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Since a decreased interferon response has been linked with certain chronic viral infections, a preliminary study was undertaken to determine whether an altered interferon response may be involved in the pathogenesis of chronic hepatitis, a complication of type B hepatitis. The production of interferon by lymphocytes from patients with chronic hepatitis was compared with the production by lymphocytes from normal subjects. The amount of interferon produced by paramyxovirus-stimulated lymphocytes from 16 patients was substantially smaller than that produced by lymphocytes from 12 healthy donors. The results indicate that decreased production of interferon may be responsible for the chronicity of the disease. However, further studies are necessary to establish causality.

In 21 subjects HBsAg positive affected by different forms of chronic hepatitis and in one carrier we compared the presence in the liver of HBsAg, HBcAg and delta studied by means of I.F. and the presence of serological markers of hepatitis B virus infection. By the I.F. test, HBsAg was present in all cases, HBcAg in 15 cases (71%), delta in 8 cases (38%). These percentages are almost the same as those of other researches in chronic hepatitis in immunodepressive treatment. About the serological markers, HBsAg and HBcAb were present in 100% of cases, while, regarding the e-anti e system, HBeAg was present in 12 cases (57%) and HBeAb in 7 (33%). In the work effected there is no relation between delta and HBeAg because in 50% of the positive delta subjects there was HBeAb. On the contrary HBcAg and HBeAg are strictly correlated. Therefore the antigens core and delta are not interdependent. We wanted to verify the existence of relation between HBcAg and HBeAg and came to the conclusion that this relation exists in 17 out of 21 subjects (81%). In our researches is clear the long persistence of the hepatic antigens without any connection with the time of treatment and the course of the various chronic hepatitis. The change in the serum from HBeAg to HBeAb occurred in many improved cases but not in all of them. We presume that the long immunodepressive treatment (about 4 years) has influenced our results.

Chromosome aberrations of short and long-term cultured lymphocytes have been studied in 12 subjects with chronic hepatitis B. Short-term cultures show "stickiness", aneuploidy, and fragmentations. Long-term cultures show minor damages, made up almost totally of "lacunae" and sporadic fragmentations. Major size chromosomes appear to be more affected, among the latter those containing sites for the interferon. This latter findings would suggest that the interferon decrease in patients might be bound, even only partially to the virus-linked chromosome alterations.

The results obtained in a study of liver biopsies from children affected by different forms of chronic hepatitis during an immunodepressive treatment, accomplished by means of immunofluorescence are summarized. The different antigens correlated to B virus, localized in the nuclei (core and delta), the immunological phenomena observed in the tissue (immunoglobulins and immunocomplexes) and in serum (autoantibodies) have been investigated. The presence of HBcAg, looking finely granular, has been found in 77% of cases of CAH, similar to that found in adults. Delta Ag has been found only in 29% of cases, in the nuclei, like core Ag, but nuclei were more large and not homogeneous. The 2 antigens could be found also in the same patient, differently from adults. The absence of the two antigens has a good prognostic significance; the presence of delta antigen has on the contrary a bad prognostic meaning; the persistence of core antigen under immunodepressive treatment may correspond to a tolerance against antigen. Immunoglobulins and/or immunocomplexes, binding complement, were found in 69% of cases. The fluorescence can be found in different patterns: nuclear, due to immunocomplexes of HBV and antibodies penetrated through impaired membranes; of hepatocyte membranes, linear, probably against auto-antigens (lipoproteins liver-specific) or neo-antigens induced by the virus; in inflammatory cells (K-cells or phagocytic monocytes); or scattered granular, may be from non-eliminated immunocomplexes. Autoantibodies in serum, tested on autologous substrates, were present in 97% of cases, in prevalence antinuclear or against hepatocytary membranes, but also against cytoplasmatic components. Important variations exist between the different forms, both as for what concerns the morphological patterns and the intensity of the reactions. A statement about the severity and the evolution of the disease, with prognostic implication could be hypothetically made in the future, after further studies.

