Steatotic Liver Disease

• Definition

  • Steatotic Liver disease (or hepatic steatosis) 

    • Excessive fat accumulation in liver (intracellular fat in >5% hepatocytes)

    • Progression from simple steatosis -> steatohepatitis -> fibrosis -> cirrhosis

      • Hepatocellular carcinoma (HCC) is associated with cirrhosis due to NAFLD (2.4-12.8% over three years)

  • Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease or NAFLD 

    • Presence of hepatic steatosis in conjunction with 1 cardiometabolic risk factor and no other discernible cause (eg. alcohol)

      • Cardiometabolic risk factors include:

        • BMI ≥25 kg/m2 (≥23 kg/m2 in Asia); WC >94 cm in men or >80 cm in women; or ethnicity-adjusted equivalent

        • Fasting serum glucose level ≥5.6 mmol/L; 2-h postload glucose level of ≥7.8 mmol/L; hemoglobin A1c ≥5.7%; T2D; or prescribed treatment for T2D

        • Blood pressure of 130/85 mm Hg or a prescribed specific antihypertensive drug treatment

        • Plasma triglyceride level ≥1.70 mmol/L or prescribed lipid-lowering treatment

        • Plasma HDL-C level ≤1.3 mmol/L or prescribed lipid-lowering treatment

  • Metabolic dysfunction–associated steatohepatitis (MASH) 

    • Hepatic steatosis with hepatic injury/inflammation on biopsy

    • Secondary causes include:

      • Obesity and other metabolic conditions (dyslipidemia, type 2 diabetes)

      • Extensive weight loss from gastric bypass or jejunoileal bypass

      • Total parenteral nutrition

      • Celiac disease (especially when treated with a gluten-free diet)

      • Genetic causes (glycogen storage disease, abetalipoproteinemia, etc)

      • Alcohol consumption

      • Medications such as amiodarone, diltiazem, steroids, tamoxifen, or antiretroviral treatment

      • Hepatitis C virus infection

  • Metabolic-associated alcoholic liver disease (MetALD) 

    • Consumption of substantial amounts of alcohol (>140 g to 340 g per week for women and >210 g to 420 g per week for men) associated with metabolic syndrome 

  • Alcoholic liver disease (ALD)

    • High consumption of alcohol (quantities exceeding 340 g per week for women and 420 g per week for men) irrespective of its association with metabolic dysfunction is still termed 

Risk factors for progression

• Obesity

• DM2

• Dyslipidemia

• Metabolic syndrome (BP, fasting glucose, HDL, TG, waist circumference)

• ALT and AST > 2 ULN

Note: Coffee consumption associated with lower risk of progression

DDx of secondary hepatic steatosis

• Macrovesicular steatosis

  • Alcohol consumption

  • Hepatitis C

  • Wilson’s disease

  • Lipodystrophy

  • Starvation

  • Parenteral nutrition

  • Abetalipoproteinemia

  • Medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids) 

• Microvesicular steatosis

  • Reye’s syndrome

  • Medications (valproate, anti-retroviral medicines)

  • Acute fatty liver of pregnancy

  • HELLP syndrome

  • Inborn errors of metabolism (e.g., LCAT deficiency, cholesterol ester storage disease, Wolman disease) 

Investigations

• Alcohol intake

• Medication review and history of steatosis-associated drugs

• Person and family history of diabetes, hypertension, cardiovascular disease, cirrhosis

• BMI, waist circumference, body weight change

Labs

• CBC (platelets)

• AST, ALT, Alk phos, Bilirubin

• Albumin

• HBsAg, Anti-HCV Ab

• Ferritin, iron

• Fasting glucose, A1C

• Lipid panel

• INR

• Consider additional testing in patients with abnormal liver tests or family history of cirrhosis

  • ANA, anti-SM, anti-LKM

  • Other: a-1 antitrypsin, ceruloplasmin, anti-TTG/IgA, TSH

Imaging

• Ultrasound first-line

• May consider MRI/CT

Management

• Exercise and Weight loss

• Avoid alcohol consumption

• Diet - Calorie-restricted (aim 1kg/week)

  • Consider referral to dietician

  • May consider Orlistat if fail lifestyle intervention and BMI>30, only continue if >5% weight loss in 3 months (max one year to avoid risk of Vitamin deficiency)

  • Benefit of bariatric surgery in NASH unclear

• Hepatitis A and B vaccination if no serologic evidence of immunity

  • Pneumoccocal vaccine and age-appropriate vaccine

• Treat comorbid conditions, such as diabetes, hyperlipidemia, hypertension, or sleep apnea

  • Statins are not contraindicated (not at increased risk of hepatotoxicity)

• Calculate risk score

  • If FIB-4>1.30 (or  Fibrosis Score ≥ F2), consider referral for fibroscan

  • If low, consider recalculate score q1-3y

Indications for additional investigation (Biopsy vs. Fibroscan)

• Peripheral stigmata of chronic liver disease (suggestive of cirrhosis)

• Splenomegaly (suggestive of cirrhosis)

• Cytopenias (suggestive of cirrhosis)

• Serum ferritin >1.5 times the upper limit of normal (suggestive of NASH and advanced fibrosis)

• >45 years of age with associated obesity or diabetes (increased risk of advanced fibrosis)

• Other:

  • ALT:AST >1

  • ALT/AST elevated > 6 months

Management of Biopsy-Proven MASH

• Medications if biopsy-proven pre-cirrhotic MASH who failed lifestyle

  • May consider Vitamin E 800 units/day in non-diabetic

    • Risk of hemorrhagic stroke, prostate cancer

  • Thiazolidinediones: Pioglitazone 30mg/day

    • Risk of weight gain, CHF, bladder CA, osteoporosis

  • Dapagliflozin 10mg PO daily may improve MASH

• MASH Cirrhosis should undergo HCC screening with serial ultrasound q6 months and endoscopy for varices screening