KASL clinical practice guidelines for the management of metabolic dysfunction-associated steatotic liver disease 2025

Purpose and scope

Nonalcoholic fatty liver disease (NAFLD) is defined as excessive fat accumulation in the liver in the absence of significant alcohol consumption. Recently, a novel concept of fatty liver disease (FLD) has emerged. When the term ‘nonalcoholic’ was first introduced, the disease identity of NAFLD was based on the exclusion of other etiologies for chronic liver disease. However, the characteristics of NAFLD have gradually been established, as it is closely associated with metabolic dysfunction such as obesity, insulin resistance, diabetes mellitus, hypertension, and dyslipidemia. The paradigm shift in FLD has transitioned from NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD), which requires the presence of at least one metabolic dysfunction.

Therefore, it is necessary to clarify the definition of MASLD and delineate the similarities and differences between NAFLD and MASLD. Moreover, resmetirom, an oral thyroid hormone receptor-beta (THR-β) agonist, demonstrated successful treatment outcomes for metabolic dysfunction-associated steatohepatitis (MASH) in a phase III clinical trial. Resmetirom was approved in March 2024 in the United States (US) as a treatment for MASH. It is necessary to share the knowledge for the clinical evidence and use of resmetirom for MASH. This guideline aimed to clarify the concept and clinical manifestations of MASLD and describe the clinical use and perspective of new pharmacologic therapy for MASH. Therefore, we reviewed Korean and international studies to prepare appropriate guidelines based on evidence, to reflect domestic conditions as much as possible. While the ‘2021 Korean Association for the Study of the Liver (KASL) Clinical Practice Guidelines for the Management of NAFLD’ was completely revised, this guideline has been substantially amended to incorporate recent advances and updated recommendations on 11 clinical issues requiring updates in medical information. This guideline includes the Korean nomenclature, definition, diagnostic criteria, clinical manifestation, and prognosis of MASLD. It also shares updates on the drugs approved for MASH treatment and definition and diagnostic criteria of MASLD in pediatrics. There is a continuity between ‘2021 KASL Clinical Practice Guidelines for the Management of NAFLD’ and the present guideline. We refer to the ‘2021 KASL Clinical Practice Guidelines for the Management of NAFLD’ for the issues not included in this guideline. Those issues are risk factors including genetic factors, diagnostic methods, HCC surveillance, prevention of HCC, lifestyle modification, and surgical treatment.

These guidelines have been developed through reviewing medical evidence by experts to provide a practical reference for the treatment, research, and education of MASLD. They are not absolute standards for treatment, and the best choice of practice for individual patients may vary depending on their specific circumstances. In cases where related studies on clinically essential issues are lacking, we tried to present consensus opinions from experts. If relevant evidence based on new research results is accumulated in the future, these guidelines can be revised and supplemented. The guidelines cannot be modified, transformed, or reproduced without permission.

Target population

The target population of these guidelines includes adults, adolescents, and pediatric patients with MASLD.

Intended users

The following guidelines aim to provide clinical information useful for the decision-making of healthcare providers involved in the diagnosis and treatment of patients with MASLD and to raise awareness of MASLD among them, ultimately reducing morbidity and mortality and increasing the quality of life for patients with MASLD. In addition, these guidelines are intended to provide specific and practical information to resident physicians, practitioners, and trainers.

Guideline development group, process, and funding source

The Clinical Practice Guideline Committee for the Management of MASLD (hereafter referred to as ‘the Committee’) was organized in accordance with proposals approved by the KASL Board of Executives. The committee consists of 13 hepatologists, one pediatrician specializing in hepatology, and one methodology expert (Supplementary Table 1). The KASL paid all expenses, and the financial support did not affect the independence of the guideline contents. Each member of the committee collected and analyzed relevant evidence from their respective field and wrote the manuscript. The timeline of the guideline development process is shown in Supplementary Table 2. Conflicts of interest among the members are summarized in Supplementary Table 3.

Literature search for evidence collection

The committee collected relevant Korean and international literature through databases, including PubMed, MEDLINE, KoreaMed, KMBASE, RISS, and KISS, and analyzed them to establish guidelines based on the latest research and evidence. Only Korean and English literature was searched, and the search terms included ‘nonalcoholic fatty liver disease’ (NAFLD), ‘metabolic dysfunction-associated fatty liver disease’ (MAFLD), and ‘metabolic dysfunction-associated steatotic liver disease’ (MASLD).

Levels of evidence and grades of recommendations

The literature collected for evidence was analyzed through systematic review, and the levels of evidence were classified using the modified grading of recommendations, assessment, development, and evaluation (GRADE) system (Table 1) [1-3]. They were categorized based on the possibility of changes in the assessment through further research as follows: high (A), with the lowest possibility; moderate (B), with certain possibility; and low (C), with the highest possibility. Specifically, depending on the type of study, randomized controlled trials start at a high level of evidence (A), and observational studies start at a low level of evidence (C). Considering factors affecting the study quality, the evidence level was raised or lowered further [2]. The strength of recommendation was suggested to be either strong (1) or weak (2), according to the GRADE system [4]. It was determined based on the clinical effects of recommendation, patient receptivity, and socioeconomic aspects, as well as the level of evidence. For example, a strong recommendation indicates that interventions could be applied in most patients with solid certainty regarding a greater possibility of desirable effects, high-quality evidence, presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicates a suggestion made with less certainty, which could be considered favorable for many patients. Alternative interventions could be chosen for ‘weak recommendations’ according to the preferences of patients or medical practitioners.

Table 1.

GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) system

List of key questions

The Clinical Practice Guideline Committee for the Management of MASLD selected the following key questions and presented evidence and recommendations for them.

1. What is the evolution of FLD?

2. What is the Korean nomenclature of MASLD?

3. What are the definition and diagnostic criteria of MASLD?

4. What are the prevalence and incidence of MASLD?

5. What is the risk of cardiovascular disease in MASLD?

6. What is the risk of hepatocellular carcinoma (HCC) in MASLD?

7. What is the risk of extrahepatic malignancy in MASLD?

8. What is the risk of liver fibrosis and cirrhosis in MASLD?

9. What are the all-cause mortality and liver-related mortality in MASLD?

10. What is the pharmacologic therapy for MASH?

11. What are the definition and diagnostic criteria in pediatric and adolescent patients with MASLD?

Internal and external review and approval process

Manuscripts and recommendations prepared by each member were reviewed for content integrity and validity during several committee meetings, and the quality of the guidelines was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) criteria. The recommendations were assessed and revised based on the critical review by the Delphi Committee, consisting of nine experts in the field of hepatology belonging to the KASL (Supplementary Table 4). The guidelines were reviewed at a meeting of an external review board comprising six specialists in the field of hepatology and at a symposium open to all KASL members and the public, following which they were further modified. The Board of Executives of KASL endorsed the final manuscript.

