Non-alcoholic steatohepatitis (NASH)
Description
Nomenclature - renamed 2023, use the new terms
| Old | New |
|---|---|
| NAFLD | MASLD - metabolic dysfunction-associated steatotic liver disease |
| NAFL (simple steatosis) | MASL |
| NASH | MASH - metabolic dysfunction-associated steatohepatitis |
| - | MetALD - MASLD + alcohol 20-50 g/day (F) or 30-60 g/day (M) |
| - | ALD - above those thresholds |
- The definition is now positive, not exclusionary: hepatic steatosis + >=1 cardiometabolic criterion (BMI/waist, dysglycaemia, hypertension, hypertriglyceridaemia, low HDL)
- No longer requires excluding alcohol - steatotic liver disease from more than one cause is now nameable
MASL vs MASH - a histological distinction
- MASL - steatosis alone, no hepatocyte injury
- MASH - hepatocyte ballooning degeneration (the defining feature) + lobular inflammation +/- fibrosis
- Ballooning is what separates them, not the amount of fat
- Alcohol thresholds separating MASLD from ALD: 20 g/day women, 30 g/day men
Epidemiology
- The commonest liver disease worldwide - ~25-30% of adults; MASH ~5%
- Leading and fastest-growing indication for liver transplantation in Australia and the US
- Metabolic co-travellers in MASH:
- ~80% overweight or obese
- 72% dyslipidaemia
- 44% type 2 diabetes
- T2DM raises the prevalence of advanced fibrosis to ~15-20% - the highest-yield group to screen
- PNPLA3 I148M and TM6SF2 variants - inc risk independent of BMI; high frequency in Hispanic populations
- Lean MASLD ~10-20%, more common in Asian populations - normal BMI does not exclude it
Aetiopathogenesis
- Insulin resistance -> inc peripheral lipolysis + inc de novo lipogenesis -> hepatic triglyceride accumulation
- Lipotoxicity (free fatty acids, ceramides), oxidative stress, mitochondrial dysfunction, ER stress -> hepatocyte injury
- Gut dysbiosis + inc intestinal permeability -> portal endotoxin -> Kupffer cell activation
- Stellate cell activation -> fibrosis
- Multiple parallel hits, not the old "two-hit" model
Fibrosis is the outcome-determining variable
- Fibrosis stage is the only histological feature independently predicting liver-related morbidity, transplantation and liver-related death
- Not steatosis grade, not the NAS activity score
- Progresses ~1 stage per decade on average (faster in MASH, and in a subgroup who progress rapidly)
Risk factors for fibrosis progression
- Age >50
- BMI >28
- Necroinflammatory activity on biopsy; ALT >2x ULN; AST:ALT >1
- Hypertriglyceridaemia
- Insulin resistance / T2DM
- Hypertension
- AST:ALT >1 in a MASLD patient suggests advanced fibrosis - in alcohol-related disease the same ratio means something different
Diagnosis
Non-invasive pathway - sequential, not single-test
1. FIB-4 first (age, AST, ALT, platelets) in anyone with steatosis or metabolic risk
- <1.3 - advanced fibrosis unlikely (<2.0 if age >65); repeat in 2-3 years
- 1.3-2.67 - indeterminate -> second test
- >2.67 - high risk -> hepatology referral
2. Second test - transient elastography (FibroScan), ELF, or another blood-based NIT
- Liver stiffness <8 kPa low risk; >=12 kPa suggests advanced fibrosis/cirrhosis
3. Biopsy where diagnosis is uncertain, other aetiologies coexist, or a treatment decision depends on it
- FIB-4 alone is not adequate to rule in or rule out - AASLD explicitly says use it as the first step of a sequence
Imaging
- Ultrasound - sensitivity poor below ~20-30% steatosis
- MRI-PDFF - the quantitative gold standard for fat; used in trials
- CAP on FibroScan - quantifies steatosis alongside stiffness
Always exclude the other causes
- Alcohol history (quantify in g/day; consider AUDIT-C, ethyl glucuronide)
- Viral hepatitis B and C
- Autoimmune - ANA, ASMA, IgG (low-titre ANA is common in MASLD - do not over-call)
- Haemochromatosis - ferritin and transferrin saturation (ferritin is raised in MASLD as an acute-phase reactant; transferrin saturation is the discriminator)
- Wilson disease if age <40; alpha-1 antitrypsin; coeliac; thyroid
- Drugs: methotrexate, tamoxifen, amiodarone, corticosteroids, valproate, antiretrovirals
Biopsy findings
- Macrovesicular steatosis, ballooning degeneration, lobular inflammation, Mallory-Denk bodies, pericellular/perisinusoidal "chicken-wire" fibrosis (zone 3)
- Histologically indistinguishable from alcohol-related steatohepatitis - the distinction is the history
Management
Verified against the AASLD MASLD Practice Guidance including the November 2025 semaglutide update, and EASL-EASD-EASO. Two drugs now have histological endpoint data: resmetirom and semaglutide.
