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Hepatitis C

Epidemiology

Hepatitis CHepatitis C virus, identified in 1988, is an RNA virus that appears to be responsible for most instances of parenterally transmitted non-A, non-B hepatitis. The virus seems to mutate frequently and appear in many subtypes. Table 49-6 summarizes the differential diagnosis of elevated liver tests suggesting non-A, non-B hepatitis other than hepatitis C. Hepatitis C virus is associated with transfusions of contaminated blood and blood products such as plasma, factor VIII, factor IX, fibrinogen, cryoprecipitate, and immune globulin.

Hepatitis C virus is also transmitted by intravenous drug abuse, hemodialysis, and organ transplantation. It appears to be transmitted rarely by familial, sexual, or maternal-infant exposure. Heterosexual transmission seems to be much less frequent than homosexual transmission of the virus.

Health-care workers exposed to a patient or the blood of a patient infected with Hepatitis C virus may acquire hepatitis C either from an accidental needle stick or without such an incident; however, the risk in such cases seems to be less than 10%. This occurrence has been documented in dialysis and oncology units and in plasmapheresis centers. Sporadic instances of hepatitis C occur and may account for 6% to 36% of the sporadic cases of hepatitis seen in urban areas. There may be unnoted percutaneous exposure among such patients. However, hepatitis C may also be transmitted by nonpercutaneous mechanisms. The epidemiology of hepatitis C has not been completely defined.

The disease is found worldwide and appears to be almost as common in economically developed countries as it is in underdeveloped countries.

Clinical presentation

Acute hepatitis

Hepatitis CThe mean incubation period for transfusion-associated hepatitis C is 7 to 8 weeks with a range of 2 to 26 weeks. Shorter incubation periods of 1 to 2 weeks have also been recorded.

The acute illness associated with hepatitis C usually cannot be distinguished from hepatitis caused by other heterotropic viruses. However, it tends to be less severe. Usually patients complain of flulike symptoms, easy fatigability, malaise, and anorexia with occasional nausea and vomiting; fever, arthralgia, and skin rash are rare.

Approximately 25% of patients with hepatitis C are icteric. Jaundice usually lasts less than a month. The serum transaminase (alanine aminotransferase, aspartate aminotransferase) levels are only moderately elevated (<800 IU/L).

Transient agranulocytosis and aplastic anemia have been observed in patients with hepatitis C.

A clinical feature characteristic of hepatitis C is its episodic, fluctuating pattern of serum transaminase (alanine aminotransferase, aspartate aminotransferase) activity. Periods of elevation of these enzyme levels are interrupted by months of normal or near-normal levels of liver enzyme activity.

Chronic disease

Hepatitis CLong-term follow-up studies in patients with hepatitis C have revealed that at least 90% of patients infected with Hepatitis C virus have chronic disease. The disease may continue to appear to resolve both biochemically and histologically, followed by intermittent or constant elevation of serum transaminases. Persistent viremia can prevail in the presence or absence of elevated alanine aminotransferase activity. In fact, spontaneous total resolution of the disease may occur in only a small proportion of infected individuals.

The progression to chronic hepatitis cannot be predicted from the clinical or biochemical severity of the acute illness. Anicteric as well as icteric disease may become chronic.

In most studies, the frequency of development of chronic liver disease from transfusion- associated hepatitis C is 85% to 90%. When biopsied, approximately 70% to 80% of these patients have chronic active hepatitis, and 10% to 20% have cirrhosis. The chronic active hepatitis in these patients is progressive and progresses to cirrhosis in most cases over 10 to 30 years.

Cofactors such as concomitant alcoholism, chronic hepatitis B or hemochromatosis are important contributors to progressive liver disease and cirrhosis in patients with chronic hepatitis.

Several studies have linked essential mixed cryoglobulinemia (an immune complex vasculitis associated with joint, skin and sometimes kidney involvement) and porphyria cutanea tarda with Hepatitis C virus infection.

Hepatitis C and hepatocellular carcinoma. There is convincingevidence that Hepatitis C virus infection is associated with the development ofhepatocellular carcinoma. Several patients have been reported to develop hepatocellular carcinoma 9 to 18 years after the onset of transfusion-associated hepatitis C.

Diagnosis

Serologic tests for Hepatitis C virus infection have been developed and continue to be in a stage of rapid evolution. Currently, second-generation enzyme-linked immunosorbent assay and recombinant immunoblot assay tests for anti-Hepatitis C virus (or HCAb) are commercially available. Using the enzyme-linked immunosorbent assay, anti-Hepatitis C virus is detected late during the course of acute hepatitis C, generally between 4 and 24 weeks after the onset of symptoms. In patients in whom chronic hepatitis C develops, anti-Hepatitis C virus appears to persist indefinitely; in patients in whom the infection resolves, anti-Hepatitis C virus reactivity disappears over the next few years. In acute hepatitis C, the antibody titers often rise slowly and may be detectable after many weeks; thus both acute and convalescence-phase samples must be tested.

