A Comparative Study of MAFLD as a Predictor for Metabolic Disease Therapies Against NAFLD in Repeated Health Check-Ups: A Novel Perspective on Fatty Liver

doi:10.21203/rs.3.rs-3947258/v1

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A Comparative Study of MAFLD as a Predictor for Metabolic Disease Therapies Against NAFLD in Repeated Health Check-Ups: A Novel Perspective on Fatty Liver

https://doi.org/10.21203/rs.3.rs-3947258/v1

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Background

A novel concept of Metabolic Associated Fatty Liver Disease (MAFLD) was proposed, incorporating metabolic abnormalities such as obesity and diabetes, which are risk factors that affect the prognosis. Non-Alcoholic Fatty Liver Disease (NAFLD), entails fat accumulation in the liver without alcohol consumption and is often linked to obesity, insulin resistance, and metabolic syndrome. However, the broad nature of the disease concept has hindered prognosis accuracy. In this study, we assess the contribution of the impact of diagnostic criteria for MAFLD on metabolic disease progression compared to conventional diagnostic criteria for NAFLD.

Methods

A total of 7,159 patient who were presented to the health screening center in Tokai University Hospital both in 2015 and 2020 were included in the study. Fatty liver was diagnosed using abdominal ultrasonography. The diagnostic criteria for NAFLD were consistent with the global guidelines based on alcohol consumption. The diagnostic criteria for MAFLD were based on the International Consensus Panel. Medications (anti-hypertensive, diabetic, and dyslipidemia medications) were evaluated by self-administration in the submitted medical questionnaire.

Result

A total of 2,500 (34.9%) participants were diagnosed with fatty liver (FL+), 1,811 (72.4%) fit both NAFLD and MAFLD diagnostic criteria (overlap), 230 (9.2%) fit only the NAFLD diagnostic criteria (NAFLD group) and 404 (16.1%) fit the MAFLD diagnostic criteria (MAFLD group) at 2015. Over the next 5 years, medication rates increased in the NAFLD group for anti-hypertensive, + 17 (7.4%); diabetes, + 3 (1.3%); and dyslipidemia, + 32 (13.9%). In contrast, the only-MAFLD group showed a more significant increase with + 49(12.1%), + 21(5.2%), and + 49(12.1%), for the respective medications, indicating a substantial rise in patients starting new medications.

Conclusion

Our analysis of repeated health check-ups on participants revealed that the diagnostic criteria for MAFLD are more predictive of future treatment for metabolic disease than conventional diagnostic criteria for NAFLD.

metabolic associated fatty liver disease(MAFLD)

non-alcoholic fatty liver disease (NAFLD)

fatty liver

metabolic disease

Metabolic dysfunction-related fatty liver disease was previously defined as non-alcoholic fatty liver disease (NAFLD), excluding alcohol-related cases. It affects approximately 25% of the world's adult population and represents a significant health and economic burden to all societies (1, 2), with the highest prevalence in South Asia, the Middle East, and South America and the lowest in Africa (2, 3). In 60% of NAFLD patients, non-alcoholic steatohepatitis (NASH) is associated with inflammatory infiltrate and progressive fibrosis (4, 5). The large patient volume with NAFLD distinguishes it from other liver diseases, emphasizing the primary focus of clinical care on identifying individuals at the highest risk of progressive liver disease (1). Additionally, a portion of NAFLD is linked to metabolic diseases such as hypertension and diabetes mellitus, posing an elevated for cardiovascular and renal dysfunction and hepatic progression (6–9). However, the heterogeneity of the NAFLD patient population concerning its major precipitating and co-existing disease-modifying factors represents a significant hurdle to identifying highly effective drug therapies (10), owing that NAFLD diagnosis involves exclusionary diagnoses such as hepatitis virus and alcohol consumption. Therefore, the International Consensus Panel introduced new diagnostic criteria for metabolic (dysfunction) associated fatty liver disease (MAFLD) in 2020 (10). The criteria for MAFLD identifies metabolic deregulatory factors as a prerequisite for the diagnosis (11). Unlike the current usage of NAFLD as a "non" disease classification, the term MAFLD, as proposed, denotes a multisystem disorder for diagnostic purposes (12). A recent report showed that MAFLD identifies patients with significant hepatic fibrosis better than NAFLD (13); however, it is unclear whether the criteria defined by MAFLD better capture the clinical characteristics of fatty liver patients and especially the long-term outcome of metabolic disease compared to NAFLD. Hence, this study aimed to assess the impact of MAFLD diagnostic criteria on the progression of metabolic diseases more precisely than NAFLD, utilizing data from routine health checkups that allowed us to track the course over 5 years.

