Cryptogenic Chronic Active Hepatitis Research Articles

Hepatocyte membrane-bound IgG and circulating liver-specific autoantibodies in chronic liver disease: relation to hepatitis B virus serum markers and liver histology.

Hepatocytes isolated from 101 biopsies were examined for membrane-bound IgG. The sera of the patients were tested for anti-liver-specific lipoprotein by radioimmunoassay and for liver membrane autoantibody (by indirect immunofluorescence on isolated rabbit hepatocytes. The seven patients with normal liver or minor nonspecific alterations were negative for membrane IgG and serum antibodies. Membrane IgG with granular distribution was found in 41 patients [21 hepatitis B virus-related chronic active hepatitis (CAH), 3 cryptogenic CAH, 3 chronic persistent hepatitis, 6 prolonged viral hepatitis, 1 alcoholic cirrhosis, and 6 primary biliary cirrhosis]. Membrane IgG with linear fluorescence pattern was detected in 12 cases (4 autoimmune CAH, 3 HBsAg-positive CAH, 2 alcoholic cirrhosis, 1 anti-HBc positive CAH, 1 cryptogenic CAH, and 1 prolonged viral hepatitis). A strong association between granular IgG and serum HBsAg was found. Nuclear localization of IgG was found in 34 patients and correlated with the positivity of granular membrane IgG. The highest prevalence of anti-liver-specific lipoprotein was found in primary biliary cirrhosis and autoimmune CAH cases which were also positive for liver membrane autoantibody. No relationship was found between the presence of membrane IgG and circulating liver-specific autoantibodies. Membrane IgG and anti-liver-specific lipoprotein correlated with the presence of moderate and severe portal inflammatory infiltration but not with piecemeal necrosis or transaminase levels. Eleven of the twelve patients with linear membrane IgG presented chronic active liver disease with moderate to severe signs of liver damage. Therefore, it is suggested that, while granular membrane IgGs are related to hepatitis B virus, antigenic expression on the hepatocyte surface and/or the presence of immune complexes, linear membrane IgG could play a role in the immunopathogenesis of liver cell damage particularly in "autoimmune" cases which present high percentages of positive cells liver-specific autoantibodies.

Idiopathic Chronic Active Hepatitis: A Diagnostic and Therapeutic Dilemma

A 56-year-old Saudi male was admitted with abnormal liver chemistry values and a > 5-month history of lethargy, malaise, anorexia, and jaundice. Extensive investigations did not establish an etiological diagnosis. Liver histology confirmed the clinically apparent aggressive hepatitis with fibrosis but gave no clue to its etiology. The patient was empirically treated with alpha-interferon for presumed non-A, non-B hepatitis, with clinical and biochemical worsening. Interferon was discontinued and the patient was started on immunosuppression. Dramatic clinical and biochemical improvement occurred, with normalization of the liver chemistry within 4 weeks. The patient has been followed-up for 12 months and has not suffered a relapse. This case highlights the etiological heterogeneity of chronic active hepatitis. The entity of autoimmune chronic active hepatitis is unclear, and perhaps it is better defined as steroid-responsive hepatitis. Steroid-responsive hepatitis should always be considered in cases of cryptogenic chronic active hepatitis.

The nature and prognosis of severe cryptogenic chronic active hepatitis

Background: Cryptogenic chronic active hepatitis may be an autoimmune or viral disease. Our aims were to determine the clinical features, human leukocyte antigen phenotype, and response to corticosteroid therapy of severe Cryptogenic chronic active hepatitis and to compare it with these other diseases. Methods: Twelve patients with Cryptogenic hepatitis were compared with 94 patients with autoimmune hepatitis and 30 patients with chronic viral hepatitis. Results: Patients with cryptogenic hepatitis were indistinguishable from those with autoimmune hepatitis by age, gender, and individual laboratory and histological findings. HLA B8 (75% vs. 49%, P = 0.2), DR3 (71% vs. 51%, P = 0.5), and A1-B8-DR3 (57% vs. 38%, P = 0.6) occurred as commonly in each group. Patients with cryptogenic hepatitis entered remission (83% vs. 78%, P > 0.9) and failed treatment (9% vs. 11%, P > 0.8) as frequently as those with autoimmune hepatitis during corticosteroid therapy. In contrast, patients with chronic viral hepatitis had lower biochemical abnormalities, less frequent multilobular necrosis at presentation, and different human leukocyte phenotypes than those with cryptogenic or autoimmune disease. Conclusions: Severe cryptogenic hepatitis has a clinical expression, genetic phenotype, and corticosteroid responsiveness that is similar to autoimmune hepatitis. It may be an autoimmune disorder that has escaped detection by conventional immunoserological markers.

Granulomatous lipophagic panniculitis and temporal arteritis in a patient with cryptogenic chronic active hepatitis.

