356.1 🎓 醫學生版

356.1.0.1 📌 一頁重點

356.1.0.1.1 Nomenclature Update (2023-2024)

356.1.1 Old → New

• NAFLD (non-alcoholic fatty liver disease) → MASLD (metabolic-associated steatotic liver disease)
• NASH (non-alcoholic steatohepatitis) → MASH (metabolic-associated steatohepatitis)
• NAFL (non-alcoholic fatty liver) → MAFL or MASL
• Lean NAFLD → lean MASLD

356.1.2 Definition

• Steatotic liver disease (SLD) + at least one cardiometabolic risk factor + no significant alcohol (< 20 g/d women, < 30 g/d men)
• Met-ALD: SLD + cardiometabolic + alcohol (intermediate)
• ALD: alcohol-attributed
• Cryptogenic SLD: no metabolic risk

356.1.2.0.1 Epidemiology

• Globally most common chronic liver disease
• Taiwan ~ 25-30% adult prevalence
• Rising with obesity, T2DM
• MASH cirrhosis = leading indication for liver transplant in many regions
• HCC risk significant (cirrhosis + non-cirrhosis)

356.1.2.0.2 Alcohol-Related Liver Disease (ALD)

356.1.2.0.2.1 Spectrum

Alcoholic Fatty Liver (Steatosis): - Reversible - Most heavy drinkers develop - Asymptomatic or mild fatigue - Normalizes with abstinence

Alcoholic Hepatitis (AH): - Acute hepatitis with histologic features - Acute on chronic - Jaundice + AST elevation + neutrophilia + hepatomegaly - AST:ALT > 2:1 classic - ALT rarely > 300 - Severe AH: - Maddrey Discriminant Function (DF) > 32 - MELD > 21 - High mortality (15-50% in 30 days for severe)

Alcoholic Cirrhosis: - End-stage - Variable progression - Decompensation: ascites, variceal bleeding, encephalopathy, HCC - Liver transplant if abstinent (6 months traditional, less strict newer)

356.1.2.0.2.2 Diagnosis

• History: heavy alcohol use (women > 20 g/d for many years; men > 30 g/d)
• Lab: AST:ALT > 2, GGT elevated, MCV elevated
• Imaging: steatosis, advanced fibrosis
• Biopsy: characteristic features (Mallory-Denk bodies, neutrophil infiltrate, hepatocellular ballooning)

356.1.2.0.2.3 Severity Assessment

Maddrey Discriminant Function (DF): - 4.6 × (PT - control PT) + bilirubin - DF > 32 = severe AH - Steroid therapy decision

MELD Score: - > 21 = severe AH - > 30 = very severe

ABIC Score, Glasgow AH Score alternatives

356.1.2.0.2.4 Treatment

Alcohol Cessation (Foundation): - Critical - Multidisciplinary - Pharmacotherapy: naltrexone, acamprosate, baclofen - Behavioral: CBT, AA, motivational interviewing

Mild-Moderate AH: - Supportive - Nutrition (often malnourished — 1.5 g/kg protein, calories) - Vitamins (thiamine, folate, B12, A, D, E, K, zinc) - Treat complications

Severe AH (DF > 32): - Corticosteroids (prednisolone 40 mg/d × 28 days) - Lille score at day 7: predicts response - < 0.45: responder; continue 28 days - > 0.45: non-responder; stop steroids; consider transplant - Pentoxifylline: no longer recommended (STOPAH trial 2015 — negative) - N-acetylcysteine: variable evidence - Treat infections aggressively (high infection risk) - Address coagulopathy

Liver Transplant: - Traditionally 6 months abstinence - Recent: select severe AH with good psychosocial support → early transplant (after first decompensation, ELITAH approach) - Outcomes good

356.1.2.0.2.5 Long-Term Management

• Continued alcohol cessation
• Surveillance for HCC if cirrhosis
• Vaccinations
• Manage complications

356.1.2.0.3 Metabolic-Associated Steatotic Liver Disease (MASLD)

356.1.2.0.3.1 Definition (2023)

• Hepatic steatosis (> 5% on biopsy or imaging) + at least one cardiometabolic risk factor + no significant alcohol use

Cardiometabolic Risk Factors: - Overweight/obesity (BMI ≥ 25 — Asians ≥ 23) - Type 2 diabetes or impaired glucose tolerance - HTN - Dyslipidemia (low HDL, high TG) - Metabolic syndrome

356.1.2.0.3.2 Spectrum

MAFL (Metabolic-Associated Fatty Liver, or MASL): - Steatosis only - Less progressive

MASH (Metabolic-Associated Steatohepatitis): - Steatosis + hepatocellular ballooning + inflammation ± fibrosis - Fibrosis progression risk - Higher mortality

