A 52-year-old man with T2DM and BMI 34 is referred for evaluation of incidentally elevated ALT and AST found on a routine metabolic panel. He has no jaundice, no abdominal pain, and no known liver history. He drinks approximately 3–4 drinks per week. Medications include metformin; he is not on a statin. An ultrasound of his liver reveals diffuse steatosis.
The Old Framework: NAFLD and NASH
The term Nonalcoholic Fatty Liver Disease (NAFLD) was coined in 1980 by Ludwig and colleagues to describe a pattern of liver injury histologically resembling alcoholic hepatitis in patients who denied significant alcohol use. It quickly became the most common chronic liver disease diagnosis in the developed world as obesity and type 2 diabetes prevalence rose through the 1990s and 2000s.
Within NAFLD, Nonalcoholic Steatohepatitis (NASH) was defined as the progressive inflammatory subtype — requiring liver biopsy to confirm: steatosis plus hepatocyte ballooning plus lobular inflammation, with or without fibrosis. The distinction mattered because NASH, unlike simple steatosis, carried meaningful risk of fibrosis progression, cirrhosis, and hepatocellular carcinoma.
- Diagnosis by exclusion: NAFLD was defined by the absence of alcohol use — not by any positive feature of the disease itself. This created inconsistency, as alcohol thresholds varied across international guidelines (14–21 drinks/week depending on guideline), and required ruling out other causes before a positive diagnosis could be made.
- Missed the MetALD population: Patients with both metabolic dysfunction and elevated alcohol use were excluded from NAFLD by definition, despite having a clinically significant and overlapping disease. This left a large subgroup without a diagnostic home.
- Stigmatizing language: "Fatty liver" implied personal culpability — the patient was overweight and ate badly. "Nonalcoholic" inadvertently prompted questions about alcohol use at the point of diagnosis, which patients found stigmatizing. The framing obscured the underlying cardiometabolic drivers.
- Pathophysiology not reflected: Neither NAFLD nor NASH conveyed that the disease is driven by metabolic dysfunction — insulin resistance, dyslipidemia, visceral adiposity — the same mechanisms driving T2DM, hypertension, and cardiovascular disease. This contributed to under-recognition in primary care and a perception that "fatty liver" was benign.
The 2023 Rename: MASLD and MASH
In 2023, a multi-society Delphi consensus involving 236 panelists from 56 countries (led by Rinella, Lazarus, Ratziu et al., J Hepatol 2023) replaced the NAFLD/NASH framework. The new terminology reflects three core principles: diagnosis by positive cardiometabolic criteria rather than exclusion, elimination of stigmatizing language, and alignment with the underlying pathophysiology.
| Old Term | New Term | Abbreviation |
|---|---|---|
| Nonalcoholic Fatty Liver Disease (NAFLD) | Metabolic Dysfunction-Associated Steatotic Liver Disease | MASLD |
| Nonalcoholic Steatohepatitis (NASH) | Metabolic Dysfunction-Associated Steatohepatitis | MASH |
The shift from "nonalcoholic" to "metabolic dysfunction-associated" is clinically meaningful. A patient can now receive a positive MASLD diagnosis based on steatosis plus confirmed cardiometabolic criteria — without first needing to exclude alcohol or other causes. This improves recognition in primary care, where the prior exclusionary framework often delayed diagnosis.
The SLD Umbrella
Steatotic Liver Disease (SLD) is now the overarching umbrella term encompassing all causes of hepatic steatosis. MASLD is the dominant subtype, accounting for approximately 75% of SLD globally. Other recognized SLD subtypes include ALD (alcohol-associated liver disease) and drug-induced steatosis.
The 2023 SLD nomenclature (multisociety Delphi consensus). MASLD and MASH are subtypes within SLD — not a replacement for the whole framework.
| Category | Men (drinks/week) | Women (drinks/week) |
|---|---|---|
| MASLD | <14 | <7 |
| MetALD | 14–35 | 7–21 |
| ALD (alcohol-associated) | >35 | >21 |
The single alcohol-threshold reference for the SLD subtypes (1 US standard drink ≈ 14 g ethanol). These define diagnostic categories, not safety limits.
