Clinical characteristics of patients with autoimmune hepatitis seropositive for anticentromere antibody

Aim: Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA‐AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other‐AIH). Methods: AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp‐2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score. Results: Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA‐AIH and other‐AIH groups. The frequency of concurrent autoimmune diseases in ACA‐AIH was significantly higher than that in other‐AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other‐AIH (2176 ± 641 vs 3013 ± 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)‐DR4 between the groups. Conclusion: These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.     

Risk factors for cancer in patients with primary biliary cholangitis and autoimmune hepatitis and primary biliary cholangitis overlap syndrome

Introduction and objectivesPrimary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC.Materials and methodsThe Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer.ResultsAmong the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk.ConclusionsThe prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.     

DR human leukocyte antigens and disease severity in chronic hepatitis C

Background/Aims: Immune mechanisms may modulate disease severity in chronic hepatitis C and the DR human leukocyte antigens may effect these mechanisms. Our aims were to evaluate the association between the DR antigens and disease severity at presentation and to seek correlation between these antigens, disease severity and autoantibodies in this condition.Methods: Sixty-four patients were assessed prospectively and classified as having mild, moderate and severe disease by clinical, laboratory and histologic criteria. Fourteen DR antigens were determined by restriction fragment length polymorphism or polymerase chain reaction-sequence specific primers. Eighty normal subjects were typed in a similar fashion.Results: Patients with mild (16), moderate (32) and severe (16) disease at presentation were indistinguishable from each other and from normal subjects by the frequencies of each DR antigen. Subjects of patients with different laboratory and histologic findings had DR frequencies comparable to those without these findings and to those of normal subjects. Patients with autoantibodies and/or concurrent immunologic diseases had mild (19% versus 32%, p=0.4), moderate (50% versus 50%) and severe (31% versus 18%, p=0.4) disease as commonly as other patients. The frequencies of the DR antigens were similar in each category of disease severity. Patients with autoimmune features differed from patients without these features (3% versus 32%, p=0.002) and normal subjects (3% versus 25%, p=0.003) by having a lower frequency of HLA DR1.Conclusions: The DR antigens are not associated with any index of disease severity at presentation. Immunologic manifestations do not identify patients with a different disease severity or a distinctive genetic predisposition for disease activity. The presence of DR 1 is associated with a lower frequency of immune manifestations.     

Analysis of the humoral and cellular response after the third COVID-19 vaccination in patients with autoimmune hepatitis

Background & aims

To explore the humoral and T-cell response to the third COVID-19 vaccination in autoimmune hepatitis (AIH).

Methods

Anti-SARS-CoV-2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age- and sex-matched controls >7 days (median 35) after the first COVID-19 booster vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of patients.

Results

Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p < .001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p = .004) or steroids (N = 27, 7326 AU/ml, p = .020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p < .001). AIH patients had a high risk of failing to develop a spike-specific T-cell response (15/34 (44%) vs. 2/16 (12%), p = .05) and showed overall lower frequencies of spike-specific CD4 + T cells (median: 0.074% vs 0.283; p = .01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148-fold increase.

Conclusion

A third COVID-19 vaccination efficiently boosts antibody levels and T-cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses.     

Clinical features of type 1 autoimmune hepatitis in adolescence and early adulthood

Aim:  The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood.
Methods:  Fifteen patients aged ≤ 30 years (group 1) were compared with 79 patients aged between 40 years and 50 years (group 2).
Results:  At presentation, patients aged ≤ 30 years accounted for 9% of the study population. Although frequencies of extrahepatic concurrent autoimmune diseases were similar between groups 1 and 2, a tendency toward a lower frequency of concurrent autoimmune thyroiditis was shown in group 1 (0 vs. 18%, P  = 0.08). Group 1 had a lower frequency of human leukocyte antigen DR4 (27 vs. 78%, P  = 0.002), and histological acute hepatitis was shown more frequently in group 1 (27 vs. 4%, P  = 0.002). However, there were no differences in frequencies of the normalization of serum transaminase levels after the introduction of corticosteroid treatment or relapse after the normalization of serum transaminase levels between the two groups.
Conclusions:  Japanese type 1 AIH patients in adolescence and early adulthood respond well to corticosteroid treatment. However, they may frequently show atypical features, and the diagnosis of type 1 AIH in adolescence and early adulthood may be difficult and should be made carefully.     

