Toxin/Alcohol LD

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    Alcohol Induced Liver Disease

    • Types:
      • Alcohol-induced Steatosis
      • Alcohol-induced Cirrhosis
      • Alcoholic Hepatitis (Acutely)

     

    • Usually asymptomatic and resolves after 4-6w of abstinence.
    • However, continued EtOH daily increases risk of progression to cirrhosis.

     

    • Cirrhosis develops in a very small portion of drinkers.
    • Chronic alcohol consumption causes several types of liver injury
      • Regular alcohol, even for a few days.. causes fatty liver (steatosis).
      • Steatosis: Hepatocytes contain microvesicular droplets of triglycerides.
      • Steatosis resolves with abstinence, but predisposis to hepatic fibrosis and cirrhosis if continue drinking.
    • Alcoholic Hepatitis
      • Liver inflammation in the context of alcohol use.
      • A treatable form of alcoholic liver disease.
      • but 40% with severe alcoholic hepatitis die in 6 months.

     

    Pathobiology

    • Alcohol --oxidation--> Acetaldehyde --> Acetate

    AlcoholMetabolism.gif

    • This process generates an excess of reducing equivalents (NADH)
      • This inhibits fatty acid oxidation, inhibits lipolysis, promotes lipogenesis. 
      • Another mechanism through PPAR-alpha and AMP kinase stimulation causes fat-storing metabolic remodeling in the liver.
      • Unclear how EtOH leads to liver disease.
    • Another theory: LPS-endotoxin (trigger of inflammation) is released from bacteria in the gut.  Long term exposure to EtOH alters gut permeability and causes penetration of LPS into portal circulation and liver.
      • Known to blood levels of LPS and gut permeability increase with EtOH liver injury.
      • LPS binds LPS binding protein --> activates Kupffer cells  --> inflammation (CD14 - monocyte differentiation antigen, TLR4, TNF-a, etc..).
      • Oxidative stress of Kupffer cells is involved.
    • AlcoholHepatitisMechanism.png
    • (Borrowed from NEJM, 2009 "Alcoholic Hepatitis" article)

     

    • Biopsy: definitive to exclude other causes, but often not required.
      • Transjugular route to decrease risk of bleeding.
    • Usually cannot find the cause of disease (i.e. NAFLD has similar findings)
    • Alcoholic Hepatitis
      • Ballooned (swollen hepatocytes)
      • Amorphous eosinophilic inclusion bodies (Malory bodies - aka alcoholic hyaline)
      • Surrounded by neutrophils
      • Steatosis
        • Large fat globules (steatosis)
      • Intrasinusoidal fibrosis (btwn endothelial cell and hepatocyte)
    • Alcoholic fibrosis
      • Perivenular fibrosis
      • Periportal fibrosis
      • Cirrhosis

     

    Alcoholic Hepatitis

    Presentation

    • JAUNDICE (rapid onset)
    • Fever, ascites
    • If severe: proximal muscle loss.
    • Physical Exam:
      • Liver enlarged and tender.
      • Jaundice
      • Can be a variety of liver disease findings, but above two are notable.

     

    Diagnosis

    • Generally EtOH hepatitis unless proven otherwise:
      • AST elevated 2-6x ULN (not >300-500 IU/mL),
        • ratio AST/ALT > 2 - 3 --> typical for alcoholic liver disease, (but finding is not specific or sensitive)
      • TBilli >86 umol/L
      • Elevated INR
      • Creatinine ↑ --> Ominous sign of impending hepatorenal syndrome.
      • WBC 
        • Neutrophils 
      • Ascites
      • Hx of heavy EtOH use.
    • DDx:
      • Non-Alcoholic Steatohepatitis
      • Acute / Chronic Viral Hepatitis
      • Drug-Induced liver injury
      • Wilson's Disease
      • Autoimmune liver disease, A-1 Antitrypsin Deficiency, pyogenic liver abscess, ascending cholangitis, decompensation of hepatocellular carcinoma, etc..
    • Biopsy not required for diagnosis (but can help r/o other causes).

