The aetiology of acute hepatitis in Zimbabwe.

The cause of acute viral hepatitis in 141 patients admitted to both Infectious Diseases Hospitals in Harare (Zimbabwe) was hepatitis A in 44, hepatitis B in 86 and hepatitis Non-A Non-B in 11. The wide distribution of hepatitis A and B viruses and early exposure to both in Zimbabwe are shown by the high positivity rate for anti-HAV antibody in patients under 10 years old (87.5%) and for anti-HBs antibody in patients over 20 (60%). Among the 86 hepatitis B cases, e and delta systems were also investigated: 66 patients (76.5%) were HBeAg positive, six (7%) anti-HBe positive and 14 (16.5%) negative for both; only one was anti-delta positive. Two cases of fulminant liver failure (both occurring in HBsAg and anti-HBc IgM positive, but delta-markers negative patients) and five cases of hepatoma (only one of whom was negative for all HBV markers) are described.

Attempt to treat acute type B hepatitis with an orally administered thymic extract (thymomodulin): preliminary results.

A double-blind trial with thymomodulin (TM) was performed in a consecutive series of 50 inpatients affected with acute type B hepatitis. Twenty-six randomly selected patients received TM (Leucotrofina, Ellem), 1 ampoule b.i.d. per os for 30 days, and 24 patients received the same amount of placebo for the same period. TM-treated patients showed accelerated AST and ALT decrease and an earlier HBsAg clearance. However, only the difference in ALT decrease was statistically significant in comparison with the controls (p less than 0.02). Before the treatment was started, lymphocyte subsets, as determined by monoclonal antibodies, showed a different pattern in the two groups despite strict randomization. Nevertheless, by the end of the trial, mean T4+/T8+ ratios were increased in the treated group, but remained unchanged in the control group. The trends in the two groups were significantly different (p less than 0.005). Further information is expected from a long-term follow-up.

Epidemiology and clinical outcome of hepatitis D virus infection in Turkey.

The prevalence, the epidemiology, the clinical and biochemical characteristics of hepatitis delta virus (HDV) infection were studied in patients with HBsAg-positive acute hepatitis, in those with chronic liver disease, and in apparently healthy carriers in Turkey. Fifty-eight of the 242 carriers of HBsAg (23.9%) and 31 of the 237 (13.1%) patients with acute HBsAg-positive hepatitis had serological evidence of HDV infection. Eleven of these individuals were HBsAg carriers with acute HDV superinfection. The prevalence of HDV infection was significantly (p less than 0.001) higher in patients with chronic liver disease (54/165; 32.7%) than in asymptomatic carriers of HBsAg (4/77; 5.2%). The highest prevalence (26/57; 45.6%) of HDV infection was found in patients at high risk of acquiring hepatitis virus infection (health care workers, hemodialysis patients, polytransfused patients) with chronic liver disease. Whereas the frequency of "severe" or fulminant hepatitis was similar in HBV infected patients (7.8%) and in HBV/HDV coinfected individuals (10%), the frequency of biphasic hepatitis was significantly (p less than 0.005) higher in the latter patients (30%) than in those with classical hepatitis B (7.8%). Chronic evolution of the disease was observed in 3.9% of the patients with classical hepatitis B and in 5% of those who had evidence of simultaneous HBV/HDV infection. The 10 carriers of HBsAg who survived the acute HDV superinfection developed chronic delta hepatitis. These findings indicate that HDV is endemic in Turkey and that its prevalence is highest among chronic HBsAg-positive hepatitis patients, implicating HDV as a major cause of liver disease among urban Turkis.

IgG and C3 receptors on polymorphonuclear leukocytes in phagocytosis. Role of C3-receptors in the attachment and ingestion phases.

The role of IgG and complement (C3) receptors in the adhesion and ingestion phases of immune complexes by normal human polymorphonuclear leukocytes (PMN) were examined. The immune complexes were sheep red cells (E) sensitized with IgG (EA) or IgM antibodies plus complement (EAC'). Both types of receptor sites are involved in the adhesion phase. Moreover IgG receptors are primarily involved in the ingestion phase. Nevertheless even C3-receptors may be sufficient for complete phagocytosis. Even if EAC' adhesion was still high, C3-receptor specific phagocytosis decreased parallel with the amount of the complement used for EA19S sensibilization. The role of receptor sites on human PMN in adhesion and ingestion phases is discussed.

A possible misdiagnosis in patients presenting with acute HBsAg-negative hepatitis: the role of hepatitis delta virus.

