Use of polyunsaturated phosphatidyl choline in HBsAg negative chronic active hepatitis: results of prospective double-blind controlled trial

In a prospective double-blind trial, polyunsaturated phosphatidyl choline therapy (3 g/day) was given in addition to normal maintenance immunosuppressive therapy to 15 patients with HBsAg negative chronic active hepatitis. Histological evidence of disease activity was significantly reduced in the phospholipid-treated group. The results indicate that polyunsaturated phosphatidyl choline is of value as additional treatment in the management of patients with HBsAg negative chronic active hepatitis whose disease is inadequately controlled with conventional doses of immunosuppressive therapy.     

Development of hepatocellular carcinoma in a man with auto-immune chronic active hepatitis

A 57 year old man with auto-immune chronic active hepatitis, regularly treated with immunosuppressive therapy, had hepatocellular carcinoma (HCC) 10 years after diagnosis of the hepatitis. Assays of the hepatitis C virus antibodies against capsid and non-structural proteins revealed seronegativity in serial serum samples of this patient stored in the previous 10 years during follow up. The seronegative hepatitis C antibodies excluded hepatitis C virus as the cause of the HCC. The occurrence of HCC in this case suggests the necessity of surveillance for early detection of liver cancer in patients with auto-immune chronic active hepatitis undergoing long-term immunosuppressive therapy.     

Chronic hepatitis type B in childhood: longitudinal study of 35 cases.

Clinical, virological, and histological features of hepatitis B virus infection have been examined in 35 children, aged 1 to 11 years, known to be hepatitis B surface antigen (HBsAg) carriers for at least six months when entering the study. Only 10 patients had a history of acute unresolved hepatitis: in the remaining cases the detection of HBsAg had been an occasional finding. Although 77% of the patients were asymptomatic, all had evidence of hepatic involvement and liver history showed the features of chronic persistent hepatitis in 18 cases and of chronic active hepatitis in 16 cases, with associated cirrhosis in two of them. One patient had only minimal histological changes. A high percentage of children with both chronic persistent and chronic active hepatitis had evidence of active virus replication throughout the observation period. During the follow-up study of one to eight years (mean 3.1 +/- 1.7 years), transaminase levels became consistently normal in five patients with chronic persistent hepatitis, and inflammatory infiltrates disappeared in three of them. However, only one of these children cleared HBsAg from serum. Eleven of 16 patients with chronic active hepatitis received immunosuppressive treatment but only one of them achieved a complete and protracted remission, although active viral replication persisted. On the other hand, two of five untreated patients reached complete remission after two and three years of follow-up respectively and one of them cleared HBsAg three years later. These results would suggest the possibility of a spontaneous complete remission of HBsAg positive chronic active hepatitis in children but also raise doubts about the usefulness of immunosuppressive therapy in such patients.     

Lymphocytotoxicity test against rabbit hepatocytes in chronic liver diseases.

We have studied the cytotoxicity against rabbit liver cells of lymphocytes from the peripheral blood of 71 patients with various liver diseases. The group with chronic active hepatitis and three patients with acute alcoholic hepatitis showed significantly higher mean values of lymphocytotoxicity (P less than 0.001) compared with the other patients with chronic persistent hepatitis, post-necrotic fibrosis and cirrhosis. Wilson's disease, and prolonged viral hepatitis. The mean cytotoxicity of these last groups did not differ significantly from controls. In four out of six patients with chronic active hepatitis a significant decrease of lymphocytotoxicity was found after immunosuppressive therapy with oral prednisolone. A good correlation between the lymphocytotoxicity test and histological signs of activity suggests that a cell-mediated immune aggression is present in this disease.     

Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.     

Splenectomy in Active Chronic Hepatitis

Six patients with active chronic hepatitis and hypersplenism have been studied with regard to splenectomy and immunosuppressive treatment. All patients had pancytopenia and four of them had been given immunosuppressive treatment before splenectomy, but this had to be stopped because of severe pancytopenia. All patients tolerated splenectomy, and no serious side-effects were observed. After operation all six patients tolerated immunosuppressive medication, and at follow-up examination for an average period of 21 months improvement was demonstrated in most cases.     

