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Diagnosis


DIAGNOSIS

Liver infected with hepatitis cThe diagnosis of "hepatitis C" is rarely made during the acute phase of the disease because the majority of people infected experience no symptoms during this phase of the disease. Those who do experience acute phase symptoms are rarely ill enough to seek medical attention. The diagnosis of chronic phase hepatitis C is also challenging due to the absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades into the disease.


Chronic hepatitis C may be suspected on the basis of the medical history (particularly if there is any history of IV drug abuse or inhaled substance usage such as cocaine), a history of piercings or tattoos, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing. Occasionally, hepatitis C is diagnosed as a result of targeted screening such as blood donation (blood donors are screened for numerous blood-borne diseases including hepatitis C).


There are 2 types of tests available: serologic tests and virologic tests. Serologic tests measure antibodies within the blood stream of patients exposed to HCV. Serologic tests are highly sensitive, but results vary depending on the patient population being evaluated. Antibodies develop typically 2-6 months after exposure to the hepatitis C virus. Individuals who are immunosuppressed, such as HIV patients and patients with chronic renal failure, may take many months to develop antibodies against hepatitis C after exposure. Serologic tests are generally used for screening because they are cheaper and are very sensitive.




Antibody

antibodyHepatitis C testing begins with serological blood tests used to detect antibodies to HCV. The enzyme-linked immunosorbent assay (ELISA) antibody test is highly sensitive but false-positive reactions may occur. A positive anti-HCV test is 95% accurate in patients with risk factors for hepatitis C and elevated serum ALT. Most false positives are seen in people at low risk for hepatitis C.


In the past, the recombinant immunoblot assay (RIBA) test was used frequently to confirm anti-HCV. This supplemental test is much more specific, but not more sensitive, than anti-HCV tests. It was used in the past to confirm infection in patients that tested positive but did not have risk factors or elevated ALT.


Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months after exposure, and in >97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus, but may miss patients who have not yet developed antibodies, or have an insufficient level of antibodies to detect.

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Virologic

Virologic tests measure virus levels, and they are both highly sensitive and highly specific. HCV virus will be present approximately 2-6 weeks after exposure. Virologic tests are used to confirm active infection after the screening test is positive.


In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy. There are 3 major types of HCV in the United States. The most common is genotype 1, which represents approximately 72% of HCV-infected patients in the United States. The prevalence of genotypes 2 and 3 is fairly equally split and represents the majority of the remaining approximate 25%. There are other HCV genotypes, including genotypes 4, 5, and 6, which are almost exclusively found in individuals originating from areas of the world where these particular genotypes are endemic. For example, genotype 4 is almost completely restricted to individuals who immigrate to the United States from Egypt and the Middle East, genotype 5 is predominantly from South Africa, and genotype 6 is generally from Southeast Asia.

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Genotyping

In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.


There are 3 major types of HCV in the United States. The most common is genotype 1, which represents approximately 72% of HCV-infected patients in the United States. The prevalence of genotypes 2 and 3 is fairly equally split and represents the majority of the remaining approximate 25%.


In a large study published in 2004, genotype 2 represented 17% and genotype 3 represented 10% of HCV-infected patients in the United States. There are other HCV genotypes, including genotypes 4, 5, and 6, which are almost exclusively found in individuals originating from areas of the world where these particular genotypes are endemic. For example, genotype 4 is almost completely restricted to individuals who immigrate to the United States from Egypt and the Middle East,. Genotype 5 is predominantly from South Africa, and genotype 6 is generally from Southeast Asia

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Biopsy

Liver BiopsyThe final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed.


For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments.





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Noninvasive Tests

While liver biopsy is considered the "gold standard" for assessing the severity of liver disease, it is not always accurate and has several shortcomings. Liver biopsy can under- or over-estimate the severity of hepatitis C, particularly if the biopsy is small and if it is not read by a knowledgeable expert. In addition, liver biopsy is an invasive procedure that is expensive and not without complications. At least 20 percent of patients have pain requiring medications after liver biopsy. Noninvasive means of grading and staging liver disease would be very helpful.


ALT levels, particularly if tested over an extended period, are reasonably accurate reflections of disease activity. Thus, patients with repeatedly normal ALT levels usually have mild inflammation and liver cell injury on liver biopsy. Furthermore, patients who maintain ALT levels above five times the upper limit of normal usually have marked inflammatory activity. But for the majority of patients with mild to moderate ALT elevations, the actual level is not very predictive of liver biopsy findings.


More important is a means to stage liver disease and measure fibrosis short of liver biopsy. Unfortunately, serum tests are not reliable in predicting fibrosis, particularly earlier stages (0, 1, and 2). When patients develop bridging (stage 3) fibrosis and cirrhosis (stage 4), serum tests may be helpful. The "danger signals" that suggest the presence of advanced fibrosis include an aspartate aminotransferase (AST) that is higher than ALT (reversal of the ALT/AST ratio), a high gamma glutamyl transpeptidase or alkaline phosphatase, a decrease in platelet count (which is perhaps the earliest change), elevations in serum globulins, and, of course, abnormal bilirubin, albumin, or prothrombin time. Physical findings of a firm liver, or enlarged spleen or prominent spider angionata or palmar erythema, are also danger signals. While none of these findings are completely reliable, their presence should raise the suspicion of significant fibrosis and lead to evaluation for treatment sooner rather than later.


Recently, x-ray and imaging studies have been developed that may be able to separate different degrees of fibrosis in the liver. At present, these techniques are experimental and of unproven accuracy, particularly in detecting early stages of fibrosis. The most promising technique is "elastrography," in which sound or magnetic waves are passed through the liver and the speed with which they return is measured, which provides an index of the elasticity and stiffness of the liver. Liver stiffness is used as an indirect measure of liver fibrosis. Most importantly, measuring the relative stiffness of the liver over time may provide a noninvasive way to monitor the development of fibrosis and help guide recommendations for when therapy should be recommended. Ultrasound elastrography is currently under evaluation for its reliability in measuring the degree of fibrosis in the liver in patients with hepatitis C. Ultimately, elastrography may be able to replace liver biopsy as a way of monitoring the progression of disease in chronic hepatitis C.


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Compilation: Mitchell L. Shiffman, MD, & National Institutes of Health.