Metabolic Dysfunction–Associated Steatotic Liver Disease and Steatohepatitis¶
Chapter 354 | Part 10: Disorders of the Gastrointestinal System
KEY CLINICAL POINTS¶
- MASLD/MASH replace NAFLD/NASH as the new nomenclature, emphasizing metabolic dysfunction over alcohol.
- MASLD is strongly linked to metabolic syndrome, T2DM, obesity, and insulin resistance.
- Noninvasive tests (FIB-4, ELF, VCTE) are critical for staging and risk stratification.
- Lifestyle modification and pharmacotherapy (GLP-1RAs, SGLT-2is) are first-line treatments.
- Liver transplantation is indicated for end-stage MASLD with cirrhosis and complications.
1. DEFINITION & OVERVIEW¶
MASLD (Metabolic Dysfunction–Associated Steatotic Liver Disease) and MASH (Metabolic Dysfunction–Associated Steatohepatitis) replace NAFLD/NASH. MASLD is defined by hepatic steatosis in individuals with metabolic dysfunction (e.g., obesity, T2DM) and minimal alcohol intake. MASH includes steatosis with inflammation/fibrosis. The new criteria emphasize metabolic drivers over alcohol, with near-complete overlap with historical NAFLD/NASH populations.
Table 354-1 Alternative Causes of Hepatic Steatosis¶
| Category | Examples |
|---|---|
| Alcohol-related liver disease | Alcohol abuse |
| Viral hepatitis | Hepatitis C (genotype 3) |
| Inborn errors of metabolism | Abetalipoproteinemia, Galactosemia |
| Medications | 5-Fluorouracil, Amiodarone, Tamoxifen |
| Miscellaneous | Inflammatory bowel disease, Lipodystrophy |
1.1 Disease Nomenclature¶
MASLD/MASH replace NAFLD/NASH. Key features: hepatic steatosis in individuals with metabolic dysfunction (BMI ≥ 25, T2DM, insulin resistance) and minimal alcohol ( ≤ 20 g/d for women, ≤ 30 g/d for men). MASH includes steatosis with inflammation/fibrosis. MetALD (Metabolic and Alcohol-Associated Liver Disease) is a new category for patients with both metabolic and alcohol-related risk factors.
2. EPIDEMIOLOGY¶
MASLD prevalence is 25–30% in the U.S. population, rising with obesity and metabolic syndrome. 14% of asymptomatic ≥ 50-year-olds have MASH. MASLD is a leading cause of liver transplantation in the U.S. with 3–6% of patients having MASH. Cirrhosis from MASLD increases risk of HCC, hepatic decompensation, and mortality.
2.1 Demographics¶
Prevalence varies by ethnicity: 25% in African Americans, 50% in Hispanics/Asian-Indians, 30% in whites. Obesity and truncal fat distribution are key risk factors. MASLD is increasingly documented in children/adolescents due to rising childhood obesity.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Insulin resistance, lipotoxicity, and genetic factors (e.g., PNPLA3, TM6SF2) drive MASLD. Gut microbiota dysbiosis and metabolic syndrome exacerbate inflammation. Obesity leads to hepatic steatosis via increased lipogenesis, reduced fatty acid oxidation, and oxidative stress. Fibrosis progression is influenced by comorbidities (diabetes, hypertension) and genetic variants.
3.1 Molecular Mechanisms¶
Lipotoxicity from fatty acid overload causes mitochondrial dysfunction, oxidative stress, and inflammation. PNPLA3 variants increase hepatic fat accumulation. Gut microbiota alterations enhance energy harvest and intestinal permeability, promoting systemic inflammation.
4. CLINICAL FEATURES¶
Most patients are asymptomatic. When symptoms occur, they include fatigue, right upper quadrant pain, and signs of metabolic syndrome (e.g., hypertension, dyslipidemia). Advanced MASLD may present with jaundice, ascites, variceal hemorrhage, or hepatomegaly. Complications include cirrhosis, HCC, and portal hypertension.
