NIH Consensus Development Conference on Management of Hepatitis C

Robert P. Perrillo, M.D.

Liver biopsy has traditionally been the gold standard for assessing the extent of injury and determining prognosis in chronic viral hepatitis. With the growth in our knowledge about the natural history of hepatitis C and the recent development of newer therapeutic modalities, including alpha interferon and transplantation, the number of biopsies for this condition has increased. Indirect support for this may be seen in a survey of 1,400 American Gastroenterological Association (AGA) physician members (unpublished data courtesy of J. Everhart), which revealed that most (89 percent) would recommend biopsy for symptomatic cases with a moderately elevated ALT, but a substantial number (42 percent) would also recommend biopsy in an asymptomatic patient with normal ALT. At the current time, however, uniform guidelines for the use of liver biopsy in hepatitis C are lacking, and a number of questions remain for which the literature provides no direct answer. Physicians may question, for example, the need for biopsy if all grades of histologic severity are viewed as an indication for treatment. Furthermore, the small but definite risk to the patient, the cost of biopsy, and a reliance on ALT testing may lead to questions about the relative importance of periodic histologic assessments to follow the patient's disease. Even physicians who acknowledge that biopsy provides the most useful information on disease progression may have different opinions on how long an interval should lapse before repeat histologic assessment. Thus, a consensus statement on when and how liver biopsy is useful in the diagnosis, management, and therapy of hepatitis C is needed.

Safety and Selection

A number of studies published in the past 30 years have indicated that liver biopsy can be safely performed as an outpatient procedure. (1,2) Complication rates have generally not exceeded 5 percent, and mortality from this procedure is very low (ranging from O to 0.12 percent). The procedure can be done safely on an outpatient basis. Nonetheless, since it is often done in a blind fashion, it is reasonable to conclude that liver biopsies should be done only by or with the assistance of gastroenterologists, hepatologists, transplant surgeons or other physicians (e.g., radiologists) who perform this procedure regularly.

In some instances, it may be appropriate to forgo biopsy before initiating antiviral therapy. Consideration should be given to omitting biopsy whenever this is associated with excessive risk to the patient such as in hemophilia and severely decompensated cirrhosis. Also, some experts question the need for biopsy in individuals with persistently normal ALT levels unless they are part of a research protocol.

Unique Information Provided by Liver Biopsy

There are several types of information that can only be provided by liver biopsy. A number of studies have shown that both in the acute and chronic forms of hepatitis, characteristic although not pathognomonic abnormalities are present: steatosis, portal lymphoid aggregates, and bile duct injury. (3,4) This may have particular value when more than one source of liver injury is possible (e.g., hepatitis B and C and, alcoholic liver disease). The Histologic Activity Index (HAI) or "Knodell score" is a semi-quantitative method proposed to standardize interpretation of the biopsy, allowing comparison between subsequent biopsies in the same patient and between different patients in large studies. (5) While the observations inherent to the score are still subjective, the grading system has the advantage of being simple and the numerical results can be statistically computed. Moreover, this scoring system has been shown to have relatively little intraobserver variation, and it provides a systematic means of comparing pre- and post-therapy biopsies. Liver cell dysplasia is not an uncommon abnormality in the biopsies of patients with cirrhosis due to hepatitis C, being found in as many as 16 percent. (3) Longitudinal observations are necessary to define whether the presence of dysplasia could conceivably be useful in targeted screening for hepatoma. New immunochemical and molecular techniques for localizing the virus in liver tissue may lead to greater understanding of the pathogenesis of chronic hepatitis C and can be useful in monitoring a response to therapy. (6) Rarely, the finding of talc crystals in liver tissue may lead to more accurate assessment of past intravenous drug abuse. (7)

Serum Aminotransferase Versus Liver Biopsy in Chronic Hepatitis C

Several studies have shown that serum aminotransferase levels do not accurately reflect the level of inflammatory changes and/or the presence of fibrosis in chronic hepatitis C. For example, in 1990 Schoeman et al. from Australia found that a correlation was lacking between the degree of liver function test abnormality and histologic severity in 42 patients with parenterally acquired non-A, non-B hepatitis. (8) With the advent of specific tests for hepatitis C, several other groups (see Table I ) demonstrated histological evidence for chronic hepatitis and even cirrhosis despite normal ALT values. (9-17) In several of these studies, a better correlation was seen between abnormal histology and the presence of HCV RNA in serum, casting doubt on the validity of the "healthy" carrier state.

Another way of examining the relationship between ALT level and liver histology has been to assess the relationship of the HAI score to the height of the ALT. There are no definitive studies in this area. However, in a recent study by McCormick et al. involving 59 biopsies taken from 44 patients with chronic hepatitis C, only a weak association was seen between the level of ALT and the degree of inflammatory changes, and it was deemed to be of no clinical use. (13) In another study from Scandinavia, it was observed that logarithmic values of ALT were correlated with periportal inflammation and Iymphocytic follicles but not with lobular inflammation, ballooning change, or the presence or absence of acidophilic bodies. (14)

One can conclude from the above studies that when attempting to evaluate the extent of liver injury in patients with chronic hepatitis C, liver biopsy is inherently more sensitive and accurate and provides information that can not be derived from determination of serum ALT alone.

TABLE 1. Relationship Between Serum Alanine Aminotransferase Levels, HCV RNA, and Liver Histology in Chronic Hepatitis C Virus Infection

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Role of Liver Biopsy in Defining Natural History of Hepatitis C

Serial liver biopsy remains the best way of monitoring the progression of chronic hepatitis C Cirrhosis may frequently develop in chronic hepatitis C, often with an asymptomatic course, and progression is generally slow. Early observations indicated that cirrhosis develops in 20-25 percent of patients with chronic hepatitis C after 10 years. (15,16) In one study, the mean intervals between the date of transfusion and the date of diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma were 10, 21.2, and 29 years, respectively. (17) Studies from Asia have shown that on average, it takes about 30 years for chronic hepatitis C to progress from initial infection to cirrhosis and cancer, and the disease progresses much more rapidly in elderly patients. (18) Disturbingly, even mild hepatitis has been shown to progress to more advanced disease with prolonged followup. (19) Therefore, the initial biopsy may be of less prognostic value than with many other chronic liver disorders.

Liver Histology and Antiviral Therapy

A number of studies have demonstrated that patients with severe fibrosis and/or cirrhosis respond less frequently to interferon therapy. (20) It is also known that inflammatory changes, particularly periportal necrosis, subside when a response is achieved. (21) Preliminary studies suggest that a sustained biochemical and virologic response is associated with lasting improvement in histology. (22) Further studies are necessary to assess the durability of response and determine the appropriate interval which should transpire before consideration is given to repeat histological assessment.

References

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17.Kiyosawa K, Sodeyarna T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Purcell RH, Alter HJ. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671-5.

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22.Rizzetto M, Goldin R, Marcellin P, Farrell G, Bacon B, Mostelleer M, Howe I, et al. Correlations between virologic and histologic responses in chronic hepatitis C patients: Analyses from a large intemational comparative smdy of aiph-mte feron mherapy [Abstract]. J Hepatol 1996;24:57.