A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.     

Enterically transmitted hepatitis. Hepatitis A and E viruses.

Enterically-transmitted hepatitis is caused by hepatitis A virus and hepatitis E virus. The most important agent is hepatitis A virus, which is distributed worldwide and infects all age groups. Most infections in children are minimally symptomatic and immunity is long-lasting, so severe disease tends to occur in nonimmune adults. Hepatitis E virus is found in the developing world and has a greater propensity for symptomatic infection of children. Both agents are transmitted via contaminated water, often through food vehicles.     

A benign course of histiocytosis X

A case is reported of an accurate diagnosis of chronic histiocytosis X initiated with lung affection. The disease is characterized by a benign course for 7 years in the absence of treatment in spite of associated viral infection (hepatitis B virus) which is suggested to be one of causative factors of histiocytosis X.     

Novel anti-hepatitis B agents: A focus on telbivudine

Although preventable by vaccination, hepatitis B infection is common, affecting more than 350 million individuals worldwide. Chronic hepatitis B infection is associated with the complications of chronic liver disease including cirrhosis and hepatocellular carcinoma. Current agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy and a demand for new agents and strategies continues. This review focuses on telbivudine, a novel agent in the fight against hepatitis B.     

Hepatitis A and HIV: a clinical review of disease and strategies for prevention.

Hepatitis A, also known as infectious hepatitis, remains one of the more commonly transmitted types of viral hepatitis in the United States. Given the high prevalence of this illness, clinicians need to be aware not only about the clinical manifestations of this disease, but also about the special considerations that must be taken into account for persons coinfected with HIV. Antiretroviral management during acute hepatitis infection may be complicated by elevations of serum liver enzyme tests as well as by severe manifestations of associated symptoms such as nausea and vomiting. This article provides a brief overview of the clinical course of HIV infection and includes recommendations for antiretroviral medication management during acute illness. Additionally, strategies for prevention of disease are presented, with a focus on the efficacy and use of hepatitis A vaccines in persons with HIV.     

Failure of interferon to prevent recurrent hepatitis B infection in hepatic allograft

Chronic liver disease associated with hepatitis B virus infection is both common and serious; no satisfactory treatment currently exists. Orthotopic liver transplantation is an option for patients with end-stage liver disease associated with hepatitis B virus infection despite the risk of allograft reinfection. Passive immunoprophylaxis has been attempted perioperatively to prevent graft infection but has not been beneficial. Some patients with chronic type B hepatitis have benefited clinically from antiviral therapy and, in particular, interferon, but its use has not previously been reported as an approach to prevent allograft infection. We administered recombinant leukocyte A interferon perioperatively to a patient who underwent liver transplantation for type B chronic active hepatitis and cirrhosis. Circulating hepatitis B virus DNA was found postoperatively while the patient was receiving interferon, and stainable viral antigen subsequently reappeared in the transplanted liver. Thus, the drug failed to prevent viral replication and allograft infection. Thus far, no evidence of progression of the chronic hepatitis has been noted.     

Viral hepatitis in India

Hepatitis in India is caused mainly by hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV). HAV infection occurs frequently in children, though in parts of India there is an evolving epidemiology. HEV is the most common cause of acute sporadic hepatitis in India and has been associated with several large-scale epidemics in the past. India belongs to the intermediate endemicity zone for HBV carriers. HBV is the major cause of chronic liver disease and liver cancer. Horizontal transmission of HBV plays an important role. Genotypes D, A, and C have been reported in India. HCV is transmitted mainly through suboptimal blood banking and injection practices in India. Genotype 3 is the most predominant, followed by genotype 1.     

Hepatitis A and E enterically transmitted virus infections of the liver

Hepatitis A virus (a picornavirus) and hepatitis E virus (so far unclassified) are small, non-enveloped and relatively stable RNA viruses with many similar, yet, not identical characteristics. Both viruses are transmitted preferentially by the fecal-oral route. Consequently, their spread is favoured by poor personal hygiene and inappropriate sanitary conditions. Infection can pass subclinically, take an acute and self limiting course, and can also manifest as fulminant hepatitis with liver failure. True chronic disease is unknown. Laboratory diagnosis is preferentially performed by serology, but can also be complemented by assay for viral RNA in stool or serum. Resolution of infection leads to immunity which, in the case of hepatitis A, is known to be fully protective and most likely lifelong. Available hepatitis A vaccines are able to induce a similar state of protection. Vaccines for hepatitis E are under development. Specific antiviral treatment is not yet available, neither for hepatitis A nor for hepatitis E.     

