Fulminant Hepatic Failure

and Liver Transplantation

Neville Jamieson
Department of Surgery
Addenbrooke’s Hospital
Cambridge
Clinical Syndromes of Liver Failure

Acute Liver Failure syndromes

Late-Onset Hepatic Failure

Chronic Liver Failure

Assessment of Prognosis

Scoring systems
 Fulminant hepatic
failure

• Acute liver injury

• Heralded by coagulapathy
• Resulting in encephalopathy within up to 12
weeks of onset
• In absence pre-existing liver disease
 Hyperacute liver
failure – a paradox
• Encephalopathy within 7 days
• Paracetamol, hepatitis A and B
• Long PT (INR)
• High incidence of cerebral oedema
• Early regeneration
• Reasonable prospects for survival
 Acute liver
failure

• Encephalopathy 8-28 days of jaundice

• Mixed aetiologies
• Similar characteristics as hyperacute but
with poor prospects of spontaneous
recovery
 Subacute liver
failure

• Late onset of encephalopathy

• Less dramatic derangements of coagulation
• Low incidence of cerebral oedema
• Very poor prognosis
• Sepsis often contraindicates transplantation
 LOHF - Clinical Features and
Management
Gimson et al Hepatology 1986
Ellis eta l J Hepatol 1995

Age 45 years (median) - older than FHF

Slower tempo to presentation with encephalopathy late
PT 32 (range 17-120m secs)
10% +ve viral serology
8% +ve ANF/SMA titre > 1:320; elevated IgG and response to
corticosteroids
11% potential hepatotoxic drug within 3 months
Majority have no identifiable cause

Mortality without OLT 81%; n = 21 OLT 55% 1 year survival

Acute Liver Failure Syndromes And Late Onset Hepatic Failure

Hyperacute Acute Liver Subacute LOHF

Liver failure Failure LF

Encephalopathy yes yes yes yes

Duration Jaundice
encephalopathy <7 days 8-28 d 29-84 d 12-24 w

Cerebral oedema 70% 55% 14% 5%

Peak PT (mean) 64 s 72s 46s 40s

Survival (ex OLT) 36% 7% 14% 10%

 What is the mechanism of
encephalopathy in acute liver
failure?
 THEORIES OF HEPATIC ENCEPHALOPATHY
-1
Theory Mediators Evidence For Evidence Against

Ammonia NH3 •Elevated in up •Levels do not

Toxicity to 80-90% correlate with
•Rx to reduce grade of HE
ammonia levels •Urea cycle defic
is has no coma NH3
therapeutically probably
successful epileptogenic
•NH3 induced
VER differ from
VERs in HE
 THEORIES OF HEPATIC
ENCEPHALOPATHY -2
Theory Mediators Evidence For Evidence Against

Synergistic NH3, short •Variably •VER from combined

Toxins chain fatty elevated in HE toxins differ from HE
acids,
False mercaptans •Imbalance in •Cerebral levels of
Neuro- branch chain to actopamine not
transmitters Octopamine aromatic amino increased
acids may •Cerebral injection of
promote octopamine not
production of comagenic
false •Manipulating
neurotransmitters BCAA/.AAA levels
ineffective
 THEORIES OF HEPATIC
ENCEPHALOPATHY - 3
Theory Mediators Evidence for Evidence against
GABA • GABA • GABA agonists • GABA levels in
• Endogenous induce similar human HE not
Benzo- VERs to HE in elevated - cerebral
diazepine like animal models membrane
substances • Correlation (weak) transporters may be
between upregulated
GABA/grade HE in
human ALF
• Flumazenil partially
reverses HE in
some humans
 THEORIES OF HEPATIC
ENCEPHALOPATHY - 4
Theory Mediators Evidence for Evidence against
Neurotrans enhanced • Intracerebral NH3 • Ammonia binds to
mitter neuro- + glutamate forms metabolic fraction of
imbalance depressant glutamine glutamate – effects on
GABA-ergic, depleting neuronal pool of
plus reduced glutamate for glutamate is unknown.
neuroexcitatory neuro-
glutamatergic transmission
neuro- • NMR
transmission spectroscopy in
animal models
shows increased
glutamine and
reduced glutamate
in brain during HE
 Aetiology of Acute Liver Failure in
United Kingdom and Europe.
UK Europe
Paracetamol hepatotoxicity 54.1% 2%
Viral 36.5% 70%
HAV 4.9% 4%
HBV + HDV 9.0% 45%
Other 0.6% 3%
Indeterminate 16.5% 18%
Drug reaction 6.9% 14.5%
Miscellaneous 3.9% 12%
 Drug Hepatotoxicity
Paracetamol – inadvertent, enzyme induction (alcoholics, epileptic)

Carbon Tetrachloride

Halothane/isofluorane
Anti-tuberculous drugs
gold, NSAIDs, sulphonamides, tetracycline, ketoconazole, MAOIs,
tricyclic antidepressants, flutamide, allopurinol, Na Valproate, phenytoin,
amiodarone, propylthiouracil, 2,3-dideoxyinosine (ddI).

