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Acute Liver Failure

Acute Liver Failure. Common Causes & Management José L. González, R3 John A. Donovan, MD. Presentation Outline. Introduction Acetaminophen Toxicity Idiosyncratic Drug Reactions Viral Hepatitis Complications and Management Liver Transplant & Conclusion

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Acute Liver Failure

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  1. Acute Liver Failure Common Causes & Management José L. González, R3 John A. Donovan, MD

  2. Presentation Outline • Introduction • Acetaminophen Toxicity • Idiosyncratic Drug Reactions • Viral Hepatitis • Complications and Management • Liver Transplant & Conclusion • N-Acetylcysteine for non-acetaminophen causes of acute liver failure by Dr. Donovan.

  3. Why Acute Liver Failure? • Why did I choose this topic and why is it important for clinicians? • Regenerative properties • Identification of ALF • Interventions • Liver Transplant

  4. Learning Objectives • Recognize Acute Liver failure • Understand Acetaminophen toxicity & apply appropriate treatment • Understand common causes of Viral ALF and identify the interventions that improve outcomes • Know which groups of drugs commonly cause liver injury • Identify prognostic criteria • Manage complications of ALF

  5. Defining Acute Liver Failure • INR > 1.5 • Altered mental status • Illness of < 26 weeks duration • Hyperacute < 7 days • Acute 7-21 days • Subacute > 21 days and < 26 weeks • Fulminant (2 wks) vs subfulminant (2-12 wks)

  6. What are the common causes of liver failure? • Acetaminophen 39% • Indeterminite 17% • Idiosynchratic drug rxns 13% • Viral hepatitis 12% • HBV > HAV > HEV, HSV • Autoimmune 4-5% • Wilson’s Disease 2-3% • Mushroom Poisoning • Herbal Medications • Vascular • Bud-Chiarri • Ischemic • Hepatic Vein Thrombosis • Reye’s Syndrome • Fatty Liver of Pregnancy • HELLP

  7. Acetaminophen Toxicity

  8. para- acetylaminophenol

  9. Treatment Nomogram

  10. Acetaminophen Toxicity: Treatment • GI decontamination – activated charcoal • N-Acetylcysteine • 20 hour IV protocol • 72 hour PO protocol • Liver Transplant

  11. Indications for Liver Transplant: King’s College Criteria for Acetaminophen Toxicity • Arterial pH < 7.30 after adequate fluid resuscitation OR • Grade III/IV encephalopathy AND • PT > 100 sec AND • Cr > 3.3

  12. Idiosyncratic Drug Reactions

  13. Idiosyncratic Drug Reactions • Idiosyncratic: unpredictable and dose-independent • Pattern of injury varies • Cholestatic (alkaline phosphotase) • Hepatocellular (ALT) • Mixed • Mechanism of Action • Covalent bonds disruption of cell membrane • Inhibition of cellular pathways • Abnormal bile flow • Pump dysfunction • Apoptosis via TNF and fas pathways • Inhibition of mitochondrial synthesis

  14. Idiosyncratic Drug Reactions: MOA #1 antimicrobials #2 CNS agents #3 herbal supplements - weight loss - muscle building

  15. Idiosyncratic Drug Reactions • What factors influence susceptibility? • <10 and >40 yoa, obesity, female gender, DM, etoh use, genetic variability • Importance of discontinuing medication after liver injury. • Likelihood of progression to liver failure is dependent on how long you continue to take the drug after identification of liver injury. • What is the clinical course and natural history of disease? • Repair varies : days to weeks to months

  16. Viral Causes of Acute Liver Failure

  17. Viral Causes of Acute Liver Failure • Hepatitis B: 8% +/- Hepatitis D • Hepatitis A: 4% • Hepatitis C: does not cause ALF • Hepatitis E: in developing countries • HSV, EBV

