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Cryoglobulinemia and cutaneous leukocytoclastic vasculitis associated with hepatitis C virus infection.

Hepatitis C virus infection is a frequent cause of non-A, non-B hepatitis worldwide. Resultant morbidity is significant; chronic liver disease develops in 50% of infected persons. Since serologic testing has become available there have been several reports of cutaneous findings in association with hepatitis C virus infection, including vasculitis, cryoglobulinemia, urticaria, and lichen planus. We describe a patient with cryoglobulinemia, chronic cutaneous leukocytoclastic vasculitis, and hepatitis C virus infection. Hepatitis C virus infection should be included in the differential diagnosis of the causes of cryoglobulinemia and leukocytoclastic vasculitis.

Cryoglobulinemia↗

Increased severity and morbidity of acute hepatitis in drug abusers with simultaneously acquired hepatitis B and hepatitis D virus infections.

Hepatitis D virus (delta agent) markers were present in 111 (36%) of 308 intravenous drug abusers who were positive for hepatitis B surface antigen (HBsAg), 52 of these having hepatitis D virus antigenaemia. IgM antibody to hepatitis B core antigen (anti-HBc IgM) was present in 92 out of 95 subjects tested, indicating that hepatitis D virus and hepatitis B virus infections had been acquired simultaneously. Hepatitis D virus markers were present in three out of four patients with fulminant hepatitis, and in 80 of 223 (36%) with mild or moderate hepatitis compared with four of 29 (14%) of those who were asymptomatic. These proportional differences were significant (p less than 0.001). Hepatitis D virus markers were present in twice as many patients positive for anti-HBc IgM requiring admission to hospital with acute hepatitis compared with outpatients attending a drug treatment centre. Tests on one patient showed complete disappearance of HBsAg, but hepatitis D antigen (HDAg or delta antigen) and hepatitis B e antigen (HBeAg) were still present in serum samples. All five patients with chronic active hepatitis had hepatitis D antibody (anti-HD) compared with seven of 24 (29%) with chronic persistent hepatitis (p = 0.008). Blocking anti-HD persisted for long periods after simultaneous infections with hepatitis B virus and hepatitis D virus but at lower titres than in patients with chronic liver disease.

Acute Disease↗

Prevalence and significance of hepatitis GB virus-c/hepatitis G virus viremia in a large cohort of patients with chronic hepatitis B infection, with chronic hepatitis C infection, and on renal replacement therapy in Hong Kong.

A total of 455 patients were recruited to study the prevalence of hepatitis GB virus-C/hepatitis G virus viremia in Hong Kong. There was no significant increase in the prevalence of hepatitis GB virus-C viremia in asymptomatic hepatitis B virus- and hepatitis C virus-infected patients compared to that of controls (1.56% and 7.14%, respectively, vs 3.85%, both P = NS). Renal patients as a whole had a significantly higher prevalence of hepatitis GB virus-C viremia compared to that of controls (13.95% vs 3.85%, P = 0.0271). The duration of the replacement therapy, especially for patients with peritoneal dialysis was associated with a higher chance of hepatitis GB virus-C viremia. Among renal patients, renal transplanted patients had the highest prevalence of hepatitis GB virus-C viraemia (19.1%) probably because of a higher susceptibility as a result of immunosuppression. However, hepatitis GB virus-C viraemia did not cause liver biochemistry derangement in renal transplanted patients.

Adult↗

Changing epidemiology and prevention of hepatitis A virus infection.

