Metabolic Diseases that push the indications for Liver Transplantation

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Metabolic Diseases that push the indications for
Liver Transplantation

• Deirdre Kelly
• Professor of Paediatric Hepatology
• The Liver Unit
• Birmingham Childrens Hospital
• UK

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Survival after Liver Transplantation Birmingham
Programme pre and post 1989
1.0


0.8
post 1989 n 419
0.6
Cumulative survival
0.4
pre 1989 n23
0.2
0.0
0.00
50.00
100.00
150.00
200.00
250.00
MONTHS
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Indications for Liver Transplantation in
Metabolic Disease

• Metabolic disease 2º to hepatic enzyme deficiency
• Hepatic disease leading to liver failure
• Alpha-1-antitrypsin
• PFIC
• Cystic Fibrosis
• Tyrosinaemia Type I
• Wilsons Disease
• Neonatal haemochromatosis
• Defects in bile acid synthesis

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Indications for Transplantation for Metabolic
Disease

• Metabolic disease 2º to hepatic enzyme deficiency
• Normal Liver - extra-hepatic disease
• Crigler-Najjar Type I
• Primary Oxalosis
• Familial hypercholesterolemia
• Organic Acidemias
• Urea Cycle Defects
• Factor VI deficiency
• Protein C deficiency

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Liver Transplantation in Metabolic Disease

• Aim
• - Replace missing hepatic enzyme
• - Reverse - hepatic disease
• - extra-hepatic disease
• Restore - normal quality of life
• Evaluate - risks /complications of procedure
• Technique Orthotopic/Auxiliary/Hepatocyte Tx
• Combined Liver/kidney

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Timing of Liver Transplantation for Metabolic
Disease

• Metabolic Liver Disease
• Severity and complications
• Rate of progression
• Success of medical therapy
• Presence of reversible extra-hepatic disease
• Risk of hepatic cancer
• Quality of life

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Contra Indications for Transplantation for
Metabolic Liver Disease

• Primary Oxalosis
• - Severe systemic oxalosis with cardiac disease
• Organic Acidemias
• - Severe mental handicap
• Crigler-Najjar
• - Severe kernicturus
• Niemann-Pick C
• - No response

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Auxiliary Liver Transplantation

• Advantages
• Native liver retained
• - PNF/rejection
• - Hepatic gene therapy
• Disadvantages
• Technically difficult
• Poor results (50 5YS Kyoto, 2005)
• ?Sufficient enzyme production

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Segmental Auxiliary Transplantation

• Not suitable - Oxalosis
• Severe organic acidemia
• Suitable - Crigler-Najjar Type I
• - Mild proprionic acidemia

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Auxiliary Liver Transplantation for
Crigler-Najjar Type I

• KCH (London)
• 6 recipients (7 grafts)
• Median age - 10.5 yrs
• Pre Post
• Bilirubin (?mol/L) 320 50
• Phototherapy (hrs) 16 -
• Acute rejection - 4/6
• Chronic rejection and re-tx - 1/6
• Death - 1/6

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Living Related Transplantation for Metabolic
Liver Disease

• Successful transplants
• - Proprionic acidemia - 1
• - Citrullinemia - 2
• - OTC - 3
• - PFIC - 4 (1 died)
• - Wilsons - 11

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Hepatocyte Transplantation

• Isolated hepatocytes injected via portal vein
• Indications
• Crigler najjar type 1
• Factor VIII deficiency
• Urea cycle deficiency
• Need for repeat hepatocyte infusion
• Immunosuppression

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Indications for Liver Transplantation in 30
children with Tyrosinaemia (1989-2005)
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Indications for Liver Transplantation in
Tyrosinaemia Type I

• Pre NTBC Acute/chronic liver failure
• ?Prevention of hepatic malignancy
• Post NTBC Hepatic dysplasia/malignancy
• Nodules on U/S or CT
• Hepatic histology
• Rise in AFP
• Quality of life

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Transplantation for Glycogen Storage Disease

• Rarely indicated (17 GSD Ia 2 GSD Ib)
• - Poor metabolic control
• - Cirrhosis and portal hypertension
• (III/IV)
• - Multiple adenomata
• - Hep cell Ca (I/IV)
• Labrune, 2002

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Transplantation for Glycogen Storage Disease

• Long Term outcome
• - Metabolic control
• - Catch up growth
• - Resolution of xanthomas
• Complications
• - Renal Dysfunction
• - Renal Transplantation
• - glomerular sclerosis 2º GSD
• Labrune, 2002

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Transplantation for Primary Oxalosis

• Definitive treatment is pre-emptive liver
  transplant
• 5/5 survivors (German)
• Combined liver/kidney transplant
• European experience (1984 - 2004)
• 127 transplants in 117 patients
• Mean age of Tx 16.5 yrs
• 10 year survival 70
• Outcome worse prolonged renal failure
  severe systemic oxalosis
• Jamieson, 2005 Hoppe, 2005

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Transplantation for Urea Cycle Defects

