MAFLD Versus NAFLD: Which Better Predicts the Risk of Atherosclerotic Cardiovascular Disease? (original) (raw)

Non-alcoholic fatty liver disease (NAFLD) is a progressive chronic liver disease that if untreated may progress to cirrhosis and the development of its complications including hepatocellular carcinoma (HCC) [1]. With the successful and widely-available treatment of hepatitis C virus (HCV) infection globally combined with an unfortunate booming obesity epidemic, NAFLD has emerged as the leading cause of end-stage liver disease.

Currently, a diagnosis of NAFLD is established if there is evidence of > 5% hepatic steatosis in the absence of secondary causes of hepatic fat accumulation such as alcohol or other known causes of liver disease [2]; Table 1. Nevertheless, several limitations of this disease nomenclature and definition have been recognized, including the observation that fatty liver disease associated with metabolic syndrome can indeed coexist with alcohol-associated or other chronic liver diseases. Moreover, with an improved recognition of the pathophysiology of liver disease driven by metabolic syndrome, and the need to define a disease by what it is, rather than what it is not, consensus groups have proposed a new term and definition: metabolic dysfunction-associated fatty liver disease (MAFLD).

Table 1 Characteristics of MAFLD versus NAFLD

Full size table

The proposed definition of MAFLD is based on the documentation of hepatic steatosis either by liver biopsy, imaging, or blood biomarker, in the presence of one of three coexisting conditions-namely, overweight/obesity, type 2 diabetes mellitus, or other evidence of metabolic dysfunction as listed in Table 1. Metabolic dysfunction is defined as having two or more at-risk criteria for metabolic syndrome [3]. This new definition may then coexist with the patient who has metabolic dysfunction but also consumes alcohol or also has viral hepatitis. The implications of redefining this entity are vast, including gaining an improved understanding of who may develop progressive fatty liver disease in the presence of several risk factors or demographics, creating specific targets for treatment in certain subtypes of fatty liver disease, and appreciating who is at risk for the development of cirrhosis or malignancy.

While there is a push to change the nomenclature of NAFLD, to date there is no consensus on a new definition. Part of the struggle to redefine NAFLD is that the proposed definition for MAFLD does not capture all patients who have hepatic steatosis, as documented example by Lim et al., who found that the proposed definition of MAFLD only captured 81.6% of patients with NAFLD. Others have found that 25% of patients with fatty liver did not fit under the definition of MAFLD or had metabolic dysfunction but still remain at risk for the complications of progressive fatty liver disease [3].

The consequences of this new classification change are significant, and most certainly will have implications for the outcomes of patients with metabolic dysfunction. Specifically, the current literature has established a relationship between the presence of metabolic derangements and an increased risk of atherosclerotic cardiovascular disease (ASCVD). It is hypothesized that using the newer definition of MAFLD may be a superior way to determine risk of ASCVD in patients with fatty liver disease.

In this month’s Digestive Diseases and Sciences, Kim et al. [[4](/article/10.1007/s10620-022-07512-w#ref-CR4 "Kim H. MAFLD predicts the risk of cardiovascular disease better than NAFLD in asymptomatic subjects with health check-ups. Dig Dis Sci. (Epub ahead of print). https://doi.org/10.1007/s10620-022-07508-6

            .")\] describe the results of a retrospective, cross-sectional study in a Korean patient population designed to compare patients who meet the disease definition of MAFLD, with those who met criteria for NAFLD with regard to their predicted risk of atherosclerotic cardiovascular disease (ASCVD). The authors defined MAFLD as the presence of hepatic steatosis with one of the following conditions: overweight/obesity or diabetes mellitus, or at least two manifestations of metabolic dysregulation defined as blood pressure ≥ 130/85 mmHg or requiring specific treatment, waist circumference ≥ 90 cm in men and ≥ 80 cm in woman, triglyceride levels ≥ 150 mg/dL or on specific treatment, HDL cholesterol levels < 40 mg/dL for men, < 50 mg/dL for woman, prediabetes, C-reactive protein (CRP) level > 2 mg/L, and homeostasis model assessment of insulin resistance score ≥ 2.5\. ASCVD risk was determined by a combination of calculating ASCVD score, coronary artery calcium score (CACS), and coronary artery disease quantitative stenosis grade \[[4](/article/10.1007/s10620-022-07512-w#ref-CR4 "Kim H. MAFLD predicts the risk of cardiovascular disease better than NAFLD in asymptomatic subjects with health check-ups. Dig Dis Sci. (Epub ahead of print). 
              https://doi.org/10.1007/s10620-022-07508-6
              
            .")\].

