Fatty liver disease
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Fatty Liver Disease (MASLD / NAFLD)
Nomenclature Update
The terminology has shifted. The umbrella term is now steatotic liver disease (SLD), with:
- MASLD (metabolic dysfunction-associated steatotic liver disease) replacing NAFLD
- MASH (metabolic dysfunction-associated steatohepatitis) replacing NASH
This rename reflects ~98% overlap with the old NAFLD/NASH population and more precisely ties the disease to its metabolic drivers. Patients who drink socially (up to 20-50 g/day in women, 30-60 g/day in men) can still be classified as MASLD provided metabolic risk factors are present. - Harrison's Principles of Internal Medicine 22E, p. 2745
Definition & Diagnostic Criteria
MASLD is defined as hepatic steatosis (fat in ≥5% of hepatocytes) in individuals who:
- Drink little to no alcohol, AND
- Have at least one of five cardiometabolic risk factors (central obesity, hypertriglyceridemia, low HDL, hypertension, or prediabetes/T2DM), AND
- Have no secondary cause of hepatic injury (viral hepatitis, Wilson disease, medications, etc.)
Normal liver enzymes do NOT exclude MASLD. The true upper normal for ALT is 29-33 U/L in men and 19-25 U/L in women - lower than most labs report. - Harrison's 22E, p. 2746
Epidemiology
- Global prevalence: ~25% of adults; projected to exceed 30% in the U.S. by 2030
- Highest prevalence in Hispanic and South Asian-Indian populations (~50%), intermediate in whites (~30%), lowest in African Americans (~25%)
- Now a leading indication for liver transplantation in the United States
- MASLD-related HCC is growing fastest among all liver cancer etiologies - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 786; Harrison's 22E, p. 2745
Disease Spectrum & Progression
Figure: Global NAFLD prevalence is ~25%. Of these, 79-90% have simple steatosis (NAFL) and 10-30% have NASH. About 20% are "rapid progressors" who can jump directly to advanced fibrosis (F3-F4). Fibrosis stage is the key determinant of clinical outcomes.
The spectrum from benign to severe:
| Stage | Features |
|---|---|
| Isolated steatosis (MASL) | Fat accumulation, no injury - most clinically benign |
| MASH (steatohepatitis) | Steatosis + ballooned hepatocytes + lobular inflammation |
| Fibrosis (F1-F3) | Progressive scarring; F3 = bridging fibrosis |
| Cirrhosis (F4) | End-stage; risk of HCC, hepatic decompensation |
Fibrosis stage - not inflammation - is the single most important predictor of clinical outcomes, morbidity, and mortality. - Yamada's Textbook of Gastroenterology 7e
Pathogenesis
The central driver is insulin resistance acting through several converging mechanisms:
- Free fatty acid (FFA) flux - Insulin resistance causes overactivity of lipoprotein lipase in adipocytes, flooding the liver with FFAs that are stored as triglycerides
- Reduced adiponectin - Dysfunctional adipocytes produce less adiponectin, impairing FFA oxidation in skeletal muscle and increasing hepatocyte FFA uptake
- Lipotoxicity - Accumulated lipids (especially saturated FFAs like palmitate and lysophosphatidylcholine) activate ER stress, mitochondrial dysfunction, and hepatocyte apoptosis
- Innate immune activation - Injured hepatocytes trigger Kupffer cell activation, releasing TNF-α and TGF-β, which activate hepatic stellate cells → collagen deposition → fibrosis
- Inflammasome activation - IL-1 release further amplifies inflammation
- Gut microbiome - Dysbiosis and increased gut-derived endotoxin (LPS) drive hepatic inflammation
- Genetic factors - PNPLA3 rs738409 (C>G) polymorphism significantly increases MASLD severity and HCC risk; first-degree relatives of MASH cirrhosis patients have a 12-fold higher risk of advanced fibrosis
- Robbins, Cotran & Kumar, p. 786-787; Harrison's 22E, p. 2745
Clinical Features
- Most patients are asymptomatic - discovered incidentally via elevated transaminases or hepatic echogenicity on ultrasound
- Some report fatigue, malaise, or right upper quadrant discomfort
- AST:ALT ratio typically < 1 (contrast with alcohol-related disease where ratio > 2)
- Elevated risk of cardiovascular disease (the leading cause of death in MASLD overall)
- In those with MASH/advanced fibrosis, liver-related mortality exceeds cardiovascular mortality
- Complications include decompensated cirrhosis, variceal bleeding, encephalopathy, and HCC - Robbins Basic Pathology 10e, p. 1922
Diagnosis
Non-invasive workup:
- Ultrasound: first-line; sensitive for moderate-severe steatosis but poor for fibrosis staging
- Transient elastography (FibroScan / VCTE): assesses liver stiffness as surrogate for fibrosis; controlled attenuation parameter (CAP) can quantify steatosis simultaneously
- MR elastography (MRE): more accurate than VCTE for fibrosis staging
- Serum scores: NAFLD Fibrosis Score, FIB-4 index, ELF score - used to risk-stratify and identify who needs biopsy
- FLI (Fatty Liver Index): uses BMI, waist circumference, triglycerides, GGT - predicts steatosis
Liver biopsy remains the gold standard to:
- Diagnose MASH definitively (requires steatosis + ballooning + lobular inflammation)
- Stage fibrosis accurately
- Guide treatment decisions
Biopsy is NOT required for all patients - it is reserved for those with intermediate/high non-invasive fibrosis scores or when the diagnosis is uncertain. - Sleisenger & Fordtran's GI and Liver Disease; Harrison's 22E
Differential diagnosis of hepatic steatosis includes: alcoholic liver disease, hepatitis C (genotype 3), medications (amiodarone, methotrexate, tamoxifen, valproate), Wilson's disease, lipodystrophy, parenteral nutrition, inborn errors of metabolism.
