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† Jiarong Xie and Linjie Lu contributed equally to this work.
Jiarong Xie
Footnotes
† Jiarong Xie and Linjie Lu contributed equally to this work.
Affiliations
Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou, ChinaDepartment of Gastroenterology, Ningbo First Hospital, Ningbo, China
† Jiarong Xie and Linjie Lu contributed equally to this work.
Linjie Lu
Footnotes
† Jiarong Xie and Linjie Lu contributed equally to this work.
Affiliations
Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou, ChinaDepartment of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, Haining, China
Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou, China
Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou, ChinaDepartment of Gastroenterology, Ningbo First Hospital, Ningbo, China
Corresponding author. Address: Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine. No. 79 Qingchun Road, Hangzhou 310003, China. Tel.: 0086-571-87236863.
Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaZhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou, ChinaDepartment of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, Haining, China
Recently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults.
showing that metabolic dysfunction-associated fatty liver disease (MAFLD) was associated with an increased risk of all-cause mortality in a large nationally representative population from the United States. They also found that advanced fibrosis in MAFLD was associated with higher estimates for all-cause mortality than in non-alcoholic fatty liver disease (NAFLD).
the diagnosis of which requires the presence of fatty liver in addition to any of overweight/obesity, type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. Although MAFLD was associated with an increased risk of all-cause mortality, some lean patients with MAFLD may not be at high risk of metabolism-related death. Besides, the MAFLD definition is complex and some subitems, such as HOMA-IR and high-sensitivity C-reactive protein, are not routinely measured in primary healthcare centers. Therefore, it is imperative that the MAFLD definition be validated and optimized in real-world practice, and a simplified and more applicable set of criteria is needed.
Here, we developed a simplified set of metabolic syndrome (MetS)-based criteria for MAFLD, and compared the performance of the simplified criteria with that of the original criteria in predicting all-cause mortality in a 27-year follow-up of American adults. The dataset used in our analysis was the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994, which recruited a representative sample of the US population using a complex, multistage probability design.
and waist circumference is widely regarded as an independent risk factor for MetS and also the only component of MetS that is associated with the presence of NAFLD and liver fibrosis,
Nonalcoholic fatty liver disease is prevalent in women with prior gestational diabetes mellitus and independently associated with insulin resistance and waist circumference.
we combined BMI and waist circumference as one indicator of obesity/central obesity in the simplified criteria. As both T2DM and prediabetes refer to abnormal blood glucose, we combined T2DM and prediabetes indicators into one criterion rather than listing them as separate categories. Similarly, given that the majority of individuals with HOMA-IR scores ≥2.5 had at least 2 metabolic abnormalities (Fig. 1A), we did not list HOMA-IR score separately either. Besides, because high-sensitivity C-reactive protein, an indicator of relatively low specificity, is not routinely measured in clinical practice across regions, we propose that it be excluded from the diagnostic criteria, echoing an expert consensus from the Middle East and North Africa.
(A) Upset plot for each diagnostic indicator; (B) Venn diagram in the population with fatty liver. (C) Kaplan-Meier analysis for all-cause mortality of MAFLD participants meeting different criteria. MAFLD, metabolic dysfunction-associated fatty liver disease.
To sum up, our simplified MetS-based criteria of MAFLD are described as the presence of fatty liver combined with at least 2 of the following conditions: (i) obesity/central obesity: BMI ≥25 kg/m2, or waist circumference ≥102/88 cm in US males and females, respectively; (ii) elevated blood pressure: blood pressure ≥130/85 mmHg or specific drug treatment; (iii) elevated triglycerides: ≥150 mg/dl or specific drug treatment; (iv) hyperglycemia: prediabetes or diabetes, or specific drug treatment; (v) hyperuricemia: serum uric acid >7 mg/dl in males or >6 mg/dl in females, or specific drug treatment; and (vi) HDL-cholesterol <40 mg/dl for males and <50 mg/dl for females or specific drug treatment. By utilizing UpSet plot, we visualized the intersections and their aggregates, the number of potential predictors, and the attribute statistics (Fig. 1A). Of the 4,414 participants diagnosed with fatty liver who were included for analysis, 3,756 met the MAFLD-original criteria, and 3,384 met the simplified MAFLD criteria (Fig. 1B). Kaplan-Meier analysis confirmed that individuals with fatty liver who met the simplified criteria had a significantly higher risk of all-cause mortality than those who met the original criteria (MAFLD-simplified vs. MAFLD-original: p = 0.02) (Fig. 1C). Compared with individuals who did meet the MAFLD-original criteria (MAFLD-original-free), the hazard ratio (HR) was 1.252 (95% CI 0.943–1.663) for all-cause mortality in MAFLD-original individuals after adjustment for age, sex, and race/ethnicity (p = 0.117). Meanwhile, the corresponding HR was 1.628 (95% CI 1.222–2.170) in MAFLD-simplified individuals, compared with MAFLD-simplified-free individuals (p = 0.001) (Fig. 1C). These findings showed that the simplified criteria were superior in predicting all-cause mortality in American adults with fatty liver disease.
In conclusion, the MAFLD-simplified definition proposed in our study could serve as an optimized risk stratification tool for predicting all-cause mortality in individuals with fatty liver disease. The simplified diagnostic process may better identify high-risk individuals in clinical practice.
Financial support
This work was supported by the National Natural Science Foundation of China (82070585, 81770573, 81722009), Key Research and Development Program of Zhejiang Province (2020C03033), National Key Research and Development Program (2018YFA0109800), “Ten thousand plan”-High Level Talents Special Support Plan of Zhejiang Province (ZJWR0108008), Zhejiang Provincial Program for the Cultivation of High-Level Innovation for Health Talents, Natural Science Foundation of Ningbo (202003N4233), and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2021KY991).
Authors' contributions
Study concept and design: C. Xu. Acquisition of data: J. Xie, L. Lu, and Y. Chen. Analysis and interpretation of data: J. Xie, L. Lu, Y. Chen, L. Xu, and C. Xu. Drafting of the manuscript: J. Xie, L. Lu, Y. Chen, and C. Xu. Critical revision of the manuscript for important intellectual content: C. Xu. Obtained funding: J. Xie, and C. Xu. Study supervision: C. Xu.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Supplementary data
The following are the supplementary data to this article:
Nonalcoholic fatty liver disease is prevalent in women with prior gestational diabetes mellitus and independently associated with insulin resistance and waist circumference.
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