MAFLD: Diagnostic Criteria and Initial Management
Understanding the Terminology
MAFLD (Metabolic dysfunction-Associated Fatty Liver Disease) has been replaced by the newer term MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease) in current international guidelines, though both refer to the same condition. 1 The key distinction is that MAFLD/MASLD uses positive diagnostic criteria rather than exclusion criteria, meaning you no longer need to rule out other liver diseases or quantify alcohol intake below specific thresholds to make the diagnosis. 2, 3
Diagnostic Criteria
Core Requirements (Both Must Be Present)
1. Evidence of Hepatic Steatosis 2, 4
- Ultrasound, CT, or MRI are acceptable first-line imaging modalities 2
- Controlled attenuation parameter (CAP) via FibroScan or MRI-proton density fat fraction (MRI-PDFF) provide quantitative assessment 2
- Liver biopsy remains the gold standard but is reserved for cases where it is performed for other clinical indications 2
2. At Least One Cardiometabolic Risk Factor 1, 2
Choose from three pathways:
Pathway A: Overweight or obesity (BMI ≥25 kg/m² in Caucasians, ≥23 kg/m² in Asians) 2
Pathway B: Type 2 diabetes mellitus 2
Pathway C: Evidence of metabolic dysregulation, defined as ≥2 of the following: 2
- Elevated waist circumference (≥94 cm in men, ≥80 cm in women for Caucasians)
- Elevated blood pressure (≥130/85 mmHg or on antihypertensive therapy)
- Elevated fasting triglycerides (≥150 mg/dL or on lipid-lowering therapy)
- Low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women)
- Prediabetes (fasting glucose 100–125 mg/dL or HbA1c 5.7–6.4%)
- Insulin resistance (HOMA-IR ≥2.5)
Critical Distinction from Prior Terminology
Unlike NAFLD, MAFLD/MASLD does NOT require: 2, 3
- Exclusion of concurrent alcohol consumption (unless meeting criteria for alcohol-associated liver disease: >50 g/day in females, >60 g/day in males) 5
- Exclusion of other coexisting liver diseases such as viral hepatitis or iron overload 2
Initial Risk Stratification for Fibrosis
Step 1: Calculate FIB-4 Score 6, 2, 4
FIB-4 = (Age × AST) / (Platelet count × √ALT)
Interpretation: 4
- **FIB-4 <1.3:** Low risk of advanced fibrosis (>95% negative predictive value); monitor every 3 years 4
- FIB-4 1.3–2.7: Indeterminate risk; proceed to Step 2 4
- FIB-4 >2.7: High risk of advanced fibrosis; refer to hepatology 4
Step 2: Confirmatory Testing for Indeterminate FIB-4 2, 4
- Vibration-controlled transient elastography (VCTE/FibroScan) is the preferred second-line test 2
- MR elastography is less affected by severe obesity and provides reliable fibrosis assessment 6
- Proprietary blood-based scores (Enhanced Liver Fibrosis score, FibroTest) can supplement staging 6
Fibrosis stage ≥F2 identifies patients at risk for liver-related outcomes and determines eligibility for pharmacotherapy. 6
Essential Comorbidity Assessment at Diagnosis 1, 2
Perform the following laboratory tests and evaluations:
- Metabolic panel: Fasting glucose, HbA1c, lipid panel (triglycerides, HDL, LDL), liver enzymes (AST, ALT, GGT, alkaline phosphatase) 1
- Renal function: Creatinine, eGFR 2
- Exclude other liver diseases: Hepatitis B surface antigen, hepatitis C antibody, ferritin and transferrin saturation (to rule out iron overload) 4
- Cardiovascular risk: Calculate 10-year cardiovascular risk score 2
- Screen for: Obstructive sleep apnea, polycystic ovary syndrome (in women), chronic kidney disease 1, 2
Initial Management: Lifestyle Foundations for All Patients
Weight Loss Targets 6
- 5% body weight reduction reduces hepatic steatosis 6
- 7–10% body weight reduction leads to MASH resolution and fibrosis regression 6
Dietary Pattern 6
Adopt a Mediterranean diet: 6
- Emphasize vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, unprocessed fish or poultry
- Completely eliminate sugar-sweetened beverages 6
- Minimize ultra-processed foods high in sugars and saturated fats 6
