Metabolic Dysfunction–Associated Steatotic Liver Disease

Authors, Journal, Affiliations, Type, DOI

• Authors: Giovanni Targher, M.D.; Luca Valenti, M.D.; Christopher D. Byrne, M.B., Ch.B. (contributed equally)
• Journal: New England Journal of Medicine, 2025;393:683–98
• Affiliations: University of Verona / IRCCS Sacro Cuore (Targher); University of Milan / Fondazione IRCCS Ca' Granda (Valenti); University of Southampton / University Hospital Southampton (Byrne)
• Type: Review article (updated September 25, 2025)
• DOI: https://doi.org/10.1056/NEJMra2412865

Overview

MASLD (formerly NAFLD/NASH) affects up to 38% of adults worldwide and is defined by hepatic steatosis plus at least one metabolic syndrome trait; its more severe inflammatory form, MASH (formerly NASH), affects ~30% of MASLD patients and drives progressive fibrosis, cirrhosis, and hepatocellular carcinoma. Cardiovascular disease is the leading cause of death in MASLD, with MASLD independently increasing fatal and nonfatal CV events by ×1.5 (rising to ×2.5 with advanced fibrosis), AF by ×1.2–1.5, and new-onset HF by ×1.2–1.5. In March 2024, resmetirom (thyroid hormone receptor beta-selective agonist) became the first FDA-approved drug for noncirrhotic MASH with moderate-to-advanced fibrosis; incretin-based therapies (especially semaglutide 2.4 mg, tirzepatide, and triple agonists) and SGLT2 inhibitors are emerging as hepatoprotective options with simultaneous cardiometabolic benefits.

Keywords

MASLD, NAFLD, MASH, NASH, metabolic syndrome, hepatic steatosis, liver fibrosis, FIB-4, resmetirom, semaglutide, tirzepatide, SGLT2 inhibitors, FGF21, PNPLA3, incretin, GLP-1, hepatocellular carcinoma

Key Takeaways

Nomenclature

• 1980: NASH coined (Ludwig et al., Mayo Clinic). 2020: renamed MAFLD (positive metabolic definition). 2023: multisociety consensus renamed to MASLD (steatotic liver disease) / MASH (steatohepatitis). NAFLD and MASLD definitions are nearly superimposable in the general population.
• MASLD = hepatic steatosis + ≥1 metabolic syndrome trait (overweight/obesity, abdominal obesity, hypertension, dysglycaemia, dyslipidaemia) — in the absence of significant alcohol consumption and other secondary causes.

Global Burden

• MASLD affects up to 38% of adults worldwide; 65% of adults with type 2 diabetes (meta-analysis, ~1.8 million persons).
• Global DALYs: 1.69 million (1990) → 3.67 million (2021) — ×2.2 increase over three decades. Largest increases in China and India.
• HCC incidence: 1.25/1000 person-years in MASLD overall; ~20/1000 person-years in MASLD-related cirrhosis.

Cardiovascular and Extrahepatic Risks (Key for Cardiology)

• CVD is the leading cause of death in MASLD — exceeding liver-related death in most cohorts.
• MASLD increases fatal/nonfatal CV events ×1.5 independent of traditional risk factors; rises to ×2.5 with higher fibrosis stages.
• New-onset AF: MASLD associated with ×1.2–1.5 increased risk (meta-analysis, Liver Int 2025).
• New-onset HF: MASLD associated with ×1.2–1.5 increased risk (meta-analysis, ~11 million individuals).
• New-onset type 2 diabetes: ×2.2 risk increase; ×3.4 with advanced liver disease.
• CKD: ×1.2–1.5 increased risk.
• Extrahepatic cancers: ×1.2–1.5 (especially extrahepatic GI cancers, colorectal, breast).
• Certain genotypes (e.g. TM6SF2 variant) dissociate hepatic from CV risk — lipoprotein retention in liver may paradoxically attenuate cardiovascular disease despite worsening liver disease.

