MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) - Summary Notes

• EASL-EASD-EASO Clinical Practice Guidelines, J Hepatol 2024;81:492-542
• AASLD Practice Guidance updates: 2023 base + November 2025 semaglutide update (Hepatology 2026)
• Japanese Evidence-Based CPG 2026, J Gastroenterol 2026
• CAR (Canadian) MASLD Working Group 2026, 3-part imaging guidance

1. Nomenclature & Definition (2023 Consensus)

• NAFLD is now MASLD - the term was renamed in 2023 by international consensus to reflect metabolic pathophysiology rather than a diagnosis of exclusion.
• MASLD = steatotic liver disease (SLD) with hepatic steatosis affecting ≥5% of hepatocytes (by imaging or histology) PLUS at least one cardiometabolic risk factor (CMRF):
  • Overweight/obesity (BMI ≥25 or waist circumference criteria)
  • Type 2 diabetes or prediabetes
  • Hypertension
  • Dyslipidemia
  • Insulin resistance
• Alcohol limits: <20 g/day in women, <30 g/day in men
• Other causes of hepatic steatosis must be excluded
• MASH (metabolic dysfunction-associated steatohepatitis) = prior NASH; defined by steatosis + hepatocellular injury + inflammation ± fibrosis on biopsy
• MetALD = a new subcategory for those who meet MASLD criteria but drink beyond the alcohol threshold

2. Epidemiology

• MASLD is now the most prevalent chronic liver disease worldwide
• Global prevalence estimated at ~32% of the general population
• MASH (the progressive form) affects ~20-30% of MASLD patients
• Major cause of cirrhosis, HCC, and liver transplant listing globally
• Strong association with cardiovascular disease - CVD is the leading cause of death in MASLD patients, not liver disease

3. Diagnosis

Hepatic Steatosis

• Ultrasound: first-line; widely available, but operator-dependent, limited at low steatosis grades
• Controlled Attenuation Parameter (CAP) on FibroScan: better quantification of steatosis
• MRI-PDFF: most accurate noninvasive quantification (gold standard imaging)
• Liver biopsy: not required for steatosis diagnosis; reserved for cases where etiology is uncertain

Fibrosis Assessment (Key Prognostic Factor)

• FIB-4 index = Age × AST / (Platelet × √ALT)
  • <1.30: low risk - no further testing needed
  • 1.30-2.67: indeterminate - proceed to Step 2
  • >2.67: high risk - refer to hepatologist
• NFS (NAFLD Fibrosis Score) or APRI: alternative first-step tools
• Platelet count: <150,000/mm³ suggests advanced disease

• VCTE (FibroScan): validated cutoffs:
  • ≥F2: ~8 kPa (rule-out) to ~12 kPa (rule-in)
  • ≥F3: 8 kPa (rule-out), 12 kPa (rule-in)
  • F4/Cirrhosis: >15 kPa
  • 2025 update: FDA accepted FibroScan as reasonable biopsy alternative in noncirrhotic MASH clinical trials
• MRE (MR Elastography): most accurate; F2-F3 range 3.1-4.4 kPa; F4 >5.0 kPa
• ELF (Enhanced Liver Fibrosis) score: 9.2-10.5 for F2-F3

• Indications: resolving discrepancies between NITs, differentiating MASLD from other chronic liver diseases, assessing inflammatory activity when pharmacotherapy is being considered

4. Risk Stratification for "At-Risk MASH"

• Primary NIT pathway: FIB-4 → VCTE or MRE → biopsy only if needed
• Patients with VCTE 8-15 kPa, MRE 3.1-4.4 kPa, or ELF 9.2-10.5 are candidates for pharmacotherapy
• Refer to gastroenterologist/hepatologist if:
  • Elevated fibrosis markers or disease progression
  • Intermediate FIB-4 with low platelet count
  • Persistently elevated AST or ALT

5. Management

A. Lifestyle Modification (Cornerstone of All Stages)

• Weight loss is the most effective treatment:
  • ≥5% body weight loss: improves steatosis
  • ≥7-10% loss: improves MASH histology (inflammation, ballooning)
  • ≥10% loss: can lead to fibrosis regression
• Diet: Mediterranean diet is recommended; reduces steatosis and fibrosis risk
• Physical activity: ≥150 min/week moderate-intensity aerobic exercise; resistance training is also beneficial
• Alcohol: complete avoidance recommended in MASH/advanced fibrosis; strict limits in MASLD
• Fructose/ultra-processed food avoidance: strongly recommended
• Caloric restriction 500-1000 kcal/day deficit typically used