We describe here two cases of delta hepatitis (a coinfection and a superinfection) presenting as acute HBsAg-negative hepatitis. The first patient, a parenteral drug abuser, had a biphasic course of the disease, with HBsAg detectable transiently only during the relapse. Testing for delta markers on stored sera gave evidence of HBV/HDV coinfection. The other patient, a hospital nurse, chronic asymptomatic carrier of HBsAg, developed fulminant hepatitis with the transient appearance of antibody to HBsAg. She survived massive liver necrosis, and serological analysis of HDV markers documented a hepatitis delta virus superinfection. These cases demonstrate the possible substantial repression of HBV gene products exerted by the replication of delta virus, with a likely misdiagnosis if delta markers are not determined in serial serum samples.

[Demonstration of a granulocyte defect in aged persons correlated with the presence of autoantibodies]. / Dimostrazione di un difetto granulocitario in soggetti anziani e correlazione con la presenza di auto-anticorpi

Assessment of PMN leukocyte function and search for autoantibodies were performed in 36 aged human subjects (more than 60 years of age) and in 15 younger controls (40 to 60 years of age). Autoantibodies were found in 15 of the 36 aged subjects, and in none of the controls. Leukocyte function defects were therefore correlated to old age and to markers of autoimmunity. Phagocytosis of bacteria was significantly impaired in both groups of old-aged subjects, irrespective to the presence or absence of autoimmunity. Intracellular killing of bacteria was shown to be normal in all the examined subjects. Nitroblue tetrazolium reduction by resting and latex-stimulated leukocytes was significantly impaired only in the group of old-aged subjects with autoimmunity. These leukocyte function defects are similar to those already described in human autoimmune diseases -- particularly S.I.E. -- and confirm the possible association between P.M.N. dysfunction and autoimmunity.

Monomeric (7S) immunoglobulin M antibodies to hepatitis delta virus in hepatitis type D.

The pattern of the immunoglobulin M antibody to the hepatitis delta virus distinguishes acute from chronic hepatitis D. Expression of the immunoglobulin M antibody to the hepatitis delta virus is relatively weak and short-lived in self-limited hepatitis but strong and persistent in chronic forms. To study the nature of the immunoglobulin M antibody to the hepatitis delta virus in acute hepatitis D and in chronic hepatitis D, antibody-positive sera were submitted to rate zonal centrifugation to separate monomeric 7S from pentameric 19S immunoglobulin M antibodies. Sera were from 6 patients with acute self-limited hepatitis, 4 patients with chronic hepatitis D, and 6 patients with hepatitis D progressing to chronicity. The immunoglobulin M reactivity was measured by a specific immunoassay based on capture of mu-chains by anti-mu linked on a solid phase. Only 19S antibody was found in acute hepatitis D. In contrast, all patients with chronic hepatitis D circulated 7S antibody in addition to the 19S antibody. In patients with progressive hepatitis D, both the 7S and 19S antibody variants were present at the onset of the disease. The difference in the antibody response between acute hepatitis D and chronic hepatitis D is not only temporal and quantitative but also qualitative. The expression of 7S antibody seems to be an immunologic event specific for chronic hepatitis D.

Polymorphonuclear leucocyte function during acute viral hepatitis.

Polymorphonuclear (PMN) phagocytosis was tested in three groups of 12 patients (non drug-addicts) hospitalized for acute A, B and non-A, non-B hepatitis. The same test was performed in 12 parenteral drug-addicts (P.D.A.) with non-A, non-B hepatitis, in 12 P.D.A. with type B hepatitis and in 30 P.D.A. without evidence of acute hepatitis. Percent of phagocytosis was evaluated at time of admission to hospital, at discharge and three months after the acute episode. A statistically significant reduction of phagocytosis was present in each of the non-addicts group at time of admission to hospital. At the discharge this reduction was confirmed for type B and non-A, non-B hepatitis, whereas an improvement was noted for type A hepatitis. Control tests carried out 3 months later evidenced that also in patients affected with type B and non-A, non-B hepatitis the percentages of phagocytosis had reached almost normal values. An increased percent of phagocytosis resulted from incubation of patients' PMN with normal human serum. Among drug-addicts the percentages of phagocytosis do not differ from the data recorded in non-addicts patients during the acute stage of the disease. However, three months after the acute episode, a deficit of phagocytic activity was still present in drug-addicts. These data would support the hypothesis that a serum factor impairing the PMN phagocytosis in acute hepatitis is present. Circulating immune complexes were found in the same sera. They might play an important role in inhibitory effect on neutrophils phagocytic activity.

Prolonged course and relapses of acute type A hepatitis.

Sixty-nine consecutive patients with acute type A hepatitis were followed-up to establish the natural history of the disease. Illicit drug abusers were not included in this study. 19% (13/69) of the patients at 6th month, and 6% (4/69) at 12th month showed aminotransferase (ALT) values at least two folds the upper levels. The histological examinations performed in 5 of these cases suggest that persistence of abnormal ALT levels may be related to a misdiagnosed chronic liver disease preexisting the acute type A hepatitis. Three of the 69 patients had a relapsing hepatitis with two peaks of serum ALT 6-8 weeks apart. The illness resolved uneventfully in all these patients. The exclusion of exposure to liver toxins such as alcohol or drugs, as well as other known hepatitis virus infection in these cases, suggests that the two distinct episodes of hepatitis could be the result of the sequential infection of hepatitis A and non-A, non-B viruses.

