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HEPATITIS C PROVIDER INFORMATION

The Course and Outcome of Hepatitis C
by Jay H. Hoofnagle, M.D.

Hepatitis C is caused by a small RNA virus that belongs to the family flaviviridae and is the sole member of the genus hepacivirus. First identified in 1989, the hepatitis C virus (HCV) has a single-stranded RNA genome that is ~ 9.6 kilobases in length and encodes a single, large polyprotein of ~ 3000 amino acids. The HCV polyprotein is cleaved post-translationally into multiple structural and non-structural peptides; structural components consist of a nucleocapsid core [C] and two envelope glycoproteins [E1 & E2] and the non-structural proteins are labeled NS2 through NS5. The specific functions of the individual NS proteins have not been completely elucidated. NS3 has both helicase and protease activities and the NS5 region contains the RNA-dependent RNA polymerase activity essential for RNA viral replication. These enzymatic activities are potential targets for antiviral compounds. HCV RNA also has important and highly conserved 5’ and 3’ untranslated regions (UTRs). The 5’ UTR has an internal ribosomal entry site (IRES) essential for initiation of viral protein translation and the 3’ UTR has structured RNA elements essential for both viral replication and translation.

There are neither robust cell culture systems for propagation of HCV no simple small animal models of the infection, so the replicative cycle of the virus has largely been deduced from that of other flaviviruses. HCV replicates in the cytoplasm of hepatocytes where it is not directly cytopathic. Persistent infection appears to rely upon rapid production of virus and continuous cell-to-cell spread along with a lack of vigorous T cell immune response to HCV antigens. The HCV RNA genome mutates frequently and circulates in serum not as a single species but as a population of quasispecies with individual viral genomes, differing by 1 to 5 percent in nucleotide sequence. Six major genotypes (1 to 6) and more than 50 subtypes (e.g., 1a, 1b, 2a, 2b) have been described. Different isolates of HCV differ by 5-15 percent, subtypes by 10-30 percent, and genotypes by as much as 30-50 percent in nucleotide sequence.

Hepatitis C can cause both acute and chronic hepatitis. Knowledge of the course and outcome of infection arises largely from studies in chimpanzees and previous post-transfusion and more current post-needlestick accident cases of hepatitis C. In acute hepatitis, HCV RNA can be detected in serum within one to two weeks after exposure and usually reach levels of greater than 10 times the upper limit of normal. About one-third of adults with acute infection develop clinical symptoms and jaundice, the symptomatic onset ranging from 3 to 12 weeks after exposure. In self-limited acute hepatitis C, symptoms last for several weeks and subside as ALT and HCV levels fall. Acute hepatitis C can be severe and prolonged but is rarely fulminant. Antibody to HCV as detected by enzyme immunoassay (EIA) arises at the time of or shortly after onset of symptoms, so that 30 percent of patients test negative for anti-HCV at onset of symptoms, making anti-HCV testing unreliable in diagnosis. Almost all patients eventually develop anti-HCV, although titers can be low or even undetectable in patients with immune deficiencies.

Chronic hepatitis C is marked by persistence of HCV RNA for at least six months after onset of infection. The chronicity rate of hepatitis C averages 70-80 percent, but varies by age, sex, race, and immune status. During the evolution of acute to chronic infection, HCV RNA and ALT levels can fluctuate markedly, some patients having period during which HCV RNA is undetectable and ALT levels normal. Once chronic infection is established, however, serum HCV RNA levels tend to be stable. Most patients with chronic hepatitis C have few if any symptoms, the most common being fatigue, which is typically intermittent. Right upper quadrant pain (liver ache), nausea, and poor appetite occur in some patients. Serum ALT levels are usually continuously or intermittently elevated, but the height of the elevations correlates poorly with disease activity and at least one-third of infected persons have persistently normal ALT levels. In these patients, the underlying disease is usually, but not always, mild and non-progressive. Liver histology in chronic HCV infection demonstrates chronic mononuclear cell infiltration in the parenchyma and portal areas, focal hepatocyte necrosis, and variable degrees of fibrosis.

The major long-term complications of chronic hepatitis C are cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC), which develop only in a proportion of patients and only after many years or decades of infection. Progression to cirrhosis is often silent clinically and some patients are not known to have hepatitis C until they present with the complications of end-stage liver disease or HCC. Once cirrhosis is present, the ultimate prognosis is poor.

Other complications of chronic hepatitis C can be important and affect quality of life. The major extrahepatic manifestations of chronic HCV infection are cryoglobulinemia, glomerulonephritis, seronegative arthritis, sicca syndrome, and porphyria cutanea tarda. HCV-related cryoglobulinemia is the most common: up to 40 percent of patients with chronic hepatitis C may have low levels of cryoglobulins in serum, but only 1 percent have symptomatic cryoglobulinemia with fatigue, arthralgias, skin rash, renal disease, or neuropathy.

Thus, the course of hepatitis C is variable, the severity of illness ranging from a transient, self-limited and asymptomatic infection to a chronic, progressive liver disease that leads ultimately to cirrhosis and HCC.

References:

  1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41-52.

  2. Robertson B. Meyers G. Howard C, et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses: proposals for standardization. Arch Virol 1998; 143; 143:2393-503.

  3. Farci P. Alter HJ, Wong D, et al. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N. Engl J Med 1991; 325:98-104.

  4. Alter MJ, Kniszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N. Engl J Med 1999; 341:556-62.

  5. Bellentani S, Tiribelli C. The spectrum of liver disease in the general population: lesson from the Dionysos study. J Hepatol 2001; 35:531-7.

© 2003 California Hepatitis Resource Center