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Clin Gastroenterol Hepatol. 2014 Aug;12(8):1262-6. doi: 10.1016/j.cgh.2013.11.038. Epub 2013 Dec 17.

Histologic changes in liver tissue from patients with chronic hepatitis B and minimal increases in levels of alanine aminotransferase: a meta-analysis and systematic review.

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Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, California.
University of Pittsburgh, Pittsburgh, Pennsylvania.
Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut.
Cedar Sinai Medical Center, West Hollywood, California.
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California. Electronic address:



The level of alanine aminotransferase (ALT) is a marker of hepatitis B severity and response to treatment. However, measurements of ALT level may be of limited use during the immune clearance phase of chronic hepatitis B (CHB) and can be affected by age, weight, and concomitant liver disease. We performed a literature review to determine the proportion of CHB patients with ALT levels of 1- to 2-fold the upper limit of normal who also had significant underlying liver fibrosis (stage ≥2).


We performed a Medline search of original articles published before June 2012, and their references; we also searched abstracts from the 2010 and 2011 annual meetings of the American Association for the Study of Liver Diseases and the 2011 and 2012 Digestive Disease Weeks. Studies were included that had 20 or more consecutive treatment-naive CHB patients with 6 months or more of follow-up evaluation, histologic data, and levels of ALT 1- to 2-fold the upper limit of normal. Study heterogeneity was assessed by a Forest plot and Q and I(2) analyses. Sensitivity was measured using 1-study removed analysis.


Our analysis included 8 articles and 1 abstract, comprising 683 patients. Based on random-effects modeling, 48% of patients had stage 2 or higher fibrosis (95% confidence interval, 36%-61%). In a sensitivity analysis, exclusion of the study that caused the greatest deflection of the pooled estimate produced a revised estimate of 43%. A subgroup of hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (n = 168 and 170, respectively) showed similar rates of fibrosis (41% vs 47%; P = nonsignificant).


Despite heterogeneity in the literature, a substantial proportion of patients with slight increases in ALT level have significant fibrosis. Given the possibility of advanced liver disease, the threshold for antiviral treatment must be individualized. Further studies are needed to investigate patients with modest increases in ALT level.


Cirrhosis; HBV; HBeAg; Patient Management

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