Hepatitis A

The introduction of hepatitis A vaccines in 1995 led to a drop in the number of reported cases of hepatitis A and a shift to a higher percentage of cases occurring in older age groups. The hepatitis A virus survives for extended periods in the environment. Transmission primarily is fecal-oral, although there have been rare instances of transmission through blood products. The virus appears sporadically and is spread by close personal contact, with occasional food-borne outbreaks. Older persons infected by the virus usually develop a symptomatic infection with abrupt onset, fever, and jaundice lasting two months. Children usually have an asymptomatic infection and rarely develop jaundice. Laboratory diagnosis is made by detection of antihepatitis A virus immunoglobulin M in serum. Ten to 20 percent of symptomatic patients experience a prolonged or relapsing course of illness, but chronic infection has not been reported. Fulminant infection occurs in less than 1 percent of patients and can result in emergent liver transplant or death. Prevention starts with thorough handwashing and careful food handling. Prompt disease reporting, the identification of exposed persons, and expeditious administration of immune globulin prevent secondary transmission of the disease. Physicians should consider routine vaccination of children 12 to 23 months of age based on recommendations from the Centers for Disease Control and Prevention. Vaccination for children two years or older and adults should be included in routine preventive care for those at increased risk of contracting the disease (e.g., travelers to certain countries, men who have sex with men, drug abusers, recipients of clotting factor replacement) and for persons with chronic liver disease.     

Importance of hepatitis vaccination in patients with chronic liver disease

Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.     

Molecular methods of hepatitis C genotyping

Hepatitis C virus is an RNA virus that is associated with chronic infection in the majority of people infected. Chronic infection with hepatitis C virus is the cause of significant morbidity and mortality worldwide and is associated with a large spectrum of liver disease including cirrhosis and hepatocellular carcinoma. End-stage liver disease due to chronic hepatitis C virus infection is currently the leading indication for liver transplantation in the USA. Hepatitis C virus genotyping of viral isolates circulating in the blood during chronic infection has become an important part of hepatitis C virus monitoring in chronically infected patients, and is useful as a prognostic indicator and to direct duration of therapy. This review will summarize information on hepatitis C genotyping, describe the limitations of current commercially available methods, give information on more recently developed methods, and provide a look to the future in terms of where advances in hepatitis C virus genotyping assays need to be made.     

Reversible encephalopathy secondary to paratyphoid infection and concomitant acute Hepatitis A

Reversible encephalopathy has been described in association with typhoid fever as well as nontyphoidal salmonella infections. A diagnostic dilemma as to the cause of encephalopathy may arise when there is coexistent acute viral hepatitis and suspicion of fulminant liver failure. The authors report a patient who presented with acute icteric hepatitis A infection and a concomitant febrile illness due to Salmonella paratyphi associated with progressive encephalopathy and coma. The young man developed high-grade fever and coma. Concomitant infection with S. paratyphi was diagnosed and the patient's encephalopathy resolved rapidly with antibiotic therapy. This is the first report of a putative association of S. paratyphi infection and reversible encephalopathy. Salmonella and hepatitis A virus infection are both transmitted via the fecal-oral route, and awareness of this association is important in the management of such patients.     

Epidemiology and clinical course of perinatally acquired hepatitis B infection

A report is presented on 10 children with perinatally-acquired hepatitis B virus infection. In 9 cases the mother was most probably the source of infection (vertical transmission of hepatitis B), whilst one child was infected via repeated blood transfusion. 7 mothers were of south-eastern European and/or Anatolian origin. Only 2 mothers suffered from clinically apparent liver disease (one had chronic-aggressive hepatitis with positive HBs-antigen and the other had acute hepatitis B). All the others were healthy hepatitis B carriers. Of 7 mothers examined 2 were HBe-antigen positive, and 5 were anti-HBe positive. The clinical course of infection in children varied: 2 children developed subclinical infection, 2 developed acute hepatitis B, which was fulminant with a fatal outcome in one. 6 children showed antigen persistence (HBs-antigen carriers) over the whole period of observation. In one child this antigen persistence is associated with cirrhosis of the liver, 3 children suffer from chronic-persistent hepatitis B, 2 children are healthy carriers; all children are HBe-antigen positive and, thus, seem to be highly infectious. Apart from the risk to the individual, perinatal hepatitis B infection in a certain population. Hence, preventive measures are indicated and should be carried out in form of HBs-antigen screening of pregnant women - at least of high-risk groups - and active-passive immunization of the newborns at risk. The indication for immunization should not depend on the HBe-antigen status of HBs-antigen positive mothers.     

Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise.

Chronic liver disease is the 10th leading cause of death in the United States. Hepatitis C virus infection is the most frequent cause of chronic liver disease and the most common indication for liver transplantation. Preventive care can significantly reduce the progression of liver disease. Alcohol and hepatitis C virus are synergistic in hastening the development of cirrhosis; therefore, patients with hepatitis C infection should abstain from alcohol use. Because superinfection with hepatitis A or B virus can lead to liver failure, vaccination is recommended. Potentially hepatotoxic medications should be used with caution in patients with chronic liver disease. In general, nonsteroidal anti-inflammatory drugs should be avoided; acetaminophen in a dosage below 2 g per day is the safest choice. Many herbal remedies are potentially hepatotoxic, and only milk thistle can be used safely in patients who have chronic liver disease. Weight reduction and exercise can improve liver function in patients with fatty liver.     

Peginterferon alpha/ribavirin combination therapy for the treatment of hepatitis C infection.

