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HEPATOLOGY, Vol. 36, No. 5, Suppl. 1, 2002

Several studies have shown a modest association be- tween a high quasispecies heterogeneity and more severe liver injury in chronic hepatitis C.43 In one study, quasi- species heterogeneity was less in patients with normal ALT levels compared with those with elevated levels.44 Quasispecies heterogeneity can also be confounded by features of gender, age, and duration of disease. Further studies are needed on the significance of quasispecies het- erogeneity in the natural history of hepatitis C and its association with hepatic fibrosis.

Other Factors Associated With Fibrosis. The fac- tors, which are clearly associated with the progression of fibrosis, such as age, gender, alcohol intake, and immune status account for only a part of the variability in progres- sion of fibrosis in chronic hepatitis C. Other factors, which have been suggested to be important, include ge- netic, racial/ethnic, and metabolic. The role of heterozy- gote mutations of HFE gene is controversial.45 The influence of overweight has been emphasized recently; it is believed that steatosis related to overweight is responsible for the more rapid progression of fibrosis.46-48 In addition, diabetes has been shown to be associated with fibrosis.49

Predicting Progression of Fibrosis

Most analyses of factors that correlate with fibrosis have been performed in cross-sectional studies. The fac- tors, therefore, are associated with what is found on liver biopsy histology performed at the time. The ability of these factors to predict future worsening of fibrosis has not been verified. Indeed, it is assumed, but not proven, that the estimated rate of fibrosis based on readings from an initial biopsy is likely to predict future progression of fibrosis. However, the validity of these predictions has not been confirmed in prospective studies. Indeed, in the lon- gitudinal studies, factors that correlate best with future progression of fibrosis have been age, serum ALT eleva- tions at the time of initial liver biopsy or during follow up, and degree of disease activity or grade on the initial bi- opsy.

Serum Aminotransferase Levels. In cross-sectional studies, serum ALT and aspartate aminotransferase (AST) levels have correlated weakly with disease activity (necro- inflammatory scores on liver biopsy) and little or not at all with hepatic fibrosis. In longitudinal studies, however, ALT levels at the time of an initial biopsy have correlated with future worsening of fibrosis (Table 2). In a study from the National Institutes of Health, patients with se- rum ALT levels above 5 times the upper limit of normal were the only group that had a worsening of fibrosis dur- ing an average follow-up of 3 years.18 In a study from France, patients with a mean serum ALT level above twice the upper limit of the normal range had a higher risk of



















Necroinflammatory activity











et al.17

et al.18

et al.19

Table 2. Characteristics Associated With Progression of Fibrosis in Three Series of Patients With Chronic Hepatitis C


Abbreviation: NS, not significant. *No or mild fibrosis in 100% on first liver biopsy.

progression of fibrosis on follow-up liver biopsy 3 years later.17 These findings support the clinical usefulness of monitoring ALT levels in assessing disease progression. However, the validity of this approach and the level above which the ALT elevations are predictive of more rapid progression require further delineation.

Patients with persistently normal ALT levels docu- mented on several occasions usually have mild degrees of hepatitis disease activity and either no or minimal fibro- sis.42 Among 87 patients with chronic hepatitis C with persistently normal ALT levels, Ishak fibrosis scores were

  • 0

    or 1 in 76% of patients, and no patient had cirrhosis or

severe bridging fibrosis.50 The rate of progression of fibro- sis was estimated to be 0.05 Metavir points per year in patients with normal ALT levels compared with 0.13 points per year in those with elevated ALT levels (P .001).51 Cirrhosis has been found in some patients with normal ALT levels, but this appears to be rare, occurring in less than 1% in published series. Furthermore, patients with cirrhosis and normal ALT levels will often have ab- normalities of other liver tests, such as AST, alkaline phos- phatase, bilirubin or albumin, or low platelet count or abnormalities of liver ultrasonography. In these individu- als, cirrhosis may have been due to previous episodes of active disease (and increased ALT levels) or to other fac- tors that can cause cirrhosis, such as hemochromatosis or alcohol.51

There have been several prospective studies of liver histology in patients with normal serum ALT levels. In a study from Italy, none of 37 patients had a worsening of hepatic fibrosis on follow-up liver biopsy 5 years later.52 In a study from France, there were no significant changes in the Ishak fibrosis scores among 24 patients who had a second liver biopsy 3 to 5 years later.50 On the other hand, in both of these studies, a proportion of patients (approx- imately 5% per year) developed abnormal ALT levels dur- ing follow-up.50,52 Thus, patients may have a change in disease activity over time and the lack of fibrosis progres- sion during one period may not predict future lack of progression of disease.

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