Risk factors for development of lethal sequelae after hepatitis B virus infection in humans

Serious late sequelae including chronic active hepatitis, cirrhosis, massive necrosis, and hepatocellular carcinoma may develop in patients infected with hepatitis B virus. Clinical and epidemiologic risk factors for such complications have not been identified. To examine this question, the clinical and pathologic features of the 60 patients with documented hepatitis B virus infection who underwent postmortem examination at the Johns Hopkins Hospital were reviewed. In 27 patients (45 percent), the outcome of hepatitis B infection was nonlethal, i.e., at autopsy, the liver showed either no histopathologic lesions attributable to hepatitis B infection, acute viral hepatitis, or chronic persistent hepatitis. Lethal outcomes of hepatitis B infection, i.e., chronic active hepatitis, cirrhosis, hepatocellular carcinoma, and/or massive hepatic necrosis, were present in the remaining 33 (55 percent) patients. Chronic active hepatitis was observed more frequently in whites (p less than 0.05) and males (p less than 0.05). Lethal outcomes of hepatitis B infection were correlated with recent or concomitant exposure to known hepatotoxic agents (p less than 0.05), including heavy ethanol abuse, isoniazide, hydrocarbon exposure, methyldopa, and the chemotherapeutic agents busulfan and methotrexate. In addition, a lethal outcome of hepatitis B virus, particularly massive hepatic necrosis, was positively correlated with a history of nephrolithiasis (p less than 0.005). Recent, concomitant treatment with immunosuppressive agents, given in 24 patients (40 percent), was correlated with the absence of lethal sequelae (p less than 0.005). These data suggest that patients with recent exposure to hepatotoxic agents have an increased risk of lethal sequelae following hepatitis B infection. Furthermore, the results suggest that immunosuppressive or antiinflammatory therapy may be beneficial in reducing morbidity and mortality from hepatitis B virus infection.     

Autoimmune chronic active hepatitis masquerading as acute hepatitis

An unusual clinical presentation of chronic active hepatitis is the abrupt onset of symptoms and jaundice, suggesting acute viral hepatitis. In this report, six patients had the acute onset of a severe liver disease. Five of the patients were female and ranged in age from 13 to 64 years. Marked elevations in the total bilirubin (17.1 +/- 11.4 mg/dl), AST (1,346 +/- 352 mIU/ml), and ALT (1,043 +/- 213 mIU/ml) were present (mean +/- SD). Negative serologies for hepatitis A and B were found. Liver histology showed severe hepatocellular injury. A diagnosis of autoimmune chronic active hepatitis with acute features was made on the basis of high titers of antinuclear antibody and smooth muscle antibody and the presence of hypergammaglobulinemia. As immunosuppressive therapy is a beneficial treatment of autoimmune chronic active hepatitis, an acute presentation of this liver disease should be considered as an alternative diagnosis to acute non-A, non-B hepatitis in patients with these clinical characteristics.     

Chronic active hepatitis

In order to ascertain the proportion of patients with biopsy-proven chronic active hepatitis who meet currently accepted criteria for immunosuppressive treatment, an analysis of 86 patients seen between 1973 and 1978 carrying this diagnosis was undertaken. Only 66 could be confirmed to have this lesion on blind histologic review. Nine of these 66 were on concomitant immunosuppressive therapy, four had inadequate documentation of chronicity, five consumed more than two ounces of alcohol daily, five had concurrent malignancy, two were prepubertal, and one had oxyphenisatin-induced disease. None of the remaining 40 patients met the biochemical criteria for disease activity. The disease was predominantly seen in asymptomatic middle-aged males and was of viral etiology. A small subgroup of elderly female patients was also identified whose disease was apparently nonviral. In conclusion, the vast majority of chronic active hepatitis seen at a large university center occurs in individuals for whom treatment guidelines have not been established.     

K-lymphocytes (killer-cells) in Crohn's disease and acute virus B-hepatitis.

