The role of acute hepatitis type A, B, and non-A non-B in the development of chronic active liver disease

In 19 patients followed from biopsy-verified acute viral hepatitis to chronic active liver disease and 74 patients followed to complete resolution verified by a normal liver biopsy, sera from the acute phase were studied for serologic evidence of hepatitis type A and B. Eleven of the 19 patients who developed chronic active liver disease progressed from acute hepatitis type B and 7 from acute hepatitis type non-A non-B. One patient could not be classified because the sera were exhausted. None had serological markers of actual hepatitis type A infection. Of the 74 patients with a histologically complete resolution, the acute episode could be classified as type B hepatitis in 47 and type A hepatitis in 13 patients. The remaining 14 patients were classified as having acute viral hepatitis type non-A non-B. Our findings confirm that type B and non-A non-B hepatitis may give rise to chronic liver disease, whereas type A hepatitis so far has not been demonstrated to initiate a chronic liver disease.     

Hepatitis C

The major cause of chronic post-transfusion hepatitis, the hepatitis C virus (HCV), has been identified. HCV is a single-stranded linear RNA virus with characteristics similar to the flaviviruses. A different agent, the hepatitis E virus, is associated with epidemic (enterically-transmitted) non-A, non-B hepatitis. At present, infection with HCV is recognized by the finding of anti-HCV antibodies, positive in up to 90% of patients with chronic non-A, non-B post-transfusion hepatitis. Antibodies to HCV are detected in 1% of normal volunteer blood donors and in the majority of donors implicated in post-transfusion hepatitis. HCV antibodies are also found in patients with autoimmune liver disease and hepatocellular carcinoma. Moreover, HCV infection may contribute to the pathogenesis of liver disease in alcoholic patients. The role of HCV infection in fulminant non-A, non-B hepatitis and hepatitis-associated aplastic anemia has not been elucidated as yet. Therapy of chronic non-A, non-B hepatitis with recombinant human alpha-interferon has been shown to improve or normalize aminotransferase levels in approximately 50% of patients, most of whom have evidence of HCV infection. However, relapse after cessation of treatment is common. In the future, screening blood for evidence of HCV infection may prevent most cases of non-A, non-B post-transfusion hepatitis.     

Post-transfusional vs. sporadic non-A, non-B chronic hepatitis. A clinico-pathological and evolutive study

The clinical, morphological and evolutive features of 60 patients with chronic hepatitis, presumably caused by non-A, non-B virus infection, have been retrospectively analyzed. In all the cases the disease began as an acute episode of viral hepatitis that was followed by persistently abnormal liver function tests. No patient had evidence of current or past hepatitis B virus infection and other known causes of chronic liver disease were excluded. Thirty patients had received blood transfusions in the recent past, five were drug addicts and the source of the infection was not identified in the remaining 25, in whom the disease was considered to be sporadic. Clinical or biochemical differences between patients with post-transfusional and sporadic non-A, non-B chronic hepatitis were not observed, but liver histology showed a higher proportion of patients with chronic persistent hepatitis in the sporadic (72%) than in the transfusional group (53%). On follow-up, sustained normalization of liver function tests was observed in 46% of the cases with sporadic hepatitis but only in 13% of the cases with post-transfusion hepatitis. These observations suggest that non-A, non-B chronic hepatitis is more severe in patients with transfusion-related infection than in sporadic cases.     

Autoantibodies and response to alpha-interferon in patients with chronic viral hepatitis

One hundred and fifteen patients with chronic type B, D and non-A, non-B hepatitis treated with recombinant alpha-interferon were tested for six different autoantibodies prior to or during therapy, and the course of treatment was compared in autoantibody-positive and -negative patients. Three out of 25 (12%) hepatitis B patients, 14 out of 30 (47%) hepatitis D patients and 19 out of 60 (32%) chronic non-A, non-B hepatitis carriers had baseline or post-therapy autoantibodies. The rate of response between patients with and without autoantibodies among B, D and non-A, non-B patients was, respectively, 67 vs. 79%, 23 vs. 25%, 70 vs. 61% (p = N.S.). No adverse reaction was observed in the 36 patients who had or developed nuclear, smooth muscle, parietal cells and thyroid autoantibodies during therapy. A patient with baseline antibodies against liver and kidney microsomes developed an icteric acute hepatitis at the fourth month of therapy, but five other patients with this reactivity responded to therapy uneventfully. The presence of autoantibodies before therapy or their induction following therapy is not a contraindication to the use of interferon in patients with chronic viral hepatitis.     

