MASH and MASLD

Kimberly Schuster

Background

  • Affects 30-40% of adults; >60% with T2DM. 
  • Can occur in patients with normal BMI (“lean MASLD”). 
  • Leading cause of liver transplantation in American women.

Definitions

  • Metabolic dysfunction-associated steatotic liver disease (MASLD): hepatic steatosis (>5% of hepatocytes) without secondary cause, plus ≥1 cardiometabolic criterion (overweight/obesity or elevated waist circumference, T2DM/prediabetes, hypertension, or dyslipidemia). 
  • Metabolic dysfunction-associated steatohepatitis (MASH): Hepatic steatosis + inflammation + hepatocellular injury ± fibrosis. Strongly associated with metabolic syndrome, T2DM, HTN, obesity 
  • Metabolic and alcohol related/associated liver disease (MetALD): MASLD + moderate alcohol use. Alcohol synergistically worsens injury. 
  • MASH cirrhosis: cirrhosis with current or prior histologic/clinical evidence of steatosis or steatohepatitis.

Presentation/Evaluation

  • Typically asymptomatic; found incidentally. ~70% have normal LFTs. When elevated, 2-5x ULN with ALT>AST. Does not cause RUQ pain. 
  • Workup: Exclude alternative causes and comorbid liver disease (vital hepatitis, alcohol, autoimmune, iron overload). Obtain LFTs, CBC, INR, viral hepatitis serologies, metabolic panel, HbA1c, lipid panel. If LFTs elevated, add iron studies, autoimmune markers, and A1AT level. 
    • Imaging: Ultrasound is first-line for steatosis but insensitive at mild disease. FibroScan (VCTE) is preferred for fibrosis assessment (in those with BMI <35). MRI-PDFF is most accurate for fat quantification but costly (Preferred in patients with BMI of 35 or higher). 
    • Fibrosis evaluation: 
    • Fibrosis stage (≥F3) drives morbidity and mortality and may be present with normal LFTs. All patients with suspected MASLD should undergo risk stratification using a two-step approach (FIB-4 followed by elastography). Low-risk patients may be followed in primary care; intermediate/high-risk results warrant hepatology referral. See NIT chapter for algorithm.

Management

  • Lifestyle (first-line for all patients): 
    • Mediterranean- style diet 
    • ≥5% weight loss improves steatosis, ≥10% may improve inflammation and fibrosis
    • Avoid alcohol. 
    • Increased coffee intake associated with less progression. 
  • Cardiometabolic Risk Optimization: Aggressively treat HLD, HTN, T2DM, obesity. 
  • FDA-Approved Therapies for Noncirrhotic MASH (F2-F3): 
    • Resmetiron (Rezdiffra): THR-b agonist; approved 03/2024. Histologic improvement in steatohepatitis and fibrosis. Biopsy not required; NITs acceptable for eligibility. 
    • Semaglutide 2.4mg weekly (Wegovy): GLP-1 receptor agonist; approved 08/2025. 
  • Diabetes/Obesity Medications with Liver Benefit: 
    • Tirzepatide, SLGT2 inhibitors, and pioglitazone may improve steatosis and are reasonable in patients with T2DM/obesity but are not FDA-approved for MASH. 
  • Limited/Selective Use: 
    • Statins are safe in MASLD and compensated cirrhosis. 
    • Vitamin E 800 IU/day: consider only in biopsy-proven MASH (F2+), avoid in T2DM or cirrhosis (or male patients due to association with prostate ca), safety concerns limit routine use. 
  • Not recommended: Metformin, DPP4 inhibitors, UDCA, omega-3-fatty acids do not improve fibrosis.
  • Bariatric/Metabolic Surgery: Most effective long-term intervention for eligible patients (consider referral for BMI>40 or >35 with comorbidities). Consider general weight loss center referral in those with BMI >30. 
  • Preventive Care: Vaccinate against HAV/HBV and Screen for cardiovascular disease (leading cause of death).
  • Pipeline: FGF21 agonists, GLP-1/glucagon dual agonist, PPAR agonists
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