-DQ haplotypes were varied. Oligotyping of DRB3 locus of all patients and also within the HLA-DR13 positive group showed an allele distribution comparable to controls, confirming that the stronger association lies in the DRB1 locus. On the other hand, if DRB1*1301 is the major susceptibility factor in our sample, the only amino acid different from DRB1*1302 in position 86, corresponding to pocket 1 in the peptide-presenting groove, may be important. We propose that peptide presentation leading to pathogenesis of AIH-1 may be quite stringent, but will also be affected by other strong genetic or environmental susceptibility factors, which would explain the various HLA molecules associated to the disease in the different populations.

Bittencourt PL, Goldberg AC, Cançado EL, Porta G, Carrilho FJ, Farias AQ, Palacios SA, Chiarella JM, Abrantes-Lemos CP, Baggio VL, Laudanna AA, Kalil J. · Department of Gastroenterology, University of São Paulo School of Medicine, SP, Brazil. · Am J Gastroenterol. · Pubmed #10406258 No free full text.

Abstract: OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and 2 with HLA-DR and DQ loci. METHODS: We performed HLA-DRB and -DQB1 typing by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) in 139 AIH patients. Most had AIH type 1 associated with circulating anti-smooth muscle antibody with F-actin specificity or antinuclear antibody. Twenty-eight patients presented AIH type 2 with anti-liver/kidney microsome type 1 or anti-liver cytosol type 1 antibodies. RESULTS: We observed a significant increase of DRB1*13 (70% vs 26% of controls, p < 0.00001) and DRB3 (93% vs 69% of controls, p < 0.00001) in AIH type 1 patients. Analysis of patients without DRB1*13 disclosed a secondary association with DRB1*03 (70% vs 30% of controls, p = 0.0001) and either the DRB1*13 or the DRB1*03 alleles were present in the majority of these patients (91% vs 48% of controls, p = 0.001). Comparison of DRB1*13- and DRB1*03-positive subjects revealed that the former alleles conferred susceptibility to younger patients with AIH type 1. DQB1 typing showed a significant increase in DQB1*06 (68% vs 41% of controls, p = 0.00007) in strong linkage disequilibrium with DRB1*13, and a decrease in DQB1*0301 (8% vs 47% of controls, p(c) = 0.0003). On the other hand, HLA typing of patients with AIH type 2 disclosed a significant increase in the DRB1*07 (68% vs 20% of controls, p(c) < 0.00014), DRB4 (79% vs 43% of controls, p(c) = 0.004), and DQB1*02 (86% vs 42%, p = 0.00002) alleles. After exclusion of DRB1*07, a secondary association with HLA-DRB1*03 was further observed in these patients (78% vs 30%, p = 0.007) and most of them had either DRB1*07 or DRB1*03 (93% vs 44% of controls, p(c) < 0.0001). CONCLUSIONS: Our data indicate that predisposition to AIH types 1 and 2 is associated, respectively, with the DRB1*13 or DRB1*03 and DRB1*07 or DRB1*03 alleles, and suggest that protection against type 1 disease may be conferred by DQB1*0301. In addition, the cluster of DRB1*13 in children with AIH type 1 also supports the concept that different HLA alleles might influence the onset of the disease.