Hepatitis C virus (HCV) is the primary etiologic agent of parenterally transmitted non-A, non-B hepatitis and a major cause of acute and chronic hepatitis worldwide. Although early hepatitis C research focused on infection resulting from transfusions of HCV-infected blood, subsequent studies showed that HCV is a very common cause of community-acquired viral hepatitis. A full accounting of the natural history of HCV infection is still difficult to establish because of the silent character of the acute and chronic infection and the typically protracted nature of the chronic disease.

Acute HCV Infection

The incubation period for newly acquired acute hepatitis C ranges from two weeks to six months, with an average incubation period of six to seven weeks. However, virus replication can be detected as soon as one week after exposure. Of patients with acute HCV infection, 60% to 70% have no discernible symptoms; 20% to 30% may be ill with jaundice; and 10% to 20% may have non-specific symptoms such as loss of appetite, fatigue, and abdominal pain. Antibodies to HCV (anti-HCV) become detectable during the course of illness in >=95% of HCV-infected persons. Anti-HCV can be detected in about 70% to 80% of patients at the onset of symptoms and in approximately 90% of patients within 3 months after onset.

Most patients (about 80%) who seek medical carefor symptoms related to acute hepatitis C have bilirubin levels of at least 3.0 mg/dl (average 4.1) and alanine aminotransferase (ALT) levels greater than 600 IU/l (average 1410). Only 15% of patients require hospitalization, and fulminant disease is rare. Fulminant hepatic failure is more likely to occur when patients are immunodeficient or have pre-existing liver disease.

The course of acute hepatitis C is variable, although its most characteristic feature is fluctuating, polyphasic ALT patterns. Some patients have variations of several hundreds of IU/l from week to week, and such variations are sometimes recurrent with the magnitude of the ALT elevations diminishing with time. Normalization of ALT may occur and suggest full recovery, but it is frequently followed later by symptomless ALT elevations indicating active chronic disease. This facet of hepatitis C necessitates prolonged follow-up to assure appropriate diagnosis and management. Most patients (>=85%) with acute HCV infectiondevelop persistent infection. Chronic hepatitis -- defined as persistently elevated ALT levels more than 6 months after illness onset -- develops in an average of 70%. No clinical features of the acute disease or risk factors for infection, including a history of percutaneous exposures, have been found to be predictive of chronicity.

Chronic HCV Infection

In the United States, about 40% to 60% of chronic liver disease (CLD) is associated with HCV infection. The progression of CLD is usually insidious, progressing slowly without symptoms or physical signs in the majority of patients during the first two decades after infection. Frequently, chronic hepatitis is not recognized until symptoms appear with the development of advanced liver disease. The risk that HCV-infected patients will develop severe hepatic sequelae is difficult to assess, because the number of prospective studies is small, the definitions of clinical disease differ among the studies, and histopathologic data are available only from a limited number of patients. Results from such follow-up studies have found that symptomatic liver disease was not common in patients with chronic hepatitis C. If symptoms were described by patients, fatigue was the most frequent symptom mentioned. Splenomegaly, ascites, coagulopathy, and the occurrence of bleeding esophageal varices were reported in 10% of cases. Although these studies reported that chronic active hepatitis developed in from 26% to more than 50%, and cirrhosis in 8% to 42% of HCV-infected patients an average of 3 years after onset of acute disease, longer follow-up studies of a larger number of patients indicate that during the first 20 years of HCV infection cirrhosis develops in an average of 10% to 20% of patients. Mortality due to liver disease was infrequent during this time period (range, 1.6% to 6%). HCV also appears to be a contributing cause of primary hepatocellular carcinoma (PHC). In some countries, including Japan, HCV may be the major contributing cause of PHC; in others, including the United States, HCV may play a more minor role in the etiology of PHC.

