ACUTE LIVER FAILURE

1. ACUTE LIVER FAILURE Milton G. Mutchnick, M.D. Professor of Medicine Chief, Division of Gastroenterology Wayne State University School of Medicine

2. Acute Liver Failure Rapid deterioration of liver function resulting in altered mentation and coagulopathy in a patient without preexisting cirrhosis and with an illness of less than 26 weeks duration.

3. Acute Liver Failure….AKA • Fulminant hepatic failure • Fulminant hepatitis • Subfulminant liver failure • Subacute hepatic necrosis • Subacute liver failure • Hyperacute liver failure

4. Index of Suspicion forALF • Clinical signs of moderate to severe hepatitis • Laboratory findings including an increase in the prothrombin time of 4-6sec.(INR ≥ 1.5). • Altered sensorium INR ≥ 1.5 + Altered Mental Status = ALF

5. Suspect ALF?..........Admit to ICU

6. Etiology ofALF • Acute viral hepatitis (A - E) • Mushroom poisoning • Acetaminophen • Acute fatty liver of pregnancy • Chemical agents

7. Drug-induced hepatitis • Budd-Chiari Syndrome • VOD of liver • Wilson’s disease • AIH

8. Viral Drug Poisoning Ischemia VOD Malignant Infiltrate Wilson’s Disease Microvesicular steatosis AIH Hyperthermia OLT Partial hepatectomy ALFEtiologies

9. Etiology ofALFin 342 Cases(University Hospital, London UK) Drugs-Overdose Other Acetaminophen 250 Wilson’s 3 Ecstasy 2Fatty liver of pregnancy 7 Lymphoma/ Viral Hepatitis malignant infiltrate 7 HAV 8 Sepsis 2 HBV 8 Budd-Chiari 5 Non A-E 28Ischemia 9 Miscellaneous 6 Idiosyncratic Drug Reactions Lamotrigine, cyproterone, NSAID, chloroguine, rifampin/ INH halothane, flucloxacillin

10. U.S. ALF STUDY GROUP 2003 (308 Patients, 73% Women)

11. Viral • Acute Hepatitis A-E • Reactivation of HBV • Chemotherapy • Immunosuppresion • Herpes simplex • Varicella-Zoster • EBV

12. Acute HAV andALF • ALF uncommon • Frequency 0.01% - 0.1% in • jaundiced patients • ALF occurs early • Survival (transplant- free) 75% • Age related survival

13. Acute HBV andALF • HBV alone or with HDV co-infection • (rare) • Transplant-free survival is 23% • Overall survival 77% because of • transplantation

14. HBV Markers inALF IgM Anti HBc 100% HBsAg 90% HBV DNA (Abbott) 10% *Absence of HBsAg favors better prognosis (47% v 17%). Higher frequency ALF with mutant HBV form

15. Drug InducedALF • Many drugs implicated • Acetaminophen • Halothone and derivatives • INH/ Rifampin • Tricyclics/ MAO inhibitors • Phenytoin/ NSAID • Increased risk: acetaminophen (as little as • 2gms) + ETOH median dose: 13 gm • Increased risk if drug continued after • jaundice appears

16. Poisoning andALF • Amanita mushrooms (amanatoxins) • - LD = 50 gms (3 mushrooms) • - Toxins not destroyed by cooking • - Rapid onset of HE in 4-8 days • following severe emesis and diarrhea • Solvents - chlorinated hydrocarbons • Herbal remedies • Yellow phosphorus

17. Ischemic Hepatitis and ALF • Liver cell necrosis - massive • scale • Cardiac tamponade • Acute heart failure • Pulmonary embolus • Hepatic artery thrombosis

18. Obstruction of Hepatic Veins andALF • Budd-Chiari syndrome and thrombosis of hepatic veins • VOD - Post BMT Chemotherapy, Irradiation

19. Massive Malignant Infiltration of the Liver • Attributed to ischemic • changes • Leukemia, lymphoma • Malignant histiocytosis • Metastatic Replacement

20. Other Etiologic Causes ofALF • Wilson’s Disease • can be presenting feature • usually in patients <20 yrs • can occur if patient discontinued • D-penicillamine for a few years

21. Other Etiologies (2) • Microvesicular steatosis • Acute fatty liver of pregnancy • Reye’s syndrome • Drug Induced - Valproic acid • AIH • May appear as an acute hepatitis • on initial presentation • More common if anti-LKMI antibody present • ASMA usually not present

22. Other Etiologies (3) • Hyperthermia (Heat stroke) • Direct thermal injury • Hepatic ischemia due to • -DIC • -Perfusion defect • OLT • Poor presentation of donor liver • Acute graft rejection • Thrombosis - hepatic artery, hepatic • vein, portal vein • Partial hepatectomy • Removal of 80% or more of healthy liver Removal of 50% or less in hepatic dysfunction

23. Evaluation & Diagnosisof ImpendingALF History! History! History! Sexual contacts IDU Risk Factors Pregnancy Mushrooms Medications Travel Toxic exposures

24. HISTORY • Family members with liver disease? • Recent cold sores • Onset of jaundice • Work environment- toxic agents • Hobbies • Herbal products/dietary supplements

