Metabolic dysfunction-associated fatty liver disease:... : Cardiology Plus (original) (raw)

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver and often occurs alongside metabolic syndrome[1–3]. With a global prevalence affecting approximately 25% to 30% of adults, NAFLD represents a significant public health challenge with considerable economic burdens for both patients and healthcare systems[4–8]. However, the term “NAFLD” does not explicitly link to its primary causes, such as overweight/obesity and type 2 diabetes, nor to its underlying mechanisms, including insulin resistance and chronic low-grade metabolic inflammation. Thus, diagnosing NAFLD can be challenging, particularly in patients with coexisting causes of hepatic steatosis, such as substantial alcohol consumption or viral hepatitis, creating obstacles for effective screening, diagnosis, and management[9].

To address these limitations, an international panel of experts introduced a new term in 2020, metabolic-associated fatty liver disease (MAFLD), which better reflects the metabolic pathogenesis of this liver disease[10]. The MAFLD definition incorporates diagnostic criteria that include overweight/obesity, type 2 diabetes, or at least two metabolic risk abnormalities, regardless of other conditions like alcohol use or viral hepatitis[11]. This updated terminology, “MAFLD,” is intended to replace “NAFLD” and encompass the broader spectrum of metabolic abnormalities associated with fatty liver disease[10,12]. In recent years, clinical epidemiological studies, along with retrospective cohort studies, have shown that the MAFLD definition more accurately identifies individuals at high risk for adverse liver-related outcomes and cardiovascular disease (CVD) events compared to the NAFLD definition[13–14].

While the shift in terminology aims to refine diagnostic criteria and guide treatment strategies, it has also sparked debates regarding its implications for disease progression, therapeutic development, and the potential stigma associated with terms like “fatty liver”[15–16]. In response, a new nomenclature was proposed: metabolic dysfunction-associated steatotic liver disease (MASLD)[17]. Under this framework, MASLD is classified as a subtype within the broader category of steatotic liver disease (SLD), which includes various causes of hepatic fat deposition. Specifically, MASLD excludes alcohol and other specific etiologies, such as metabolic and alcohol-related liver disease (MetALD), alcoholic liver disease (ALD), other specific SLD causes, and cryptogenic SLD[18]. This framework further distinguishes MASLD and MetALD, depending on alcohol consumption, where MASLD refers to hepatic steatosis with at least one cardiometabolic risk factor and no other identifiable causes[19], while MetALD applies to individuals with higher levels of alcohol consumption (140–350 g/week for females, 210–420 g/week for males). MASLD thereby underscores the intricate connection between liver fat accumulation and metabolic dysfunction, intentionally excluding the impact of significant alcohol consumption.

Overall, compared to the term “NAFLD,” the new nomenclatures—MAFLD and MASLD—seek to standardize diagnostic criteria with a “positive” approach, reduce stigma, enhance awareness and patient identification, and promote consistency in clinical practice and research (Figure 1). While widely accepted by experts, this naming convention has also generated ongoing debate within the field[20–22].

Figure 1.:

Comparison of diagnostic criteria between NAFLD, MAFLD, and MASLD definitions. BMI: body mass index; HbA1c: glycated hemoglobin; HDL-C: high-density lipoprotein cholesterol; MAFLD: metabolic dysfunction-associated fatty liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease; MetALD: metabolic and alcohol-related/associated liver disease; NAFLD: non-alcoholic fatty liver disease.

WHAT CARDIOLOGISTS SHOULD KNOW ABOUT THESE DEBATES?