Natural History

• Spectrum: isolated steatosis → MASH (lipotoxic hepatocellular damage + lobular inflammation, ~30% of MASLD) → fibrosis F0–F4 → cirrhosis → HCC.
• Fibrosis stages: F0 (none), F1 (perisinusoidal/portal), F2 (perisinusoidal + portal/periportal), F3 (septal/bridging), F4 (cirrhosis). Clinically significant fibrosis ≥F2 is a strong predictor of all-cause death and liver complications.
• Time to cirrhosis: ~30–35 years from F0/F1; ~19–20 years from F2; 5–6 years from F3.
• Key drivers of progression: Visceral adiposity, insulin resistance, type 2 diabetes (predominant), obesity, hypertension. Primary hypothyroidism increases risk; oestrogens are protective. Fructose, saturated/trans fats, and alcohol accelerate progression; Mediterranean diet is protective.
• Genetics (heritability ~50%): PNPLA3 I148M = most common genetic determinant — increases risk of MASH, fibrosis, cirrhosis, and HCC. TM6SF2 variant increases liver-specific risk but reduces CV risk (lipoprotein retention). Polygenic risk scores may identify MASLD subtypes.

Risk Stratification and Case Finding

• Sequential approach for patients at risk (T2DM, multiple metabolic risk factors, elevated liver enzymes):
  1. FIB-4 index (first-line noninvasive marker): <1.30 = low risk (manage in primary care); 1.30–2.67 = indeterminate → additional testing; >2.67 = high risk → hepatologist referral.
  2. Additional testing for indeterminate: Enhanced Liver Fibrosis (ELF) test, vibration-controlled transient elastography (FibroScan), magnetic resonance elastography, or liver histology.
• At-risk MASH = MASH + clinically significant fibrosis (≥F2) = key treatment indication accepted by regulatory agencies.
• 2024 European EASL-EASD-EASO guidelines recommend: weight-loss trial with GLP-1 RA or other incretin-based polyagonists, with reassessment within 1 year, before second-stage evaluation.

Pharmacotherapy

Lifestyle (Cornerstone)

• ≥5% sustained weight loss → reduces steatosis; 7–10% → reduces inflammation; ≥10% → reduces fibrosis. Adherence to long-term dietary intervention is often insufficient.

Resmetirom (First FDA-Approved Drug, March 2024)

• Oral thyroid hormone receptor beta (THR-β)-selective agonist; liver-directed. Approved for noncirrhotic MASH with moderate-to-advanced fibrosis (F2–F3).
• MAESTRO-NASH phase 3 (n=966; F1–F3 MASH; 52 weeks; 80 mg or 100 mg vs placebo):
  • MASH resolution without worsening fibrosis: 62.9% (100 mg) vs 34.3% (placebo)
  • ≥1 stage fibrosis reduction without worsening MASH: 36.8% (100 mg) vs 22.4% (placebo)
  • Also reduced LDL-C, triglycerides, and Lp(a); neutral weight and insulin resistance
  • Side effects: nausea and diarrhea (usually transient/mild); free T4 reduced ~15–20% (no effect on TSH or free T3)
• Long-term safety (endocrine, gonadal, bone surveillance) warranted; no validated response predictors; no pharmacotherapy approved for cirrhotic MASLD.

GLP-1 Receptor Agonists

• Semaglutide 2.4 mg/week (ESSENCE phase 3, part 1, n=800; F2–F3 MASH; 72 weeks):
  • Superior to placebo on both histologic co-primary endpoints (MASH resolution without worsening fibrosis; ≥1 stage fibrosis reduction without worsening MASH)
  • 32.7% vs 16.1% had MASH resolution with fibrosis reduction (secondary)
  • In MASH-related cirrhosis (phase 2b, n=71; 48 weeks): reduced liver fat but did NOT reduce fibrosis or resolve MASH — GLP-1 RA may not benefit advanced/cirrhotic disease
  • Real-world: GLP-1 RA use associated with lower risk of new-onset cirrhosis, hepatic decompensation, and HCC vs DPP-4 inhibitors or other glucose-lowering agents
• Tirzepatide (SYNERGY-NASH phase 2b, n=190; F2–F3; 52 weeks): MASH resolution 56–62% (5/10/15 mg) vs 44% (placebo); ≥1 stage fibrosis reduction 51–55% vs 30%; ~15% body weight reduction
• Survodutide (GLP-1 + glucagon receptor dual agonist, phase 2b, n=293; 48 weeks): MASH improvement 47–62% vs 14%; fibrosis reduction 32% vs 18%; 10–15% weight loss; notable: increased heart rate and high discontinuation rate (20% vs 3%)
• Retatrutide (GIP + GLP-1 + glucagon triple agonist, phase 2a, n=98; 48 weeks): ~80% reduction in liver fat at highest doses; >85% resolution of hepatic steatosis — most potent liver fat reduction yet reported