  18. Acute Hepatitis B leading to ALF • HBV: DNA virus • Antivirals: nucleoside or nucleotide analogs • Lamivudine, adefovir, tenofovir, entecavir • Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B: • Serologies for acute Hep B: IgM anti-hepatitis B virus core antibody • Retrospective cohort study, n = 33 • 10 patients received lamivudine • Endpoints: 1 week, overall survival • 1wk: 90% vs 65% Overall: 70% vs 26%

  19. Acute Hepatitis B: Factors associated with increased mortality

  20. Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B

  21. Management and Prognosis Acute Liver Failure

  22. What are the potential outcomes? • 1. Recovery because of a successful intervention • NAC for acetaminophen toxicity • Antivirals for acute hepatitis B • 2. Spontaneous recovery with supportive care • 3. Death • 4. Rescue by liver transplant

  23. Predicting Outcomes in Acute Lifer Failure • Most important predictive factors: • Degree of encephalopathy • Suggested laboratory markers: • Factor V • AFP • Serum Phosphate • VII/V ratio > 30 • Gc globulin • Clinical algorithms: • King’s College Criteria • APACHE II

  24. King’s College Criteria, non-acetaminophen • INR > 6.5 OR • Any 3 of the following 5: • Age < 10 or > 40 • Serum bilirubin > 18 • Jaundice to encephalopathy interval > 7 days • INR > 3.5 • Unfavorable Etiology • Non-A, non-B hepatitis, halothane, idiosyncratic drug reaction, Wilson’s

  25. APACHE II Scoring Table

  26. Predicting Outcomes • Which variable or clinical algorithm do we use? • Meta-analysis of Prognostic Criteria • No prospective trials as of yet • Why is sensitivity important? • False negatives: death due to withholding liver transplants • Why is specificity important? • False positives: liver transplants in those that don’t need them

  27. Meta-analysis of Prognostic Criteria: Need for Transplant • Reviewed raw data • Arterial pH, PT, Cr, Factor V, Gc-globulin • King’s College Criteria, APACHE II score • Prospective study needed

  28. Clinical Course and Management Common Complications of Acute Liver Failure

  29. Complications of Acute Liver Failure: • CNS disturbances • Hepatic encephalopathy • Cerebral edema • Hemodynamic Collapse • Infections • Coagulopathy and bleeding • Renal failure • Metabolic derangements

  30. Cerebral Edema • (astrocytes) NH3 glutamine + edema • Degree of encephalopathy correlates w/ cerebral edema • Grade I-II: 25-35% risk • Grade III: 65% risk • Grade IV: 75% risk • Uncal herniation • Compromises cerebral blood flow  hypoxic brain injury

  31. Intracranial Pressure • CPP = MAP – ICP • CPP > 60mmHg • ICP < 20mmHg

  32. Intracranial Pressure • CPP = MAP – ICP • CPP > 60mmHg • ICP < 20mmHg

  33. Treatments for raised ICP: How useful are they? • HOB > 30º • Decreased patient stimulation • Hyperventilation • Barbiturates • Mannitol • Corticosteroids • Hypertonic Saline • Hypothermia (32-33ºC)

  34. Hemodynamic Failure • Decreased SVR • Renal failure, pulmonary failure and cardiovascular collapse • Restoration of hemodynamics: • Crystalloid initially • Once euvolemic, studies show albumin is better than crystalloid • Pressors • Alpha adrenergics (epi- and norepi-) • Not used: Dopamine, Vassopressin • No benefit of NAC, prostaglandins and steroids

  35. Infections • Etiology • Bacterial (90%): gram negative organisms, staphylococci • Fungal (30%) • SIRS has been shown to decrease survival rate • Should we use prophylactic antibiotics? • Decrease # of infections • But no improvement in outcomes • Routine surveillance blood, sputum, urine cultures and CXR

