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 Liver failure Failure Encephalopathy Duration Jaundice encephalopathy Cerebral oedema Peak PT (mean) Survival (ex OLT) <7 days 70% 64 s 36% 8-28 d 55% 72s 7% 29-84 d 14% 46s 14% 12-24 w 5% 40s 10% yes yes Subacute LOHF LF yes yes

What is the mechanism of encephalopathy in acute liver failure?

THEORIES OF HEPATIC ENCEPHALOPATHY -1
Theory
Ammonia Toxicity

Mediators
NH3

Evidence For

Evidence Against

•Elevated in up •Levels do not to 80-90% correlate with grade of HE •Rx to reduce 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 Toxins chain fatty elevated in HE acids, False mercaptans •Imbalance in Neurobranch chain to transmitters Octopamine aromatic amino acids may promote production of false neurotransmitters

•VER from combined toxins differ from HE •Cerebral levels of actopamine not increased •Cerebral injection of octopamine not comagenic •Manipulating BCAA/.AAA levels ineffective

THEORIES OF HEPATIC ENCEPHALOPATHY - 3
Theory
GABA

Mediators

Evidence for

Evidence against

• GABA • GABA agonists • GABA levels in induce similar human HE not • Endogenous VERs to HE in elevated - cerebral Benzoanimal models membrane diazepine like substances • Correlation (weak) transporters may be upregulated between 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 neuroglutamatergic 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 Viral HAV HBV + HDV Other Indeterminate Drug reaction Miscellaneous 54.1% 36.5% 4.9% 9.0% 0.6% 16.5% 6.9% 3.9% 2% 70% 4% 45% 3% 18% 14.5% 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% 40% 20% 0%
na nc U nk y no w n Vi D ru ra l g in ac du et ce am d in op he Pr n eg na nc y ne ga tiv e

Died Survived

n=72 n=87

ro Se

M

al

ig

Aetiology

Classification
Complications and Outcome vary by aetiology
Outcome of ALF admissions to KCH 2000-2002
Aetiology NANBNC Drug induced Viral Paracetamol Pregnancy Other n 21 14 9 145 12 37 Died/Transplanated (%) 95% 79% 78% 29% 8% 84%

Aetiology and Outcome

Paracetamol Severe ALF
admissions KCH 1997-2001

Patient numbers

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

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 problems
- cerebral - cardiovascular - renal - infection - pulmonary - metabolic - nutrition - coagulation Evolution of disease Monitoring Measurement and manipulation of physiological parameters

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 Cerebral oedema Haemodynamics Orthotopic liver transplantation

Continuous haemodiafiltration Nurse at 10oc maximise MAP and CBF iv Mannitol for raised ICP monitor O2 delivery and consumption keep Hb 10g/dl If needing ionotropes/vasoconstrictors add PGI2 50-70% 1 year survival

Intracranial Pressure in Acute Liver Failure - male 26 years
35 30 25 20 15 10 5 0 1 4 7
0..5 g/kg Mannitol OLT

ICP mmHg

10

13

16

19

Time

22

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

• Extracorporeal non-biologic • Extracorporeal biologic
- circuits with hepatocytes from human cell lines or pigs - whole organs

Liver support devices

• 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 PT > 100 sec Creatinine > 300 µmol/l Grade III/IV coma Shakil et al 1999 pH < 7.3 PT > 100 sec Creatinine > 300 µmol/l Grade III/IV coma

95% 67%

78% 86%

81% 83%

69% 100%

80% 79%

72% 86%

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 O’Grady et al 1989 Any three of five above PT > 100 s Shakil et al 1999 Any three of five above PT > 100 s 96% 100% NPV 82% 26% PA 96% 46%

91% 98%

42% 505

74% 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 9%
Metabolic diseases : 3592 Acute hepatic failure : 5166 * Others : 1779

6%
Cholestatic diseases : 6256

3%

11%

Cancers : 7318

Cirrhosis : 33845

13%
* Others : Budd Chiari : 567 Parasitic diseases : 54

58%
Benign liver tumors or Polycystic diseases : 635 Other liver diseases : 523

Primary Indication of Liver Transplantation in Pediatric Patients
05/1968 - 12/2005
Acute hepatic failure : 221 Metabolic 9% Cirrhosis : 123 9% diseases : 230 5% 9% Acute hepatic failure : 466 15%

ELTR
12/2005

Metabolic diseases : 818 26%

Cirrhosis : 337 11%

Cancers : 66 3%

Cholestatic diseases : 1827 74%

Cancers : 157 5%

Cholestatic diseases : 1385 44%

0 to 2 Years
(2467 children)

2 to 15 Years
(3163 children)

Evolution of Primary Diseases leadingELTR 12/2005 to Liver Transplantation in Europe
05/1968 - 12/2005
100%

80%

60%

40%

20%

0% 6880 83 86 89 92 95 98 2001 2004

Cirrhosis : 34684 Acute hepatic failure : 5313

Cancers : 7824 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

Patient Survival according to Indication
01/1988 - 12/2005
(%) 100 Total Log Rank test p = 0.0001 83 80 78 68 76 63 62 53 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 1 2 3 4 5 6 7 8 9 45 40 71 61 64 58

ELTR
12/2005

Cirrhosis : 33767 Cancers : 7300 Acute hepatic failure : 5156

60 56

60

0 10 Yrs

Survival of Children >= 2 yrs according to Indication
01/1988 - 12/2005
(%) 100 80 60 40
p Log Rank :

ELTR
12/2005

90 86 83 72

88 83 79 69

86 82 76 67

82 80 72 65

80 79 69 63

20 0 0

Cholestatic vs Metabolic : 0.005 Cholestatic vs Cirrhosis : 0.006 Metabolic vs Cirrhosis : 0.001

ACHF vs Cholestatic : 0.001 ACHF vs Metabolic : 0.001 ACHF vs Cirrhosis : 0.02

1

2

3

4

5

6

7

8

9

10 Yrs

Acute hepatic failure : 465 Metabolic disease : 817

Cholestatic disease : 1384 Cirrhosis : 315

Survival of Elderly Recipients (>= 60 Years)ELTR 12/2005 according to Indication
01/1988 - 12/2005
(%) 100 80 80 78 60 60 54 40 AHF vs Cancers : 0.0001 (Wilcoxon test) 20 AHF vs Cirrhosis : 0.0001 Cancers vs Cirrhosis : 0.0001 0 0 1 2 3 4 5 6 7 8 9 10 Yrs 52 72 66 64 53 56 47 42 50 38 35

Cirrhosis : 6226 Cancers : 1973 Acute hepatic failure : 355

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

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