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Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States
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August 07, 2021
We noted a strong association between MAFLD and all-cause mortality in this longitudinal, US nationally representative, population-based study. While individuals with MAFLD had a 17% higher risk for all-cause mortality with statistical significance, NAFLD did not increase the risk of all-cause mortality after adjusting for metabolic risk factors. Furthermore, advanced fibrosis in MAFLD was associated with higher estimates for all-cause mortality than in NAFLD. These findings suggest that MAFLD is strongly associated with all-cause mortality, independently of known metabolic risk factors
A diagnosis of NAFLD warrants recommendations for lifestyle modifications in a multidisciplinary approach to reduce hepatic fat content, exercise ideally with weight loss, and targeted treatment of individual metabolic components, including diabetes, high blood pressure, and dyslipidemia. It is important to perform a metabolic risk assessment to identify high-risk subpopulations who are at increased risk of all-cause mortality among individuals with NAFLD. Well-designed prospective studies are needed to assess and confirm our observations. ......international experts recently proposed a new term, metabolic dysfunction-associated fatty liver disease (MAFLD) with a broader diagnostic criteria.[[4]] The diagnostic criteria of MAFLD requires the presence of metabolic risk factors in the setting of hepatic steatosis, includes individuals with other concomitant liver diseases, and excludes those with hepatic steatosis who do not fulfill the metabolic risk criteria
The aim of our study was to investigate the independent longitudinal association of NAFLD and MAFLD on all-cause and cause-specific mortality in a nationally representative sample of US adults. For this study, we utilized the NHANES III dataset, the survey for which was conducted from 1988 to 1994 in the US. NAFLD was defined as the presence of hepatic steatosis without significant alcohol consumption (> 21 drinks/week in men and > 14 drinks/week in women) and/or viral hepatitis (positive serum hepatitis C antibody and/or positive serum hepatitis B surface antigen). We defined MAFLD as the presence of metabolic risk factors in the setting of hepatic steatosis, including individuals with other concomitant liver diseases and significant alcohol consumption based on the diagnostic criteria proposed by an international expert panel.[[4]] MAFLD was diagnosed as the presence of hepatic steatosis with 1 or more of the following: (1) overweight or obese (body mass index ≥ 25 kg/m2) (2) diabetes mellitus (3) at least 2 metabolic risk abnormalities. Metabolic risk abnormalities consisted of (1) waist circumference ≥ 102 cm for men and 88 ≥ cm for women, (2) blood pressure ≥ 130/85 mmHg or specific drug treatment, (3) fasting plasma triglycerides ≥ 150 mg/dl or specific drug treatment, (4) plasma HDL-cholesterol < 40 mg/dl for men and < 50 mg/dl for women or specific drug treatment, (5) prediabetes (fasting glucose 100-125 mg/dl or hemoglobin A1c 5.7%-6.4%, (6) homeostasis model assessment of insulin resistance score ≥ 2.5, (7) plasma high-sensitivity C-reactive protein level > 2 mg/L.[[4]]
Our findings provide further support to the idea that nonalcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may provide a better understanding of predictors that may increase the risk of death.
A total of 7,761 individuals who fasted ≥ 8 hours were included in this analysis. The weighted prevalence of NAFLD and MAFLD was 29.5% (95% CI: 27.1-32.1) and 25.9% (95% CI: 23.6-28.3), respectively. As shown in Figure 1, the weighted prevalence of concordant MAFLD and NAFLD (MAFLD(+)/NAFLD(+)) was 23.5% (95% CI: 21.3-25.8).
Discussion
We noted a strong association between MAFLD and all-cause mortality in this longitudinal, US nationally representative, population-based study. While individuals with MAFLD had a 17% higher risk for all-cause mortality with statistical significance, NAFLD did not increase the risk of all-cause mortality after adjusting for metabolic risk factors. Furthermore, advanced fibrosis in MAFLD was associated with higher estimates for all-cause mortality than in NAFLD. These findings suggest that MAFLD is strongly associated with all-cause mortality, independently of known metabolic risk factors.....
