Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2021; 13(12): 2104-2112
Published online Dec 27, 2021. doi: 10.4254/wjh.v13.i12.2104
Liver function tests and metabolic-associated fatty liver disease: Changes in upper normal limits, does it really matter?
Roberta Forlano, Benjamin H Mullish, Ameet Dhar, Robert D Goldin, Mark Thursz, Pinelopi Manousou
Roberta Forlano, Benjamin H Mullish, Ameet Dhar, Mark Thursz, Pinelopi Manousou, Liver Unit/Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London W2 1NY, United Kingdom
Robert D Goldin, Centre for Pathology, Department of Medicine, Imperial College London, London W2 1NY, United Kingdom
Author contributions: Forlano R performed the research and wrote the paper; Mullish BH, Dhar A, Goldin RD, Thursz MR provided clinical advice and contributed to the draft; Manousou P designed the research and supervised the report.
Supported by National Institute of Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London; NIHR Academic Clinical Lectureship, No. CL-2019-21-002; European Association for The Study of the Liver, PhD fellowship Juan Rodes 2018.
Institutional review board statement: This study was considered a service evaluation project, using routinely collected patient data, therefore no ethical approval was required under the UK policy framework for health and social care.
Informed consent statement: The Informed consent is not required.
Conflict-of-interest statement: No conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Pinelopi Manousou, MD, PhD, Senior Lecturer, Liver Unit/Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Exhibition Road, London W2 1NY, United Kingdom.
Received: April 21, 2021
Peer-review started: April 21, 2021
First decision: June 23, 2021
Revised: July 2, 2021
Accepted: November 15, 2021
Article in press: November 15, 2021
Published online: December 27, 2021

Metabolic-associated fatty liver disease (MAFLD) is the commonest cause of abnormal liver function tests (LFTs). Current upper normal of limit (UNL) of LFTs was derived from a “healthy” population, where undiagnosed MAFLD and viral hepatitis might be suspected.


To evaluated potential implications of changes in UNL of alanine aminotransferase (ALT) in MAFLD.


We retrospectively assessed consecutive first referrals with a diagnosis of MAFLD from 2010 to 2017. The conventional UNL of ALT was 45 IU/L for men and 34 IU/L for women, while a low UNL of ALT was 30 IU/L for men and 19 IU/L for women. The UNL of aspartate aminotransferase (AST) was 40 IU/L.


Total 436 patients were enrolled; of these, 288 underwent liver biopsy. Setting a lower UNL reduced the percentage of those with significant disease despite normal ALT; specifically, patients with advanced fibrosis (F ≥ F3) or definite “metabolic-associated steato-hepatitis (MASH)” (NAS ≥ 5) within normal ALT decreased from 10% to 1% and from 28% to 4% respectively. However, the proportion of those with elevated ALT and no evidence of advanced fibrosis or “definite MASH” increased from 39% to 47% and from 3% to 19%. Overall, LFTs performed poorly in distinguishing “definite MASH” from simple steatosis (receiver operating characteristic areas under the curves 0.59 for ALT and 0.55 for AST).


Liver function tests might both under- and overestimate MASH-related liver disease. Reducing the UNL might not be beneficial and imply an increase in healthcare burden. Risk stratification in MAFLD should rely on a combination of risk factors, not on LFTs alone.

Keywords: Metabolic-associated fatty liver disease, Liver function tests, Alanine aminotransferase, Fibrosis, Stiffness

Core Tip: In the United Kingdom, the hepatologists receive increasing demand for secondary care services to investigate liver function tests (LFTs), especially with the suspicion of metabolic-associated fatty liver disease (MAFLD). With current upper normal limit (UNL), patients without liver diseases but elevated LFTs is high (27%), as well as those with significant fibrosis or metabolic-associated steato-hepatitis and normal LFTs (10%). Here, we aimed to evaluate the potential implications of changes in UNL of LFTs. Our data show that reducing the UNL would lead to an increase in overall healthcare burden. In MAFLD, the risk-stratification should rely on a combination of risk factors, rather than on LFTs alone.