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

Wilsons disease

AIH
 ALF
Etiologies

Viral Wilsons Disease

Drug Microvesicular
Poisoning steatosis
Ischemia AIH
VOD Hyperthermia
Malignant Infiltrate OLT
Partial hepatectomy
 Etiology of ALF in 342 Cases
(University Hospital, London UK)
Drugs-Overdose Other
Acetaminophen 250 Wilsons 3
Ecstasy 2 Fatty liver of pregnancy 7
Lymphoma/
Viral Hepatitis malignant infiltrate 7
HAV 8 Sepsis 2
HBV 8 Budd-Chiari 5
Non A-E 28 Ischemia 9
Miscellaneous 6
Idiosyncratic Drug Reactions
Lamotrigine, cyproterone, NSAID,
chloroguine, rifampin/ INH
halothane, flucloxacillin
U.S. ALF STUDY GROUP 2003
(308 Patients, 73% Women)
40
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 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
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

Wilsons 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
Reyes 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
 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 Died before

Transplanted
Survivors Transplantation
N=89
n=132 n=87
(29%)
(43%) (28%)
 Transplanted
N=89
(29%)

Alive Died
N=75 N=14
(84%) (16%)
Approach to Suspected ALF
Etiology and Pathogenesis

Evaluation and Diagnosis

Complications

Management

Prognosis

Current and future treatment

approaches