Aetiology of acute sporadic non-A,non-B viral hepatitis in India

Non-A, non-B (NANB) hepatitis viruses are now classified as hepatitis E (enterically transmitted) and hepatitis C (parenterally transmitted). India experiences a large number of epidemics of the enteric disease every year. In addition, about 70% of the sporadic cases among adults are also due to NANB hepatitis. With the availability of an immunoblot assay for the detection of anti-HEVIgM and the polymerase chain reaction (PCR) for the detection of HCV-RNA, serum samples from epidemic and sporadic NANB patients were screened for these markers. We found that a large number of cases from the epidemics were HEV, though a few remained undiagnosed, while of the sporadic cases only a few could be diagnosed as HCV or HEV; a large proportion remained undiagnosed. © 1993 Wiley-Liss, Inc.     

A histologic comparison of hepatitis B with non-A, non-B chronic active hepatitis

The histopathologic aspects of 62 cases of chronic active hepatitis (CAH) were examined to compare hepatitis B surface antigen (HBsAg)-positive with HBsAg-negative (non-A, non-B) cases. Epidemiologically, the two groups were distinct. Homosexuals and young, male users of intravenous drugs accounted for most of the cases of hepatitis B CAH, whereas older men and women with a history of blood transfusions represented a large percentage of the HBsAg-negative cases. However, there were no pathologic differences between the two diseases, in severity of inflammatory activity, degree of architectural damage, appearance of the bile ducts, or prevalence of cirrhosis. In a population of hospitalized patients, these two diseases cannot be distinguished microscopically unless hepatocytes that contain HBsAg are demonstrated. Although our current understanding of non-A, non-B CAH is limited, the disease not necessarily remit spontaneously, and progression to cirrhosis can be expected in some cases.     

Ultrastructural features in chronic non-A, non-B (NANB) hepatitis: A controlled blind study

Liver biopsies from 12 patients with chronic Non-A, Non-B (NANB) hepatitis, 7 with hepatitis B surface antigen (HBsAg) positive chronic liver disease, 1 HBsAg positive normal carrier, and 4 patients with non-viral liver disease, were examined by electron microscopy for cytoplasmic and nuclear changes. Aggregates of particles measuring 20-35 nm in diameter were noted in the nuclei of 8 of 12 patients with NANB chronic hepatitis, but not in the other groups. The tubular changes seen in the endoplasmic reticulum (ER) of chimpanzees with NANB hepatitis were not noted in biopsies from any of our patients.     

Characterization and demonstration of human liver-specific protein (LSP) and apo-LSP

Liver-specific protein (LSP) prepared by standard methods from five normal human livers showed significant variations in terms of quantitative yield, lipid/protein ratio and migration characteristics of different components on SDS-polyacrylamide gel electrophoresis. This heterogeneity is probably related to varying amounts of different molecular species in the LSP preparations. Delipidation and re-chromatography of the LSP preparation appeared to result in relative enrichment of apo-LSP which showed immunological identity with LSP. Rabbit antiserum to LSP gave a precipitin line of identity with standard antisera to human LSP (anti-LSP) from two other laboratories. After extensive absorption, anti-LSP showed selective reactivity with a surface membrane antigen on a human hepatocellular carcinoma cell line (PLC/PRF/5) that exhibits functional and morphological characteristics of differentiated hepatocytes. The antiserum did not react with cell lines derived from other organs as determined by the indirect fluorescent antibody technique. The surface staining of viable PLC/PRF/5 cells was eliminated by absorption with LSP and apo-LSP, but not with the equivalent kidney fractions. These findings support the concept of a liver-specific antigen and suggest that the PLC/PRF/5 cell line may serve as a source of homogeneous LSP.     