The diagnostic criteria for MAFLD/MASLD represent an evolution from NAFLD, focusing more on the metabolic origins and long-term cardiometabolic complications of the disease. The main controversy is twofold:

Terminology and stigma: one major concern with terminology is the potential for social stigma associated with certain terms. For instance, words like “obesity” or “non-alcoholic” may carry negative societal and psychological connotations. Alternative terms are therefore being considered to reduce this stigma, although perspectives vary across languages and cultures. In some Indian languages, for instance, “fatty” can have positive connotations, associated with health rather than negativity. In Chinese, both “fatty liver disease” and “steatotic liver disease” are commonly translated as “脂肪肝,” blurring the distinction between MASLD and MAFLD.
Scientific and diagnostic perspectives: another area of debate is whether the transition to MASLD terminology reflects scientific advancement or is driven more by political correctness. Differing perspectives on identifying metabolic risk factors can influence diagnostic criteria and classifications, leading to varied viewpoints among experts and academic bodies. MAFLD defines the condition as hepatic steatosis in conjunction with overweight/obesity, type 2 diabetes, or metabolic dysregulation, which requires at least two of seven metabolic risk factors. In contrast, MASLD requires at least one of five metabolic factors and excludes a prerequisite to rule out other liver diseases or excessive alcohol intake. Despite these differences, both terms underscore the role of metabolic dysfunction in liver disease progression and its impact on long-term cardiometabolic health.

For cardiologists, understanding these distinctions is crucial, as metabolic dysfunction linked to MAFLD/MASLD plays a key role in systemic conditions like atherosclerosis, thereby significantly contributing to CVD development and progression.

TIME TO CHANGE THE PERSPECTIVE AMONG CARDIOLOGISTS REGARDING MAFLD/MASLD

For years, fatty liver disease has been viewed primarily as a hepatic condition, rather than a multisystem disease with significant implications for cardiometabolic complications[23–24]. This perception stemmed from a focus on metabolic risk factors, such as obesity, insulin resistance, and atherogenic dyslipidemia, all of which are established risk factors for CVD. Consequently, cardiologists may not have prioritized MAFLD/MASLD as a condition directly linked to CVD, despite the shared metabolic factors and close interplay between MAFLD/MASLD and cardiovascular health[25]. Recent insights challenge this view, suggesting that MAFLD/MASLD is not merely a consequence of metabolic factors but also a significant contributor to CVD risk (Figure 2)[13–14,23].

Figure 2.:

MAFLD/MASLD for cardiologists. MAFLD/MASLD should be considered a risk factor for atherosclerotic CVD, which remains the leading cause of mortality in patients with this liver condition. Additionally, MAFLD/MASLD is associated with an increased risk of HF, permanent AF, and AS. Patients with CVD, particularly those with multiple metabolic disorders, should have their liver disease severity monitored. This can be done using non-invasive blood-based scores and imaging methods, such as the FIB-4 index and vibration-controlled transient elastography (FibroScan®). AF: atrial fibrillation; AS: aortic valve sclerosis; ASCVD: atherosclerotic cardiovascular disease; CVD: cardiovascular disease; FIB-4: Fibrosis-4; HF: heart failure; MAFLD: metabolic dysfunction-associated fatty liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease.

In the last decade, the association between MAFLD/MASLD and elevated risk of fatal and nonfatal CVD events has been confirmed across numerous meta-analyses and cohort studies[26–30]. Recent data indicate that individuals with MAFLD/MASLD face a substantial risk of atherosclerotic CVD, particularly in the presence of liver fibrosis[31–34]. A comprehensive meta-analysis of 36 longitudinal cohort studies, including data on approximately 5.8 million middle-aged individuals followed for a median of 6.5 years, showed that MAFLD/MASLD is associated with notably higher long-term risk of fatal and nonfatal CVD events (pooled random-effects hazard ratio [HR]: 1.45, 95% confidence interval [95% CI]: 1.31–1.61), even when controlling for age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors[35]. This risk is further heightened in those with advanced liver disease, especially at higher fibrosis stage (pooled random-effects HR: 2.50, 95% CI: 1.68–3.72)[35]. The American Heart Association’s 2022 statement also underscores that MASLD/MAFLD is a recognized risk factor for atherosclerotic CVD, the leading cause of death among these patients[36].