Clinical aspects and prognosis of patients with inflammatory bowel disease associated with autoimmune liver diseases

Background and aimsInflammatory bowel diseases (IBD) are chronic conditions that may be accompanied by autoimmune liver disease (AILD), most commonly primary sclerosing cholangitis (PSC). The objective of this study was to evaluate the behaviour of patients with IBD associated with AILD and compare a PSC group with a non-PSC group.MethodsMedical records of patients with IBD associated with PSC, autoimmune cholangitis, primary biliary cholangitis, small-duct PSC, autoimmune hepatitis (AIH) and overlapping syndromes were assessed.ResultsFifty-four patients were included: 48 (88.9%) had ulcerative colitis and six (11.1%) had Crohn's disease; 35 (64.8%) had PSC and 19 (35.2%) did not have PSC. There was no difference in outcomes (surgical treatment for IBD, liver transplantation or death) between the groups. Time since the diagnosis of IBD was associated with surgical treatment of IBD (p = 0.041; OR: 1.139, 95% CI: 1.006–1.255). Time since the diagnosis of AILD (p = 0.003; OR: 1.259, 95% CI: 1.1–1.396), as well as portal hypertension at diagnosis (p = 0.014; OR: 18.22, 95% CI: 1.815–182.96), were associated with liver transplantation. In addition, previous diagnosis of AIH was associated with de novo IBD (p = 0.012; OR: 7.1, 95% CI: 1.215–42.43).ConclusionBoth groups had similar disease behaviour. A longer time since the diagnosis of IBD increased the risk for surgical treatment (13.9%/year). A 25.9%/year increase in liver transplantation was observed after the diagnosis of AILD, which was increased 18.22 times by the presence of portal hypertension. In addition, the diagnosis of AIH was associated with an increase in the number of diagnoses of de novo IBD (7.1).     

Liver transplantation for autoimmune hepatitis in Peru: outcomes and recurrence

Background. Liver transplantation is the only therapy for end-stage liver disease. Cirrhosis secondary to autoimmune hepatitis (AIH) is an indication in 4-6% of adult transplants. Aims. To describe the outcomes and recurrence of AIH in liver transplant patients.Material and methods. Twenty patients were retrospectively studied. Results. The female/male ratio was 3:1, the median age was 36.7 years (range, 16 to 39 years), and the median MELD score was 18.5. According to serological analysis, 19 patients were AIH type 1 and one patient was AIH type 2. AIH was associated with human leukocyte antigen (HLA) DR13+ and DR4+. The overall 5-year patient and graft survival rates were 94 and 85%, respectively. Three (15.7%) cases of recurrent AIH were diagnosed based on histological evidence. Clinical and histological features of acute and chronic rejection were present in four (20%) and three (16.6%) patients, respectively. Conclusion. AIH frequently affected young women, was the most frequent indication for liver transplantation. Rejection and recurrence were commonly associated with AIH, but did not affect patient survival. No significant relationship between HLA-DR type and recurrence was found. Rapid progression to cirrhosis should be considered in severe recurrences.     

Relationship between autoimmune liver disease and autoimmune thyroid disease: a cross-sectional study

Abstract

Background: A high prevalence of autoimmune thyroid disease (AITD) has been observed in patients with autoimmune liver disease (AILD); however, data on the clinical relationship between AILD and AITD remain scant. We aimed to evaluate the relationship between AILD and AITD.

Methods: We performed a retrospective study using medical records from 324 patients with AILD, 113 of whom had concurrent AITD.

Results: Patients with autoimmune hepatitis (AIH) were more likely to develop AITD (45.8%), followed by autoimmune hepatitis-primary biliary cholangitis overlap syndrome (AIH-PBC OS) (39.5%) and PBC (22.6%). Patients with concurrent AILD and AITD showed higher levels of immunoglobulin G (IgG) (21.5?g/L vs 16.3?g/L, p?<?.0001) and gamma globulin (γ-globulin) (27.1% vs 21.9%, p?<?.0001). IgG was positively correlated with thyroid antibodies [thymoglobulin antibody (TGAb) and thyroperoxidase antibody (TPOAb)] (r?=?0.396, 0.322; p?<?.0001, p?=?.002, respectively). TPOAb positivity was highest in PBC patients with concurrent AITD (83.9%). Patients with concurrent PBC and AITD were significantly older than those with PBC alone (p?=?.0004). Patients with concurrent AIH and AITD had a higher homogenous nuclear pattern of antinuclear antibody positivity compared to those with AIH alone (p?=?.019). Thyroid dysfunction in AILD patients with concurrent AITD was principally characterized by Hashimoto’s thyroiditis (65.5%), and diffuse lesions were mainly found by thyroid ultrasound (53.1%).