Treatment
1. Lifestyle Modification (Cornerstone)
| Weight Loss Goal | Histologic Benefit |
|---|---|
| ≥5% body weight | Improves steatosis, ballooning, inflammation |
| ≥7% body weight | Improves NAFLD Activity Score (NAS) |
| ≥10% body weight | Resolves MASH histologically; fibrosis stabilizes or improves |
- Diet: Moderate caloric restriction (500-750 kcal/day deficit); Mediterranean diet preferred; avoid high-fructose corn syrup and saturated fats; reduce simple carbohydrates
- Exercise: Aerobic + resistance training 3-4x/week (~400 kcal expenditure per session); best results when weight loss is achieved
- Coffee: 2-3 cups/day associated with decreased fibrosis risk
- Sustained weight loss is achievable in only a minority of patients long-term - Sleisenger & Fordtran's, Table 87.3
2. Pharmacotherapy
Currently FDA-approved (as of 2024-2025):
- Resmetirom (Rezdiffra) - selective thyroid hormone receptor-beta (THR-β) agonist; the first FDA-approved drug specifically for MASH with liver fibrosis (F2-F3). A 2024 systematic review and meta-analysis (PMID: 39187533) confirmed its efficacy and safety in MASLD/MASH.
Other agents used in practice (off-label or supported by evidence):
- Pioglitazone (TZD): improves insulin sensitivity; reduces steatosis, inflammation, and ballooning; may reduce fibrosis; used in MASH with T2DM and even in non-diabetics
- Vitamin E (800 IU/day): antioxidant; reduces steatosis and inflammation in non-diabetic adults with biopsy-proven MASH; a 2024 Cochrane review (PMID: 39412049) evaluated the evidence
- GLP-1 receptor agonists (semaglutide, liraglutide): significant weight loss + direct hepatic effects; a 2025 meta-analysis (PMID: 40489581) confirmed GLP-1-based therapies improve MASLD/MASH histologically
- Statins: safe in MASLD/MASH; reduce cardiovascular risk (primary mortality driver); do not significantly improve liver histology
- SGLT2 inhibitors, metformin: improve metabolic parameters but less robust liver-specific evidence
3. Bariatric/Metabolic Surgery
Indicated in eligible patients (BMI ≥35 or ≥30 with metabolic comorbidities). A meta-analysis of 32 studies (3,093 biopsies) showed:
- Steatosis resolution: 66%
- Inflammation resolution: 50%
- Ballooning degeneration resolution: 76%
- Fibrosis resolution: 40%
RYGB (Roux-en-Y gastric bypass) produces greater liver improvement than purely restrictive procedures (sleeve gastrectomy). - Current Surgical Therapy 14e
Complications
| Complication | Notes |
|---|---|
| Cirrhosis | Risk increases with fibrosis stage; F4 is compensated/decompensated cirrhosis |
| HCC | Can arise even in non-cirrhotic MASLD; NAFLD now the fastest-growing cause of HCC in the U.S. |
| Cardiovascular disease | Leading cause of death in MASLD overall; must be actively managed |
| Liver transplant | MASLD is a top indication; recurrence can occur post-transplant if metabolic factors uncontrolled |
Pediatric MASLD
A growing problem due to epidemic childhood obesity. Children show a different histologic pattern compared to adults:
- Inflammation and scarring are more prominent in portal tracts and periportal regions
- Mononuclear infiltrates predominate (vs. neutrophilic in adults)
- Robbins Basic Pathology 10e, p. 1926
Key recent evidence updates (2024-2025):
- Resmetirom received FDA approval for MASH with fibrosis - first drug approved for this indication [PMID 39187533]
- GLP-1 receptor agonists (especially semaglutide) are showing strong histologic benefit in MASH clinical trials [PMID 40489581]
- Cochrane review (2024) on Vitamin E for NAFLD provides updated evidence base [PMID 39412049]
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