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.     

Histomorphologic picture of chronic non-A, non-B hepatitis

Basing on several international studies on the light microscopic pattern of acute non-A, non-B hepatitis we tried to discover the histological criteria of its chronic course by means of a detailed analysis of 181 liver biopsies of 94 patients suffering from chronic non-A, non-B hepatitis (a homogeneous group without competing noxious agents). In accordance with the relevant literature we found a rate of chronic courses of about 60% with chronic persistent hepatitis (2/3) and chronic lobular hepatitis (1/3) predominating. A transition into liver cirrhosis was not stated. As changes typical of the chronic non-A, non-B hepatitis cell ballooning (89%), changes of cell nuclei (88%), eosinophilic changes of cytoplasm (73%), focal sinusoidal cell activation (92%) and microvesicular steatosis (59%) were ascertained with the chronological analysis showing that there were no changes of these criteria up to the 6th year of disease. Its cause is seen in an incomplete elimination of the hepatitis viruses as a result of inefficient immune defence.     

Light microscopic morphology of acute hepatitis non-A,non-B. A comparison with hepatitis type A and B

ABSTRACT— Liver biopsies from a total of 240 patients with acute hepatitis A (86 patients), B (78 patients) and non-A, non-B (76 patients) were blindly evaluated for quantitative and qualitative light microscopic differences. No qualitative differences separate the three types of hepatitis, but the frequency and degree of some histological features seem to be characteristic of acute human non-A, non-B hepatitis. The degree of focal necrosis and portal inflammation was less pronounced in the non-A, non-B group as compared to the hepatitis A and B groups (P<0.01). Twenty-six percent of the non-A, non-B liver biopsies showed steatosis as compared with 10% and 6% in the hepatitis A and B groups, respectively (P<0.01). Bridging necrosis only occurred in liver biopsies from patients with non-A, non-B and B hepatitis. Abnormal bile ducts were detected in a total of five patients, three of whom were found in the non-A, non-B group. A comparison between histological findings in non-A, non-B patients with and without a possible intravenous exposure revealed that steatosis, cholestasis, large piecemeal necrosis and confluent necrosis occurred with the highest incidence in the patients without intravenous exposure, indicating that non-A, non-B hepatitis may be caused by more than one etiological agent.     

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.     

Histological changes of the liver by treatment of chronic non-A,non-B hepatitis with recombinant leukocyte interferon alpha

We have treated 17 patients with non-A, non-B chronic hepatitis by recombinant interferon alpha (0.3-9 megaunits for 4-28 weeks). In six patients, serum aminotransferase levels fell to normal or near-normal range during treatment. The mean levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 17 patients fell from 156 +/- 80 (mean +/- SD) and 213 +/- 135 at the beginning of treatment to 94 +/- 49 and 112 +/- 71, respectively, at the end of treatment. In 12 patients, liver biopsies were performed before and after (or during) the treatment, and histological activity indices (HAI) were blindly examined by two independent observers. For comparison, we examined histological changes of pre- and posttreatment liver biopsies of 19 patients who were treated by recombinant interferon for chronic hepatitis B. Mean HAI scores improved from 10.0 to 5.4 after treatment in non-A, non-B chronic hepatitis. The most marked reduction was noted in scores of portal inflammation and hepatocellular degeneration and/or necrosis. No such reduction was observed in B-viral chronic hepatitis. These data indicated that rapid biochemical resolution by the treatment was related to histological improvement of the liver in our patients with non-A, non-B hepatitis.     

Application of a numerical scoring system for assessment of histological outcome in patients with chronic posttransfusion non-A, non-B hepatitis with or without antibodies to hepatitis C