Release of the guideline and plan for updates

The KASL Clinical Practice Guideline for the management of MASLD will be released at the Liver Week 2025 (May 29, 2025). The Korean version of the guideline is available on the KASL website (http://www.kasl.org). The KASL plans to update the guidelines when significant new evidence emerges, and revisions are deemed necessary to enhance Korea’s national health.

Evolution of the nomenclature

Korean nomenclature

As explained earlier, the new concept of FLD has led to changes in its English nomenclature. Consequently, there is a need to establish the Korean nomenclature for this new concept.

Establishment of the Korean nomenclature for MASLD

With the proposal of a new nomenclature for FLD, discussions on an appropriate Korean designation have become necessary. Although the AASLD and the EASL proposed using the term ‘steatotic’ instead of ‘fatty’, both terms translate into the same Korean word, ‘지방’ [17,18]. In December 2023, the KASL recognized the importance of internationally unified and accurate terminology and approved the organization of the ‘NAFLD Nomenclature Revision Consensus Task Force’. In February 2024, the ‘NAFLD Nomenclature Revision Consensus Task Force’ under the KASL was established, initiating work to define new terminology for FLD and revise it into Korean [19]. The NAFLD Nomenclature Revision Consensus Task Force, composed of eight experienced liver specialists in Korea, aimed to revise the terminology to reflect the nature of FLD accurately and improve patients’ understanding of their condition. As a part of this effort, the NAFLD Nomenclature Revision Consensus Task Force first conducted a survey to gather opinions from the KASL members. The survey results showed that the terms ‘FLD’ and ‘SLD’ received the most responses for being uniformly named as ‘지방간질환’ in Korean. For the Korean names ‘MAFLD’ and ‘MASLD,’ the survey responses indicated a preference for uniformly naming them as ‘대사이상지방간질환’ or ‘대사이상관련지방간질환’ [19]. After extensive discussions and consideration of the survey results, the NAFLD Nomenclature Revision Consensus Task Force decided to term SLD in Korean the same as the existing term for ‘FLD’ that is, as ‘지방간질환’ despite the differences in their English terminologies. Accordingly, the Korean names for MAFLD and MASLD were also naturally decided to be the same. Considering the above, the NAFLD Nomenclature Revision Consensus Task Force concluded that ‘대사이상지방간질환’ is the most appropriate Korean term for MAFLD and MASLD, and that ‘대사이상지방간질환’ and ‘대사이상관련지방간질환’ carry the same medical meaning. However, the former was deemed more appropriate as it is easier to communicate in real practice and explain to Korean patients [19]. Additionally, considering that MASLD is very common in Korea, affecting approximately 25–30% of the population, it was determined that a shorter name would be easier to apply than a longer one. Lastly, the NAFLD Nomenclature Revision Consensus Task Force concluded that while the English names can be easily communicated using the abbreviations MAFLD or MASLD, the absence of such abbreviations in Korean makes the more concise term ‘대사이상지방간질환’ more suitable as the Korean nomenclature. Thus, the KASL coined the Korean terms for MAFLD and MASLD (Fig. 1).

Figure 1.

Evolution and nomenclature of fatty liver disease. NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; MAFLD, metabolic dysfunction-associated fatty liver disease; APASL, Asian Pacific Association for the Study of the Liver; MASLD, metabolic dysfunction-associated steatotic liver disease; KASL, Korean Association for the Study for the Liver.

[Summary]

• A new concept of FLD, MASLD, has been recently introduced to emphasize metabolic dysfunction as the pathophysiological mechanism of NAFLD.

• The Korean term for MASLD is ‘대사이상지방간질환’.

NAFLD

NAFLD is defined as a condition characterized by hepatic fat accumulation on pathological, radiological, or biochemical examinations in the absence of secondary causes such as significant alcohol consumption, drug-induced liver injury, or viral hepatitis [20]. NAFLD encompasses the diagnostic categories of NAFL, NASH, and NAFLD-related cirrhosis. Although the upper limit of significant alcohol consumption varies between studies, ranging from 10 to 40 g of pure alcohol per day, making it difficult to provide a definitive threshold, the ‘2021 KASL Clinical Practice Guideline for NAFLD’ defines significant alcohol consumption as >210 g/week for men, and >140 g/week for women [21]. Diagnosing NAFLD requires the exclusion of other chronic liver diseases, including significant alcohol consumption.

MAFLD

In 2020, MAFLD was proposed as ‘a diagnosis when hepatic steatosis is confirmed by pathological, radiological, or biochemical examination, along with the presence of overweight/obesity (body mass index [BMI] ≥23 kg/m² for Asians and ≥25 kg/m² for Western populations), type 2 diabetes mellitus (T2DM), or metabolic abnormalities’. Unlike NAFLD, the diagnosis of MAFLD does not require the exclusion of excessive alcohol consumption and can be made regardless of the presence of other chronic liver diseases. Additionally, it was suggested that the disease progression of MAFLD be described by activity grade and fibrosis stage rather than a dichotomous classification of steatohepatitis or simple steatosis [14,22]. However, limitations of MAFLD include the lack of input from various stakeholders, such as patient advocacy groups, during its formulation; the continued use of the term ‘fatty’; inclusion of metabolic risk factors such as homeostatic model assessment for insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hs-CRP), which are not frequently used in clinical practice; and exclusion of the concept of steatohepatitis, making it difficult to apply prior clinical trial results of NASH treatments.

MASLD

The most recently proposed term, MASLD, is defined as the ‘presence of hepatic steatosis along with at least one cardiometabolic risk factor’ [17,18]. Cardiometabolic risk factors are identified when at least one of the following five conditions is present: (1) BMI ≥23 kg/m² in Koreans and Asians or ≥25 kg/m² in Western populations; or a waist circumference ≥90 cm for men and ≥85 cm for women in Korea, or ≥94 cm for men and ≥80 cm for women according to the World Health Organization (WHO) [23,24], (2) fasting blood glucose ≥100 mg/dL, postprandial 2-h blood glucose ≥140 mg/ dL, HbA1c ≥5.7%, or a diagnosis of T2DM or antidiabetic medication use; (3) blood pressure ≥130/85 mmHg or antihypertensive medication use; (4) triglycerides ≥150 mg/dL or lipid-lowering medication use; or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for men and <50 mg/dL for women, or lipid-lowering medication use [25]. The WHO has proposed the criteria for abdominal obesity in the Asia-Pacific region as a waist circumference ≥90 cm for men and ≥80 cm for women. However, considering the average waist circumference of Korean adults, the criteria in Korea are set at ≥90 cm for men and ≥85 cm for women. As the diagnostic criteria for abdominal obesity vary by country and ethnicity, it is necessary to take these differences into account and apply them appropriately [24,26]. The term MASLD encompasses various disease conditions, including metabolic dysfunction-associated steatotic liver (MASL), MASH, and cirrhosis. MASLD is classified as a subtype of the newly proposed category of SLD. In addition to MASLD, SLD includes MASLD with increased alcohol consumption (MetALD), which refers to moderate alcohol intake, defined as 30–60 g/day for men and 20–50 g/day for women; alcohol-related liver disease (ALD), associated with either significant alcohol consumption in the absence of cardiometabolic risk factors or excessive alcohol consumption in the presence of cardiometabolic risk factor(s); specific etiology SLD caused by drugs or monogenic disease; and cryptogenic SLD (Fig. 2) [17]. Besides alcohol amount, binge drinking and the period of alcohol use would be considered to differentiate the diagnosis of MASLD, MetALD, and ALD. Since current drinking pattern may not fully reflect their past alcohol exposure, it is important to assess a more detailed history of alcohol use. However, there is a lack of evidence on binge drinking and the period of alcohol use to differentiate the diagnosis of MASLD, MetALD, and ALD. Further researches are needed to determine how drinking history and episodic heavy drinking should be considered in clinical practice. When MASLD coexists with another SLD subtype, the condition can be classified as a combination etiology.

