Robert J. Fontana, MD, and Anna S.F. Lok, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

Patients with chronic hepatitis C (CHC) are at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC). However, specific symptoms and physical findings of chronic liver disease are frequently absent until patients develop hepatic decompensation. Thus, clinical examination is often unreliable in assessing the severity of liver disease in patients with CHC. Liver histology is the gold standard for establishing the severity of liver injury and fibrosis, but this procedure is associated with risks of complications, discomfort, and expense. In addition, sampling error may occur leading to erroneous staging. Nonetheless, information on the extent of hepatic fibrosis or stage of liver disease is important for prognostication as well as for decisions on treatment. As a result, practicing physicians are in need of simple, safe, inexpensive, and reliable means to non-invasively assess the severity of liver disease in patients with CHC.

The initial evaluation of patients with CHC should include a thorough history and physical examination. A PCR assay for HCV RNA is recommended to confirm the presence of viremia because up to 30 percent of individuals who test positive for HCV antibody (anti-HCV) may have resolved infection or a false positive EIA result. Quantitative HCV RNA levels and HCV genotypes do not correlate with disease severity, but these results are useful in predicting

the likelihood of an antiviral treatment response. The initial evaluation should include acomprehensive metabolic panel, prothrombin time, and complete blood counts (CBC) with platelets. Serum aspartate and alanine aminotransferase (AST/ALT) levels reflect liver injury, but the correlation with histologic necroinflammatory activity as well as the severity of hepatic fibrosis is poor (1,2) . Serum albumin and bilirubin levels and prothrombin time reflect hepatic function, but these values usually remain normal even in patients with compensated cirrhosis.

Thus, routine blood tests cannot differentiate early (minimal fibrosis) from advanced (compensated cirrhosis) stage of liver disease. Among the routine blood tests, decreased platelet count is the earliest indicator of cirrhosis (3) . Other investigators have found that as patients progress from chronic viral hepatitis to cirrhosis, there is reversal of AST/ALT ratio to >1. (4)

Ultrasound is often recommended as part of the initial evaluation of patients with CHC. Ultrasound and other imaging techniques such as CT and MRI can be used to diagnose cirrhosis based on the presence of an enlarged spleen, small nodular liver, ascites, or varices. In addition, these techniques may detect HCC. However, current imaging is unable to assess the extent of hepatic fibrosis and to diagnose early cirrhosis.

Other novel but less well-established non-invasive means of assessing disease severity in patients with compensated CHC are under development. Serum fibrosis markers that reflect the balance between fibrogenesis and fibrolysis have been proposed as a simple, non-invasive means of assessing hepatic fibrosis. (5,6) To date, none of these markers alone correlates well with hepatic fibrosis. Whether a panel of markers such as hyaluronic acid, YKL-40, and PIIINP will replace

liver biopsies remains to be determined. (7,8) Contrast-enhanced ultrasound doppler has also been proposed as a simple, non-invasive means of detecting advanced hepatic fibrosis. (9) However, this method has not yet been validated and will require sophisticated instruments and operators  for optimal performance. Radionuclide liver spleen scans can detect the presence of portal hypertension but are insensitive in the diagnosis of early cirrhosis. Similarly, the use of various metabolic probes to assess functional liver mass has been reported to be reliable in differentiating patients with compensated from decompensated liver disease, but these studies are cumbersome and have not been proven to be useful in distinguishing patients with various stages of hepatic fibrosis. (10)

The optimal frequency and types of tests that should be performed for monitoring CHC patients who are not on antiviral therapy have not been determined. In general, tests for CBC and platelets and a comprehensive metabolic panel should be performed every six months. As discussed above, a progressive decrease in platelet counts or a reversal of the AST/ALT ratio suggests the development of cirrhosis. Repeat testing of anti-HCV, HCV RNA level, or HCV genotype is unnecessary and does not provide any information on the stability or progression of liver disease. For patients with known cirrhosis, alfa-fetoprotein testing and ultrasound should be included although the efficacy of these tests in HCC surveillance is low. Upper endoscopy should be performed in patients with cirrhosis, especially those with clinical evidence of portal hypertension, to determine the need for prophylaxis against variceal bleeding. Patients with decompensated cirrhosis may need more frequent monitoring to determine the optimal timing for transplant evaluation. Monitoring may be less frequent in patients with persistently normal aminotransferases and those with minimal hepatic fibrosis after a long duration of infection (slow progressors). Because of the variable natural course of CHC and the possibility of sampling error, many hepatologists recommend repeat liver biopsies in 4–5 years in patients who decide not to receive antiviral treatment based on the finding of early disease at initial evaluation. The availability of non-invasive tests that correlate with progression of hepatic fibrosis will obviate the need for repeat liver biopsies.

References

1. McCormick SE, Goodman ZD, Maydonovitch CL, Sjorgen MH. Evaluation of liver histology, ALT elevation, and HCV RNA titer in patients with chronic hepatitis C. Am J Gastroenterol 1996;91:1516–22.

2. Haber MM, West AB, Haber AD, Reuben A. Relationship of aminotransferases to liver histological status in chronic hepatitis C. Am J Gastroenterol 1995;90:1250–7.

3. Poynard T, Bedossa P, Metavir and Clinivir Cooperative Study Groups. Age and platelet: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. J Viral Hepat 1997;4:199–208.

4. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734–9.

5. Oberti F, Valsesia E, Pilette C, et al. Non-invasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology. 1997;113:1609–16.

6. Wong VS, Hughes V, Trull A, et al. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepatitis 1998;5:187–192.