Key Facts

NAFLD (now renamed MASLD under the 2023 nomenclature) is the hepatic manifestation of metabolic syndrome and the most common chronic liver disease in the Western world. Most patients have simple steatosis, but ~20% develop steatohepatitis which can progress to cirrhosis.

Epidemiology

Global prevalence ~25-30%. In the UK, affects approximately 1 in 3 adults. Prevalence of NASH/MASH is ~3-5%. Incidence is rising in parallel with obesity and diabetes epidemics. NAFLD-related cirrhosis is now the fastest-growing indication for liver transplantation. Increasingly recognised in children.

Aetiology

• Metabolic syndrome: strongest association — obesity, insulin resistance, T2DM, dyslipidaemia, hypertension
• Genetic: PNPLA3 I148M variant (strongest genetic risk factor — ~3x risk), TM6SF2
• Other associations: PCOS, hypothyroidism, obstructive sleep apnoea
• Drugs: tamoxifen, amiodarone, methotrexate, corticosteroids, valproate

Pathophysiology

"Multiple hit" hypothesis (replaced "two-hit"):

• Insulin resistance → increased hepatic de novo lipogenesis + increased free fatty acid flux from adipose tissue → hepatic triglyceride accumulation (steatosis)
• Lipotoxicity → oxidative stress, ER stress, mitochondrial dysfunction → hepatocyte injury → inflammation (steatohepatitis)
• Gut microbiome dysbiosis → increased gut permeability → portal endotoxaemia → Kupffer cell activation
• Hepatic stellate cell activation → fibrogenesis → progressive fibrosis → cirrhosis

Fibrosis stage is the strongest predictor of liver-related outcomes and overall mortality.

Typical Presentation

• Usually asymptomatic — incidental finding on USS or blood tests
• Fatigue (common but non-specific)
• Vague RUQ discomfort
• Hepatomegaly (in early disease)

Advanced Disease

• Features of cirrhosis and portal hypertension
• Stigmata of chronic liver disease

Associations to Screen For

• Type 2 diabetes / impaired fasting glucose
• Dyslipidaemia
• Hypertension
• Obesity (central)
• Cardiovascular disease (leading cause of death in NAFLD — NOT liver disease)

Red Flags

• Features of decompensated cirrhosis (ascites, variceal bleeding, encephalopathy)
• Rapidly progressive liver disease
• HCC (surveillance in NAFLD cirrhosis)

Bedside

• BMI, waist circumference: central obesity assessment
• Blood pressure: hypertension screening

Bloods

• LFTs: ALT often mildly raised (1-3× ULN); ALT:AST ratio typically <1 (unlike ALD); may be normal even with significant disease
• FBC: thrombocytopaenia suggests advanced fibrosis/cirrhosis
• HbA1c/fasting glucose: diabetes screening
• Lipid profile: dyslipidaemia
• FIB-4 score: age × AST / (platelet count × √ALT) — non-invasive fibrosis assessment
  • <1.30: low risk
  • 1.30-2.67: indeterminate → further testing (ELF or FibroScan)

  • 2.67: high risk → hepatology referral

• ELF test: serum fibrosis biomarker panel (HA, PIIINP, TIMP-1); <7.7 low risk, 7.7-9.8 intermediate, >9.8 advanced fibrosis
• Exclude other causes: hepatitis B/C serology, autoantibodies, immunoglobulins, iron studies, caeruloplasmin, alpha-1 antitrypsin

Imaging

• USS abdomen: hepatic steatosis (bright/echogenic liver); insensitive for fibrosis
• Transient elastography (FibroScan): liver stiffness measurement; >8 kPa suggestive of significant fibrosis; >12.5 kPa suggests cirrhosis; CAP >280 dB/m confirms steatosis
• MRI-PDFF (proton density fat fraction): most accurate quantification of steatosis (research/clinical trials)

Special Tests

• Liver biopsy: gold standard for confirming NASH and staging fibrosis; indicated when non-invasive tests are discordant, diagnostic uncertainty, or clinical trial enrolment
  • NAS (NAFLD Activity Score): steatosis + lobular inflammation + hepatocyte ballooning; ≥5 = definite NASH
  • Fibrosis staged F0-F4
• Cardiovascular risk assessment (QRISK3): cardiovascular disease is the leading cause of death

Non-pharmacological

• Weight loss: most important intervention; >5% improves steatosis; >7-10% improves steatohepatitis and fibrosis
• Exercise: 150-200 min/week moderate-intensity — improves hepatic steatosis even without weight loss
• Dietary modification: Mediterranean diet (evidence of benefit); reduce refined carbohydrates and fructose
• Avoid alcohol: even moderate intake may be harmful in NAFLD
• Bariatric surgery: consider if BMI >35 (or >30 with T2DM); resolves NASH in >80% (STAMPEDE, observational data)

Pharmacological

• No drug currently licensed for NAFLD/NASH in the UK (as of 2025)
• Pioglitazone 30 mg OD: improves NASH histology in non-diabetic NASH (PIVENS trial — off-label use; weight gain, fluid retention, fracture risk)
• Vitamin E 800 IU OD: improves NASH histology in non-diabetic, non-cirrhotic NASH (PIVENS trial — off-label; concerns about all-cause mortality at high dose)
• GLP-1 receptor agonists: semaglutide 2.4 mg/week SC — improved NASH resolution (STEP, SURPASS weight loss data; NASH-specific trials ongoing); liraglutide (LEAN trial)
• Resmetirom (thyroid hormone receptor-beta agonist): FDA-approved in US for NASH with fibrosis F2-F3 (MAESTRO-NASH trial); UK approval anticipated
• Manage metabolic comorbidities: statins (safe in NAFLD and indicated for CVD risk), metformin/SGLT2i/GLP-1RA for diabetes, anti-hypertensives

Surgical/Interventional

• Bariatric surgery: for morbid obesity with NAFLD (see above)
• Liver transplantation: for decompensated NAFLD cirrhosis

Referral Criteria

• Hepatology referral: FIB-4 >2.67, ELF >9.8, FibroScan >12.5 kPa, suspected cirrhosis
• Bariatric surgery assessment: BMI criteria met
• Cardiovascular risk management (often the priority)

Simple steatosis has a benign hepatic prognosis — progression to NASH is slow. ~20% of NAFL patients develop NASH. Of NASH patients, ~20-30% progress to fibrosis over 10 years. NASH cirrhosis develops in ~5-10% of NASH patients. HCC can occur in NASH even without cirrhosis (unlike most other liver diseases). Cardiovascular disease is the leading cause of death in NAFLD — not liver disease. Overall mortality is increased 1.5-2× compared to age-matched controls. Fibrosis stage is the strongest predictor of outcomes (F3-F4 = significantly increased liver-related and all-cause mortality).

Non-Invasive Fibrosis Assessment Pathway (NICE NG49)

NAFLD vs ALD Comparison