Amanita phalloides/ a-amanitin

Ecstasy (methylenedioxymethamphetamine),

Chinese herbal remedies Estes et al Arch surg 2003;138;852

Rarer causes

Pregnancy-related (Acute Fatty Liver of Pregnancy, HELLP)

Budd-Chiari syndrome
Wilson’s Disease
Disseminated Malignancy (Breast, Gastric)
Lymphoma (Non-Hodgkin's, Histiocytic Medullary Reticulosis)
Sepsis
Biventricular heart failure
Hyperthermia (Heat shock)

Autoimmune chronic active liver disease

Aetiology and Outcome for 295 patients with acute
liver failure in the United States.
Schoidt et al Liver Transplant Surg 1999 5 29-34

Spontaneous
Survival

Survived
Transplanted

Died
 Liver Failure

Irrespective of the tempo during which it presents liver

failure is not just associated with hepatic
encephalopathy but also renal impairment, reduced
host defenses and enhanced risk of sepsis, high output /
low vascular resistance state.
A syndrome analogous to Multi-Organ Failure
 Outcome

• If we accept that the best outcome is

recovery with your own liver how can we
best achieve this?
• Optimise treatment and support bridge to
recovery where possible
• Transplant when necessary
• Any other options
Mortality vs APACHE II
Survival for different aetiologies; grade III/IV
Liver ITU, Kings College Hospital 1999-2003

100%
Percent of patients

80%

60% n=72
Died
40% Survived n=87

20%

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Aetiology
 Classification
Complications and Outcome vary by aetiology
Outcome of ALF admissions to KCH 2000-2002
Aetiology n Died/Transplanated (%)

NANBNC 21 95%

Drug induced 14 79%

Viral 9 78%

Paracetamol 145 29%

Pregnancy 12 8%

Other 37 84%
Aetiology and Outcome
 Paracetamol Severe ALF
admissions KCH 1997-2001
Patient numbers

140
120
100
Survived
80
Transplanted
60
Died
40
20
0
1997 1998 1999 2000 2001

Year
 LIVER FAILURE
IN CHRONIC LIVER DISEASE
- Spontaneous deterioration of chronic liver disease
Alcoholic hepatitis
Relapse of CALD
- Precipitated deterioration in Liver Function
Sepsis (chest infection, UTI, Spontaneous
Bacterial Peritonitis, Septicaemia)
Renal Impairment
Metabolic disturbance
Gastrointestinal haemorrhage
Portal vein thrombosis
Hypoperfusion of liver
 Approaches to managing ALF

1. Monitor patient
2. Support the patient and manage complications
3. Intervene where necessary
4. Support/Bridge devices
5. Assess and transplant when appropriate
6. Two stage procedure
 Management
Recognition of Evolution of disease
problems
- cerebral
- cardiovascular Monitoring
- renal
- infection Measurement and
- pulmonary manipulation of
- metabolic physiological
- nutrition parameters
- coagulation

Multisystem Involvement
Complications of Acute Liver Failure

3.Cerebral oedema (80%)

4.Cardiopulmonary Haemodynamic Dysfunction
High Cardiac Output, low vascular resistance, hypoxaemia
6.Host Defence Dysfunction/Sepsis (80%)
Hypocomplementaemia/Kupffer cell dysfunction
8.Renal failure (50%)
9.Coagulation Disturbance
Prolonged INR
11.Metabolic Disturbance
(Hypoglycaemia, Low Na, K, PO4)
13.Pancreatitis
MANAGEMENT OF ACUTE LIVER FAILURE
Metabolic support 10% dextrose, monitor Na+, K+, Mg +, PO4-.
Sepsis Microbiological surveillance
Antibiotics/antifungals
Prophylaxis equivocal
Renal dysfunction Continuous haemodiafiltration
Cerebral oedema Nurse at 10oc
maximise MAP and CBF
iv Mannitol for raised ICP
Haemodynamics monitor O2 delivery and consumption
keep Hb 10g/dl
If needing ionotropes/vasoconstrictors add PGI2
Orthotopic liver 50-70% 1 year survival
transplantation
 Intracranial Pressure in Acute Liver
Failure - male 26 years
35
0..5 g/kg Mannitol OLT
30
25
ICP mmHg

