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Hepatology
Original research
Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease
  1. Hyeok-Hee Lee1,2,
  2. Han Ah Lee3,
  3. Eun-Jin Kim1,2,
  4. Hwi Young Kim3,
  5. Hyeon Chang Kim1,2,
  6. Sang Hoon Ahn4,5,
  7. Hokyou Lee1,2,
  8. Seung Up Kim4,5
  1. 1 Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea
  2. 2 Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, South Korea
  3. 3 Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, South Korea
  4. 4 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
  5. 5 Yonsei Liver Center, Severance Hospital, Seoul, South Korea
  1. Correspondence to Prof. Hokyou Lee, Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea; hokyou.lee{at}yuhs.ac; Prof. Seung Up Kim, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; ksukorea{at}yuhs.ac

Abstract

Objective We explored clinical implications of the new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing its prevalence and associated cardiovascular disease (CVD) risk.

Design From nationwide health screening data, we identified 9 775 066 adults aged 20–79 who underwent health examination in 2009. Participants were categorised into four mutually exclusive groups: (1) MASLD; (2) MASLD with increased alcohol intake (MetALD); (3) MASLD with other combined aetiology (the three collectively referred to as MASLD/related steatotic liver disease (SLD)); and (4) no MASLD/related SLD. SLD was determined by fatty liver index ≥30. The primary outcome was CVD event, defined as a composite of myocardial infarction, ischaemic stroke, heart failure or cardiovascular death.

Results The prevalence of MASLD, MetALD and MASLD with other combined aetiology was 27.5%, 4.4% and 1.5%, respectively. A total of 8 808 494 participants without prior CVD were followed up for a median of 12.3 years, during which 272 863 CVD events occurred. The cumulative incidence and multivariable-adjusted risk of CVD were higher in participants with MASLD/related SLD than in those without (HR 1.38 (95% CI 1.37 to 1.39)). Multivariable-adjusted HR (95% CI) of CVD events was 1.39 (1.38 to 1.40) for MASLD, 1.28 (1.26 to 1.30) for MetALD and 1.30 (1.26 to 1.34) for MASLD with other combined aetiology compared to the absence of any of these conditions. CVD risk was also higher in participants with metabolic dysfunction-associated fatty liver disease or non-alcoholic fatty liver disease than in those without the respective condition.

Conclusion Over one-third of Korean adults have MASLD/related SLD and bear a high CVD risk.

  • CARDIOVASCULAR DISEASE
  • NONALCOHOLIC STEATOHEPATITIS
  • FATTY LIVER
  • LIVER
  • CARDIOVASCULAR COMPLICATIONS

Data availability statement

No data are available.

https://doi.org/10.1136/gutjnl-2023-331003

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The new nomenclature and definition of metabolic dysfunction-associated steatotic liver disease (MASLD) have been proposed to describe fatty liver conditions associated with metabolic abnormalities.

    • Separate disease entities, including MASLD with increased alcohol intake (MetALD) and MASLD with other combined aetiology, have been introduced to characterise individuals with steatotic liver disease (SLD) and cardiometabolic risk factors who are excluded from the MASLD definition.

    WHAT THIS STUDY ADDS

    • Approximately one-third of Korean adults are classified as having MASLD and related SLD—namely MASLD, MetALD and MASLD with other combined aetiology.

    • The presence of MASLD and related SLD, as well as individual entities, is associated with a higher risk of cardiovascular disease.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study suggests that the new nomenclature and definition of MASLD (and related SLD) may facilitate identifying those with metabolically complicated SLD.

    Introduction

    The increasing prevalence of obesity and metabolic syndrome has contributed to hepatic steatosis and steatohepatitis becoming highly prevalent liver diseases, affecting an estimated 30% of the global population.1 Although the nomenclature of non-alcoholic fatty liver disease (NAFLD) has been widely used to describe fatty liver diseases associated with metabolic dysfunction, this concept has been consistently criticised for several reasons. First, while NAFLD is associated with a higher risk of cardiovascular disease (CVD) in general,2 the lack of metabolic components in its definition limits the accurate stratification of the risk for CVD or advanced liver fibrosis.3–6 Second, the terms ‘nonalcoholic’ and ‘fatty’ in NAFLD can be perceived as stigmatising on a personal or social level, potentially eliciting shame among affected individuals.7

