Cellular and Molecular Mechanisms of Autoimmune Hepatitis.

Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.

Glutathione-S-Transferase M1 null genotype in autoimmune hepatitis.

Autoimmune hepatitis is associated with genes located in the major histocompatibility complex. The search for genes at other loci that may play a role in disease susceptibility and/or severity is an area of active investigation in autoimmune liver diseases. Genes for glutathione-S-transferases, enzymes that are widely distributed and collectively metabolize carcinogens, pollutants, drugs, and a broad spectrum of harmful, foreign compounds have been associated with liver disease. The objective of this study was to search for a relationship between the glutathione-S-transferase Ml null genotype and autoimmune hepatitis using polymerase chain reaction analysis. The findings indicate that the frequency of the null genotype is not increased in patients with autoimmune hepatitis when compared to control subjects. These results coupled with similar ones in primary biliary cirrhosis do not support a role for this mutation in autoimmune liver disease.

Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial.

Hepatic iron concentration has consistently been observed as being directly correlated with the response to interferon therapy in chronic hepatitis C virus (HCV). We therefore conducted a randomized, controlled trial comparing iron reduction by phlebotomy with iron reduction followed by retreatment with interferon in 96 patients with chronic hepatitis C who had previously not responded to a course of interferon. During the initial phase when all patients were undergoing phlebotomy, we found that serum alanine transaminase (ALT) activities decreased but by less than 50% from baseline in 67 patients (89%), decreased by more than 50% in 12 patients (13%) and became normal in 9 patients (9%) with no overall change in HCV-RNA levels. Subsequently no patient in either treatment group achieved a sustained virologic response. Improvements in necroinflammatory changes were noted in liver biopsy specimens in those patients receiving phlebotomy plus interferon (mean index 8.59 vs. 7.37, P <. 05). A slight but not statistically significant decrease in histologic activity index was noted in those subjects treated by phlebotomy alone (mean index 8.4 vs. 7.75, P not significant). We conclude that, although prior phlebotomy therapy does not improve the rate of sustained response to interferon retreatment, it does result in less liver injury manifested by a decrease in serum transaminase activity and a slight improvement in liver histopathology.

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration. Consensus Interferon Study Group.

OBJECTIVE: The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection. METHODS: Patients (n = 472) received either CIFN 9 microg or IFN alpha-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation. RESULTS: Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN a-2b (31%) (p = 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN alpha-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 microg, compared with those treated with IFN alpha-2b (7% vs 0%, p = 0.03). CONCLUSIONS: Both genotype and baseline viral concentration were independent factors that affected response to interferon.

Can you recognize autoimmune hepatitis?

Because there is no single diagnostic test for autoimmune hepatitis, it may initially be indistinguishable from other liver disorders. However, early recognition is important because nearly all patients respond well to corticosteroid therapy. Dr Krawitt discusses diagnostic clues and appropriate management to help prevent serious liver damage and improve patients' quality of life.

Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study.

BACKGROUND & AIMS: A hepatic iron index (hepatic iron concentration divided by age) of more than 1.9 has been proposed as useful to identify patients with homozygous hereditary hemochromatosis (HHC). There are limited data on the diagnostic use of the hepatic iron index in patients with HHC in the United States. This study evaluated the hepatic iron index in the diagnosis of HHC in a multicenter U.S. study. METHODS: Hepatic iron concentration was measured in 509 patients undergoing liver biopsy. The diagnosis of HHC was made using clinical, biochemical, and histopathologic criteria. RESULTS: Fifty-five patients met criteria for HHC; hepatic iron index was > 1.9 in 51 of 55 (93%) patients with HHC but in none of 454 patients with other liver diseases; hepatic iron concentration was > 71 mumol/g dry weight in 54 of 55 patients with HHC but only 1 of the other 454 patients. CONCLUSIONS: A hepatic iron index of > or = 1.9 can identify most U.S. patients with HHC but is < or = 1.9 in 7%. A "threshold" hepatic iron concentration of 71 mumol/g can almost always distinguish patients with HHC from patients with other liver diseases and may be a useful adjunct to the hepatic iron index in the diagnosis of HHC in the diverse U.S. population.

Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consensus Interferon Study Group.

This multicenter, randomized, controlled, double-blind, phase III study in 704 patients with chronic hepatitis C infection compared treatment with consensus interferon (CIFN), a non-natural recombinant type-1 interferon, with a standard regimen of recombinant interferon alfa-2b (IFN-alpha2b). Patients were randomized to receive CIFN at doses of 3 microg or 9 microg, or 15 microg IFN-alpha2b (3 million units), subcutaneously three times weekly for 24 weeks, followed by 24 weeks of observation. Efficacy was assessed by normalization of serum alanine transaminase (ALT) concentration and decrease in serum hepatitis C virus (HCV) RNA concentration below the limit of detection by reverse-transcription polymerase chain reaction (RT-PCR) (100 copies/mL). The beneficial effect of CIFN was greater with the 9-microg dose than the 3-microg dose. The sustained ALT and HCV RNA response rates were 20.3% and 12.1%, respectively, in the 9-microg CIFN cohort and 19.6% and 11.3%, respectively, in the 15-microg IFN-alpha2b cohort. However, patients receiving 9 microg of CIFN had a greater reduction in serum HCV RNA concentrations compared with patients receiving 15 microg IFN-alpha2b over the course of treatment (P < .01). Similarly, analysis of patients infected with HCV genotype 1 showed a greater reduction in serum HCV RNA concentration over the course of treatment for the 9-microg CIFN group when compared with the 15-microg IFN-alpha2b group (P < .01). In addition, a greater percentage of patients infected with HCV genotype 1 treated with 9 microg CIFN had undetectable HCV RNA concentrations when compared with patients in the 15-microg IFN-alpha2b cohort at the end of treatment (24% vs. 15%; P = .04). Improvements in liver histology were noted in all three treatment groups; 52% to 55% of the patients in the three cohorts had at least a 2-unit improvement in the Knodell score at the end of the posttreatment period. The adverse-events profiles were characteristic of treatment with type-1 interferon, and the incidences of anti-interferon antibody formation did not significantly differ among the three treatment groups. These results show that administration of 9 microg CIFN three times weekly for 6 months is safe and is effective in reducing serum HCV RNA concentration.

Renal failure associated with hepatitis C virus infection. Improvement in renal function after treatment with interferon-alpha.

Hepatitis C virus infection can result in mixed cryoglobulinemia and associated clinical syndromes including membranoproliferative glomerulonephritis. Reports regarding the efficacy of interferon-alpha (IFN-alpha) in the treatment of patients with membranoproliferative glomerulonephritis and chronic hepatitis C infection have been inconclusive regarding improvement of renal function. We describe two patients with chronic hepatitis secondary to hepatitis C virus complicated by mixed cryoglobulinemia and membranoproliferative glomerulonephritis who developed severe renal failure which resolved after treatment with standard doses of IFN-alpha 2b.

Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy. Collaborative Study Group.