Total lymphocyte counts, B-, T-, C'3 receptor-bearing lymphocytes, and K-cell activity were studied in peripheral blood in patients with Crohn's disease and inflammatory liver disease. Patients with active untreated Crohn's disease and acute virus B hepatitis exhibited a markedly increased K-cell activity measured in a plaque assay when compared with normal controls (P less than 0.01). Patients with immunosuppressive treated Crohn's disease, HBsAg-positive chronic active hepatitis, and cirrhosis of the liver showed only a slight increase of K-cell activity (P less than 0.01). In the postacute phase of hepatitis (four to 12 weeks from onset) K-cell activity fell to normal levels. The number of B-lymphocytes showed a relative and absolute decrease in all groups of patients. With the exception of patients with acute HBsAg-positive hepatitis and the post-acute phase of hepatitis all the other groups showed statistically decreased absolute numbers for C'3 receptor-bearing lymphocytes. The significant decrease in K-cell activity and the number of T-lymphocytes in Crohn's disease treated with immunosuppressive drugs was interpreted as an effect of azathioprine and prednisone on these lymphocyte subpopulations.     

Autoimmune chronic active hepatitis: changing reactivity for antibodies to hepatitis C virus after immunosuppressive treatment

Thirty-three patients fulfilling stringent criteria for autoimmune chronic active hepatitis (CAH) were tested for antibodies against hepatitis C virus (anti-HCV) with an enzyme immunoassay. Eleven of the 33 (33%) patients were anti-HCV-reactive in a serum drawn before initiation of immunosuppressive therapy. Anti-HCV-reactive patients had significantly higher median s-IgG level (32.3 g/l) than nonreactive patients (23.5 g/l) (p less than 0.01). When in remission with normalized s-IgG levels as a result of the immunosuppressive therapy, only 1 of the 11 initially reactive patients was still reactive. Sera from patients with acute autoimmune CAH and high s-IgG levels may be nonspecifically reactive for anti-HCV.     

Immunosuppressive serum factors in viral hepatitis. III. Prognostic relevance of rosette inhibitory factor and serum inhibition factor in acute and chronic hepatitis

Two immunosuppressive serum factors, serum inhibition factor (SIF) and rosette inhibitory factor (RIF), were studied in sera from patients with acute and chronic viral hepatitis. In a study of 30 patients with acute viral hepatitis, an association was found between RIF, SIF, and biochemical and virological parameters in 27 patients (90%), 25 of whom recovered completely; two had a protracted course. In three patients, the clinical course was not reflected by the immunosuppressive factors. In 26 patients with chronic persistent hepatitis, 3 had RIF and 7 had SIF of low activity. In patients with HBsAg-positive and -negative chronic active hepatitis, 32 of 47 had RIF and 24 had SIF. SIF activity was significantly increased in HBsAg positive as compared to -negative cases. There was no correlation between RIF and SIF activity at any stage of viral hepatitis. Although SIF was demonstrated in patients with various infectious and other inflammatory diseases, RIF was infrequently detected in nonviral liver disorders, and was not present in any of the nonhepatic diseases tested. It was confirmed that RIF is associated with the beta-lipoprotein fraction. RIF was easily separated from SIF by density gradient ultracentrifugation. The evaluation of SIF and RIF may be helpful in determining the outcome of acute viral hepatitis. In chronic hepatitis, RIF was a better indicator of disease activity than was SIF. These clinical data support previous findings that SIF may be related to the immune response whereas RIF is associated with liver cell damage.     

Liver dysfunction after chemotherapy in lymphoma patients infected with hepatitis C

Reactivation of hepatitis B virus (HBV) infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented complication. However, data on the consequence of chemotherapy on the course of hepatitis C virus (HCV) infection in HCV+ patients have been controversial. Here, we review the current knowledge about the complications related to HCV in lymphoma patients receiving chemotherapy/immunosuppressive therapy. Although less frequent than HBV, these complications occur in a subset of patients with mortality rates up to 45%. Therefore, baseline screening for HBV and HCV before initiation of chemotherapy is crucial. High-risk patients having chronic active hepatitis, high baseline HCV viral load, HBV co-infection and receiving cytotoxic drugs, corticosteroids and rituximab (particularly if combined) should be closely monitored for serum transaminase, bilirubin and HCV RNA levels.     