Figure 2.

Diagnostic algorithm for MASLD. The specific etiology of SLD includes drug-induced liver injury (e.g., corticosteroids, tamoxifen, amiodarone, irinotecan, methotrexate, lomitapide, valproate, and 5-fluorouracil), monogenic diseases (e.g., lysosomal acid lipase deficiency, Wilson’s disease, hypobetalipoproteinemia, inborn errors of metabolism), and other conditions such as HCV genotype 3 infection, malnutrition, celiac disease, HIV, and environmental exposure to agents associated with steatosis (e.g., hydrocarbon inhalation). BMI, body mass index; M, male; F, female; WC, waist circumference; SLD, steatotic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, MASLD with increased alcohol consumption; ALD, alcohol-related liver disease; MASH, metabolic dysfunction-associated steatohepatitis.

Comparison of the definitions and diagnostic criteria of NAFLD, MAFLD, and MASLD

The definitions of NAFLD, MAFLD, and MASLD differ in terminology, diagnostic methods for hepatic steatosis, alcohol consumption thresholds, and diagnostic criteria (Table 2). NAFLD includes the terms ‘nonalcoholic’ and ‘fatty’ and diagnoses hepatic fat accumulation through blood tests, imaging, or histological examination. Diagnosis requires the absence of significant alcohol consumption (<30 g/day for men and <20 g/day for women). Cardiometabolic risk factors are not included in the diagnostic criteria. NAFLD is diagnosed by excluding other chronic liver diseases and causes of hepatic steatosis.

Table 2.

Comparison of the definitions and diagnostic criteria of NAFLD, MAFLD, and MASLD

In contrast, MAFLD excludes the term ‘nonalcoholic’ and emphasizes ‘metabolic dysfunction’. Diagnosis of MAFLD can be made when hepatic steatosis is confirmed by blood tests (e.g., fatty liver index [FLI], hepatic steatosis index) [27,28], imaging, or histological examination, along with the presence of overweight/obesity, T2DM, or two or more metabolic risk factors. Unlike NAFLD or MASLD, MAFLD does not have an alcohol consumption threshold and does not require the exclusion of other causes of chronic liver disease or hepatic steatosis. Additionally, MAFLD differs from MASLD, as the former includes metabolic risk factors such as HOMA-IR and hs-CRP.

MASLD also emphasizes ‘metabolic dysfunction’ but differs from MAFLD by using the term ‘steatotic’ instead of ‘fatty’. MASLD is diagnosed through imaging or histological examination when at least one cardiometabolic risk factor is present. It also differs from MAFLD, as significant alcohol consumption must be absent (<30 g/day for men and <20 g/day for women), and other causes of SLD must be excluded.

Concerns have been raised regarding whether findings from studies on patients with NAFLD can be directly applied to those with MASLD. In a French cohort of 2,187 patients diagnosed with NAFLD through liver biopsy, MASLD diagnostic criteria were also applied. The results showed a concordance rate of 98.4%, with only 1.6% of patients not meeting the MASLD criteria [29]. In a Swedish cohort study of 1,333 patients with NAFLD, 99.7% of them met the MASLD criteria. The overall survival rates and liver-related outcomes exhibited similar trends between the two groups [30]. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) in the US reported a MASLD prevalence of 31.3%, with a concordance rate of 99% between NAFLD and MASLD [31]. In a Korean study analyzing 2,535 individuals who underwent magnetic resonance imaging proton density fat fraction (MRI-PDFF) at five health check-up centers, 992 individuals (39.1%) were diagnosed with SLD, 745 (29.4%) with MASLD, and 735 (29.0%) with NAFLD. Among those with MASLD, 94.5% (704/745) were also classified as having NAFLD. Similarly, 95.8% (704/735) of those with NAFLD were classified as having MASLD. The 31 patients who did not meet the MASLD criteria were all identified as having cryptogenic SLD [32].

Prevalence

In Korea, the prevalence of NAFLD diagnosed using ultrasonography was reported to be 25.2% in 2009, based on a study of 141,610 health check-up participants [33]. A systematic review including 61 studies conducted in Korea reported a 30.3% prevalence of NAFLD among 837,897 Korean individuals, with a 41.1% prevalence in men and 20.3% in women [34]. A meta-analysis of 237 studies conducted in Asia and published between 1999 and 2019 reported a 32.9% prevalence of NAFLD diagnosed using ultrasonography in Korea [35] and a global meta-analysis reported a 34.6% prevalence of NAFLD [36]. These findings suggest that the prevalence of NAFLD in Korea, Asia, and worldwide is relatively similar. When transient elastography (TE) was used to define fatty liver with a controlled attenuation parameter (CAP) score ≥250 dB/m, the prevalence of NAFLD was reported to be 42.9% [37]. A study using liver biopsy data from living liver donors in Korea reported a 51.4% NAFLD prevalence [38]. The prevalence of MAFLD diagnosed using ultrasonography was 33.9% among 6,775 health check-up participants from 13 institutions in Korea [39]. When fatty liver was defined as an FLI ≥30 among health check-up participants, the prevalence of MAFLD was 37.3% [40].

The prevalence of MASLD varies depending on the study population, definition, and diagnostic methods. The prevalence of MASLD diagnosed using ultrasonography was found to be 33.5% among 7,918 health check-up participants in Korea [41]. When fatty liver was defined as ≥5% liver fat content on MRI-PDFF, the prevalence of MASLD among 2,535 health check-up participants from five institutions in Korea was 29.5% [32]. In the same population, the prevalence of NAFLD was 29.1%. In a single health screening center in Korea, when fatty liver was defined as ≥5% liver fat content on MRI-PDFF, the prevalence of MASLD was found to be 25.2% [42]. In the same cohort, the prevalence of MAFLD was 29.5%, and that of NAFLD was 25.9%. In 2009, a study of 9,775,066 health check-up participants found that when fatty liver was defined as an FLI ≥30, the prevalence of MASLD was 27.5%, with 39.5% in men and 17.4% in women [43]. In the same population, the prevalence of MAFLD was 36.1%, and that of NAFLD was 27.6%. It is generally known that MASLD is more prevalent in men than in women; however, its prevalence tends to be higher in postmenopausal women [44]. A 2010 Korean study of 351,068 health check-up participants reported a MASLD prevalence of 47.2% when fatty liver was defined as an FLI ≥60 [45]. In the Ansung–Ansan cohort of 9,497 participants, when fatty liver was defined as an FLI ≥30, the prevalence of MASLD was reported to be 38.3% [46]. When fatty liver is defined based on the FLI, there tends to be some variation in prevalence estimates, often indicating a higher incidence.

