Common Causes & Management José L. González, R3 John A. Donovan, MD

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

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.

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

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)

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

GI decontamination – activated charcoal N-Acetylcysteine 20 hour IV protocol 72 hour PO protocol Liver Transplant

Arterial pH < 7.30 after adequate fluid resuscitation OR Grade III/IV encephalopathy AND PT > 100 sec AND Cr > 3.3

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

#1 antimicrobials #2 CNS agents #3 herbal supplements - weight loss - muscle building

What factors influence susceptibility? 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

Hepatitis B: 8% +/- Hepatitis D Hepatitis A: 4% Hepatitis C: does not cause ALF Hepatitis E: in developing countries HSV, EBV

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 = patients received lamivudine Endpoints: 1 week, overall survival 1wk: 90% vs 65%Overall: 70% vs 26%

Factors associated with increased mortality

Acute Liver Failure

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

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

INR > 6.5 OR Any 3 of the following 5: Age 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

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

Reviewed raw data Arterial pH, PT, Cr, Factor V, Gc-globulin King’s College Criteria, APACHE II score Prospective study needed sensitivityspecificity King’s College Criteria92%69% APACHE II92%81%

Common Complications of Acute Liver Failure

CNS disturbances Hepatic encephalopathy Cerebral edema Hemodynamic Collapse Infections Coagulopathy and bleeding Renal failure Metabolic derangements

(astrocytes) NH 3  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

CPP = MAP – ICP CPP > 60mmHg ICP < 20mmHg

CPP = MAP – ICP CPP > 60mmHg ICP < 20mmHg

HOB > 30º Decreased patient stimulation Hyperventilation Barbiturates Mannitol Corticosteroids Hypertonic Saline Hypothermia (32-33ºC)

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

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

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

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

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

Lactic acidosis w/ compensatory respiratory alkalosis Hypokalemia Hypoglycemia (40%) Hypophosphatemia Hypomagnasemia Early nutrition is important

Indicated when prognostic criteria suggest a high likelihood of death 2004 UNOS data 5845 transplants491 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

Orthotopic Liver Transplant Auxiliary liver transplant Xenotransplantation Artificial / Bioartificial Hepatic Assist Devices Detoxify, metabolize and synthesize Hepatocyte Transplantation

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

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: 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: Ganem, D., and Prince, A. Hepaitis B Virus Infection – Natural History and Clinical Consequences. N Engl J Med. 2004; 350: Ghabril, M., Chalasani, N., Bjornsson, E. Drug-induced liver injury: a clinical update. Current Opinion in Gastroenterology 2010; 26: Goldberg, Eric et al. Acute liver failure: Prognosis and management www.uptodate.com 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.com Miyake, Y., Iwasaki, Y., Takaki, A. Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B. Inter Med 2008; 47: Navarro, Victor J. and Senior, John R. Drug Related Hepatotoxicity. N Engl J Med. 2006; 345: 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: Polson, Julie and Lee, William M. AASLD Position Paper: The Management of Acute Liver Failure www.aasld.org