In situ characterization of mononuclear cell phenotype in intrahepatic lymphoid follicles in patients with chronic viral hepatitis.

The author examined liver biopsy specimens obtained from 596 patients with chronic viral hepatitis to clarify the role of lymphoid follicle formation in the portal spaces. Lymphoid follicles were observed more frequently in chronic hepatitis non-A non-B than in chronic hepatitis B and were also common in patients with anti-hepatitis C virus-positive non-A non-B hepatitis. Immunohistology revealed that these hepatic lymphoid follicles resembled the lymphoid follicles of synovial tissue in rheumatoid arthritis. In situ hepatitis B virus markers were examined in 40 patients with chronic hepatitis B showing lymphoid follicles. Among these, hepatitis B surface antigen (HBsAg) was detected in liver cells as well as in the center of the follicles in 19 patients (47.5%). By immune electron microscopy, the author confirmed the HBsAg-positive cells in the lymphoid follicles as follicular dendritic cells. These cells appeared to be a site for antigen trapping in the follicles, therefore, the intrahepatic lymphoid follicles are suggested to play a role in immune response to HBsAg in chronic hepatitis B.     

Autoantibodies and response to α-interferon in patients with chronic viral hepatitis

One hundred and fifteen patients with chronic type B, D and non-A, non-B hepatitis treated with recombinant α-interferon were tested for six different autoantibodies prior to or during therapy, and the course of treatment was compared in autoantibody-positive and -negative patients. Three out of 25 (12%) hepatitis B patients, 14 out of 30 (47%) hepatitis D patients and 19 out of 60 (32%) chronic non-A, non-B hepatitis carriers had baseline or post-therapy autoantibodies. The rate of response between patients with and without autoantibodies among B, D and non-A, non-B patients was, respectively, 67 vs. 79%, 23 vs. 25%, 70 vs. 61% (p = N.S.). No adverse reaction was observed in the 36 patients who had or developed nuclear, smooth muscle, parietal cells and thyroid autoantibodies during therapy. A patient with baseline antibodies against liver and kidney microsomes developed an icteric acute hepatitis at the fourth month of therapy, but five other patients with this reactivity responded to therapy uneventfully. The presence of autoantibodies before therapy or their induction following therapy is not a contraindication to the use of interferon in patients with chronic viral hepatitis.     

Hepatitis A and non-A, non-B viral hepatitis in S?o Paulo, Brazil: epidemiological, clinical and laboratory comparisons in hospitalized patients

During a 33-month period, 295 patients with acute viral hepatitis were admitted to a state hospital for civil servants and their dependents in S?o Paulo, Brazil. Seventy-nine per cent (232) were HBsAg negative. To define the contribution of non-A, non-B viral hepatitis to hepatitis morbidity in this population, further serological studies were performed in 147 confirmed HBsAg-negative patients. One hundred and twelve (76%) were serologically classified as hepatitis A based on identification of IgM antibody to hepatitis A virus. Thirty patients (20%) without IgM antibody to hepatitis A virus, HBsAg, or anti-HBc were categorized as the non-A, non-B hepatitis group. The remaining five patients had probable hepatitis B (IgM antibody to hepatitis A virus negative, HBsAg negative, anti-HBs negative but anti-HBc positive). These data suggest that all three etiological forms of viral hepatitis are endemic in S?o Paulo. Epidemiological, clinical, and laboratory features were compared to the hepatitis A and non-A, non-B hepatitis groups. Patients with non-A, non-B hepatitis were significantly older than patients with hepatitis A (mean age +/- S.D.: 30 +/- 22 years vs. 9 +/- 9 years, p less than 0.001). Contact with hepatitis or jaundice was recognized in 26 (23%) of 112 hepatitis A patients and 3 (10%) of 30 non-A, non-B patients, a difference which was not statistically significant. Parenteral exposures were identified in 13 (43%) of 30 patients with non-A, non-B hepatitis and 23 (21%) of the 112 hepatitis A patients. Blood transfusion in the 2 months preceding onset of illness was reported in 5 (17%) of the 30 non-A, non-B patients and in none of the hepatitis A group (p less than 0.001). Although prodromal symptoms and fever were more common in patients with hepatitis A, neither these nor other clinical features appeared to be distinguishing characteristics. Similarly, mean peak SGPT levels, peak SGPT levels of greater than or equal to 1,000 IU/per liter, and the mean duration of SGPT elevations for each group were not significantly different. Mean peak serum bilirubin levels were slightly higher in the non-A, non-B group than in the hepatitis A group (7.6 +/- 8.0 mg per dl vs. 5.1 +/- 2.7, p less than 0.01) and peak bilirubin levels greater than or equal to 10 mg per dl were found in 27% of the non-A, non-B group and 5% of the hepatitis A group (p less than 0.001). Whether the higher bilirubin levels reflect an agent-related phenomenon or an older population of affected patients is uncertain.     