Detection of serum inhibitory factor for lymphocyte stimulation in chronic viral hepatitis: relationship with the replication level

Sera from 111 patients with chronic viral hepatitis and from 55 cases with other liver disorders were assayed for serum inhibitory factor. The prevalence of this immunosuppressive factor was very similar between chronic hepatitis B (61%), chronic hepatitis delta (57%) and chronic hepatitis C (68%). At the same time, serum inhibitory factor was never detected in the other disorders studied. The presence of this inhibitory factor was detected in a significantly higher percentage (p less than 0.05) of HBeAg, HBV-DNA positive cases (75%) than in anti-HBe positive, HBV-DNA negative cases (44.4%). In chronic hepatitis delta, this immunosuppressive factor was also related to HDV-RNA positivity. The detection of this serum immunosuppressive factor in chronic viral hepatitis and its association with a high viral replication level implies a possible role of this factor in the immune pathogenic mechanism in infectious viral hepatitis.     

Differential distribution of hepatitis B surface antigen and hepatitis B core antigen in the liver of hepatitis B patients.

One hundred liver biopsies from 100 patients with clinical presumptive diagnosis of hepatitis were examined by immunofluorescence for the presence of hepatitis B surface antigen (HBSAg) and hepatitis B core antigen (HBcAg). Of the 60 HBsAg-positive livers, 51 were diagnosed as chronic hepatitis on histological grounds, 6 as acute hepatitis, and 3 as "near-normal liver." From the 60 tissue-positive cases, 3 subjects were HBsAg seronegative. HBcAg was detected in 44 livers, all of which also had HBcAg in the localized in the cytoplasm and the membranes of the hepatocytes, and HBcAg in the nuclei and in 4 cases also in the cytoplasm. Predominant HBsAg expression in the cytoplasm was observed in near-normal liver, chronic persistent hepatitis, and cirrhosis with little activity. This correlated with the amount of ground glass hepatocytes in the biopsies. HBcAg and membrane-localized HBsAg were minimal in those conditions. HBcAg was most prevalent in patients with chronic aggressive hepatitis and active cirrhosis treated with immunosuppressive drugs, whereas the amounts of HBsAg and HBcAg in nontreated patients of those two groups and in acute hepatitis with signs of transition to chronicity were almost equal. HBsAg expression in liver cell membranes was most prominent in active forms of chronic hepatitis (chronic aggressive hepatitis and in active cirrhosis) and in acute hepatitis with signs of transition to chronicity. This observation correlated in the presence of HBcAg in the biopsies of those patients. In acute hepatitis both HBsAg and HBcAg were detected rarely and no membrane expression of HBsAg was observed. The over-all results show a significant relationship between the different degrees of accumulation of HBsAg and HBcAg in the liver and the various histological types of hepatitis and further suggest an interplay of both hepatitis B virus and host immune response in the development and pathogenesis of hepatitis B.     

Exacerbation of chronic hepatitis B during chemotherapy due to testicular seminoma

Chronic hepatitis B is often asymptomatic until it progresses to advanced stage. The natural course of disease includes flares and periods of decreased inflammatory activity. Immune decline status is proven risk factor for exacerbation of viral hepatitis. Anticancer chemotherapy in chronic HBsAg carriers is known to promote viral replication. Return of immunocompetence after withdrawal of immunosuppressant might result in liver damage. We describe case of a patient with chronic HBV infection who developed hepatitis flare subsequently to the cessation of anti-viral treatment and introduction of chemotherapy due to testicular seminoma. Patients with history of HBV infection who receive immunosuppressive treatment are at risk of HBV reactivation or exacerbation of hepatitis. During immunosuppressive treatment enhanced HBV replication and inhibition of CTL without evident liver injury is observed. Restoration of immune system after withdrawal of immunosuppressant allows recognizing increased expression of HBV antigens in hepatocytes. Intensive elimination of infected hepatocytes could occur resulting in liver tissue necrosis, active hepatitis and liver decompensation. It is recommended for HBV infected patients on immunosuppressive treatment to receive antiviral therapy, particularly with the lowest risk for the selection of mutations, regardless the stage of infection.     