A numerical scoring system was applied and compared to the conventional histological classification to assess the histological status of liver specimens from 37 patients with chronic posttransfusion non-A, non-B hepatitis followed for 7 to 105 months (mean 35 months). Four histological categories of alterations were assessed and scored: piecemeal necrosis (PMN), fibrosis and cirrhosis, lobular necrosis and portal inflammation. Sequential liver biopsies were obtained from 19 patients. PMN was generally mild but still predictive of progressing fibrosis. Thus, in none of the biopsies from four patients with initial PMN score 0 was there any increase in the fibrosis score in the follow-up biopsy, while in 10/15 (67%) patients with an initial PMN score of greater than or equal to 1 the fibrosis score increased with time (p = 0.033). Lobular necrosis and portal inflammation were not predictive of progressing fibrosis. Judging from the scoring method, 22% of all the 37 patients displayed cirrhosis and 27% bridging fibrosis in the latest liver biopsy performed. Patients with antibodies to hepatitis C did not differ in histological status or outcome from those without antibodies to hepatitis C. It is concluded that the scoring system can be used to monitor the histological long-term follow-up in patients with chronic posttransfusion non-A, non-B hepatitis, and offers a means of predicting the histological outcome.     

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.     

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.     

Histological improvement of chronic hepatitis B, and non-A, non-B with interferon treatment: application of a numerical scoring system for evaluating sequential morphologic changes

In order to assess the sequential changes of liver pathology after interferon therapy, 70 liver biopsy specimens, collected from 23 HBeAg-positive patients with chronic hepatitis B and 12 patients with chronic non-A, non-B hepatitis, were studied using a numerical scoring system proposed by Knodell et al. The biopsy specimens were obtained immediately prior to the administration of interferon and within one week following the termination of interferon therapy. Three patients with chronic hepatitis B were negative for DNA-polymerase (DNA-P) prior to the interferon administration. Ten patients (50%) lost DNA-P activity. HBeAg became negative in 8 patients (34.8%), of whom 2 seroconverted to anti-HBe. Serum alanine aminotransferase levels normalized in 9 patients with chronic hepatitis B, and non-A, non-B hepatitis. The total Histological Activity Index (HAI) scores in both patients with chronic hepatitis B, and non-A, non-B decreased significantly (P less than 0.001 and P less than 0.005, respectively) after interferon treatment. There was also a significant improvement (0.02 less than P less than 0.001) in each histological category except for fibrosis. When the changes of the HAI scores in patients with chronic hepatitis B were correlated to the outcome in the DNA-P and HBeAg/anti-HBe system after treatment, the histological improvement did not significantly correlate to the outcome of these serological parameters.     

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)     

Histological improvement of chronic hepatitis B,and non-A,non-B with interferon treatment: Application of a numerical scoring system for evaluating sequential morphologic changes

In order to assess the sequential changes of liver pathology after interferon therapy, 70 liver biopsy specimens, collected from 23 HBeAg-positive patients with chronic hepatitis B and 12 patients with chronic non-A, non-B hepatitis, were studied using a numerical scoring system proposed by Knodell et al. The biopsy specimens were obtained immediately prior to the administration of interferon and within one week following the termination of interferon therapy. Three patients with chronic hepaitits B were negative for DNA-polymerase (DNA-P) prior to the interferon administration. Ten patients (50%) lost DNA-P activity. HBeAg became negative in 8 patients (34.8%), of whom 2 seroconverted to anti-HBe. Serum alanine aminotransferase levels normalized in 9 patients with chronic hepatitis B, and non-A, non-B hepatitis. The total Histological Activity Index (HAI) scores in both patients with chronic hepatitis B, and non-A, non-B decreased significantly (P<0.001 and P<0.005, respectively) after interferon treatment. There was also a significant improvement (0.02<P<0.001) in each histological category except for fibrosis. When the changes of the HAI scores in patients with chronic hepatitis B were correlated to the outcome in the DNA-P and HBeAg/anti-HBe system after treatment, the histological improvement did not significantly correlate to the outcome of these serological parameters.     

The long-term prognosis of non-transfusion-associated non-A, non-B hepatitis. A clinical, epidemiological, and histological investigation

In a prospective study of the natural course of acute hepatitis, 157 of 1020 patients with biopsy-verified acute hepatitis could be classified as having hepatitis type non-A, non-B. We here report on the long-term prognosis for these 157 patients. The main type of exposure was drug addiction (40%), whereas 40% had no known hepatitis exposure. Only two patients had received blood products (blood transfusion and factor VIII). Follow-up liver biopsy (mean histological follow-up, 22 months) in 94 of the 157 patients showed chronic liver disease in 15-that is, cirrhosis in 6, suspicion of cirrhosis in 2, chronic aggressive hepatitis in 5, and chronic persistent hepatitis in 2. There was a striking predominance of elderly women with no known hepatitis exposure and with a high frequency of autoantibodies in serum among the patients with progression to chronicity, whereas chronic non-A, non-B hepatitis in drug addicts or after blood transfusions seems to be a limited problem. A comparison of histological features in the initial biopsies from patients with progression to chronicity or complete resolution showed piecemeal necrosis and abnormal bile duct epithelium to be of prognostic value.     

