Non-alcoholic fatty liver disease (NAFLD)
Exam Tips
- NAFLD is commonly incidental; normal ALT or normal ultrasound does not exclude disease.
- In early NAFLD, ALT is often higher than AST, but this pattern may reverse with advanced fibrosis/cirrhosis.
- For UK exams, prioritise non-invasive fibrosis stratification (for example FIB-4 first-line) over routine biopsy.
- Distinguish simple steatosis from NASH conceptually: inflammation/ballooning and fibrosis risk define NASH severity.
- Most deaths in NAFLD are cardiovascular, so management must include aggressive CVD risk-factor control.
Definition
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease defined by excess triglyceride accumulation in more than 5% of hepatocytes in people without harmful alcohol intake or another dominant secondary cause. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), where steatosis is accompanied by hepatocyte injury and inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma.
Pathophysiology
NAFLD is driven mainly by insulin resistance and adipose tissue dysfunction, causing increased free fatty acid flux to the liver, de novo lipogenesis, and reduced lipid export/oxidation. Hepatic fat accumulation can remain relatively benign (simple steatosis) or trigger lipotoxicity, oxidative stress, mitochondrial dysfunction, and inflammatory cytokine signaling, leading to hepatocyte ballooning and fibrogenesis (NASH). Progressive fibrosis is mediated by hepatic stellate cell activation and is the key determinant of liver-related and all-cause mortality; genetic susceptibility (for example PNPLA3 variants) modifies risk and response to lifestyle change. See Figure: progression model from steatosis -> NASH -> fibrosis -> cirrhosis/HCC.
Risk Factors
- Central obesity and increased waist circumference
- Type 2 diabetes mellitus or impaired glucose regulation
- Hypertension
- Atherogenic dyslipidaemia (high triglycerides, low HDL)
- Metabolic syndrome
- Obstructive sleep apnoea
- Polycystic ovary syndrome and hypothyroidism
- Family history of NAFLD
- Higher-risk ethnic groups (including Hispanic and some Asian populations)
- Rapid weight loss, total parenteral nutrition, refeeding states, jejunoileal bypass
- Drug exposure (for example amiodarone, tamoxifen, corticosteroids, methotrexate, diltiazem, some NSAIDs)
- Other liver disease associations (for example hepatitis C, Wilson disease)
Clinical Features
Symptoms
- Often asymptomatic and found incidentally
- Fatigue
- Non-specific malaise
- Right upper quadrant discomfort/ache
Signs
- Overweight/obesity with central adiposity
- Features of insulin resistance/metabolic syndrome
- Mild hepatomegaly (occasionally)
- Usually no chronic liver disease stigmata unless advanced fibrosis/cirrhosis
Investigations
Management
Lifestyle Modifications
- Weight reduction is first-line: target 7-10% body weight loss (greater loss gives greater NASH/fibrosis benefit).
- Calorie-deficit diet (Mediterranean-style pattern commonly advised), reduce refined carbohydrates/fructose-rich drinks, and avoid crash dieting.
- Regular physical activity (aerobic plus resistance training), even without major weight loss.
- Treat cardiovascular risk aggressively: smoking cessation, BP control, lipid management, diabetes optimisation.
- Keep alcohol intake below NAFLD diagnostic thresholds and advise minimisation in established liver disease.
Pharmacological Treatment
Weight-management pharmacotherapy (adjunct to lifestyle, not NAFLD-specific licensing)
- Orlistat 120 mg orally three times daily with meals containing fat
- Semaglutide (Wegovy) 0.25 mg subcutaneously once weekly, titrated every 4 weeks to maintenance 2.4 mg once weekly
Use according to UK obesity criteria/services. Orlistat causes GI adverse effects and reduces absorption of fat-soluble vitamins; avoid in chronic malabsorption/cholestasis. Semaglutide is contraindicated in pregnancy and should be used cautiously with pancreatitis history and severe GI disease.
Cardiometabolic risk reduction
- Atorvastatin 20 mg orally once daily (typical primary prevention start dose; adjust to lipid targets/risk)
Statins are used for CVD risk, not to directly treat steatosis; they are generally safe in NAFLD. Avoid initiation in active liver disease or persistent unexplained transaminase elevations greater than 3x ULN; check baseline and follow-up liver enzymes per guidance.
Specialist off-label therapy for selected NASH patients
- Pioglitazone 15-45 mg orally once daily
- Vitamin E (alpha-tocopherol) 800 IU orally once daily
Usually specialist-led, often for biopsy-proven NASH after risk-benefit discussion. Pioglitazone: avoid in heart failure, active bladder cancer, or high fracture risk; causes weight gain/oedema. Vitamin E: caution regarding long-term safety signals (for example haemorrhagic stroke/prostate cancer concerns in some datasets).
Surgical / Interventional
- Metabolic/bariatric surgery in eligible patients with severe obesity can improve steatosis and NASH and reduce metabolic risk; requires MDT assessment and long-term nutritional follow-up.
Complications
- Progressive liver fibrosis and cirrhosis
- Portal hypertension and variceal haemorrhage
- Hepatocellular carcinoma
- Liver failure and infection vulnerability in advanced disease
- Incident type 2 diabetes and worsening metabolic syndrome
- Chronic kidney disease
- Cardiovascular events (myocardial infarction, ischaemic stroke, atrial fibrillation) and cardiovascular mortality
Prognosis
Outcome is stage-dependent. Simple steatosis often follows a relatively indolent course, with a low long-term risk of cirrhosis (around 0-4% over 10-20 years), whereas NASH carries substantially higher risk of fibrosis progression, cirrhosis, liver failure, and HCC. Fibrosis stage is the strongest prognostic marker, and mortality risk rises steeply as fibrosis advances; cardiovascular disease remains the commonest cause of death.