Implications of Normal ALT and Initially Mild Liver Disease

By Liz Highleyman

Traditionally, hepatitis C treatment has not been recommended for patients with persistently normal alanine aminotransferase (ALT) levels or initially absent or mild fibrosis, since they are believed to have a low risk of progression to severe liver disease. It is well known, however, that some such patients do develop advanced fibrosis, cirrhosis, and liver cancer.

A study presented at the Digestive Disease Week conference in Los Angeles in May, and two published recently in medical journals, add to the conflicting data about the implications of normal ALT and initially mild liver disease.

In the DDW study, A.M. Loaeza and colleagues aimed to compare liver fibrosis stage and degree of necroinflammatory activity in chronic hepatitis C patients with normal and elevated ALT. The study included 158 treatment-naïve individuals with available liver biopsy results and a known duration of infection. The mean age was 50 years and 64% were women.

Persistently normal ALT was defined as three or more ALT measurements within the normal range during a six-month period in a patient who had detectable serum HCV RNA. Advanced fibrosis was defined as a METAVIR score of F2 or higher.

Results

61% of subjects had elevated ALT (mean 139 IU/L) and 39% had normal ALT (mean 47.8 IU/L). Subjects with normal ALT had been infected with HCV for a mean 22.4 years, compared with 26.0 years in the elevated ALT group. The liver fibrosis progression rate was 0.102 METAVIR points per year among patients with normal ALT, compared with 0.125 points per year in the elevated ALT group (P = 0.352). 31 patients (50.0%) with normal ALT and 58 patients with elevated ALT (60.4%) had advanced fibrosis (P = 0.25). There was a significant association between elevated ALT and both grade A3 necroinflammatory activity (odds ratio 4.6; 95% CI 1.02-21.5; P < 0.05) and stage F4 fibrosis, that is, cirrhosis (odds ratio 5.9; 95% CI 2.9-12.1; P < 0.001). Normal ALT was associated with stage F0, or absent fibrosis (odds ratio 0.4; 95% CI 0.17-0.94; P < 0.05).

Conclusion

The researchers concluded that severe necroinflammatory activity and cirrhosis were more frequent in patients with elevated ALT. But while the absence of liver fibrosis was observed more frequently among patients with normal ALT, half of this group still did have significant fibrosis. Given the lack of validated non-invasive markers of liver fibrosis, they recommended that patients with persistently normal ALT -- especially those with long-term infection -- should continue to be considered for liver biopsies.

ALT and Immunological Response

In a study published in the May 2006 Journal of Viral Hepatitis, M. Persico and colleagues compared epidemiological, immunological, and histological findings in 40 chronic hepatitis C patients with elevated ALT and 24 individuals with persistently normal ALT. Age, sex, and body mass index (BMI) were not significantly different in the two groups. The researchers evaluated immunological response to different HCV antigens by measuring hepatic proliferative activity index (proliferating cell nuclear antigen, or PCNA, in liver cells). Patients were followed for 10 years.

Results

The median liver histology stage was significantly higher among patients with elevated ALT compared with the persistently normal ALT group (2.5 [range 2-6] vs 1.5 [range 1-2]; P < 0.01). Among subjects with persistently normal ALT, histological stage did not increase significantly from baseline through year 5 and year 10. Interferon-gamma production was similar in the elevated and persistently normal ALT groups. The PCNA level was significantly higher in patients with elevated ALT compared with the persistently normal ALT group (8% [range 4%-15%] vs 5% [range 3%-8%]; P < 0.05). Among subjects with persistently normal ALT, PCNA level did not differ significantly at baseline, year 5, and year 10.

Conclusion  

The researchers concluded that their study “confirms that progression to cirrhosis is slow or absent in persistently normal ALT patients after 10 years of follow-up.” Accordingly, they added, “the hepatic proliferative activity index is low and seems to be stable over time.  

Initially Mild Fibrosis

In the same issue, S. Boccato and colleagues reported on a study of the rates of and risk factors for fibrosis progression in patients with initially mild chronic hepatitis C. The analysis included 106 patients (mean age 42 years) with chronic HCV infection who had minimal or no evidence of fibrosis on their first biopsy (METAVIR stage F0-F1). Patients were prospectively followed without treatment, and underwent repeat biopsy after five or more years (mean interval 7.8 years).

Results

60% of patients showed evidence of fibrosis progression, including 13 of 27 (49%) who initially had no fibrosis (F0) and 51 of 79 (65%) who initially had minimal fibrosis (F1). 36% of patients who initially had stage F1 fibrosis progressed to stage F3 (advanced fibrosis) or F4 (cirrhosis). Fibrosis progression was associated with age (P < 0.0001), elevated baseline and follow-up ALT levels (P = 0.005), histological activity score (P = 0.004), presence of steatosis on the initial biopsy (P = 0.002), and alcohol consumption (P = 0.008).

Conclusion

The authors concluded that progression of liver fibrosis occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years, and that advanced fibrosis or cirrhosis develops in one-third of those who had stage F1 fibrosis on initial biopsy. Thus, they recommended that antiviral therapy should be considered for patients with mild chronic hepatitis C.

References

AM Loaeza, F. Sanchez-Avila, J. Gallegos-Orozco, and others. Liver fibrosis and necroinflammatory activity in chronic hepatitis C patients with persistently normal aminotransferases. Abstract S1050. Digestive Disease Week 2006. May 20-25, 2006. Los Angeles, CA.

M Persico, S Perrotta, E Persico, and others. Hepatitis C virus carriers with persistently normal ALT levels: biological peculiarities and update of the natural history of liver disease at 10 years. Journal of Viral Hepatitis 13(5): 290-296. May 2006.

S Boccato, R Pistis, F Noventa, and others. Fibrosis progression in initially mild chronic hepatitis C. Journal of Viral Hepatitis 13(5): 297-302. May 2006.