20
15
10
5
0
10

13

16

19

22
1

Time
Intracranial Hypertension:overall
strategy

• Prevention - N-acetylcysteine, phenytoin,

hypothermia, liver support devices
• Standard management - mannitol, sodium
thiopentone, neuronal oxygenation
• Salvage options - low tidal-wave
hyperventilation, hypothermia, hepatectomy
• Cure - successful liver transplantation
 Causes of death in
ALF
• Cardiovascular
• Neurological
• Sepsis
• Multi-organ failure
• Failure to obtain donor liver
• Post-transplant death
Supportive measures
 Liver support
devices
• Extracorporeal non-biologic
• Extracorporeal biologic
- circuits with hepatocytes from
human cell lines or pigs
- whole organs

• Intrahepatic or intrasplenic hepatocyte

infusions
 MARS
Albumin Dialysis using the
molecular absorbent recirculating
system

Mitzner et al.
Current opinion in nephrology and hypertension 10 777-783 (2001)
Extracorporeal liver assist device
“ELAD”
Cross Section - H&E
Cross Section – Scanning EM
 Artificial and Bioartificial Support Systems for
Acute and Acute-on-Chronic Liver Failure A
sytematic review
Kjaergard et al. JAMA (2003) 289 217-222

A meta-analysis

• 582 references 12 randomised trials 483 patients

– Blood exchange
– Charcoal haemoperfusion
– ELAD
– HepatAssist
– BioLogic-DT
– MARS
• Adverse events – coagulopathy, sepsis, DIC
• Possible benefit in acute-on-chronic liver failure None in ALF
 In the ideal world…..
• Identify transplant candidates as early as possible
• Accurately predict outcome with and without
transplantation
• Exclude patients who would not get a long-term
benefit e.g. psychosocial indications, futility
• Offer transient transplant status to those with
capacity to regenerate
 Use of prognostic models
• Critical to minimise ‘unnecessary transplantation’

• King’s College criteria, Factor V levels, MELD,

serum lactate, serum phosphate

• Least satisfactory performance for all models in

paracetamol induced cases – 17-40% error rate
 Selection for Liver Transplantation
Paracetamol Hepatotoxicity
Positive Negative
Predictive Predictive Predictive
Value Value Accuracy
O’Grady et al 1989
pH < 7.3 95% 78% 81%
PT > 100 sec
Creatinine > 300 µmol/l 67% 86% 83%
Grade III/IV coma
Shakil et al 1999
pH < 7.3 69% 80% 72%
PT > 100 sec
Creatinine > 300 µmol/l 100% 79% 86%
Grade III/IV coma
 Selection for Liver Transplantation
Non-Paracetamol Aetiologies
PT > 50 sec ; Jaundice to encephalopathy > 7 days ; Age < 10 and > 40 yrs
Bilirubin > 300 µmol/l ; Aetiology NonA-NonB or Drug -induced

PPV NPV PA
O’Grady et al 1989
Any three of five above 96% 82% 96%
PT > 100 s 100% 26% 46%

Shakil et al 1999
Any three of five above 91% 42% 74%
PT > 100 s 98% 505 79%
 Listing without prognostic models
• All patients with acute liver failure listed
• Decision based on clinical status when organ
becomes available
• Appeals as pragmatic policy that gives the
individual patient the best opportunity
• US Liver Failure group – 59% of patients listed
for paracetamol ALF survived without
transplantation
• High rate of unnecessary transplantation
 Early identification

• 50% of patients referred to transplant

centres are listed for liver transplantation
• 70-80% of these receive transplants
• 65-80% of these survive
 Transplant options in acute
liver failure

• Auxiliary liver transplantation

• Two-step procedure
• Living related liver transplantation
• Standard cadaveric liver transplantation
 ELTR
Primary Diseases leading to Liver 12/2005
Transplantion in Europe
01/1988 - 12/2005
Metabolic diseases : 3592 Acute hepatic failure : 5166
6% 9%
* Others : 1779
Cholestatic 3%
diseases : 6256
11%

Cancers : 7318 Cirrhosis : 33845

13% 58%

* Others : Budd Chiari : 567 Benign liver tumors or Polycystic diseases : 635
Parasitic diseases : 54 Other liver diseases : 523
 Primary Indication of Liver ELTR
12/2005
Transplantation in Pediatric
Patients
05/1968 - 12/2005

Acute hepatic Acute hepatic

failure : 221 failure : 466
Metabolic
9% 9% Cirrhosis : 123 Metabolic Cirrhosis : 337
15%
diseases : 230 5% diseases : 818 11%
9% 26%

Cancers : 66
3% Cholestatic diseases : Cholestatic
1827 Cancers : 157 diseases : 1385
74% 5% 44%

0 to 2 Years 2 to 15 Years
(2467 children) (3163 children)
 ELTR
Evolution of Primary Diseases leading12/2005
to Liver Transplantation in Europe
05/1968 - 12/2005
100%

80%

60%

40%

20%

0%

68- 83 86 89 92 95 98 2001 2004

80 Cirrhosis : 34684 Cancers : 7824

Acute hepatic failure : 5313 Others : 12088
Acute liver failure - the
toxic liver
The anhepatic state
A treatment option?