OBJECTIVE: To study 1) the geographic distribution and clinical significance of hepatitis C virus (HCV) genotypes in the United States and 2) the influence of HCV genotypes on response to interferon therapy. DESIGN: Hepatitis C virus genotype was determined in 179 stored serum samples obtained from patients who were positive for antibody to HCV and for HCV RNA by using polymerase chain reaction. SETTING: Tertiary referral centers in four geographic regions of the United States. PATIENTS: Patients who visited medical centers in the Midwest (50 patients), Northeast (42 patients), Southeast (35 patients), and West (52 patients). MEASUREMENTS: Chaotropic lysis and isopropanol precipitation were used to extract RNA from serum. Polymerase chain reaction was done on the NS5 region and was followed by automated direct sequencing and genotyping of desalted amplification products. RESULTS: 104 patients (58%) had subtype 1a; 38 (21%) had subtype 1b; 4 (2%) had subtype 2a; 23 (13%) had subtype 2b; 8 (5%) had subtype 3a; and 2 (1%) had subtype 4a. Examination of the known risk factors for acquiring HCV showed no association between genotype and mode of acquisition (blood transfusion, injection drug use, employment at a health care facility) or histologic findings at presentation (mild active hepatitis, moderately active hepatitis, or cirrhosis). Sixty-eight percent of patients with genotype 1a, 80% of patients with genotype 1b, and 37% of patients with genotype 2a or 2b had severe hepatitis. Thirteen of 46 (28%) patients with genotype 1a and 4 of 15 (26%) patients with genotype 1b had a complete biochemical response after 6 months of interferon therapy. In contrast, 10 of 14 (71%) patients with genotype 2a or 2b had a complete response to interferon therapy. Five of 39 (13%) patients with genotype 1a, 1 of 14 (7%) patients with genotype 1b, and 2 of 11 (18%) patients with genotype 2a or 2b had a sustained biochemical response. CONCLUSIONS: In the United States, HCV genotypes 1a and 1b are the predominant genotypes in patients with chronic hepatitis C. Genotype is not correlated with mode of virus acquisition or with histologic findings at presentation. Patients with HCV genotype 1a or 1b had more severe liver disease and lower rates of response to interferon therapy than did patients with HCV genotype 2a or 2b. These findings may have implications for predicting outcome and selecting patients for interferon treatment.

Absence of anti-LKM-1 antibody in hepatitis C viral infection in the United States of America.

Several studies from Europe have observed a relationship between hepatitis C virus infection and anti-liver/kidney microsome-1 (anti-LKM-1) positive chronic hepatitis. It has been suggested that hepatitis C may induce an autoimmune phenomenon that leads to the development of a specific type (type II anti-LKM-1 positive) autoimmune chronic hepatitis. We evaluated 204 sera from patients with well-documented hepatitis C infection from two centres in the United States of America and compared them with sera from 428 French patients from three centres. We evaluated the serological prevalence of anti-smooth muscle antibodies, anti-nuclear antibodies, anti-liver cytosol antibodies, and anti-mitochondrial antibodies subtype anti-M2 in patients with chronic hepatitis C. The two groups were matched in their ages, gender, mode of transmission of hepatitis C infection and severity of liver disease. Anti-LKM-1 was not observed in the patients from the USA at a time when it was noted in 3.7% of French patients. There were no differences, however, in the expression of other auto-antibodies, which were often in low titres. Absence of anti-LKM-1 in USA sera in comparison with French sera suggests that there may be differences in induction of anti-LKM-1 related to environmental and/or host genetic factors, and/or genomic variation in the hepatitis C virus.

Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis.

BACKGROUND/AIMS: The asialoglycoprotein receptor (ASGPR) is an established, liver-specific autoantigen. This multicenter study investigated the specificity of anti-ASGPR autoantibodies for autoimmune hepatitis (AIH) in different ethnic groups. METHODS: Nine hundred fourteen sera from European, Japanese, and North American (U.S.) patients with chronic inflammatory liver disorders were tested. An enzyme-immunoassay using human ASGPR and a radioimmunoassay against rabbit ASGPR, performed independently on coded sera, were compared. RESULTS: The highest frequency (76%) of anti-human ASGPR was found in AIH patients (11/24 U.S.; 21/25 European; 28/30 Japanese), particularly in those with active disease before treatment (53/62, 85%), and decreased in titer with response to immunosuppressive therapy. These antibodies were found at low titers in 43 (11%) of 385 patients with viral hepatitis and in 25 (7.6%) of 328 patients with other chronic inflammatory liver disorders (P < 0.0005 compared with all AIH patients). Twenty of 37 sera tested by enzyme-immunoassay and radioimmunoassay were positive, and nine were negative for anti-ASGPR by both assays (78% concordance); six sera were exclusively positive on human substrate. CONCLUSIONS: Circulating anti-ASGPR autoantibodies are closely associated with autoimmune hepatitis independent of geographic or ethnic criteria. Two anti-ASGPR assays currently in use show high reliability.

