Lack of evidence for hepatitis B virus (HBV) infection in fulminant non-A,non-B hepatitis

We studied eight patients who had orthotopic liver transplantation for fulminant hepatic failure in the course of acute non-A, non-B hepatitis. HBV DNA was searched for extensively in the liver tissue by PCR using several sets of primers in conventional and heminested reactions. All patients were negative for HBV DNA in liver tissue by all assays employed; furthermore, they were negative for HEV RNA, HCV RNA, and HBV DNA in serum. Although the causative role of HEV and HCV in fulminant non-A, non-B hepatitis cannot be excluded, our data do not support a causative association between this syndrome and HBV infection.This study was supported by Grant CR20 from the Mayo Clinic and Foundation. D.H.P. is supported by Public Health Service grants AI 32403, AR 41497, and AI 30548 from the National Institutes of Health.     

Acute viral hepatitis in Lebanon: evidence for a HAV-like non-A non-B hepatitis

Ninety-three cases of acute viral hepatitis in adult Lebanese patients were followed-up prospectively for a period ranging from 6 to 18 months. These included 33 hepatitis A (HAV), 32 hepatitis B (HBV) and 21 non-A, non-B hepatitis (NANB) cases. The clinical and seroepidemiologic characteristics of the three types were evaluated. HAV was characterized by a short prodroma (less than 1 week) and a high IgM level. HBV did not differ from similar cases reported in the Western world except for a complete absence of male homosexuals and drug addicts as a possible route of transmission. NANB hepatitis in Lebanon is mainly a sporadic infection similar to HAV except that the prodromal phase is prolonged (greater than 14 days) and IgM levels are within normal limits. The failure to develop chronicity in NANB suggests that the virus of sporadic NANB may be different from that which causes post-transfusional (PTH) NANB.     

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.     

Transient abnormality in carbohydrate metabolism during enterically transmitted non-A, non-B acute viral hepatitis

Blood glucose, plasma insulin and free fatty acids (FFA) responses, during the 2 h oral glucose tolerance test (OGTT) with 75 g of dextrose, were measured in 30 consecutive patients with acute enterically transmitted non-A, non-B hepatitis. All of these parameters during the OGTT were compared with 10 age-, sex- and weight-matched healthy volunteers from the same community. The fasting blood sugar, insulin and FFA were not different from normal controls (P greater than 0.05). According to the WHO criteria, the blood glucose response during OGTT in these patients was normal in 23%, impaired in 33% and diabetic in 43%. There was significant hyperinsulinaemia (P less than 0.001) in patients with impaired and diabetic GGT and it persisted even at the end of 2 h. None of the abnormal liver function tests correlated with blood sugar, insulin and FFA response during the OGTT. All abnormal responses during the OGTT were, however, transient and returned to normal in all the patients after the recovery from acute hepatitis.     

Detection of hepatitis C virus-specific antigens in semen from non-A,non-B hepatitis patients

Semen samples from nine patients clinically diagnosed as having non-A, non-B hepatitis (NANBH) were tested by an ELISA using antibodies raised in rabbits against HCV-specific specific antigens. The semen from all nine patients had elevated levels of HCV-specific antigen in comparison to semen from five healthy donors. Semen from five of the nine patients had significant levels of the HCV-specific antigen. Seven of the eight serum samples from these patients were reactive with the standard C-100 HCV ELISA. Eight of these nine patients had serum reactive for HCV-specific antibodies in our ELISA using HCV-specific antigens. This more direct evidence for viral presence supports the earlier epidemiological data suggesting that HCV could be transmitted sexually.     

Acute sporadic non-A, non-B viral hepatitis of adults in India—Epidemiological and immunological studies

On the basis of tests for specific IgM class antibodies in the serum, infections by hepatitis A virus, hepatitis B virus and hepatitis non-A, non-B virus accounted for 7%, 37.8% and 54.2% respectively of 286 cases of acute sporadic viral hepatitis in adults from three different regions of India. Epstein-Barr virus and cytomegalo virus were insignificant (0.5–1%) aetiological agents. Approximately one-quarter of all non-A, non-B (NANB) cases were additionally HBsAg carriers; there were significant differences in regional frequencies. NANB hepatitis commonly affected individuals in the mid-fourth decade and occurred throughout the year with small peaks in different seasons. No antigen-antibody reaction could be demonstrated in various immunological tests including radioimmunobinding using acute and convalescent phase sera. Neither were virus-like particles visualized in acute phase sera on electron and immuno-electron microscopy. However, rhesus monkeys inoculated with acute phase serum from a case of NANB hepatitis developed distinct hepatocellular changes at 43–55 days after inoculation, which had some features of similarity with experimental NANB hepatitis of other simian species. Sporadic NANB hepatitis is a major health problem throughout India and intensive study is needed on its epidemiology and aetiology.     