    A new nomenclature, metabolic dysfunction-associated fatty liver disease (MAFLD), has been suggested.3 8 With its definition lacking specific exclusion criteria, MAFLD encompasses metabolically complicated fatty liver conditions superimposed on chronic liver diseases with varying aetiologies, entities that are not covered by the NAFLD definition.9 The incorporation of cardiometabolic risk factors in the diagnostic criteria of MAFLD also facilitates identifying those at high CVD risk.10 11 However, conflicting views regarding the clinical profiles of MAFLD, particularly in comparison with NAFLD, have been reported.4 9 12

    Recently, an international expert panel of the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Latin American Association for the Study of the Liver proposed a new terminology: metabolic dysfunction-associated steatotic liver disease (MASLD). The definition of MASLD requires the presence of steatotic liver disease (SLD) and at least one cardiometabolic risk factor, while maintaining the alcohol and concomitant liver disease exclusion criteria of NAFLD.13 Separate disease entities, such as MASLD with increased alcohol intake (MetALD) and MASLD with other combined aetiology, have also been proposed to characterise individuals with SLD and cardiometabolic risk factors who are excluded from the MASLD definition.

    Using a nationwide health screening and claims database, we (1) assessed the prevalence of and CVD risk associated with MASLD and related SLD—namely MASLD, MetALD and MASLD with other combined aetiology; and (2) compared these findings with those of MAFLD and NAFLD.

    Methods

    Data source

    We used a nationwide database of the National Health Insurance Service (NHIS), a sole provider of universal healthcare coverage in South Korea. The NHIS database encompasses sociodemographic information, reimbursement claims with the International Classification of Disease, 10th revision (ICD-10) diagnosis codes, and mortality data of the entire Korean population.14 The NHIS also provides biennial general health examinations to all Korean adults, during which questionnaire-based lifestyle information and clinical and biochemical measurements are collected from health-screening facilities that are designated and overseen for quality control by the Korean government.15 Further details on the NHIS database and health examination are available elsewhere.14 15

    Study population

    In 2009, a total of 10 476 733 adults aged 20–79 years underwent NHIS health examinations, the records of which were used as the baseline. After excluding 701 667 participants with incomplete data on key variables, 9 775 066 remained for a cross-sectional analysis of the prevalence and characteristics of MASLD and related SLD (online supplemental figure 1). In a longitudinal analysis of the association of MASLD and related SLD with CVD risk, we further excluded 950 931 participants with prior coronary heart disease, cerebrovascular disease, or heart failure (HF) and 15 641 with <1 year of follow-up, yielding a final study cohort of 8 808 494 participants (online supplemental figure 1).

    Supplemental material

    Key variables

    Data on health-related lifestyles and clinical and biochemical measurements were collected during the baseline health examination. Weekly alcohol consumption was calculated using self-reported frequency (occasions per week) and amount (drinks per occasion) with assumption that 1 drink contains 10 g of ethanol.15 16 Blood pressure (BP)-lowering, glucose-lowering, or lipid-lowering drug use, concomitant liver disease and Charlson Comorbidity Index (CCI)17 were assessed based on insurance claims during a 2-year lookback period from the baseline. Concomitant liver diseases were defined by ICD-10 codes and included viral hepatitis (B15–B19), alcohol-related liver disease (K70), toxic liver disease (K71), biliary cholangitis (K74.3–K74.5), autoimmune hepatitis (K75.4), Wilson’s disease (E83.0) and haemochromatosis (E83.1). The CCI is a comorbidity score composed of 12 conditions described elsewhere.17 In our study, liver diseases and diabetes were excluded from the CCI as they are essential diagnostic components of MASLD.13

    SLD was defined as a fatty liver index (FLI)≥30 (online supplemental table 1).4 18 FLI has been recognised as a suitable alternative to imaging modalities by the international clinical practice guidelines, particularly for use in large epidemiological studies.8 19 The area under the receiver operating characteristic curve (AUROC) of FLI was 0.87 in the Korean population.20 MAFLD and NAFLD were defined according to a previous study,4 in line with the international expert consensus statement and clinical practice guidelines.8 19 21