Chronic non-A, non-B hepatitis: lack of correlation between biochemical and morphological activity, and effects of immunosuppressive therapy on disease progression

A study was made of 52 patients considered to probably have chronic non-A, non-B hepatitis who were seen during an eight-year period at Westmead Hospital, Sydney. The patients were followed for a median of 28 months to assess the natural history of the disease and, in a small number of patients, the effect of immunosuppressive therapy on disease progression was examined. In 94% of cases, infection appeared to have been acquired by a parenteral route; the remainder were sporadic infections. Fifty-six per cent of the patients had mild constitutional symptoms and the remainder were asymptomatic. Similarly, 54% of patients had no signs of chronic liver disease and none exhibited signs of hepatic decompensation. Liver biopsies were performed in 42 patients; chronic active hepatitis with or without cirrhosis was present in 90%. However, neither the presence of symptoms nor the degree of biochemical abnormality were predictive of disease severity as determined histologically. Among eight patients treated with corticosteroids (with or without azathioprine), six underwent follow-up liver biopsy. Quantitative analysis of inflammatory and fibrotic changes indicated significant (p < 0.01) progression of histological severity during a median 33 months (range 7–98 months) between biopsies with cirrhosis developing in four instances. In contrast, among the seven untreated patients rebiopsied after a median of 16.0 months (range 11–37 months) there was no overall change in histological severity and only one patient developed cirrhosis. It is concluded that histological assessment is required in all patients suspected of having chronic non-A, non-B hepatitis as other means of assessment are unreliable. At present, immunosuppressive therapy cannot be recommended for patients with this form of chronic viral hepatitis; as well as being unhelpful, such treatment may accelerate disease progression.     

Non-A, non-B chronic hepatitis is chronic hepatitis C: a sensitive assay for detection of hepatitis C virus RNA in the liver.

To study the role of hepatitis C virus in non-A, non-B chronic hepatitis, 49 liver biopsy samples from 40 patients with non-A, non-B chronic hepatitis and 9 control patients were analyzed by complementary DNA/polymerase chain reaction. Two segments of the HCV genome, one in the nonstructural region and the other in the noncoding region, were amplified by two sets of primer pairs. With use of the nonstructural region primers, hepatitis C virus RNA was detected in 24 (60%) of 40 patients with non-A, non-B chronic hepatitis. Of these 40 patients, RNA was detected in 19 (70%) of 27 patients positive for antibody to hepatitis C virus and in 5 (38%) of 13 patients negative for antibody to hepatitis C virus. However, with the noncoding region primers, hepatitis C virus RNA was detected in 38 (95%) of 40 patients with non-A, non-B chronic hepatitis. Of these patients, the RNA was detected in 26 (96%) of 27 patients positive for antibody to hepatitis C virus and also in 12 (92%) of 13 patients positive for antibody to hepatitis C virus. Hepatitis C virus RNA was not detected in any of the control patients. Sequence analysis showed homology between our samples and the prototype to be only 66% to 77% in the nonstructural region but 99% to 100% in the noncoding region. We conclude that almost all patients with non-A, non-B chronic hepatitis in Japan are currently infected with hepatitis C virus, regardless of the presence or absence of antibody to hepatitis C virus.(ABSTRACT TRUNCATED AT 250 WORDS)     

The chronic sequelae of non-A, non-B hepatitis.

