Dr Neerav Goyal discusses the various aspects of acute liver failure that includes the criteria, pre transplant issues, critical care management, overall survival.

1. ACUTE LIVER FAILURE
Dr Neerav Goyal
Senior Consultant and Head
Apollo Liver Transplant, Hepatobiliary and Pancreatic Surgery Unit
Indraprastha Apollo Hospital, New Delhi

2. • Introduction
• Criteria
• Pre transplant issues
• Critical care management
• When to offer &When to say No
• Transplant outcome
• Overall survival
• Evidence

3. ACUTE LIVER FAILURE
• ALF is a life-threatening, rare medical emergency
that arises from massive acute hepatic necrosis
• Defined:
1. Presence of hepatocellular dysfunction
(coagulopathy, jaundice)
2. Encephalopathy
3. No prior history of liver disease

4. Definitions of ALF

5. Which Definition to be followed?

6. Definitions of ALF
Onset Defining event Illness duration
Trey and Davidson,
1970
First symptoms Encephalopathy 8 weeks
Bernuau et al, 1986 Jaundice Encephalopathy 2 weeks-Fulminant
2-12 weeks- Subfulminant
O’Grady et al,
1993
Jaundice Encephalopathy 1 week- Hyperacute
1-4 weeks-Acute
5-12 weeks-Subacute

7. • Interval between onset of
acute hepatic injury
(jaundice) and onset of
liver failure
(encephalopathy with or
without coagulopathy
(Icterus-encephalopathy
interval; IEI)
• Between 4 weeks (Indian
definition)2–4 to 24 weeks
(AASLD–ALF study group)

8. What is the significance of the jaundice to
encephalopathy interval?

10. What is the significance of the grade of
hepatic encephalopathy?

11. Hepatic encephalopathy and spontaneous
recovery
Trey C, CMAJ 1972
Survival Grade 2 HE Grade 3 HE Grade 4 HE
65-70% 40-50% <20%

12. What are common etiological factors for ALF?

14. What are the main prognostic determinants in
ALF?

15. Prognostic Criteria
• Four key determinants:
1. Aetiology
2. Rate Of Progression Of The Disease
3. Age Of The Patient
4. Laboratory Markers Of Disease Severity

17. Kings College Hospital Criteria

18. • Overall specificity of 82% for non-paracetamol aetiologies
and 92–95% for paracetamol-related ALF
• Nonparacetamol aetiologies, involving 1105 patients in 18
studies
• Specificity increased to 93% in patients with more advanced
encephalopathy
• 88% when the criteria were applied dynamically
• Second meta-analysis of paracetamol-induced ALF involved
8 studied and reported a specificity of 92% , sensitivity of
69%

19. Reason for criteria
The probability of spontaneous recovery must be
compared with the risks of surgery and
immunosuppression
• King’s college hospital poor prognostic criteria
• Clichy (Paris)criteria
• Acute liver failure study group of Japan criteria
• MELD score
• ALF in-hospital mortality score (ALFIHMS)

20. King’s vs MELD

21. 380 patients with ALF
ALF early dynamic (ALFED) model was constructed
Whether the levels of predictive variables remained persistently high or
increased over 3 days above the discriminatory cut-off values
Demonstrated excellent discrimination with an area under the receiver
operator characteristic curve of 0.91 & 0.92

22. • ALFED score of > 4 had a high positive predictive value
(85%) and negative predictive value (87%)
• Accurately predicted outcome in patients with ALF, which
may be useful in clinical decision-making

23. CASE 1
• Mr. X
• 27/male
• Jammu
• Admitted with
- History of jaundice for past 24 days
- History of hepatic encephalopathy for past 3 days

24. • No h/o any fever/prodromal symptoms/upper GI
bleed / abdominal distension
• Patient was started on ATT following surgery for
intestinal perforation (3 m back - Intensive Phase)
• H/o jaundice after 5 weeks
• Stopped ATT however Jaundice continued to increase
• Developed Encephalopathy ~ 4 weeks following
jaundice

25. Examination
• PR- 130/min
• BP-100/70 mm Hg
• Temp: febrile (101 F) Icterus present
• RS- NAD CVS-S1,S2 normal
• CNS- Pupil dilated reacting to light
• P/A: Soft, Non Distended, Non Tender, Scar mark
of previous surgery present, no e/o free fluid

26. • ATT induced ALF- Which drugs are most
reponsible?
• How often do you see DILI as a cause of ALF and
which drugs in clinical practice?

