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Clinical Features
Differential Diagnosis
Methods of Detection

Four million Americans are infected with the hepatitis C virus (HCV), and 30,000 new cases are expected annually. Hepatitis C is now responsible for 20% of all cases of hepatitis and causes about 10,000 deaths annually in the United States. It is the most common cause of chronic liver disease and is the most frequent reason for liver transplantation in the United States, accounting for 20% of all liver transplants. The disease will become even more of a problem during the next several decades, as most infected patients are currently in the third decade of life. Immunoprophylaxis is not available, but there is great hope that treatment can reduce the morbidity of the disease significantly. Non-A, non-B hepatitis was originally recognized more than 15 years ago, but the lack of a diagnostic test markedly limited knowledge and understanding of the disease. In a novel approach, Choo and colleagues in 1989 used molecular biology to clone HCV. These new techniques enabled the hepatitis C agent to be identified even though it could not be grown or serologically defined. Sensitive serologic tests are now available, and the risk for transfusion-related hepatitis is down to one case per 100,000 units transfused.
HCV is an RNA virus of the flavivirus family. Its heterogeneous populations of viruses is now well-appreciated. HCV can be divided into subtypes by nucleotide sequences. Variations in these subtypes explain some of the variability in disease progression, response to therapy, and complexities of vaccine development.
Like hepatitis B, hepatitis C is perpetuated by the large reservoir of asymptomatic patients with the disease. Before 1989, hepatitis C was the major cause of post-transfusion hepatitis, and transfusion was the most important mode of transmission of the disease. HCV is now rarely caused by blood transfusion because of the development of sensitive serologic screening methods. Parenteral drug use now accounts for more than half of all HCV infections. Most of the additional cases occur in patients who received transfusions or were exposed to blood products before 1990. Body piercing and tattooing are likely to increase as causes of HCV, although no specific data are yet available on their importance in the transmission of HCV. The issue of sexually transmitted HCV remains controversial, but the Centers for Disease Control reports that 10% of patients with the disease had no risk factor other than sexual contact with a person who had hepatitis or sexual activity with multiple partners. HCV RNA has not been found in the semen of seropositive patients. The risk for transmission of HCV by sexual contact can be increased by coinfection with HIV or other sexually transmitted diseases.
Another mode of transmission appears to be frequent blood contact in persons employed in the medical or dental professions. Hemodialysis patients also appear to have an increased risk for HCV infection, with 10% to 30% of long-term hemodialysis patients affected. Infection from mother to infant is a possible mode of transmission, although this path is uncommon.
Current estimates are that in patients with a firm clinical diagnosis of post-transfusion hepatitis, about 80% are positive for anti-HCV. One group estimates the current risk for post-transfusion hepatitis to be one case per 100,000 units transfused, down from as high as 450 cases per 100,000 units transfused before 1986.
Clinical Features
HCV RNA is present in the bloodstream 1 to 3 weeks after initial exposure. Liver injury usually develops in 7 to 8 weeks. Patients usually remain asymptomatic. A prodrome of nonspecific symptoms, such as malaise, fatigue, low-grade fever, and gastrointestinal symptoms, occur in one fourth of patients exposed. These symptoms are clinically indistinguishable from those of other forms of viral hepatitis. Fulminant liver failure is extremely rare. The rise in aminotransferases may well be the first evidence of disease. Because most patients are totally asymptomatic, their being infected with HCV would be missed were enzyme monitoring not conducted. Several studies have shown that peak levels of alanine aminotransferase (ALT) are not as high in HCV infection as is commonly seen in HBV or HAV infection. HCV infection most commonly exhibits a fluctuating pattern of ALT activity, sometimes with such protracted periods of normal (or near-normal) levels that it becomes difficult to determine whether the acute disease has subsided or chronic hepatitis has developed. Prospective studies of transfusion recipients in whom HCV infection develops report the incidence of jaundice to be 15% to 25% in this population. In contrast, HBV infection more frequently causes overt jaundice. Infrequently reported features include microvesicular steatosis, eosinophilic changes, and sinusoidal cell activation. Perhaps the most significant and alarming feature of HCV infection is its propensity to progress to chronic liver disease. In about 80% of patients, chronic hepatitis with viremia develops.
Almost two thirds of patients have abnormal ALT levels, but as noted, most of these patients are symptomatic. Disease progression is variable, with cirrhosis of the liver developing in 20% of patients within 20 years. Hepatocellular carcinoma occurs in hepatitis C infection, probably as a result of inflammation and regeneration. Extrahepatic signs have included arthritis, keratoconjunctivitis, and lichen planus, and laboratory data may include mixed cryoglobulinemia. Patients with compensated cirrhosis have an excellent 5-year survival, about 91%.