4.1 Complications¶
Cirrhosis increases risk of hepatic decompensation, HCC, and mortality. MASLD is an independent risk factor for metabolic syndrome and T2DM. Obesity and insulin resistance drive disease progression.
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish MASLD from alcohol-related liver disease, viral hepatitis (e.g., HCV genotype 3), drug-induced steatosis, and hereditary metabolic disorders. Exclude autoimmune liver disease, iron overload, and Wilson’s disease.
6. INVESTIGATIONS & DIAGNOSIS¶
Noninvasive tests (FIB-4, ELF, VCTE, MRE) assess fibrosis. Liver biopsy remains the gold standard for histologic confirmation. Elevated ALT/AST with metabolic risk factors or minimal alcohol use suggests MASLD. Exclude viral hepatitis, autoimmune liver disease, and other causes.
Table 354-2 Medications Associated with Hepatic Steatosis and Steatohepatitis¶
| Medication | Liver Finding | Mechanism |
|---|---|---|
| 5-Fluorouracil | Macrovesicular steatosis | Unknown |
| Amiodarone | Macrovesicular steatosis, steatohepatitis, fibrosis | Decreases b-oxidation, increases lipid peroxidation |
| Cocaine | Microvesicular steatosis | Inhibits b-oxidation |
| Fluoxetine | Macrovesicular steatosis | Increases lipid accumulation |
| L-Asparaginase | Microvesyicular steatosis | Inhibits lipoprotein export |
6.1 Diagnostic Algorithm¶
Algorithm for risk stratification: FIB-4 <1.3 (low risk) vs ≥ 2.67 (high risk). Secondary tests include VCTE, ELF, or MRE. Liver biopsy is reserved for indeterminate cases or advanced fibrosis.
7. MANAGEMENT & TREATMENT¶
Lifestyle modification (diet, exercise) is foundational. Pharmacotherapy includes GLP-1RAs (semaglutide, liraglutide), SGLT-2is, and pioglitazone. Bariatric surgery is effective for severe obesity. Liver transplantation is indicated for end-stage cirrhosis. Avoid corticosteroids unless for severe alcoholic hepatitis.
7.1 Pharmacologic Therapies¶
Resmetirom (THR-B agonist) and GLP-1RAs (e.g., semaglutide) reduce liver fat and fibrosis. SGLT-2is improve glycemic control and reduce liver enzymes. Metformin may reduce HCC risk in T2DM but has limited histologic benefit in NASH.
8. PROGNOSIS & COMPLICATIONS¶
MASLD progression to cirrhosis/hypertension/HCC is influenced by obesity, diabetes, and fibrosis stage. Early intervention with lifestyle changes and noninvasive monitoring improves outcomes. Advanced fibrosis ( ≥ F2) increases risk of decompensation and mortality.
9. SPECIAL CONSIDERATIONS¶
MASLD in pregnancy (acute fatty liver of pregnancy) and pediatric populations (linked to childhood obesity). Global health burden: 30% prevalence worldwide, with rising rates in Latin America, Middle East, and South Asia. Bariatric surgery is effective but contraindicated in decompensated cirrhosis.
9.1 Global Health¶
MASLD is a major cause of chronic liver disease globally, with rising economic burden (~$103 billion/year in the U.S.). Disparities exist by ethnicity (higher in Hispanics/Asians, lower in African Americans). Multistakeholder collaboration is needed for prevention and treatment.
10. KEY POINTS & CLINICAL PEARLS¶
- MASLD/MASH replace NAFLD/NASH; emphasize metabolic drivers over alcohol. 2. Noninvasive tests (FIB-4, VCTE) guide staging and management. 3. Lifestyle modification and GLP-1RAs/SGLT-2is are first-line therapies. 4. Bariatric surgery improves MASH and reduces liver-related mortality. 5. Early intervention prevents fibrosis progression and HCC.