EtOH/NAFLD Liver Disease

Question 1

Non-alcoholic Fatty Liver Disease (NAFLD): Terminology

Answer 1

• Alcohol-like liver disease in individuals who do not consume excessive alcohol.
• Histologic Spectrum of Liver Damage (require biopsy)
  
  • NAFL → Fatty Liver (Steatosis)
  • NASH → Fatty Liver + Inflammation + Increased hepatocyte death (Steatohepatitis)
• Spectrum of Hepatic Pathology:
  
  • NAFL → NASH → Cirrhosis → HCC

Question 2

Non-alcoholic Fatty Liver Disease (NAFLD): Epidemiology

Answer 2

• Very common and prevalent
• NAFLD common in Middle east
• Morbidly obese & Gastric bypass people + DM2 (Insulin resistance) + CVD + Metabolic Syndrome + Microbial Dysbiosis within the colon are at high risk of NAFLD.
• High prevalence in certain in certain ethnic groups genes → TM6SF2 & PNPLA3 (has lipolytic activity)

Question 3

Non-alcoholic Fatty Liver Disease (NAFLD): Pathophysiology (Insulin resistance is underlying defect in NAFLD)

Answer 3

• Triglycerides are the lipid type that accumulates in NAFLD → Disruption of the balance in the liver → causes triglycerides to be over synthesized and uptake by the liver → which initiates inflammatory response by TNF-a to increase & Hormone Adiponectin (Inhibit FA Uptake, enhance insulin sensitivity) to decrease imbalance → NAFL + NASH + Insulin Resistance
• More Pro inflammatory and less anti inflammatory

Question 4

Non-alcoholic Fatty Liver Disease (NAFLD): Diagnosis

Answer 4

• Liver Ultrasound
• AST & ALT may be elevated or Normal
• Markers for Metabolic Syndrome: Hyperglycemia, Elevated HbA1C, Hyperlipidemia.
• Elastography (Fibroscan) → to Establish Severity
  Liver Biopsy → is Gold Standard but Invasive
• DM2 suggest bridging Fibrosis
• Clinical prognosis depends on histology:
  
  • Steatosis (Benign) but Steatohepatitis increases risk of Cirrhosis
  • Signs of Portal HTN identify high risk group

Question 5

Non-alcoholic Fatty Liver Disease (NAFLD): Treatment

Answer 5

• Weight Loss, Weight loss surgery, Exercise in Absence of weight loss decrease steatosis
• Vitamin E improves Steatosis & Inflammation (Don’t give Pts with DM2)
• Pioglitazone improves inflammation in NASH in Non-diabetic Pts.

Question 6

Alcoholic Liver Disease (ALD): Epidemiology

Answer 6

• 50% of ESLD mortality
• 230 g of alcohol for 20 years (Male >21 units, Women 7-14 units)

Question 7

Alcoholic Liver Disease (ALD): Histology

Answer 7

Question 8

Alcoholic Liver Disease (ALD): Alcohol Metabolism

Answer 8

• Alcohol is oxidized by 3 enzymes → Alcohol dehydrogenase, Microsomal ethanol oxidizing system (MEOS), & Catalase (Peroxisomes & Mitochondria)
• Acetaldehyde → highly reactive & toxic (ALDH2)

Question 9

Alcoholic Liver Disease (ALD): Risk Factors

Answer 9

• Affecting Factors:
  
  • Malnutrition,
  • Gender (Female),
  • Hereditary Variations (ADH2*2 & ADH3*1 fast alcohol Metabolism, ALDH2*2 avoid EtOH)
  • Hep C & Hep B.
  • Japanese ppl easily get toxicity

Question 10

Alcoholic Liver Disease (ALD): Pathogenesis

Answer 10

Redox Alteration (Excess NADH shifts redox to FA synthesis & decrease gluconeogenesis.) → Oxidation production & Oxidation Damage (due to lipid peroxidation & DNA Damage in Mitochondria) → Acetaldehyde Toxicity (Acetaldehyde metabolism is shunted in alcoholics to produce O2 Radicals that impairs mitochondrial B- oxidation of FAs) → Mitochondrial Injury (Megamitochondria due to altered lipid membrane & microvesicular steatosis) → Cytokines (Increase TNF-a, IL-8, IL6, TGF-B, and key player → Kuppfer cell Activation (Primed by ETOH to be hypersensitive) → Neoantigens → Fibrosis (Stellate Cells, activated become proliferative and produce collagen)

Question 11

Alcoholic Liver Disease (ALD): Treatment

Answer 11

• Proper Nutrition (STOP Alcohol consumption)
• PTU (Propylthiouracil) – Corticosteroids -Colchicine
• Pentoxifylline – Polyunsaturated Lecithin
• Antioxidants Vitamin A & E