Detection of 2',5' oligoadenylate synthetase activity in acute viral hepatitis with special reference to histologic features in the acute stage.

We measured the sequential changes in 2',5' oligoadenylate synthetase activity in 21 patients with acute viral hepatitis (5 with type A, 6 with type B, and 10 with type non-A, non-B hepatitis) by radioimmunoassay. Liver biopsies were performed during the acute phase in all patients. Among patients with acute hepatitis A and B, the 2',5' oligoadenylate synthetase levels were transiently elevated at the time of the peak alanine aminotransferase level in the patients in whom a liver biopsy showed acute hepatitis or non-specific reactive hepatitis. Of 10 patients with acute non-A, non-B hepatitis, 4 showed a similar 2',5' oligoadenylate synthetase activity pattern and liver histology to those observed in acute hepatitis A and B. In the remaining 6, the 2',5' oligoadenylate synthetase levels remained elevated for 3.5 to 6 months while the alanine aminotransferase was elevated. Liver biopsy in these patients showed chronic hepatitis. Persistent detection of raised 2',5' oligoadenylate synthetase activity levels during the acute stage of non-A, non-B hepatitis may thus be an indicator of progression of the disease.     

Interferon alpha and gamma positive mononuclear cells and HLA antigen expression on hepatocyte membrane in the liver in chronic type B and non-A, non-B hepatitis

To evaluate the role of local interferon on pathogenesis in chronic type B and non-A, non-B chronic hepatitis, we examined the cellular localization of interferon alpha and gamma, and the expression of HLA antigens in cryostat liver sections from 33 chronic carriers of HBs antigen and 10 patients with non-A, non-B chronic hepatitis, using an immunoperoxidase procedure with monoclonal antibodies. Infiltrating mononuclear cells were the main cell element staining positive for interferon alpha or gamma. Among type B chronic liver disease, the percentages of both interferon alpha- and gamma-positive mononuclear cells were highest in patients with chronic active hepatitis, and their levels were higher in patients who had serum HBe antigen, indicating that local expression of interferon closely correlates with activity of disease and virus replication. On the other hand, both the frequency of interferon alpha or gamma positive cells, and the intensity of HLA class I antigens on hepatocytes were much lower in patients with non-A, non-B, chronic active hepatitis in comparison with those with type B chronic active hepatitis. These findings suggested that locally produced interferons have role of varying degrees on the host defence mechanism in chronic hepatitis, reflecting disease activity and the etiology of the disease.     

Interferon alpha in hepatitis type B and non-A, non-B. Defective production by peripheral blood mononuclear cells in chronic infection and development of serum interferon in acute disease

The production in vitro of interferon alpha and gamma by peripheral blood mononuclear cells of 25 patients with chronic hepatitis B and 13 patients with chronic hepatitis non-A, non-B was compared to that of healthy controls. Following induction by Molt 4 leukemia cells (P less than 0.001) and influenza A/X31 virus (P less than 0.01), there was a significantly lower interferon alpha response in patients with chronic hepatitis B and chronic hepatitis non-A, non-B. Yields of interferon gamma in patients with chronic hepatitis were comparable to those of normal individuals. The degree of interferon deficiency did not correlate with severity of liver disease. In patients with chronic hepatitis B, viral replication (presence or absence of HBeAg) was not related to the defect in interferon alpha production. Three of 10 patients with acute hepatitis B had measurable antiviral activity in the serum for 3-5 days after the onset of jaundice.     