Participants and methods

This study is a retrospective analysis of the electronic medical records of 7,159 patients, (4,004 males and 3,155 females), who were presented to the Health Screening Center in Tokai University Hospital, Japan both in 2015 and 2020. The fatty liver diagnosis was made through abdominal ultrasonography, employing five different parameters: liver-to-kidney contrast, liver parenchymal brightness, bright vessel walls, deep beam attenuation, and gallbladder wall definition (12). The diagnostic criteria for NAFLD were defined by the presence of a fatty liver, diagnosed through ultrasonography in participants without an alternative cause for secondary liver steatosis, such as excessive alcohol consumption (> 30 g per day for men or > 20 g per day for women) or positive hepatitis B and C viral infection. The diagnostic criteria for MAFLD were based on the guidelines of the International Consensus Panel (10, 14). Medications (anti-hypertensive, diabetic, and dyslipidemia medications) were evaluated through a self-administered medical questionnaire submitted by the participants.

Statistical analysis

We used SPSS Version 19.0 (SPSS, Chicago, Illinois, USA) for statistical analysis. Continuous data was summarized using means and standard deviations. Categorical data was presented in relative frequencies and counts, and the categorical outcomes were analyzed using the χ2 test. The comparison of normally distributed continuous variables was analyzed using the Student's t-test analysis. Statistical significance was set as P ≤ 0.05.

1. The population of MAFLD, NAFLD, and overlapped both diagnoses.

The participant characteristics are summarized in Fig. 1. Out of all patients, 2,500 had fatty liver, while 65% (4,659) did not have fatty liver. There were 1,811 patients in the overlap group who met both diagnostic criteria for NAFLD and MAFLD. Moreover, there were 230 patients in the group that met only the diagnostic criteria for NAFLD (NAFLD/non-MAFLD) and 404 patients in the group that met only the diagnostic criteria for MAFLD (MAFLD/non-NAFLD). Then, we compared the MAFLD/non-NAFLD group, which was not covered by conventional diagnostic criteria to the NAFLD/non-MAFLD group.

2. Clinical and biochemical characteristics of patients with NAFLD/non-MAFLD group and MAFLD/non-NAFLD group

Participants with MAFLD/non-NAFLD exhibited higher body weight, BMI, and waist circumference, along with elevated serum liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ GTP) and lactate dehydrogenase (LDH) and an unfavorable metabolic profile such as blood sugar(BS), HbA1c, triglyceride (TG), and low HDL, compared to their NAFLD/non-MAFLD counterparts (Table 1). However, there was no significant difference in creatinine levels between the two groups. The medical history data from 2015 indicated that participants with MAFLD/non-NAFLD had significantly higher frequencies of hypertension, diabetes, and dyslipidemia compared to their NAFLD/non-MAFLD counterparts (Table 2).

3. Prospective difference in the number of treatment patients for metabolic disease over five years in 2020 (Δnumber of patients)

In Table 2, the diagnostic criteria for MAFLD indicated a significantly higher current history of metabolic disease. Therefore, we hypothesized that this data would be progressive. To address this question, we compared the rate of increase in medications over the next 5 years. The results showed that the NAFLD/non-MAFLD group exhibited increases of + 17 (7.4%) and + 3 (1.3%) for anti-hypertensive and diabetes medications, respectively. In contrast, the MAFLD/non-NAFLD group showed substantial increases of + 49(12.1%) and + 21(5.2%) for anti-hypertensive and diabetes medications indicating a marked increase in the number of patients taking new medications (Table 3). However, the number of patients receiving dyslipidemia medications showed no significant differentiation between the two groups: +32 (13.9%) in NAFLD groups and + 49(12.1%) in MAFLD groups. In summary, these results suggest that hypertension and diabetes mellitus progress when the diagnostic criteria for MAFLD are met.