    MASLD and related SLD

    MASLD was defined as the presence of SLD and one or more of the following cardiometabolic risk factors: (1) body mass index ≥23 kg/m2 or waist circumference ≥90 cm (for males) or≥80 cm (for females); (2) fasting glucose ≥100 mg/dL or type 2 diabetes or glucose-lowering drug use; (3) BP≥130/85 mm Hg or BP-lowering drug use; (4) triglyceride ≥150 mg/dL or lipid-lowering drug use; or (5) high-density lipoprotein cholesterol <40 mg/dL (for males) or<50 mg/dL (for females) or lipid-lowering drug use.13 Those with increased or excessive alcohol intake (weekly intake ≥210 g (for males) or ≥140 g (for females)) or with concomitant liver disease were excluded from MASLD.13

    Individuals with SLD and ≥1 cardiometabolic risk factor who reported increased alcohol intake (weekly intake 210–420 g (for males) or 140–350 g (for females)) were classified as MetALD. Those with concomitant liver disease in addition to SLD and ≥1 cardiometabolic risk factor, without increased or excessive alcohol intake, were classified as MASLD with other combined aetiology. In the present study, MASLD, MetALD and MASLD with other combined aetiology were collectively referred to as ‘MASLD and related SLD’.

    Outcomes

    The primary outcome was CVD event, defined as a composite of the first hospitalisation for myocardial infarction (MI) (ICD-10: I21–I23), first hospitalisation for ischaemic stroke (ICD-10: I63), first hospitalisation for HF (ICD-10: I50), or cardiovascular death (ICD-10: I00-I99).4 The accuracy of the hospitalisation codes in the NHIS database has been previously validated.22 The secondary outcomes were individual components of the primary outcome. Participants were followed up from the baseline health examination until the occurrence of an outcome event, death or 31 December 2021, whichever came first. Death and its cause were ascertained through a linkage to the Statistics Korea mortality database.

    Statistical analysis

    Participant characteristics were presented as median (IQR) or number (%), as appropriate. We estimated the cumulative incidence of CVD events using the Kaplan-Meier method. Incidence rates were calculated as the number of outcome events per 1000 person years of follow-up. We calculated HRs and 95% CIs of the outcomes using Cox proportional hazards models, which were adjusted for age, sex, household income quartile, residential area, CCI, tobacco use, physical activity and estimated glomerular filtration rate. Covariables were selected a priori based on their potential associations with SLD and CVD.23 24 Cardiometabolic risk factors, alcohol consumption and concomitant liver disease were not adjusted for in our analyses, as they constitute the diagnostic criteria for MASLD. The proportionality of hazards was confirmed via graphical inspection of log-minus-log plots and Schoenfeld residuals.

    We conducted six sensitivity analyses. First, we stratified our main analysis by age, sex, overweight/obesity, diabetes, hypertension and dyslipidaemia. Second, we adopted a higher cut-off of FLI≥60, instead of ≥30, to define SLD. Third, we repeated our main analysis using different biochemical hepatic steatosis models—hepatic steatosis index ≥36 or simple NAFLD score≥8 (online supplemental table 1).20 25 The simple NAFLD score was previously derived from the Korean population and validated in an external Korean cohort with an AUROC of 0.80 in males and 0.85 in females against ultrasound-detected fatty liver.20 Fourth, we assessed CVD risk according to the presence of MASLD or NAFLD after excluding participants with increased or excessive alcohol intake or with concomitant liver disease (ie, exclusion criteria for both MASLD and NAFLD) from the reference group. Fifth, we additionally adjusted for lipid-lowering drug use in our Cox regression models. Sixth, we stratified participants with MASLD and related SLD based on the presence of advanced liver fibrosis (defined as BARD score≥2)26 (online supplemental table 1) and estimated their cumulative incidence of CVD events. All statistical analyses were conducted using SAS V.9.4 (SAS Institute) and R V.4.0.3 (R Foundation for Statistical Computing).

    Patient and public involvement

    Patients or the public were not involved in the design, conduct, reporting or dissemination of this study.