MASLD requires hepatic steatosis (by imaging, biomarker, or biopsy) plus at least one of the following five cardiometabolic criteria:
- Overweight/Obesity: BMI ≥25 kg/m² (≥23 kg/m² in Asian populations) or waist circumference >94 cm (men) / >80 cm (women)
- Hyperglycemia: Fasting glucose ≥100 mg/dL, HbA1c ≥5.7%, or established type 2 diabetes mellitus (T2DM)
- Hypertension: Blood pressure ≥130/85 mmHg or use of antihypertensive therapy
- Hypertriglyceridemia: Plasma triglycerides ≥150 mg/dL or on lipid-lowering therapy
- Low HDL: Plasma HDL-cholesterol <40 mg/dL (men) or <50 mg/dL (women), or on lipid-lowering therapy
MASLD follows a well-characterized progressive continuum. The transition from simple steatosis to MASH is driven by lipotoxicity, oxidative stress, and inflammatory signaling; fibrosis stage is the dominant predictor of liver-related outcomes.
- Hepatic steatosis ≥5% of hepatocytes on histology; or steatosis detected on imaging/biomarker
- No inflammation, ballooning, or fibrosis — distinguishes simple steatosis from MASH
- Approximately 20% of patients with steatosis have underlying MASH on biopsy — steatosis alone carries low short-term progression risk
- Management: lifestyle counseling, weight loss, cardiometabolic risk reduction; repeat FIB-4 in 1–3 years
Non-invasive assessment is the recommended initial approach for all patients with suspected MASLD. The 2023 AASLD Practice Guidance establishes a stepwise strategy: FIB-4 first, followed by second-line testing for indeterminate scores.
FIB-4 Index — First-Line (AASLD 2023)
FIB-4 is a simple, validated, laboratory-based fibrosis index calculated from routine clinical values:
| FIB-4 Score | Interpretation | Recommended Action |
|---|---|---|
| < 1.30 | Low risk of advanced fibrosis | Reassure; lifestyle counseling; recheck in 1–3 years |
| 1.30 – 2.67 | Indeterminate — cannot exclude advanced fibrosis | Proceed to second-line testing (VCTE or ELF) |
| > 2.67 | High risk of advanced fibrosis (F3–F4) | Refer to hepatology; consider liver biopsy |
VCTE (FibroScan) — Preferred Second-Line
Vibration-controlled transient elastography (VCTE) measures liver stiffness measurement (LSM) in kilopascals (kPa) as a surrogate for hepatic fibrosis. It is the preferred second-line test after an indeterminate FIB-4.
| LSM (kPa) | Interpretation | Clinical Significance |
|---|---|---|
| < 8 kPa | F0–F1: likely no significant fibrosis | Low risk; lifestyle management; recheck per FIB-4 schedule |
| 8 – 15 kPa | F2–F3: significant to advanced fibrosis | Treatment decision zone; F2–F3 threshold for resmetirom/semaglutide |
| > 15 kPa | F3–F4: advanced fibrosis to cirrhosis range | Refer hepatology; evaluate for cirrhosis complications; HCC surveillance if cirrhosis confirmed |
ELF Score — Second-Line / Adjunct
Liver Biopsy — When Still Indicated
- Non-invasive testing remains indeterminate despite FIB-4 and VCTE/ELF and clinical decision is time-sensitive
- Suspicion of competing or superimposed etiology (e.g., autoimmune hepatitis, drug-induced liver injury)
- Enrollment in a clinical trial requiring histologic confirmation
Lifestyle modification remains the cornerstone of treatment for all stages. Pharmacotherapy is now available for MASH with fibrosis ≥F2. Use filters to browse by category.
