Liver failure

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

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 ≥ 1.5 + 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 250 Wilson’s 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

10. U.S. ALF STUDY GROUP 2003
(308 Patients, 73% Women)
0
5
10
15
20
25
30
35
40
ACM HBV HAV Indet Other

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

12. Acute HAV and ALF
• 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)
 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. 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. 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
308 Patients
Spontaneous
Survivors
n=132
(43%)
Transplanted
N=89
(29%)
Died before
Transplantation
n=87
(28%)

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

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