Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD
Abstract
:1. Introduction
2. The Old and the New: From NAFLD to MASLD Definitions
3. Conditions Associated with NAFLD
3.1. Definitions of MetS and Its Components Intertwined with NAFLD
3.1.1. Overweight/Obesity and Their Association with NAFLD
3.1.2. Diabetes and Its Association with NAFLD
3.1.3. HTN and Its Association with NAFLD
3.1.4. Dyslipidemia and Its Association with NAFLD
3.2. Cardiovascular Disease and Its Association with NAFLD
3.3. Other Clinical Conditions and Their Association with NAFLD
4. Diagnosis and Screening of MASLD
5. Management of MASLD
5.1. Primary Prevention
5.2. Treatment of MASLD
5.3. Secondary Prevention of CVD
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | Non-Alcoholic Fatty Liver Disease (NAFLD) | Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) | Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) |
---|---|---|---|
Hepatic steatosis > 5% assessed by liver histology or imaging techniques | ✔ | ✔ | ✔ |
Hepatic steatosis > 5% assessed through blood biomarkers/scores | X | ✔ | X |
Absence of significant alcohol consumption (≥30 g/day in men, ≥20 g/day in women) | ✔ | X | ✔ |
Exclusion of other causes of steatosis | ✔ | X | ✔ |
Presence of a cardiometabolic criteria (metabolic dysfunction) | X | ✔ | ✔ |
1. Overweight/Obesity (BMI ≥ 25 kg/m2 in Caucasians [23 kg/m2 in Asians]) 2. T2D (Based on widely recognized international guidelines) 3. Lean/normal weight (BMI < 25 kg/m2 in Caucasians or BMI < 23 kg/m2 in Asians) if present at least two metabolic abnormalities: A—WC ≥ 102 cm (M), ≥88 cm (F) in Caucasians (or ≥90 cm (M), ≥88 cm (F) in Asians B—Plasma HDL–C ≤ 40 mg/dL [1 mmol/L] (M) and ≤50 mg/dL [1.3 mmol/L] (F) OR lipid-lowering treatment C—Plasma TG ≥ 150 mg/dL [1.70 mmol/L] OR lipid-lowering treatment D—BP ≥ 130/85 mmHg OR specific antihypertensive drug treatment E—Prediabetes (Fasting Serum Glucose ≥ 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/L] OR HbA1c ≥ 5.7 to 6.4% [39 to 47 mmol/mol]) F—Homeostasis model assessment of insulin resistance score ≥ 2.5 G—Plasma high sensitivity C-reactive protein level > 2 mg/L | BMI ≥ 25 kg/m2 [23 kg/m2 in Asians] OR WC > 94 cm (M) 80 cm (F) OR ethnicity adjusted measurements Fasting Serum Glucose ≥ 100 mg/dL [5.6 mmol/L] OR 2 h post-load glucose levels ≥ 140 mg/dL [7.8 mmol/L] OR HbA1c ≥ 5.7% [39 mmol/mol] OR T2D OR treatment for T2D Plasma HDL–cholesterol ≤ 40 mg/dL [1 mmol/L] (M) and ≤50 mg/dL [1.3 mmol/L] (F) OR lipid-lowering treatment Plasma TG ≥ 150 mg/dL [1.70 mmol/L] OR lipid-lowering treatment BP ≥ 130/85 mmHg OR specific antihypertensive drug treatment | ||
Embraces the concept of a multifactorial aetiology | X | ✔ | ✔ |
National Cholesterol Education Program/Adult Treatment Panel III | International Diabetes Federation | Unifying Metabolic Syndrome Statement | |
---|---|---|---|
Criteria | At least 3 of the following criteria | Central obesity, plus at least 2 of the following criteria | At least 3 of the following criteria |
Waist Circumference/Obesity | |||
Abdominal obesity a Men ≥ 102 cm (40 in) Women ≥ 88 cm (35 in) | Central Obesity * WC—ethnicity specific: a. Europids, Sub-Saharan Africans, Middle East, Eastern Mediterranean ≥94 cm (M), ≥80 cm (F) b. South Asians, Chinese, Ethnic central and South Americans ≥90 cm (M), ≥80 cm (F) c. Japanese ≥85 cm (M), ≥90 cm (F) | Elevated WC ** Population specific and country specific definitions | |
Fasting plasma glucose | |||
≥100 mg/dL (5.6 mmol/L) | ✔ b | ✔ | ✔ |
Or | |||
prior T2D diagnosis | X | ✔ | X |
Or | |||
pharmacological therapy for high glucose | X | X | ✔ |
High-density lipoprotein cholesterol | |||
Men < 40 mg/dL (1.04 mmol/L) Women < 50 mg/dL (1.30 mmol/L) | ✔ | ✔ | ✔ |
Or | |||
Targeted therapy for this lipid disorder | X | ✔ | ✔ |
Triglycerides | |||
≥150 mg/dL (1.7 mmol/L) | ✔ | ✔ | ✔ |
Or | |||
Targeted therapy for this lipid disorder | X | ✔ | ✔ |
Blood Pressure | |||
SBP ≥ 130 mmHg | ✔ | ✔ | ✔ |
Or | |||
DBP ≥ 85 mmHg | ✔ | ✔ | ✔ |
Or | |||
Treatment for HTN | X | ✔ | ✔ |
Test | Advantages | Disadvantages |
Fibrosis index based on 4 factors (FIB-4) score FIB-4 score = age (years) × AST (U/L)/(platelet count (109/L) × √ALT (U/L) | -Easy to calculate -Commonly measured parameters -Widely validated -Cost-effective -Good alternative for initial screening | -Reduced accuracy in specific populations (individuals under 35 years of age, those over 65, people with significant alcohol consumption, and patients with other underlying liver conditions). -No information on aetiology -Not perfect for early-stage fibrosis -Accuracy influenced by coexisting conditions |
