MAFLD vs. NAFLD: Shared Features and Potential Changes in Epidemiology, Pathophysiology, Diagnosis, and Pharmacotherapy
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease globally, posing a significant burden on human health. It is a multifactorial condition influenced by genetic, metabolic, and environmental factors, closely associated with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). Insulin resistance is considered the primary pathophysiological mechanism driving NAFLD. Over the years, research has expanded our understanding of its pathogenesis, diagnosis, and treatment, leading to a reevaluation of its definition and therapeutic strategies. Recently, experts have proposed renaming NAFLD to metabolic (dysfunction) associated fatty liver disease (MAFLD) to better reflect the role of metabolic dysfunction in its development. This article explores the shared features and potential changes in epidemiology, pathophysiology, diagnosis, and pharmacotherapy between MAFLD and NAFLD.
Epidemiology
NAFLD affects approximately 25.24% of the global population, with the highest prevalence in the Middle East and South America. Its incidence has risen in parallel with the increasing prevalence of obesity and T2DM. Diabetic individuals have a three-fold higher risk of developing chronic liver disease, primarily due to NAFLD. In China, the overall prevalence of NAFLD is 29.88%, with higher rates among individuals with T2DM (51.83%) and obesity (66.21%). The prevalence of NAFLD in lean or nonobese individuals is also notable, with 5.1% of the general population having lean NAFLD and 12.1% having nonobese NAFLD.
The redefinition of NAFLD to MAFLD emphasizes metabolic dysfunction and eliminates the need to exclude significant alcohol intake or other chronic liver diseases. This change is expected to increase the prevalence of MAFLD, as it includes individuals with metabolic abnormalities even in the absence of obesity. Additionally, the coexistence of MAFLD with other liver diseases, such as viral hepatitis or alcoholic liver disease (ALD), further contributes to its rising prevalence.
Pathophysiology
The pathogenesis of NAFLD has evolved from the “two-hit” hypothesis to a “multiple-hit” model. The “two-hit” theory proposed that hepatic fat accumulation (first hit) followed by inflammatory cytokines, oxidative stress, and mitochondrial dysfunction (second hit) led to nonalcoholic steatohepatitis (NASH) and fibrosis. However, the “multiple-hit” hypothesis incorporates additional factors, including insulin resistance, lipotoxicity, inflammation, cytokine imbalance, innate immunity activation, and gut microbiota, all influenced by genetic and environmental factors.
Insulin resistance remains central to the development of NAFLD/MAFLD. In T2DM, insulin resistance impairs hepatic glucose metabolism while promoting lipogenesis, leading to hepatic steatosis. Genetic studies have identified several variants associated with NAFLD, including PNPLA3, TM6SF2, GCKR, MBOAT7, and HSD17B13. These genes are also linked to metabolic disorders, supporting the inclusion of metabolic dysfunction in the MAFLD criteria. Interestingly, some genetic variants, such as PNPLA3 and TM6SF2, are associated with both NAFLD and other liver diseases, such as ALD and viral hepatitis, highlighting the interconnectedness of these conditions.
Glucotoxicity and lipotoxicity are key contributors to NAFLD/MAFLD. High-carbohydrate diets and hyperglycemia exacerbate insulin resistance and inflammation, while high-fat diets and dyslipidemia promote hepatic fat accumulation and lipotoxicity. Chronic low-grade inflammation, driven by pro-inflammatory cytokines such as IL-6 and TNF-alpha, further exacerbates insulin resistance and liver damage. These mechanisms underscore the bidirectional relationship between metabolic dysfunction and hepatic steatosis.
Diagnosis
The diagnosis of MAFLD relies on evidence of hepatic steatosis, detected through imaging, blood biomarkers, or liver biopsy. Noninvasive imaging techniques, such as ultrasound, CT, and MRI, are commonly used, though their sensitivity decreases with mild steatosis. Transient elastography (FibroScan) with controlled attenuation parameter (CAP) has gained popularity for simultaneously assessing liver stiffness and steatosis, particularly in T2DM patients. Blood biomarkers, including NAFLD fibrosis score (NFS) and fibrosis-4 index (FIB-4), are useful for excluding advanced fibrosis but are less effective in early-stage detection. Novel serum markers, such as cytokeratin 18 fragment (CK18-F) and miRNAs, show promise for noninvasive screening.
Liver biopsy remains the gold standard for diagnosing NAFLD/MAFLD, particularly for confirming NASH and assessing fibrosis severity. However, its invasiveness, cost, and variability limit its use for widespread screening. Noninvasive methods are preferred for initial assessment, with biopsy reserved for cases requiring definitive diagnosis or staging.
Pharmacotherapy
Currently, no FDA-approved drugs specifically target NASH, the progressive form of NAFLD/MAFLD. Treatment focuses on addressing metabolic dysfunction and preventing disease progression. Insulin sensitizers, such as pioglitazone and metformin, and antioxidants, such as vitamin E, have shown efficacy in improving hepatic steatosis and inflammation. Pioglitazone, a PPAR-gamma agonist, improves insulin sensitivity and liver histology, while vitamin E reduces oxidative stress. However, their long-term use is limited by side effects, including congestive heart failure and hemorrhagic stroke.
Newer antidiabetic agents, such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown promise in treating MAFLD. GLP-1 RAs, including liraglutide and semaglutide, improve glycemic control, promote weight loss, and reduce liver fat. SGLT2 inhibitors, such as empagliflozin, enhance glucose excretion and improve liver histology in T2DM patients with NASH. These drugs also offer cardiovascular benefits, addressing the leading cause of mortality in NAFLD/MAFLD patients.
Statins, traditionally used for lipid-lowering, may reduce the risk of hepatocellular carcinoma (HCC) in diabetic patients with NAFLD. Farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA), have shown efficacy in reducing NASH activity and fibrosis. However, OCA’s side effects, including pruritus and increased LDL cholesterol, necessitate further research into selective FXR modulators.
Conclusion
The redefinition of NAFLD to MAFLD reflects a paradigm shift in understanding fatty liver disease, emphasizing its metabolic underpinnings. The rising prevalence of obesity and T2DM is expected to drive an increase in MAFLD cases globally. The complex interplay of genetic, metabolic, and environmental factors in MAFLD underscores the need for early screening and intervention. While current pharmacotherapy focuses on managing metabolic dysfunction, ongoing research into novel therapeutic targets offers hope for more effective treatments. Addressing MAFLD requires a multifaceted approach, integrating lifestyle modifications, pharmacological interventions, and targeted therapies to improve patient outcomes.
doi.org/10.1097/CM9.0000000000001263
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