Common Causes & ManagementJosé L. González, R3John A. Donovan, MD

• 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.

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

• 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 resuscitationOR

• 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?• <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:• 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: • 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 < 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

• 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 – ICPCPP > 60mmHgICP < 20mmHg

CPP = MAP – ICPCPP > 60mmHgICP < 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 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

• 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• 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

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• Polson, Julie and Lee, William M. AASLD Position Paper: The Management of Acute Liver Failure. www.aasld.org 2005