Incidence

The incidence of NAFLD in Korea has been increasing. A Korean study that followed 5,237 men for >4 years reported the incidence rate of NAFLD to be 74.1 cases per 1,000 person-years [47]. Among health check-up participants, when diagnosed using ultrasonography, the incidence rate was reported to be approximately 48.2 cases per 1,000 person-years (13.4–77.7 cases) [48-54]. A meta-analysis of 237 studies from Asia, published between 1999 and 2019, reported an incidence rate of 45.1 cases per 1,000 person-years in Korea [35], and a global meta-analysis reported an incidence rate of 60.2 cases per 1,000 person-years [36]. Studies on MASLD incidence remain limited, highlighting the need for further research to assess its incidence accurately. It is expected that the incidence will likely increase, similar to the trend observed for NAFLD.

CVD

MASLD has been shown to follow a natural history, including clinical outcomes and mortality rates comparable to those of NAFLD [30,55]. This has led to the proposition that previous research findings on NAFLD could be extended to MASLD [56]. Cohort studies diagnosing NAFLD based on histological or imaging criteria have consistently shown an increased incidence of CVD and related mortality compared to non-steatotic controls. However, some variations exist depending on the diagnostic method for hepatic steatosis, type of CVD, and adjustment factors used in the analysis [57-59].

In a Swedish study involving biopsy-proven patients with NAFLD followed for 13 years, the incidence of CVD was 24.3 cases per 1,000 person-years, while the CVD-related mortality rate was 7.2 deaths per 1,000 person-years. Notably, the risk of CVD-related mortality remained significantly elevated even after adjusting for confounding factors such as age, sex, diabetes, and obesity (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.27–1.48) [57]. In a recent meta-analysis of 79 studies on NAFLD diagnosed through histological or imaging methods, the incidence of CVD was reported as 24.77 cases per 1,000 person-years, closely aligning with previous research findings. Additionally, the meta-analysis reported a CVD-related mortality rate of 4.5 deaths per 1,000 person-years [59]. Another meta-analysis comprising 36 studies on NAFLD further confirmed a significant elevation in the risk of CVD-related mortality (HR 1.30, 95% CI 1.08–1.56) [60].

Using data from the US NHANES, a 23-year longitudinal cohort study that defined hepatic steatosis via ultrasound demonstrated that individuals with MAFLD had a significantly increased risk of CVD-related mortality even after adjusting for age, sex, and other confounding factors (HR 1.33, 95% CI 1.22–1.44) [58]. A cohort study based on national health screening data from the National Health Insurance Service (NHIS) in Korea, which defined MAFLD using an FLI ≥30, demonstrated that the incidence of CVD was 3.18 cases per 1,000 person-years and the CVD-related mortality rate was 0.47 deaths per 1,000 person-years. The study further confirmed a significant increase in the risk of CVD-related mortality (HR 1.46, 95% CI 1.41–1.52) [40].

In a 12-year observational study based on national health screening data from the NHIS in Korea, where MASLD was defined using an FLI ≥30, the incidence of CVD was 3.79 cases per 1,000 person-years, compared to 2.06 cases per 1,000 person-years in the control group. The CVD-related mortality rate was 0.8 deaths per 1,000 person-years in the MASLD group, while the control group had a rate of 0.5 deaths per 1,000 person-years. The risk of CVD-related mortality was significantly elevated in the MASLD group relative to the control group (HR 1.13, 95% CI 1.11–1.15) [43]. Another study based on the NHIS in Korea, wherein MASLD was defined using an FLI ≥60 and followed for 9 years, reported an annual CVD incidence of 8.5 cases per 1,000 person-years, compared to 6.2 cases per 1,000 person-years in the control group [45]. Both studies demonstrated that the incidence of CVD was higher in individuals with MASLD than in non-steatotic controls. However, a recent 23-year follow-up study using data from the US NHANES, which defined hepatic steatosis using ultrasound, found that, even after adjusting for risk factors such as age and sex, the risk of CVD-related mortality in individuals with MASLD did not show a significant increase compared to the control group (HR 1.11, 95% CI 0.98–1.27). In contrast, the risk of CVD-related mortality was significantly increased in MAFLD when including viral hepatitis and alcohol-related liver disease (HR 1.13, 95% CI 1.01–1.27) [61].

A scoring system for predicting the risk of CVD in individuals with NAFLD has been validated. The Framingham Risk Score and Atherosclerotic CVD Risk Score, which use indicators such as age, sex, total cholesterol and high-density lipoprotein cholesterol levels, blood pressure, diabetes, and smoking status, have been shown to be applicable in predicting the 10-year risk of CVD in individuals with NAFLD [62,63]. The Systematic COronary Risk Evaluation 2 (SCORE2) model and the SCORE2-Older Persons model, developed in Europe, can be used to estimate the 10-year CVD risk in patients with NAFLD [64]. Recent studies suggesting minimal differences between the patient populations of NAFLD and MASLD imply that CVD risk prediction models developed for NAFLD may also be applicable to MASLD. However, further investigation is warranted to substantiate this hypothesis.

HCC

HCC is the third leading cause of cancer-related mortality worldwide, and the increasing prevalence of MASLD continues to contribute to the development of HCC significantly [65]. Consequently, further epidemiological research on the incidence of HCC within the framework of the evolving spectrum of SLD is essential.

In patients with NAFLD, the incidence of HCC is extremely low in the absence of progressive hepatic fibrosis (F0-2) [66]. However, in patients with cirrhosis related to NAFLD, the annual incidence of HCC exceeds 1.5%. Therefore, clinical suspicion of cirrhosis warrants surveillance for HCC [66]. A cohort study based on national health screening data from the NHIS in Korea found that the incidence of HCC was higher in patients with MAFLD compared to those without hepatic steatosis (0.37 cases per 1,000 person-years vs. 0.24 cases per 1,000 person-years). When stratified by the presence of other chronic liver diseases, MAFLD was not associated with HCC in patients with concurrent chronic liver conditions. In contrast, in patients without other chronic liver diseases, MAFLD emerged as an independent cause of HCC (adjusted HR 1.84, 95% CI 1.09–3.11) [67].