Liver biopsy features of acute hepatitis C compared with hepatitis A,B, and non-A,non-B,non-C

ABSTRACT— The diagnosis of acute hepatitis C (AHC) often can only be suspected because current serologic tests remain negative for over 3 months. Because histologic features might provide useful clues, we reviewed 85 liver biopsy specimens from 85 patients with acute viral hepatitis, comparing 22 cases of AHC with 23 cases of acute hepatitis A (AHA), 30 cases of acute hepatitis B (AHB), and 10 cases of acute hepatitis non-A, non-B, non-C (AHNC). AHC was characterized by dense portal lymphoid aggregates (7 cases) and Poulsen-Christoffersen-type cholangitis (8 cases); these lesions were not found in any other type of acute viral hepatitis, and thus appeared to be diagnostic. Sinusoidal inflammatory infiltrates also were common in AHC, particularly in biopsy specimens obtained during the early phase of the disease. These inflammatory infiltrates did not appear to affect adjacent hepatocytes. Necrosis in AHC usually was spotty and accompanied by mixed inflammatory cells. In AHNC, necrosis was also spotty but, as an added feature, pigmented macrophages predominated in them. In AHA, necrosis was predominantly periportal, whereas in AHB, severe zone-3 necrosis predominated. Fatty changes were predominantly microvesicular; they were common in AHC but were also found in other groups. Collectively, the described histologic features allowed diagnosis of AHC in biopsy specimens with reasonable confidence. However, histologic findings failed to predict the prognosis in individual cases.     

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.     

Prevalence of antibody to hepatitis C virus in prospectively followed acute non-A,non-B hepatitis,from different epidemiological categories

ABSTRACT— We have studied the prevalence of antibody against hepatitis C virus (anti-HCV) and its relation to the time of onset of the symptoms in 57 patients with acute non-A, non-B hepatitis: 16 post-transfusion, 25 drug addicts and 16 sporadic cases. In the 1st month after the onset of illness, anti-HCV was positive in 25% of patients with post-transfusion hepatitis, 44% of drug addicts and 25% of sporadic hepatitis. In the 3rd month this antibody was detected in 75%, 88% and 31.2%, and in the 6th month in 87.5%, 96% and 31.2%, respectively. The prevalence in the 3rd and 6th months was significantly higher in post-transfusion patients and drug addicts than in sporadic cases. In the 6th month the prevalence of anti-HCV in patients who progressed towards chronicity was also significantly higher than in those with acute resolving non-A, non-B hepatitis (94% vs 50%, p<0.001). These results show that HCV is probably the main agent in acute post-tranfusion non-A, non-B hepatitis and in those occurring in drug addicts, and that in a high proportion of these patients the anti-HCV can be detected in the 3rd month after the beginning of the symptoms. On the other hand, the relation of hepatitis C virus with sporadic acute non-A, non-B hepatitis may be doubtful.     

Outcome of acute symptomatic non-A,non-B hepatitis: a 13-year follow-up study of hepatitis C virus markers

ABSTRACT— Thirty-nine of 61 prospectively followed patients who had had acute non-A, non-B hepatitis in 1978 were clinically reexamined in 1991 and tested for antibodies to hepatitis C virus (anti-HCV) with a second generation ELISA and RIBA and for HCV RNA by PCR. Acute hepatitis C was diagnosed in stored sera from 1978 in 24 patients, who were found still to be anti-HCV positive in 1991, and 16 of them were also HCV RNA positive. The majority of anti-HCV positive patients with or without HCV RNA had elevated serum ALT levels 13 years after onset of their acute hepatitis C. After 13 years follow-up, 1.6% of the patients had died of end-stage liver disease, 8% of anti-HCV positive patients had histologically confirmed liver cirrhosis, 79% of anti-HCV positive patients were judged to have chronic infection, whereas 21% seemed to have recovered. To conclude, we found that a majority of our patients with acute symptomatic hepatitis C continued to be viraemic 13 years after onset of hepatitis C, and that all continued to be anti-HCV positive by second-generation ELISA.     

Treatment of chronic sporadic-type non-A,non-B hepatitis with lymphoblastoid interferon: Gamma GT levels predictive for response

The aim of this study was to evaluate the efficacy of human lymphoblastoid interferon- treatment in chronic sporadic-type non-A, non-B hepatitis. We also aimed to determine if histological or liver function data could predict either response or relapse. Sixty patients with chronic sporadic-type non-A, non-B hepatitis were randomized in two groups of 30. One group was treated with interferon- (3 MU thrice weekly) for one year; the other group was untreated controls. The treated group was followed for another year after interferon withdrawal. Liver function tests were performed during treatment. Liver biopsy was carried out before and a year after randomization. We evaluated rate of response [normalization of alanine aminotransferase (ALT) levels for at least three consecutive months] and rate of relapse (ALT rebound after therapy suspension). We also looked at possible predictive factors for response and relapse. In the treatment group the rate of response was 55% (16/29). No control patient exhibited ALT normalization. Among the responders, 31% (5/16) relapsed after interferon withdrawal. Low gamma GT and female sex are positive predictive factors of response (P<0.01 andP<0.02 respectively). Presence of portal and periportal inflammation at the second liver biopsy was correlated with relapse (P<0.05). In conclusion, human lyphoblastoid interferon- treatment for one year is beneficial in patients suffering from chronic sporadic-type non-A, non-B hepatitis. Low pretreatment gamma GT levels and female sex are positive predictors of response in this patient population. Low degrees of portal and periportal inflammation, posttreatment, predict maintenance of response.     