Ringe et al. Ann Surg 218 3-9 (2003)

Total Hepatectomy
and the “toxic liver”

Ringe et al. Ann Surg 218 3-9 (2003)

 60 hr of anhepatic state without
neurologic deficit
Detry et al. Transplant International 19 (2006) 769

• 34 yr old lady with ESLF underwent LRLT

with a left lobe graft.
• Day 1 necrotic graft removed
• 60 hrs later underwent cadaveric liver
transplant
• Extubated day 7 – neurologically intact
• Subsequently died with Aspergillus sepsis
and MOF
Ready for graft implantation
Following anhepatic period
Arterial
conduit
in place

IVC Porto-caval
shunt
Auxiliary Partial Orthotopic Liver
Transplantation (APOLT)
Gubernatis et al. World J. Surgery 1991

Donor
Left Lobe
Graft
 APOLT
– a comment from
Professor Christoph Broelsch
EHPBA Athens 1995

• This is a great operation

• This is a surgeons operation

• It is a shame there is no indication for

performing it.
 Pros and cons of APOLT

• Avoids need for lifelong immunosuppression

– Nephrotoxicity
– Malignancy
– Dyslipidaemia
– Expense of medication
• Results inferior to those of whole organ transplantation in
short term
• More complex surgical procedure
• Graft failure and technical issues
• Smaller volume graft may result in slower recovery and
increase potential for cerebral injury
Renal Failure post transplant
Ojo et al. NEJM 2003
Ojo et al NEJM 2004
APOLT
Segmental Liver Anatomy
Couinaud - Etudes anatomique et chirugicale 1957
Right Lobe APOLT

Bismuth et al. Ann Surg 224 712-726 (1996)

 Right sided APOLT
Sequential scintigraphy

Bismuth et al. Ann Surg 224 712-726 (1996)

 Right sided APOLT
Venous phase angiogram at 10 months

Bismuth et al. Ann Surg 224 712-726 (1996)

APOLT

Azoulay et al. Ann Surg 234 723-731 (2001)

 APOLT
A Reappraisal
2001

Azoulay et al. Ann Surg 234 723-731 (2001)

 APOLT
A Reappraisal – the published
experience

Azoulay et al. Ann Surg 234 723-731 (2001)

Auxiliary Partial Orthotopic Living Donor
Liver Transplantation: Kyoto Experience

Kasahara et al. Am J Transplant (2005) 5 558-566

6 cases - all died

 Best candidates for auxiliary
transplantation
• Good regenerative potential - paracetamol,
hepatitis A
• No viral pool for re-infection - some
hepatitis B patients
• Possibly not seronegative hepatitis
• Absence of severe complications
 Recipient Selection

Auxiliary Liver Transplantation

- Less than 40 years

- Especially children
- Haemodynamically stable
- No fibrosis on liver biopsy

Avoid:
- Older recipients
CHOICE OF GRAFTS FOR AUXILIARY
LIVER TRANSPLANTATION
• Left lateral segment
• Left lobe
• Right lobe
• Whole liver
• Heterotopic auxiliary or orthotopic

• Right lobe preferred (for adults)

– Larger functioning mass
– Technical advantages - vessels
– Orthotopic placement
 Outcome of APOLT
Kings College Hospital
• Standard - 74% one year and 55% ten year
survival (ELTR data), but some centres 80-90%
one year survival
• Auxiliary - 72% 3.5 yr survival
– 8 off immunosuppression
– 10 regenerating and weaning
– 4 showing no sign of regenerating (King’s data)
 Live donors and ALF
• Children
– An excellent option – a perfect graft with the
full volume the child requires
• Adults
– Problematic – a smaller graft than a full size
cadaveric transplant in a sick patient
– Live donor grafts do worse in high MELD
patients
Hong Kong 1997
 Lo et al. Hong Kong
Ann Surg 1997 226 261-270