With a more extended follow-up period of the median 23 years, we confirm that NAFLD per se is not associated with increased risk of all-cause and cause-specific mortality. The metabolic milieu or an associated epiphenomenon may exert a relatively stronger influence on MAFLD than NAFLD, despite our attempts to adjust for body mass index, diabetes, hypertension, HDL-cholesterol, waist circumference, fasting triglycerides, and c-reactive protein. Association between MAFLD and all-cause mortality remained significant when adjusted for or stratified by the metabolic risk factors suggesting that hepatic steatosis per se in the context of metabolic dysregulation (the heart of the MAFLD definition)[[19]] was associated with all-cause mortality. Diagnostic criteria of MAFLD also included insulin resistance and inflammation, resulting in a significant association between MAFLD and all-cause mortality plausibly associated with the systemic release of several proinflammatory cytokines, adiponectin, and oxidative and ER stress mediators.[[20]] Also, individuals with MAFLD(+)/NAFLD(-), who had concomitant liver disease (significant alcohol consumption and/or viral hepatitis) and metabolic abnormalities, demonstrated higher hazards for cancer-related mortality, which contributed to the increased risk of all-cause mortality among subjects with MAFLD. As there is no current approved pharmacological treatment for NAFLD or MAFLD, lifestyle modification is the primary strategy for preventing and managing NAFLD or MAFLD.[[21],[22]] With recognizing a significant link between metabolic abnormalities in NAFLD and all-cause mortality, incorporating lifestyle modifications directed toward control of blood glucose, obesity, blood pressure, triglycerides, and HDL cholesterol, should be considered in designing therapeutic strategies for individuals with MAFLD.[[23]] In addition, future integration of weight-loss medications in the management of MAFLD and NAFLD appears very promising.[[24],[25]]
Introduction
There has been an ever increasing recognition of nonalcoholic fatty liver disease (NAFLD) as the leading cause of chronic liver disease in the United States (US), with a prevalence of up to 30%.[[1]] Over the next decade, the burden of NAFLD is projected to grow due to the worsening obesity epidemic and lack of approved pharmacologic treatment. With no evidence of plateauing in the prevalence of diabetes and obesity in an aging society, it is expected that advanced hepatic fibrosis and end-stage liver disease among individuals with NAFLD will further increase.[[2]] A previous study using the Third National Health and Nutrition Examination Survey (NHANES III) reported that NAFLD per se is not associated with an increase in all-cause and cause-specific mortality.[[3]] Although there was substantial 15-year follow-up mortality data in the previous study, a longer follow-up period may help establish an independent association between NAFLD and all-cause mortality. These assumptions are based on the gradual histologic damage and slow progression of hepatic fibrosis among individuals with NAFLD. In addition, controversy persists about the nomenclature on how best to define this disease entity. In this regard, a panel of international experts recently proposed a new term, metabolic dysfunction-associated fatty liver disease (MAFLD) with a broader diagnostic criteria.[[4]] The diagnostic criteria of MAFLD requires the presence of metabolic risk factors in the setting of hepatic steatosis, includes individuals with other concomitant liver diseases, and excludes those with hepatic steatosis who do not fulfill the metabolic risk criteria.[[4],[5]] This proposed term, MAFLD has led to a hot debate between experts and a consensus is needed.[[5],[6]] The proposed new terminology from NAFLD to MAFLD is not simply a change to a better-suited name but also a shift in the phenotypic characteristics of individuals who meet the criteria for MAFLD.[[5],[6]] Recent studies showed that most individuals with hepatic steatosis met the criteria for both NAFLD and MAFLD (80-90%).[[5],[7]] However, a nonnegligible proportion of individuals met the criteria for one but not the other condition. As expected, individuals who met the definition of NAFLD but not MAFLD had no or mild metabolic risk factors, whereas those with MAFLD but not NAFLD had more metabolic risk factors and concomitant liver disease. These significant differences in the diagnostic criteria for the two terms are pivotal in predicting the future outcomes. The discordant subgroups that met the criteria for one but not the other definition may differ in their impact on all-cause and cause-specific mortality than groups with the concordant definition. Therefore, assessing the all-cause and cause-specific mortality associated with NAFLD or MAFLD may help understand differences and similarities in these clinical entities. The aim of our study was to investigate the independent longitudinal association of NAFLD and MAFLD on all-cause and cause-specific mortality in a nationally representative sample of US adults.
Highlights
• Metabolic dysfunction-associated fatty liver disease (MAFLD) increased all-cause and cardiovascular mortality.
• NAFLD was associated with increased all-cause mortality among individuals with known metabolic risk factors.
• Advanced fibrosis in MAFLD was associated with higher estimates for all-cause mortality than in NAFLD.
Abstract
Background & Aims
Recently, international experts have put forward a modified criterion to redefine nonalcoholic fatty liver disease (NAFLD) as metabolic-associated fatty liver disease (MAFLD). It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on the all-cause and cause-specific mortality in US adults.
Methods
We analyzed data from 7,761 participants in the Third National Health and Nutrition Examination Survey and their linked mortality through 2015. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other known liver diseases. MAFLD was defined based on the criteria proposed by an international expert panel. The Cox proportional hazard model was used to study all-cause mortality and cause-specific mortality between MAFLD and NAFLD with adjustments for known risk factors.
Results
During a median follow-up of 23 years, individuals with MAFLD had a 17% higher risk for all-cause mortality (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.04-1.32). Furthermore, MAFLD was associated with a higher risk for cardiovascular mortality. NAFLD per se did not increase the risk of all-cause deaths. Individuals who met both definitions were noted to have a higher risk for all-cause mortality (HR: 1.13, 95% CI: 1.00-1.26). Also, MAFLD without NAFLD had 1.7-fold higher all-cause mortality (HR: 1.66, 95% CI: 1.19-2.32). Individuals with advanced fibrosis and MAFLD had higher estimates for all-cause mortality than those with advanced fibrosis and NAFLD.
Conclusions
In this US population-based study, MAFLD was associated with increased risk of all-cause mortality, while NAFLD demonstrated no association with all-cause mortality after adjusting for metabolic risk factors.
Lay Summary
Our findings provide further support to the idea that nonalcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may provide a better understanding of predictors that may increase the risk of death.
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