Screening for metabolic dysfunction-associated fatty liver disease: Time to discard the emperor’s clothes of normal liver enzymes?

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver condition worldwide. Current liver enzyme-based screening methods have limitations that may missed diagnoses and treatment delays. Regarding Chen et al, the risk of developing MAFLD remains elevated even when alanine aminotransferase levels fall within the normal range. Therefore, there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early intervention. This paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD: Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores.

Key Words: Metabolic dysfunction-associated fatty liver disease, Non-alcoholic fatty liver disease, Alanine aminotransferase, Liver enzymes, Screening, Noninvasive liver fibrosis scores

Core Tip: Screening and risk assessment procedures for metabolic dysfunction-associated fatty liver disease by liver enzymes may result in underdiagnosis and treatment delays. To improve the screening methods, it is feasible to lower the normal thresholds for liver enzymes and promote the use of noninvasive liver fibrosis scores.

INTRODUCTION

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver condition worldwide. Current liver enzyme-based screening methods have limitations that may missed diagnoses and treatment delays. Regarding the article published in the World Journal of Gastroenterology, the risk of developing MAFLD remains elevated even when alanine aminotransferase (ALT) levels fall within the normal range. Therefore, there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early intervention. This paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD: Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores.

NEW PROSPECTIVE ON MAFLD SCREENING

MAFLD affects approximately 30% of the global adult population[1], contributing to a growing burden of multisystem disease and imposing substantial economic costs on society. Screening for MAFLD presents challenges, particularly during its early stages when it often manifests without symptoms. Therefore, healthcare providers must remain vigilant when evaluating liver disease in patients, particularly regarding the progression of liver fibrosis. Presently, liver disease screening primarily focuses on detecting abnormalities in liver enzymes or markers related to liver function, which can result in missed diagnoses and delays in treatment initiation. Unlike screening for conditions such as hypertension and diabetes, relying solely on a single parameter, using liver enzyme assessments for MAFLD is simplistic and commonly used but not ideal for monitoring liver disease progression.

Recent evidence indicates that MAFLD can be present even within the normal range of ALT values. In this context, Chen et al[2] conducted a retrospective analysis to explore the optimal ALT cut-off points for diagnosing MAFLD. Their findings revealed that a significant proportion of participants with MAFLD exhibited normal ALT levels, accounting for 83.13% of cases. Notably, the study identified a high-normal ALT level range of 18.6-40 U/L, emphasizing that sustained alterations in ALT levels can cumulatively increase the risk of new-onset MAFLD[2]. Large-scale epidemiological studies, such as the Dallas Heart Study, have reported normal ALT levels in 79% of MAFLD patients, while Gawrieh et al’s observational study[3] found that 43% of MAFLD patients had normal serum ALT levels[3]. Moreover, the risk of developing MAFLD remains elevated even when ALT levels fall within the normal range, as metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis can occur even when ALT levels are below the upper limit of normal, specifically in individuals with plasma ALT < 40 U/L[4]. Castera et al[5] conducted a prospective multicenter study and found a high prevalence of MASH (58%) despite a low ALT threshold[5]. Similarly, a meta-analysis by Li et al[6] revealed the unreliability of ALT in predicting liver injury in patients infected with hepatitis B. The meta-analysis found that about 1/3 of treatment-naïve chronic hepatitis B patients experienced significant histological changes with ALT levels at or below 40 IU/L. In contrast, only about 1/5 of patients showed significant fibrosis, even with ALT levels at or below 20 IU/L.

Two screening methods have been proposed for individuals at risk of MAFLD. The first method involves lowering the normal thresholds for liver enzymes, particularly ALT. By assembling a large-scale cohort of MAFLD patients from various nations, the upper threshold of normal ALT values can be reevaluated based on distinct age and gender characteristics, employing statistical methodologies such as performing receiver operating characteristic curve analysis. Lowering these thresholds enables the early detection of abnormal liver function, prompting further screening and facilitating earlier recognition of MAFLD, thus potentially reducing disease burden. However, this approach may result in some patients being inaccurately labeled as having abnormal liver function, leading to potential social implications. Additionally, clinicians may overlook certain beneficial medications, such as statins, due to concerns related to this label.

Promoting the use of noninvasive liver fibrosis scores may offer a more suitable and convenient method for assessing MAFLD. Analogous to the introduction of an age-adjusted estimated glomerular filtration rate (eGFR) in nephrology, which has become widely adopted for evaluating kidney function. This indicator has since been widely used in assessing renal function and determining appropriate medication dosages[7]. Various noninvasive scoring systems have been approved for accurate diagnosis and clinical monitoring of liver fibrosis[8,9]. Unfortunately, these noninvasive scoring methods were only discussed and used among hepatologists, and not widely used by other clinicians. Fibrosis-4 index (FIB-4) is a simple available blood-based marker of liver fibrosis that can be calculated using only commonly clinical parameters including age, platelet count, aspartate aminotransferase and ALT. Despite the similarity between noninvasive scoring systems, such as the FIB-4, and the eGFR calculation, their use remains limited mainly to subspecialists[10]. A patient with an elevated FIB-4 index, even with normal liver enzymes, indicates a higher likelihood of advancing liver fibrosis, warranting further evaluation through techniques such as vibration-controlled transient elastography or liver biopsy[11]. However, promoting the use of liver fibrosis scoring systems faces significant challenges, including limited awareness among clinicians and the public, which necessitates additional efforts to facilitate their widespread adoption.

CONCLUSION

In summary, current screening and risk assessment procedures for liver enzymes are outdated, resulting in the underdiagnosis of a substantial number of patients with MAFLD. There is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of disease diagnosis and enable early intervention. The widespread adoption of noninvasive liver fibrosis scores should be prioritized as a crucial topic for discussion.