Beyond accelerating coronary atherosclerosis, MAFLD/MASLD affects other cardiac structures, raising risks for cardiomyopathy (mainly left ventricular diastolic dysfunction and hypertrophy leading to heart failure), cardiac valvular calcification (mainly aortic valve sclerosis), arrhythmias (mainly permanent atrial fibrillation), and some conduction abnormalities[37–38]. Heart failure with preserved ejection fraction (HFpEF), increasingly recognized as an inflammatory cardiometabolic disorder with varied subtypes and presentations[39], shares many characteristics with MAFLD/MASLD. Often dubbed “MASH of the heart,” HFpEF mirrors left ventricular diastolic dysfunction related to hypertensive remodeling[40], which shows an intriguing overlap with the pathophysiology of MAFLD/MASLD. There is a well-established bidirectional relationship between heart failure with reduced ejection fraction (HFrEF) and liver disease[41–42]. However, the connection between HFpEF and MAFLD/MASLD remains less understood, representing a promising area for future research[43–45].

A meta-analysis of 11 cohort studies, including about 11.2 million middle-aged individuals from various countries over a median 10-year follow-up, revealed that MAFLD/MASLD was linked to a 1.5-fold increase in new-onset heart failure risk (pooled HR: 1.50, 95% CI: 1.34–1.67), independent of diabetes, hypertension, and other common CVD risk factors[46]. Additionally, research indicates a strong independent association between MAFLD/MASLD and certain cardiac arrhythmias, especially permanent atrial fibrillation, beyond traditional CVD risks[47]. Preliminary evidence also suggests that MAFLD/MASLD correlates with an increased likelihood of cardiac calcifications, particularly in the aortic and mitral valves, highlighting a range of CVD implications for this patient population[37–38].

TIME TO SHIFT CLINICAL PRACTICE AMONG CARDIOLOGISTS REGARDING MAFLD/MASLD

MAFLD/MASLD can progress to more severe forms, such as metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma, significantly impacting morbidity and mortality[48]. Evaluating liver health in patients with established CVD is crucial for comprehensive risk management, as advanced liver fibrosis (stages F3–F4 on liver histology) is associated with an increased risk of CVD events[49]. However, patients with liver fibrosis (especially those with normal or only moderately increased serum liver enzymes), often do not consult with hepatologists due to the disease’s typically asymptomatic nature. These patients are frequently managed by cardiologists for coexisting CVD, yet several factors contribute to the under-recognition of MAFLD/MASLD in these settings.

First, despite growing awareness of the link between MAFLD/MASLD and CVD, many cardiologists may not prioritize liver disease within their practice due to a primary focus on cardiovascular management. MAFLD/MASLD’s chronic nature, usually lacking acute symptoms, may not prompt immediate investigation during routine cardiology visits, especially in time-constrained clinical settings where non-cardiovascular issues might only be addressed if symptomatic or prominently noted in the medical history. Third, screening for MAFLD/MASLD may be unfamiliar to cardiologists, as they typically rely on liver function tests or imaging such as ultrasound or computed tomography (CT), which have limitations in accurately assessing liver fibrosis. Without a robust screening framework, liver fibrosis in cardiovascular patients may go unnoticed, delaying necessary interventions. Fourth, current cardiovascular guidelines inconsistently recommend routine screening for MAFLD/MASLD, likely due to the limited treatment options beyond lifestyle modifications. This inconsistency in guideline recommendations, combined with the strong correlation between MAFLD/MASLD and CVD, contributes to clinical inertia among cardiologists and primary care providers. As a result, patients with MAFLD/MASLD are typically referred for cardiovascular concerns rather than hepatological evaluation[15,16]. However, a growing recognition of the interrelatedness of metabolic risk factors—such as obesity, diabetes, chronic kidney disease, and CVD—has led the American Heart Association to adopt a new framework: the cardiovascular-kidney-metabolic syndrome[50]. MASLD/MAFLD plays a key pathogenic role in the development of this syndrome, highlighting the need for holistic care approaches to improve cardiovascular, kidney, and metabolic health, as well as related outcomes for affected populations[50].

