Invited critical reviewUpper limit of normal for alanine aminotransferase: Quo vadis?
Introduction
The cutoff serum alanine aminotransferase (ALT) value to be used to discriminate between healthy and diseased livers has not been clearly defined. Several studies have recently questioned whether previously established values defining the upper limit of normal (ULN) for ALT are sufficiently sensitive, and have suggested that the ULN should be revised. This review highlights the evidence for a redefinition of ALT ULN, and also discusses the current skepticism.
Section snippets
Point: why and how ALT ULN should be redefined
The serum ALT value has long been used as a surrogate marker of liver injury [1]. Thus it is the most widely used laboratory parameter for the evaluation of liver disease in daily clinical practice. However, the available literature indicates that the ALT values do not correlate well with the severity of liver disease as found by liver biopsy in subjects with chronic liver diseases of different etiologies [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. This is particularly true when
Physiology of aminotransferases
Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of aminotransferases. The aspartate aminotransferase (AST) and ALT are abundant hepatic enzymes that catalyze the transfer of alpha-amino groups from aspartate and alanine to the alpha-keto group of ketoglutaric acid to generate oxalacetic and pyruvic acids, which are important contributors to the citric acid cycle [23]. Both enzymes require pyridoxal-5′-phosphate (P-5′-P) for maximum
Factors modulating ALT activity
Several factors, other than liver disease, influence what is considered to be the normal value of ALT. These variables should be taken into account to optimize the determination and interpretation of truly healthy ALT standards.
Proposals to redefine ALT ULN
Several authors have proposed the updating of ULN for serum ALT levels (Table 1). In 1998, in a prospective study from France investigating factors associated with ALT variability in a cohort of 1033 blood donors (mean age, 30 years), Piton et al. [18] suggested that definitions of normal ALT values should be adjusted for gender and BMI to reduce artificial heterogeneity in blood donor selection and in hepatitis C clinical studies. They found that ALT was independently and highly associated with
Counterpoint: why the current ALT ULN should not be redefined
Several studies have shown that subjects with elevated ALT levels as defined by the Prati criteria [12] but within the normal ranges according to the older criteria, have increased liver-related mortality or may show active hepatic inflammation or be cases of chronic HBV or HCV infection [101], [102], [103], [104]. Likewise, studies have reported cirrhosis in 8–12% of adult patients with NAFLD who had elevated ALT levels by using the new criteria but within the current normal range according to
Conclusions
Physicians should be cautious in interpreting the normal range of serum ALT levels, while laboratories should think very carefully how to ascertain an “optimal” upper limit of normal for ALT. Laboratories should consider the scientific difficulties and problems that we have highlighted and, if possible, participate in discussions with clinicians to reach consensus on the best way ahead. An abnormal, as well as normal, ALT result after the application of the proposed lower ALT standards must
Conflict of interest
The authors have nothing to disclose and declare no potential conflict of interest.
Abbreviations
- ALT
alanine aminotransferase
- AST
aspartate aminotransferase
- BMI
body mass index
- CAP
College of American Pathologists
- CI
confidence interval
- HBsAg
hepatitis B surface antigen
- HBV
hepatitis B virus
- HCV
hepatitis C virus
- HIV
human immunodeficiency virus
- HDL-C
high-density lipoprotein cholesterol
- LDL-C
low-density lipoprotein cholesterol
- MetS
metabolic syndrome
- NAFLD
nonalcoholic fatty liver disease
- NHANES
National Health and Nutrition Examination Survey
- OR
odds ratio
- P-5′-P
pyridoxal-5′-phosphate
- SAFETY
screening ALT for
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