Part One Association Of MAFLD With Diabetes, Chronic Kidney Disease, And Cardiovascular Disease: A 4.6-Year Cohort Study in China
Jun 15, 2023
Abstract
1. Context
In 2020, the terminology of metabolic dysfunction–associated fatty liver disease (MAFLD) was proposed to replace nonalcoholic fatty liver disease (NAFLD).
2. Objectives
This work aimed to investigate the prevalence and incidence of MAFLD and evaluate its effects on incident extrahepatic diseases.
3. Methods
A total of 6873 individuals, with a 4.6-year follow-up, were included in this study. Associations of MAFLD and NAFLD with diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) were examined using logistic regression and Cox proportional hazards models.
4. Results
The prevalence of NAFLD and MAFLD was 40.3% (95% CI, 39.2%-41.5%) and 46.7% (95% CI, 45.6%-47.9%), respectively. Additionally, 321 (4.7%) and 156 (2.3%) participants had MAFLD with excessive alcohol consumption and hepatitis B virus (HBV)infection. During the follow-up period, the incidence of NAFLD and MAFLD was 22.7% (95% CI, 21.3%-24.0%) and 27.0% (95% CI, 25.5%-28.4%). MAFLD was associated with higher risks of incident diabetes (risk ratio [RR] 2.08; 95% CI, 1.72-2.52), CKD (RR 1.64; 95% CI, 1.39-1.94), and CVD (hazard ratio 1.44; 95% CI, 1.15-1.81). Similar associations for NAFLD were observed. Furthermore, the MAFLD subgroups with excessive alcohol consumption (RR 2.49; 95% CI, 1.64-3.78) and HBV infection (RR 1.98; 95% CI, 1.11-3.52) were associated with higher risks of incident diabetes.
5. Conclusion
The change from NAFLD to MAFLD did not greatly affect the associations with diabetes, CKD, and CVD. MAFLD further identified those patients with metabolically fatty liver combined with excessive alcohol consumption and HBV infection, who had increased risks of incident diabetes compared with those of non–fatty liver.
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Keywords
metabolic dysfunction–associated fatty liver disease, nonalcoholic fatty liver disease, diabetes, chronic kidney disease, cardiovascular disease.
Introduction
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a global prevalence of 25.24% (1) and 29.2% (2) in China. NAFLD often coexists with other liver conditions, such as alcoholic fatty liver disease and viral hepatitis, and these usually exert synergistic effects on the liver disease progression (3, 4). In addition, there is a lack of evidence supporting the currently recommended cutoff of alcohol consumption for NAFLD. Given the heterogeneous pathogenesis of metabolic dysfunction–associated fatty liver disease (NAFLD) and inaccuracies in the definition of NAFLD, experts suggested replacing the term NAFLD with MAFLD in 2020 (5).
MAFLD is more inclusive in the etiology of fatty liver diseases than NAFLD and is defined based on evidence of hepatic steatosis and simultaneously accompanied by the presence of at least one of the following conditions: overweight/obesity, diabetes, or metabolic dysregulation (5). However, the current data on whether MAFLD definition was more feasible than NAFLD in clinical practice were scarce and inconsistent. Three cross-sectional studies showed that compared with NAFLD, the definition of MAFLD was more practical for identifying more patients at risk of liver disease progression (6, 7) and more patients at prevalent risk of chronic kidney disease (CKD) (8), whereas 2 studies (9, 10) reported that the MAFLD definition did not significantly affect the prevalence in contrast to NAFLD and a cohort study with a 7.5-year follow-up indicated that the presence of MAFLD did not increase mortality (11).
However, to our knowledge, the evidence of the associations of MAFLD with extrahepatic diseases based on large-scale, community-based cohort studies is limited. Therefore, we aimed to (i) investigate the prevalence and incidence rates of MAFLD and NAFLD among middle-aged and elderly Chinese individuals; and (ii) evaluate the associations of MAFLD and NAFLD with diabetes, CKD, and cardiovascular disease (CVD) using a retrospective cohort dataset.
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Materials and Methods
1. Study Design and Participants
The Shanghai Nicheng Cohort Study, a community-based cohort study, was designed to prospectively investigate the prevalence, incidence, and related factors of cardiometabolic diseases (12, 13). The detailed introduction of this study was previously reported (12). Briefly, a total of 17 212 individuals aged 45 to 70 years completed the baseline survey between 2013 and 2014. Among them, 10 075 participants aged 55 to 70 years were invited to participate in the follow-up survey in 2018, and 7230 finally attended with a follow-up rate of 71.8%. We excluded 357 participants because of missing data for abdominal ultrasonography (N = 338) or lacking data for a diagnosis of MAFLD (N = 19). Finally, 6873 participants were included in this study (Fig. 1). The ethics committee of the Shanghai Sixth People’s Hospital approved this study (approval No. 2018- 010). All participants provided written informed consent.
