This document provides an overview of a presentation on Acute Liver Failure given by Julia Wendon of Kings College London. The summary includes: 1) The presentation defined acute liver failure and its subtypes, discussed its etiology and management of organ dysfunctions. 2) Management strategies for acute liver failure were discussed, including early transfer to transplant centers, ventilation support if needed, fluid management, and consideration for transplantation. 3) Studies on the use of extracorporeal membrane oxygenation to support patients with acute liver failure and multi-organ dysfunction were summarized.

1. Pulsion, Excalez MAB member
Fresenius, Ashai Kasei consultancy
julia.wendon@kcl.ac.uk
Acute Liver Failure : what tomorrow may
bring ?
Julia Wendon
Kings College London and Kings College Hospital
London

2. Definitions
Aetiology
Management of organ dysfunctions
Who to consider for transplantation

3. Acute Liver Failure
Bernal et al, Lancet 2010

5. Hyperacute < 7 days
Acute 1 -4 weeks
Subacute 4-12 weeks
Hperacute + acute
HE, cerebral oedema
Sub acute
jaundice, ascites
late HE
Acute Liver Failure
Primary liver injury
Coagulaopthy
Encephalopathy
No preexisting liver disease

6. ALF:Aetiology
Bernal & Wendon NEJM 2013Incidence : 1.6 -6.2 million / year

7. Bone marrow stained for T cell marker
CD3
in situ hybridization for EBV

8. Transfer issues
1. Early transfer to a Tp centre
2. Elective ventilation if GCS
changing or < 8-9
3. Observe pupils
4. Fluid
5. Noradrenaline
6. Mannitol for pupil abnormalities

9. Cardiovascular support
and management
Retrograde cerebral and
coronary perfusion
Full support no
native cardiac function
No pulsatility

10. ECMO & liver disease
LIVER NEEDING ECMO N =
ECMO
survival
%
Survival to
discharge
(or 90 days)
%
ALL liver patients 20 16 80 % 13* 65 %
11 ALF, 7 elective OLT, 2 CLD … of which 12 VV, 8 VA with being 5 eCPR
ALL elective liver transplants 7 6 86 % 6 86 %
3 VV, 3 VA … of which 1 was eCPR
ALL liver transplants 15 11 73 % 8 53 %
9 VV, 6 VA … of which 4 were eCPR
* One late death from HAT at 5 months

11. ALF & ECMO - Demographics
Aetiology Age Gender
1 SALF† 23 F
2 Avascular* 29 M
3 POD 17 F
4 PPOD‡ 26 F
5 HH** 29 M
6 Status/POD 44 M
7 Wilsons 11 M
†Sub-acute liver failure
*Penetrating trauma, HA ligated, prolonged
Pringle manoeuvre
‡Polypharmacy OD
**Suspected myocarditis and hepatitis

12. ALF & ECMO - Severity of liver disease
AST IU/L INR Lactate Bilirubin HE III-IV
All 8531 6 13.1 282 6
SALF 57 5.4* 8 312 1
Avascular 6000 3* 12 159 1
POD 9966 9.7 11 325 1
PPOD 12650 5.35* 18 227 1
HH 12200 6.1* 15 219 unknown
Status HH 18180 5* 13.2 94 1
Wilsons 667 7.36* 14.4 636 1
*INR supported
6/7 (86%) pts
fulfilled KCH
criteria for ELT

13. Extra-hepatic organ failure
All VV
SOFA 22 (20-24)
CPR 5 (71%)
RRT 7 (100%)
ICH 6 (86%)
Plt 40 (20-77)
Norepinephrine
μg/kg/min
1.02 + other
PPlat 37 (32-40)
Murray 3.8 (3-4)

14. Outcomes – ALF & ECMO
ECLS duration Weaned ECLS Discharge or
90d survival
All 8d (1-20) 6/7 (86%) 5/7 (71%)
VV ECMO 11d (5-20) 4/5 (80%) 3/5 (60%)
VA ECMO 5d (4-6) 2/2 (100%) 2/2 (100%)
ECMO pre ELT 8d (3-21) 3/4 (75%) 2/4 (50%)*
• 86% wean rate
• 71% 90 day survival off ECMO
• All patients transplanted (n = 4) survived OLT procedure
• 100% had excellent early graft function – normal D1 lactate
• One died at 5 months from HAT