Detection by immunofluorescence of an antigen-antibody system in patients with acute and chronic non-A,non-B hepatitis

ABSTRACT— An antigen-antibody system has been identified by immunofluorescence in patients with non-A, non-B hepatitis. The non-A, non-B antigen was localized in the hepatocyte nuclei of liver biopsies from patients with acute post-transfusion or sporadic non-A, non-B hepatitis and in those from patients with chronic post-transfusion non-A, non-B hepatitis, the percentage of positive cells being most prominent in patients receiving immunosuppressive treatment. Absence of the antigen in normal livers and in livers from patients with type B hepatitis infection indicated its specific association with non-A, non-B infection. Antibody reacting with the nuclear antigen became detectable in serum during post-transfusion acute non-A, non-B hepatitis in 11 out of 15 cases; it was absent before transfusion. Six out of 12 cases of sporadic acute non-A, non-B hepatitis were also found to produce the antibody, which was repeatedly found to be absent during the acute phase in five patients with type A and in eight with type B hepatitis. The non-A, non-B antibody, mainly an IgM antibody, persisted in serum for prolonged periods of time after onset, both in patients showing biochemical resolution of their illness and in those who continued to have liver damage after the acute phase. Accordingly, eight out of nine patients withchronic non-A, non-B hepatitis were found positive for the antibody in serum, seven at the time the non-A, non-B antigen was detected in their liver. Thus this non-A, non-B associated antigen-antibody system shares remarkable similarities of behaviour with the “core” system of the hepatitis B virus.     

Acute non-A, non-B hepatitis--clinical, epidemiological and histological characteristics

Among 73 consecutive patients with biopsy documented acute non-toxic hepatitis, half of the patients (49%) had acute type B hepatitis, while 27 patients (37%) had acute type A infection. One patient had a significant rise in antibodies against cytomegalovirus. The remaining 10 patients (14%) fulfilled the criteria of hepatitis type non-A, non-B. The main type of exposure for hepatitis A was visit to endemic hepatitis areas (41%), and for type B it was drug addiction (46%). Half of the patients with hepatitis non-A, non-B had no known hepatitis exposure while some had visited endemic hepatitis areas or were drug addicts. The patients with non-A, non-B hepatitis had significantly less biochemical changes as compared to the patients with hepatitis B. In contrast, the histological findings showed the greatest activity in the biopsies from patients with hepatitis B and non-A, non-B. Follow-up liver biopsies in half of the patients with non-A, non-B hepatitis showed no signs of chronic active liver disease. It is concluded that hepatitis type non-A, non-B is a significant problem in Denmark.     

Detection of hepatitis B virus DNA in paraffin-embedded liver tissues in chronic hepatitis B or non-A, non-B, hepatitis using the polymerase chain reaction

We developed a polymerase chain reaction assay for the direct detection of hepatitis B virus in paraffin-embedded liver tissue and applied this assay to determine whether hepatitis B virus DNA exists in livers with chronic hepatitis non-A, non-B. Fifty five liver biopsy samples were studied: 11 from patients with HBeAg-positive chronic hepatitis (paraffin-embedded) and 44 from patients with chronic hepatitis non-A, non-B (21 paraffin-embedded; 25 fresh frozen). Thirty three (75%) of the non-A, non-B cases were positive for hepatitis C virus antibodies. Approximately 1 to 10 ng of DNA was extracted from the paraffin-embedded tissue and amplified using oligonucleotide (23-mer) primers specific for the S gene (positions 261 to 692). The beta-globin gene was used as an internal control for sensitivity because this is a single copy gene and allows for relative quantification. In each of the chronic hepatitis B livers, the expected 432-base-pair amplification product for hepatitis B virus DNA and beta-globin gene product were both detected. On the other hand, in the 21 paraffin-embedded chronic hepatitis non-A, non-B livers, no hepatitis B virus DNA was detected, although beta-globin gene was observed in all. Furthermore, in all 25 frozen non-A, non-B livers, beta-globin gene was observed, but no hepatitis B virus band was seen. The limit of detection of hepatitis B virus DNA by this method was estimated to be one genomic copy of hepatitis B virus DNA per cell.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatitis C.