2. Clinical Data Collection and Measurements
At baseline and follow-up surveys, a standardized questionnaire was used to collect data concerning demographics, educational background, smoking status, alcohol consumption, leisure-time exercise, medical history, and medication use. Excessive alcohol consumption was defined as more than 140 g weekly of alcohol consumption in men and more than 70 g weekly in women. Current smoking was defined as having smoked at least 1 cigarette per day over the past year. Leisure-time exercise was categorized into less than 30 minutes/day and 30 minutes/day or more. The measurements of height, weight, waist circumference, and blood pressure were performed using the established standard methods (14). Body mass index (BMI) was calculated as weight (in kilograms) divided by the square of height (in meters).
Overnight fasting (at least 10 hours) venous blood samples and random urine samples were collected. Fasting plasma glucose (FPG) was assessed by the glucose oxidase method. Glycated hemoglobin A1c (HbA1c) was assessed by high-performance liquid chromatography. Triglycerides were assessed by an enzymatic colorimetric method. High-density lipoprotein cholesterol was assessed by a direct method. Fasting insulin was assessed by an electrochemiluminescence immunoassay. Urine creatinine, urine albumin, and high-sensitivity C-reactive protein (hs-CRP) were assessed by the rate of nephelometry assay. Serum creatinine was assessed by the sarcosine oxidase–PAP (phenol-aminophenazone peroxidase) method. Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) were assessed by an enzyme-linked immunosorbent assay using the Hepatitis B Virus Surface Antigen (ELISA) Diagnostic Kit (Cat# 30811010101, RRID: AB_2892704) and the Hepatitis C Virus (ELISA) Diagnostic Kit (Cat# 30811060102, RRID: AB_2892705), respectively. Insulin resistance was quantified through the homeostasis model assessment of insulin resistance (HOMA-IR), calculated as FPG (mmol/L) × FINS (μU/ mL)/22.5 (15).
Abdominal ultrasonography was performed using an ultrasound system (Z.One Ultra, Zonare Medical Systems Inc) by experienced ultrasonographers.
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3. Definitions
Fatty liver was diagnosed according to the Asia-Pacific Guidelines (16).
MAFLD was diagnosed based on ultrasound evidence of fatty liver in addition to the presence of at least 1 of the following 3 criteria, namely overweight/obesity (defined as BMI ≥ 23.0 in Asia), diabetes, or metabolic dysregulation (5). Metabolic dysregulation was defined as the presence of at least 2 of the following metabolic abnormalities in those with lean/normal weight (defined as BMI < 23.0 in Asia): (1) waist circumference greater than or equal to 90 cm in Asian men and greater than or equal to 80 cm in Asian women; (2) blood pressure greater than or equal to 130/85 mm Hg or specific drug treatment; (3) triglycerides greater than or equal to 1.70 mmol/L or specific drug treatment; (4) high-density lipoprotein cholesterol less than 1.0 mmol/L for men and less than 1.3 mmol/L for women or specific drug treatment; (5) prediabetes (FPG = 5.6-6.9 mmol/L and/or HbA1c = 5.7%-6.4% in participants without a prior diabetes diagnosis); (6) HOMA-IR greater than or equal to 2.5; and (7) hs-CRP level greater than 2 mg/L (5). MAFLD was further categorized into 2 subgroups: MAFLD with excessive alcohol consumption and HBV infection.
NAFLD was based on ultrasound evidence of fatty liver, in the absence of excessive alcohol consumption and other concomitant liver diseases (viral hepatitis, total parenteral nutrition, hepatolenticular degeneration, drug-induced hepatitis, autoimmune hepatitis, etc) (16).
Diabetes was defined as having a self-reported history of diabetes, and/or FPG greater than or equal to 7.0 mmol/L, and/or HbA1c greater than or equal to 6.5% (17). The estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (18). CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 or urinary albumin-to-creatine ratio greater than or equal to 30 μg/mg (19). According to participants’ self-reports, nonfatal CVD included coronary heart disease and stroke. Coronary heart disease was determined as having a history of angina pectoris, myocardial infarction, a surgical history of coronary angiography, coronary stent implantation, and/or coronary artery bypass, and stroke included a history of cerebral hemorrhage and/or cerebral infarction.
4. Statistical Analysis
Continuous variables were presented as medians (interquartile ranges), and categorical variables were presented as frequencies (proportions). To address potential confounding, logistic regression models were used to estimate the odds ratio (OR) and 95% CI for prevalent diabetes, and to estimate risk ratio (RR) and 95% CI for incident diabetes and CKD; and Cox proportional hazards models
were used to estimate the hazard ratio and 95% CI for incident CVD. Model 1 was adjusted for age and sex, and model 2 was additionally adjusted for educational background, smoking status, and leisure time exercise. Missing data were not imputed, and participants with missing data for a variable were not included in the analysis involving that particular variable. All statistical analyses were conducted using SPSS, version 22.0 (SPSS Inc). A 2-tailed P value of less than .05 was considered to be statistically significant.
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Yebei Liang 1, Hongli Chen,1, Yuexing Liu,1, Xuhong Hou,1 Li Wei,1 Yuqian Bao,1 Chunguang Yang,1 Geng Zong,2,3 Jiarui Wu,4 and Weiping Jia 1
1 Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200233, China;
2 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
3 Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China;
4 CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
