Digestive Problems
Diseases: Liver: Viral Hepatitis
There are five viral hepatitis diseases (A, B, C, D and E), each caused by a different virus; all five can lead to acute hepatitis, and B, C, and D can cause chronic hepatitis. Antibody blood tests detect infection by any of the hepatitis viruses, but protective vaccination is available (and recommended) only for hepatitis A and B viruses. The symptoms of hepatitis are abdominal pain, anorexia, jaundice, nausea, vomiting, fever and joint pain.
One third of reported U.S. cases of hepatitis are infectious hepatitis, caused by hepatitis virus A (HAV). The infection is spread by direct contact with infected feces, or indirectly through infected fecal contamination of food or water, and so rigorous personal hygeine is essential in limiting spread of HAV, although only the elderly and those suffering from HIV/AIDS are usually at risk of dying. HAV vaccination is recommended for travellers, those at high risk of HAV infection, and those with liver disease. Hepatitis B virus (HBV) infection is reported in 300,000 Americans yearly, 10% of whom develop chronic liver disease and an increased risk of liver cancer. HBV is spread by exposure to infected body fluids (urine, semen, blood clotting products), by nursing mothers, and by unprotected sex. There is no cure for HBV, although interferon alpha is effective in up to 50% of patients with chronic hepatitis B.
About 200,000 new U.S. cases of hepatitis C are reported yearly, mostly among African-American and Hispanic males; about 3 million Americans are chronically infected with HCV. The disease is primarily spread by contaminated blood or needles, but unproected sex and mother-to-child transmission may also occur. As with HBV, there is no cure for HCV, although about 50% of acute cases recover spontaneously. Interferon alpha is also effective in reducing severity of HCV disease. Hepatitis D virus (HDV) can be found in the setting of acute HBV infection, in which case the co-infection goes into remission, or else in the setting of chronic HBV, when persistent HDV infection develops, eventually leading to chronic liver disease. HDV is spread by contaminated blood and needles and by unprotected sex. Finally, hepatitis E virus (HEV), a common third-world disease (transmission has not been documented in the U.S.) causes acute hepatitis which usually resolves itself; with no prevention or cure available, travellers are recommended to observe strict hygeine.
Studies of hepatitis viruses at the molecular level continue to clarify mechanisms of pathogenesis and thereby identify potential therapeutic targets. Recent studies of HCV genomic RNA reveal that the 3' terminal region forms a stable stem-loop structure which binds specifically to two cellular proteins widely distributed in normal human tissues (lung heart, kidney, stomach, small intestine, and colon), an interaction which play a role in HCV replication or encapsidation in these sites. Host cell endoplasmic reticulum chaperone proteins such as calnexin, calreticulin, and BiP have been found to participate (productively in the case of calnexin) in the folding mechanism of the two HCV envelope glycoproteins E1 and E2, thereby mediating viral assembly and export. An important advance in in vitro characterization of HCV has been expression of heterologous HCV structural protein cDNA in insect cells infected with recombinant baculoviruses. This model system allows the study of structural protein assembly into enveloped virus-like particles with biophysical properties similar to putative virions isolated from infected humans. Clearly, this approach offers novel targets for vaccine development. The receptor for tumor necrosis factor, earlier implicated in HCV pathogenesis in a study of interferon alpha therapy in chronic HCV infection, has now been reported to bind specifically, through its cytoplasmic tail, to HCV core protein, promoting cell death by TNF-induced apoptosis. In the case of HBV, phosphorylation of the core protein is known to effect important functions in the viral replication cycle, including RNA packaging, DNA synthesis and recognition of envelope proteins. A recent report identifies a core particle-associated 46 kDa serine kinase which specifically binds and phosphorylates the C-terminal portion of recombinant HBV core protein.
Lastly, further details of viral interaction with host cell surface receptors were uncovered in a study of HAV binding to mutagenized versions of an integral membrane glycoprotein of African green monkey kidney cells. This protein shows sequence homology with members of the immunoglobulin superfamily, and has an N-terminal Cys-rich region with two N-glycosylation sites. HAV binding was shown to require an intact Cys region, and the first of these two glycosy;lation sites. Again, these data provide important foci for vaccine development and pharmacological intervention in HAV therapy.