Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention

Abstract

The newly proposed term "metabolic dysfunction-associated fatty liver disease" (MAFLD) is replacing the old term "non-alcoholic fatty liver disease" (NAFLD) in many global regions, because it better reflects the pathophysiology and cardiometabolic implications of this common liver disease. The proposed change in terminology from NAFLD to MAFLD is not simply a single-letter change in an acronym, since MAFLD is defined by a set of specific and positive diagnostic criteria. In particular, the MAFLD definition specifically incorporates within the classification recognized cardiovascular risk factors. Although convincing evidence supports a significant association between both NAFLD and MAFLD, with increased risk of CVD morbidity and mortality, neither NAFLD nor MAFLD have received sufficient attention from the Cardiology community. In fact, there is a paucity of scientific guidelines focusing on this common and burdensome liver disease from cardiovascular professional societies. This Perspective article discusses the rationale and clinical relevance for Cardiologists of the newly proposed MAFLD definition.

Keywords: Cardiovascular disease; Metabolic dysfunction-associated fatty liver disease (MAFLD); Non-alcoholic fatty liver disease (NAFLD); Pharmacotherapies; Risk factors.

Fig. 1

Comparison of diagnostic criteria between NAFLD and MAFLD definitions. Hepatic steatosis is detected either by imaging techniques, blood biomarkers and scores or by liver histology. The definition of NAFLD is based on the evidence of hepatic steatosis in the absence of excessive alcohol consumption, chronic viral hepatitis, or other competing causes of hepatic steatosis. The definition of MAFLD is based on the evidence of hepatic steatosis in the presence of at least one of the following three metabolic conditions, overweight/obesity, type 2 diabetes, or the presence of at least two of the following metabolic abnormalities: (1) waist circumference ≥ 102/88 cm in Caucasian men and women (or ≥ 90/80 cm in Asian men and women); (2) blood pressure ≥ 130/85 mmHg or specific drug treatment; (3) plasma triglycerides ≥ 150 mg/dl (≥ 1.70 mmol/L) or specific drug treatment; (4) plasma high-density lipoprotein (HDL)-cholesterol < 40 mg/dl (< 1.0 mmol/L) for men and < 50 mg/dl (< 1.3 mmol/L) for women or specific drug treatment; (5) prediabetes (i.e., fasting glucose levels 100 to 125 mg/dl [5.6 to 6.9 mmol/L], or 2-h post-load glucose levels 140 to 199 mg/dl [7.8 to 11.0 mmol] or HbA1c 5.7% to 6.4% [39 to 47 mmol/mol]); (6) Homeostasis model assessment (HOMA) of insulin resistance score ≥ 2.5; and (7) plasma high-sensitivity C-reactive protein (CRP) level > 2 mg/L. Thus, MAFLD diagnosis does not require exclusion of other liver diseases but as a prerequisite it must have evidence of metabolic dysregulation. NAFLD non-alcoholic fatty liver disease, MAFLD metabolic dysfunction-associated fatty liver disease

Fig. 2

Timescale of the recognition of metabolic dysfunction-associated fatty liver disease (MAFLD) amongst cardiovascular societies

Fig. 3

Comparative effects of MAFLD-only and NAFLD-only on the risk of fatal and nonfatal CVD events and all-cause mortality. The figure shows the forest plots of the effects of the MAFLD-only or the NAFLD-only status on the risk of CVD mortality and events and all-cause mortality in cohort studies that simultaneously used the MAFLD and NAFLD definitions. The NAFLD-only status is defined as presence of NAFLD but not MAFLD; the MAFLD-only status is defined as presence of MAFLD but not NAFLD. The reference category in these statistical analyses is the absence of both NAFLD and MAFLD. Data are expressed as hazard ratios and 95% confidence intervals (in parenthesis). (A) CVD events [14, 28]: the MAFLD-only status was associated with a higher risk of CVD events than the NAFLD-only status; (B) CVD mortality [14, 29, 30]: either the MAFLD-only status or NAFLD-only status was not associated with CVD mortality; (C) all-cause mortality [29, 30]: the MAFLD-only status was associated with a higher risk of all-cause mortality than the NAFLD-only status. Abbreviations: CVD: cardiovascular disease; MAFLD: metabolic dysfunction-associated fatty liver disease; NAFLD: non-alcoholic fatty liver disease

Fig. 4

Putative shared pathophysiological mechanisms in MAFLD and CVD. MAFLD is closely associated with metabolic dysfunction and typical features of the metabolic syndrome. These metabolic risk abnormalities include visceral adipose tissue deposition, systemic low-grade inflammation, increased activity of RAAS systems, enhanced oxidative stress and insulin resistance. These metabolic risk abnormalities induce progression of coronary atherosclerosis, including vascular inflammation, lipids deposition, vascular remodeling, endothelial injury, as well as hypercoagulability, thereby contributing to increased risk of CVD. CVD cardiovascular disease, MAFLD metabolic dysfunction-associated fatty liver disease, RAAS renin–angiotensin–aldosterone system

Fig. 5

Comparative effects of MAFLD and NAFLD on the risk of fatal and nonfatal CVD and all-cause mortality independently of cardiometabolic risk factors. The figure shows the forest plots of the effects of MAFLD and NAFLD on the risk of CVD mortality and events and all-cause mortality after adjustment for coexisting cardiometabolic risk factors, in cohort studies that simultaneously used the MAFLD and NAFLD definitions. Data are expressed as hazard ratios and 95% confidence intervals (in parenthesis). A CVD events [14, 50, 52]: MAFLD is associated with a greater risk of CVD events than NAFLD B CVD mortality [30, 47]: the risk for CVD mortality is attenuated after adjustment for cardiometabolic risk factors in MAFLD or NAFLD; C all-cause mortality [30, 47, 50]: MAFLD is associated with a higher risk of all-cause mortality but this association is diminished after adjustment for cardiometabolic risk factors. CVD cardiovascular disease, MAFLD metabolic dysfunction-associated fatty liver disease, NAFLD non-alcoholic fatty liver disease

Fig. 6

Assessment of lifestyle interventions and pharmacotherapies on CVD risk and liver histology features. ACC Acetyl-CoA carboxylase, ACEi angiotensin converting enzyme inhibitor, ARBs angiotensin II receptor blockers, CVD cardiovascular disease, GLP-1RA glucagon-like peptide 1 receptor agonist, NASH non-alcoholic steatohepatitis, PCSK9 proprotein convertase subtilisin/kexin type 9, SGLT-2i sodium-glucose cotransporter 2 inhibitor