Re-evaluation of Serum Alanine Aminotransferase Upper Normal Limit and Its Modulating Factors in a Large-Scale Population Study

Moshe Leshno; Anat Beth-Or; Hana Strul; Laurie Blendis; Ehud Kokia; Dina Noff; Shira Zelber-Sagie; Bracha Sheinberg; Ran Oren; Zamir Halpern


Liver International. 2006;26(4):445-450. 

In This Article

Abstract and Introduction

Background: The upper normal limit (ULN) of serum alanine-aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have 'normal' or near-'normal' ALT levels, and because possible modulators are often ignored in determining normal range.
Aim: To estimate the ULN for serum ALT and to identify factors modulating it.
Subjects and Methods: We reviewed medical records of subjects aged 15–90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the 'healthy' population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels.
Results: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic-regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels.
Conclusions: In this first large-scale study of 'healthy' population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.

Serum alanine aminotransferase (ALT) is a valid laboratory parameter for evaluation and follow-up of liver diseases and hepatocellular damage. The upper limit of the normal range (ULN) varies in different laboratories according to the commercial kit used and the reference population chosen by each manufacturer to establish the normal range.

The currently accepted range of normal values for serum ALT levels was recently challenged[1,2]by research groups, who claimed that the true normal values are significantly lower than those listed by kit manufacturers, and that an updated, reliable ULN is needed. No such ULN has yet been established in a large-scale population-based study, despite its importance as an aid to the classification and management of patients with liver diseases, and in particular with hepatitis B (HBV) and C (HCV). In addition, serum ALT is a surrogate marker for the diagnosis of patients with non-alcoholic fatty liver disease (NAFLD), the most common cause of elevated serum ALT levels in otherwise serologically negative patients.[3,4] In the absence of proper screening tools (such as a reliable 'healthy' ULN for serum ALT) for NAFLD, its diagnosis remains problematic.

Recent studies[1,5] have shown that serum ALT levels can be modulated by a number of factors, including age, gender, body mass index (BMI), fasting blood glucose, and serum triglyceride (TG) levels. These factors are usually not taken into account when the normal ALT range is determined.

This study was undertaken with the aim to show that the 'healthy' ULN for serum ALT, based on samples taken from a large community-based population, is lower than that of the manufacturer, and to identify potential modulating factors for ALT levels.