Milton G. Mutchnick, M.D.Professor of Medicine

Chief, Division of Gastroenterology

Wayne State UniversitySchool of Medicine

ACUTE LIVER FAILURE

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.

Acute Liver Failure….AKA

• Fulminant hepatic failure

• Fulminant hepatitis

• Subfulminant liver failure

• Subacute hepatic necrosis

• Subacute liver failure

• Hyperacute liver failure

Index of Suspicion for ALF

• 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

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

Etiology of ALF

• Acute viral hepatitis (A - E)

• Mushroom poisoning

• Acetaminophen

• Acute fatty liver of pregnancy

•Chemical agents

• Drug-induced hepatitis

• Budd-Chiari Syndrome

• VOD of liver

• Wilson’s disease

• AIH

ALFEtiologies

• Viral• Drug• Poisoning• Ischemia• VOD• Malignant Infiltrate

• Wilson’s Disease• Microvesicular

steatosis• AIH• Hyperthermia• OLT• Partial hepatectomy

Etiology of ALF in 342 Cases (University Hospital, London UK)

Drugs-Overdose OtherAcetaminophen 250 Wilson’s 3Ecstasy 2 Fatty liver of pregnancy 7

Lymphoma/Viral Hepatitis malignant infiltrate 7HAV 8 Sepsis 2HBV 8 Budd-Chiari 5Non A-E 28 Ischemia 9

Miscellaneous 6Idiosyncratic Drug ReactionsLamotrigine, cyproterone, NSAID,chloroguine, rifampin/ INHhalothane, flucloxacillin

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

0

5

10

15

20

25

30

35

40

ACM HBV HAV Indet Other

Viral

• Acute Hepatitis A-E

• Reactivation of HBV Chemotherapy Immunosuppresion

• Herpes simplex

• Varicella-Zoster

• EBV

Acute HAV and ALF

• ALF uncommon

• Frequency 0.01% - 0.1% in jaundiced patients

• ALF occurs early

• Survival (transplant- free) 75%

• Age related survival

Acute HBV and ALF

• HBV alone or with HDV co-infection (rare) • Transplant-free survival is 23%

• Overall survival 77% because of transplantation

HBV Markers in ALF

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

Drug Induced ALF• Many drugs implicated

AcetaminophenHalothone and derivativesINH/ RifampinTricyclics/ MAO inhibitorsPhenytoin/ NSAID

• Increased risk: acetaminophen (as little as 2gms) + ETOH median dose: 13 gm

• Increased risk if drug continued after jaundice appears

Poisoning and ALF

• 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

Ischemic Hepatitis and ALF

• Liver cell necrosis - massive scale

• Cardiac tamponade

• Acute heart failure

• Pulmonary embolus

• Hepatic artery thrombosis

Obstruction of Hepatic Veins and ALF

• Budd-Chiari syndrome and thrombosis of hepatic veins • VOD - Post BMT Chemotherapy, Irradiation

Massive Malignant Infiltration of the Liver

• Attributed to ischemic changes

• Leukemia, lymphoma

• Malignant histiocytosis

• Metastatic Replacement

Other Etiologic Causes of ALF

• Wilson’s Disease

can be presenting feature usually in patients <20 yrs

can occur if patient discontinued D-penicillamine for a few years

Other Etiologies (2)

• Microvesicular steatosisAcute fatty liver of pregnancyReye’s syndromeDrug Induced - Valproic acid

• AIH May appear as an acute hepatitis on initial presentation More common if anti-LKMI antibody present ASMA usually not present

Other Etiologies (3)• Hyperthermia (Heat stroke)

Direct thermal injuryHepatic ischemia due to

-DIC-Perfusion defect

• OLTPoor presentation of donor liver Acute graft rejectionThrombosis - hepatic artery, hepatic

vein, portal vein• Partial hepatectomy

Removal of 80% or more of healthy liver Removal of 50% or less in hepatic dysfunction

Evaluation & Diagnosisof Impending ALF

History! History! History!

Sexual contactsIDU

Risk FactorsPregnancy Mushrooms

Medications Travel Toxic exposures

HISTORY

• Family members with liver disease?

• Recent cold sores

• Onset of jaundice

• Work environment- toxic agents

• Hobbies

• Herbal products/dietary supplements

Physical Exam

Determine presence or absence of pre-existing liver disease

Hepatic tenderness

Hepatic decompensation

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

Laboratory Tests (2)If under 35 years of age Ceruloplasmin Serum & urine copperArterial blood gasArterial lactatePregnancy testAutoimmune markers – ANA, ASMA, Ig levelsHIV statusAmylase & lipase

Liver Biopsy

Reserved for diagnostic dilemma -

AIH, HS

(Transjugular approach)

Diagnosis of ALF

Hallmarks - occurs simultaneously or in succession

• Altered mentationClinicalEEGArterial Ammonia

• CoagulopathyPT 4 sec prolonged (INR≥ 1.5)

• Arterial pH<7.3 if acetaminophen ingested (cause for immediate transfer for OLT)

Management of ALF(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

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

Cerebral EdemaCerebral Perfusion Pressure

Mean Arterial Pressure – ICP = Cerebral Perfusion Pressure (CPP) Ideal ICP<20-25mm Hg Ideal CPP>50-60mm Hg

Imazaki, et alWhen CPP<40 for 2 hrs. 0 of 7 patients recoveredWhen CPP>50 6 of 8 patients recoveredImproved ICP first sign of spontaneous recovery

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

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)

Multiple Organ Failure

Hepatic damage increased riskof infection

Failure of clearance

Endotoxemia

Gut leakMOF Activation of

macrophages

Tissue Circulating Release ofHypoxia changes cytokines

TNF, IL-1, IL-6

Williams, Sem Liver Dis, Vol 16, No.4, 1996

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.

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

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, pneumothoraxlactic acidosis, cardiac tamponade

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

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

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

Current Treatment

Transplantation

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

OUTCOME RESULTS U.S. ALF STUDY GROUP

308 Patients

SpontaneousSurvivors

n=132(43%)

TransplantedN=89(29%)

Died beforeTransplantation

n=87(28%)

TransplantedN=89(29%)

AliveN=75(84%)

DiedN=14(16%)

Approach to Suspected ALF• Etiology and Pathogenesis

• Evaluation and Diagnosis

• Complications

• Management

• Prognosis

• Current and future treatment approaches