    Results

    Characteristics and prevalence of MASLD and related SLD

    Among the 9 775 066 participants (median age, 47 years; 45.4% females) in our cross-sectional analysis, 2 686 615 (27.5%) had MASLD, 430 993 (4.4%) had MetALD and 142 550 (1.5%) had MASLD with other combined aetiology. The prevalence of MASLD was higher in males than in females and increased with age. The trends for MetALD and MASLD with other combined aetiology were similar, except that the prevalence of MetALD was the highest between the ages of 40 and 64 years. In general, the prevalence of MASLD was similar to that of NAFLD, whereas the combined prevalence of MASLD and related SLD was lower than that of MAFLD (figure 1).

    Figure 1
    Figure 1

    Prevalence of MASLD and related SLD, MAFLD and NAFLD. *MASLD with other combined aetiology. MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; SLD, steatotic liver disease.

    Participants with MASLD and related SLD, MAFLD or NAFLD were older and more likely to be male, had higher household income and exhibited worse cardiovascular risk profiles compared to those without each condition (online supplemental table 2). Among participants with MASLD and related SLD, those with MASLD were older and more likely to be female, reported lower alcohol intake, current smoking rate and physical activity level, were more frequently on BP-lowering, glucose-lowering and lipid-lowering drugs, and had more comorbidities than those with MetALD. Compared to participants who had MASLD with other combined aetiology, those who had MASLD were younger and more likely to be smoking, were less frequently on BP-lowering, glucose-lowering and lipid-lowering drugs, and had fewer comorbidities (table 1).

    View this table:
    Table 1

    Baseline characteristics of the participants

    Primary analyses

    In total, 8 808 494 participants without prior CVD were included in the longitudinal analysis. The participant characteristics of the longitudinal analysis were comparable to those of the cross-sectional analysis (online supplemental table 3). During a median follow-up of 12.3 years, 272 863 incident CVD events occurred. The cumulative incidence of CVD events was higher in participants with MASLD and related SLD than in those without the condition (figure 2A). Among individuals with MASLD and related SLD, the cumulative incidence was the highest among those with MASLD and lowest among those with MetALD (figure 2B).

    Figure 2
    Figure 2

    Cumulative incidence of cardiovascular disease events according to the presence of MASLD and related SLD.*MASLD with other combined aetiology. MASLD, metabolic dysfunction-associated steatotic liver disease; SLD, steatotic liver disease.

    After multivariable adjustment, the risk of CVD was 1.38 (95% CI 1.37 to 1.39) times higher in participants with MASLD and related SLD than in those without the condition—HR was 1.39 (95% CI 1.38 to 1.40) for MASLD, 1.28 (95% CI 1.26 to 1.30) for MetALD and 1.30 (95% CI 1.26 to 1.34) for MASLD with other combined aetiology (table 2). When compared with MASLD, multivariable-adjusted risk of CVD was lower in MetALD (HR 0.92; 95% CI 0.90 to 0.94) and in MASLD with other combined aetiology (HR 0.93; 95% CI 0.91 to 0.96) (online supplemental table 4). MASLD and related SLD, as well as individual entities, was also associated with higher risks of all secondary outcomes—including MI, ischaemic stroke, HF and cardiovascular death—in comparison with the absence of MASLD and related SLD (table 3).

    View this table:
    Table 2

    Cardiovascular disease risk according to the presence of MASLD and related SLD

    View this table:
    Table 3

    Risk of secondary outcomes according to the presence of MASLD and related SLD

    The cumulative incidence and multivariable-adjusted risk of CVD were higher in participants with MAFLD or NAFLD than in those without the respective condition (online supplemental figure 2), (online supplemental table 5). Overall, the cumulative CVD incidence was comparable among individuals with MASLD, MASLD and related SLD, MAFLD and NAFLD (online supplemental figure 3). However, the incidence rate of CVD varied among those without MASLD and related SLD, without MAFLD, and without NAFLD (table 2, online supplemental table 5).