A high rate of false-positive anti-Hepatitis C virus reactions was reported in patients with alcoholic liver disease and autoimmune chronic active hepatitis when the first-generation enzyme-linked immunosorbent assay test was being used. In these patients, anti-Hepatitis C virus positivity was correlated with the degree of hypergammaglobulinemia. In such cases, the recombinant immunoblot assay test improves the accuracy of the diagnosis. A positive test for anti-Hepatitis C virus by recombinant immunoblot assay provides confirmation of an enzyme-linked immunosorbent assay result, but a negative, indeterminant reaction cannot be interpreted as proof of a false-positive enzyme-linked immunosorbent assay reaction. The second-generation enzyme-linked immunosorbent assay test uses recombinant proteins from various regions of the Hepatitis C virus genome as antigens, and recombinant immunoblot assay uses four such proteins. By broadening the spectrum of antibodies detected, these assays have proved to be more sensitive and specific than the first-generation anti-Hepatitis C virus assays.

Hepatitis C virus RNA. Hepatitis C virus RNA cannot be detected in serum by the standard techniques such as northern blot analysis because the virus circulates in low levels. However, it can be detected by polymerase chain reaction in both serum and liver. Studies indicate that most patients with acute hepatitis C circulate Hepatitis C virus RNA during the incubation period and the symptomatic phase of the disease. Forty to seventy percent of patients with chronic hepatitis C have Hepatitis C virus RNA in their serum. Direct polymerase chain reaction for Hepatitis C virus RNA in serum may be the best means to confirm the presence of Hepatitis C virus infection and to quantify levels of Hepatitis C virus RNA in serum and the liver and thus become an important means of assessing the effectiveness of antiviral therapy.

Genotyping of Hepatitis C virus has been possible and has revealed few major genotypes: I (A and B), II, III, intravenous. Genotypes intravenous and I are most prevalent in the United States, comprising about 70% of infections. Genotypes V and I are also more resistant to the treatment modalities currently available.

Treatment of interferon monotherapy. Antiviral therapy for chronic non-A, non-B hepatitis preceded the identification of Hepatitis C virus as the causative agent for this disease. Several large multicenter trials using interferon-О±-2b (3 million units) three times per week for 24 weeks revealed that approximately 50% of the patients responded to therapy as measured by biochemical tests. However, relapse was common among the responders within 6 to 12 months after discontinuation of therapy. Sustained biochemical remissions have been seen in less than one fourth of the treated patients. However, when virologic criteria determination by polymerase chain reaction (quantitative Hepatitis C virus-RNA) is considered, the relapse rate is nearly 90%. Therefore, the likelihood of a sustained response to a 6-month course of interferon-О± (3 million units given three times a week SC) is approximately 10%. When such therapy is continued for 12 months, the sustained response rate goes up to 20%. Higher doses of interferon-О±(5-10 million units) may also reduce relapse rates but are associated with increased side effects and noncompliance. In interferon therapy, those patients who have positive Hepatitis C virus RNA by polymerase chain reaction assay at 3 months into therapy are unlikely to respond thereafter. Some authorities recommend discontinuation of therapy at this point. Other authorities concur that all patients be treated for 12 months. Interestingly, histologic improvement has been observed not only in patients who respond to therapy, but also in those patients whose biochemical and virologic improvement falls short of criteria for a successful response. The value of maintenance of interferon therapy is still debated, and trials are in progress.

Trials to improve the cure rates using initial high induction doses, cotreatment with ursodeoxycholic acid, nonsteroidal antiinflammatory drugs, ot rhymocin use of other interferons such as recombinant-О±-26 and -2a, leukocyte-derived, consensus interferon-О±, and interferon-ОІ preparations have not shown any meaningful advantage of any one preparation over the others.

Polyethyleneglycol-interferon (Polyethylene glycol-IFN). Trials using interferon-О± bound to polyethylene glycol (Polyethylene glycol), administered once a week instead of three times a week, have shown better response rates, nearly double of what has been seen with non-Polyethylene glycol interferons. Polyethylene glycol-IFN is administered in a weight-based dosage regimen.

Combination therapy of interferon-О± with ribavirin, an oral guanosine nucleoside analog has been shown to greatly improve sustained response rates in naive and relapsing patients. In treatment naive patients, interferon-О± (3 million units given SC three times a week) in combination of oral ribavirin (800-1,200 mg per day for 12 months) achieves sustained virologic response rates of approximately 30%. These rates are higher (up to 40%-50%) for patients with low viral loads and with HC, genotypes II and III combination therapy for 24 weeks achieves the same efficacy as combination therapy administered for 48 weeks (6 months). The impact of combination therapy on interferon monotherapy nonresponders is less impressive. Combination therapy of interferon-О± with ribavirin is now acceptable as first-line therapy. When Polyethylene glycol-IFNs are combined with ribavirin, sustained response rates exceeding 50% have been reported. This rate rises to 60% to 70% in non-genotype I Hepatitis C virus-infected patients. Polyethylene glycol-interferon with ribavirin therapy has been approved by the U.S. Food and Drug Administration.

Prevention

There is no vaccine for hepatitis C at this time. Prophylaxis with serum immunoglobulin is not effective.

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