May-Nov 1996 18 Tx – 7 high urgency

Donor Recipient
2002

2003
 Liu et al Hong Kong
Transplantation (2003) 75 S33-S36
86 cases Jan 1999-March 2002
 ELTR
Patient Survival 12/2005

according to Indication
01/1988 - 12/2005
Cirrhosis : 33767
(%) Cancers : 7300
100 Total Log Rank test p = 0.0001 Acute hepatic failure : 5156

83
80 76
78 71
64
63 60
68 61
60 58
62 56
53
40 45
40
p Log Rank :
20 Acute Hepatic Failure vs Cirrhosis : 0.0001
Cancers vs Cirrhosis : 0.0001
Acute Hepatic Failure vs Cancers : 0.0001 (Wilcoxon test)
0
0 1 2 3 4 5 6 7 8 9 10 Yrs
 ELTR
Survival of Children >= 2 yrs 12/2005
according to Indication
01/1988 - 12/2005
(%)
100
90 88 86
86 83 82 80
80 83 82
79 80 79
76 72 69
72 69 67
60 65 63

40

p Log Rank :
20 Cholestatic vs Metabolic : 0.005 ACHF vs Cholestatic : 0.001
Cholestatic vs Cirrhosis : 0.006 ACHF vs Metabolic : 0.001
Metabolic vs Cirrhosis : 0.001 ACHF vs Cirrhosis : 0.02
0
0 1 2 3 4 5 6 7 8 9 10 Yrs

Acute hepatic failure : 465 Cholestatic disease : 1384

Metabolic disease : 817 Cirrhosis : 315
 Survival of Elderly Recipients (>= 60 Years)ELTR
12/2005
according to Indication
01/1988 - 12/2005
(%)
100 Cirrhosis : 6226
Cancers : 1973
80 Acute hepatic failure : 355
80
72
78 66

60 64 56
53
50
60 47
54 52
40 38
42

AHF vs Cancers : 0.0001 (Wilcoxon test) 35

20 AHF vs Cirrhosis : 0.0001
Cancers vs Cirrhosis : 0.0001

0
0 1 2 3 4 5 6 7 8 9 10 Yrs
 Conclusions
• Liver transplantation is a key management
option in ALF
• Defining the best treatment for an
individual patient remains difficult
• The place of APOLT remains unclear
• Living donor transplants are an option but
perhaps with a higher risk for adult
recipients
 John Bellany
Transplant Recipient 1988
 John Bellany
Transplant Recipient 1988
 Liver transplantation
John Bellany 1942 - present
 UK Criteria for Super-Urgent
Transplantation
Paracetamol poisoning

• Category 1: Aetiology: Paracetamol poisoning: pH <7.25 more than

24 hours after overdose and after fluid resuscitation
• Category 2: Aetiology: Paracetamol poisoning: Co-existing
prothombin time >100 seconds or INR >6.5, and serum creatinine
>300 μmol/l or anuria, and grade 3-4 encephalopathy
• Category 3: Aetiology: Paracetamol poisoning: Serum lactate more
than 24 hours after overdose >3.5 mmol/l on admission or >3.0
mmol/l after fluid resuscitation
• Category 4: Aetiology: Paracetamol poisoning: Two of the three
criteria from category 2 with clinical evidence of deterioration (eg
increased ICP, FiO2 >50%, increasing inotrope requirements) in the
absence of clinical sepsis
 UK Criteria for Super-Urgent
Transplantation
• Category 5: Aetiology: Seronegative hepatitis, hepatitis A, hepatitis B, or an
idiosyncratic drug reaction. Prothrombin time >100 seconds or INR >6.5, and any grade
of encephalopathy
• Category 6: Aetiology: Seronegative hepatitis, hepatitis A or hepatitis B or an
idiosyncratic drug reaction. Any grade of encephalopathy, and any three from the
following: unfavourable aetiology (idiosyncratic drug reaction, seronegative hepatitis),
age >40 years, jaundice to encephalopathy time >7 days, serum bilirubin >300μmol/l,
prothrombin time >50 seconds or INR >3.5
• Category 7: Aetiology: Acute presentation of Wilson’s disease, or Budd-Chiari
syndrome. A combination of coagulopathy, and any grade of encephalopathy
• Category 8: Hepatic artery thrombosis on days 0 to 14 after liver transplantation
• Category 9: Early graft dysfunction on days 0 to 7 after liver transplantation with at least
two of the following: AST >10,000, INR >3.0, serum lactate >3 mmol/l, absence of bile
production
• Category 10; any patient who has been a live liver donor who develops severe liver
failure within 4 weeks of the donor operation
• These are the only indication for entry onto the super-urgent transplant waiting list
 With thanks to

• Colleagues at Addenbrookes
• Patients
• And particularly
– Alex Gimson
– John O’Grady