A. Lifestyle - the foundation for everyone
- Weight loss targets are dose-dependent:
- >=5% -> reduces steatosis
- >=7% -> resolves MASH
- >=10% -> regresses fibrosis
- Mediterranean-style diet; eliminate fructose-sweetened beverages
- 150-300 min/week moderate exercise - benefits liver fat independent of weight loss
- Minimise or stop alcohol - alcohol and metabolic drivers are synergistic, not additive
- Coffee (2-3 cups/day) associated with less fibrosis
B. Pharmacotherapy - for MASH with F2-F3 fibrosis
| Drug | Basis |
|---|---|
| Resmetirom (THR-beta agonist) | First approved MASH drug. MASH resolution + fibrosis improvement (MAESTRO-NASH). Not for cirrhosis |
| Semaglutide 2.4 mg weekly | ESSENCE: MASH resolution 62.9% vs 34.3%, fibrosis improvement 36.8% vs 22.4% at 72 weeks. Added to AASLD guidance Nov 2025 |
| Pioglitazone | MASH resolution, esp. with T2DM. Weight gain, fluid retention, fracture risk |
| Vitamin E 800 IU/day | Non-diabetic, non-cirrhotic biopsy-proven MASH. Long-term safety debated |
| Other GLP-1/GIP agonists, tirzepatide | Emerging; strong metabolic benefit |
- No recommendation on combining resmetirom and semaglutide - no trial data
- Bariatric/metabolic surgery - the most effective intervention for MASH with obesity; resolves MASH in the majority and improves fibrosis. Not in decompensated cirrhosis
C. Treat the metabolic disease - this is where the mortality is
- Statins are safe and indicated in MASLD, including in compensated cirrhosis - do not withhold for raised transaminases; cardiovascular disease is what kills these patients
- SGLT2 inhibitors and GLP-1 agonists preferred for T2DM in MASLD
- Blood pressure, lipids, absolute cardiovascular risk assessment
- Vaccinate against hepatitis A and B
D. If cirrhotic
- 6-monthly ultrasound +/- AFP for HCC
- Variceal screening endoscopy (or Baveno non-invasive criteria)
- Avoid resmetirom in decompensated disease
- Transplant assessment - MASH is now a leading transplant indication; cardiovascular assessment is the limiting factor
Associations
- Metabolic syndrome - central obesity, T2DM, dyslipidaemia (inc TG, dec HDL), hypertension
- Type 2 diabetes - bidirectional; MASLD predicts incident T2DM
- Obstructive sleep apnoea - independent of BMI
- PCOS
- Hypothyroidism, hypopituitarism, hypogonadism
- Chronic kidney disease - independent association
- Colorectal adenomas and colorectal cancer
- Psoriasis
- Sarcopenia (sarcopenic obesity - worse fibrosis)
- Genetic: PNPLA3, TM6SF2, MBOAT7 (risk); HSD17B13 (protective)
Natural history & complications
The 25% rule
- ~25% of simple steatosis progresses to MASH
- ~25% of MASH progresses to cirrhosis
- ~25% of cirrhosis decompensates
Causes of death - in order
1. Cardiovascular disease - the leading cause
2. Malignancy (extrahepatic)
3. Liver-related death
- This is why the management is cardiometabolic, not only hepatic
HCC
- ~1-2% per year in MASH cirrhosis -> 6-monthly surveillance
- A meaningful proportion of MASLD-HCC arises without cirrhosis - but surveillance in non-cirrhotic MASLD is not currently recommended (too low yield across too large a population)
Prognostic
- Fibrosis stage is everything. F3-F4 drives all-cause and liver-related mortality
- F0-F1 - liver-related mortality close to background
- ~20% of MASH cirrhosis is "cryptogenic cirrhosis" in retrospect - steatosis disappears as fibrosis advances (burnt-out MASH)
Monitor
- FIB-4 every 1-3 years by risk band; elastography where indicated
- HbA1c, lipids, blood pressure, weight
- Cirrhosis: HCC surveillance, varices, decompensation
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