15. Renal
Na
Lactate
Glu

16. 3%) had ALF and 22
tation or died. Despite
mean TEG parameters
meters were normal in
measure of ultimate clot
with platelet counts
higher in patients with
venous ammonia con-
of liver injury assessed
ry response syndrome.
coagulant factor V and
reases in anticoagulant
vated factor VIII levels.
Acute liver injury and acute liver failure (ALI/ALF) are syndromes
defined by ‘‘coagulopathy’’ on the basis of increased prothrombin
time (PT)/INR; ALF represents a more severe liver injury resulting
in hepatic encephalopathy [1]. Thrombocytopenia frequently
accompanies ALI/ALF, although its pathogenesis remains poorly
defined [2]. Consequently, patients with ALI/ALF have been
assumed to have a bleeding diathesis [3], even though most ser-
ies report a low incidence of spontaneous, clinically significant
bleeding [4]. Although invasive procedures such as intracranial
pressure (ICP) monitor placement are also rarely associated with
bleeding complications (<5% [5]), coagulation factor and platelet
transfusion remain a routine practice despite potential adverse
effects [6].
In patients with cirrhosis, who also have thrombocytopenia
and elevated INR, a concept of ‘‘re-balanced hemostasis’’ has been
proposed to explain the fact that patients rarely bleed outside of
the consequences of portal hypertension [7]. As shown by Tripodi
[8], thrombin generation is normal in patients with cirrhosis pro-
vided that thrombomodulin is added to the reaction mixture to
activate the anticoagulant protein C system. These and other
authors have explained the maintenance of hemostasis in
patients with cirrhosis by the fact that decrements in procoagu-
lant proteins are matched by decrements in anticoagulant pro-
teins, such as proteins C and S, and antithrombin (AT) [9].
In contrast to conventional coagulation tests such as the PT/
INR and the activated partial thromboplastin time (aPTT) which
assay only clot formation time in a plasma environment, throm-
boelastography (TEG) assesses overall hemostasis, the cumulative
effects of procoagulant and anticoagulant proteins, fibrinogen,
platelets, and red blood cells. Component measurements of the
Journal of Hepatology 2012 vol. 56 j 129–136
tic encephalopathy; Hemos-
March 2011; accepted 6 April
patology, P.O. Box 980341,
A 23298-0341, USA. Tel.: +1
er failure; INR, international
mboelastogram/thromboelas-
pressure; AT, antithrombin;
reaction time of TEG; K-time,
EG; SIRS, systemic inflamma-
nt; LY-30, clot lysis in 30 min;
body mass index; APAP, ace-
essure; OLT, orthotopic liver
D, model for end-stage liver
protease with thrombospon-
TEG parameters in patients with ALI/ALF reflect specific
phases of blood clot formation and are associated with specific
aspects of the clinical syndrome. The R-time mirrors activation
of the coagulation cascades and procoagulant factor levels. Con-
sistent with the well-recognized importance of the INR and factor
V in predicting outcome in patients with ALF [21,22], the R-time
directly correlated with the SIRS, specific laboratories which pre-
dict poor outcome (lactate and phosphate), complications of the
ALI/ALF syndrome other than hepatic encephalopathy, and poor
outcome. R-time was significantly higher in patients with infec-
tion, those requiring CVVH, and in those with bleeding complica-
tions. The TEG was, in fact, more sensitive than the INR for
predicting bleeding, since the INR was not significantly different
in those who bled and those who did not (p = 0.14). This observa-
tion supports those of Chau et al. [23], who noted that variceal re-
bleeding in patients with cirrhosis was predicted by TEG but not
INR. Similarly, the platelet count, factor levels, and fibrinogen
Feature R time K time α-Angle Maximum amplitude
Coagulation Parameters:
INR 0.32* 0.17 -0.24 -0.23
PTT 0.60**** 0.07 -0.07 -0.06
Platelets 0.01 -0.50*** 0.58**** 0.73****
Fibrinogen -0.22 -0.44** 0.34* 0.57****
Factor V -0.30* -0.25 0.24 0.34*
Factor VII 0.08 -0.02 -0.06 0.17
Factor VIII -0.27 -0.31* 0.38** 0.33*
Protein C Activity -0.19 0.02 -0.14 -0.04
Protein S Activity -0.14 0.11 -0.20 -0.14
Antithrombin Activity -0.14 -0.02 -0.06 0.17
SIRS Components:
Pulse 0.18 -0.43** 0.29* 0.44**
Respirations 0.46*** -0.34* 0.15 0.31*
Temperature -0.20 0.03 0.02 -0.06
WBC 0.29* -0.13 0.19 0.30*
Chemistries:
Lactate 0.58**** 0.16 -0.23 0.01
Ammonia (venous) 0.13 -0.37** 0.38** 0.38**
Phosphate 0.47*** -0.04 0.00 0.25
Creatinine 0.11 -0.05 0.13 0.23
Total Bilirubin -0.14 -0.16 0.22 0.10
⁄
p <0.05, ⁄⁄
p <0.01, ⁄⁄⁄
p <0.001, ⁄⁄⁄⁄
p 60.0001 indicates significant correlation.
0 1 2 3 4
30
40
50
60
70
80
Maximum
amplitude(mm)
SIRS (N)
Fig. 2. Maximum amplitude of clot formation according to the number of
SIRS concurrently determined in patients with acute liver injury/failure on
admission to study. Data represent mean values with lower/higher 95%; width of
columns reflect number of patients with indicated number of SIRS (p = 0.024 for
trend).
Liver Int 2013
Coagulation
Journal of Hepatology
2012 vol. 57 780–786
Mallett et al