Chronic infection with the hepatitis C virus is widespread in the United States. This disease is associated with a progression of fibrosis of the liver leading to liver cirrhosis in as many as 20% of cases. The current standard of care for the treatment of chronic hepatitis C infection is combination therapy with pegylated interferon alpha plus ribavirin. In more than 50% of patients, this regimen has been shown to induce a sustained viral response, defined as undetectable hepatitis C viral ribonucleic acid (RNA) for 6 months after the end of treatment. Typically, patients are treated for 24 or 48 weeks. A number of possible adverse events are associated with combination therapy, and patient empowerment through supportive nursing care is critical to facilitating patient adherence to treatment. This article provides an update on information concerning the diagnosis and treatment of chronic hepatitis C infection. This information can be tailored to provide patient-focused assessment, education, and treatment.     

The natural history of childhood-acquired hepatitis C infection in patients with inherited bleeding disorders

BACKGROUND: Although many patients with inherited bleeding disorders have been infected with hepatitis C in early childhood, the natural history of infection in this patient group remains poorly defined. STUDY DESIGN AND METHODS: A total of 212 patients with inherited bleeding disorders born between 1976 and 1992 were evaluated for hepatitis C virus (HCV) infection, spontaneous clearance, and (by noninvasive tests) progressive liver disease. RESULTS: A total of 120 of 212 patients had been exposed to non-HCV-inactivated clotting products, and 68 of these 120 patients (57%) were anti-HCV-positive. Of these patients, 44 (65%) had chronic hepatitis C (HCV RNA-positive) and 24 (35%) showed spontaneous clearance (HCV RNA-negative). Five patients with hepatitis C were coinfected with hepatitis B virus and/or human immunodeficiency virus (HIV). Multivariate analysis indicated that hepatitis C infection was independently associated with longer treatment period (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9) and exposure to a larger number of donors (OR, 2.1; 95% CI, 1.1-3.9). Spontaneous HCV clearance was associated with a younger age at first exposure to clotting product (p = 0.02). After a mean infection period of 21 years, evidence of cirrhosis was present in 2 patients (5%), both of whom were coinfected with HIV. CONCLUSION: Spontaneous HCV clearance is associated with young age at infection. Despite frequent childhood-acquired hepatitis C infection among patients with inherited bleeding disorders, progression to cirrhosis after 21 years of infection is rare. The diagnosis of cirrhosis without biopsy, however, remains challenging in this population, and new, noninvasive means must be developed to accurately identify cirrhotic patients.     

Conditions associated with hepatocellular carcinoma

The most important condition associated with hepatocellular carcinoma is chronic hepatitis B virus infection. This article summarizes the information linking hepatocellular carcinoma with conditions other than hepatitis B virus infection.     

Persisting HIV-1 replication triggered by acute hepatitis A virus infection

We report the case of two patients in whom acute hepatitis A was associated with a marked and prolonged increase in human immunodeficiency virus type 1 (HIV-1) viral load. Although in one patient the rise in HIV-1 RNA might also have been related to the interruption of antiretroviral therapy, we also observed a similar pattern in the other patient who had a stable undetectable plasma viraemia prior to acute hepatitis and never received treatment with anti-retrovirals. Our observation supports the hypothesis that immune activation that is induced by acute hepatitis A virus (HAV) infection may trigger HIV-1 replication. This highlights the importance of maintaining antiretroviral therapy throughout the acute phase of hepatitis A and of preventing HAV infection through active immunization.     

A method for detecting specific anti-C100 protein antibodies of IgM isotype in hepatitis C virus infection

Summary A method for the determination of specific IgM antibodies to C100 protein, a hepatitis C virus-associated antigen, was developed which employed fraction of serum proteins by gel chromatography and an enzyme-linked immunosorbent assay. Detection of IgM anti-C100 proved to be specific and reproducible in purified IgM fractions. Separation of IgM from IgG was necessary before IgM could be measured, because of the detrimental effect of the simultaneous presence of IgG antibodies with anti-C100 rectivity on IgM determination. IgM anti-C100 was not found in sera containing rheumatoid factors or IgM antibodies to other hepatotropic viruses. IgM anti-C100 was detected in 19 (44%) of 43 patients with hepatitis C virus-related chronic liver disease. When compared with the histological picture of liver disease, IgM anti-C100 was absent in patients with minimal changes and was most common (66.7%) in patients with progressive disease. It is suggested that IgM anti-C100 could reflect an active state of hepatitis C virus infection.     

Therapeutic vaccination against chronic hepatitis B virus infection

Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV) infection are among the most serious human health problems in highly endemic regions. Despite the existence for many years of effective vaccines against HBV, more than 370 million people remain persistently infected with HBV today. Currently available therapies fail to provide long-term control of viral replication in most patients. Viral persistence has been associated with a defect in the development of HBV-specific cell-mediated immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of terminating this persistent infection. The immunogenicity of HBV envelope- or capsid-based vaccines, new formulations for recombinant vaccines as well as DNA-based vaccines are currently under investigation in clinical trials. Although improvements are still required, vaccination would be the therapeutic procedure with the lowest cost and the potentially greatest benefit.