Physical Activity 6
- ≥150 minutes/week of moderate-intensity aerobic activity (e.g., brisk walking) 6
- OR ≥75 minutes/week of vigorous-intensity activity (e.g., running) 6
Alcohol Avoidance 6
- Advise complete alcohol avoidance, especially in patients with advanced fibrosis or cirrhosis 6
Pharmacologic Management: Non-Cirrhotic Disease
MASH-Targeted Therapy (Fibrosis Stage F2–F3) 6
Resmetirom is the first FDA-conditionally approved agent (March 2024) for adults with non-cirrhotic MASH and moderate-to-advanced fibrosis (F2/F3). 6 Phase III data demonstrate superior histologic resolution of steatohepatitis and fibrosis with an acceptable safety profile. 1, 6
Key safety monitoring: 6
- Measure liver enzymes at 12 weeks to detect drug-induced liver injury 6
- Educate patients about gallbladder complications (cholelithiasis, acute cholecystitis); report abdominal pain, nausea, vomiting, or fever 6
- Statin dose limits during resmetirom therapy: rosuvastatin or simvastatin ≤20 mg/day; pravastatin or atorvastatin ≤40 mg/day 6
Dual-Benefit Therapies for Comorbid Diabetes or Obesity 6
GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and GLP-1/GIP co-agonist tirzepatide are preferred first-line agents in non-cirrhotic MASH, providing glycemic control plus hepatic benefit. 6 Semaglutide has received FDA conditional approval for MASH with moderate-to-advanced fibrosis. 6, 7
SGLT2 inhibitors (empagliflozin, dapagliflozin) are alternative options showing moderate reductions in liver fat and serum ALT. 6
Metformin should be continued in patients with compensated cirrhosis (if eGFR >30 mL/min) because discontinuation may increase mortality; however, metformin alone does not improve MASH histology. 6
Non-incretin weight-loss drugs (orlistat, phentermine-topiramate, naltrexone-bupropion) are NOT recommended due to inconclusive efficacy data. 6
Pharmacologic Management: Cirrhotic Disease 1, 6
- No MASH-targeted pharmacotherapy is currently recommended for patients with cirrhosis 1, 6
- Metformin may be used in compensated cirrhosis if eGFR >30 mL/min; it is contraindicated in decompensated disease 6
- Insulin is the preferred glucose-lowering agent in decompensated cirrhosis 6
- GLP-1 agonists and SGLT2 inhibitors can be used cautiously in compensated cirrhosis with close monitoring 6
Bariatric Surgery 6
Bariatric surgery is indicated for non-cirrhotic MASLD patients with BMI >40 kg/m² or BMI >35 kg/m² plus comorbidities; it yields durable liver improvement, diabetes remission, and better cardiometabolic risk profiles. 6, 7 In compensated cirrhosis, bariatric surgery may be considered after multidisciplinary assessment for portal hypertension. 6
Monitoring and Surveillance
Non-Cirrhotic Patients 4
- Repeat FIB-4 at least every 3 years in patients with low-risk scores (<1.3) 4
- Monitor weight, BMI, and/or waist circumference at least annually 4
- Screen for emergence of type 2 diabetes (in individuals without) at least annually 4
Cirrhotic Patients 1, 6
- Hepatocellular carcinoma surveillance with ultrasound ± alpha-fetoprotein every 6 months 1
- Surveillance for portal hypertension (esophageal varices screening) 1, 6
- Nutritional counseling to prevent sarcopenia; provide high-protein diet (1.2–1.5 g/kg/day) with total calories ≥35 kcal/kg/day 6
- Evaluate for liver transplantation in decompensated cirrhosis 1, 6
Common Pitfalls to Avoid
- Do NOT impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss 6
- Do NOT prescribe metformin in decompensated cirrhosis or when eGFR <30 mL/min due to lactic acidosis risk 6
- Do NOT withhold statins solely because of liver disease; they remain safe and cardioprotective 6
- Do NOT rely solely on patient self-report for alcohol consumption; use validated questionnaires (AUDIT-C) and biomarkers when available 5
- Ultrasound alone cannot rule out cirrhosis; use FIB-4, elastography, or MR elastography for definitive fibrosis staging 6