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Nonalcoholic Fatty Liver Disease (NAFLD)

BASICS

Description

  • NAFLD is a spectrum of liver diseases:
  • NAFL: Reversible fatty infiltration of liver (no cell injury/fibrosis)
  • NASH: Fatty liver with inflammation, hepatocyte injury, and possible fibrosis
  • NASH Cirrhosis: Cirrhosis with current/past evidence of steatosis/steatohepatitis
  • Not due to other causes (alcohol, viral hepatitis, medications)

EPIDEMIOLOGY

  • Most common chronic liver disease in the US/industrialized nations
  • Up to 90% of asymptomatic mild aminotransferase elevation not caused by alcohol/other etiology is NAFLD
  • Predicted to be most frequent indication for liver transplant by 2030
  • Prevalence: 10–46% (US); 58–74% of obese, 90% morbidly obese, 69–87% with T2DM, 50% with dyslipidemia
  • Affects adults (40s–50s), children (9.6% pediatric prevalence, rising with obesity)
  • Sex: Male = Female

ETIOLOGY AND PATHOPHYSIOLOGY

  • Key mechanism: Insulin resistance β†’ ↑ lipolysis, triglyceride synthesis, hepatic FA uptake
  • NAFL: Excessive triglyceride accumulation, impaired FA removal
  • NASH: "Multiple hit" (insulin resistance, hormones, oxidative stress, genetics, gut microbiota) β†’ inflammation, cell injury
  • Genetics: Some familial clustering, higher prevalence in first-degree relatives

RISK FACTORS

  • Obesity (BMI >30), central obesity, metabolic syndrome
  • Type 2 DM, hypertension, dyslipidemia, CVD, CKD
  • Protein-calorie malnutrition, long-term TPN
  • Severe weight loss (starvation, bariatric surgery)
  • Exposure: organic solvents, vinyl chloride, hypoglycin A
  • Drugs: steroids, tamoxifen, MTX, amiodarone, antiretrovirals, valproic acid, etc.
  • Smoking, increasing age, cholecystectomy

Pregnancy

  • Acute fatty liver of pregnancy (rare, serious; 3rd trimester; 50% w/ preeclampsia)

Pediatric

  • Prevalence rising with childhood obesity
  • Vitamin E may benefit

GENERAL PREVENTION

  • Maintain healthy BMI, prevent/optimize DM control, avoid hepatotoxins, alcohol:
  • ≀2 units/day (men); ≀1 unit/day (women)
  • Avoid hepatotoxic meds

COMMONLY ASSOCIATED CONDITIONS

  • Central obesity, metabolic syndrome, T2DM, hypertension, dyslipidemia
  • CVD, arrhythmias, CKD, hypothyroidism, hypogonadism, OSA, PCOS, GH deficiency
  • Preeclampsia (pregnancy)

DIAGNOSIS

  • No routine screening (lack of proven drug therapy/unclear long-term screening benefit)
  • Suspect in patients with asymptomatic elevated aminotransferases and metabolic risk factors
  • Often asymptomatic (possible fatigue, RUQ discomfort)

Physical Exam

  • May be normal or show liver tenderness, hepatomegaly, splenomegaly
  • Advanced: stigmata of CLD, portal hypertension, jaundice

Diagnosis Requires:

  • Hepatic steatosis by imaging/biopsy
  • No significant alcohol use
  • Exclusion of other causes
  • No coexisting chronic liver disease

Labs/Imaging

  • AST/ALT: may be elevated, usually <3–4x ULN; AST/ALT <1
  • Lipid profile: ↑ cholesterol, ↑ LDL, ↑ TG, ↓ HDL
  • Ferritin: elevated
  • Other labs to exclude other causes: celiac, Ξ±1-antitrypsin, iron, copper, hepatitis serologies, ANA, etc.
  • Imaging:
  • US (first-line): hyperechoic liver
  • Elastography (FibroScan, VCTE, ARFI, MRE): fibrosis assessment
  • Noninvasive scoring: NAFLD fibrosis score, FIB-4, APRI
  • Liver biopsy: gold standard (for uncertain/progressive cases; only if management will change)

Histology Scoring

  • NAS (NAFLD Activity Score): steatosis (0–3), inflammation (0–3), ballooning (0–2); β‰₯5 = NASH likely
  • Fibrosis staging (0–4)

DIFFERENTIAL DIAGNOSIS

  • Viral hepatitis, alcoholic liver disease, autoimmune hepatitis, drug/toxin hepatitis, celiac, hemochromatosis, Wilson disease, muscle disorders

TREATMENT

General Measures

  • Weight loss: Cornerstone; aim for 5–10% of body weight
  • Diet: Mediterranean (reduces liver fat); avoid excess alcohol
  • Exercise: Aerobic 5x/week, β‰₯150 min/week
  • Treat metabolic syndrome: Control DM, HTN, dyslipidemia, obesity
  • Vaccinate: Hepatitis A/B, pneumococcal, influenza
  • Avoid hepatotoxins

Medications

  • No definitive drug therapy for NAFL/NASH
  • Consider:
  • Pioglitazone (TZD): For NASH (with or without T2DM; best in T2DM)
  • Vitamin E 800 IU/d: Only in biopsy-proven NASH, non-diabetic, no ↑ prostate CA/stroke risk
  • GLP-1 agonists (semaglutide, liraglutide): Improve histology, weight loss
  • Statins: CV risk reduction, safe in compensated cirrhosis
  • SGLT-2 inhibitors: Reduce steatosis in T2DM (unclear on fibrosis)
  • Limited/controversial: Metformin, UDCA, pentoxifylline, omega-3, aspirin, coffee, aramchol, fibroblast growth factor analogues, silymarin

Procedures

  • Bariatric surgery: For severe obesity/NAFLD unresponsive to lifestyle
  • Liver transplant: For end-stage liver disease (NASH may recur in new liver)

Referral

  • To hepatology if persistent AST/ALT ↑, advanced fibrosis, or concerning biopsy/imaging findings

ONGOING CARE

  • Annual LFTs, periodic US/CT (every 2–4y) if at risk
  • Repeat liver biopsy if fibrosis progression suspected (β‰₯5y after baseline)
  • Fibrosis stage is strongest predictor of mortality
  • HCC screening in noncirrhotic NAFLD: Not yet established

DIET

  • Low saturated/trans fats, low simple carbs, avoid excess alcohol

PATIENT EDUCATION

  • Importance of lifestyle change (nutrition, activity, alcohol avoidance)
  • Support for sustained weight loss

PROGNOSIS

  • NASH is the progressive form; can lead to cirrhosis, HCC, cholangiocarcinoma, liver failure
  • Cirrhosis in up to 20%; HCC in up to 42% (even without cirrhosis)
  • Transplant effective, but NAFLD recurs if risk factors persist

COMPLICATIONS

  • Decompensated cirrhosis, portal hypertension, ascites, encephalopathy, variceal bleed, hepatorenal/hepatopulmonary syndromes

ICD-10 CODE

  • K76.0 Fatty (change of) liver, not elsewhere classified

Clinical Pearls

  • NAFLD is the most common chronic liver disease in the US and children; rising with obesity
  • Spectrum: NAFL β†’ NASH β†’ fibrosis β†’ cirrhosis
  • Lifestyle changes with sustained weight loss are cornerstone of therapy
  • NASH is the only progressive form and may occur even in absence of cirrhosis