HCV is the most common cause of chronic liver disease and the leading indication for liver transplantation in the United States. It is responsible for 8000 to 10,000 deaths annually. In this article, we review the principal diagnostic guidelines for hepatitis C.
In the 1970s, it became evident that most patients with blood transfusion-related hepatitis did not have hepatitis A or B. The disease was therefore named non-A, non-B hepatitis. The culprit organism in nearly all cases of post-transfusion hepatitis (as well as in most cases of hepatitis in injection drug users and hemophiliac patients, and those with sporadic chronic hepatitis) was identified by molecular cloning techniques in 1989 and designated hepatitis C virus (HCV).1,2
HCV is a small enveloped virus with a single-stranded RNA genome and an associated RNA polymerase that is responsible for viral replication. It is a member of the flavivirus family, which includes West Nile virus, yellow fever virus, and dengue virus.
HCV is the most common cause of chronic liver disease and the leading indication for liver transplantation in the United States. It is responsible for 8000 to 10,000 deaths annually. The overall prevalence of HCV infection has not changed during the past decade, but the age-specific prevalence has shifted to older persons, which indicates a previous hepatitis C epidemic.3
In this article, we review the principal diagnostic guidelines for hepatitis C. In a companion piece, we discuss treatment approaches.
Before HCV was identified and screening was initiated, blood transfusion was a common source of HCV transmission.4 Specific blood-product screening with HCV antibody testing has been in place since 1990; it was further refined in 1992. Consequently, the risk of transfusion-acquired hepatitis has been reduced to about 1 in 100,000. Even when transmission by transfusion was common, however, most infections probably occurred as a result of exposure by way of injection drug and intranasal cocaine use. The principal risk factors for HCV infection are listed in the Table.5
The percentage of patients who progress to cirrhosis once chronic hepatitis C is established is unknown, nor is it possible to predict the course in any individual patient. Most patients with HCV infection do not succumb to their disease, but the high prevalence of infection in the population ensures a major burden of morbidity and mortality.
Cirrhosis develops within 20 years in about 20% of patients after transfusion.6 Patients with cirrhosis not only face the usual risks of hepatic failure and portal hypertension but also have a substantial risk (1% to 4% per year) of hepatocellular carcinoma (HCC). However, the risk of HCC is remote in the absence of cirrhosis. Periodic screening (eg, every 6 months) of cirrhotic patients with a-fetoprotein tests and sonography to detect early cancer is essential.
Risk factors for more rapid progression of hepatic fibrosis in patients with chronic hepatitis C include age more than 40 years at acquisition of infection, male sex, heavy alcohol consumption (more than 30 to 50 g/d), and coinfection with HIV or hepatitis B virus.
Acute HCV infection is usually asymptomatic. Most patients with hepatitis C present long after chronic infection has become well established. The most common scenario is for patients to have unexpected elevations in liver enzyme levels at the time of routine examinations, evaluations for other conditions, or attempted blood donations. When this occurs, subsequent specific testing will reveal HCV infection.
Elevated liver enzyme levels without a history of exposure do not in themselves constitute a diagnosis of hepatitis C. However, unexplained liver enzyme elevations mandate an HCV antibody test. There is no such thing as an elevation that is "too mild" to warrant concern. It is also imperative to ask patients about previous risk factors and tests for HCV even if liver enzyme levels are normal, because up to 30% of HCV-infected patients have persistently normal serum alanine aminotransferase (ALT) levels.7 Although these patients are more likely to have mild disease than are those with elevated ALT, mild disease is by no means ensured, and such patients require individualized evaluation.
The symptoms of acute HCV infection include nausea, generalized malaise, loss of appetite, arthralgias, jaundice, and dark urine.6 Peak serum ALT elevations may be higher than 2000 U/L but are usually lower,8 and illness may persist for 2 to 12 weeks. Acute infection progresses to chronicity in about 75% to 80% of patients, but recent studies have shown that those who present with clinical illness, especially jaundice, have a better chance of clearing infection spontaneously than those who remain asymptomatic.9 Fulminant hepatitis from acute HCV infection is extremely rare.
Liver enzymes. In patients with chronic hepatitis C, as in patients with hepatocellular injury from other causes, abnormalities in ALT and aspartate aminotransferase (AST) levels are more frequent than abnormalities in levels of cholestatic markers such as alkaline phosphatase. Isolated alkaline phosphatase elevations should always raise the possibility of other types of liver disease, such as primary biliary cirrhosis, granulomatous hepatitis, infiltrative disease, or biliary tract obstruction. There is at best only a partial correlation between liver enzyme abnormalities and liver pathology.7 Fluctuations in ALT levels--sometimes into the normal range--are common in chronic hepatitis C.8 Conflicting data exist on the predictive value of an AST:ALT ratio of 1 or higher for advanced fibrosis or cirrhosis,10,11 but an AST level that is higher than an ALT level in a nonalcoholic patient suggests advanced fibrosis, as does a reduced platelet count or low albumin level.
