Chronic Hepatitis B Patients May Have Significant Liver Disease Despite Normal ALT  

By Liz Highleyman

Elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are often measured as indicators of liver injury. However, the enzymes are actually markers of liver inflammation, and may not accurately reflect fibrosis progression.

Two studies presented at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007) added to the evidence that patients with chronic hepatitis B may experience significant liver disease progression even if they maintain persistently normal ALT.

Current treatment guidelines recommend that antiviral therapy should be considered for chronic hepatitis B patients with a high HBV viral load and/or biopsy-proven significant liver disease even if they have an ALT level ≤ 2 times the upper limit of normal (x ULN).

Study 1

In the first study, J. Park and colleagues evaluated histological findings in 105 treatment-naive Korean chronic hepatitis B patients who expressed hepatitis B surface antigen (HBsAg) for at least 6 months, had detectable serum HBV DNA, and had normal or slightly elevated serum ALT levels (≤ 2 x ULN) for 12 months; the mean patient age was 37 years.

All participants underwent percutaneous liver biopsy. Histological assessment was based on the METAVIR classification. “Significant histology” was defined as ≥ grade A2 or ≥ stage F2. Serum ALT levels were tested in at least 3 consecutive samples within a 12-month period, and all values were less than 2 x ULN.

Results

• All 105 patients had HBV DNA titers above 10⁵ copies/mL.

• The mean ALT level at biopsy was 42 IU/L (range 8-75)

• 36 patients had persistently normal ALT levels.

• Overall, significant fibrosis was observed in 63 patients (60.0%) and significant histology was found in 69 patients (65.7%).

• In a multivariate analysis, serum ALT level and age at study entry were independent factors associated with significant histology.

• Compared with the lowest ALT levels (< 0.5 x ULN), the odds ratios for significant histology were:

- Patients with ALT 0.5-1 x ULN: 1.1;

- Patients with ALT 1-1.5 x ULN: 3.9;

- Patients with ALT 1.5-2 x ULN: 8.0.

• Compared with patients younger than 20 years, the odds ratios for significant histology based on age were:

- Patients in their 20s: 7.1;

- Patients in their 30s: 14.2;

- Patients in their 40s: 24.4

- Patients over 50: 38.8.

The researchers concluded that, “A large proportion of chronic hepatitis B patients with high viral load and ALT 2 times or less than the ULN had significant liver disease on liver biopsy.”

“Our findings warrant a more accurate evaluation in a practical setting and, if confirmed, would have a great impact on future treatment approaches for patients awaiting potential antiviral therapy,” the added.

Study 2

In the second study, H. Gui and colleagues aimed to identify predictors of significant histological findings in chronic hepatitis B patients with normal ALT and low HBV viral load.

This study included 139 Chinese chronic hepatitis B patients with persistently normal ALT measured on at least 3 occasions at intervals of more than 2 months over a period of 12 or more months; all underwent percutaneous liver biopsy. These patients were compared with 135 control subjects with elevated ALT during the same period who had no prior antiviral treatment.

In this study, “significant histological findings” were defined more narrowly than in the previous study: necroinflammation with a histological activity score of 4 or greater and/or Ishak fibrosis stage of 3 or greater.

Results

• The ALT values of all 139 patients with persistently normal ALT were normal from 1 to 30 years, with a median of 6 years.

• 66 patients (47.5%) with persistently normal ALT had normal liver histology, while 33 (23.7%) had significant histological findings, and 13 (9.4%) had cirrhosis.

• When compared to individuals within ALT 0-0.75 x ULN, patients with 0.75-1 x ULN had a higher rate of significant histological findings (43.5% vs 19.8%; P=0.029).

• In the subgroup of patients with persistently normal ALT, the rate of significant histological findings increased sharply after the age of 40 years (P=0.005).

• However, the subgroup of patients with persistently normal ALT and significant histological findings was not identified by HBV viral load or hepatitis B “e” antigen (HBeAg) status.

“We found 23.7% of chronic hepatitis B patients with persistently normal ALT regardless of HBeAg status or viral load levels had significant histological findings including inflammation and fibrosis,” the investigators concluded.

Based on these findings, they recommended that, “Liver biopsy should be considered in chronic hepatitis B patients with persistently normal ALT and detectable viral load, even low viral load, especially in those older than age 40 years and [with] higher ALT within 0.75-1 x ULN.”

12/04/07

References

J Park, Y Park, D Kim, and others. A High Prevalence of Significant Liver Disease in Asymptomatic Hepatitis B Patients with High Viral Load; Candidates for Antiviral Therapy. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA, November 2-6, 2007. Abstract 942.

H Gui, Q Xie, H Wang, and others. Predictors Of Significant Histological Findings In Chronic Hepatitis B Patients With Persistently Normal ALT Levels. AASLD 2007. Abstract 936.