Cryoglobulins and infectious diseases.

The relationship between infectious diseases due to various pathogenetic factors and cryoglobulin production mechanisms has been investigated. Cryoglobulins have been evidenced in infections caused by very heterogeneous pathogens, i.e. leptospirosis, psittacosis, Mediterranean tick typhus, brucellosis, gram-negative bacterial septicemias, in which they had never been previously reported. In type A hepatitis a high cryoglobulin prevalence (91%) has been confirmed during the acute phase, with a rapid decrease both in prevalence and concentration in the subsequent stages of the disease. Cryoglobulins were all of type III and were mainly represented by IgM; anti-HAV-IgM antibodies have been evidenced in all but one cryoprecipitates. In non-A, non-B hepatitis a lower cryoglobulin prevalence (44.7%) was shown during the acute phase and the same fast decrease has been noted in the subsequent stages. Cryoglobulins were all of type III and in some cases polyclonal IgG was the only Ig class present in cryoprecipitates. The cryoglobulin prevalence in the acute phase of HBsAg-positive hepatitis amounted to 73.4%; all the cryoprecipitates were of type III. No correlation between the presence of cryoglobulins and HBeAg positivity or between cryoglobulins and delta agent infections was found. In all the cases studied the presence of cryoglobulins was related to the persistence of liver damage. Cryoglobulins were not found in HBsAg chronic carriers, while they have been evidenced, by a preliminary study, in 41.6% of HTLV-III antibody-positive subjects complaining of a persistent generalized lymphadenopathy without clinical or laboratory signs of liver impairment. No HTLV-III antibodies were found by ELISA method in the type III cryoprecipitates.

Detection and further characterization of a newly described microsomal autoantibody associated with chronic delta infection.

Sera from 162 patients with acute or chronic hepatitis and from patients with autoimmune diseases have been investigated for autoantibodies by indirect immunofluorescence on human and animal tissues. A small proportion (14.2%) of young patients with chronic delta hepatitis has been found positive for cytoplasmic staining which was maximal in hepatocytes and renal proximal tubules. This autoantibody has been found to react with microsomal antigenic determinant different from the classic liver-kidney microsomal LKM antigen as demonstrated by fluorescence absorption experiments with purified subcellular organelles and by fluorescence-blocking tests. The microsomal autoantibody displayed also organ and species-specificity different from those shown by the LKM-positive sera. The positive patients showed persistence of the microsomal autoantibody during the follow-up without other serological markers of autoimmunity. There was no evidence of a particular course of chronic delta hepatitis in patients positive for the microsomal autoantibody.

Hepatitis B virus-associated coinfection and superinfection with delta agent: indistinguishable disease with different outcome.

Markers of hepatitis B virus (HBV) and delta agent were prospectively tested in sera of 107 intravenous drug abusers with acute hepatitis positive for hepatitis B surface antigen (HBsAg) associated with delta infection and compared with the findings in addicts with acute classical hepatitis B. On the basis of the presence and titer of IgM antibody to hepatitis B core antigen, 86 of the addicts with delta infection had simultaneously acquired HBV and delta agent, and 21 were chronic carriers of HBsAg experiencing acute delta superinfection. The frequencies of biphasic and severe hepatitis were significantly higher (P less than .05) in delta agent-infected patients than in controls, but the acute clinical and biochemical features of the two varieties of delta disease were not distinguishable. However, in analogy to the clinical outcome of classical hepatitis B, all patients with nonfatal acute HBV/delta coinfection had self-limited illness, whereas 20 of 21 HBsAg carriers superinfected by delta agent developed chronic active hepatitis.

Milan as possible starting point of LAV/HTLV III epidemic among Italian drug addicts.

Sera collected between 1978 and 1985 from 716 parenteral drug-addicts admitted to our Clinic with viral hepatitis were tested for antibodies to HTLV III. None of the patients was showing symptoms suggestive of LAV/HTLV III infection at the time of sera collection. Positivity for HTLV III antibody was found and confirmed (by ELISA) in 212 subjects (29.6%). The earliest positivity appeared in a serum sample collected in February 1979. These and other data point to Milan as to the actual source of the Italian PDAs-linked LAV/HTLV-III epidemic.

Autoantibody pattern in non-A, non-B hepatitis.