Transfusion-associated hepatitis C virus (non-A, non-B) infection

Non-A, non-B (NANB) is a term used to describe viral hepatitis not due to hepatitis B virus or hepatitis A virus. Two forms of NANB hepatitis have been identified: (1) an epidemic type usually transmitted enterically and (2) a parenterally transmitted form caused by hepatitis C virus. While the latter often is assumed to be transfusion transmitted, data from surveillance programs suggest that the incidence of NANB transfusion-associated hepatitis (TAH) is decreasing. Strategies for preventing TAH include viral inactivation, testing for surrogate markers of NANB, and the appropriate use of blood components. Whether alanine aminotransferase and antibody to hepatitis B core antigen screening of donated blood will be effective in reducing the incidence of TAH is yet to be established. Specific tests for anti-hepatitis C virus may resolve problems associated with surrogate testing.     

IgM-antibody response to hepatitis C virus antigens in acute and chronic post-transfusion non-A, non-B hepatitis.

A specific IgM solid-phase enzyme-linked immunoassay for the diagnosis of a recent infection by hepatitis C virus (HCV) was developed. The assay utilizes a structural antigen encoded by sequences at the 5' end of HCV (core region) and non-structural (NS) antigens encoded by the NS-3 (33c) and NS-4 (c100-3) regions of the HCV genome. Serial serum samples from several clinically diagnosed post-transfusion non-A, non-B hepatitis patients were analyzed for anti-HCV IgM. This antibody was frequently but transiently detected. Anti-HCV core IgM was more frequently detected than anti-c100-3 or anti-33c IgM. In individuals who resolved their HCV infection or progressed to chronicity, anti-HCV IgM was produced transiently at or near the onset of clinically diagnosed acute hepatitis.     

Inactivation of hepatitis B virus and non-A, non-B hepatitis by chloroform

To determine whether a non-A, non-B hepatitis agent contained essential lipids, we extracted with chloroform a dilution of human plasma that contained approximately 10(4) chimpanzee infectious doses of non-A, non-B hepatitis virus and then tested for infectivity in chimpanzees. In addition, we treated a serum containing hepatitis B virus in the same way. Both of these samples were also sham extracted as controls. Known chloroform-sensitive and chloroform-resistant viruses were added directly to the hepatitis-containing serum or plasma as internal controls or to fetal calf serum as external controls and were assayed for infectivity in vitro after chloroform extraction or sham extraction. All infectivity of the diluted plasma that contained at least 10(4) chimpanzee infective doses of non-A, non-B hepatitis agent and all infectivity of the serum that contained 10(3.5) chimpanzee infective doses of hepatitis B virus were destroyed by chloroform. The chloroform-sensitive control viruses were completely inactivated, but the chloroform-resistant control viruses lost less than 0.5 log10 of infectivity. Sham-extracted non-A, non-B hepatitis agent-containing plasma was shown to maintain its infectivity in chimpanzees that had initially been inoculated with the chloroform-extracted plasma. Thus, both hepatitis type B and non-A, non-B hepatitis appear to be caused by viruses that can be inactivated by a lipid solvent.     

Unusual viruslike particles in chronic non-A, non-B hepatitis in childhood

Liver biopsies from 16 children with clinical and pathologic evidence of chronic hepatitis have been examined by electron microscopy for cytoplasmic and nuclear changes. Parallel studies by radioimmunoassay on sera from the same patients support the diagnosis of all these cases as non-A, non-B hepatitis (NANB). Ultrathin sections of the liver biopsies demonstrated in one case intranuclear hepatitis B virus-like core particles, 25 nm diameter. In a second biopsy from the same patient, the corelike particles could still be observed. This finding could be used either to support the thesis that a NANB virus is a member of the hepadnavirus group or to reflect the existence of seronegative cases of chronic HBV infection. Furthermore, we have observed in some mononuclear cells from the inflammatory infiltrate of a portal tract, some structures that resemble virus budding. There is a striking similarity between the morphology of these particles (which are enveloped and possess projections) and the ultrastructure of retrovirus.     

Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report

We treated 10 patients who had chronic non-A,non-B hepatitis with recombinant human alpha interferon in varying doses (0.5 to 5 million units) daily, every other day, or three times weekly for up to 12 months. In 8 of the 10 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. In two of these patients, the interferon therapy was stopped after four months, and in both cases, a prompt return of aminotransferase activities to pretreatment values occurred. Prolonged treatment was associated with a sustained improvement in aminotransferase levels; in three cases, biopsy specimens obtained after one year of therapy showed marked improvement in hepatic histology, even though low doses of alpha interferon had been used. These preliminary findings, although not adequately controlled, suggest that long-term, low-dose alpha interferon therapy may be effective in controlling the disease activity in some patients with chronic non-A,non-B hepatitis. A prospective controlled trial is now needed to assess the role of interferon therapy in this disease.     

Interference between non-A, non-B and hepatitis B virus infection in chimpanzees

Pre-existing chronic or concurrent acute non-A, non-B (NANB) virus infection has been found to interfere with hepatitis B virus (HBV) replication and to delay and moderate markedly the appearance of disease related to HBV infection in chimpanzees. The mechanism for this phenomenon remains unclear. These findings are of practical significance for vaccine safety testing and evaluation of methods for virus inactivation in chimpanzees. The possible occurrence of dual NANB and HBV infection requires that prolonged follow-up be carried out. Attempts to carry out inactivation studies on materials containing both types of virus may also provide misleading observations.     

Two distinct types of non-A,non-B hepatitis in a cardiovascular surgical unit

The incidence of non-A, non-B hepatitis in a cardiovascular surgical unit was examined among the 204 patients who received blood transfusion and extracorporeal circulation while undergoing open heart surgery during April 1979 to December 1981. Among 115 adult patients (20 to 69 years old) 46 (43%) developed non-A, non-B hepatitis, whereas the incidence in younger patients (1 to 19 years old) was much lower (21.8%, 19 out of 89). When monthly incidence was examined during the study period, two nosocomial epidemics, the first during September 1979 to February 1980 and second during October 1980 to January 1981, were found. When clinical features such as maximum ALT level and the proportion of icterus were examined, the features of the above two epidemics were taken to be different from those consistently observed through the study period. The epidemic type hepatitis not only resulted in more severe clinical features than the nonepidemic type, but the sera of the former contained immune complexes at a higher rate (80%) than did the latter (7.6%).     

Sporadic acute hepatitis in hospital employees: mainly non-A, non-B type

Eighty-two patients with sporadic acute viral hepatitis were detected at Okayama University Hospital between January 1982 and March 1989. Thirty of them had non-A, non-B hepatitis (NANBH); 20 had hepatitis A (HA); and 32 had hepatitis B (HB). Ten (33%) of NANBH, five (25%) of HA, and nine (28%) cases of HB were hospital employees. Two (20%) of 10 hospital employees with NANBH developed chronic hepatitis. Antibody to hepatitis C virus (anti-HCV, ELISA) was tested in 10 patients with NANBH (five hospital and five non-hospital employees). Forty percent of both hospital and non-hospital employees had anti-HCV. The percentage of hospital employees among patients with NANBH was similar to that of those among patients with HB. Therefore, it appears that NANBH as a disease entity may be a source of a significant occupational hazard in personnel who either examine or care for patients with hepatitis.     

Guillain-Barré syndrome and other neurologic syndromes in hepatitis A, B, and non-A, non-B

Guillain-Barré syndrome and other neurologic syndromes occur rarely as complications of viral hepatitis, although a causal association has not been established. Seven cases of serologically documented hepatitis A have been reported with Guillain-Barré syndrome; all recovered, with mild neurologic residua in four. Eight cases of serologically documented acute hepatitis B have been reported with Guillain-Barré syndrome; all recovered, with mild neurologic residua in two. In one case, immune complexes of hepatitis B surface antigen and its antibody were present in the cerebrospinal fluid. Other neurologic syndromes have also been reported in patients with serologically defined viral hepatitis, including mononeuritis, auditory neuritis, and seizures. Chronic hepatitis B and mononeuritis multiplex are found together in 31-54% of patients with periarteritis nodosa. The mechanisms for these associations are unknown, but may include direct cytotoxicity of the virus or immune-mediated damage. Vasculitis of the vasa nervorum plays an intermediate role in at least some cases.