17. Karvellas
Intensive Care Med 2009
Clin Gastroenterol Hepatol.
2014 Nov;12(11)
Antibiotic prophylaxis does not decrease
blood stream infections not impact upon
mortality
Bacteraemia was associated with mortality
In USA study as compared to UK study

18. Functional monocyte deactivation in ALF
0
200
400
600
800
1000
1200
0 20 40 60 80
hladr
Observed
Logarithmic
IL-10pg/ml
r= -0.8; p<0.001
↓ monocyte HLA-DR, ↑circulating IL-10
Strong correlation with severity of liver injury, organ failure & outcome
Antoniades et al, Hepatology ‘06; Berry et al Liv Int ‘10

19. Monocytopaenia in ALF
Monocytes Neutrophils
Antoniades et al, Hepatology 2012
Hepatic micro
environment favors
resolution inflammation
Increased IL6,10,TGFbeta
No difference for Il-1,INF,
IL-12,17,23

20. ALF plasma exerts anti-inflammatory effects on
monocytes/macrophages
• Incubation of healthy volunteer CD14+
monocytes and monocyte-derived macrophages
with ALF plasma (24-48hours)
• LPS stimulation (100mcg/ml) & TNF-a, IL-6, IL-10
levels
Antoniades et al, gastroenterology 2016
ALF
LPS

21. Sequential and regional SLPI
variations
*p=0.03
Inflamed liver is a source of production of SLPI
Antoniades et al, Hepatology. 2014 Apr;59(4):1564-76
SLPI Main physiological target is neutrophil elastase/inhibit neut released proteases during
tissue injury Ameliorating tissue injury/wound healing
Inhibits monocyte driven T cell proliferation/Th1 responses (Guerrieri et al, Immunology ‘11)

22. Can we alter these observations ?
HEPATOLOGY 2014;59:1564-1576
• Secretory Leucocyte Protease Inhibitor
– anti-inflammatory mediator in tissue microenvironment – macrophage NF-kB
– Macrophages secrete SLIP following phagocytosis of apoptotic cells
– Immune modulatory role in sepsis
Antoniades CG

23. NH4 cut off 124 : pH, cerebral
oedema + NH4 predict outcome
Bhatia V Gut 2005
Clemmensen et al
Hepatology 1999;
29:648-653
Bernal W Hepatology 2007

24. Grade III/IV coma
Young people
Haemodynamic instability ; pressors
Fever, SIRS, low Na
Elevated NH4 (>150)
Renal failure
Non-Acetaminophen 33/170 (19%)
Acetaminophen 55/210 (26%)
Bernal W Hepatology 2008 2007

25. Reduction in ICP
in treatment group
(p<0.005)
Murphy et al Hepatology
2004;39(2):464-70
Reduced risk of intracranial
hypertension (p<0.05)
Hypertonic saline and
Cerebral oedema
Randomized control trial
Grade IV HE with ICP bolt
SOC vs Na 145-150
Treatment resistance
consider iv indomethacin

26. 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
1973-78 1979-93 1984-88 1989-93 1994-98 1999-03 2004-08
Period
%DevelopingICH

27. Ann Intern Med. 2013;159:522-531.

28. Larsen et al J Hepatology 2016

29. R. Todd Stravitz, HEPATOLOGY 2013;58:304-313)
Larsen et al Journal of Hepatology 2016
CD68 (Yellow) and Fibrin (Red

30. PE resulted in a significant decrease in circulating histone –
associated DNA
Monocytes
PE reduce TNF vs SoC and IL-6
Early PE reduced surface expression of
CD163 (p=0.0250),
CD64 (p=0.0042)
CCR7 (p=0.0008)
without change in number of cells nor their apoptosis
Neutrophils
decreased IL-8 and expression of L-selectin
Lymphocytes
no change in numbers CD8-T, NK-T, NK – cells,regulatory T
Decreased production of IL-10, IL-4 and TGF-B following
endotoxin challenge

31. Transplantation and prognostic markers

32. Gut 2012;61:1068e1075
Ramesh Kumar,

33. Bernal et al 2016

34. D1: INR 6.5 rising to 8.5, CK 150K, ALT 9,000 , ARF, lactate 6 - D2 INR 5, lactate 3.0, ALT 7000
Found outside club - fitting – intubated and brought to ED : Temp 41 seizure control : D0

35. 70% successful weaning of Immunosuppression
4/8 survived without OLT

36. Teams make things work
julia.wendon@kcl.ac.uk