A study based on the NHIS in Korea, which followed participants for 13 years, found that the incidence of HCC was 0.24% in the non-MASLD group and 0.62% in the MASLD group. The age-standardized 5-year cumulative incidence of HCC was 0.09% in the non-MASLD group and 0.18% in the MASLD group [68]. According to an additional domestic study using data from the NHIS on individuals who underwent biennial health screenings, the incidence of HCC was significantly elevated in individuals with MASLD compared to those without MASLD, over a follow-up period exceeding 10 years (adjusted HR 2.94, 95% CI 2.68–3.21) [69]. A domestic study using data from 29,060 hospital health checkup patients found that the annual incidence of HCC in individuals with MASLD was 0.18 cases per 1,000 person-years [70]. A study conducted in Taiwan, which followed 5,203,878.9 person-years of patients with SLD, identified 1,392 new cases of HCC, yielding an annual incidence rate of 26.8 cases per 100,000 person-years. Among these patients, the incidence of HCC in those with MASLD was higher, at 30.7 cases per 100,000 person-years [71]. In a study involving 220 patients with MASLD-related decompensated cirrhosis, 40 (18.2%) developed HCC during an average follow-up period of 3.2 years [72].

Extrahepatic malignancy

Patients with NAFLD exhibit a significantly higher prevalence of extrahepatic malignancies compared to control groups. A meta-analysis of 10 studies demonstrated that the presence of NAFLD is associated with an increased prevalence of extrahepatic malignancies [73]. NAFLD was associated with a 1.5- to 2-fold increase in the prevalence of gastrointestinal cancers, including esophageal, gastric, pancreatic, and colorectal cancers. Additionally, the prevalence of lung cancer, breast cancer, gynecological malignancies, and urological cancers increased by an average of 1.2–1.5 times in patients with NAFLD. A meta-analysis of 22 studies further demonstrated that NAFLD is associated with an increased risk of various extrahepatic cancers, including thyroid, pancreatic, gastrointestinal, urological, breast, and lung cancers. The risk ranged from a 1.3-fold increase (lung cancer: HR 1.25, 95% CI 1.11–1.40) to a 2.6-fold increase (thyroid cancer: HR 2.63, 95% CI 1.27–5.45 [74]. In a study of 25,947 Koreans who underwent health checkups in 2004, patients with hepatic steatosis showed a significantly higher incidence of overall malignancies compared to those without hepatic steatosis (HR 1.32, 95% CI 1.17–1.49) [75]. Notably, men with NAFLD exhibited a significantly higher incidence of colorectal cancer, while women showed a markedly increased risk of breast cancer. A meta-analysis of 64 studies reported that the incidence of extrahepatic malignancies in patients with NAFLD was 10.58 cases per 1,000 person-years, with notably higher rates of uterine, breast, prostate, colorectal, and lung cancers [76]. However, among patients with NAFLD, the progression to liver fibrosis or cirrhosis was not associated with a further increase in the incidence of extrahepatic malignancies [76].

MAFLD significantly contributes to an increased risk of extrahepatic malignancies. Analysis of data from the NHIS in Korea demonstrated that MAFLD is associated with an increased prevalence of 23 distinct extrahepatic malignancies. This risk was significantly amplified in individuals with multiple metabolic abnormalities compared to those with a single metabolic risk factor [77]. In an analysis involving 151,391 patients from China, MAFLD was found to elevate the risk of developing extrahepatic malignancies by 1.1 folds (HR 1.05, 95% CI 0.99–1.11), with a statistically significant increase observed in the incidence of thyroid, renal, prostate, and breast cancers [78]. Various studies have highlighted abdominal obesity, elevated BMI, T2DM, and the presence of multiple metabolic abnormalities as key risk factors for the development of extrahepatic malignancies [79]. To date, the prevalence and incidence of extrahepatic malignancies in patients with MASLD have not been extensively studied. A recent Australian study reported that the incidence of various malignancies was twice as high in individuals with MASLD compared to those without it. Furthermore, patients with cirrhosis and T2DM were at an even greater risk of developing extrahepatic malignancies [80]. Although additional studies are warranted, the comparable clinical course of MASLD and the former definition of NAFLD suggest that the incidence of extrahepatic malignancies in MASLD is likely elevated relative to that in control populations (Fig. 4).

Figure 4.

MASLD-related extrahepatic malignancies. MASLD, metabolic dysfunction-associated steatotic liver disease.

Liver fibrosis and cirrhosis

While NAFL is typically associated with a favorable prognosis, some patients with NASH may develop advanced liver diseases, including cirrhosis and HCC. In particular, the presence of advanced fibrosis in NASH significantly increases the risk of complications such as cirrhosis and liver-related mortality [20,81].

A meta-analysis of 151 studies published since 2000 reported that among overweight individuals with NAFLD, the prevalence of liver fibrosis (F1–4) was 46.6% (95% CI 26.6–67.7), that of advanced fibrosis (F3–4) was 6.7% (95% CI 4.4–10.0), and that of cirrhosis (F4) was 2.5% (95% CI 1.6–3.7). In overweight individuals with NASH, the prevalence was even higher, with the prevalence of liver fibrosis at 72.6% (95% CI 49.4–87.8), that of advanced fibrosis (F3–4) at 19.4% (95% CI 7.6–41.1), and that of cirrhosis (F4) at 1.7% (95% CI 0.4–6.6) [82]. Another meta-analysis reported that among non-obese patients with NAFLD, 29.2% had significant liver fibrosis (≥F2), and 3.2% had cirrhosis [83]. Various cohort studies and meta-analyses following patients with NAFL and NASH have reported diverse rates of fibrosis progression. One study involving 55 patients with NAFLD reported a fibrosis progression rate of 27% over 3 years based on serial biopsies conducted at 3-year intervals [84]. In another study of 70 patients with biopsies performed at intervals of >1 year, the fibrosis progression rate was 29% over an average follow-up of 3.7 years [85]. A separate study of 108 patients who underwent serial biopsies reported an annual fibrosis progression rate of 0.08±0.25 stages per year and a cumulative progression rate of 42% over a follow-up period of 6.6 years [86]. In a meta-analysis of 11 cohort studies, including 411 biopsy-confirmed patients with NAFLD, the annual liver fibrosis progression rate was 0.13 stages. Progression by at least one stage was estimated to take 14.3 years for NAFL and 7.1 years for NASH, with fibrosis progression occurring approximately twice as fast in NASH compared to NAFL [87]. Moderate alcohol consumption has been identified as a factor influencing fibrosis progression in patients with NAFLD. A study of 58,927 patients with NAFLD in Korea reported that men and women consuming 10.0–29.9 or 10.0–19.9 g of alcohol per day, respectively, had a 1.29–1.31 times higher risk of fibrosis progression compared to non-drinkers (fibrosis-4 [FIB-4] index: 95% CI 1.18–1.40, NAFLD fibrosis score [NFS]: 1.23–1.40) [88]. Furthermore, a meta-analysis of 32 cohort and cross-sectional studies found that moderate alcohol consumption increased the risk of progressive fibrosis by 1.39 times (95% CI 1.22–1.57) in cohort studies, although no significant association was observed in cross-sectional studies [89].