Hepatitis A virus infection is a world-wide public health problem and commonly found in many developing countries, especially in areas where the infection pattern is changing from hyperendemic to hypoendemic. Due to improvement of living standard, infections during childhood have been deferred towards adulthood. Hepatitis A infection in early childhood is usually subclinical, while symptomatic hepatitis A occurs with increasing age. In Southeast Asia, hepatitis A antibody prevalence had considerably declined among the children and adolescents. These data probably reflect the remarkable improvement of hygienic conditions and of effective health education. An increase in the number of susceptible populations could result in an outbreak and become a problem in the near future, particularly in schools, communities and among high risk groups. Therefore, preventive measures are essential in reducing the infection rate. In addition to personal hygiene, immunoprophylaxis represents another promising measure. The hepatitis A vaccines have proven to be safe and efficacious in several clinical trials and are available in many countries. However, the vaccine is very expensive for those residing in developing countries. If possible, reducing the usage of vaccine to one single dose and thus lowering the price would facilitate the implementation of mass vaccination campaigns and thus contribute to the control and possibly to the eventual eradication of the disease.

Hepatitis A↗

Immunopathogenesis of hepatitis C virus infection.

Hepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined.

Animals↗

Immunology of hepatitis C virus infection.

Hepatitis C virus (HCV) is known for its ability to establish persistent infection and cause chronic hepatitis in most infected individuals. The pathogenesis of hepatic injury and the precise mechanisms underlying viral persistence are unknown. Accumulating evidence indicates that successful elimination of HCV is associated with the induction and maintaining of strong helper T-cell and cytotoxic T-cell responses against multiple viral epitopes. In contrast, patients who develop chronic HCV infection are characterized by the lack of strong viral-specific helper T-cell responses. The failure to mount and maintain strong HCV-specific T-cell responses may be determined by the genetics, especially the major histocompatibility complex background, of the host. However, it is likely that other host and viral factors are also involved in determining the outcome of HCV infection. Available data suggest that HCV is not cytopathic to hepatocytes and that liver injury associated with chronic HCV infection is likely to be mediated by immune responses against HCV-infected hepatocytes. In addition to hepatitis, HCV infection may also cause breaching of immune tolerance, leading to autoimmune disorders. Although the lack of a small animal model and a tissue culture system has impeded research on hepatitis C virus (HCV) infection, recent studies in humans and chimpanzees have significantly enhanced our understanding of the interaction between HCV and the host's immune system. This review focuses on the most recent advances in our understanding of the immunology of HCV infection. In particular, the possible mechanisms of how HCV establishes chronic infection are discussed. The pathogenesis of liver injury, the immunogenetics of HCV infection, and the effect of HCV infection on host's immune function are also reviewed.

Journal Article↗

Hepatitis D infectivity profile among hepatitis B infected hospitalised patients in Calcutta.

450 hospitalised cases of hepatic and non hepatic disorders and 100 normal individuals were examined for serum Hepatitis B Surface antigen and Delta Virus antigen by ELISA to find out its association with different clinical disorders. 105 patients (23.3%) and 2 control (2%) were positive for HBsAG. 60 cases with jaundice (26%) were HBsAg positive. 65% of HBsAg positive jaundiced patients had serum bilirubin level more than 2 mg per dl with a mean SGPT level of 488 iu/L. Only two cases were positive for HDV antigen among 60 HBsAg positive jaundice patients indicating a lower rate of prevalence of infection (3.3%). 62 (59%) out of 105 HBsAg positive cases did not show any history of blood transfusion or surgical interference indicating a positive HBV transmission through needle prick during investigative procedures.

Alanine Transaminase↗

Treatment of autoimmune and extrahepatic manifestations of hepatitis C virus infection.

Hepatitis C virus (HCV) infects mononuclear cells and may be responsible, as are other viruses, for immunologic disorders. The immunologic abnormalities observed in HCV infections are usually non-specific (i.e. cryoglobulinemia, immune complex deposits, autoantibodies). The association with cryoglobulinemia is clear and cryoglobulinemia-related symptoms are usually improved by interferon alpha treatment, although patients often relapse after the end of treatment. The relationship with other immunologic abnormalities is less clear. The occurrence of antismooth muscle or anti-nuclear antibodies does not seem significantly different in hepatitis C infection than in other hepatic disorders, particularly hepatitis B. However, anti-liver kidney microsomal (LKM1) antibodies are present significantly more often than in patients with other liver diseases. When clinical, histologic and biological findings suggest HCV infection with chronic hepatitis, interferon alpha or combination therapy with ribavirin are treatment options When the clinical context and results of laboratory tests suggest an autoimmune disorder or overlap syndromes (i.e. both autoimmune and viral hepatitis), interferon should not be given as a first intention, since revelation or exacerbation of autoimmune hepatitis has been reported with interferon. A marked prevalence of anti-HCV antibodies has also been reported in patients with sialadenitis, lichen planus and thyroiditis. Interferon may induce or worsen these immunologic diseases, but there are very few studies showing improvement of these manifestations with interferon.

