An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis.

A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.

Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation.

Hepatitis B virus (HBV) variants with precore mutation(s) resulting in the absence of HBeAg production have been associated with the occurrence of fulminant hepatitis in Japan, Israel, and southern Europe, where the prevalence of this HBV strain appears common. In areas such as United States, where HBV infection is not endemic, the role of this mutant virus in fulminant hepatitis is unknown. We developed an amplification refractory mutation detection system to detect specifically the presence of the G to A mutation at nucleotide position 1898, which is the most frequently observed mutation resulting in a precore stop codon. In addition, this method provided a quantitative measurement of the relative ratio of one strain to the other. Using this system, we tested HBV strains for the presence of the stop codon mutation in sera from 40 cases of fulminant hepatitis B occurring in the United States. Serum HBV DNAs from 28 patients were analyzed successfully. A mixture of wild-type and mutant strains in various ratios were observed in 15 patients, wild type exclusively in 11, and mutant exclusively in 2. Four of these patients had undergone liver transplantation for HBV-associated cirrhosis and developed fulminant HBV-associated hepatitis after transplantation. Pre- and posttransplant serum samples from one patient were analyzed: a mixture of wild-type and mutant HBV strains was detected in both samples. Our study demonstrated that both wild-type and mutant HBV strains are associated with fulminant hepatitis, and that in some patients in the United States, factors other than precore mutations contribute to the development of fulminant hepatitis.

Immunogenicity of hepatitis B vaccine in oncology patients receiving chemotherapy.

We evaluated the immunogenicity and safety of three 40 micrograms doses of hepatitis B vaccine in oncology patients receiving chemotherapy. Of 76 patients screened for entry into the study, 13 (17%) already had been exposed to hepatitis B and were ineligible; 26 chose to join the study. The cumulative life-table response rate during the 12-month observation period was 70.8%; adequate immune response was linked to survival, 73% in survivors completing the study and 9% in nonsurvivors. Adverse effects were minor. We conclude that hepatitis B vaccine is safe and usually effective in inducing immunity in oncology patients younger than 60 years of age who are receiving chemotherapy.

Therapy for acute and chronic hepatitis.

Review of therapy for acute and chronic hepatitis indicates no available medication is effective in acute, severe acute, or fulminant hepatitis. Management should include observation in acute hepatitis and meticulous medical care in severe acute and fulminant hepatitis. The only patients with chronic active hepatitis in whom steroid therapy has been shown effective are those who are hepatitis B surface antigen (HBsAG) negative and have symptomatic disease with morphologically severe lesions. Insufficient data have been generated to determine the need for and response to therapy in patients with asymptomatic or mild HBsAG-negative or HBsAG-positive disease or symptomatic, severe HBsAG-positive disease. Among the more novel therapies being evaluated, transfer factor and levamisole do not hold great promise. In contrast, antiviral chemotherapy with interferon and vidarabine may benefit patients with chronic hepatitis B, but this remains to be better defined. Finally, it has become apparent how crucial to objective evaluation is the properly executed randomized controlled trial. In the future, we can look forward to new therapy modes based on a better understanding of the immunopathogenesis of acute and chronic hepatitis.

Cutaneous vasculitis associated with acute and chronic hepatitis.

We encountered 11 patients who had rashes associated with hepatitis. Five of six acute hepatitis cases, but only one of five chronic hepatitis cases, were related to hepatitis B. Nine of the 11 patients had rash in the absence of clinically overt liver disease. Skin biopsy specimens showed histologic evidence of cutaneous vascular injury; specimens of urticarial and maculopapular rashes, which were seen in this series only with acute hepatitis, showed a primarily lymphocytic venulitis with focal necrosis, while palpable purpura, which was seen in this series only in chronic hepatitis, showed a primarily neutrophilic necrotizing vasculitis involving small vessels. One patient had lichen planus-like lesions. Demonstration of vascular deposits of immunoglobulins, complement, and fibrin in skin, as well as hypocomplementemia, circulating immune complexes, and mixed cryoglobulinemia, in these patients suggests that cutaneous lesions associated with liver disease resulted from immune complex-mediated vascular injury.