Most of the published data on chronic hepatitis C comes from cross-sectional studies of asymptomatic persons identified as anti-HCV positive through routine screening and of patients with established liver disease referred to specialists for evaluation. Among volunteer blood donors who were anti-HCV positive, about 60% had elevated ALT levels when serial testing was performed, and of the donors with elevated ALT levels who subsequently underwent liver biopsy, chronic active hepatitis or cirrhosis was found in more than 60%. However, chronic active hepatitis also was found in 8% to 35% of anti-HCV positive donors with normal ALT levels at the time of donation; studies that used polymerase chain reaction (PCR) for direct detection of virus found that these donors were also HCV RNA positive.

A high frequency of severe chronic liver disease has also been reported among patients referred to specialists for evaluation of their HCV-associated chronic liver disease. Moderate to severe chronic hepatitis has been identified in up to two-thirds of these patients, and PHC in up to 10%. Progression from milder to more severe forms of chronic liver disease has been reported to occur at rates of 5% to 10% per year.

Most studies indicate, however, that progression to CLD generally takes many years. The risk for a person with chronic hepatitis C developing PHC appears to be 1% to 5% after 20 years, with striking variations in rates in different geographic areas of the world. Once cirrhosis is established, however, the rate of development of PHC may be as high as 1% to 4% per year. Instances of PHC in HCV-infected persons with non-cirrhotic livers have been reported.

Epidemiological, clinical, and virological factors predicting severity of liver disease have not been well defined. Among factors that have been considered are modality of infection, patient age and duration of disease, genotype, serum load, degree of variation of HCV, and host immunity and environmental co-factors (hepatitis B and alcohol). The most convincing data show that age >40 years, male gender, and ingestion of >=50 g of alcohol per day increase the severity of liver disease.

Extrahepatic Manifestations

Extrahepatic manifestations that have been associated with chronic HCV infection include type II cryoglobu-linemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda. In several studies, 80% to 95% of patients with type II cryoglobulinemia (essential mixed cryoglobulinemia) were found to have evidence of HCV infection, whereas patients with type I cryoglobulinemia (monoclonal only) had no evidence of infection. Typical clinical manifestations of type II cryoglobulinemia include arthralgias, Raynaud syndrome, and purpura; peripheral neuropathy and glomerulonephritis occur occasionally. Substantial improvement in cutaneous vasculitis has been observed in HCV-infected patients who responded to interferon treatment, and clinical relapse occurred in patients whose HCV infection recurred after interferon treatment was discontinued. Characteristic histopathologic findings of membranoproliferative glomerulonephritis, including deposition of IgG, IgM and C3 in glomeruli, have been observed in renal biopsy specimens of patients with HCV infection and proteinuria. Improvement in renal function has been noted in HCV-infected patients who initially responded to interferon, but viremia and renal disease relapsed after cessation of therapy. In studies of patients with porphyria cutanea tarda (PCT), a disease caused by a deficiency of hepatic uroporphyrinogen decarboxylase, 60% to 80% of patients with sporadic (non-familial) PCT have been found to be infected with HCV, whereas patients with familial PCT had no evidence of infection. Typical clinical manifestations of PCT include hepatic dysfunction and lesions on light exposed areas of the skin, consisting of enhanced facial pigmentation, increased fragility to trauma, erythema, and ulcerative lesions. Extrinsic factors, such as alcohol consumption, estrogens and iron overload, appear to be required to trigger clinical illness in predisposed persons. HCV infection may also act as one of these triggering factors, which could account for the long-standing association of PCT with chronic liver disease. No data are available to assess the efficacy of interferon treatment in patients with PCT and chronic hepatitis C.

Other extrahepatic conditions have been reported in patients with HCV infection, including Sjögren syndrome, autoimmune thyroiditis, lichen planus, Mooren corneal ulcers, and idiopathic pulmonary fibrosis. However, definitive associations of these conditions with HCV infection have not been established. Diseases with possible infectious etiologies that have not been found to be associated with HCV infection include aplastic anemia and biliary atresia.