Chronic Hepatitis B Patients with Normal or Minimally Elevated ALT and Detectable HBV DNA May Experience Active Liver Disease Progression

By Liz Highleyman

Elevated serum levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are a sign of liver inflammation. Traditionally it has been thought that elevated liver enzymes predict progression to advanced liver fibrosis and cirrhosis in individuals with chronic hepatitis B or C.

Several studies, however, have shown that liver disease progression can also occur in people with normal or only minimally elevated ALT and AST. This was confirmed by an analysis presented at the Digestive Disease Week 2008 conference last month in San Diego.

As background, the study investigators noted that there are limited data regarding histological activity in chronic hepatitis B patients who have active viral replication (indicated by detectable serum HBV DNA) but normal or minimally elevated ALT.

The MELT study was a cross-sectional evaluation of individuals with chronic hepatitis B infection who were surface antigen (HBsAg) positive for at least 6 months with HBV DNA of at least 4 log10 copies/mL. Participants had 2 normal or minimally elevated serum ALT measurements obtained at least 3 months apart, defined as < 1.2 x the upper limit of normal (ULN) if hepatitis B "e" antigen (HBeAg) positive, or < 1.5 x ULN if HBeAg negative. The patients had not started hepatitis B treatment at the time of liver biopsy.

Data were also included for participants previously enrolled in 2 placebo-controlled trials of adefovir (Hepsera) who met all other MELT entry criteria.

A total of 63 patients were evaluated. About half were men, the median age was 40 years, 67% were Asian, 18% were Caucasian, and 13% were African American; 56% were HBeAg negative and 44% were HBeAg positive.

Factors associated with active histological disease (Knodell necro-inflammatory
score > 5 and Ishak fibrosis score > 1) were evaluated by stepwise multiple logistic regression.

Results

• Around the time of biopsy, the median HBV DNA level was 6.5 log10 copies/mL.

• The median AST level was 32 U/L and the median ALT level was 46 U/L.

• 52% had ALT above the ULN.

• Overall, 27% of patients had histological evidence of active liver disease.

• By stepwise multiple logistic regression, the following factors were significantly associated with active histological disease:

• AST level: OR 4.95 per 5 U/L increment;
• HBeAg positive status: OR 17.8;
• Male sex: OR 13.6;
• ALT level: OR 0.71 per 5 U/L increment.

Conclusion

"About one fourth of patients with chronic hepatitis B and normal or minimally elevated ALT in this evaluation had histological evidence of active liver disease, with AST, HBeAg positive status, and male gender most significantly associated with active histological disease," the investigators concluded.

"These findings could have significant implications on antiviral treatment," they added. "The natural history of HBV infection and whether antiviral treatment is necessary in these types of patients requires further study."

6/06/08

Reference
K-Q Hu, E Schiff, KV Kowdley, and others. Histologic evidence of active liver injury in HBeAg-positive and HBeAg-negative chronic hepatitis B patients with normal or minimally elevated alanine transaminase. Digestive Disease Week (DDW) 2008. San Diego, CA. May 17-22, 2008. Abstract T1006.