1. Chief, Division of Gastroenterology
ACUTE LIVER FAILURE
Milton G. Mutchnick, M.D.
Professor of Medicine
Chief, Division of Gastroenterology
Wayne State University
School of Medicine

2. 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.

3. Acute Liver Failure….AKA
Fulminant hepatic failure
Fulminant hepatitis
Subfulminant liver failure
Subacute hepatic necrosis
Subacute liver failure
Hyperacute liver failure

4. 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 ≥ Altered Mental Status = ALF ≥

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

6. Etiology of ALF Acute viral hepatitis (A - E) Mushroom poisoning
Acetaminophen
Acute fatty liver of pregnancy
Chemical agents

7. Drug-induced hepatitis
Budd-Chiari Syndrome
VOD of liver
Wilson’s disease
AIH

8. ALF Etiologies Viral Drug Poisoning Ischemia VOD Malignant Infiltrate
Wilson’s Disease
Microvesicular steatosis
AIH
Hyperthermia
OLT
Partial hepatectomy

9. Etiology of ALF in 342 Cases (University Hospital, London UK)
Drugs-Overdose Other
Acetaminophen Wilson’s
Ecstasy Fatty liver of pregnancy 7
Lymphoma/
Viral Hepatitis malignant infiltrate
HAV Sepsis
HBV Budd-Chiari
Non A-E Ischemia
Miscellaneous
Idiosyncratic Drug Reactions
Lamotrigine, cyproterone, NSAID,
chloroguine, rifampin/ INH
halothane, flucloxacillin

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

11. Viral Acute Hepatitis A-E Reactivation of HBV Chemotherapy
Immunosuppresion
Herpes simplex
Varicella-Zoster
EBV

12. Acute HAV and ALF Frequency 0.01% - 0.1% in jaundiced patients
ALF uncommon
Frequency 0.01% - 0.1% in
jaundiced patients
ALF occurs early
Survival (transplant- free) 75%
Age related survival

13. Acute HBV and ALF HBV alone or with HDV co-infection (rare)
Transplant-free survival is 23%
Overall survival 77% because of
transplantation

14. 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

15. 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

16. 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

17. Ischemic Hepatitis and ALF
Liver cell necrosis - massive
scale
Cardiac tamponade
Acute heart failure
Pulmonary embolus
Hepatic artery thrombosis

18. Obstruction of Hepatic Veins and ALF
Budd-Chiari syndrome and thrombosis of hepatic veins
VOD - Post BMT Chemotherapy, Irradiation

19. Massive Malignant Infiltration of the Liver
Attributed to ischemic
changes
Leukemia, lymphoma
Malignant histiocytosis
Metastatic Replacement

20. 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

21. 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

22. 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

23. Evaluation & Diagnosis of Impending ALF
History! History! History!
Sexual contacts
IDU
Risk Factors
Pregnancy Mushrooms
Medications Travel Toxic exposures

24. HISTORY Family members with liver disease? Recent cold sores
Onset of jaundice
Work environment- toxic agents
Hobbies
Herbal products/dietary supplements

25. Physical Exam Determine presence or absence
of pre-existing liver disease
Hepatic tenderness
Hepatic decompensation

26. Laboratory Tests (1) ALT, AST, Alk Phos, Glu, Bilirubin
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

27. 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

28. Reserved for diagnostic dilemma - (Transjugular approach)
Liver Biopsy
Reserved for diagnostic dilemma -
AIH, HS
(Transjugular approach)

29. 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)

30. 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

31. 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

32. 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

33. 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

34. 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)

35. 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

36. 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.

37. 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

38. (CI = cardiac output/body surface area)
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

39. 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

40. 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

41. 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

42. Current Treatment
Transplantation

43. 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

44. OUTCOME RESULTS U.S. ALF STUDY GROUP

46. Approach to Suspected ALF
Etiology and Pathogenesis
Evaluation and Diagnosis
Complications
Management
Prognosis
Current and future treatment
approaches