Research on the prevalence and incidence of liver fibrosis and cirrhosis in MAFLD and MASLD remains scarce. A prospective study of 202 biopsy-confirmed patients with MAFLD reported the following prevalence of liver fibrosis stages: F1: 40.6%, F2: 6.9%, F3: 24.8%, and F4: 2.5%, with a 27.3% prevalence of advanced fibrosis (F3–4) [90]. Moreover, a study of 969,253 patients with MAFLD without cirrhosis from the US Veterans Affairs Database, tracking patients from 2010 to 2020, reported 5-year and 10-year cirrhosis incidence rates of 2.42% (95% CI 2.39–2.45) and 3.70% (95% CI 3.66–3.74), respectively [91]. A recent Korean study investigated the epidemiology of SLD, which is defined as an FLI ≥30, in a cohort of 9,497 individuals from the Ansung–Ansan cohort, with biennial follow-ups from 2002 to 2020. The study found that 26.7% of individuals with MASLD had significant liver fibrosis, defined using age-adjusted FIB-4 criteria (FIB-4 ≥1.3 for individuals aged 35–64 years and FIB-4 ≥2.0 for those aged ≥65 years). After adjusting for factors influencing fibrosis, the risk of developing significant liver fibrosis was 1.39 times higher (95% CI 1.25–1.55) in the MASLD group compared to those without SLD [46]. Another Korean study conducted from January 2017 to May 2020, involving 7,918 health check-up participants who underwent magnetic resonance elastography (MRE), reported that the average liver stiffness measurement (LSM) in individuals with MASLD was 2.3 kPa, which was consistent with the overall average of all participants. The proportion of individuals with progressive liver fibrosis (MRE LSM ≥3.6 kPa) was found to be very low, at 2.4% [41]. The prevalence of liver fibrosis and progressive liver fibrosis varies across studies owing to differences in diagnostic methods and criteria. A study conducted between 2009 and 2010 involving 369,094 health check-up participants in Korea found that individuals with MASLD had a 1.71-fold increased risk (95% CI 1.58–1.85) of developing cirrhosis and 1.45-fold increased risk (95% CI 1.29–1.62) of developing decompensated cirrhosis compared to those without SLD. Additionally, in the MASLD population, alcohol consumption was associated with a significantly higher risk of cirrhosis and decompensated cirrhosis, with respective risks of 2.31 folds (95% CI 2.05–2.61) and 1.77 folds (95% CI 1.47–2.14) compared to the MASLD group without significant alcohol intake [92]. Recent studies have reported that moderate alcohol consumption (100–200 g/week for men and 100–130 g/week for women) in individuals with MASLD increases the risk of significant liver fibrosis (LSM ≥8 kPa) by 2.71 folds (95% CI 1.77–4.13) [93]. Consequently, moderate or low levels of alcohol intake in individuals with MASLD could potentially influence liver fibrosis, highlighting the need for caution. However, further studies, including prospective research, are needed to provide more definitive evidence on this matter.

As outlined, the progression of liver fibrosis and the development of cirrhosis in patients with MASLD are significant determinants of disease severity and prognosis. Liver fibrosis is generally assessed using liver biopsy as the gold standard. However, noninvasive methods can be used when biopsy is not practical. For diagnosing liver fibrosis in patients with MASLD, transient elastography, shear wave elastography, and MRE are potential diagnostic tools, whereas serum markers can be used to exclude the presence of progressive liver fibrosis [94]. For detailed information on the methods and accuracy of individual noninvasive tests, refer to the ‘2024 Korean Society of Hepatology Clinical Practice Guidelines for Noninvasive Assessment of Liver Fibrosis in Chronic Liver Disease’ [94].

Mortality

During a median follow-up of 14.2 years, the all-cause mortality in patients with biopsy-proven NAFLD (n=10,568) and matched controls (n=49,925) was 28.6 and 16.9/1,000 person-years, respectively. All-cause mortality was higher in patients with NAFLD than in matched controls (adjusted HR 1.93, 95% CI 1.86–2.00) [95]. A meta-analysis revealed that the leading causes of death in NAFLD were cardiovascular disease, extrahepatic malignancy, and liver-related events. All-cause mortality from CVD, extrahepatic malignancy, and liver-related events in NAFLD were 5.54, 4.21, and 1.75/1,000 person-years, respectively [96]. Several cohort studies showed that liver fibrosis is closely associated with mortality in patients with NAFLD [97,98]. The critical factor for mortality is the stage of liver fibrosis in patients with NAFLD. Significant fibrosis (≥F2) is an independent factor for all-cause and liver-related mortality in NAFLD, which increases in the presence of significant fibrosis (≥F2) [99]. Compared to controls, all-cause mortality increased in NAFL (HR 1.71, 95% CI 1.64–1.7), NASH without fibrosis (HR 2.14, 95% CI 1.93–2.38), non-cirrhotic fibrosis (HR 2.44, 95% CI 2.22–2.69), and cirrhosis (HR 3.79, 95% CI 3.34–4.30) in a large cohort study based on biopsy [95]. Therefore, all-cause and liver-related mortality were associated with the presence of steatohepatitis and fibrosis in patients with NAFLD [95]. T2DM is also a risk factor for mortality in patients with NAFLD. A US study using NHANES data showed that all-cause mortality was higher in patients with NAFLD and T2DM than in individuals without both of these (HR 1.35, 95% CI 1.19–1.52) or in those with NAFLD without T2DM (HR 1.60, 95% CI 1.38–1.85) [100]. A Korean study using KNHANES data showed that the use of anti-diabetic drugs, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, reduced liver-related events and mortality in 87,178 patients with NAFLD and T2DM [101].

During a median follow-up of 22.83 years, there was no significant difference in all-cause mortality between NAFLD (n=2,736) and MASLD (n=2,600) in a US study using NHANES data. All-cause mortality in patients with NAFLD and MASLD was 20.19 and 21.109/1,000 person-years, respectively (P>0.05) [55]. There was a similar tendency of all-cause mortality between NAFLD and MASLD, although patients with MASLD were slightly older and had a slightly increased CVD-related mortality [55]. Another US study using NHANES data investigated the all-cause mortality of 2,264 patients with MASLD with a median follow-up duration of 27.1 years. All-cause mortality in MASLD was higher in patients with advanced fibrosis than in those without it (HR 1.53, 95% CI 1.13–2.06) [102]. A recent Korean study using KNHANES data also revealed that all-cause mortality is higher in patients with MASLD than in those without it (HR 1.32, 95% CI 1.18–1.48) [103]. All-cause mortality increased in patients with MASLD with significant fibrosis (HR 1.68, 95% CI 1.42–2.00) and in those with T2DM (HR 1.85, 95% CI 1.55–2.21). MASLD with significant fibrosis and T2DM were at high risk of all-cause mortality (HR 2.29, 95% CI 1.77–2.98) [103]. Liver transplantation was done in 31 patients (14%), and death occurred in 73 (33.1%) during a median follow-up of 3.2 years among 220 patients with MASLD-related decompensated cirrhosis [72].