27. CASE 2
• Mr. D
• 30/M
• R/O Delhi
• H/O Fever with prodromal symptoms for 10 days
• Evaluated locally and found to be jaundiced
• Developed Encephalopathy 2 weeks after initial
symptoms

28. • No history s/o CLD
• No comorbidity
• No h/o any substance abuse
• No h/o any previous surgery

29. Examination
• Comatose (Gr IV Encephalopathy)
• Icterus +++
• Pupil: B/L reacting
• P: 107/min BP: 106/80 mm Hg RR: 20/min
• RS/CVS:NAD
• CNS: No e/o any focal neurological deficit
• P/A: non distended/No organomegaly/No e/o free
fluid/ Liver Span ~10 cm

30. • Gr IV Encephalopathy with INR 9.1 (Absolute
Criteria)
• CT Brain: Normal
• On etiological work up : Anti HEV I g M (Positive)
• Diagnosis : Fulminant Hepatic Failure (HEV Related)

31. Case 3
• Master J
• 7 Yr./M
• R/o Nagpur
• H/o vomiting and fever for 1 month
• History of dark urine
• Evaluated in a multispecialty hospital in Nagpur and
found to have deranged LFT along with
coagulopathy (Referred)

32. • Drowsy, Icterus +
• Blood pressure – 160/80, Pulse – 72, RR – 24/min
• RS/CVS:NAD
• CNS: No e/o any focal neurological deficit
• P/A: non distended/No organomegaly/No e/o free
fluid

33. • Patient was admitted and evaluated
• Hepatic encephalopathy(Gr 3) and INR was 7.5
• S. Ceruloplasmin : 16.67
• 24 urinary copper : High
• KF rings +
• CT liver Angio : essentially normal liver, patent PV and
minimal ascites
• Diagnosed as acute Wilson’s disease
• Family was counseled, prognosis explained & advised
regarding need of emergency liver transplant
• His encephalopathy worsened over night

34. • Wilsons disease: Acute Liver Failure

35. What are the goals of Management?

36. Goals in ALF Managment
Intensive medical management1.
Identify patients not achieving
sufficient liver regeneration
Emergency liver transplantation
2.

37. • Major complications usually associated with death
1. Cerebral edema
2. Seizures
3. Infections
4. Bleeding due to coagulopathy
5. Renal failure
6. Electrolyte and acid base imbalance
7. Hypoglycaemia

38. Cerebral edema
• Cerebral edema Most common cause of mortality
• ALF 58% have CE at admission
• Mortality rate 82% with CE
44% without CE
• Recent data suggest that cerebral edema is less frequent
- Acharya SK et al. Hepatology 2006
- O Grady et al.Lancet 2003

39. Intracranial pressure
• Normal ICP:
• 7–15 mmHg (supine), −10 mmHg (vertical
position).
• CPP= MAP-ICP
• Goals:
★ICP < 20–25 mm Hg.
★CPP at 60–70 mm Hg

40. Cerebral auto-regulation
ALF-loss of auto-regulation

41. Should we measure ICP?

42. Should we measure ICP?
• Survival of patients with grade III-IV HE not
improved by ICP monitoring
• Vaquero J, Liver Transpl 2005
• Keays RT, J Hepatol 1993
• Schmidt L, Crit Care Med 2006
• No information on long term neurological sequel
• Intracranial bleed in 10.3%

