ACUTE LIVER FAILURE

Milton G. Mutchnick, M.D.

Professor of Medicine Chief, Division of Gastroenterology

Wayne State University School of Medicine

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

ALF Etiologies

• • • • • •

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 Acetaminophen 250 Ecstasy Viral Hepatitis HAV HBV Non A-E 8 8 28 2 Other Wilson’s 3 Fatty liver of pregnancy 7 Lymphoma/ malignant infiltrate 7 Sepsis Budd-Chiari Ischemia Miscellaneous 2 5 9 6 Idiosyncratic Drug Reactions Lamotrigine, cyproterone, NSAID, chloroguine, rifampin/ INH halothane, flucloxacillin

U.S.

ALF

STUDY GROUP 2003

40

(308 Patients, 73% Women)

35 30 25 20 15 10 5 0 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 HBsAg HBV DNA (Abbott) 100% 90% 10% *Absence of HBsAg favors better prognosis (47% v 17%). Higher frequency ALF with mutant HBV form

Drug Induced

ALF

•

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

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 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

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

Evaluation & Diagnosis of Impending ALF History!

History!

History!

Sexual contacts IDU Pregnancy Medications Risk Factors Mushrooms 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 copper Arterial blood gas Arterial lactate Pregnancy test Autoimmune markers – ANA, ASMA, Ig levels HIV status Amylase & lipase

Liver Biopsy

Reserved for diagnostic dilemma AIH, HS (Transjugular approach)

Diagnosis of ALF

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)

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 Edema Cerebral 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

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 Failure of clearance increased risk of infection Endotoxemia Gut leak MOF Tissue Hypoxia Circulating changes Activation of macrophages Release of 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, pneumothorax lactic 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 Spontaneous Survivors n=132 (43%) Transplanted N=89 (29%) Died before Transplantation n=87 (28%)

Alive N=75 (84%) Transplanted N=89 (29%) Died N=14 (16%)

Approach to Suspected ALF

•

Etiology and Pathogenesis

•

Evaluation and Diagnosis

•

Complications

•

Management

•

Prognosis

•

Current and future treatment approaches