Non-Alcoholic Fatty Liver Disease (NAFLD): A Comprehensive Review

Nomenclature note (2023): A multi-society consensus renamed NAFLD to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and NASH to MASH (Metabolic dysfunction-Associated SteatoHepatitis). Both terms are used in this review as the literature is transitioning.

1. Definition and Spectrum

• Robbins & Kumar Basic Pathology, p. 609–612
• Sleisenger & Fordtran's GI & Liver Disease, p. 1354–1365

2. Epidemiology

• Global prevalence: ~25–30% of the general adult population; 30–40% in Western nations.
• MASLD affects approximately 60–70% of individuals with T2DM and 70–80% of those with obesity.
• A 2023 meta-analysis in Gut (PMID 37491159) of 156 studies (n=1,832,125) found:
  • NAFLD prevalence in T2DM: 65%
  • NASH prevalence in T2DM: 31.6%
  • Clinically significant fibrosis (F2–F4) in T2DM with NAFLD: 35.5%
  • Advanced fibrosis (F3–F4): 15%
• Demographics: More common in males; postmenopausal women have disproportionately advanced disease. Hispanics have the highest ethnic prevalence (~45–58%), followed by Caucasians and African Americans.
• Children: Pediatric NAFLD prevalence is 7.6% in the general population, rising to 34.2% in pediatric obesity clinics.
• NAFLD is now the leading indication for liver transplantation in the USA.

3. Pathogenesis

Robbins & Kumar Basic Pathology — Pathogenesis (A) and Natural History (B) of NAFLD

3a. Hepatic Steatosis

• Insulin resistance → impaired suppression of adipose tissue lipolysis → increased free fatty acid (FFA) delivery to the liver
• Increased de novo lipogenesis (DNL) driven by hyperinsulinemia
• FFA esterification → triglyceride accumulation → macrovesicular steatosis
• Impaired VLDL export further traps lipids

3b. Progression to Steatohepatitis (NASH)

• Lipotoxicity: accumulation of toxic lipid species (diacylglycerols, ceramides, free cholesterol) beyond triglycerides
• Mitochondrial dysfunction: impaired β-oxidation, reactive oxygen species (ROS) overproduction
• ER stress: unfolded protein response activation → hepatocyte apoptosis
• Gut-liver axis: dysbiosis → increased intestinal permeability → portal delivery of LPS → Toll-like receptor 4 activation in Kupffer cells
• Kupffer cell activation → TNF-α, IL-1β, IL-6 → stellate cell activation → fibrogenesis
• Dietary fat and gut microbiome composition modulate disease severity

3c. Genetic Susceptibility

4. Clinical Features & Diagnosis

Symptoms

Laboratory Findings

• Elevated ALT > AST (AST:ALT ratio typically <1, distinguishing it from alcohol-related liver disease where ratio >2)
• Elevated triglycerides, glucose, HbA1c
• Normal or mildly elevated bilirubin

Imaging

Noninvasive Fibrosis Markers

• FIB-4 index (age × AST / [platelets × √ALT]) — widely used screening tool
• NAFLD Fibrosis Score (NFS)
• Enhanced Liver Fibrosis (ELF) score

Liver Biopsy

5. Natural History & Complications

• Cardiovascular disease is the #1 cause of death in NAFLD
• NASH is associated with higher HCC risk than simple steatosis
• HCC incidence is highest in the Western Pacific/Southeast Asia
• Decompensated cirrhosis rates are increasing over time

6. Treatment

6a. Lifestyle Modification (First-Line)

• Weight loss ≥7–10% of body weight improves steatosis; ≥10% can resolve NASH and reduce fibrosis
• Low-carbohydrate or Mediterranean diet: A 2023 systematic review in Nutrients (PMID 37242133) showed Mediterranean diet significantly reduces liver enzymes, central obesity, and lipid levels in NAFLD
• Physical exercise: Both aerobic and resistance training reduce hepatic fat independent of weight loss
• Alcohol abstinence strongly recommended

6b. Bariatric Surgery

• Indicated for BMI >35 with NAFLD
• Consistently improves/resolves NASH and fibrosis in multiple studies

6c. Pharmacotherapy

FDA-Approved (2024)

• Phase III MAESTRO-NASH trial (2024): significant NASH resolution and fibrosis improvement vs. placebo
• First FDA-approved drug specifically for MASH with moderate-to-advanced fibrosis (March 2024)

• A 2023 meta-analysis in Diabetes & Metabolic Syndrome (PMID 37717295, n=2,413) showed:
  • ↓ ALT by 14.07 U/L (p<0.001)
  • ↓ Liver fat content by 4.97% (p<0.001)
  • ↓ Liver stiffness by 0.96 kPa (p=0.04)
  • ↑ GI adverse events (nausea, vomiting, diarrhea)
• Conditionally FDA-approved (subcutaneous 2.4 mg weekly) for MASH with moderate-to-advanced fibrosis (2024)

Other Agents Under Investigation

6d. Liver Transplantation

• NAFLD/NASH is a leading and growing indication for LT in the USA
• Posttransplant survival is comparable to other indications
• Higher waitlist mortality due to cardiovascular and renal comorbidities
• Donor livers with >30% macrovesicular steatosis carry increased graft failure risk
• Yamada's Textbook of Gastroenterology, p. 2139

7. Special Populations

• Pediatric NAFLD: Histologically distinct — portal-predominant inflammation, mononuclear rather than neutrophilic infiltrates; managed with lifestyle modification primarily
• Lean NAFLD: Occurs in ~10–20% of NAFLD patients with BMI <25; may have worse metabolic profile and fibrosis despite normal weight
• Post-transplant NAFLD recurrence: Risk factors include weight gain, metabolic syndrome, immunosuppressants (especially corticosteroids and calcineurin inhibitors)

8. Monitoring & Surveillance

• Periodic FIB-4/NFS to track fibrosis progression
• Liver ultrasound + AFP every 6 months for HCC surveillance in those with NASH cirrhosis
• Cardiology referral — cardiovascular risk assessment is essential
• Screen for T2DM, hypertension, dyslipidemia, CKD, and depression (incidence rate 29.1/1,000 PY)

9. Recent Advances (2024–2026)

1. Resmetirom FDA approval (March 2024) — first-ever disease-specific pharmacotherapy
2. Semaglutide conditional approval for MASH
3. EASL-EASD-EASO Clinical Practice Guidelines 2024 — updated screening, diagnosis, and management recommendations for MASLD
4. Liver stiffness measurement (FibroScan) validated as a surrogate endpoint for liver-related outcomes
5. APASL 2025 guidelines providing specific guidance on resmetirom patient selection, monitoring, and emerging drug combinations
6. GWAS studies identifying 17+ genetic loci, advancing precision medicine in NAFLD

Key References

Textbook sources: Robbins & Kumar Basic Pathology, p. 609–612 | Sleisenger & Fordtran's GI & Liver Disease, p. 1354–1365 | Yamada's Textbook of Gastroenterology, p. 2139 | Harrison's Principles of Internal Medicine 22E