B. Pharmacotherapy (2024-2026 Approved/Recommended)

1. Resmetirom (Rezdiffra) - First-ever FDA-approved drug for MASH (March 2024)

• Thyroid hormone receptor-β (THR-β) selective agonist
• Indication: MASH with moderate-to-advanced fibrosis (F2-F3)
• Dose: 80 mg/day (BMI <35) or 100 mg/day (BMI ≥35), oral
• MAESTRO-NASH trial: significant histologic improvement vs. placebo in MASH resolution and fibrosis improvement
• Also improves lipid profile (reduces LDL, ApoB, triglycerides)
• Contraindicated in cirrhosis (F4), pregnancy

2. Semaglutide (Wegovy) - FDA Accelerated Approval August 2025 for MASH

• GLP-1 receptor agonist
• Indication: MASH with moderate-to-advanced fibrosis (F2-F3)
• Dose: 2.4 mg/week SC (same as obesity indication)
• ESSENCE Phase 3 Trial (72 weeks):
  • MASH resolution without fibrosis worsening: 62.9% vs. 34.3% placebo (p<0.001)
  • ≥1 stage fibrosis reduction without MASH worsening: 36.8% vs. 22.4% placebo (p<0.001)
• AASLD November 2025 guidance: prefer NIT-based patient selection (VCTE, MRE, ELF) over biopsy
• Not approved for MASH cirrhosis (F4); use with caution in compensated cirrhosis if given for another indication
• Monitor: GI side effects (nausea, diarrhea - usually transient), gallbladder disease, pancreatitis, AKI (from dehydration), thyroid C-cell tumors, retinopathy, lean mass loss

3. Pioglitazone (Thiazolidinedione)

• Recommended in patients with MASH + type 2 diabetes or prediabetes (AASLD, EASL)
• Improves MASH histology (steatosis, inflammation, ballooning)
• Dose: 30-45 mg/day
• Concerns: weight gain, fluid retention, risk of heart failure, osteoporosis with long-term use

4. Vitamin E

• Recommended for non-diabetic adults with biopsy-confirmed MASH
• Dose: 800 IU/day
• Improves steatosis and inflammation but no fibrosis benefit
• Not recommended in diabetics, men with high prostate cancer risk, or with significant cardiovascular disease

5. SGLT2 Inhibitors (e.g., empagliflozin, dapagliflozin)

• Beneficial in MASLD patients with type 2 diabetes
• Evidence supports reduction in steatosis, liver enzymes
• Guideline-endorsed for metabolic comorbidity management; not yet primary MASH therapy

6. GLP-1/GIP Dual Agonist (Tirzepatide - Mounjaro/Zepbound)

• Phase 3 trials (SYNERGY-NASH) showing strong histologic improvement
• Expected regulatory approval pending; watch for 2026 updates

C. Bariatric/Metabolic Surgery

• Considered in MASLD patients with obesity and metabolic disease not controlled with lifestyle/pharmacotherapy
• Meta-analysis (2025, PMID 40982201): both RYGB and sleeve gastrectomy improve hepatic steatosis and fibrosis markers
• RYGB generally more effective for fibrosis regression than sleeve gastrectomy
• Can achieve remission of MASH in a significant proportion

D. Managing Comorbidities

• Hypertension: treat per standard guidelines; ARBs/ACEi preferred
• Dyslipidemia: statins are safe and recommended in MASLD (no hepatotoxicity concern at standard doses); reduce cardiovascular risk
• Type 2 diabetes: GLP-1 RAs + SGLT2i are preferred agents (dual metabolic + hepatic benefit)
• Cardiovascular risk: assess and manage aggressively - CVD is the #1 killer in MASLD

6. Screening for Cirrhosis Complications and HCC

• Cirrhosis screening: once F3-F4 established, screen for varices with upper endoscopy
• HCC surveillance: ultrasound ± AFP every 6 months in all cirrhotic MASLD patients
• Note: HCC in MASLD can occur in non-cirrhotic patients with advanced fibrosis - surveillance criteria evolving
• FibroScan LSM >10 kPa associated with increased HCC risk

7. Monitoring Treatment Response (Noninvasive)

• ALT: decrease ≥17 U/L or ≥20% from baseline
• VCTE LSM: decrease ≥30%
• MRE LSM: decrease ≥20%
• ELF: decrease ≥0.5

8. Special Populations

9. Key Recent Updates (2025-2026)

Quick Reference Algorithm

Suspected MASLD
     ↓
1. Confirm steatosis: US/CAP/MRI-PDFF
2. Confirm ≥1 CMRF, exclude alcohol excess and other causes
     ↓
MASLD confirmed → FIB-4 index
     ↓
FIB-4 <1.30      FIB-4 1.30-2.67       FIB-4 >2.67
Low risk         Intermediate             High risk
Lifestyle Rx     ↓                        Refer hepatology
                 VCTE or MRE
                 ↓
         F0-F1: Lifestyle Rx
         F2-F3: Lifestyle Rx +
                Pharmacotherapy
                (Resmetirom OR
                 Semaglutide)
         F4: Refer, manage
             cirrhosis complications