Detection of anti-liver cell membrane antibody using a human hepatocellular carcinoma cell line

A radioimmunometric technique for the detection of autoantibodies to liver membrane antigens has been developed using Alexander cells, a human hepatocellular carcinoma cell line. After incubation of Alexander cells with serum, antimembrane antibodies were detected by addition of 125I-labeled Protein A. Binding ratios in 15 children with uncontrolled autoimmune chronic active hepatitis and in seven children with primary sclerosing cholangitis were significantly higher than in 18 age-matched normal controls. Nine patients with inactive autoimmune chronic active hepatitis, 13 with alpha 1-antitrypsin deficiency and five with fulminant hepatic failure had ratios similar to controls. In nine patients with Wilson's disease, there was a modest but significant increase in binding ratio. In four children with autoimmune chronic active hepatitis, binding ratios fell during effective immunosuppressive therapy. Sera from patients with systemic lupus erythematosus or rheumatoid arthritis gave normal results, excluding that binding derives from Fc-mediated immune complex capture. A positive correlation was found between Alexander cell binding values and anti-liver-specific protein antibody titers, suggesting that the two assays detect antibodies against shared antigenic determinants. The Alexander cell assay is a simple, rapid and sensitive technique to detect antibody to liver cell membrane antigens.     

Gaucher's disease in a patient with chronic active hepatitis

Gaucher's disease, an inherited metabolic disorder, may cause hepatic fibrosis, but hepatic inflammation does not occur as part of the disorder. The case of an 18-year-old girl of Ashkenazic Jewish ancestry with chronic active hepatitis and coexistent Gaucher's disease is presented. The clinical course of remissions and exacerbations of the disease activity was typical of "autoimmune" chronic active hepatitis and seemed unaffected by the coexistence of Gaucher's disease. Steroid and immunosuppressive treatment resulted in prompt resolution of the chronic hepatitis. Gaucher's disease results in B cell stimulation and polyclonal gammopathy, which may have contributed to the hypergammaglobulinemia associated with idiopathic ("autoimmune") chronic hepatitis in this case.     

Carcinoma of the Cervix After Treatment with Prednisone and Azathioprine for Chronic Active Hepatitis

A 24-year old woman with chronic active hepatitis developed carcinoma of the cervix, in situ , after receiving 1,000 gm. of azathioprine and 250 gm. of prednisone during a period of 5½ years. This occurrence emphasizes one of the risks of immunosuppressive therapy and we recommend careful surveillance for cancer in patients so treated. The evidence that hepatitis may be associated with an increased incidence of cancer of the cervix is reviewed.     

Persistent elevation of the aminoterminal peptide of procollagen type III in serum of patients with acute viral hepatitis distinguishes chronic active hepatitis from resolving or chronic persistent hepatitis

We measured the serum concentration of the aminoterminal propeptide of collagen type III (PIIIP) in 22 patients with acute viral hepatitis (19 hepatitis B, 3 hepatitis non-A, non-B). Nine patients showed persistent biochemical remission, 13 patients developed chronic active hepatitis (CAH); 6 of those underwent therapy with methylprednisolone and azathioprine. Thirteen patients with chronic persistent viral hepatitis (CPH) and 38 healthy individuals were also investigated. In the control group, PIIIP values were 9.5 +/- 2.25 ng/ml (chi +/- SD; range 4-14 ng/ml). All patients with acute hepatitis showed elevated PIIIP values (range 20-125 ng/ml). In the 9 patients with biochemical resolution, PIIIP normalized after a maximum of 6.5 months (range 7.5-14 ng/ml). In CAH, PIIIP was persistently elevated on the day of the diagnostic biopsy (range 15.6-35.7 ng/ml). In comparison, the patients with chronic persistent hepatitis showed a range of 5.0-15.4 ng/ml. Differences between controls and CAH and CPH/CAH were statistically highly significant (P less than 0.001). Treatment of patients with CAH by immunosuppression resulted in normal PIIIP values in 3 and persistently elevated values in 3. One additional patient had normal PIIIP after treatment with an increased dose of methylprednisolone of 16 mg p.d. Serum concentrations of PIIIP offer a non-invasive index for the development of chronic active hepatitis from acute viral hepatitis. This blood test may also be useful for monitoring immunosuppressive treatment in CAH.