MAFLD is not only about fat accumulation in the liver, but also a metabolic risk factor that contributes to the development and progression of the disease, including obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia (10). The term MAFLD is used to facilitate an accurate diagnosis and management. Therefore, this study redefines and evaluates fatty liver patients using both new MAFLD diagnostic criteria and NAFLD criteria. This allows for a detailed evaluation of patient populations that have been overlooked by conventional diagnostic criteria for NAFLD. The results of this study show that the group that met the diagnostic criteria for MAFLD/non-NAFLD had metabolic disorders compared to the NAFLD/non-MAFLD group. Additionally, the 5-year longitudinal data indicate the need for therapeutic intervention in managing these metabolic diseases, particularly hypertension and diabetes. In contrast, dyslipidemia showed no difference in the patient population that met MAFLD/non-NAFLD diagnostic criteria. Metabolic disorders pose a risk for chronic kidney disease and cardiovascular events, new fatty liver diagnosis may contribute to patient outcomes. Recent reports suggest that MAFLD identifies patients with chronic kidney disease better than NAFLD (15), and similar findings are supported by a nationwide cohort study (16). Furthermore, a Korean nationwide cohort study with a mean duration of 10 years indicated that MAFLD is a better identifier for patients with cardiovascular disease than NAFLD (17). Thus, the redefinition of fatty liver appears to contribute to mortality factors beyond cirrhosis. Although this study did not precisely track the occurrence of chronic kidney disease or cerebrovascular events, our focus was on metabolic disorders.

There have been several reports of direct hepatic effects. The diagnostic criteria for MAFLD should be a better indicator of liver fibrosis than conventional NAFLD (18, 19). A multi-population study from Geneva, Switzerland, showed that while there is an upward trend in the number of patients with HCC caused by fatty liver, the frequency of cases meeting the diagnostic criteria for MAFLD is also high (20). Therefore, viral hepatitis and alcoholic hepatitis can also be defined as MAFLD. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death (21).

This study had some limitations. First, was the inaccurate survey of medications due to the self-reporting system. However, we believe that this shortfall is compensated for by the large number of participants included in the study. Second, there was no evaluation of fibrosis of the liver, such as elastography. Liver injuries, including NASH, lead to liver fibrosis, which is a separate prognostic factor from metabolic diseases. Therefore, a parallel study assessing liver fibrosis over time would be more valuable. Therefore, further research is required to address the challenge.

Since a new name; metabolic dysfunction-associated steatotic liver disease instead of NAFLD and metabolic dysfunction-associated steatohepatitis (MASH) instead of NASH, were recommended in an attempt to link the names to cardiometabolic risk (22), the relationship between metabolic diseases and fatty liver will gain increased attention. Therefore, the results of this study will be used as a basis for further research.

This study demonstrated that the diagnostic criteria for MAFLD are more predictive of future treatment for metabolic disease than conventional diagnostic criteria for NAFLD. Furthermore, the relationship between metabolic diseases and fatty liver will continue to be studied along with the proposal of a new disease concept called MAFLD and MASH.

MAFLD; metabolic associated fatty liver disease, NAFLD; non-alcoholic fatty liver disease, NASH; non-alcoholic steatohepatitis, MAFLD; metabolic dysfunction-associated fatty liver disease, MASH; metabolic dysfunction-associated steatohepatitis. BS; blood sugar, TG; triglyceride, AST; aspartate aminotransferase, ALT; alanine aminotransferase , γGTP; γ-glutamyl transpeptidase, LDH; lactate dehydrogenase

Acknowledgments

The authors would like to thank the members of the Support Center for Medical Research and Education, Tokai University, for their experimental support and also Editage (www.editage.com) for English language editing.

Funding information

This work was supported by the Japan Society for the Promotion of Science (22K08042 to J.I.)

Ethics approval and consent to participate

This study was performed in accordance with the World Medical Association Declaration of Helsinki. Participants were recruited on an opt-out basis. All data, including medical history, physical measurements, and blood tests were collected anonymously from the medical records of Tokai University Hospital. The privacy of participants was completely protected by unlikable anonymization. This study was approved by the Ethics Committee of Tokai University (17R-221). Informed consent is waived in view that this is a retrospective study by the Ethics Committee of Tokai University.

Consent for publication

All authors gave their consent for publication.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests

Author contributions

Conceptualization, J.I. and S.T.; data curation, J.I. and N.S.; formal analysis, J.I., S.T., and N.S.; funding acquisition, J.I.; investigation, F. S., A. K., H. M., and T. S.; methodology, F. S. and A. K.; project administration, Y. N. and K. A.; resources, H. M., T. S., M. I., K. Y., T. O., N. K., S. T., Y. N.; supervision, K.O., K.S., Y.M., K.T., Y.A., M.Y., N.K., C.Y., N.I., K.M., A.B., H.S., and T.K.; writing – original draft preparation, J.I., S.T., S.N., and Y.N.; writing – review and editing, all members.

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Tables 1 to 3 are available in the Supplementary Files section.

No competing interests reported.

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A Comparative Study of MAFLD as a Predictor for Metabolic Disease Therapies Against NAFLD in Repeated Health Check-Ups: A Novel Perspective on Fatty Liver

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Abstract

Background

Methods

Result

Conclusion

Figures

Background

Methods

Participants and methods

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1