43. Should we measure ICP?
Vaquero J, Liver Transpl 2005
• Frequent bedside clinical evaluation diagnose <25%
episodes of ICH detected by ICP monitoring.
• Keays RT. J Hepatol 1993

44. ICP monitoring- Is there a middle path?
• Ammonia levels
• Jugular bulb oxygen saturation
• Cerebral A-V difference of O2 saturation
• Trans-cranial Doppler examination
• Optic Nerve Sheath Diameter

45. Any specifics for nursing care?

46. Nursing care
• Head position- Neutral and 300
elevation
• Avoid stimulation
• Treat fever aggressively

47. What measure would you take to decrease ICP?

48. Hyperosmolar therapy
• Mannitol
• Hypertonic saline
• Surrogate goals in absence of ICP monitoring:
- Serum Osm 310-320 mOsm/Kg.
- Serum sodium:145-150 mmol/L.

49. Mannitol
• Response 15 to 60 min after bolus
• In 20% paradoxical rise in ICP
• Best in mild to moderate ICH
• Better survival with mannitol (47.1% vs. 5.9%)
Canalese J. Gut 1982

50. How to use mannitol in ALF?
• Use if preserved renal function.
• Boluses iv. 0.25–0.5 g/kg when ICP >25 mmHg for
>10 minutes.
• Repeat if ICP remains > 25 mmHg and serum
osmolality < 310 mOsm/L.

51. Hypertonic saline
• Target level: 145-155 mmol/L
• Monitor sodium every 6 hours
• Correction <12 mmol/L in 24 hours or 16 mmol/L in
48 hours
• Small RCT- incidence and severity of ICH reduced
in patients with induced hypernatremia
Murphy N, Wendon J. Hepatology 2004

52. How to use hypertonic saline in ALF?
• 3% NS 250 cc bolus over 10-15 minutes (~4 cc/kg).
• Keep Na<160 and Osm<330 (?? upto 360).
• Problems
- Hyperchloremic acidosis
- Volume expansion.
- Demyelination
- Small brain hemorrhages
- Aggravation of coagulopathy

53. Barbiturates
• Thiopentone loading dose 3-5mg/kg (maximum
500mg) over 15 minutes, followed by a
continuous infusion at 0.5-2.0mg/h
• Must be used with continuous ICP and arterial
BP monitoring
• ICP normalized in 8/12 with unresponsive ICT
Forbes et al. Hepatology 1989

54. When not to use barbiturates in ALF?
• Problems:
- Hypotension.
- Anergy and poikilothermia
- Hypokalemia

55. Hypothermia
• Normalization of cerebral blood flow
• ↓ Brain ammonia delivery/uptake
• ↓ Anaerobic glycolysis & oxidative stress in
astrocytes
• ↓ Brain ECF glutamate
• External cooling blankets suffice
32o -35o C

56. Hypothermia
- Cardiovascular instability
- Shivering (paralysis needed)
- Worsening coagulation
- Reduced platelets
- Increased infection risk
- ? impairment of hepatic regeneration

57. Ammonia and ICT
Kaplan-Meier plot of ICH in 165 ALF patients
according to arterial ammonia on admission.
Bernal W. Hepatology 2007Clemmesen JO. Hepatology 1999
Arterial ammonia in 30 patients who did not
develop CH and 14 patients who died from CH

58. Role of Ammonia
Arterial ammonia levels >124 mmol/l
78.6% sensitive and 76.3% specific for predicting mortality
Bhatia V. Gut 2006

59. Anti-ammonia measures
• Lactulose
• L-Ornithine L-Aspartate
• Sodium Benzoate

60. L-Ornithine L-Aspartate
Blinded RCT of LOLA vs. Placebo in ALF patients.
92 patients received LOLA, 93 received placebo
Acharya SK et al. Gastroenterology. 2009

61. Hyperventilation
• Prophylactic hyperventilation no reduction in
ICH
• pCO2 reduction to 25-30mm Hg decrease ICP
once cerebral edema begins to develop
• Ede et al. J Hepatol 1986
• JVO2 monitoring mandatory.
Normal JVO2: 60%-80%.

