Aliakbarian M, M.D

ACUTE LIVER FAILURE

Acute Liver Failure

Definition

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….

• 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

ALF

Etiologies

• Viral

• Drug

• Poisoning

• Ischemia

• VOD

• Malignant Infiltrate

• Wilson’s Disease

• Microvesicular

steatosis

• AIH

• Hyperthermia

• OLT

• Partial hepatectomy

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

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

Obstruction of Hepatic Veins

and ALF

• Budd-Chiari syndrome

and thrombosis of hepatic

veins

• VOD - Post BMT

Chemotherapy, Irradiation

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

Risk Factors

Pregnancy 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 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 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

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

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

OUTCOME RESULTS U.S. ALF

STUDY GROUP

308 Patients

Spontaneous

Survivors

n=132

(43%)

Transplanted

N=89

(29%)

Died before

Transplantation

n=87

(28%)

Transplanted

N=89

(29%)

Alive

N=75

(84%)

Died

N=14

(16%)

Approach to Suspected ALF

• Etiology and Pathogenesis

• Evaluation and Diagnosis

• Complications

• Management

• Prognosis

• Current and future treatment

approaches