Antiviral Agents↗

Prevention of hepatitis A virus infection.

Hepatitis A virus infection is major cause of acute hepatitis in the United States, accounting for approximately 75,000 cases of clinical illness each year. These infections occur among persons in every age group and are associated with a variety of exposures related to fecal-oral transmission. Recently, the U.S. Food and Drug Administration approved licensure of two inactivated hepatitis A vaccines. Both vaccines are highly immunogenic and have been licensed in pediatric and adult formulations. The prevention of hepatitis A virus infection is directly related to many aspects of family practice, and family physicians may see patients in a variety of settings that warrant administration of hepatitis A vaccine. Groups for whom vaccination is currently recommended include international travelers, children in communities with high rates of hepatitis A virus infection, men who have sex with men, Illicit drug users, patients with chronic liver disease and persons with clotting factor disorders.

Hepatitis A↗

What is (cost) effective in patients with chronic hepatitis C virus infection?

Hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma. Chronic hepatitis C infection is a leading cause of chronic liver disease and the most common indication for liver transplantation. Combination therapy of interferon alpha and ribavirin is currently the standard regimen for chronic hepatitis C. This combination can achieve viral clearance in approximately 40% of patients, and improve histology and prognosis. The most cost-effective approach to guide duration of combination therapy is HCV genotyping. Cost effectiveness cannot be improved further by taking other well-defined predictive factors for sustained virological response into account. Recent insights into HCV kinetics and the correlation between initial viral decline and sustained virological response will allow us to optimize and individually tailor antiviral treatment Individualized treatment according to the initial viral decline, together with further improvements in drugs (e.g. by long-acting pegylated interferons), will have new impact on antiviral efficacy and cost effectiveness.

Antiviral Agents↗

Hepatitis G virus infection in hepatitis C virus-positive patients co-infected or not with hepatitis B virus and/or human immunodeficiency virus.

This was a retrospective study to evaluate the prevalence and impact of hepatitis G virus (HGV) infection in hepatitis C virus (HCV)-positive drug addicts, according to the serological status of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. Two hundred and thirty-five randomly selected intravenous drug addicted patients (147 French, 88 Italian) were studied. All patients were positive for antibodies to HCV (anti-HCV). HGV RNA positivity was measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Comparisons of HCV RNA positivity rate, and biological and histopathological variables, were made between HGV RNA-positive and negative patients, according to their HBV and HIV status. HGV prevalence was around 30% in both French and Italian groups. No clear association between HGV infection and a particular HCV genotype was observed. The rate of HCV RNA positivity did not differ between HGV-positive and HGV-negative patients after stratification for hepatitis B surface antigen (HBsAg) and HIV positivity. Histological severity of the underlying chronic hepatitis did not differ according to the HGV status; however, in HIV-positive HBsAg-negative patients, the hepatitis activity was moderately increased in HGV-positive patients. A striking negative influence of HBsAg positivity on HCV replication was observed in HIV-negative patients; an HCV RNA-positive rate of 25% was found in HBsAg-positive patients vs 86% in HBsAg-negative patients; similar significant results were observed in HIV-positive patients, although to a lesser extent. The underlying chronic hepatitis was significantly more severe in HBsAg-positive than in HBsAg-negative HIV-negative patients. Hence, HGV infection is highly prevalent in anti-HCV positive drug addicts but the co-infection with HCV does not seem to influence HCV replication nor to worsen the underlying chronic hepatitis, in HIV-negative patients at least. Reciprocal influence between HBV, HCV and HIV appears rather complex, HBsAg carriage seeming to exert per se a negative effect on HCV replication, particularly in HIV-negative patients, suggesting that interactions between hepatitis viruses should always be analysed in the light of HIV status.