    Sensitivity analyses

    First, MASLD and related SLD, as well as individual entities, was associated with a higher CVD risk than the absence of MASLD and related SLD regardless of age, sex, overweight/obesity, diabetes, hypertension and dyslipidaemia (online supplemental table 6). Second, the association of MASLD and related SLD with CVD risk became more prominent when we adopted a higher cut-off of FLI ≥60 to define SLD (online supplemental table 7). The prevalence of MASLD and related SLD, MAFLD and NAFLD using a cut-off of FLI≥60 is illustrated in online supplemental figure 4. Third, the use of different biochemical hepatic steatosis models (ie, hepatic steatosis index≥36 or simple NAFLD score≥8) did not appreciably alter our main findings (online supplemental table 8). Fourth, when we excluded participants with increased or excessive alcohol intake or with concomitant liver disease (ie, exclusion criteria for both MASLD and NAFLD) from the reference groups, multivariable-adjusted CVD risk in association with the presence of MASLD (HR 1.44; 95% CI 1.43 to 1.46) was virtually identical to that of NAFLD (HR 1.44; 95% CI 1.43 to 1.46) (online supplemental table 9), and was also similar to that of MAFLD without any participant exclusion (HR 1.43; 95% CI 1.42 to 1.44) (online supplemental table 5). Fifth, an additional adjustment for lipid-lowering drug use did not materially alter the association of MASLD and related SLD with CVD risk (online supplemental table 10). Sixth, participants with MASLD and advanced liver fibrosis showed a higher cumulative CVD incidence than those with MASLD but without advanced liver fibrosis. The findings were also similar for participants with MetALD or MASLD with other combined aetiology (online supplemental figure 5).

    Discussion

    In this nationwide cohort study of approximately 9 million Korean adults, about one-third of the participants were classified as having MASLD and related SLD. Overall, the combined prevalence of MASLD and related SLD was higher than that of NAFLD but lower than that of MAFLD, while the prevalence of MASLD was similar to that of NAFLD. Participants with MASLD, MetALD or MASLD with other combined aetiology exhibited a significantly higher risk of CVD events than those without any of these conditions. The results were consistent for secondary outcomes and across various subgroups.

    The present study provides several clinically relevant implications. First, we described the prevalence and characteristics of MASLD and related SLD, representing some of the first data on MASLD since its introduction. The prevalence of MASLD and related SLD was higher in males than in females and increased gradually with age. These findings are consistent with the expectation, considering that metabolic syndrome is more common in males and that its prevalence increases with age.27 Across both sexes and all age groups, the combined prevalence of MASLD and related SLD was lower than that of MAFLD. This discrepancy can be attributed to the exclusion of individuals with excessive alcohol intake (weekly intake ≥420 g (for males) or ≥350 g (for females)) from the definitions of MASLD and related SLD, a criterion that is not applied in the MAFLD definition. Moreover, incorporating metabolic criteria into the NAFLD definition to create a new definition for MASLD did not result in an appreciable difference in prevalence between MASLD and NAFLD.4

    Second, our study demonstrated that participants with MASLD and related SLD had a higher CVD risk than those without, extending prior knowledge on the association of MAFLD or NAFLD with CVD risk.2 10 11 The cumulative CVD incidence of MASLD and related SLD was comparable to that of MAFLD, implying that the simplified metabolic criteria used in the definition of MASLD and related SLD—without incorporating high-sensitivity C reactive protein and fasting insulin level criteria present in the MAFLD definition—may also identify a high CVD risk. Furthermore, MASLD, MetALD and MASLD with other combined aetiology each conferred a higher CVD risk (with MASLD posing the highest risk) than the absence of the conditions. When viewed alongside previous reports that have indicated an increased risk of adverse outcomes conferred by superimposed fatty liver or metabolic dysfunction on viral hepatitis or alcoholic liver disease,28–30 our findings suggest that MASLD, MetALD and MASLD with other combined aetiology are distinct disease entities that may identify patients at high CVD risk.