Since a decreased interferon response has been linked with certain chronic viral infections, a preliminary study was undertaken to determine whether an altered interferon response may be involved in the pathogenesis of chronic hepatitis, a complication of type B hepatitis. The production of interferon by lymphocytes from patients with chronic hepatitis was compared with the production by lymphocytes from normal subjects. The amount of interferon produced by paramyxovirus-stimulated lymphocytes from 16 patients was substantially smaller than that produced by lymphocytes from 12 healthy donors. The results indicate that decreased production of interferon may be responsible for the chronicity of the disease. However, further studies are necessary to establish causality.

Serological evidence of infection with the hepatitis B virus associated delta agent (delta) was found in 34 of 270 Italian children with HBsAg-positive liver disease. In different histological forms of chronic HBsAg hepatitis the prevalence of delta infection increased in parallel with the activity of the disease and was maximal in children with cirrhosis. During two to seven years of follow up the hepatitis deteriorated in 38% of the 34 patients with delta infection and ameliorated only in 9%. By contrast the disease usually ran a mild course in the 236 delta-negative carriers of HBsAg, with remission in 55% of these children and deterioration in only 7%. The outcome of chronic hepatitis associated with delta infection was not influenced by treatment with steroids and azathioprine. Chronic delta infection in children is usually accompanied by serious liver disease, that has a tendency to progress and is unresponsive to conventional immunosuppressive treatment.

On liver biopsies of 20 children with different forms of chronic HBsAg-positive hepatitis, submitted to immunodepressive treatment, the presence and the distribution of core and delta antigens and their correlation with the different clinical forms have been studied with the direct immunofluorescence technique. Core antigen was present in 11 patients, delta antigen in 4 patients: both antigens in 3 cases. The percent rate of positive nuclei varied from 5 to 80%. All subjects negative for both antigens showed a favourable course. Delta antigen seems to be associated to forms with unsatisfactory course notwithstanding therapy, particularly to relapses and recurrences of chronic hepatitis in such a way as to hypothesize the possible responsibility either of another hepatitic virus (non A, non B virus) or of a different virus. Core morphological expression frequent in chronic hepatitis submitted to immunodepressive treatment, corresponded approximately to the finding thus far reported for the adults. The interpretation of these results, though difficult, shows remarkable interest for the pathogenetic and therapeutic considerations which follow.

The results of immunosuppressive treatment (a corticosteroid-azathioprine combination) in 104 children suffering from chronic HBsAg-positive hepatitis are reviewed. A recovery and/or improvement of the majority of the cases treated was observed after two to seven years of therapy, in contradiction to the opinion of other authors who treated adult patients. A biochemical and/or bioptic deterioration was observed in some cases in which treatment was interrupted too soon; this was followed by an improvement when treatment was re-initiated. No serious side-effects were observed with the combination treatment.

Forty-two children with HBsAg positive chronic hepatitis who received immunosuppressive therapy underwent multiple liver biopsies over periods ranging from one to five years. The presence of HBsAg, HBcAg, deltaAg, antinuclear antibodies and immune complexes was studied using immunofluorescent techniques. The data were correlated with the clinical status of the patients. The presence of HBsAg, HBcAg and deltaAg remained unchanged throughout the study in most positive patients. All 30 HBcAg positive cases were still positive at the end of the study. One of the negative cases became positive. Eight of the ten delta antigen positive cases showed no change. Intrahepatic immunoglobulins, immune complexes and antinuclear antibodies showed a decrease in positivity in a significant number of patients. Fifteen of the 36 patients positive for intrahepatic immunoglobulins became negative during the study, as did 12 of the 29 immune complex positive subjects and 22 of the 33 antinuclear antibody-positive cases. The persistence of HBV antigens seems to be independent of the clinical course. On the other hand, the persistence of positive immunological indices corresponds to a less favourable outcome.