62. What should be goals of cardiovascular
management?

63. Management of circulation- Goals
• Ensure adequate vascular filling (CVP: 8-12 cm
water)
• Avoid over hydration and hypotonic fluids –
increase in ICP
• Vasopressor agents (NorAdr) if MAP < 60
mmHg despite adequate fluids
• Hypotension in spite of above - a sign of
bacterial or fungal sepsis
Goal: MAP > 60mmHg

64. Choice of vasopressor
• Norepinephrine > Dopamine
• ? Terlipressin
• Avoid epinephrine
Steiner LA. Crit Care Med. 2004

65. What role does NAC play?

66. Gastroenterology. 2009 September ; 137(3): 856–864

67. NAC dosing in
non-acetaminophen ALF
• Initial loading dose of 150 mg/kg/hr over one
hour
• Followed by 12.5 mg/kg/hour for 4 hours
• Then continuous infusions of 6.25 mg/kg for
the remaining 67 hours (Total 72 hours)

68. Prophylactic drugs usage?

69. Prophylactic anti-seizure drugs
• Subclinical seizure activity- exacerbation of
cerebral edema
• All patients with deep HE should be treated
with prophylactic phenytoin
Ellis et al, Hepatology 2000
• RCT 42 ALF patients – no benefit
Bhatia V, et al. J Hepatol 2004

70. Glucose homeostasis
100-200mg/dL<100mg/dL >200mg/dL
√X X
Hypoglycemia Infection risk
Increased cerebral lactate

71. Correction of bleeding diathesis
• Clinically significant bleeding uncommon (<10%)
• Prophylactic FFP not recommended
• Maybe...
• Profound coagulopathy (INR >7 with abnormal
TEG) , FFP and cryoprecipitate transfusion to
maintain INR between 5-7

72. Infections in ALF-Consequences
1. Neurological deterioration
2. Aggravation of liver damage
3. Increased mortality

73. Infection and neurological deterioration
Deteriorated
Improved
100%
84.8%
15.2%
Infection during grade I-II HE predicts worsening HE

74. Infection and mortality
n=268
p <0.001
RR for mortality: 2.11 (1.54-2.90)
Infection is an independent predictor of mortality

75. Sites of infections in ALF

76. Recommendations for managing renal failure?

77. Renal failure
• 40%–80% of patients
• Associated with a poor prognosis
• More frequently in acetaminophen induced ALF
(70%) and less frequently in ALF due to other
causes (30%)
• Renal failure is reported in 10% of patients from
India
- - Acharya SK et al. Hepatology 2006
- O Grady et al.Lancet 2003

78. Role of CRRT and Bio-arteficial Liver Assist
Devices ?

79. Renal replacement therapy
• CRRT >IRRT (especially if cerebral edema)
• Heparin avoided
• Bicarbonate buffer preferred over citrate and
lactate
• Biocompatible dialysis membranes like
polysulphone or polyacrylnitrate
• Route Femoral
• Avoid hyponatremia and other electrolyte
changes

80. Artificial liver support
Excretory function
Synthetic and
Biotransformatory process
Dialysis √
(Ammonia)
×
Exchange transfusion
Plasmapheresis
√
(Protein bound molecules)
×
Bioartificial
extracorporeal devices √ √
Charcoal hemoperfusion
√
(Mercaptans, GABA, AAA, and
FA)
×
Albumin dialysis √ ×

81. Case 1: ATT induced ALF
King´s college Criteria
Age 28 N
Jaundice 27 mg/dl Y
INR 4.4 Y
Non A/Non B ATT Induced Y
Jaundice to
encephalopathy
20 days Y

