The dilemma of disease progression in hepatitis C patients with normal serum aminotransferase levels

Infection with the hepatitis C virus afflicts 2.7 million persons in the United States (1). Acute infection is typically asymptomatic, but persistent infection develops in approximately 85% of patients who are exposed to the virus, with the remaining 15% undergoing what is believed to be “spontaneous clearance.” In patients who develop persistent infection, the spectrum of disease manifestations is broad. At most, 20% of chronically infected patients progress to potentially life-threatening complications of hepatitis C, such as cirrhosis, liver failure, or hepatocellular carcinoma (2,3). The remainder manifest varying degrees of symptoms, viremia, abnormalities in serum aminotransferase levels, and histologic activity on liver biopsy, but never develop cirrhosis or its complications. One of the great mysteries in the natural history and pathophysiology of hepatitis C virus–related disease is to determine what combination of viral and host factors act to produce this marked variability in disease manifestations. Many factors have been examined—such as viral genotype and load, quasispecies variation, and the degree of elevation in serum alanine aminotransferase levels— none of which have been shown to be associated with the severity of liver disease in cross-sectional studies. The value of these measurements in identifying patients at risk for disease progression is not known, however. The degree of hepatic fibrosis, and to a lesser extent the degree of hepatic inflammation, may be predictive of future disease progression (4). Whether disease progression is consistent over time is also not known. Unless liver biopsy specimens have been obtained during several years of follow-up, it is not possible to know the rate of fibrosis progression in any individual patient, but performing serial liver biopsies is not currently the standard of care. Without such information, physicians who treat patients with chronic hepatitis C infection must make an educated guess about an individual patient’s past rate of fibrosis and future risk of disease progression. Such knowledge would be potentially important in deciding the appropriateness of therapy. There is an interesting quirk in the development of guidelines for the evaluation and treatment of patients with hepatitis C infection. Although practitioners typically rely on liver histology, particularly the degree of fibrosis, to make decisions about the appropriateness of treatment, almost all studies examining treatment efficacy use endpoints such as absence of hepatitis C viral RNA in serum or normalization of serum alanine aminotransferase levels to demonstrate efficacy. Although some studies have shown improvements in hepatic inflammation with antiviral therapy, these studies typically lack sufficiently long periods of follow-up to demonstrate clear effects on fibrosis progression. Biochemical and virologic endpoints seem to be reasonable surrogates for improvements in disease, although they are not conclusive. Demonstration that improvements in these surrogate markers reduces the incidence of life-threatening complications will require decades of posttreatment follow-up with appropriate untreated control groups, and these studies are unlikely ever to be performed. The 1997 National Institutes of Health Consensus Conference concluded that treatment of hepatitis C virus–infected patients with normal serum alanine aminotransferase levels was not beneficial and should not be undertaken routinely (5). This conclusion, however, did not provide a clear definition of what constitutes a “normal” alanine aminotransferase level. These levels may fluctuate substantially in the course of the infection, and patients may have normal levels at one time and abnormal levels at another. Also, some patients who have antibodies to the hepatitis C virus and normal aminotransferase levels may actually have cleared the infection, so it is important to establish whether a particular patient is viremic before deciding about treatment. Several studies have looked at the use of interferon monotherapy for the treatment of patients with chronic hepatitis C virus infection who have normal serum alanine aminotransferase levels (6 – 8). The endpoint of sustained viral clearance 6 months after completing therapy was achieved in approximately 20% of the patients in these studies, similar to the rate seen for patients with Am J Med. 2000;109:66 – 67. From the San Francisco Veterans Administration Medical Center, University of California, San Francisco, California. Requests for reprints should be addressed to Kenneth R. Hirsch, MD, San Francisco Veterans Administration Medical Center, University of California, San Francisco, California.