Conclusions: The high incidence of AILD concomitant with AITD, the higher levels of serum IgG and γ-globulin, and the strong correlation between thyroid antibodies and IgG suggest that close screening for AITD and accurate physical examinations should be performed for all patients with AILD.     

Association of HLA-DR14 with the Treatment Response in Japanese Patients with Autoimmune Hepatitis

Background

Influence of human lymphocyte antigen (HLA) on the therapeutic response in autoimmune hepatitis (AIH) is not known.

Aims

To evaluate if HLA-DR types influence biological and histological responses to corticosteroids in patients with AIH.

Methods

During 28 years from 1979 through 2007, 48 patients with definite diagnosis of AIH received long-term corticosteroid therapy (median 9 years [range: 5–28 years]) in a single Japanese center. They were followed for transaminase levels and received liver biopsy before and after the treatment.

Results

DR4 was detected in 32 and DR14 in 11 patients; seven possessed both DR4 and DR14. DR4 was more frequent in AIH patients than in the general population (67% vs. 22%), while DR14 was comparably frequent between them (23% vs. 17%). Overall, biochemical response was achieved in 43 (90%) of the 48 patients. The sustained biochemical response to a maintenance prednisolone dose < 10 mg was gained more frequently in the patients with than without DR14 (10/11 [91%] vs. 10/37 [27%], P < 0.001). Marked histological improvement with a decrease in histology activity index (HAI) score by > 2 points was achieved in 31 of the 32 (97%) biochemical responders. Histological aggravation with an increase in HAI score occurred in 4 of the 16 (25%) patients without biochemical response (non-responders and relapsers combined), but in none of the 32 responders.

Conclusion

Long-term immunosuppressive treatment can improve the outcome of Japanese patients with AIH, and DR14 is associated with excellent biochemical response.     

Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with type 1 autoimmune hepatitis in Japanese.

Aim: Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Although the HLA DR4 allele is associated with type 1 AIH in Japanese, the exact genetic etiology of AIH remains undefined. The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed by T-cells that acts largely as a negative regulator of T-cell responses, and polymorphisms of CTLA4 have been reported to be associated with susceptibility to various autoimmune diseases. Therefore, we sought to clarify whether CTLA4 single-nucleotide polymorphisms are associated with disease susceptibility in Japanese patients with type 1 AIH. Methods: We genotyped 76 patients with AIH and 100 ethically matched controls for allelic determinants using TaqMan genotyping assays at four polymorphism sites: -1722 and -318 in the promoter; +49 in exon 1 and +6230 in the 3' untranslated region. Results: We observed no difference in the distribution of the alleles, genotypes, or haplotypes between patients and controls. Compared with -1722 C/C patients, -1722 T/T patients were younger (56 vs. 63 years; P = 0.01) and had significantly lower serum levels of aspartate aminotransferase (313 vs. 763 IU/L; P = 0.031) and bilirubin (1.1 vs. 8.6 mg/dL; P = 0.027). Analysis of allelic frequencies revealed no significant difference between patients with and without the HLA DR4 allele. Conclusion: These data suggest that the CTLA4 polymorphism is not associated with susceptibility to type 1 AIH in the Japanese population.     

Type 1 autoimmune hepatitis in Turkish patients: absence of association with HLA B8

BACKGROUND: There is very little information about autoimmune hepatitis (AIH) in populations other than of white European or Japanese descent. GOALS: To investigate the presenting features, immunogenetic background, and response to standard immunosuppressive therapy in native Turkish patients with AIH. METHODS: Retrospective analysis of all patients referred between 1994 and 2000 to our hepatology clinic in Ankara who fulfilled international criteria for definite or probable type 1 or type 2 AIH. RESULTS: Seventeen patients (15 female; median age, 31 years; range, 13-56 years) were identified. All had type 1 AIH. Clinical and laboratory features were broadly similar to those reported for white or Japanese patients. Five had the HLA DR3 allotype and 10 had DR4; however, in contrast to white and Japanese patients, DR4 was not associated with an older age at onset. Importantly, no patient had the B8 allotype (vs. 10.9% in 110 healthy Turkish subjects). Thus, none had the classic A1-B8-DR3 autoimmune haplotype: a major distinction from white individuals. CONCLUSIONS: There appears to be genetic differences in type 1 AIH between Turkish and other populations. Genotyping of Turkish patients to identify alleles that may confer susceptibility or resistance to AIH may progress understanding of the genetic basis of the disease.     

Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation

Background/aims: Celiac disease (CD) is associated with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. We investigated the following: (i) the prevalence of tissue transglutaminase antibodies (tTGAs) and endomysial antibodies (EMAs) in end‐stage autoimmune liver disease (ESALD), (ii) the correlation among auto‐antibodies and the human leucocyte antigen (HLA) haplotype, and (iii) the effect of liver transplantation on antibody kinetics. Methods: Pretransplantation sera from 488 patients (310 with ESALD, and 178 with non‐autoimmune disease) were tested for tTGAs. Positive samples were also tested for EMAs, and retested 6–12 and ≥24 months post‐transplantation. Results were correlated with the HLA type of the recipient. Results: Serological evidence of CD was found in 3% (ESALD) vs. 0.6% (non‐autoimmune) of the patients (five‐fold increased risk in ESALD). The prevalence of tTGAs (14.2 vs. 5.4%, P=0.0001) and EMAs (4.3 vs. 0.78%, P=0.01) was significantly higher in patients with the HLA‐DQ2 or HLA‐DQ8 haplotypes. tTGAs and EMAs normalized in 94 and 100%, respectively, without gluten exclusion post‐transplantation. Post‐transplantation, of the five patients with symptoms of ‘classical’ CD, three improved. Intestinal lymphoma was diagnosed in another two cases with clinically ‘silent’ CD. Conclusions: Patients with ESALD, especially those who are HLA‐DQ2 or HLA‐DQ8 positive had a high prevalence of CD‐associated antibodies. Both tTGAs and EMAs decreased post‐transplantation without gluten withdrawal. Immunosuppression may improve symptoms of CD, but might not prevent progression to intestinal lymphoma.     

Corticosteroid-Responsive Cryptogenic Chronic Hepatitis: Evidence for Seronegative Autoimmune Hepatitis

Cryptogenic chronic hepatitis (CCH) is diagnosed in patients with persistently elevated aminotransferase levels of unknown etiology. The workup of CCH patients must include a liver biopsy in order to exclude the largely unrecognized diagnosis of seronegative autoimmune hepatitis (SAIH). Patients with SAIH have demographic, biochemical, and histologic features of autoimmune hepatitis (AIH) and may be treated effectively with corticosteroids. Recognition and treatment of SAIH are necessary to prevent progression to end-stage liver disease. We performed a retrospective review of a database of 3507 patients seen at our institution over a 5-year period. Thirty patients with conventional AIH and an additional six patients with SAIH were identified. The two groups were similar with respect to mean age, gender, and baseline biochemistries. Of the 20 AIH patients who had pretreatment liver biopsies, 85% had moderate to severe interface hepatitis, compared to 83.3% of patients with SAIH. In the SAIH group, 83.3% had advanced fibrosis (stage 3 or 4), versus 40% in the conventional AIH group (P = 0.16). All patients were treated with corticosteroids followed by azathioprine. The mean time to remission (normal ALT) was similar in both groups, 2.6 vs. 2.7 months. Within 3 months, 88.9% of AIH patients and 66.7% of SAIH patients were in remission. We conclude that a trial of corticosteroids is a reasonable therapeutic measure in patients with chronic hepatitis that has features of AIH despite negative autoantibody markers. In most patients, clinical remission will be seen within 3 months, possibly avoiding progression to end-stage liver disease.     

Significance of human leukocyte antigens DR3 and DR4 in chronic viral hepatitis

Immune mechanisms have been implicated in chronic viral hepatitis, and these may be influenced by genetic factors. To determine if disease severity in chronic viral hepatitis is associated with the human leukocyte antigens DR3 and/or DR4, 109 patients were evaluated prospectively. The frequencies of DR3 and DR4 in these patients were compared to those in 80 normal subjects. Patients with DR3 and/or DR4 had the same occurrence of severe disease as patients with other DR antigens (21% versus 30%,P=0.3). Patients with DR3, however, had higher serum gamma globulin and immunoglobulin G levels than patients with DR4 and a greater frequency of severe disease (36% vs 12%,P=0.046). Patients with DR4 had concurrent immunologic diseases more commonly than patients with DR3 (44% vs 9%,P=0.005) and patients with other DR antigens (44% vs 9%,P=0.0002). Patients with DR4 but not DR3 had severe disease less frequently than other patients (9% vs 31%,P=0.02). The frequencies of DR3 in patients with severe disease (37% vs 18%,P=0.06) and DR4 in patients without severe disease (44% vs 30%,P=0.07) were different than those in normal subjects but not to a statistically significant level. We conclude that patients with DR3 and DR4 have different clinical and laboratory findings and disease severity. Patients with DR4 have milder disease than patients with other DR antigens. Disease severity, however, is not closely associated with DR3 or DR4.     