PPAR Agonists

• Pioglitazone (PPAR-γ; meta-analysis, ~500 patients, 5 phase 2 trials): reduces fibrosis and resolves MASH regardless of T2DM status; weight gain +2.7%.
• Lanifibranor (pan-PPAR agonist; NATIVE phase 2b, n=247; 24 weeks): MASH resolution and fibrosis improvement vs placebo; weight gain ~2.5%; phase 3 (72 weeks, F2–F3) ongoing.

FGF21 Analogues

• Efruxifermin, pegbelfermin, pegozafermin — meta-analysis of 5 phase 2 trials (~600 patients): MASH resolution and fibrosis improvement; neutral weight; mild-moderate GI AEs.
• SYMMETRY trial (efruxifermin in compensated cirrhosis, n=181; 96 weeks): Cirrhosis reversal (≥1 stage fibrosis reduction without MASH worsening) 29% vs 11% — first signal of cirrhosis reversal with a MASH therapy. Phase 3 trials ongoing.

SGLT2 Inhibitors

• Established cardiovascular and renal benefits; also hepatoprotective.
• Meta-analysis (12 phase 2 RCTs; 24 weeks): reduced liver fat (MRI) and liver enzymes.
• Dapagliflozin phase 2b (n=154; 48 weeks; with or without T2DM): MASH resolution 23% vs 8%; fibrosis reduction 45% vs 20%.
• Real-world: SGLT2i associated with lower risk of liver events vs other glucose-lowering drugs (except GLP-1 RAs).

Future: Combination Therapy

• No head-to-head comparisons between any agents yet.
• Anticipated next frontier: semaglutide 2.4 mg + resmetirom (or PPAR agonists or FGF21 analogues) ± genetic-targeted therapy.
• Genotyping (PNPLA3, TM6SF2) may predict treatment response and identify distinct MASLD subtypes warranting different approaches.

Limitations of the Document

• Review article — no novel primary data.
• Global MASLD burden estimates rely on heterogeneous study designs; accuracy uncertain.
• Resmetirom phase 3 data (MAESTRO-NASH) are 52-week surrogate outcomes; long-term hard outcomes (cirrhosis, liver death) remain unproven.
• Semaglutide ESSENCE phase 3 (part 2, 240 weeks, liver clinical outcomes) ongoing — current data are surrogate histologic endpoints only.
• No pharmacotherapy for cirrhotic MASLD yet; semaglutide safe but ineffective in cirrhosis (phase 2b).
• No validated stoppage rules for ineffective resmetirom.
• Genetic heterogeneity (PNPLA3/TM6SF2 subtypes) means population-level treatment recommendations may not apply uniformly to individuals.
• All incretin head-to-head comparisons are absent.

Key Concepts Mentioned

• entities/MASLD — central subject
• entities/Semaglutide — ESSENCE phase 3 MASH data; GLP-1 class evidence in MASLD
• entities/Tirzepatide — SYNERGY-NASH MASH data
• entities/Atrial-Fibrillation — MASLD as AF risk factor ×1.2–1.5
• entities/HFpEF — MASLD as HF risk factor; shared pharmacotherapy (GLP-1 RA, SGLT2i)

Key Entities Mentioned

• entities/MASLD — main subject
• entities/Semaglutide — ESSENCE phase 3 MASH superior to placebo
• entities/Tirzepatide — SYNERGY-NASH MASH resolution 56–62%

Wiki Pages Updated

• Created wiki/sources/masld-nejm-2025.md
• Created wiki/entities/MASLD.md
• Updated wiki/entities/Semaglutide.md
• Updated wiki/entities/Tirzepatide.md
• Updated wiki/entities/Atrial-Fibrillation.md
• Updated wiki/wikiindex.md
• Updated wiki/sourceindex.md
• Appended log.md