25. Physical Exam Determine presence or absence of pre-existing liver disease Hepatic tenderness Hepatic decompensation

26. Laboratory Tests(1) • Drug screening • ALT, AST, Alk Phos, Glu, Bilirubin • Lytes, Albumin, Mg, Phos., • CBC with differential • Coags: PT, PTT • Anti HAV IgM • Anti HBc IgM/ Anti HBsAg/ • Anti-HCV

27. Laboratory Tests (2) • If under 35 years of age Ceruloplasmin Serum & urine copper • Arterial blood gas • Arterial lactate • Pregnancy test • Autoimmune markers – ANA, ASMA, Ig levels • HIV status • Amylase & lipase

28. Liver Biopsy Reserved for diagnostic dilemma - AIH, HS (Transjugular approach)

29. Diagnosis ofALF • Hallmarks - occurs simultaneously or in • succession • Altered mentation • Clinical • EEG • Arterial Ammonia • Coagulopathy • PT 4 sec prolonged (INR≥ 1.5) • Arterial pH<7.3 if acetaminophen ingested (cause for immediate transfer for OLT)

30. Management ofALF(1) • Directed towards prevention of complications • ICU setting • Central line(s)-10% dextrose • Pulmonary artery pressure and CO • Inform Transplant Service and transfer with • onset of HE • Monitor VS and urinary output (Foley) • strict I&O • Laboratory Testing every 4-6hr • electrolytes, BUN, creatinine, CBC, platelets, • PT, PTT, ALT, AST, T. bilirubin, Alk Phos, Albumin

31. Management (2) • Maintain gastric pH above 5 • - protonix IV • Preparation for endotracheal intubation • Prepare to initiate monitoring intracranial • pressure • Enteral feeding tubes for grade 3 or 4 coma

32. Cerebral EdemaCerebral Perfusion Pressure Mean Arterial Pressure – ICP = Cerebral Perfusion Pressure (CPP) Ideal ICP<20-25mm Hg Ideal CPP>50-60mm Hg Imazaki, et al When CPP<40 for 2 hrs. 0 of 7 patients recovered When CPP>50 6 of 8 patients recovered Improved ICP first sign of spontaneous recovery

33. Management (3) Cerebral Edema & Intracranial Hypertension (Most serious complications of ALF) Clinical signs of elevated ICP (Intracranial Pressure) -sluggish pupillary response -increased limb-muscle tone -none Monitoring ICP -usually reserved for grade 3 or 4 coma -awaiting OLT

34. Management (4) Cerebral Edema - General Measures -quiet environment -elevate head 10°-20° -avoid sedation (use restraints) -avoid Valsalva-like maneuvers -mental status assessments q1-2h -mannitol if signs of impending uncal herniation (0.5mg/kg, lolus q4-8h) when ICP<30-40mm -assisted ventilation (in all grade 3 and 4)

35. Multiple Organ Failure Hepatic damage increased risk of infection Failure of clearance Endotoxemia Gut leak MOF Activation of macrophages Tissue Circulating Release of Hypoxia changes cytokines TNF, IL-1, IL-6 Williams, Sem Liver Dis, Vol 16, No.4, 1996

36. Management (5) • Hemodynamic Complications include: • Hypotension, tachycardia, vascular volume decrease with capillary leak and vasodilation • Volume expansion (central line) • FFP or 4.5% albumin, 10% dextrose • Maintain pulmonary capillary wedge • pressure 12mm-14mm Hg • Minimize salt solutions (ascites, • interstitial accumulation) • Inotropic/pressor support(epi, norepi, dopamine), • but not vasopressin.

37. Management (6) • Coagulopathy/Bleeding Diathesis • FFP or platelets given in presence of bleeding • Conventional treatment of GI bleeding • DIC thrombocytopenia • Metabolic Complications • Prevent hypoglycemia • Phosphate and magnesium levels • monitored - replace early • Enteral feeding, 60gm protein/24 hrs • No role for high branched-chain AA • Monitor for lactic acidosis secondary to • tissue hypoxia, sepsis

38. Role of Cardiac Index • (CI = cardiac output/body surface area) • ALF associated with high CI • Presence of low CI (<4.5L/min) • is bad prognostic sign • Look for - • blood loss, pneumothorax • lactic acidosis, cardiac tamponade

39. Management (7) Renal Failure - In 42% to 82% of ALF poor prognostic sign - Rising creatinine and oliguria - Metabolites of acetaminophen are nephrotoxic leading to acute renal failure similar to ATN and loss of phosphate -HRS

40. Additional Complications • ARDS • Sepsis • - Severe complement deficiency • - Decreased PMN motility • - Decreased Kupffer cell function • and removal of endotoxins • - Increased levels of TNF and IL-6

41. Prognostic Factors • Dependent on Etiology • Younger patients do better (<40 and >10) • Presence of cerebral edema • Delay between jaundice and HE of more • than 3 weeks - poorer prognosis • MOF - poor prognosis

42. Current Treatment Transplantation

43. Temporary Measures • Hemodialysis - no proven benefit on survival • Charcoal hemoperfusion - no proven benefit • Resins (Cation or anion - exchange) - not proven • Extracoporeal liver perfusions - may be bridge • to OLT • Hepatocyte transplants (peritoneum) - uncertain • Capillary hollow-fiber system - unproven, • ?bridge

44. OUTCOME RESULTS U.S.ALFSTUDY GROUP

46. Approach to SuspectedALF • Etiology and Pathogenesis • Evaluation and Diagnosis • Complications • Management • Prognosis • Current and future treatment • approaches