Alcoholic Hepatitis Review – Summary

Risk Factors

  • highest risk w/ > 120g ETOH/day (1 drink = 14 g) – 5.7% point prevalence
  •  30-60 g ETOH/day = 1% point prevalence

Clinical Findings

  • Jaundice + liver failure after years of ETOH abuse, typically 40-60 yo
  •  Key clinical finding: rapid onset of jaundice
    • other findings: fever, ascites, proximal muscle loss, encephalopathy (severe cases)
  • Labs: AST:ALT > 2
    • Incr. Cr = indication of hepatorenal syndrome and poor prognosis
  • Expect to have months to years of ascites and hepatic encephalopathy after ETOH abstinence
    • If continued jaundice or onset of renal failure after abstinence – bad news

Histology

  • Mallory Bodies: amorphous eosinophilic inclusion bodies
  • Steatosis: presence of large fat globules in hepatocytes
  • Intrasinusoidal Fibrosis: fibrosis in space between endothelial cells and hepatocyte

Mechanism

  • ETOH -> Acetaldehyde -> Acetate
    • Oxidative metabolism generates reducing equivalents (reduced NAD which is NADH)
    • Incr. NADH blocks fatty acid oxidation & TCA -> Incr. Lipids
  • Gut permeability: altered by ETOH which leads to incr. LPS-endotoxin systemically
    • LPS + Binding protein activate CD14 on Kupffer cells -> activation
  • Kupffer Cell Activation (LPS + CD14 binding): activates CD14 + TLR4 + MD2
    • Downstream actiation of EGR1 (activates TNF-Alpha), NF-kB, TRIF
      • Absence of EGR1 prevents ETOH-induced liver injury in mice
  • Activation of Kupffers leads to free radical production via CYP450 2E1
    • Mitochondrial damage, endoplasmic reticulum apoptosis and lipid synthesis
  • TNF-Alpha = key mediator of hepatocellular injury
    • Decr TNF-R1 = decr. TNF-alpha
    • Seems to target mitochondria -> release of mitochondria cytochrome c & fas ligand
      • Leads to hepatic apoptosis & sensitivity to natural killer T cells

Diagnosis

  • Key Findings: AST:ALT > 2, T Bili > 5, Incr. INR, incr. neutrophils + ASCITES & HX ETOH ABUSE
  • Differential: NASH, viral hep (acute or chronic), toxins, Wilson’s (fulminant), autoimmune, A1AT deficiency, pyogenic hepatic abscess, ascending cholangitis, HCC decompensation
  • Bx is helpful but NOT required for dx or prognosis
  • Screen for bacterial infection: PNA, SBP, UTI

Assessing Severity

  • Maddrey’s, Glasgow and MELD are 3 scores
  • MELD: assesses pt risk of death while waiting for txp
    • Score 21 or greater: 90 day mortality of 20%

Treatment

  • Issues to Address
    • 1) Ascites: sodium restriction, diuretics
    • 2) Hepatic Encephalopathy: lactulose, gut cleansing abx (Rifampin)
    • 3) Vitamin deficiencies: thiamine
    • 4) Delirium Tremens: benzodiazepines
    • 5) Hepatorenal Syndrome: monitor creatinine, albumin + vasoconstrictors (ex. terlipressin, midodrine & octreotide, norepinephrine)
  • Abstinence: most important aspect of tx – psych support, role for baclofen?
  • Corticosteroids: may reduce inflammation in VERY SEVERE CASES ONLY
    • MOA: inhibit activator protein 1 and NF-kB, reduction in proinflammatory cytokines (ex. IL-8, TNF-alpha)
    • Prednisolone 40mg QD x 28 days
    • Indications: Maddrey’s score of 32 or MELD of 21 or greater
    • Calculate Lille score after 7 days of tx – score > 0.45 = no response to steroids & 6 month survival < 25% – unresponsive in 40% steroid cases
  • Pentoxifylline (phosphodiesterase inhibitor): one RCT showing reduced short-term mortality
    • May have a role in decreasing incidence of hepatorenal syndrome
  • What not to give
    • TNF-Alpha inhibitors (Infliximab, Etanercept): may incr. mortality 2/2 infxn
    • Anabolic steroids: no benefit
    • Antioxidants: no benefit
    • Colchicine, PTU, Insulin & Glucagon: no benefit
  • Liver Txp: technically a 6 month wait period of abstinence, but need to eval if mortality is expected to be less than 6 months

 

Source: NEJM – Alcoholic Hepatitis

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