Autoimmune hepatitis: classification, heterogeneity, and treatment.

Autoimmune hepatitis, a chronic necroinflammatory disorder of unknown etiology, is characterized by immunologic and autoimmunologic features. It is more prevalent in women than in men, and genetic factors appear to play a major role in the disease. The classification of autoimmune hepatitis is based on circulating autoantibody status; however, heterogeneity is distinguished not only by autoantibodies, but by histologic differences, a variety of clinical features, immunogenetic status, and probably pathogenesis. Presentation extends from the asymptomatic to the severely ill patient. Although patients may present with or without evidence of circulating autoantibodies, hyperglobulinemia is a rather consistent laboratory feature. Because the disease is generally steroid-responsive, therapeutic remission rates of 60-80% have been achieved with prednisone or a combination of prednisone and azathioprine, and many patients can be maintained with these drugs alone or in combination. There are no firm guidelines for decisions regarding withdrawal or reduction of medication. When treatment failures occur, orthotopic liver transplantation may be required.

Alpha-fetoprotein glycosylation is abnormal in some hepatocellular carcinoma, including white patients with a normal alpha-fetoprotein concentration.

Lectin-affinity analyses with Lens culinaris agglutinin (LCA) and other lectins have demonstrated that the glycosylation of alpha-fetoprotein (AFP) secreted by hepatocellular carcinomas (HCC) is frequently altered when the serum AFP concentration is increased. To determine if AFP LCA-binding properties are altered in patients with HCC whose serum AFP concentration is normal, the percentage of LCA-binding AFP in serum from white newborns, white normal adults, white patients with chronic hepatitis and hereditary tyrosinemia and white and black patients with HCC were determined. The serum LCA-binding AFP fraction was low in newborns (1-4%) and normal adults (1-8%). There was a significant increase in LCA-binding AFP in patients with chronic hepatitis (10-24%) and hereditary tyrosinemia (5-35%). The AFP LCA-binding fraction was clearly abnormal (greater than 40%) in three of the white patients with an HCC and a normal serum AFP concentration, and the range of values (10-63%) in these HCC patients was similar to that seen in both white and black patients with HCC accompanied by increased AFP concentrations.

Long-term management of Crohn's disease with mesalamine capsules (Pentasa). Pentasa Crohn's Disease Compassionate Use Study Group.

Current long-term treatment of Crohn's disease is unsatisfactory. Based on the Crohn's Disease Activity Index (CDAI), this multicenter trial enrolled patients with either active Crohn's disease (CDAI > or = 150) or disease in remission (CDAI < 150). The primary measure of therapeutic response was mean change in CDAI from baseline to final visit. All patients began treatment with a dosage of < or = 4 g/day of mesalamine that ranged from 3.7 g at baseline to 3.4 g at final visit. Overall, 467 patients were enrolled: 333 (active disease) and 134 (remission). The median study participation time was 14 months. For patients entering with active disease, the mean reduction in CDAI was 77 points, with 42% (122/289) achieving remission by their final visit. For patients entering in remission, there was an increase in mean CDAI from 90 at baseline to 96 at final visit, with 79% (95/120) of patients in remission at final visit and 72% (31/43) in remission continuously after 12 months of therapy. From baseline to final visit, the mean prednisone dose decreased 5 mg/day in patients with active disease and 11 mg/day in patients in remission. Mesalamine was well tolerated and no adverse laboratory trends were observed. These results suggest that controlled-release mesalamine shows promise as a steroid-sparing agent and as a safe and effective long-term therapy for the induction of and maintenance of remission of mild-to-moderate Crohn's disease.