Until recently the diagnosis of non-A, non-B hepatitis was made by excluding other detectable viral infections of the liver. Progress in molecular biology made it possible to develop assays which can trace antibodies against the hepatitis C virus. This virus plays a major role in the pathogenesis of transfusion-related and sporadic non-A, non-B hepatitis and possibly of other liver diseases. Although the genome of a few isolates of the hepatitis C virus has already been decoded, the viral particles have not yet been visualized.     

Rapidly progressive non-A, non-B hepatitis in patients with human immunodeficiency virus infection

No information is available on the role of non-A, non-B hepatitis in the various hepatic abnormalities described in patients with the acquired immune deficiency syndrome. Of 97 patients referred with suspected non-A, non-B hepatitis, 3 were found to have antibody to the human immunodeficiency virus. These latter 3 patients all developed symptomatic cirrhosis within 3 yr of onset of hepatitis. Such a rapid progression of liver disease was rare in patients with non-A, non-B hepatitis who did not have simultaneous human immunodeficiency infection. These findings suggest that human immunodeficiency virus infection may potentiate the liver injury of chronic non-A, non-B hepatitis.     

Incidence and features of liver disease in patients on chronic hemodialysis

We examined the incidence and features of liver disease and the presence of serologic markers of hepatitis B virus (HBV) infection in 134 patients on hemodialysis for 2 to 14 years. Twenty-three patients (17%) had had a single episode of acute hepatitis while on dialysis and two patients had had two episodes, which were attributed to infection by hepatitis B virus in 7 instances and by hepatitis non-A, non-B virus in 20. Chronicity supervened in 4 cases of hepatitis B (57%) and in 14 cases of hepatitis non-A, non-B (70%). A prolonged rise of serum aminotransferases, which was not preceded by acute hepatitis, was detected in 23 additional patients (17%). Acute hepatitis and prolonged hypertransaminasemia were more frequent in patients dialyzed at a hospital unit than in patients dialyzed outside the hospital or at home. These observations indicate that development of acute and chronic liver disease, mainly hepatitis non-A, non-B, is frequent in patients on chronic hemodialysis, particularly in those dialyzed in hospital. Serologic evidence of current or past infection by HBV was detected in 57 patients (42%) with sustained positivity of HBV serum markers. Transient positivity for anti-HBc, anti-HBs, or both, possibly related to passive transmission of antibodies by blood transfusion, was observed in 20 patients (15%). These findings indicate that periodic, repeated testing for HBV serum markers is necessary only in a minority of patients on long-term hemodialysis.     

Role of hepatitis C virus in non-B chronic liver disease.

To assess the contribution of the recently identified hepatitis C virus to chronic liver diseases of unknown cause and chronic hepatitis attributed by exclusion to non-A, non-B hepatitis, we tested for antibody to hepatitis C in hepatitis B surface antigen-negative patients with a spectrum of chronic liver diseases. Antibody to hepatitis C virus, a marker of hepatitis C infection, was detected with a first-generation radioimmunoassay at the following frequencies in the following patient groups: 69% of transfusion-associated non-A, non-B hepatitis; 53% of non-transfusion-associated non-A, non-B hepatitis; 26% of hepatitis B surface antigen-negative hepatocellular carcinoma; 8% of cryptogenic cirrhosis; 5% to 7% of autoimmune chronic liver diseases; 19% of patients with miscellaneous types of chronic liver disease; and 0.67% of healthy controls. Among non-transfusion-associated cases, 81% with a history of intravenous drug use but only 18% with occupational exposure as health workers had antibody to hepatitis C virus. Among cases of hepatocellular carcinoma, 63% of Japanese patients but only 11% of American patients had evidence of hepatitis C infection. Comparison in a subgroup of 79 serum samples of a second-generation radioimmunoassay with the first-generation assay demonstrated a 12% increase in antibody frequency from 30% to 42%. We conclude that hepatitis C plays a substantial role in transfusion-associated and non-transfusion-associated non-A, non-B hepatitis as well as in hepatocellular carcinoma, especially in Japan, a limited role in cryptogenic cirrhosis, and essentially no role in autoimmune chronic liver diseases. Application of more sensitive immunoassays will increase the frequency of antibody seropositivity in all subgroups, but relative distinctions among risk groups are likely to remain.     