A human T-cell clone cytotoxic for hepatocytes from patients with chronic non-A, non-B hepatitis

A human T-cell clone (TA-NB-2) which could lyse hepatocytes from patients with chronic non-A, non-B (NANB) hepatitis was established (Proc Natl Acad Sci USA 1989;86:2883–2887). TA-NB-2 cells belonged to CD3⁺ CD8⁺ cytotoxic T lymphocytes, and recognized the target hepatocytes by T-cell receptor without restriction by major histocompatibility complex (MHC) antigens. TA-NB-2 cells significantly lysed hepatocytes from 22 of 23 patients with chronic NANB hepatitis, whereas they lysed hepatocytes from only one of 17 control patients with chronic type B hepatitis, acute hepatitis B or acute hepatitis A. TA-NB-2 cells also significantly lysed hepatocytes from 4 of 5 patients with autoimmune liver disease. The results suggest that TA-NB-2 cells specifically recognize a NANB hepatitis-related antigen expressed on NANB hepatitis virus-infected hepatocytes by T-cell receptor in non-MHC-restricted manner. The results also suggest that most, if not all, cases of chronic NANB hepatitis are caused by one agent and that a portion of cases of autoimmune liver disease may be induced by infection with a NANB hepatitis virus. The authors are grateful to Sachiyo Terada for her skillful technical assistance. This study was supported in part by a Grant-in-Aid for Cancer Research (63-8) from the Ministry of Health and Welfare, Japan.     

Long-term follow-up of chronic hepatitis non-A,non-B – with special reference to hepatitis C

ABSTRACT— One hundred and twenty-seven patients with histologically verified chronic non-A, non-B hepatitis were followed for up to 23 years (mean 6.3 years). Thirty-nine were infected by blood transfusion, 58 were drug-addicts and 30 had no obvious source of infection. Chronic persistent hepatitis (CPH) was diagnosed in 84 (66%), while 43 patients (34%) had chronic active hepatitis (CAH) with or without cirrhosis. Patients with CPH were significantly younger (29.7 years vs 46.8 years; p<0.01), irrespective of the type of virus exposure. Antibodies to hepatitis C virus (anti-HCV) were detectable in 91 patients (72%) and 36 (28%) were anti-HCV negative. Fifteen patients with acute onset, and negative for anti-HCV at the start, became positive during follow-up; 12 of them within 4.5 months. We found no differences among anti-HCV positive and anti-HCV negative patients in liver function tests, resolving rate, morphological progression in serial biopsies or mortality rate. Five previously anti-HCV positive patients became negative during follow-up and in two of them this was accompanied by decreasing hepatic inflammation.     

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.     

Chronic hepatitis C: the virus, its discovery and the natural history of the disease

The identification of hepatitis A and hepatitis B led to the recognition that a third virus was capable of causing blood-borne hepatitis. The pathogen responsible for this nonA, nonB hepatitis was identified in the late 1980s and subsequently named hepatitis C. Since the discovery of hepatitis C there has been a pandemic of research publications describing the natural history of the infection and it is now known that this virus can cause serious liver damage in a proportion of infected patients. It is now clear that the effects of infection with hepatitis C and alcohol misuse are additive and that there is an increased risk of hepatic complications in infected patients who abuse alcohol.     

Clinico-pathological study of acute non-A,non-B post-transfusion hepatitis: histological features of liver biopsies in acute phase

ABSTRACT— A follow-up study of acute non-A, non-B post-transfusion hepatitis with a mean follow-up period of 30 months was carried out in 24 patients in whom liver biopsy was done within 3 months of onset. Of the 24, 13 patients (54%) developed chronic biochemical liver disease with elevated serum aminotransferases for more than 6 months, and in 11 the elevated liver enzymes were normalized within 6 months. Although there were no statistically significant differences in the mean peak values of liver enzymes, length of incubation period and number of transfusions between the chronic and resolved groups, the former tended to have a slow rise and multiple peaks of serum liver enzymes. Analysis of the liver biopsies made in the acute phase revealed that limiting plate erosion, hepatocellular degeneration, and poor regenerative activities were indicative of subsequent transition to chronicity. Multiple biopsies were taken in five patients who were followed for an average of 29 months, and the subsequent histological diagnosis was chronic persistent hepatitis in two, chronic active hepatitis in two and cirrhosis in one.     

Clinical predictors of response to recombinant interferon-α treatment in patients with chronic non-A, non-B hepatitis (hepatitis C)

SUMMARY. Chronic non-A, non-B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon-α (IFN) treatment at a dose of 3 × 10⁶ units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH-C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty-three adult patients who had participated in a large multi-centre treatment trial were included in the study group: 84 had been treated with 3 × 10⁶ units of recombinant IFN-α-2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 × 10⁶ units rIFN in the same dosage schedule. Forty-one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m^-2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two-tailed, P < 0.15). By multivariate analysis, however, only the 3 × 10⁶ dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 × 10⁶ units of rIFN, seven variables [body weight, surface area, dose m^-2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12–16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.