    Third, the association of MASLD and related SLD with the risk of CVD remained consistent across different types of CVD events—including MI, ischaemic stroke, HF and cardiovascular death—and subgroups. We also observed increased risks of individual types of CVD events in association with MASLD, MetALD and MASLD with other combined aetiology, although the strengths of the associations displayed some variability. Interestingly, among individuals with MASLD and related SLD, the incidence rate of CVD events was higher in those who were lean than in those who were overweight or obese. This finding is consistent with those of previous studies showing that the risks of adverse health outcomes are higher in the lean MAFLD or NAFLD group than in the overweight/obese MAFLD or NAFLD group.4 31

    Fourth, we explored the potential influence of advanced liver fibrosis on CVD risk. In all groups of MASLD, MetALD and MASLD with other combined aetiology, participants with advanced liver fibrosis exhibited a higher CVD risk than those without. Our results are supported by a number of previous studies,31–34 including the one that demonstrated a gradual increase in CVD risk with higher levels of liver fibrosis among 10 422 patients with biopsy-proven NAFLD.31 However, conflicting results have also been reported by a recent study, which reported no significant association between the degree of fibrotic burden and CVD incidence in 1773 patients with biopsy-proven NAFLD.35 Further validation studies, preferably using biopsy or imaging findings or the Fibrosis-4 index, are required to demonstrate the risk of CVD conferred by liver fibrosis in individuals with MASLD and related SLD.

    Study strengths and limitations

    To the best of our knowledge, this is the first study to report the prevalence and CVD risk of MASLD and related SLD. By leveraging a nationwide database covering the entire Korean population, we assessed the risk of CVD events for each disease entity (MASLD, MetALD and MASLD with other combined aetiology) and conducted various subgroup and sensitivity analyses. The large sample size and long-term follow-up also allowed us to explore each individual CVD outcomes separately.

    However, our study has several issues that remain unresolved. First, despite the use of a nationwide health claims database based on universal single-payer health insurance, some variables or risk factors may not have been accounted for. Unmeasured confounders, including dietary habits or genetic predispositions, could have affected the association of MASLD and related SLD with CVD risk in our study. Second, owing to the observational nature of the study, the causality between MASLD/related SLD and CVD risk could not be established. Third, SLD and liver fibrosis were defined using non-invasive biochemical scores instead of biopsy or imaging findings, which could have led to misclassifications. Furthermore, the incorporation of cardiometabolic risk factors (ie, triglyceride, body mass index and waist circumference) in the FLI formula renders it difficult to discern the influence of SLD on CVD risk from that of cardiometabolic risk factors. However, the indices employed in our study have been extensively validated,20 25 and the utility of non-invasive surrogates in large epidemiological studies is acknowledged by international guidelines.8 19 Fourth, the lower cut-off of FLI≥30 was originally designed to rule out SLD and thus may have introduced some false positivity when defining SLDs. Nonetheless, the association of MASLD and related SLD with a higher CVD risk remained robust, if not stronger, when we used a higher cut-off of FLI≥60. Lastly, our findings may not be generalisable to populations of other races/ethnicities. The results should be interpreted in light of a markedly higher incidence rate of stroke than that of MI in the Korean population, a notable difference compared with the Western population.36 37

    Conclusions

    Approximately one-third of Korean adults are classified as having MASLD and related SLD according to the newly proposed definition. The presence of MASLD and related SLD, as well as individual entities, is associated with a higher risk of CVD events. The new nomenclature and definition of MASLD may help reduce stigma and improve the identification of patients with metabolically complicated SLD.

    Data availability statement

    No data are available.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study complied with the Declaration of Helsinki; the study protocol was approved by the Institutional Review Board of Severance Hospital, Seoul, Korea (Y-2020-0135). Written informed consent was waived, as this study was based on deidentified administrative data.

    Acknowledgments

    This study used the National Health Insurance Service database (NHIS-2022-1-683).

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • H-HL and HAL are joint first authors.

    • Twitter @HHLee_MD, @hokyoulee

    • Contributors H-HL, HAL, HL and SUK conceptualised and designed the study. H-HL, HAL, HYK, SHA, HL and SUK performed the literature search. E-JK, HL, H-HL and HAL conducted analysis. All authors contributed to the interpretation of data for the work. HCK, HL and SUK supervised the project. H-HL and HAL drafted the manuscript. HYK, HCK, SHA, HL and SUK critically revised the manuscript for important intellectual content. All authors gave final approval of the version to be submitted. HL and SUK serve as guarantor for the study.

    • Funding This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant number 2022R1I1A1A01065244); the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (grant number 2022R1F1A1066181); and the faculty research grant of Yonsei University College of Medicine (grant number 6-2022-0128).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.