Impact of cardiometabolic factors in MASLD

High BMI and central obesity are associated with poor prognosis in patients with MASLD. Compared to BMI 25– 30 kg/m², severe obesity (≥50 kg/m²) has a higher risk of hepatic decompensation, obesity-related extrahepatic cancers, and all-cause mortality [104]. The US NHANES III shows that all-cause mortality increase as waist circumference and waist-to-hip ratio increases in patients with MASLD [105]. T2DM is an independent risk factor for fibrosis progression in patients with MASLD. In 447 patients with biopsy-proven MASLD, fibrosis progression with ≥1-stage increase in participants with T2DM compared to participants without T2DM (adjusted HR, 1.69, 95% CI 1.17–2.43) [106]. A meta-analysis reveals that participants with T2DM had a significantly higher risk of hepatic decompensation and HCC development in MASLD [107]. Also, diabetes is a risk factor for all-cause mortality in patients with MASLD. A Korean study showed that all-cause mortality is higher in MASLD patients with diabetes than in those without it (HR 1.85, 95% CI 1.55–2.21) [103]. A cohort study diagnosing MASLD using transient elastography showed that the severity of liver fibrosis worsened as the number of cardiometabolic risk factors increased [93]. A prospective cohort study in Korea, which followed 10,038 patients with MASLD for 17.5 years using a FLI ≥30, found that hypertension significantly increased the risk of cardiovascular disease (aHR 1.94, 95% CI 1.63–2.31). The same study reported that an increase in cardiometabolic risk factors was associated with a higher risk of cardiovascular disease [46]. A 9-year study using NHIS in Korea, where MASLD was defined using an FLI ≥30 found that MASLD with hypertension had the highest cardiovascular disease-related mortality compared to other cardiometabolic risk factors. Additionally, MASLD patients with low HDL exhibited the highest all-cause, liver-related, and cancer-related mortality [108].

General principle of use

As the need for MASH treatment has increased, clinical studies on various drugs have been conducted to improve MASH and liver fibrosis. The complex pathophysiology of MASH and its interaction with other metabolic diseases remain poorly understood. As a result, the current therapeutic agents for MASH are under development, targeting a wide range of targets. Here, the mechanisms of their use are introduced and effects of previously introduced and newly developed drugs are discussed.

Antioxidants

Vitamin E, an antioxidant, improves intrahepatic inflammation by reducing oxidative stress that worsens NASH [109,110]. In the large-scale randomized phase III PIVENS study, high-dose vitamin E (800 IU/day) administration for 96 weeks showed significant improvement in intrahepatic inflammation as measured by histological examination compared to the control group (43% vs. 19%, P=0.001). However, no improvement in liver fibrosis was observed [111]. The resolution rate of NASH, a secondary endpoint, was 36% in vitamin E, which was higher than 21% in the control group. However, long-term administration of vitamin E increases the incidence of prostate cancer and hemorrhagic stroke; hence, caution is required for long-term use [112]. Furthermore, controversial, high-dose vitamin E (>400 IU/day) administration may be associated with increased mortality; thus, caution is advised regarding safety [113-115]. However, a retrospective study showed that in 236 patients with advanced liver fibrosis or cirrhosis due to histologically proven NASH, regardless of the presence of T2DM, the use of vitamin E (800 IU/day) for >2 years reduced the risk of death, liver transplantation, and decompensated cirrhosis, but no difference was observed in the incidence of HCC, vascular disease, or extrahepatic cancer [116]. Additional studies are needed to evaluate the histological efficacy of vitamin E on MASH and liver fibrosis.

Selective THR-β agonist

Recently, on March 14, 2024, the US Food and Drug Administration (US FDA) approved resmetirom for the first time as a drug treatment for NASH [155]. This drug was developed to target a selective THR-β agonist. It selectively acts on intrahepatic THR-β to induce conversion of T4 to T3 in the liver, improves damaged mitochondrial function, lowers intrahepatic lipid accumulation, and induces improvement of intrahepatic inflammation and liver fibrosis. (Fig. 5) A phase III clinical trial was conducted on patients with NASH with F2/F3 liver fibrosis without cirrhosis [156,157].

Figure 5.

Intrahepatic mechanism of action of selective thyroid hormone receptor-β agonists. THR, thyroid hormone receptor; T4, thyroxine; T3, tri-iodothyronine; DNL, de novo lipogenesis; LDL, low-density lipoprotein; Apo B, apolipoprotein B; Lp(a), low lipoprotein(a); CoA, coenzyme A; RXR, retinoid X receptor; THR, thyroid hormone receptor; TRE, tetracyclin-responsive element; CPT1a, carnitine palmitoyltransferase 1; mcad, medium-chain acyl-coenzyme A dehydrogenase; Pdk4, pyruvate dehydrogenase kinase 4; UCP2, uncoupling protein 2; LDL-R; low-density lipoprotein receptor; FAS, fatty acid synthase; ACC-1, acetyl coenzyme A carboxylase; CYP7A1, cholesterol 7 alpha-hydroxylase; HMG-CoA, 3-hydroxyl-3-methyl-glutaryl-coenzyme A; SHBG, sex hormone binding globulin.

The relative liver-specific expression of selective THR-β agonists lowers blood cholesterol and triglyceride levels, increases intrahepatic bile acid synthesis, and plays an important role in intrahepatic fatty acid oxidation [158,159]. In a multicenter, randomized, double-blind, placebo-controlled study (MAESTRO-NASH) involving 1,759 patients with NASH with histologically diagnosed F2/F3 liver fibrosis, resmetirom, a selective THR-β agonist, showed significant improvement in steatohepatitis in 25.9% of the 80-mg group and 29.9% of the 100-mg group without worsening of liver fibrosis compared to placebo (9.7%) (P<0.001) [157]. Improvement in liver fibrosis of one or more stages was observed in 24% of the 80-mg group and 26% of the 100-mg group, which was statistically significant compared to 14% of the placebo group (P<0.001). Compared with baseline, at 24 weeks after treatment, the reduction in LDL-C levels was 13.6% in the 80-mg group and 16.3% in the 100-mg group, compared with 0.1% in the placebo group (P<0.001) [157]. The most common adverse effects were diarrhea and nausea, which occurred more frequently in the resmetirom group than in the placebo group. However, the incidence of serious adverse events was similar across the study groups (10.9% in the 80-mg group, 12.7% in the 100- mg group, and 11.5% in the placebo group). It. is important to take the patient’s medical history and to monitor any of these adverse effects each time they visit the hospital. In conclusion, resmetirom demonstrated histologic improvement in steatohepatitis and fibrosis in adult patients with NASH without cirrhosis and F2/F3 fibrosis in a large phase III study, with its safety profile being similar to that of the placebo group. Therefore, resmetirom can be administered in these conditions.