An elderly woman receiving long term treatment with prednisone and azathioprine for cryptogenic chronic active hepatitis developed granulomatous lipophagic panniculitis and temporal arteritis. The lymphoplasmahistiocytic inflammatory reaction pattern is common to this patient's three diseases. It is suggested that an aberration of the defence mechanisms, immunological or otherwise, is responsible for this unusual occurrence. The triple association of chronic active hepatitis, granulomatous panniculitis and temporal arteritis has not been reported previously.

Frequency and Significance of Antibody to Hepatitis C Virus in Severe Corticosteroid-Treated Cryptogenic Chronic Active Hepatitis

To determine the frequency and significance of antibody to hepatitis C virus (anti-HCV) in severe cryptogenic chronic active hepatitis (CAH), we tested sera from 17 corticosteroid-treated patients by an enzyme immunoassay. Specificity of the antibodies to HCV-encoded antigens was assessed by recombinant immunoblot assay. The findings in patients with and without anti-HCV were contrasted, and the frequency of seropositivity was compared with that in patients who had other types of chronic liver disease and in normal adults. Only three patients (18%) with severe cryptogenic CAH had anti-HCV. Sera from two of these patients were reactive by recombinant immunoblot assay; the other sample produced an indeterminate reaction. The frequency of seropositivity in patients with cryptogenic disease was not statistically different from that in patients with autoimmune CAH (6%), hepatitis B surface antigen-positive CAH (9%), or alcoholic liver disease (0%), but it was significantly less than in those with posttransfusion CAH (18% versus 75%; P less than 0.01). Seropositive patients tended to have lower serum aspartate aminotransferase, gamma-globulin, and bilirubin levels than seronegative counterparts, and they did not have histologic features of confluent necrosis at initial assessment. Two of the three seropositive patients, both of whom had been reactive by recombinant immunoblot assay, entered remission during therapy, and one, with an indeterminate reaction, died of liver failure. We conclude that anti-HCV occurs infrequently in severe corticosteroid-treated cryptogenic CAH. Seropositive patients may have less severe inflammatory activity than seronegative counterparts. Cryptogenic disease may improve during corticosteroid treatment, a result suggesting an underlying immunologic disorder in some patients.

Auto‐immune features in patients with idiopathic chronic active hepatitis who are seronegative for conventional auto‐antibodies

In patients with chronic active hepatitis (CAH), the absence of the conventional serum auto-antibodies (antinuclear, smooth muscle and liver-kidney microsomal) is often taken as evidence against an auto-immune aetiology and as indicative that the disease is unlikely to respond to immunosuppressive therapy. We report 12 British patients (11 female) who presented with histologically florid CAH (11 with cirrhosis or fibrosis and seven with ascites) but without significant titres of these antibodies or any other demonstrable aetiological feature (cryptogenic CAH), who have been followed up for a median of 5.25 years (range: 0.75-16 years). Ten had hypergammaglobulinaemia and/or specific elevations of serum IgG concentrations at presentation and five of 10 patients tested were found to have the HLA allotypes B8 and DR3. Remission was initially induced with prednisolone with or without azathioprine in all patients. Six patients subsequently relapsed on one or more occasions, either spontaneously while on maintenance therapy or during attempts to withdraw corticosteroids, and required increases or reintroduction of immunosuppressive therapy to regain disease control. Retrospective analysis of pretreatment samples from 11 of the patients revealed that all had been seropositive at presentation for auto-antibodies against the liver membrane lipoprotein preparation known as liver-specific membrane lipoprotein (LSP) and/or against the hepatic asialoglycoprotein receptor (ASGP-R), titres of which subsequently fluctuated in direct relation to response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Features and Prognostic Implications of Severe Corticosteroid-Treated Cryptogenic Chronic Active Hepatitis

To assess the nature and prognosis of severe chronic active hepatitis of unknown cause, we compared 26 patients who had been fully screened for etiologic factors with 112 patients who had autoimmune chronic active hepatitis after similar durations of corticosteroid therapy (17(+)/- 2 versus 23 (+)/- 2 months), and follow-up versus 103 +/- 7 months). Patients with cryptogenic disease could not be distinguished from those with autoimmune disease on the basis of age, sex distribution, duration of illness, immunoglobulin levels, frequency of concurrent immunologic disorders, or histologic findings. Serum gamma-globulin levels were higher (3.4 +/- 0.1 versus 2.5 +/- 0.2 g/dl, P = 0.007) and albumin levels were lower (2.9 +/- 0.1 versus 3.3 +/- 0.1 g/dl, P = 0.003) in patients with autoimmune disease than in those with cryptogenic disease, but individual findings did not differentiate the patients. Remission (69 versus 75%), treatment failure (23 versus 13%), relapse after drug withdrawal (67 versus 68%), progression to cirrhosis (57 versus 36%), and death from hepatic failure (12 versus 11%) occurred as commonly in patients with cryptogenic as in those with autoimmune disease. Patients with different constellations of immunoserologic findings were similar clinically. We conclude that patients with severe chronic active hepatitis who have been fully screened for etiologic factors cannot be distinguished from patients with autoimmune disease of comparable severity. These two groups of patients have a similar prognosis after corticosteroid therapy, and such treatment should be considered in these highly selected patients.