     

     

    Work-up

    • Blood work: CBC, Lytes, Creat, Urea, INR, TBilli, etc...
      • If Ascitic fluid - culture and cells.
      • (R/O pneumonia, SBP, UTI)
    • Abdo U/S: R/O hepatic abscess, HCC, biliary obstruction (all can mimic EtOH hepatitis)
    • Assessing severity to decide whether to use corticosteroids (Many scoring systems)
      • Maddrey's discriminant function
        • Most common, longest use
        • 4.6*[(PT-control PT) + serum bili (mg/dl)]
          • Value ≥ 32 is threshold for treatment (50% short term mortality).
      • Glasgow Score
        • Used in study to show pts with high Maddrey's function will benefit from steroids. (Forrest 2007, Gut)
        • Uses Age, WBC, Urea nitrogen, Tbili, PT.
        • Treat if score >9
        • Not tested outside of Glasgow, UK.
      • Model for End-Stage Liver Disease (MELD)
        • Retrospective studies only. (based on Tbili, Creatinine, INR)
        • In one study: As good as, or better, than Maddrey's score for predicting mortality.
        • If score is >21 --> 90-day mortality 20%  --> treshold to treat
        • ≥18 was recently shown similar prognostic implications as MDF score ≥32.
      • Lille score
        • Response of serum bili after 7 day treatment.
        • Used to decide whether to stop steroids after 1 week of treatment.
        • Not tested outside of France (as of 2009)

    Treatment

    • Generally: Alcohol absitence and prevention strategies
    • General measures / Supportive care:
      • Ascites: salt restriction, diuretics.
      • Hepatic encephalopathy: Lactulose, gut-cleansing antibiotics.
      • Infections: treat w/ abx.
      • Anorectic: Enteral Feeding if needed - 1.5g/kg of body weight even if encephalopathic. 
      • Thiamine + other vitamins if needed.
      • Alcohol Withdrawal: Short-acting benzos / CIWA. (even though can precipitate encephalopathy).
      • Hepatorenal Syndrome (HRS): Albumin, vasoconstrictors (terlipressin, midodrine and octreotide, or norepinephrine).
    • Abstinence from EtOH!!!
      • Need immediate and lifetime abstinence.
    • CORTICOSTEROIDS
      • Using steroids is controversial (Many studies and Meta-analysis findings).
        • Recent meta-analysis (as of 2009) did not favour steroid use, but evidence base compromised by heterogeneous trials with high risk of bias.  But meta-analysis showed mortality benefit in subgroup with Maddrey's discriminant function > 32
        • Three recent studies (as of 2009): administers steroids for 28 days --> improved 1-mo survival with severe EtOH hepatitis (Maddrey's ≥32) 85% survival vs. placebo 65%.
        • Conclusion: Indication for treatment with corticosteroids

          (OR Pentoxifylline if steroids contraindicated by infection or renal failure)

           

          • Maddrey's Discriminant Function ≥32
            OR
          • MELD ≥ 18
          • IN THE ABSENCE OF:
            • Sepsis
            • Hepatorenal Syndrome (HRS)
            • Chronic HepB infection
            • GI bleeding

           

          (NNT = 5 pts to prevent 1 death.) 