Cirrhosis + HCC: - Eventually progress - Even non-cirrhotic MASH can develop HCC

356.1.2.0.3.3 Risk Factors

• Obesity (≥ 80% of T2DM have MASLD)
• Type 2 DM
• Metabolic syndrome
• HTN
• Dyslipidemia
• PNPLA3, TM6SF2, GCKR polymorphisms (genetic)
• High fructose intake
• Sleep apnea
• Sarcopenic obesity

356.1.2.0.3.4 Clinical Presentation

• Often asymptomatic
• Fatigue
• Vague RUQ discomfort
• Hepatomegaly
• Cirrhosis features in advanced

356.1.2.0.3.5 Diagnosis

Imaging: - US: hyperechoic liver (sensitivity 60-80%); cheap, non-invasive - CT: hypodense liver - MRI: most sensitive; MR-PDFF (proton density fat fraction) - CAP (controlled attenuation parameter) on FibroScan: steatosis

Non-Invasive Fibrosis Scores: - FIB-4 score (age + AST + ALT + platelets): widely used screening - NAFLD Fibrosis Score (NFS) - ELF (Enhanced Liver Fibrosis) - FibroScan (transient elastography): steatosis (CAP) + fibrosis (LSM) - MR elastography: most accurate; expensive

Liver Biopsy: - For uncertain cases - Staging fibrosis - Distinguishes MASH from MAFL - NASH CRN scoring (NAS score)

356.1.2.0.3.6 Management

Lifestyle (Foundation): - Weight loss ≥ 5-10% — gold standard - Mediterranean diet - Caloric restriction - Exercise (≥ 150 min/week moderate) - Limit fructose - Coffee (may be protective; some evidence)

Pharmacotherapy (Recent + Emerging):

Resmetirom (Rezdiffra) — NEW 2024: - First FDA-approved MASH drug (March 2024) - Thyroid hormone receptor-β (THR-β) agonist - For non-cirrhotic MASH with fibrosis F2-F3 - MAESTRO-NASH trial - Improves histology + fibrosis

GLP-1 Receptor Agonists: - Semaglutide (Wegovy, Ozempic): STEP, SUSTAIN trials; ↓ MASH, weight loss - Liraglutide (Saxenda, Victoza) - Dulaglutide

GIP/GLP-1 Co-Agonist: - Tirzepatide (Mounjaro, Zepbound): SURPASS, SYNERGY-NASH trials - Even more weight loss - Strong effect on MASH

Other GLP-1 + Combination: - Survodutide (GLP-1/glucagon): phase 3 - Retatrutide (GLP-1/GIP/glucagon): phase 3, ~ 24% weight loss

Pioglitazone: - For MASH + T2DM - PPAR-γ agonist - Weight gain side effect - Improves NASH

Vitamin E: - 800 IU/d for non-diabetic non-cirrhotic MASH - PIVENS trial - Concerns: prostate cancer in men (?)

Bariatric Surgery: - Most effective for severe obesity - Roux-en-Y, sleeve gastrectomy - Improves MASH histology - Some have rebound (rare)

FXR Agonists: - Obeticholic acid (Ocaliva): approved for PBC but tested for MASH; FDA rejected for MASH 2023 - Other FXR agonists in trials

SGLT2 Inhibitors: - Modest MASH benefit - Useful for DM + CKD comorbidity

Statins: - Safe in MASLD/MASH - Useful for CV risk reduction - Possible mild MASH benefit

356.1.2.0.3.7 HCC Surveillance

• MASH cirrhosis: every 6 months US ± AFP
• Non-cirrhotic MASH: increasing recognition of HCC risk; guidelines evolving

356.1.2.0.3.8 Coexistence ALD + MASLD (MetALD)

• New category 2023
• Significant alcohol + metabolic risk
• Manage both

356.1.2.0.4 Differential Diagnosis

• Viral hepatitis (B, C)
• Autoimmune hepatitis
• Wilson disease
• Hemochromatosis
• Alpha-1 antitrypsin
• Drug-induced steatosis (amiodarone, methotrexate, valproate, tamoxifen, steroids, antiretrovirals)
• HIV
• TPN

356.1.2.1 🩺 床邊速查

• MASLD/MASH (2023 renaming from NAFLD/NASH): steatosis + cardiometabolic risk
• MASLD Taiwan prevalence ~ 25-30%
• ALD spectrum: steatosis → alcoholic hepatitis → cirrhosis
• Alcoholic hepatitis AST:ALT > 2; ALT rarely > 300; Maddrey > 32 = severe
• Severe AH treatment: corticosteroids + Lille score day 7
• MASLD treatment foundation: weight loss ≥ 5-10% + Mediterranean diet + exercise
• MASH pharmacotherapy 2024: resmetirom (Rezdiffra) FDA 2024 + GLP-1 RA (semaglutide) + tirzepatide + pioglitazone (DM) + vit E (non-DM)
• Bariatric surgery: most effective for severe obesity + MASH

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