Differential Diagnosis
Acute hepatitis may be caused by several pathologic conditions, the most common of which are viral infections and ingestion of drugs or toxins such as isoniazid, acetaminophen, aspirin, methyldopa, propylthiouracil, halothane, sulfonamides, and nitrofurantoin. This variety makes serologic testing and medication history of paramount importance to the physician investigating hepatocellular disease. When the drug and toxin history are unrevealing, the following need to be excluded for accuracy of diagnosis: infection with viruses known to cause hepatitis (HAV, HBV, HCV, Epstein-Barr virus, cytomegalovirus, and, given the right setting, HIV and HEV), alcoholic liver disease, nonalcoholic steatohepatitis, Wilson’s disease, hemochromatosis, a1-antitrypsin deficiency, congestive heart failure, severe hypotension, and biliary tree disease. Other known causes of elevations in ALT and aspartate aminotransferase in serum are autoimmune disease, obesity (fatty liver), exercise, thyroid disease, syphilis, and a poorly defined, nonviral hepatocyte injury associated with homologous blood transfusion.
Methods of Detection
As in the investigation of any disease process, the initial steps should always be completion of a careful history and physical examination, with particular attention paid to risk factors for HCV and signs and symptoms of chronic liver disease. A history of prior transfusion of blood products, IV drug use, multiple sexual partners or sexual contact with a person known to have hepatitis, membership in a household with a known hepatitis case, and employment as a health care worker have all been suggested as risk factors.
Before 1989, testing for HAV, HBV, and HDV was available, but the agent of parentally acquired non-A, non-B hepatitis remained elusive. Fortunately, through major efforts of virologists, microbiologists, and immunologists, this period came to an end in 1989 when a radioimmunoassay, capable of detecting the presence in serum of antibody to the infectious cDNA clone belonging to HCV, became available. From these experiments followed the development of the enzyme-linked immunosorbent assay (ELISA) now widely used as a diagnostic tool for HCV infection. Enzyme immunoassays are now automated and inexpensive. Second-generation enzyme immunoassays (EIAs) are 92% to 95% sensitive. Depending on the population studied, 25% to 60% of blood donors with positive results by EIA will have positive results by the “gold standard” polymerase chain reaction (PCR) test.
Hence, the EIA has become an excellent screening test for HCV. A negative test result in a low-risk person rules out the disease. A positive EIA result needs to be confirmed by the recombinant immunoblot assay (RIBA). RIBA is a more specific test than the EIA, and a negative RIBA result means that the patient is very unlikely to have HCV infection. Patients who have positive EIA and RIBA results are very likely to be infected with HCV. An assay for HCV RNA by PCR can confirm viremia; however, a single PCR test result could be negative. These patients should be followed by repeated PCR testing and measurement of ALT levels. Patients who are candidates for antiviral therapy should undergo a liver biopsy to assess the severity of hepatitis. Quantitative testing for HCV RNA is not routinely necessary.
There are six genotypes and 30 subtypes of HCV RNA. Patients with serotypes 2 and 3 are more likely to respond to interferon alfa than patients with serotype 1. However, genotyping is not yet a standard approach to management, and patients with genotype 1 should not be excluded from treatment on that basis.
Although the response of patients with HBV infection to corticosteroids or immunosuppressive agents is well-known, little information is available about HCV in this regard. At least two studies, however, have shown that in liver disease caused by HCV, corticosteroids are of no benefit and may in fact worsen the clinical picture (as is true for HBV infection). A relentless, worldwide effort to identify a successful treatment for chronic hepatitis has included methods such as immunosuppression, immunostimulation with bacille Calmette-Guérin (BCG) or levamisole, the use of extracts from plants such as Phyllanthus canarus, and antiviral therapy with adenine arabinoside monophosphate (Ara-AMP), acyclovir, and interferon alfa. Interferon therapy has been most promising.
The interferons are a family of glycoproteins produced primarily by monocytes and transformed lymphocytes, usually in response to viral infections. Although not entirely understood, the interferons appear to act through immunomodulatory mechanisms by binding to specific cell receptors on infected cells and activating intracellular enzymes with several antiviral actions. Interferon also enhances both T-cell-mediated and natural killer cell cytotoxicity. Several types of interferon have been developed and made available through recombinant techniques. Of these, interferon alfa has definitively been shown to have anti-HCV activity. Randomized, double-blind, controlled trials in the United States have shown a complete response (normalization of ALT levels) in 48% of recipients and a partial response in another 14% after 24 weeks of interferon therapy. Most investigators agree that a dose approximating 3 million units three times weekly for 6 months is needed to obtain a response (complete or partial) in more than half of treated subjects (as many as 50% do not respond at all). Treatment is recommended for persons in whom cirrhosis is most likely to develop—including patients with persistently elevated ALT, those who test positive for HCV RNA, and those for whom liver biopsy shows portal bridging and fibrosis. Side effects of interferon alfa therapy generally are fatigue, malaise, weight loss, and mild leukopenia and thrombocytopenia. Unfortunately, a sustained response following cessation of therapy is not to be expected. Overall, only about 20% to 50% of patients treated with interferon alfa for 6 months appear to have a sustained response (one study reports a 10% sustained response rate). The benefit of larger doses or an extended treatment period, or both, remains unproven, as does the question of maintenance doses. The combination of interferon alfa and oral ribavirin has recently received FDA approval and appears to yield a more sustained response. (SLB)
Alberti A. Diagnosis of hepatitis C: facts and perspectives. J Hepatol 1991;12:279.