Adult↗

Hepatitis C virus RNA and antibody response in the clinical course of acute hepatitis C virus infection.

Hepatitis C virus RNA, anti-hepatitis C virus immune response and biochemical markers of liver injury were investigated in 17 patients with acute non-A, non-B hepatitis. At the first observation, 1 to 3 wk from the clinical onset, all patients had hepatitis C virus RNA in their serum, and most (15 of 17) were positive for second-generation anti-hepatitis C virus enzyme immunoassay. Follow-up serum samples were available for 10 patients. The rate of recombinant immunoblot assay-confirmed anti-hepatitis C virus enzyme immunoassay reactivities increased from 67% in the first 3 wk to 86% after 21 wk. Elevated ALT levels were associated with hepatitis C virus RNA positivity in most of cases, but the viral nucleic acid was also detected in sera with normal or slightly increased enzyme values. None of the single antibodies tested were related to hepatitis C virus RNA positivity or to the clinical phase of the infection. Therefore hepatitis C virus RNA determination might provide important additional information as compared with anti-hepatitis C virus markers, allowing earlier diagnosis, discrimination of active infection and, possibly, prognostic evaluation.

Acute Disease↗

Global epidemiology of hepatitis C virus infection.

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.

Blood Transfusion↗

Detection of hepatitis C virus antigen by immuno-histochemical staining: a histological marker of hepatitis C virus infection.

Hepatitis C virus has been recognized as a major cause of non-A, non-B viral hepatitis. Although serologic tests have been commercialized, no specific histological or immuno-histochemical markers for hepatitis C virus infection are available for routine use. In an effort to detect hepatitis C virus antigen in liver tissue we investigated the immuno-reactivity to monoclonal antibodies on frozen liver tissue from a chimpanzee and patients with chronic non A, non B hepatitis. Monoclonal antibodies were developed in mice immunized with a synthetic peptide derived from hepatitis C virus core antigen. One monoclonal antibody was reactive and showed typical cytoplasmic granules in chimpanzee hepatocytes. Using this monoclonal antibody a similar staining pattern was found in the liver biopsies of 21 out of 28 chronic non-A, non-B hepatitis patients, positive for hepatitis C virus-RNA and anti-HCV. The granular immuno-reactivity was abolished after pre-incubation of this monoclonal antibody with infected chimpanzee liver or with hepatitis C virus synthetic peptide but not with normal chimpanzee or human liver tissue. There was no reactivity in four patients with hepatitis C virus-RNA-negative, anti-HCV-positive chronic non-A, non-B hepatitis, in 11 patients with chronic type B hepatitis or in 12 hepatitis C virus-RNA-negative, anti-HCV-negative patients with various liver diseases. However, staining was found in three out of four additional chronic type B hepatitis patients suspected of co-infection with non-A, non-B agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

Histopathology of hepatitis C virus infection.

Hepatitis C can cause a range of hepatic histopathology. The virus may cause an acute hepatitis indistinguishable from any other acute viral hepatitis, but it is more likely to be associated with steatosis, bile duct injury, and portal lymphoid aggregates. Chronic infection with hepatitis C can range from mild nonspecific changes, presumably representing a hepatitis C carrier state, to end-stage liver disease with cirrhosis and hepatocellular carcinoma. Between these are chronic hepatitis of varying severity. Steatosis, portal lymphoid aggregates, and bile duct injury, while not specific, are very characteristic of chronic hepatitis C. Reputed precursors of hepatocellular carcinoma, including liver cell dysplasia and adenomatous hyperplasia, frequently follow the development of cirrhosis and are presumed to predispose to the development of malignancy. New techniques for localizing the virus in liver tissue will undoubtedly lead to greater understanding of the pathogenesis of hepatitis C-related diseases.