Immunogenetic susceptibility to diabetes mellitus in patients with liver disease

Background/Aim: Genetic, environmental, metabolic and infectious influences, such as hepatitis C virus (HCV) infection, are thought to impact on the development of diabetes in patients with liver disease. As specific human leucocyte antigen (HLA) alleles provide the major genetic risk factors for type 1 diabetes, our aim was to investigate whether HLA class I and II alleles constitute additional risk factors for diabetes in patients with liver disease. Methods: We evaluated two independent databases of 193 and 728 adult patients with chronic liver disease for the diagnosis of diabetes and the presence of specific HLA subtypes. Results: In each database, 24 and 19% of patients met criteria for diabetes. In the first database, specific class I and II alleles were observed more frequently in diabetics compared with non‐diabetics: Cw7 (50 vs. 32%, P=0.04), DR51 (17 vs. 3%P=0.003) and DQ6 (37 vs. 18%, P=0.02). In the second database, DQ6 was observed in 16% of diabetics vs. 8% of non‐diabetics (P=0.04). The DR2–DR51–DQ6 haplotype was higher in patients with diabetes in both databases (22 vs.7%, P=0.02 and 12 vs. 5%, P=0.02). In a subgroup analysis of patients with HCV infection, increased frequencies of Cw7, DR2/DR51, DQ6 and DR2–DR51–DQ6 were also observed to be higher in subjects with diabetes compared with those without diabetes. Conclusions: Patients with chronic liver disease, especially those with HCV infection, have an immunogenetic risk for diabetes characterized by the presence of Cw7, DR51, DQ6 and DR2–DR51–DQ6.     

HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis

BACKGROUND/AIMS: Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS: Frequencies of HLA class II alleles were compared between the 60 Caucasian children with type 2 AIH and 313 control subjects. The anti-LKM1 antibody reactivity directed against antigenic sites of CYP2D6 was analysed by ELISA. RESULTS: HLA-DQB1 *0201 allele was found to be the primary genetic determinant of susceptibility to type 2 AIH by conferring the highest odd-ratio (OR = 6.4). HLA-DRB1 *03 allele was significantly increased (P < 0.0001) among patients with both anti-LKM1 and anti-LC1 autoantibodies as well as in those with only anti-LC1(+) compared to those with anti-LKM1(+) alone. In contrast, HLA-DRB1 *07 allele was significantly associated (P < 0.0001) with anti-LKM1(+) alone compared to groups with both anti-LKM and anti-LC1 or with LC1+ alone. Children with the DRB1 *07 allele develop anti-LKM1 autoantibodies having a more restricted specificity (2 epitopes) than to those having HLA-DRB1 *03 allele (5 epitopes). CONCLUSIONS: The HLA-DR locus is involved in autoantibody expression, while the DQ locus appears to be a critical determinant for the development of type 2 AIH.     

Genetic distinctions between autoimmune hepatitis in Italy and North America

AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P= 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P= 0.01) and in controls (16% vs 34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P= 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.     

Evidence of a Genetic Basis for the Different Geographic Occurrences of Liver/Kidney Microsomal Antibody Type 1 in Hepatitis C