          (Info as of 2009, based on Lucey et all, NEJM 2009)


           
      • Most common: prednisolone 40mg/day for 28 days or shorter.  When finished, can stop all at once or taper over 3 weeks. 
      • 40% don't respond to steroids.
    • Pentoxifylline
      • Phosphodiesterase inhibitor with many effects including TNF-a transcription.
      • Sidhu et al (2012) prospective trial and Akriviadis et al (2000) RCT:  Reduced short-term mortality in EtOH hepatitis.
        • 101 pts with Maddrey's >32 given placebo vs. pentoxifylline 400mg TID for 28 days.
        • 24% died in pentoxifylline vs. 46% placebo.
        • TNF-a levels not different between two groups (suggests effect unrelated to TNF-a).
        • Analysis of deaths suggest it prevents HRS.
      • Another study (Mathurin et al, 2013): Prednisolone  vs. Prednisolone + Pentoxifylline = no benefit.
      • Trial dose: 400 mg orally, three times a day x 3-4 weeks.
      • Conclusion: Worth considering in some pts where corticosteroids are contraindicated (less evidence).
      • Indicated if patients have contraindication to prednisolone (i.e. SBP/infection, etc..)
    • Nutritional Support:
      • All pts with EtOH hepatitis are malnourished, and risk of death is related to degree of malnutrition.
      • Parenteral and enteral feeding improves nutrition, but no effect on short-term survival. 
      • One trial showed that enteral feeding (2000kcal/day) vs. prednisolone  = same survival @ 28d and 1y.
    • Liver Transplant
      • Liver transplant usually contraindicated in EtOH hepatitis.  Period of abstinence will allow recovery. 
      • Most U.S. programs require 6mo of abstinence.  (Many who don't recover in 3mo die) --> dilemma.
      • Return to EtOH remains a concern.
      • Can consider if severe and no response to medical management.
    • Experimental: Anti-TNF-a therapy:
      • Infliximab and etanercept studied in EtOH hepatitis. (two non-randomized and one randomized trial).
      • Promising results led to one bigger trial:
        • Infliximab + prednisolone vs. placebo + prednisolone in pts with Maddrey's ≥32.
        • Trial stopped early: Increase in infections, and non-significant increase in deaths in infliximab cohort.
        • Dose was critisized as too high (10mg/kg TID on days 1, 14, 28) vs. 5mg/kg in other studies.
      • Etanercept: short-term benefit in small pilot study, but worse 6-mo survival in larger study.  Do not use.
      • Other therapies (no benefit): Anabolic-androgenic steroids, antioxidants (vitamin E), silymarin (Milk thistle), colchicine, propylthiouracil, IV insulin, glucagon.

    Prognosis

    • Generally very good if mild syndrome with appropriate treatment, but not guaranteed.
    • Recovery requires abstinence from alcohol.
      • Fever and jaundice may resolve in several weeks. 
      • Ascites + Hepatic encephalopathy may persist months to years.
    • Continued jaundice or renal failure ==> poor prognosis.

     

    Drug or Toxin-Induced Liver Disease

    • The most common cause of liver injury requiring transplantation.
    • Risk factors are age and female sex, 71% of cases are caused by prescription medications (9% are herbal/supplements).
    • Acetaminophen (most common): Dose-dependent injury
    • Idiosycratic:
      • Antibiotics (amoxicillin-clavulanate, but severe fulminant failure is rare)
      • CNS agents (phenytoin, valproic acid)
      • Immunomodulatory agents
      • Lipid-lowering agents
    • Symptoms: Fatigue, nausea.
      • Abdo pain, jaundice, pruritis (severe!)
      • Fever, rash, eosinophilia => hypersensitivity reactions.
      • Jaundice => 10% mortality without transplantation.
    • Labs:
      • coagulopathy, mental status changes, jaundice seen in fulminant liver failure.
      • Exclude viral hepatitis (Hep A/B/C), alcoholic liver disease, autoimmune liver disease, metabolic liver disease.
      • CT/MR imaging to r/o biliary tract disease often required.
      • Liver biopsy: if uncertain.  (eosinophilia, granulomas, necrosis, cholestasis, hepatitis). 
    • Diagnosis:
      • When liver injury markers resolve with withdrawal of the offending agent.
    • Management:
      • Discontinue offending agent.
      • Recent trial: Mortality could be improved with NAC for idiosyncratic drug induced liver injury.
      • Acetaminophen toxicity: N-Acetylcysteine
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