HLA display and composition of the inflammatory infiltrate in non replicating HBV-related and cryptogenic chronic active hepatitis

HLA display and composition of the inflammatory infiltrate in non replicating HBV-related and cryptogenic chronic active hepatitis

Treatment of chronic active hepatitis and other liver diseases with corticosteroid agents.

The term chronic active hepatitis covers aetiologically different conditions with similar histological features. Autoimmune chronic active hepatitis - the type that was described originally - is the only type which responds well to prednisolone therapy. Autoimmune chronic active hepatitis can be differentiated from other types by serological and other markers. Treatment with prednisolone should be given for at least two years, with adjustment of dosage according to the serum levels of aspartate transaminase; maintenance does should be 8-12 mg a day. Azathioprine (50-100 mg a day) may be given concurrently as a corticosteroid-sparing agent. Prednisolone therapy in patients with autoimmune chronic active hepatitis enhances the quality of life and survival is prolonged greatly; currently the survival rate after 10 years for prednisolone-treated cases is at least 70%. Prednisolone is not effective in hepatitis B-associated chronic active hepatitis and may be deleterious. In cryptogenic chronic active hepatitis, in which markers of autoimmunity or hepatitis B viral infection are lacking, a trial of prednisolone therapy may be given for three months, and continued only if the indices of disease activity indicate a response. Corticosteroid agents have not proved of benefit in other liver diseases, including alcoholic hepatitis and acute liver failure, and a beneficial effect in primary biliary cirrhosis is yet to be established.

Influence of Aetiology, Clinical and Histological Features on Survival in Chronic Active Hepatitis: An Analysis of 204 Patients

To determine which clinical and laboratory features may influence survival in patients with chronic active hepatitis, we undertook a retrospective study of 204 patients seen on this unit over a 15-year period and applied logistic regression analysis. One hundred and six patients had autoimmune chronic active hepatitis, 69 'cryptogenic' chronic active hepatitis (no autoimmune markers or other aetiological factors identified), and 29 were HBsAg-seropositive. Variceal haemorrhage, encephalopathy and ascites were common presenting features in the cryptogenic group while the presence of jaundice and other immunopathic diseases did not differ between the groups. Cirrhosis was more common at presentation in the cryptogenic group. Remission was induced with corticosteroids and azathioprine in 82 per cent of patients with autoimmune chronic active hepatis and in 77 per cent of patients with cryptogenic chronic active hepatitis and the annual relapse rate was similar in the autoimmune and cryptogenic groups. Five-year survival was 87 per cent in the autoimmune group, 65 per cent in the cryptogenic group, and 80 per cent in those with HBsAg-positive disease, and on logistic regression analysis, the presence of cirrhosis at presentation was the only independent factor which adversely affected survival. Overall survival in the cirrhotic patients at five and 12 years was 63 and 48 per cent respectively compared with 95 and 92 per cent in those without cirrhosis.

Geographic differences in HBV related, autoimmune, and cryptogenic chronic active hepatitis.

To clarify the importance of ethnic and geographic factors in chronic active hepatitis (CAH), HBV markers and autoantibodies (AMA, ANA, SMA), have been compared in 158 patients with biopsy-proven CAH from New York City and in 92 patients with CAH from Milan. HBsAg-positive CAH was more frequently observed in Milan (49%) than in New York City (27%). However, among HBsAg-positive patients, HBcAg, HBeAg, and epidemiologic risk factors for acquisition of HBV infection were more frequently found in New York than in Italy. The prevalence of HBsAg-negative, anti-HBc-positive CAH and cryptogenic CAH was similar in the two cities, while autoimmune CAH was more frequently observed in New York (20%) than in Milan (2%). In particular, the prevalence of autoimmune hepatitis was higher among Jewish patients than among patients of Anglo-Saxon or Latin ethnic background in New York. Thus, environmental and/or ethnic factors may influence the prevalence of the four major types of CAH.

Outcome of chronic active hepatitis: influence of histocompatibility antigens and triggering factors.

Twenty-five patients with chronic active hepatitis triggered by external factors (viruses or drugs) and 20 patients with cryptogenic chronic active hepatitis were studied for two to five years. The first group showed a significantly higher frequency of clinical and biochemical resolution at the end of the observation period than did the second group. The group with cryptogenic disease had a predominance of females carrying the histocompatibility antigen HLA-B8, whereas the group with virus- or drug-induced hepatitis did not differ from normal controls in regard to the distribution of HLA antigens. HLA-B8 and HLA-B12 were found in all but two patients in the group with cryptogenic hepatitis; this group of patients had elevated levels of gamma-globulin and autoantibodies in their sera more frequently than did the group with virus- or drug-induced disease. The results suggest that there are at least two types of chronic active hepatitis: one genetically determined, with signs of enhanced immunoreactivity and with a low degree of healing in five years; and another type triggered by external factors and without predisposing genetic factors. The data suggest that the clinical outcome is more favorable for patients with the second type of chronic active hepatitis.