FIRST STEP IN IMPLEMENTING CLINICAL PRACTICE CHANGES AMONG CARDIOLOGISTS

Cardiologists should incorporate non-invasive screening tools, such as vibration-controlled transient elastography (FibroScan®) or serum biomarkers/scores (e.g., the Fibrosis-4 [FIB-4] index, NAFLD Fibrosis Score), to assess liver fibrosis in at-risk patients. These methods provide valuable information without the need for invasive liver biopsy[51–52]. The FIB-4 index is calculated using the following formula: age × aspartate aminotransferase (U/L)/(platelet count [109/L] × alanine aminotransferase 1/2 [U/L])[53]. The FIB-4 index is a cost-effective tool for ruling out advanced liver fibrosis, particularly in patients with type 2 diabetes, CVD, chronic kidney disease, and other cardiometabolic risk factors[54–55]. Dynamic changes in the FIB-4 index may help predict the progression of liver fibrosis, facilitating individualized risk stratification for long-term liver-related events and mortality[52,56]. The FIB-4 index also demonstrates good specificity and negative predictive value for excluding advanced liver fibrosis[56]. FibroScan® is a non-invasive ultrasound-based technology that liver stiffness measurement (LSM) and liver fat attenuation (controlled attenuation parameter, [CAP])[57], which are used to assess the degree of liver fibrosis and steatosis[58]. Current hepatology and diabetes guidelines emphasize case-finding strategies for MAFLD/MASLD with liver fibrosis, especially in individuals with type 2 diabetes or obesity[59–60]. Recent clinical practice guidelines from the American Association for the Study of Liver Diseases (AASLD), the American Diabetes Association (ADA), and the European Association for the Study of Liver (EASL)–European Association for the Study of Diabetes (EASD)–European Association for the Study of Obesity (EASO) scientific societies strongly recommend a stepwise approach, beginning with the FIB-4 index, followed by imaging techniques like FibroScan® to rule in or rule out advanced liver fibrosis[59–61].

LIFESTYLE MODIFICATIONS AND PHARMACOLOGICAL INTERVENTIONS BENEFICIAL FOR MAFLD/MASLD AND CVD

Lifestyle modifications, including a hypocaloric diet, regular exercise, and weight management, play a critical role in managing both MAFLD/MASLD and CVD, and in reducing associated risks[62–65]. Weight-loss strategies that significantly reduce body weight and maintain it long-term have shown promise in alleviating both conditions[66]. Specifically, a weight loss of ≥10% can lead to histological improvements in metabolic-associated steatohepatitis (MASH) and liver fibrosis. A more modest weight reduction of 5% to 10% can improve hepatic steatosis and necroinflammation, though it does not appear to significantly affect fibrosis[67]. Based on this evidence, current MAFLD/MASLD management guidelines strongly recommend a ≥5% weight loss for most patients, regardless of their initial body weight[68–69]. For patients with morbid obesity, bariatric surgery is an effective treatment for MAFLD/MASLD, including cirrhosis[68–69]. Moreover, evidence suggests that weight loss surgery in patients with morbid obesity and chronic heart failure can enhance heart transplantation success rates[70] and, in some cases, may even eliminate the need for a transplant altogether[71–72].

Emerging evidence also indicates that newer glucose-lowering medications may help slow the progression of MAFLD/MASLD[73]. Sodium-dependent glucose transporters 2 (SGLT-2) inhibitors, which lower blood glucose by preventing renal glucose reabsorption[74], have shown early promise in improving liver tissue characteristics in MAFLD/MASLD[75]. Although SGLT-2 inhibitors are not yet recommended specifically for treating MAFLD/MASLD in patients with type 2 diabetes, accumulating studies suggest that these drugs have beneficial extrahepatic effects, including significant reductions in cardiovascular and renal outcomes, as well as fewer hospitalizations for heart failure[76]. Glucagon-like peptide-1 (GLP-1) receptor agonists, which improve insulin resistance and reduce body weight (on average 3–5 kg)[77–79], are not currently indicated for MASH treatment, but they have demonstrated benefits in patients with type 2 diabetes by lowering the risk of cardiovascular mortality and hospitalizations[80–82]. These medications may offer valuable treatment options for patients with both MAFLD/MASLD and CVD. Additionally, statins and renin-angiotensin-aldosterone system (RAAS) inhibitors, commonly prescribed for atherosclerotic CVD and heart failure, are safe for patients with or without MAFLD/MASLD, despite the lack of clear evidence for their liver-specific benefits in MASH[69,83–85]. However, recent studies suggest that statin use may be associated with a slower progression of LSM, reduced all-cause mortality, and a lower incidence of liver-related outcomes in patients with MASLD[85].