- ≥5% body weight loss: improves hepatic steatosis
- ≥7–10% body weight loss: MASH histologic resolution
- ≥10% body weight loss: fibrosis improvement (≥1 stage)
- Mediterranean dietary pattern + 500–1000 kcal/day deficit
- Aerobic exercise 150–300 min/week of moderate intensity; independently improves steatosis regardless of weight change
- First pharmacotherapy FDA-approved specifically for MASH with liver fibrosis
- Mechanism: selective thyroid hormone receptor-beta (THR-β) agonist; reduces hepatic lipid synthesis and steatosis
- Indication: MASH with fibrosis stage F2 or F3
- Dose: 80 mg QD (weight <100 kg) or 100 mg QD (weight ≥100 kg)
- MAESTRO-NASH: MASH resolution 25.9% (80 mg) / 29.9% (100 mg) vs. 9.7% placebo; fibrosis improvement 24–26% vs. 14.2% placebo (dose-dependent) at 52 weeks
- No biopsy required — F2–F3 can be established by FibroScan LSM or ELF score
- Contraindications: cirrhosis (not studied); concurrent strong CYP3A4 inhibitors
- Wegovy 2.4 mg/week SC: FDA-approved for MASLD with F2–F3 fibrosis (August 2025)
- Phase 3 ESSENCE trial: 62.9% MASH resolution vs. 34.3% placebo; fibrosis ≥1 stage improvement 36.8% vs. 22.4% placebo (PMID 40305708)
- Preferred when T2DM is present — dual benefit for liver disease and glycemic control
- Ozempic 0.5–1 mg/week: preferred for T2DM without weight indication; beneficial cardiometabolic effects
- 800 IU/day alpha-tocopherol (PIVENS trial)
- For non-diabetic, non-cirrhotic adults with biopsy-confirmed MASH
- Do NOT use in: T2DM, MASH cirrhosis, men with elevated prostate cancer risk (SELECT trial signal for increased prostate cancer incidence)
- Pan-PPAR agonist (PPARα, δ, γ)
- Phase 3 NATiV3 trial — positive results for MASH resolution and fibrosis improvement
- Regulatory review pending
Pipeline Summary Table
| Agent | Mechanism | Trial / Status |
|---|---|---|
| Lanifibranor | Pan-PPAR agonist (PPARα, δ, γ) | Phase 3 NATiV3 — positive MASH resolution and fibrosis results; regulatory review pending |
Cardiometabolic Therapy Guidance
- Statins: Safe in MASLD; transaminase elevation is not a contraindication; may reduce HCC risk; use per standard CVD indications. Monitor LFTs at baseline and 12 weeks.
- SGLT-2 inhibitors: Reduce hepatic steatosis and inflammation; benefit in heart failure (HFrEF and HFpEF) and CKD makes them particularly attractive in the metabolic syndrome context. Preferred in T2DM with MASLD.
- GLP-1 receptor agonists: Semaglutide now FDA-approved for MASLD F2–F3; liraglutide has earlier supportive data. Preferred when T2DM present — dual liver and glycemic benefit.
- Hypertension: ARBs and ACE inhibitors are reasonable first-line agents (potential antifibrotic benefit via angiotensin pathway suppression); no antihypertensive class is specifically contraindicated in MASLD.
HCC Surveillance in MASLD-Related Cirrhosis
- Abdominal ultrasound every 6 months ± serum alpha-fetoprotein (AFP) — standard per AASLD guidance
- If ultrasound is technically inadequate (high BMI, poor acoustic window): use abbreviated MRI protocol (non-contrast T1 + T2 or HASTE sequence) as a surveillance alternative
- Begin surveillance at the time of cirrhosis diagnosis; continue indefinitely
- HCC can occur without cirrhosis in MASLD — unique among major liver diseases; however, there is no consensus surveillance protocol for non-cirrhotic MASLD with F3 fibrosis; clinical judgment should guide practice in this population
Self-Assessment — Flip Cards
Tap each card to reveal the answer and explanation.