Discusses the advantages of various diagnostic tests for HCV (ELISA, RIBA, RIBA-2, and PCR) and points to PCR as the “gold standard” indicator of infection.
Alter MJ. Non-A, non-B hepatitis: sorting through a diagnosis of exclusion. Ann Intern Med 1989;110:583.
Two epidemiologically distinct types of non-A, non-B hepatitis are probably caused by different viruses. One type is transmitted parenterally, and the other by the fecal-oral route.
Alter MJ. Clinical, virological and epidemiological basis for the treatment of chronic non-A, non-B hepatitis. J Hepatol 1990;11:S19.
Changes in donor selection and transfusion practices with the advent of screening for non-A, non-B hepatitis have led to a decline in post-transfusion non-A, non-B infection—from 5% to 10% before 1985 to 2% to 4% in 1990.
Alter MJ, et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med 1992;327:1899.
The rate of chronic hepatitis among patients with community-acquired hepatitis C is high, but progression to liver failure is unusual.
Bennett WG, et al. Estimates of the cost effectiveness of a single course of interferon-a2b in patients with histologically mild chronic hepatitis C. Ann Intern Med 1997;127:855.
A metaanalysis of five prospective trials of interferon alfa in hepatitis C. Based on the natural history of hepatitis C, standard interferon therapy for 12 months should increase the life span of patients with hepatitis C at a reasonable cost, below that of some well-accepted interventions.
Choo QL, et al. Isolation of cDNA clone derived from a blood-borne non-A, non-B hepatitis genome. Science 1989;244:359.
Report of the cloning of the major virus responsible for blood-borne non-A, non-B hepatitis.
Davis GL. Recombinant alpha-interferon treatment of non-A, non-B (type C) hepatitis: review of studies and recommendations for treatment. J Hepatol 1990;11:S72.
ALT levels can be normalized in 38% of patients with hepatitis C by giving 2 to 3 million units of recombinant interferon alfa-2b three times per week; however, relapse rates are approximately 50% when the drug is stopped.
Davis GL, et al. Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter randomized, controlled trial. N Engl J Med 1989;321:1501.
Three million units of interferon alfa three times weekly for 24 weeks controls disease activity (normalizes ALT levels); however, relapse is common after treatment.
Dewar TN. Non-A, non-B hepatitis. West J Med 1990;153:173.
Outlines the experimental approach that has led to the identification and characterization of HCV and its role in non-A, non-B hepatitis, and summarizes what is known about preventing and treating the disease.
DiBisceglie AM, Hoofnagle JH. GI drug column: antiviral therapy of chronic viral hepatitis. Am J Gastroenterol 1990;85:650.
Interferon alfa is the most promising drug studied thus far in the treatment of chronic viral hepatitis.
DiBisceglie AM, et al. Recombinant interferon alpha therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321:1506.
Recombinant interferon alfa reduced disease activity in chronic hepatitis C as assessed by serial testing of serum aminotransferase activities and histology of liver biopsy specimens.
Donahue JG, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992;327:369.
Because of blood donor screening, the risk for HCV transmission by transfusion of blood and blood products has decreased to 0.57% from 3.84% before 1986.
Everhart JE, et al. Risk for non-A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 1990;112:544.
Conclusive evidence of HCV transmission to family members or sexual contacts of adult patients with well-documented disease was not demonstrated in this study.
Farrell GC. Treatment of chronic hepatitis C with alpha-interferon. J Gastroenterol Hepatol 1991;1:36.
Clinical response to interferon alfa occurs in approximately 50% of hepatitis C patients; relapse rate following discontinuance of the drug varies from 40% to 80%.
Garcia G, Gentry KR. Chronic viral hepatitis. Med Clin North Am 1989;73:971.
Points out the common clinical problem of chronic viral hepatitis and reviews the treatment of chronic hepatitis B, delta hepatitis, and non-A, non-B viral hepatitis (hepatitis C).
