ALD and NAFLD Flashcards
Define ALD
Alcoholic liver disease
Fatty liver/steatosis
• Hepatocytes contain macrovesicular droplets of TAGs
• With abstinence = returns to normal
• Steatosis predisposes to fibrosis and cirrhosis
Alcoholic hepatitis
• From sustained interval of excessive drinking
Characterized:
• Ballooned hepatocytes
• Eosinophilic inclusion bodies of cytokeratin elements (Mallory bodies)
• Neutrophilic infiltrates in hepatic lobule
• Filamentous collagenization between hepatocytes; radiating from central vein
o End-stage of chronic alcoholic liver damage → cirrhosis
o Note: all 3 manifestations may occur in same biopsy
Define NAFLD/NASH
Non-alcoholic steatohepatitis/NASH and Non-alcoholic fatty liver disease/NAFLD
o >5% of hepatocytes have macrosteatosis in absence of alcohol use
o Covers spectrum of disorders
Describe the epidemiology of NAFLD/NASH.
Direct link between prevalence of obesity and NAFLD/NASH
• In patients with Class II obesity (BMI >35) undergoing bariatric surgery:
• NAFLD = 91%
• NASH = 37%
Prevalence of elevated serum aminotransferases = 8%
• But does not account for people with normal aminotransferases and increased macrovesicular liver fat
• Also, liver enzymes could be elevated for other reasons
Prevalence of NASH ~ 15% of U.S. adults
Explain the mechanisms of ALD
o Normally: alcohol metabolized by oxidation → acetaldehyde → acetate
o Generates excess reducing equivalents (NADH)
o Changes in NADH/NAD+ ratio inhibits fatty acid oxidation and TCA cycle = promotes lipogenesis
Trigger of inflammatory process = endotoxin
• Associated with lipopolysaccharide (LPS) in Gram-negative bacteria ‘
• With chronic alcohol exposure → alters gut permeability → allows LPS/endotoxin to translocate from bowel to portal blood
LPS/endotoxin binds Kupffer cells via receptor complex → cascade of events:
• Cytokine release = TNF-a
• Reactive oxidative species
Immediate result: alcoholic hepatitis
Persistent inflammation, lipid peroxidation, oxidant generation → activation of hepatic stellate cells (HSC) → produce collagen → fibrosis
Explain the mechanisms of NAFLD/NASH
o Remain unclear
o Resistance to insulin = factor in progression to fibrosis
NAFLD = state of oxidative stress
• Oxidative stress may be a factor leading NASH to fibrosis
o Adipocytes = metabolically active
• Adipokines may have role in profession from NAFLD → NASH → cirrhosis
Risk factors for development of ALD
- Dose of alcohol
- Gender (females have greater risk)
- Co-morbid diseases: chronic HCV, chronic HBV, hemachromatosis, a-1-antitrypsin deficiency, obesity
- Inherited propensity: PNPLA 3
- Protective factors
Clear associations with NASH/NAFLD
- Morbid obesity
- Truncal obesity
- Metabolic syndrome (at least 3: impaired glucose tolerance, abdominal obesity, hypertrigyceridemia, low HDL, HT)
- Type II diabetes
- Obstructive sleep apnea
- Polycystic ovary syndrome
Clinical presentation & pathology of NASH/NAFLD
o Mild elevations in liver enzymes (especially ALT and AST)
o Imaging: fatty liver = bright image; see fat on CT and MRI
Biopsy:
• NAFLD: bland macrosteatosis
• NASH: pericentral filamentous fibrosis, macrovesicular fat deposition in hepatocytes, leukocytes infiltrating lobule
Progression to cirrhosis = hepatocytes may lose TAG content
• “Cryptogenic cirrhosis”
Describe the approach to management of ALD
Abstinence from alcohol = psychosocial interventions
• Only treatment needed for alcoholic fatty liver
Severe life-threatening alcoholic hepatitis = corticosteroids
Alcoholic cirrhosis:
• Decompensated cirrhosis = previously stable patient with cirrhosis who has some trigger leading to clinical instability
• Common trigger = recent excessive alcohol use
• Abstinence associated with improved survival
Liver transplant
• Still controversial in patients with recurrent relapses
Nutritional support
• Improves nutritional status but does NOT decrease mortality
Fibrotic progression accelerated if also have viral hepatitis B or C
• Possible that antiviral therapy can decrease progression of fibrosis
Describe the approach to management of NAFLD/NASH.
All treatment begins with weight loss
Treatment directed to metabolic syndrome:
• Obesity = diet/exercise, pharmacologic anti-obesity agents, bariatric surgery
• Diabetes = metformin, thiazolidinediones
• Dyslipidemia = fibrates
• HT = anti-hypertensives
Treatment directed to the liver:
• Anti-oxidants
• Anti-cytokines = Anti-TNF-a, pentoxifylline
• Ursodeoxycholic acid (UDCA)
• Treatment of co-incident = HCV infection
• Liver transplantation
• NASH can recur (may be exacerbated by immune suppressants)