Role of hepatitis C virus in non-B chronic liver disease.

To assess the contribution of the recently identified hepatitis C virus to chronic liver diseases of unknown cause and chronic hepatitis attributed by exclusion to non-A, non-B hepatitis, we tested for antibody to hepatitis C in hepatitis B surface antigen-negative patients with a spectrum of chronic liver diseases. Antibody to hepatitis C virus, a marker of hepatitis C infection, was detected with a first-generation radioimmunoassay at the following frequencies in the following patient groups: 69% of transfusion-associated non-A, non-B hepatitis; 53% of non-transfusion-associated non-A, non-B hepatitis; 26% of hepatitis B surface antigen-negative hepatocellular carcinoma; 8% of cryptogenic cirrhosis; 5% to 7% of autoimmune chronic liver diseases; 19% of patients with miscellaneous types of chronic liver disease; and 0.67% of healthy controls. Among non-transfusion-associated cases, 81% with a history of intravenous drug use but only 18% with occupational exposure as health workers had antibody to hepatitis C virus. Among cases of hepatocellular carcinoma, 63% of Japanese patients but only 11% of American patients had evidence of hepatitis C infection. Comparison in a subgroup of 79 serum samples of a second-generation radioimmunoassay with the first-generation assay demonstrated a 12% increase in antibody frequency from 30% to 42%. We conclude that hepatitis C plays a substantial role in transfusion-associated and non-transfusion-associated non-A, non-B hepatitis as well as in hepatocellular carcinoma, especially in Japan, a limited role in cryptogenic cirrhosis, and essentially no role in autoimmune chronic liver diseases. Application of more sensitive immunoassays will increase the frequency of antibody seropositivity in all subgroups, but relative distinctions among risk groups are likely to remain.

Aplastic anemia and non-A, non-B hepatitis.

Severe aplastic anemia is a rare but important complication of hepatitis. The agent(s) responsible for the hepatitis in these cases have not been well defined. Sixteen patient with hepatitis-associated aplastic anemia were studied for evidence of recent infection with hepatitis A virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and Toxoplasma. Results were compared with data from 10 randomly selected patients with aplastic anemia unassociated with hepatitis. Of the 16 patients, recent acute hepatitis A infection could be excluded in at least 14 patients. Hepatitis B surface antigen (HBsAg) was present in only one patient. A diagnosis of recent hepatitis B infection could not be excluded with confidence in two others. Tests for cytomegalovirus, Epstein-Barr virus, and Toxoplasma gave negative results. No patient with aplasia unassociated with hepatitis had evidence of recent hepatitis A infection, and the frequency of hepatitis B antibodies in this group was indistinguishable from that in patients with hepatitis. These data indicate that most cases of hepatitis that preceded aplastic anemia were not caused by hepatitis A virus or hepatitis B virus; non-A, non-B agents were probably involved in at least 13 of the 16 cases studied.

Hepatitis in an adult with rubella.

Rubella accompanied by serum aminotransferase elevations occurred in a 24-year-old woman. Although not generally recognized, hepatic involvement in adult rubella was the probable cause of her liver function test abnormalities. Sporadic hepatitis labeled as non-A, non-B may result from infection by common viruses such as rubella.

Elevated thyroxine levels due to increased thyroxine-binding globulin in acute hepatitis.

Two patients are presented who had unexpected increases in serum thyroxine concentration due to acquired thyroxine-binding globulin excess associated with asymptomatic hepatitis. Serum hormone concentrations were also analyzed retrospectively in 10 outpatients with viral hepatitis. Acute hepatitis is associated with an increase in serum thyroxine and thyroxine-binding globulin concentrations and a corresponding decrease in the triiodothyronine resin uptake. In five patients, serum thyroxine concentration (mean +/- SD) was elevated at 21.08 +/- 5.86 micrograms/dl during illness, and decreased to 10.18 +/- 2.96 micrograms/dl during full recovery (p less than 0.05); serum thyroxine-binding globulin concentration was elevated at 2.14 +/- 0.36 mg/dl during illness, and decreased to 1.18 +/- 0.16 mg/dl during recovery (p less than 0.01). Interpretation of thyroid function test results can be difficult in patients with hepatitis. When serum thyroxine is elevated, careful attention to a decrease in the triiodothyronine resin uptake is essential to avoid the incorrect diagnosis of hyperthyroidism. Occasionally, this change in the triiodothyronine resin uptake may be the first evidence of occult hepatic inflammation.