Acute and convalescent sera from 44 patients with non-A, non-B hepatitis were tested for organ and non-organ specific autoantibodies by indirect immunofluorescence. In the acute-phase sera, 36.4% of the patients were positive for smooth muscle antibodies. Brush border antibodies and anti-reticulin antibodies were detected in 13.6% of the patients. Only two patients (4.5%) were positive for anti-nuclear antibodies. The autoantibody pattern did not relate to the different epidemiology, sex, a previous hepatitis B virus infection or to the biochemical liver function tests. The autoantibody pattern did not differ statistically in patients who recovered (23 cases) and in patients who progressed to chronic liver disease (21 cases), even if a higher frequency of smooth muscle antibodies was detected in the latter group. Convalescent sera screening showed that the clinical course of the disease did not relate to the behaviour of smooth muscle antibodies, brush border antibodies and anti-reticulin antibodies. However, an increase (28.6%) in anti-nuclear antibodies in patients who progressed to chronic liver disease was observed. The clinical significance of the presence of serological markers of autoimmunity in patients with chronic sequelae following acute non-A, non-B hepatitis is discussed.

Serological response to the hepatitis delta virus in hepatitis D.

Sera from 74 hepatitis B surface antigen-positive individuals, who presented with acute hepatitis delta virus (HDV) infection which ran a self-limited course in 58 and progressed to chronicity in 16, were tested over time for HDV markers. In self-limited disease the serum pattern varied from early HD-antigenaemia followed by IgM and IgG anti-HD seroconversion, to the appearance of IgM and IgG anti-HD without antigenaemia, or the isolated expression of either the IgM or the IgG antibody. The typical case of IgM anti-HD was transient and appeared with a mean delay of 10-15 days from admission in the different serological subgroups. The IgG antibody usually developed several weeks later during convalescence. In contrast, patients with disease destined to become chronic had a brisk IgM antibody response and IgG anti-HD was detectable with a mean delay of 15 days; generally, the IgM and the IgG antibody persisted over the follow-up time. IgM antibody to HDV is often the only serological test positive in the clinical stage of hepatitis D and repeated testing for this marker is necessary to diagnose acute HDV co-infection. The serological follow-up provides important prognostic information: waning of IgM confirms resolution of HDV infection, persistence predicts chronicity.

Attempted treatment of fulminant viral hepatitis with human fibroblast interferon.

Beta-interferon was administered by intravenous infusion to 16 patients affected with fulminant hepatitis B virus infection in third or fourth-grade coma. Ten patients presented a superinfection or a co-infection due to the delta (delta)-agent. None had detectable interferon (IFN) activity before therapy was begun. Besides fever, no significant side-effects were observed during treatment. Both the IFN-treated group as well as the "historical" control group, made up of 70 cases of fulminant virus hepatitis, not treated with IFN and observed during a previous ten year-period, received supportive therapy; survival rates were similar in both groups. Furthermore, the presence or absence of the delta-agent did not appear to affect survival rates significantly.

Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection.

Serum or liver markers of hepatitis delta virus (HDV) infection were found in 20 of 22 (90%) Italian patients presenting with an ostensible type B hepatitis that ran an accelerated course to cirrhosis. The features of the illness conformed to a syndrome of HDV infection in young males carrying the hepatitis B surface antigen (HBsAg); a latent HBsAg state was documented in many patients by a history of prior exposure to the hepatitis B virus (HBV) or by the absence of IgM antibodies to the HB core antigen. Characteristic of the disease were the clinical overture as a severe hepatitis, the lobular involvement by an extensive necroinflammatory reaction, the exuberant expression of intrahepatic hepatitis delta antigen and an atypical HBV profile of inactive infection or accelerated seroconversion from HBeAg to anti-HBe. Superimposed upon HBV infection, HDV may create a rapidly progressive course which resembles very aggressive hepatitis B but is infrequently observed in hepatitis B alone.

Problems in the management of chronic hepatitis B with interferon: experience in a randomized, multicentre study.

In a multicentre trial, 82 patients known to be hepatitis B e antigen and hepatitis B virus DNA positive for at least 1 year, with elevated serum alanine aminotransferase levels and chronic liver lesions on biopsy, were randomized to receive either recombinant interferon alfa-2a at a dose of 4.5 million units thrice weekly for 4 months or no treatment. At the end of therapy, viral DNA clearance and aminotransferase normalization were significantly (p less than 0.05) more frequent in treated patients than in controls. After 16 months' follow up, the difference was still significant for hepatitis B e antigen clearance and transaminase normalization. Hepatitis B virus DNA reactivation was observed during follow up in 43% of treated patients and 50% of controls. Improvements in liver inflammation were observed in patients on interferon. High pre-treatment serum aminotransferase levels, female sex and a low score for fibrosis in the initial biopsy were predictive factors significantly (p less than 0.05) associated with termination of hepatitis B virus replication in treated cases. These results indicate that interferon is effective in inducing clearance of HBV from serum and improvement of biochemical and histological parameters of liver disease. However, a more prolonged regimen of therapy may be required to obtain stable suppression of hepatitis B virus replication.