The authors found that of their roughly 2,100 patient cohort, about 47% had fatty liver with 46% and 41% meeting criteria for MAFLD and NAFLD, respectively. Interestingly, about 39% of patients met criteria for both MAFLD and NAFLD. The authors found that patients with either MAFLD or NAFLD had a significantly greater proportion of high CACS, CAD, higher grade of coronary artery stenosis, and 10-year ASCVD risk than those without MAFLD or NAFLD. Importantly, participants who met the criteria for NAFLD alone were not observed to have increased coronary risk compared with those who met criteria for MAFLD. This indicates that the disease definition of MAFLD is superior to NAFLD at identifying patients with hepatic steatosis who are truly at increased risk of cardiovascular outcomes related to metabolic syndrome [[4](/article/10.1007/s10620-022-07512-w#ref-CR4 "Kim H. MAFLD predicts the risk of cardiovascular disease better than NAFLD in asymptomatic subjects with health check-ups. Dig Dis Sci. (Epub ahead of print). https://doi.org/10.1007/s10620-022-07508-6

            .")\].

Nguyen et al. also examined the different patient characteristics and mortality with MAFLD or NAFLD finding that the MAFLD definition identified patients who had a poorer prognosis for cardiovascular disease and all-cause mortality [5]. Kim et al. examined a US patient population and similarly found a 17% higher risk of all-cause mortality as well as higher risk of cardiovascular mortality for those with MAFLD versus NAFLD [6]. The current study by Kim et al. adds to the body of literature supporting the use of MAFLD criteria as a superior way to identify those at risk for ASCVD.

Nevertheless, utilizing a newer nomenclature to define fatty liver disease may also have its limitations. The inclusion of other etiologies of chronic liver disease under the umbrella of MAFLD will most certainly impact a patient’s prognosis [7]. There may be difficulty in understanding the contributions of these other etiologies, such as viral hepatitis or alcohol use disorder in determining a patient’s prognosis or risk of cardiovascular disease. Furthermore, as numerous studies have highlighted, MAFLD fails to capture all patients with hepatic steatosis, excluding patients are still at risk for the development of ASCVD and poor outcomes [[8](/article/10.1007/s10620-022-07512-w#ref-CR8 "Lim GEH, Tang A, Ng CH, Chin YH, Lim WH, Tan DJH, Yong JN, Xiao J, Lee CW, Chan M, Chew NW, Xuan Tan EX, Siddiqui MS, Huang D, Noureddin M, Sanyal AJ, Muthiah MD. An observational data meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD. Clin Gastroenterol Hepatol. 2021. https://doi.org/10.1016/j.cgh.2021.11.038

            .")\].

As the understanding of the driving factors for the development of fatty liver disease advances, it is time for the disease definition to reflect what is present, and not what is lacking. A change in nomenclature is the correct first step in understanding which patients require closer monitoring or a significant intervention. As atherosclerotic cardiovascular disease continues to be the leading cause of death in the developed world, recognizing the contribution of metabolic dysfunction and associated fatty liver disease is essential. Nevertheless, before concrete conclusions can be drawn, further studies are needed to explore the clinical consequences of a change in nomenclature.

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  1. Division of Digestive Health and Liver Diseases, Miami VA Medical Center, University of Miami Miller School of Medicine, University of Miami, 1201 NW 16th Street, Miami, FL, 33125, USA
    Andrew R. Scheinberg & Binu V. John
  2. Department of Gastroenterology and Hepatology, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL, USA
    Andrew R. Scheinberg
  3. Division of Gastroenterology and Hepatology, Miami VA Medical Center, Miami, FL, USA
    Andrew R. Scheinberg & Binu V. John

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  1. Andrew R. Scheinberg
  2. Binu V. John

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Scheinberg, A.R., John, B.V. MAFLD Versus NAFLD: Which Better Predicts the Risk of Atherosclerotic Cardiovascular Disease?.Dig Dis Sci 67, 4606–4608 (2022). https://doi.org/10.1007/s10620-022-07512-w

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