Anaphylactic reaction and cardiopulmonary arrest following intravenous cyclosporine.

Cyclosporine, a new immunosuppressive agent useful in recipients of a variety of organ transplants, has been associated with a number of adverse effects, most notably nephrotoxicity. This report describes a woman about to undergo liver transplantation in whom intravenous administration of cyclosporine was associated with an apparent anaphylactic reaction resulting in cardiopulmonary arrest. Similar reactions have thus far not been reported after oral administration of cyclosporine. Intravenous cyclosporine must be administered under close supervision and should be avoided in any patients with a history of prior allergic reactions to the drug or to a component of its intravenous formulation.

Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy.

Fibrosing cholestatic hepatitis (FCH) has recently been described after solid organ transplantation in patients with hepatitis C virus (HCV) infection. Typically, FCH is characterized by an ominous clinical course leading to progressive hepatic failure and death if liver transplantation is not performed. Two HCV-infected patients underwent cadaveric renal transplantation for end-stage renal disease resulting from membranous nephropathy and diabetic nephropathy. The time intervals between transplantation and the biopsy diagnosis of FCH for the two patients were 7 months and 10 years. Both patients presented with jaundice, hyperbilirubinemia, and mild-to-moderate elevations in serum aspartate aminotransferase. One patient was also found to have type II mixed cryoglobulinemia. Interferon-alpha therapy was begun after a diagnosis of FCH was established by liver biopsy. Liver test abnormalities normalized rapidly. When cholestatic hepatic deterioration develops in an HCV-infected organ allograft recipient, the diagnosis of FCH should be considered and a liver biopsy performed. Our observations indicate that FCH can respond to antiviral therapy.

Impact of hepatitis on renal transplantation.

In order to delineate the incidence, etiology, and impact of liver disease in renal transplant patients, we reviewed 405 consecutive transplants performed between 1970 and 1980. Hepatic dysfunction of at least 2 weeks' duration was diagnosed in 42 patients (10.4%). Of 28 patients acquiring hepatitis in the first post-transplant year, 26 (92.8%) developed chronic hepatitis; of 14 acquiring hepatitis after the first year, 9 (64.2%) developed chronic hepatitis. Of the 42 patients, 19 (45.2%) died, as compared with 16% of the nonhepatitis patients (P less than 0.001). Only one of these patients died of liver failure, with 15 of the 19 (78.9%) dying of extrahepatic infection. In addition, 12 of the 23 survivors (52.1%) suffered life-threatening infections from which they recovered, as compared with 20% of the nonhepatitis patients (P less than 0.01). Conversely, graft survival was significantly increased among the hepatitis patients (73% 1-year cadaveric allograft survival as compared with 50% for the nonhepatitis patients (P less than 0.01)). The etiology of the liver disease was identified in the minority of patients: 5 (11.9%) with hepatitis B, with none occurring since 1973; 10 (23.8%) with evidence of cytomegalovirus infection; and 1 (2.3%) with azathioprine toxicity. We conclude that the major cause of liver disease in renal transplant patients is non-A, non-B hepatitis, and furthermore, that this disease has a marked immunosuppressing effect resulting in increased allograft survival and a marked increase of life-threatening extrahepatic infection.

Immunogenicity of hepatitis B vaccine in renal transplant recipients.