Antibodies to liver/kidney microsome type 1 occur in Italian patients with hepatitis C, but rarely develop in North American patients. Our goals were to compare the frequencies of the HLA markers associated with autoimmune expression in Italian and North American patients with chronic hepatitis C and to determine genetic bases for regional differences in antibody production. HLA B8, DR3, DR4, DR7, DR11, DR13, DQ2, and the B8-DR3-DQ2 haplotype were determined by microlymphocytotoxicity and polymerase chain reaction in 105 Italian patients (50 with microsomal antibodies), 100 North American patients (none with microsomal antibodies), and Italian and North American healthy control subjects. Italian patients with microsomal antibodies differed from North American patients without these antibodies by having a higher frequency of HLA DR7 (54% vs. 27%, P=0.002). HLA DR7 occurred more frequently in seropositive Italian patients than in seronegative counterparts (54% vs. 11% P < 0.0001), Italian healthy control subjects (54% vs. 29%, P=0.0009), and North American healthy control subjects (54% vs. 19%, P < 0.0001). The frequency of HLA DR7 was similar in North American patients and controls (27% vs. 19%, P=0.2), but it was lower than in Italian controls (19% vs. 29%, P=0.059). Seropositive Italian patients had a lower frequency of HLA DR11 than seronegative Italian patients and Italian controls (18% vs. 34%, P=0.07, and 18% vs. 35%, P=0.02, respectively). In contrast to seropositive Italian patients, North American patients had HLA DR4 (30% vs. 12%, P=0.02), HLA DR13 (29% vs. 10%, P=0.01), and the B8-DR3-DQ2 haplotype (23% vs. 6%, P=0.01) more often. Similarly, HLA DR4 and the B8-DR3-DQ2 phenotype were more frequent in North American patients than in Italian controls (30% vs. 16%, P=0.005, and 23% vs. 7%, P=0.00002, respectively). HLA DR7 is associated with the development of microsomal antibodies in Italian patients with chronic hepatitis C. The lower frequency of HLA DR7 in North America could contribute to the rarity of these antibodies in this region. HLA DR11 may be protective against the development of microsomal antibodies in Italian patients, whereas HLA DR4, HLA DR13, and the B8-DR3-DQ2 haplotype may be protective in North American patients.     

Peripheral CD8+/CD25+ lymphocytes may be implicated in hepatocellular injuries in patients with acute-onset autoimmune hepatitis

Background The mechanism of liver injuries in autoimmune hepatitis (AIH) is not fully understood, especially because the onset is insidious and the clinical courses fluctuate with spontaneous exacerbation and improvement even without immunosuppressive therapies.Methods Eleven patients with acute-onset AIH, some of whom were without hypergammaglobulinemia or anti-nuclear antibodies, and 41 patients with chronic AIH were compared serologically, biochemically, and histologically to determine differences in liver injuries between patients with acute-onset and chronic AIH. All patients fulfilled the diagnostic criteria according to a scoring system proposed in 1999.Results Lymphocytes with CD8+/CD25+ markers in pretreatment blood were significantly more prevalent in acute-onset than chronic AIH patients (24% vs 14%; P < 0.05). After treatment, however, CD8+/CD25+ lymphocytes were fewer in patients with acute-onset than in those with chronic AIH at 1 and 2 weeks (P = 0.0001). No other differences were noted in clinical characteristics or immunological parameters between patients with acute-onset and those with chronic AIH. In a patient with typical acute-onset AIH, CD8+/CD25+ lymphocytes increased and decreased in parallel with the activity of liver disease.Conclusions Activated CD8+ T lymphocytes with CD25 markers may be implicated in the development of acute-onset AIH.     

Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study

To investigate whether sclerosing cholangitis with an autoimmune serology characteristic of autoimmune hepatitis (AIH) and AIH are distinct entities, we studied 55 consecutive children with clinical and/or biochemical evidence of liver disease and circulating antinuclear (ANA), anti-smooth muscle (SMA), and/or liver-kidney-microsomal type 1 (LKM1) autoantibodies. They underwent liver biopsy, direct cholangiography, sigmoidoscopy, and rectal biopsy at presentation. Twenty-eight were diagnosed as AIH in the absence and 27 autoimmune sclerosing cholangitis (ASC) in the presence of radiological features of cholangiopathy. Twenty-six ASC and 20 AIH had ANA and/or SMA; 1 ASC and 8 AIH LKM1 autoantibody. Similarities between the 2 conditions included most clinical and biochemical parameters and a lower frequency of HLA DR4. Inflammatory bowel disease and histological biliary changes were more common in ASC; coagulopathy, hypoalbuminemia, lymphocytic periportal hepatitis, and HLA DR3 were more common in AIH. Histological biliary changes were observed in 65% of ASC and 31% of AIH patients. Eighty-nine percent responded to immunosuppression. Follow-up liver biopsies from 17 ASC and 18 AIH patients had similarly reduced inflammatory activity and no progression to cirrhosis. Sixteen follow-up cholangiograms from AIH patients and 9 from ASC patients were unchanged, while 8 ASC patients showed a progressive cholangiopathy. One child with AIH and ulcerative colitis developed sclerosing cholangitis 8 years after presentation. At 2 to 16 years (median, 7 years) from presentation, all patients are alive, including 4 ASC patients who underwent liver transplantation. In conclusion, ASC and AIH are similarly prevalent in childhood; cholangiography is often needed to distinguish between these 2 entities, which are likely to lie within the same disease process.