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
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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)
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Acetaminophen 39%
Indeterminite 17%
Idiosynchratic drug rxns 13%
Viral hepatitis 12%
• HBV > HAV > HEV, HSV
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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
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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?
• <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
• 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:
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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%
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:
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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:
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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
• 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
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Reviewed raw data
Arterial pH, PT, Cr, Factor V, Gc-globulin
King’s College Criteria, APACHE II score
Prospective study needed
sensitivity
specificity
King’s College Criteria
92%
69%
APACHE II
92%
81%
Common Complications of Acute Liver Failure
• CNS disturbances
• Hepatic encephalopathy
• Cerebral edema
• Hemodynamic Collapse
• Infections
• Coagulopathy and bleeding
• Renal failure
• Metabolic derangements
• (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
CPP = MAP – ICP
CPP > 60mmHg
ICP < 20mmHg
CPP = MAP – ICP
CPP > 60mmHg
ICP < 20mmHg
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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
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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 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
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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
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Bailey, B., Amre, D., and Gaudreault, P. Fulminant hepatic failure secondary to acetaminophen poisoning: A systemic review and metaanalysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003; 31: 299-305
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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
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Ganem, D., and Prince, A. Hepaitis B Virus Infection – Natural History and Clinical Consequences. N Engl J Med. 2004; 350: 1118-29
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Ghabril, M., Chalasani, N., Bjornsson, E. Drug-induced liver injury: a clinical update. Current Opinion in Gastroenterology 2010; 26:222226
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Goldberg, Eric et al. Acute liver failure: Prognosis and management. www.uptodate.com 2011
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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
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Heard, K. and Dart, R. Acetaminophen poisoning in adults: Treatment. www.uptodate.com 2011
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Miyake, Y., Iwasaki, Y., Takaki, A. Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B. Inter Med 2008; 47: 1293-1299
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Navarro, Victor J. and Senior, John R. Drug Related Hepatotoxicity. N Engl J Med. 2006; 345: 731-739
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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.
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Polson, Julie and Lee, William M. AASLD Position Paper: The Management of Acute Liver Failure. www.aasld.org 2005