To evaluate the immunogenicity of hepatitis B vaccine in renal transplant recipients, we administered three 40-microgram doses of vaccine to 17 patients who had previously undergone transplantation and were on immunosuppressive therapy. Life-table analysis revealed a cumulative antibody response rate of only 17.6% at 12 months, and the three responders had low titers of antibody to hepatitis B surface antigen. There were no serious adverse effects and no episodes of graft rejection in responders or nonresponders. In addition, the ratio of helper/inducer (T4) to suppressor/cytotoxic (T8) T cells in vaccinees bore no relationship to the immunogenicity of the vaccine. These data indicate that hepatitis B vaccine is weakly immunogenic in renal transplant recipients and illustrate the need for vaccination prior to transplantation for maximal protection against hepatitis B virus infection.

Hepatitis A virus: virologic, clinical, and epidemiologic studies.

The last decade has borne witness to accelerated expansion of our understanding of hepatitis A virus. The agent of type A hepatitis is an RNA virus with a mean diameter of 27 nm. and biochemical-biophysical properties of an enterovirus. A variety of sensitive specific serologic techniques have been developed with which to identify hepatitis A virus and antibody, and both chimpanzees and marmosets have been studied extensively as experimental animal models. As a result of these studies, in vitro cultivation of hepatitis A virus has finally been accomplished, and a commercial radioimmunoassay for IgM antibody to hepatitis A virus has been developed for the rapid diagnosis of hepatitis A virus infection during acute illness. Clinically the illness caused by hepatitis A virus is relatively mild, often subclinical, and of limited duration and does not progress to chronic liver disease. This relative clinical benignity is reflected, according to preliminary histologic observations, in the sparing of the centrozonal area of the liver lobule. Rarely, however, hepatitis A virus can cause fulminant hepatitis. Type A hepatitis is transmitted almost exclusively by the fecal-oral route, and its spread is enhanced by epidemiologic settings favoring dissemination of enteric infections. Hepatitis A virus does not contribute to transfusion associated or other types of percutaneously transmitted hepatitis. Exposure to the virus increases as a function of age and decreasing socioeconomic class, but the incidence of hepatitis A virus infection in urbanized societies is decreasing. There is no evidence for the existence of chronic hepatitis A virus carriage; natural perpetuation of hepatitis A virus in urban communities appears to depend on a reservoir of nonepidemic, clinically inapparent cases. Until a vaccine, now being developed, becomes available, prevention of hepatitis A virus infection will continue to depend on maintenance of high standards of environmental and personal hygiene and on timely administration of immune serum globulin. Such prophylaxis may confer long lasting passive-active immunity but more frequently prevents infection entirely.

Interpretation of various serological profiles of hepatitis B virus infection.

Serial serum specimens from 149 patients with clinically diagnosed hepatitis were tested for five hepatitis B serological markers: hepatitis B surface antigen and its antibody (anti-HBs); hepatitis B e-antigen and its antibody (anti-HBe); and antibody to hepatitis B core antigen (anti-HBc). The times of appearance, disappearance, and persistence of these markers were used to differentiate various serological profiles obtained from the study. Four distinctive profiles were found to be associated with acute hepatitis B followed by recovery, and three with chronic hepatitis. These serologic profiles were assessed as diagnostic and prognostic guides for clinical management of the disease.

The high-risk liver allograft recipient. Should allocation policy consider outcome?

The Boston Center for Liver Transplantation has accumulated one of the larger series of liver allograft recipients. This review has provided an opportunity to examine recent pronouncements by Medicare regarding patient selection and survival and to question whether the current allocation scheme best utilizes a scarce supply of donor liver allografts. Patients with primary biliary cirrhosis, sclerosing cholangitis, and metabolic derangements have enjoyed excellent survival: in aggregate, 78.9% at 1 year. In contrast, patients suffering from acute hepatic failure, patients requiring life support, or patients with primary graft failure who need a second liver transplant did poorly compared with other recipient groups: 45% 1-year survival. This center's experience reflects a more realistic expectation of patient survival because it considers the high-risk recipient by diagnosis and urgency status. This study also suggests that assessment of outcome should be a component of allocation planning in the future.

Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.