Anti-HCV antibody. The initial diagnostic step in the identification of hepatitis C infection is the measurement of anti-HCV antibody by enzyme-linked immunosorbent assay (ELISA or EIA). This test screens the patient's serum against 3 different viral antigens. Although the EIA in current use is 99% sensitive in chronic hepatitis C, it is less reliable in acute infection, and a negative EIA result does not exclude the diagnosis of HCV infection in a patient with acute hepatitis.
A third-generation test, EIA-3, decreases the time needed for detection of seroconversion.12,13 Nevertheless, in patients with acute hepatitis, a polymerase chain reaction (PCR) test for HCV RNA should be performed along with an EIA (see below), because patients with acute HCV infection become viremic before antibody appears.
The specificity of EIA is a greater problem than the sensitivity. Many patients who have cleared the infection spontaneously continue to express the antibody. Because antibody may persist in patients with resolved infection, a positive EIA result does not necessarily denote active viremia. Moreover, some patients (including those with autoimmune liver disease or other causes of hyperglobulinemia) appear to express HCV antibody even if they do not have a history of or risk factors for HCV infection. A recombinant immunoblot assay, which tests serum against 4 different antigen bands on nitrocellulose, eliminates such false-positive findings because its results are negative in patients with no history of actual infection. Ultimately, however, all patients with positive EIA results should undergo further testing--including a PCR--for HCV RNA, irrespective of the presence or absence of risk factors or levels of ALT.
PCR. This test confirms the presence of the virus by detecting viral RNA in the serum or liver. If a quantitative PCR is ordered, it will also provide a viral load. The cutoff for many commercial versions of this test is a viral load of 50 IU/mL, or about 100 HCV RNA copies/mL. It is extremely rare for a patient with untreated chronic hepatitis C to have a viral load anywhere near this low; thus, negative test results essentially rule out the presence of active infection.
A viral load of 2 million copies or more (800,000 IU/mL) is classified as a high viral load; a number lower than this is considered a low viral load. This cutoff is somewhat arbitrary, but it has been used in many trials to distinguish levels of viremia that are associated with a greater or lesser response to treatment. Thus, a high viral load is associated with a lower chance of response to treatment in patients with genotype 1, the most common HCV genotype in the United States. It is useful to record the viral load before the initiation of antiviral therapy because measurements of viral decline at critical time points are used to predict the likelihood of cure.
Branched-chain DNA (b-DNA). B-DNA testing is another way to quantify the viral load. The cutoff for this test is 500 IU/mL; this number signifies that the virus may be present at low levels, but the test is not sensitive enough to detect it. This test is relatively cost-effective and measures linearity over a broad dynamic range, which has been a limitation of past PCR assays.
Genotype. Currently, 6 genotypes and several subtypes of HCV are known; there is a substantial degree of geographic variation.1 In the United States, genotypes 1, 2, and 3 are common and genotype 1 is predominant. HCV genotype is the most important determinant of response to interferon-based antiviral therapy and helps decide the duration of treatment: 12 months of therapy are recommended for genotype 1, while 6 months are recommended for genotypes 2 and 3. We strongly recommend that quantitative PCR results and genotype be obtained before the patient is referred to a specialist, because this information is critical in the initial discussion with the patient.
Liver biopsy. A liver biopsy is not essential in diagnosing HCV infection, but it is an invaluable tool used to grade and stage the degree of chronic liver disease with regard to inflammation and, even more important, fibrosis (Figures 1, 2, and 3). Many hepatologists perform liver biopsies in nearly all consenting patients with chronic hepatitis C to assess the degree of damage. This is an important factor in such decisions as whether to initiate therapy, how aggressively to treat in the event of significant adverse effects, whether to prolong treatment in virologic nonresponders because of putative histologic benefits (a topic of much interest at present but no universal consensus), and as a baseline against which to compare future biopsies to assess for interval progression. There is an approximately 1:1000 risk of significant hemorrhage associated with biopsy. Transient postprocedure discomfort is much more common; it is generally manageable with analgesics. Puncture of other organs, including lungs, kidney, and gallbladder, may occur rarely; many clinicians, including the senior author, use ultrasonography in all cases to prevent this possibility entirely.
Serum fibrosis testing. Recently, several serum fibrosis tests have become widely available. Although not yet FDA-approved, they aid in the evaluation of liver fibrosis without the need for a biopsy. These tests are an alternative for patients in whom the biopsy is contraindicated or when a patient declines a biopsy. A recent study shows that one such test has a specificity of 70% to 89% and a sensitivity of 33% to 80%.14 Liver biopsy remains the gold standard for the staging and grading of chronic liver disease. In the future, however, it is likely that the use of fibrosis markers will increase, and perhaps substantially supplant, liver biopsy.
Liver stiffness measurement. This noninvasive experimental test for the evaluation of liver fibrosis in patients with chronic HCV infection is based on transient elastography. According to a recent report, liver stiffness measurement is a promising and reliable method.15 It is not yet routinely available.
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