Gerber MA, et al. Histopathology of community-acquired chronic hepatitis C. Mod Pathol 1992;5:483.
In this study, liver biopsy specimens of patients known to be HCV-positive showed chronic persistent hepatitis (45%), chronic active hepatitis (35%), and chronic lobular hepatitis (2%).
Halfon P, et al. Indeterminate second-generation hepatitis C recombinant immunoblot test: detection of hepatitis C virus infection by polymerase chain reaction. J Infect Dis 1992;166:449.
Most patients with indeterminate results on immunoblot tests for HCV had positive results on PCR tests. HIV-positive patients were often HCV-negative on PCR tests.
Hess G. Treatment of chronic hepatitis C. J Hepatol 1991;1:17.
Review article documents the effectiveness of interferon alfa in chronic hepatitis C and also points out its shortcomings.
Hoofnagle JH, DiBisceglie AM. Treatment of chronic type C hepatitis with alpha interferon. Semin Liver Dis 1989;9:259.
Treatment with interferon alfa (and possibly beta) in hepatitis C leads to a marked decrease in serum aminotransferases, which is sustained following discontinuance of the drug in approximately 50% of cases.
Houghton M, et al. Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease. Hepatology 1991;14:381.
HCV is a major etiologic agent in non-A, non-B hepatitis, and advances in the study of its molecular biology have implications for the diagnosis, treatment, and control of the disease.
Hsia PC, Seeff LB. Non-A, non-B hepatitis: impact of the emergence of the hepatitis C virus. Adv Intern Med 1991;37:197.
Reviews the history, prevalence, presentation, complications, and treatment of hepatitis C.
Jacyna MR, Thomas HC. Parenterally acquired non-A, non-B hepatitis 10 years on: advances in diagnosis and therapy. Postgrad Med J 1990;66:1000.
Twenty percent of patients with chronic non-A, non-B hepatitis have no detectable anti-HCV, which suggests that one or more other parenterally transmitted agents exist.
Lumreras C, et al. Clinical, virological, and histologic evolution of hepatitis C virus infection in liver transplant recipients. Clin Infect Dis 1998;26:48.
Prospective study to define the clinical course of hepatitis C in liver transplant patients. Hepatitis C was often associated with early graft hepatitis.
Management of hepatitis C. NIH Consensus Statement 1997;15:1–41.
Independent report of a consensus panel on the diagnosis and treatment of hepatitis C. Includes an updated bibliography.
Marcellin P, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-a therapy. Ann Intern Med 1997;127:825.
Patients with hepatitis C who have been treated with interferon alfa and have persistently normal ALT levels with no HCV RNA after 6 months usually have a sustained response, histologic improvement, and no intrahepatic HCV RNA.
Osmond DH, et al. Risk factors for hepatitis C virus seropositivity in heterosexual couples. JAMA 1993;269:361.
Provides little evidence for sexual transmission of HCV.
Pereira BJG, et al. Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and in the recipients of their organs. N Engl J Med 1992;327:910.
Recipients of organs from HCV antibody-positive patients became infected with HCV.
Phillips DL. What to do with the patient with a positive HCV antibody test. Hawaii Med J 1991;50:254.
Describes the steps physicians might follow when antibody to HCV is identified in a patient.
Sherlock S, Dushelko G. Hepatitis C virus updated. Gut 1991;21:966.
Describes the methods of several investigators in their quest for a better definition of hepatitis C and for other potential non-A, non-B agents.
Terada S, Katayama K. Minimal hepatitis C infectivity in semen. Ann Intern Med 1992;117:171.
HCV RNA was not detected in the semen of seropositive patients.
Van der Poel CL, et al. Confirmation of hepatitis C virus infection by new, four-antigen recombinant assay. Lancet 1991;337:317.
This study finds the four-antigen RIBA to be a good confirmatory test for HCV infection in samples positive on C-100 ELISA; specificity of the four-antigen RIBA was confirmed by comparison with PCR testing, the gold standard.
Weinstock HS, et al. Hepatitis C virus infection among patients attending a clinic for sexually transmitted diseases. JAMA 1993;269:392.
HCV was not common in non-IV drug users presenting at a clinic for patients with sexually transmitted diseases.
Williams AE, Dodd RY. The serology of hepatitis C virus in relation to post-transfusion hepatitis. Ann Clin Lab Sci 1990;20:192.
The assay for anti-HCV is highly specific for the agent of non-A, non-B hepatitis, but the test is somewhat deficient for the diagnosis of acute-phase illness.
Zonaro A, et al. Detection of serum hepatitis C virus RNA in acute non-A, non-B hepatitis. J Infect Dis 1991;163:923.
Determination of HCV RNA by PCR can provide early information on the pathogen causing hepatitis. Viral RNA may be present before seroconversion.

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