Twenty-six of 388 patients (6.7%) followed prospectively after open-heart surgery developed non-A, non-B hepatitis. Of these 26, 12 had an elevated (often fluctuating) serum alanine aminotransferase (SGPT) for greater than 1 year. Liver biopsy, done in eight of 12, showed chronic active hepatitis in six and chronic persistent hepatitis in two; one patient with chronic active hepatitis had early cirrhosis. Anicteric patients with peak SGPT greater then 300 IU/L were at greatest risk of developing chronic hepatitis. Chronic non-A, non-B hepatitis was symptomatically mild and unaccompanied by physical signs or laboratory evidence of autoimmune disease or severe chronic liver disease. In all 12 patients there was spontaneous improvement in serum transaminase over a period of 1 to 3 years, and four patients had sustained normalization of SGPT. Thus chronic active hepatitis is a common sequela of acute non-A, non-B hepatitis but may have a better prognosis than chronic active hepatitis of other causes.     

Chronic Viral Hepatitis in Thalassemic Liver Disease: A Long-Term Study in Patients with Acute Hepatitis with Nontransfusion-Dependent Thalassemia Minor

To evaluate the effective role of hepatitis viruses in thalassemic (Th) liver disease, we carried out a long-term study in 42 subjects with nontransfusion-dependent Th minor hospitalized for an episode of acute viral hepatitis. 10 patients had serologic evidence of hepatitis A, 23 of hepatitis B and 9 of hepatitis non-A, non-B. In the follow-up chronic hepatitis was detected histologically in 5/23 patients with hepatitis B and 5/9 with hepatitis non-A, non-B. All hepatitis A patients recovered completely. The prevalence in 7 out of 10 patients with chronic hepatitis of piecemeal necrosis and of inflammatory changes over hepatic siderosis and fibrosis evidenced a determinant role of chronic viral infection in the development of liver damage in these patients. Thus, heterozygous nontransfusion-dependent Th patients seem to have a high risk of developing a chronic inflammatory liver disease especially after an episode of non-A, non-B hepatitis. Therefore, in our geographical area, chronic hepatitis of viral origin should be taken into account, among other pathogenetic factors, in many cases of cryptogenic thalassemic liver disease.     

Acute hepatitis non-A,non-B; are there any specific light microscopic features?

ABSTRACT— Coded examination of liver biopsies from a total of 24 patients with acute hepatitis non-A, non-B revealed two main histological trends: (a) acute viral hepatitis with confluent necrosis (sublobular and bridging) carrying a relatively good prognosis and taking a chronic course in only four out of 14 patients (29%); and (b) acute viral hepatitis with severe portal infiltration rich in lymphocytes and plasma cells, lymph follicles with germinal centers and bile duct lesions, as described by Poulsen & Christoffersen. The latter group showed a very high tendency to transition to chronic hepatitis (six out of seven patients, 86%) or a course characterized by one or multiple acute relapses (one out of seven patients, 14%). Bile duct lesions, if present in biopsies of patients with acute hepatitis, are of diagnostic and prognostic value. They point to the etiological possibility of a hepatitis non-A, non-B and, at the same time, they indicate a high likelihood of evolution to chronic liver disease.     

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.     

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.     

Post-transfusion hepatitis type non-A, non-B in southern Sweden: occurrence and clinical significance

Two prospective studies of the occurrence and clinical significance of post-transfusion hepatitis non-A, non-B were performed in Malm?, Sweden. In both studies, patients of a broad clinical spectrum were followed up 6 and 12 weeks after transfusion. In a 7 week study from 1983, hepatitis non-A, non-B occurred in 9/173 transfused patients (5.2%) versus 1/203 untransfused controls (0.5%) (p less than 0.01). In a 6 month study from 1984-85, the incidence of hepatitis non-A, non-B had declined to 2.4% (18/739 transfused patients). The mean number of transfused units was about 5 in both studies and most patients had subclinical disease. Despite similar transfusion volumes to patients above or below 70 years of age, hepatitis non-A, non-B was predominantly seen among patients less than 70 years. In the 1984-85 study, hepatitis non-A, non-B incidence was 1.2% in recipients greater than or equal to 70 years, 3.4% in recipients less than 70 years and 4.5% in recipients less than 40 years. One year after the initial hepatitis non-A, non-B episode, 4/18 patients (22%) had biochemical signs of chronic hepatitis.