However, there is a lack of data on the efficacy and safety of long-term resmetirom use. The approved drug (resmetirom) may not be readily available to the general public due to its currently estimated high cost, especially in Asia. The number of patients who responded was only 20–30% of the entire treatment group. In addition, most of the enrolled patients belonged to the Western population, and considering the different characteristics between Western and Asian population, further validation of existing research results in a larger Asian population would be more helpful for the generalizability of drug (resmetirom) use. In addition, there remain issues such as whether to discontinue the drug and when to discontinue it. Therefore, although with FDA’s accelerated approval, resmetirom can be used, attention should be paid to the long-term follow-up results on its use up to 54 months, which will be reported in the future.

Other drugs undergoing phase III clinical trials

Phase III clinical trials are in progress on drugs targeting various mechanisms, such as glucagon-like peptide-1 (GLP-1) receptor agonist (semaglutide), pan-PPAR agonist (lanifibranor), fibroblast growth factor 21 (FGF21) agonist (pegozafermin and efruxifermin), glucagon/GLP-1 receptor agonist (survodutide), and fatty acid synthase (FASN) inhibitor (denifanstat) (Table 3). The phase III clinical trial of SGLT2 inhibitor (dapagliflozin) ended in March 2024, and the results are expected to be announced soon. In the case of dapagliflozin, the results of the phase III clinical trial for NASH have not been announced yet; therefore, it is difficult to use it immediately to improve steatohepatitis and liver fibrosis. However, it can be used for the treatment of each accompanying disease in patients with dyslipidemia accompanied by T2DM, heart failure, and chronic renal failure. The phase III clinical study of semaglutide for metabolic dyslipidemia completed patient enrollment in August 2024. However, the clinical results have not yet been announced; therefore, it is difficult to use it currently to improve steatohepatitis and liver fibrosis. However, if the final results of the phase III clinical study confirm positive therapeutic effect on steatohepatitis, it can be used to improve obesity and T2DM as well as steatohepatitis and liver fibrosis in patients with metabolic dyslipidemia. Studies of lanifibranor, pegozafermin, efruxifermin, survodutide, and denifanstat are currently enrolling patients, and the results of these studies are expected. Another clinical study is related to the drug aramchol, a stearoyl-CoA desaturase 1 (SCD 1) inhibitor. The open-label Part I study achieved its study objectives, but the double-blind Part II study has now been suspended [160,161]. In addition, obeticholic acid, a farnesoid X receptor (FXR) agonist, was studied in patients with NASH with F1-3 fibrosis. However, the FDA rejected its approval owing to safety issues related to hepatotoxicity and skin itching [162,163]. The drugs in phase III clinical trials are summarized in Table 3.

Table 3.

Drugs for treating MASH in phase III clinical trials (as of December 18, 2024)

Nomenclature of SLD in children and adolescents

The term ‘NAFLD’ has been in use for decades in pediatrics. However, the term ‘nonalcoholic’ has been controversial in pediatrics because it might be misleading about fatty liver in children and adolescents. Inborn errors of metabolism cause fatty liver in children. It did not exactly differentiate fatty liver from alcohol use disorder in adolescents. Patients with NAFLD tend to be unmotivated to modify their lifestyles actively because the term ‘fatty’ was felt to be stigmatizing to the Western population [164]. Some have suggested that the term ‘NAFLD’ does not reflect metabolic dysfunction, which is the disease characteristic. In this context, ‘MAFLD’ was suggested considering metabolic dysfunction in FLD in adults [14] and children [165] in 2020. However, MAFLD also includes the term ‘fatty’, and it does not differentiate other causes of the development of hepatic steatosis from metabolic dysfunction.

A multisociety Delphi consensus statement on new FLD nomenclature was released in 2023. The term ‘SLD’ was adopted as a comprehensive concept on intrahepatic fat accumulation [18]. Instead of NAFLD, MASLD was suggested as a new concept of fatty liver, considering metabolic dysfunctions such as obesity, insulin resistance, and T2DM. The diagnostic criteria of MASLD are intrahepatic fat accumulation in the presence of at least one of the cardiometabolic risk factors in adults [166]. The same cardiometabolic risk factors are applied to children and adolescents for defining the diagnostic criteria of MASLD [18].

Diagnosis of MASLD in pediatrics

NAFLD is exclusive of other causes for intrahepatic fat accumulation [167,168]. The diagnostic criteria of MASLD was the presence of hepatic steatosis with at least one of the cardiometabolic risk factors in pediatrics (Table 4) [18]. Hepatic steatosis in MASLD is defined based on an imaging study or liver biopsy.

Table 4.

Diagnostic criteria of cardiometabolic factors in MASLD in children and adolescents

Perspective on MASLD in pediatrics

A multi-society of pediatric gastroenterology in Europe, North America, Latin America, and Asia endorsed ‘MASLD’ as a new nomenclature in January 2024 [169]. The diagnosis of SLD in pediatrics is based on the pathophysiological mechanism of hepatic steatosis in children and adolescents (Fig. 6). However, there is a possibility that the diagnosis of MASLD overlap is underestimated because of Wilson’s disease, autoimmune hepatitis, and inborn errors of metabolism on hepatic steatosis [170]. MASLD is closely associated with insulin resistance, T2DM, and dyslipidemia [171,172].

Figure 6.

Steatotic liver disease and subgroup in pediatrics.

The prevalence of MASLD overlap in pediatrics will increase as the prevalence of overweight or obesity increases [173]. In pediatrics, ‘metabolic liver disease’ is an inborn error of metabolism such as urea cycle disorder, organic acidemia, aminoaciduria, lysosome disorder, and fatty acid oxidation disorder. However, the term ‘metabolic’ in MASLD means metabolic syndrome related to insulin resistance rather than an inborn error of metabolism. Therefore, if SLD is atypical (with no cardiometabolic risk factor) in pediatrics, an inborn error of metabolism or inherited single gene defects causing metabolic disease are suspected [169].

Consideration in the diagnosis of MASLD in pediatrics

If MASLD is suspected in pediatrics, various etiologies for chronic liver disease should be considered. Autoimmune disease, Wilson’s disease, viral hepatitis, alcohol use disorder, and drug-induced liver injury would be checked regardless of the presence of cardiometabolic risk factors [169]. These considerations depend on clinical situations. Early investigation for the diseases mentioned above should be considered if SLD in pediatrics possesses the ‘red flags,’ which are young age (<8 years), BMI z-score <1, neurodevelopmental delay, significant splenomegaly, synthetic dysfunction, or a history suggestive of an alternative diagnosis [180]. Additionally, other causes for SLD can be investigated if hepatic steatosis does not improve after weight reduction is performed in children and adolescents with obesity [169]. Alcohol-related liver disease is uncommon as a primary etiology of SLD in pediatrics. Further studies are needed to clarify several issues on MASLD in pediatric patients and adolescents as follows: (1) the concordance rate between NAFLD and MASLD in the same cohort of pediatric patients and adolescents; (2) large-scale studies for epidemiology and natural course of pediatric MASLD; and (3) impact of other causes for SLD on MASLD overlap in pediatrics [169].