Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease: Clinical implications

Abstract

In this editorial, we comment on the article by Chen et al recently published in 2024. We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase (ALT) would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease (MAFLD). This is important given the increasing prevalence of MAFLD and obesity globally. Currently, a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT. The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered, particularly as their study found that 83.12% of their study population with a diagnosis of MAFLD had a normal ALT. The main advantages of screening would be to identify patients and provide intervention early, the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis. However, there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered. Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity, although studies have not yet shown a significant improvement in fibrosis regression. It would also require a huge amount of resource if a reduced ALT level alone was used as criteria; it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk. Currently, there is not a good argument to recommend widespread screening with a reduced ALT level as this is unlikely to be cost-effective. This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories. Although studies previously have suggested a more pragmatic approach in screening those over the age of 60, this is likely to change with the increasing incidence of obesity within the younger age groups. The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

Keywords: Alanine aminotransferase; Metabolic-dysfunction associated fatty liver disease; Metabolic syndrome; Fibrosis; Cirrhosis; Semaglutide

Core Tip: Alanine aminotransferase (ALT) is a surrogate marker for metabolic-dysfunction associated fatty liver disease (MAFLD) but is not specific for histological inflammation. The rationale to reduce the upper limit of normal for ALT to help identify more cases of MAFLD remains controversial. It is more important to identify patients who may display elements of the metabolic syndrome and support modifying these to maintain a lower level of ALT. This will become increasingly important as more targets for therapy are identified that may justify treating these patients early to prevent progression to fibrosis.