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
2
Other
Wilson’s
Fatty liver of pregnancy
Lymphoma/
Viral Hepatitis
malignant infiltrate
HAV
8
Sepsis
HBV
8
Budd-Chiari
Non A-E
28
Ischemia
Miscellaneous
Idiosyncratic Drug Reactions
Lamotrigine, cyproterone, NSAID,
chloroguine, rifampin/ INH
halothane, flucloxacillin
3
7
7
2
5
9
6
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
• 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
Medications
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
increased risk
of infection
Failure of
clearance
Endotoxemia
Gut leak
MOF
Tissue
Hypoxia
Activation of
macrophages
Circulating
changes
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%)
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