82. HOSPITAL COURSE
• Admitted in ICU as a referred case of acute liver
failure
• At time of admission was fulfilling king`s college
criteria (4/5)
• Features of severe sepsis
(fever/tachycardia/hypotension)
• At time of admission was in grade 4
encephalopathy

83. • Electively intubated and kept on ventilatory
support
• For hypotension required inotropic support
• Management started as per ALF protocol
• Relatives appraised regarding patient condition
and need for optimization followed by liver
transplant
• No potential donor in family

84. • Patient condition continued to be critical
• Persistent Hyper- bilirubinemia (Up to 57mg/dl)
associated with coagulopathy(Up to 5.1)
• In view of no potential donor with detoriating liver
and renal profile Plasmapheresis and CRRT started
• Required 3 sessions of plasmapheresis

85. • Patient condition stabilized with improvement in
liver and renal profile
• Inotropes were stopped
• Extubated on day 9 when regained sensorium
• Shifted to ward after 2 weeks
• Discharged after 25 days of admission with serum
bilirubin of 7 mg/dl
• Doing well in follow up with completely recovered
liver profile

86. When not to transplant?

87. Contraindication for LT in ALF
• Pt’s outside different prognostic criteria
• Active and resistant alcohol dependence/ substance abuse
• Documented previous history of noncompliance with
medical or psychiatric therapy
• Medically unfit to survive LT
• Brainstem Herniation
• Active Sepsis

88. • Under Went LRLT(Right lobe without MHV) with
anterior sector reconstruction, Single duct (Duct to
duct)
• Underwent uneventful surgery and was shifted to
ICU
• POD 2 developed Intra abdominal bleed
• Laparotomy done, Bleed from drain site
• Extubated on POD 5
Case 2: Hep E

89. • Immunosuppression started from POD 5
• Shifted to ward on POD 9
• Discharged on POD 19
• Doing well on follow up

90. Case-3: Fulminant Wilson’s
• Under Went LRLT(Right lobe without MHV) with
anterior sector reconstruction, Single duct (Duct to
duct)
• Uneventful surgery
• Extubated POD1
• In view of persistent drowsiness and fall in
saturation, he was re-intubated
• Extubated on POD 4

91. • Immunosuppression started from POD 2
• Shifted to ward on POD 10
• Uneventful Recovery
• Discharged on POD 18
• Doing well on regular follow up

92. Outcome

94. • Results of liver transplantation for ALF are acceptable in the
context of the severity of the illness and limited therapeutic
alternative
• Survival rates at 1 year are 7% to 15% below those obtained
for elective transplants in patients with chronic liver disease
• Compare favourably when compared with the 64.4%
survival rate seen in patients in intensive care immediately
prior to transplantation
• Relative risk of death was 1.6 3 months after liver
transplantation
- Mcphil M et al. Int Care Med 2009

95. • Beyond the first year, the survival curve flattens out, so that
in Europe at 10 years, the gap in survival between these 2
groups has fallen from 15% to 5%
• 1-year survival for deceased donor liver transplantation was
78.6%, and for living donor liver transplantation, it was 87%
- Merlon m et al.AJT 2008

96. LDLT in ALF
• Safe and effective alternative
• Survival comparable to DDLT
• Less infectious complication in recipient
• Less waiting time
• Good graft quality from healthy donor

97. P=0.21
NS
P=0.001

98. LDLT vs DDLT
Outcome of 14 patients with acute liver failure evaluated for LDLT. Abbreviations:
DDLT, deceased donor liver transplantation; LD, living donor; LDLT, living donor liver
transplantation; txp, transplant

99. • Results of living donor liver transplantation for ALF
in a Japanese experience of 42 patients were very
comparable to overall outcomes
• 80% 1-year survival and 68% 10- year survival
• Study indicated that the results were influenced by
the ratio of the graft to standard liver volume
• 1-year survival rate of 87.1% in those with a ratio 50%
versus 80.7% in those with volumes in the 40% to
50% range
- Kayishama H JACS 2008
- Lee SG et al . Journ Hepat 2007