Tuesday, June 6, 2023

Usefulness of health checkup for screening metabolic dysfunction-associated fatty liver disease and alcohol-related liver disease in Japanese male young adults – Scientific Reports

Regular health checkups at schools are an important opportunity to not only improve student welfare but also detect rising health disorders16. In Japan, regular health checkups for students based on the School Health and Safety Act are provided for students from preschool to university16. With the established health checkup system, the screening of MAFLD and ALD may contribute to early treatment intervention; thus, improving the outcomes of CLD. However, since MAFLD is a relatively newly defined term, very few attempts have been made to screen for MAFLD during health checkups, especially among young adults. Furthermore, the prevalence and screening methods for ALD in young adults remain unclear. Therefore, this study fills the gap between the rising etiologies of CLD and the use of regular health checkup in young adults for early detection and treatment/intervention to improve CLD outcomes.

Our study found a relatively high prevalence of NAFLD (17%), MAFLD (11%), ALD (1%), and excessive alcohol intake (4%) among the male graduate students. Japanese male young adults with NAFLD or MAFLD were mainly characterized by overweight/obesity and metabolic risk abnormalities, whereas none of them had type 2 diabetes. Furthermore, we demonstrated that serum ALT levels, BMI, and AUDIT are powerful screening parameters to identify high-risk male graduate students. This study, therefore, expanded our knowledge on the risks of CLD in Japanese male young adults and provided simple screening methods to identify students at risk for advanced CLD and severe outcomes.

As for the prevalence of NAFLD, a recent Japanese meta-analysis showed that the overall prevalence of NAFLD in Japan is 26% and males have a higher prevalence than females (34% vs. 16%)17. Furthermore, the prevalence of NAFLD in Japan is predicted to increase17. Despite the accumulated evidence of NAFLD prevalence, very few attempts have been made to determine at-risk individuals among young adults. The prevalence of NAFLD in our study (17%) seems reasonable, given that the Global Burden of Disease data have shown that the prevalence of NAFLD is approximately 9%, 16%, and 21% among ages 15–19, 20–24, and 25–29 years, respectively4. When comparing NAFLD with MAFLD in our study, the prevalence of MAFLD was lower than that of NAFLD among relatively young particpants18. However, MAFLD prevalence was higher than that of NAFLD in other studies with older participants7,19. Reviewing the results of our study with young participants and other studies with older participants, we assumed that metabolic changes due to aging are a strong driver of MAFLD and that the prevalence of MAFLD exceeds that of NAFLD around middle age. A large cohort study revealed that MAFLD, but not NAFLD, was associated with an increased risk of all-cause mortality8. Given the impact of MAFLD on outcomes, early detection and intervention of MAFLD, especially in young population, may play a critical role in preventing the future burden of CLD.

As MAFLD has a stronger impact on mortality than NAFLD8, effective and convenient markers for MAFLD are urgently required. For large-scale screening of MAFLD, serum biomarkers are reasonable and preferred because imaging techniques are impractical in terms of cost effectiveness and availability11. The guidelines of NAFLD recommend the FIB-4 index or NAFLD fibrosis score, both of which comprise serum ALT levels, to stratify the risk of advanced fibrosis and avoid unnecessary liver biopsy10,11. Although these scoring methods are useful and well-validated for screening patients with advanced fibrosis, their use in health checkup setting is not yet common because platelet count and serum albumin levels are not mandatory for school health checkup including university. Therefore, there is a need for a simple screening method to detect NAFLD and MAFLD in early stage to offer an opportunity to prevent disease progression.

Our study revealed that a simple measurement of serum ALT levels may be sufficient to detect high-risk populations and is an ideal biomarker to identify NAFLD and MAFLD in terms of AUCs. We also found that the optimal cutoff value of ALT showed relatively high sensitivity and specificity for identifying MAFLD in this study. There are only a few reports on noninvasive biomarkers of MAFLD, which are poorly investigated compared to that of NAFLD. Although liver function tests have been the most traditional approach to investigate CLD, recent guidelines have concluded that this strategy lacks evidence for both screening and diagnostic methods and requires further investigation20. However, our study provides meaningful evidence that measurement of serum ALT levels is an easy and practical approach for screening MAFLD among male young adults. The results of our study also strengthen the importance of biochemical analysis to stratify the risk of CLD during health checkups, even among young adults.