  36. Coagulopathy • Coagulopathies: • Prolonged PT • Platelet dysfunction • Reduction in factors II, VII, IX and X • Defective production of procoagulant factors: • Proteins C and S • Antithrombin III • Upregulation of factor VIII • End Result: • Clinically significant spontaneous bleeding is relatively unusual in ALF, even during liver transplant. • Overuse of blood products

  37. Correction of coagulopathies: • Vitamin K • Platelets if clinically significant bleeding or < 10k • Limited role for prophylactic FFP, platelets, cryoprecipitate • Giving FFP takes away your best prognostic indicator • Recombinant VII

  38. Renal Failure • RF contributes to mortality and overall poor prognosis • Multi-factorial • Pre-renal • ATN (from prolonged pre-renal state vs nephrotoxic agents) • HRS • CVVD > HD

  39. Metabolic Disturbances • Lactic acidosis w/ compensatory respiratory alkalosis • Hypokalemia • Hypoglycemia (40%) • Hypophosphatemia • Hypomagnasemia • Early nutrition is important

  40. Liver Transplant

  41. Liver Transplant • Indicated when prognostic criteria suggest a high likelihood of death • 2004 UNOS data • 5845 transplants 491 for acute liver failure = 8.4% • Of patients w/ ALF, 29% receive a transplant. • Survival rates in pre-transplant era ~ 15% vs 40% now • Better prognosis: acetaminophen, HAV, ischemia, AFLP • Worse prognosis: HBV, AIH, Wilson’s Bud-Chiari

  42. Variations of Transplants • Orthotopic Liver Transplant • Auxiliary liver transplant • Xenotransplantation • Artificial / Bioartificial Hepatic Assist Devices • Detoxify, metabolize and synthesize • Hepatocyte Transplantation

  43. Summary • ALF: INR > 1.5, AMS, < 26 weeks duration • Acetaminophen: charcoal, NAC • Viral: HBV>HAV, tx w/ antivirals • Idiosyncratic drugs  ALF: 1. antimicrobials, 2. CNS agents, 3. herbal supplements. • ID Prognostic criteria: APACHE II vs King’s College, Age, AMS, etiology • Manage complications: increased ICP, hemodynamic instability, RF, coagulopathies, metabolic derrangements

  44. American Association for the Study of Liver Diseaseswww.aasld.orgSpecial Thanks to Dr. Donovan

  45. Bibliography • Bailey, B., Amre, D., and Gaudreault, P. Fulminant hepatic failure secondary to acetaminophen poisoning: A systemic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003; 31: 299-305 • Craig, D.G.N, Lee, A., Hayes, P.C. et al, Review article: the current management of acute liver failure. Alimentary Pharmacology and Therapeutics 2010; 31: 345-348 • Ganem, D., and Prince, A. Hepaitis B Virus Infection – Natural History and Clinical Consequences. N Engl J Med. 2004; 350: 1118-29 • Ghabril, M., Chalasani, N., Bjornsson, E. Drug-induced liver injury: a clinical update. Current Opinion in Gastroenterology 2010; 26:222-226 • Goldberg, Eric et al. Acute liver failure: Prognosis and management. www.uptodate.com2011 • Gotthardt, D., Riediger, C. Weiss, K.H., et al. Fulminant hepatic failure: etiology and indications for liver transplantation. Nephrology Dialysis Transplantation 2007; 22: viii5-viii8 • Heard, K. and Dart, R. Acetaminophen poisoning in adults: Treatment. www.uptodate.com2011 • Miyake, Y., Iwasaki, Y., Takaki, A. Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B. Inter Med 2008; 47: 1293-1299 • Navarro, Victor J. and Senior, John R. Drug Related Hepatotoxicity. N Engl J Med. 2006; 345: 731-739 • Ostapowicz, G., Fontana, R.J., Shiodt, F.V. Results of a prospective study of acute liver failure a 17 tertiary care centers in the United States. Ann Intern Med 2002; 137: 947-954. • Polson, Julie and Lee, William M. AASLD Position Paper: The Management of Acute Liver Failure. www.aasld.org2005

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