Prevalence of anti-HCV among Chinese patients with acute and chronic liver disease

To assess whether the hepatitis C virus plays an important role in Chinese patients with acute and chronic liver disease, antibodies to HCV (anti-HCV) were measured by enzyme immunoassay in 67 patients with type A and B acute viral hepatitis, 165 patients with non-A, non-B (NANB) hepatitis, 438 patients with chronic hepatitis, 200 patients with postnecrotic liver cirrhosis, 72 patients with alcoholic liver disease, 55 patients with non-alcoholic fatty liver, 24 patients with toxic and drug-induced hepatitis, and 20 patients with other chronic liver diseases. Anti-HCV was not detected in sera from patients with type A and B acute viral hepatitis, toxic and drug-induced hepatitis, primary biliary cirrhosis, Wilson's disease, or lupoid hepatitis. The anti-HCV prevalence was found to be highest in patients with NANB hepatitis (59% in sporadic and 73.2% in transfusion-associated), 16.4% in non-alcoholic fatty liver, 5.6% in alcoholic liver disease, 6.8% in chronic hepatitis, and 16% in postnecrotic liver cirrhosis. In patients with chronic hepatitis, the anti-HCV prevalence was significantly higher in HBsAg-negative (15/34, 44.1%) than in HBsAg-positive cases (15/404, 3.7%; P less than 0.0001). The results indicate that HCV is a major agent of NANB hepatitis and plays an important role in HBsAg-negative chronic liver disease in Taiwan.     

Hepatic involvement in patients with human immunodeficiency virus infection: discrepancies between AIDS patients and those with earlier stages of infection

The effect of human immunodeficiency virus (HIV) infection on type and severity of liver disease was studied in 61 HIV-positive patients who did not have AIDS and in 45 AIDS patients. Liver biopsies revealed viral hepatitis in 12 of 18 non-AIDS patients but in only 4 of 34 AIDS patients (P less than .0005, Fisher's exact test). Acute, non-A non-B, and chronic active hepatitis B were seen exclusively in the non-AIDS group; however, chronic persistent hepatitis B was seen in both groups. In 9 of 18 AIDS patients intra vitam liver histopathology established diagnoses of opportunistic infections or tumors. Tissue reaction to certain pathogens, such as hepatitis B virus, mycobacteria, and cryptococci, seems to be milder in AIDS patients than in others who are HIV positive or the expected reaction of the normal host. This is likely because of impaired cell-mediated immunity in patients with advanced HIV disease.     

Long-term follow-up of chronic post-transfusion non-A, non-B hepatitis: clinical and histological outcome

A chart review of chronic hepatitis cases at the Department of Infectious Diseases, Roslagstull Hospital, Karolinska Institute, Stockholm, Sweden, revealed 37 patients with chronic non-A, non-B hepatitis, caused by blood transfusions or intravenous gammaglobulin infusions. They had been followed up long-term, mean 46 months (range 10-149). During the initial hepatitis episode most patients had been anicteric and 13/37 (35%) asymptomatic. Yet, the majority developed progressive liver disease with chronic active hepatitis, with or without histological signs of cirrhosis. Thus, 10/18 (56%) on whom a liver biopsy had been performed within 7-12 months had chronic active hepatitis, four (22%) with histological signs of cirrhosis, and of the five patients biopsied after greater than or equal to 5 years of follow-up, three (60%) had histological signs of cirrhosis. Accordingly, as the duration of follow-up increases, an increasing number of patients with post-transfusion non-A, non-B hepatitis seem to develop cirrhosis.