Another interesting finding in our study was that serum ALT levels were significantly higher in participants with overlapping conditions than in those with NAFLD only. Hepatocellular damage is the pathophysiological component of CLD and, therefore, serum ALT levels have a strong impact on liver-related and all-cause mortality21. Since obesity plays an important role in the development of nonalcoholic steatohepatitis22, our results may reflect that the pathogenesis of MAFLD has a stronger impact on hepatocellular damage than that of NALFD. This can be a reasonable explanation as previous studies have shown that MAFLD has a worse survival rate than NAFLD8. Therefore, it is reasonable to focus on MAFLD as a target for screening and intervention in the health checkup setting.

In addition to serum ALT levels, BMI was also a robust marker to identify MAFLD and NAFLD among Japanese male young adults in terms of AUCs. Interestingly, the cutoff values of BMI to identify MAFLD (22.9 kg/m2) and NAFLD (21.5 kg/m2) were lower than the cutoff value for obesity proposed by the Japan Society for the Study of Obesity (≥ 25 kg/m2)23. A recent study has suggested that even normal weight population can develop NAFLD because of fat accumulation and reduced muscle mass24. Since BMI strongly correlates with visceral adipose tissue23, our study suggests even nonobese male young adults can develop MAFLD and NAFLD, and BMI could be a robust marker to stratify the risk of these CLDs.

The prevalence of and screening methods for alcohol misuse and ALD among young male adults were investigated in our study. In general, the prevalence of excessive alcohol intake depends on the definition and cohort, and ranges from 10 to 40% in the Japanese population14,25,26. In addition, the prevalence of ALD in the Japanese population is around 2% based on a recent review27. In our study, approximately 4% of students consumed ≥ 20 g/day of alcohol, and 1% had ALD. A previous study of alcohol use in Japanese college students showed that 13% of students had excessive alcohol intake28. This discrepancy can be explained by the difference in region, academic degree, and decreased social opportunity for drinking because of coronavirus disease 2019. For screening, the AUDIT and AUDIT-C were the only methods used to identify the risk factors for cirrhosis. Ideally, all participants should be assessed by AUDIT for ALD screening; however, our data show that the AUDIT-C, a shortened AUDIT, can be a reasonable alternative considering the limited time available to complete health checkups. Accumulated evidence has shown that a high proportion of patients with ALD do not exhibit any clinical or biochemical abnormalities13, and our study also confirmed that there is no difference in biochemical parameters between participants with and without ALD in Japanese male young adults. Therefore, identifying excessive alcohol intake is a fundamental step for screening ALD. A recent Japanese nationwide survey revealed that cases of liver cirrhosis associated with ALD is increasing and, therefore, it is essential to identify alcohol misuse and ALD among young adults to reduce the burden of CLD29. This report contains the first evidence of the usefulness of AUDIT and AUDIT-C for screening ALD among Japanese young adults.

The clinical relevance of our findings should be explained. We found that health checkup is an important opportunity to identify, MAFLD, NAFLD, and ALD in Japanese male young adults. However, it is impractical to provide liver ultrasonography to all individuals based on our cutoff values because the values were relatively low considering the commonly used cutoff values20,21. In addition, ultrasonography is costly and requires well-trained examiner. Given that very few attempts have been made on the screening of CLD in younger population, we believe that our findings have meaningful implication as using health checkups to assess and inform individuals about their risk for CLD may help them to make lifestyle modification that reduces the future burden of CLD.

This study had several limitations. First, this was a single-center study that included only males and our results may not be applicable to other regions and females. Especially, females were initially excluded from the study considering the sex differences of obesity, type 2 diabetes, other metabolic abnormalities, and normative values of liver enzymes20,21,30. Second, liver biopsy was not performed in this study and liver steatosis was diagnosed only by ultrasonography. The small number of ALD cases may have limited the statistical power of our study. Third, we lacked data on well-validated scores, such as FIB-4 index and NAFLD fibrosis score, and future studies should evaluate the clinical relevance of these scores in younger populations. Therefore, a multicenter study that includes both males and females is required to validate our results. Despite these limitations, this study may have important implications for screening and identifying the prevalence of MAFLD and excessive alcohol intake among male young adults in a health checkup setting.

In conclusion, our study provides the first evidence of the prevalence of MAFLD and ALD in young Japanese male adults. Furthermore, simple measurements of serum ALT levels, BMI, AUDIC, and AUDIT-C are useful for screening CLDs. Our study may guide the establishment of strategies for MAFLD and ALD identification in younger generations, and confirm the importance of health checkups for early detection and intervention in reducing the future burden of CLD.

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