NAFLD fibrosis score (NFS) NFS = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × impaired fasting glucose/diabetes (yes = 1, no = 0) + 0.99 × (AST/ALT ratio) − 0.013 × platelet count (×109/L) − 0.66 × albumin (g/dL) | -Easy to calculate -Commonly measured parameters -Widely validated -Cost-effective -Good alternative for initial screening | -Reduced accuracy in specific populations (individuals with very high or very low BMI, significant alcohol consumption, or other underlying liver diseases). -No information on aetiology -Not perfect for early-stage fibrosis -Accuracy can be influenced by coexisting conditions -Requires multiple variables |
Enhanced liver fibrosis (ELF) score ELF score = 2.278 + 0.851 ln (hyaluronic acid) + 0.751 ln (PIIINP) + 0.394 ln (TIMP-1) | -Widely validated -High accuracy for detecting fibrosis | -Cost -No information on aetiology -Not perfect for early-stage fibrosis -Accuracy affected by coexisting conditions (obesity, diabetes, kidney disease) -Limited availability |
Liver Stiffness Measurement-Vibration Controlled Transient Elastography Liver (LSM- VCTE) [FibroScan] It assesses liver stiffness using ultrasound-based elastography (e.g., FibroScan), with values measured in kilopascals (kPa), and liver steatosis using the Controlled Attenuation Parameter (CAP), with values measured in decibels per meter (dB/m). | -Widely validated -High accuracy for detecting fibrosis -Quick and easy with real-time results | -Cost -No information on aetiology -Not perfect for early-stage fibrosis -Accuracy can be impacted by coexisting conditions, such as obesity, ascites, liver congestion, and others. -Possible operator dependence -Limited availability |
FibroScan-AST (FAST) score FAST = VCTE [Liver Stiffness Measurement (LSM), Controlled Attenuation Parameter (CAP)] + AST FAST score = e−1.65 + 1.07 × ln (LSM) + 2.66*10−8 × CAP3 − 63.3 × AST−1/1 + e−1.65 + 1.07 × ln (LSM) + 2.66*10−8 × CAP3 − 63.3 × AST−1 | -Widely validated -Enhanced accuracy for detecting fibrosis -Quick and easy | -Cost -No information on aetiology -Not perfect for early-stage fibrosis -Accuracy can be impacted by coexisting conditions, such as obesity, ascites, liver congestion, and others. -Possible operator dependence -Limited availability |
Magnetic resonance imaging (MRI), MRI proton density fat fraction (MRI-PDFF) measures liver steatosis Magnetic resonance elastography (MRE) (Standard MRI machines utilizing a phase contrast technique, along with specialized software, to evaluate liver stiffness by analysing the propagation of mechanical waves through the liver tissue. MRI-iron-corrected T1 mapping (cT1) | -Widely validated -Highly accurate for detecting fibrosis -Better for heterogeneous liver disease -Provides detailed imaging of the entire liver -Can be combined with other parameters (MAST = MRE + MRI-PDFF + AST; MEFIB = MRE + FIB-4) | -Cost -No information on aetiology -Requires specialized equipment and expertise -Limited availability |
Area | Past | Present | Future |
---|---|---|---|
Treatment | Lifestyle Modifications Management of MetS components, comorbidities, and cardiovascular disease. | Lifestyle Modifications Stronger emphasis on managing MetS components with preferred pharmacologic treatments, addressing comorbidities, and implementing an integrated approach to cardiovascular risk. | Lifestyle Modifications Stronger emphasis on managing MetS components with personalized pharmacologic treatments, addressing comorbidities, and implementing an integrated approach to cardiovascular risk. |
No specific drug approved | Resmetirom (Only in US) | Resmetiron (global use) Potential approval of new drugs, including Semaglutide, Tirzepatide, Survodutide, Retatrutide, Efruxifermin, Pegozafermin, and Lanifibranor. Combination therapy Specific treatments for individuals with MASH- related cirrhosis | |
Bariatric surgery Liver transplantation | Bariatric surgery Liver transplantation | Bariatric surgery Liver transplantation |
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Pecani, M.; Andreozzi, P.; Cangemi, R.; Corica, B.; Miglionico, M.; Romiti, G.F.; Stefanini, L.; Raparelli, V.; Basili, S. Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD. J. Clin. Med. 2025, 14, 2750. https://doi.org/10.3390/jcm14082750
Pecani M, Andreozzi P, Cangemi R, Corica B, Miglionico M, Romiti GF, Stefanini L, Raparelli V, Basili S. Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD. Journal of Clinical Medicine. 2025; 14(8):2750. https://doi.org/10.3390/jcm14082750
Chicago/Turabian StylePecani, Marin, Paola Andreozzi, Roberto Cangemi, Bernadette Corica, Marzia Miglionico, Giulio Francesco Romiti, Lucia Stefanini, Valeria Raparelli, and Stefania Basili. 2025. "Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD" Journal of Clinical Medicine 14, no. 8: 2750. https://doi.org/10.3390/jcm14082750
APA StylePecani, M., Andreozzi, P., Cangemi, R., Corica, B., Miglionico, M., Romiti, G. F., Stefanini, L., Raparelli, V., & Basili, S. (2025). Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD. Journal of Clinical Medicine, 14(8), 2750. https://doi.org/10.3390/jcm14082750