In a randomized, controlled trial that demonstrated the efficacy of interferon alfa-2b 3 million units three times a week for 24 weeks in controlling chronic hepatitic C (non-A, non-B), the Sickness Impact Profile (SIP) was used to evaluate the impact of disease and treatment on health-related quality of life (HRQOL). The SIP was self-administered by 160 patients before treatment, at the end of treatment, and at the study endpoint. Before treatment, patients with chronic hepatitis C scored significantly (P < 0.05) higher (worse) than an historical control group of the general population in mean total SIP score and in all categories except eating. The highest degree of impairment was observed in the work, sleep and rest, and recreation and pastimes categories. After treatment, patients who received interferon alfa-2b had significant (P < or = 0.05) improvement in work, sleep and rest, and recreation and pastimes scores. Numerical improvement was observed in total score, physical and psychosocial dimension scores, and most individual category scores. Mean SIP scores were unchanged or slightly worsened in untreated control patients. In responders (patients with improvement in serum alanine aminotransferase levels), the largest improvement was seen in work scores. The SIP appears to be a reliable and valid instrument for describing the impact of chronic hepatitis C on HRQOL but lacks disease-specificity and the ability to reflect clinically relevant changes. Thus the SIP is not the best instrument to evaluate the HRQOL effects of treatment with interferon alfa-2b in patients with chronic hepatitis C.

The cost-effectiveness of hepatitis B vaccine.

We evaluated the cost-effectiveness of different strategies for use of hepatitis B vaccine. For populations with high prevalences of immunity and high attack rates, screening for prior immunity and vaccinating susceptibles is the lowest cost strategy. For populations with low prevalences of immunity but with high attack rates, vaccination without screening is most cost-saving. For populations with low prevalences of immunity and low attack rates, a non-vaccination policy is least costly. Vaccination will be cost-saving for populations with annual attack rates of five per cent, if direct medical costs only are considered or, for populations with annual attack rates on the order of one per cent, if indirect medical costs are included.

Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial.

Seventy-five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic encephalopathy. The control group received 4 g of enteral neomycin daily along with 25% dextrose by a central venous catheter. The experimental group received a placebo resembling neomycin and isocaloric dextrose plus a modified amino acid mixture enriched with branched-chain amino acids to 36% and deficient in aromatic amino acids and methionine. Thirty patients in the F080 group and 29 in the control group completed the trial. The group receiving the modified amino acid mixture demonstrated a statistically significant improvement in encephalopathy as compared to the neomycin group, while maintaining nitrogen equilibrium. Survival and discharge from the hospital were statistically greater in the group treated with the modified amino acid solution and hypertonic dextrose. Treatment of hepatic encephalopathy in the presence of hepatic decompensation with an amino acid solution formulated for its treatment seems to produce faster, more complete recovery with improved capacity for nutritional support.

Relationship of hepatitis A antigen to viral hepatitis.

Progress in research on hepatitis type A has begun to accelerate because of the recent discovery of an antigen associated specifically with hepatitis type A infection and the development of tests for antibody to the antigen. Hepatitis A antigen is associated with 27 nm virus-like particles found in the liver and stool of animals experimentally infected with hepatitis type A and in the stool of humans experimentally or naturally infected with the virus. The density of the particulate antigen when isolated from the liver is 1.34, but antigen particles with densities ranging from 1.32 to 1.40 have been detected in stool. However, antigens from the liver and from the stool appear to be antigenically related. Using immune electron microscopy as a serologic tool for detecting antibody to hepatitis A antigen, we detected antibody in convalescent sera from 100 per cent of patients experimentally or naturally infected with hepatitis type A. In contrast, patients with hepatitis type B or non-B hepatitis not epidemiologically compatible with a diagnosis of hepatitis type A did not have a serologic response to hepatitis A antigen. Antibody was found in approximately 50 per cent of normal individuals tested; the frequency was directly related to age. By the use of immune electron microscopy for the detection of hepatitis A antigen and antibody, the temporal relationship of antigen, antibody and liver damage was determined in experimentally infected humans and chimpanzees. On the basis of serologic comparisons, hepatitis type A does not appear to be related to experimental hepatitis caused by the GB agent of Deinhardt, nor is the hepatitis A antigen serologically related to the fecal antigen of Cross.