Elsevier

Clinica Chimica Acta

Volume 422, 25 June 2013, Pages 29-39
Clinica Chimica Acta

Invited critical review
Upper limit of normal for alanine aminotransferase: Quo vadis?

https://doi.org/10.1016/j.cca.2013.03.030Get rights and content

Highlights

  • Why upper limit of normal (ULN) for alanine aminotransferase (ALT) should be redefined?

  • How a well-defined healthy group is generated for ALT ULN?

  • Factors modulating ALT activity

  • Skepticism concerning the need to update the current ALT ULN

Abstract

Several studies suggest that a substantial number of patients with normal serum alanine aminotransferase (ALT) levels, defined by current thresholds, have ongoing hepatic necro-inflammation and fibrosis, and are at risk of liver disease progression. A major problem lies in the definition of normality. The current upper limit of normal (ULN) for ALT was established in the 1980s when reference populations were likely to include many persons with hepatitis C virus infection and nonalcoholic fatty liver disease. Because ALT may be influenced, not only by liver disease, but also by other medical conditions, changing lifestyle factors and demographic determinants, the current ALT ULN threshold has recently been challenged. This review not only highlights current evidence on why and how ALT ULN should be redefined, but also discusses the current concerns about updating the ULN threshold for ALT.

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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