Acute Disease↗

Existing and future therapeutic options for hepatitis C virus infection.

Hepatitis C virus (HCV) infection is an important cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver failure worldwide. Chronic hepatitis C virus infection is treated with interferon-a (IFN-alpha), pegylated interferon-alpha (PEG-IFNalpha) alone or in combination with ribavirin; however, a significant fraction of patients either fail to respond or relapse after cessation of therapy. Efforts to identify and develop highly specific and potent HCV inhibitors have intensified recently. Each of the virally encoded replication enzymes has been a focus of studies as well as viral receptors and the host immune system. This review summarizes recent progress in the search for novel anti-HCV agents.

Antiviral Agents↗

Clinical manifestations and diagnosis of hepatitis A virus infection.

Hepatitis A is an acute, necroinflammatory disease of the liver which results from infection by the hepatitis A virus (HAV). The mean incubation period is approximately 30 days. Although the disease is usually self-limited, the severity of illness is age-dependent. In children, hepatitis A is usually asymptomatic, while in adults, symptomatic infection is characteristic and jaundice is common. Fulminant hepatitis A is rare and is also age-dependent. The onset of hepatitis A is often abrupt and characteristic prodromal symptoms are followed, within a few days to a week, by dark urine and jaundice. Mild to moderate tenderness over an enlarged liver is usually detected. Serum alanine and aspartate aminotransferase levels usually both rise rapidly during the prodromal period, reach peak levels and then decrease by approximately 75% per week. Serum bilirubin concentrations reach peak levels later and decline less rapidly than serum aminotransferases. Nonetheless, the period of jaundice persists for < 2 weeks in approximately 85% of cases. Nearly all adult patients with clinically apparent disease experience complete clinical recovery with restoration of normal serum bilirubin and aminotransferase values by 6 months. Relapses and prolonged cholestasis are unusual manifestations of hepatitis A, and even in these circumstances, recovery is the rule and chronic hepatitis is not seen. The diagnosis of hepatitis A requires the detection of immunoglobulin M antibody to HAV in a patient who presents with, or has recently had, clinical features of hepatitis (icteric or anicteric disease) or in an individual with inapparent, asymptomatic infection in whom serum aminotransferase elevations may be detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

[Physiopathology of hepatitis B virus infection].

Hepatitis B associated antigen (HB-Ag) may be observed in the serum in subjects either apparently healthy or exhibiting a number of disease symptoms. Its incidence among the Geneva voluntary blood donors is 0.48% with 54% exhibiting the surface antigen ad and 34% ay. While the HB-Ag positive blood donors appeared clinically healthy, minor pathology was found in the majority of them (thrombocytopenia, histological evidence of inflammatory foci, of persistent hepatitis and of chronic aggressive hepatitis). In 82 patients suffering from hepatitis B the same ad-ay type distribution of the HB-Ag has been found. In 11 out of 31 patients increased Clq binding suggests the presence of circulating complexes. Diminutions in the level of complement components also indicates participation of complement in the formation of immunocomplexes. In 2 out of 3 patients with Hb-Ag positive polyarteritis nodosa, the Clq binding test was also positive. The pathophysiologic implications of hepatitis B infection are discussed in connection with the authors and other findings. It appears that the main defense mechanism leading to elimination of the viruses within the hepatocytes lies in cell mediated immunity. Hepatitis would then represent the side reaction of this defense mechanism. Antibodies are probably useful in preventing the virus from entering the cell, but also in the course of the cell mediated defense mechanism (elimination of viral material liberated during the T-cell hepatocellular interaction). Immune complexes may be operative in certain extrahepatic manifestations such as arthralgia. Polyarteritis nodosa may result from local antibody interaction with antigen fixed within arterial walls.

Antibodies↗