OPTIMIZING SYNERGISTIC MANAGEMENT STRATEGIES FOR CVD AND MAFLD/MASLD

Effective management of patients with coexisting CVD and MAFLD/MASLD requires a holistic, interdisciplinary approach[23]. Cardiologists are increasingly incorporating interventions for MAFLD/MASLD into their treatment protocols, while also contributing to research exploring the connection between liver disease and CVD. Hepatologists play a crucial role in assessing liver disease risks and managing liver-related complications, while cardiologists, endocrinologists, and nutrition specialists focus on addressing cardiometabolic risk factors through coordinated weight management, lifestyle modifications, and the treatment of metabolic abnormalities, including obesity, dysglycemia, hypertension, and dyslipidemia. The goal is to reduce liver fat accumulation, manage conditions such as MASH and liver fibrosis, optimize liver health, and improve cardiometabolic outcomes. Close collaboration among these specialists ensures a comprehensive patient assessment, individualized treatment strategies, and streamlined care pathways, supported by multidisciplinary coordination and patient education.

FUTURE DIRECTIONS

Future research should focus on advancing our understanding of the pathophysiological mechanisms linking MAFLD/MASLD and CVD. Well-designed prospective studies are needed to clarify how specific metabolic risk factors, such as insulin resistance and atherogenic dyslipidemia, contribute to CVD outcomes in patients with MAFLD/MASLD. Biomarker discovery and validation efforts should prioritize identifying novel biomarkers that can predict CVD risk in this population. Additionally, there is an urgent need to develop evidence-based guidelines specifically tailored to the management of MAFLD/MASLD and its impact on CVD. Updated guidelines, incorporating diagnostic criteria, risk assessment algorithms, and treatment recommendations that reflect the complex cardiovascular-liver-metabolic interactions, will require continuous education and collaboration across medical specialties to ensure optimal patient care and outcomes. The evolution of clinical guidelines that integrate MAFLD/MASLD considerations could standardize approaches to diagnosis, risk assessment, and management within cardiovascular practice.

CONCLUSION

The recent shift in nomenclature from NAFLD to MAFLD/MASLD marks an important step toward aligning liver disease diagnosis with metabolic abnormalities. Cardiologists are increasingly recognizing MAFLD/MASLD not only as a liver disease but also as a significant risk factor for CVD, which remains the leading cause of death in this patient population. By incorporating routine screening for liver disease into cardiovascular assessments and embracing a multidisciplinary approach to patient care, clinicians can improve early detection, risk stratification, and management of these interconnected conditions. Adopting these new paradigms and fostering collaboration across specialties will ultimately improve patient outcomes and ensure comprehensive management of individuals with MAFLD/MASLD and cardiovascular comorbidities.

FUNDING

CDB is supported in part by the Southampton National Institute for Health and Care Research (NIHR) Biomedical Research Centre (No. NIHR203319).

AUTHOR CONTRIBUTIONS

XDZ and MHZ designed the study. XDZ drafted the manuscript. XDZ and LLC prepared the figures. XDZ, GT, CDB, MDS, and MHZ contributed to writing and proofreading the manuscript. All authors contributed to the manuscript for important intellectual content and approved the submission.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest with regard to the content of this manuscript.

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

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Keywords:

Non-alcoholic fatty liver disease; Cardiology; Hepatology; Cardiovascular disease