• Ornithine Transcarbamylase Deficiency /
  Citrullinemia
• 14/16 survivors (Whitington,1998)
• 3/3 survivors (Paris)
• 5/5 survivors (Texas)
• 3/3 survivors (UCLA)
• 2/2 survivor living related (Japan)
• Complete correction, stable neurology
• Adult citrullinemia type II
• 7/7 6 neurological improvement (Japan)
• Busittil,1998 Whitington,1998 Kasahara, 2001
  Ban,2001 McBride,2004Ikeda, 2001Jan,1994

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Transplantation for Organic Acidemias

• Rationale 1 Poor quality of life
• 2 Frequent metabolic crises
• 3 Poor neurological outcome
• 9 recipients (7-PA 2 MMA)
• Median age 15 m (7-29)
• Grafts 1 whole
• 3 split
• 5 reduced (2 regrafts)

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Transplantation for Organic Acidemia

• Optimum Management
• Stabilise metabolic status pre transplant
• - Dialysis - pre/peri/post transplant
• - IV Dextrose (6 mg/kg/min)
• - IV Carnitine (100 mg/kg/day)
• - IV Sodium Bicarbonate (0.5-1mmol/kg)
• Exclude Sepsis
• Ammonia gt100 ?mol/L
• Lactate gt3.0 mm/L

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Transplantation for Organic Acidemia

• Post-operative complications in 9 patients
• 4 Primary non function HVT (1)
• PVT (1)
• 3 Hepatic dysfunction PVT (1)
• HAT (2)
• Peri-Operative Deaths 6/9

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Transplantation for Organic Acidemia

• High Risk Technical difficulties
• - No portal hypertension/ascites
• - Little tolerance for hepatic dysfunction
• - Need for renal support/metabolic control

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Transplantation for Organic Acidemia
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Transplantation for Organic Acidemias

• Outcome for Proprionic Acidemia
• 2/7 survivors
• Median F/U 9.7 yrs
• Normal dietary tolerance
• 70 correction of biochemical defect
• Normal renal function
• Developmental improvement in both

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Transplantation for Organic Acidemias

• Propionic Acidemia
• 2/9 survivors (Birmingham)
• 1/2 survivors (Paris)
• 1 survivor auxiliary (London)
• 1 survivor living related (Kyoto)

Saudabray,1995 vant Hoff, 1998 Nyhan, 2002
Chakrapani,2002 Yorifuji,2002Rela,1997
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Transplantation for Organic Acidemia
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Transplantation for Organic Acidemias

• Outcome Methylmalonic Acidemia
• 1/2 survivor
• Survived 8.14 yrs
• Partial correction of biochemical defect
• Restricted diet/carnitine/ sod bicarbonate
• Renal dysfunction
• Progressive neurological deterioration

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Transplantation for Organic Acidemias

• - Methylmalonic acidemia
• 2/2 deaths (Birmingham)
• 1 with progressive neurology (US)
• 1 successful Liver/Kidney Tx (London)
• Developmental improvement on restricted
  diet

Saudabray,1995 vant Hoff, 1998 Nyhan, 2002
Chakrapani,2002 Yorifuji,2002Rela,1997
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Liver Transplantation for Metabolic Liver Disease
Scientific Registry of Transplant Recipients
1990 -1999

• Liver Disease Tx
• ?1AT 261
• GSD 15
• FH 4
• Tyr 55
• N Haem 4
• Wilsons 67
• Mitoch Dis 2
• Oxalosis 54
• Urea cycle 42
• Organic acid 6 Kayler, 2003

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Actuarial Survival Post Liver Transplantation
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Actuarial Survival Post Liver
Transplantation Birmingham Paediatric Liver
Transplant Programme 1983 - 2005
1.0
EHBA (187)
0.8
Metabolic (25)
Cumulative survival
0.6
Fulminant (57)
0.4
0.2
0.0
0.00
5.00
10.00
15.00
20.00
Kaplan Meier Curve
Survival post transplant (years)
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Liver Transplantation for Metabolic Disease

• - Effective therapy for replacing hepatic enzyme
  deficiency
• Crigler Najjar Type 1
• Urea Cycle Defects
• Primary Oxalosis
• Tyrosinemia
• Requirement for more appropriate therapy
• Organic acidemias
• Glycogen Storage Disease

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Liver Transplantation for Metabolic Disease

• Future management
• ?Gene therapy
• ?Hepatocyte Transplantation
• ? Stem cell Transplantation

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Selection for Liver Transplantationfor Metabolic
Liver Disease

• Wilsons Disease
• Acute liver failure
• Advanced chronic liver disease
• Portal Hypertension
• Failure of Penicillamine therapy

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Selection for Liver Transplantationfor Metabolic
Liver Disease

• Neonatal Haemochromatosis
• - Acute liver failure
• unresponsive to anti oxidant cocktail
• N-acetyl cysteine
• desferrioxamine
• prostaglandin
• selenium
• vitamin E

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Combined Organ Transplantation for Metabolic
Disease

• Kidney/Liver Tx
• Primary oxalosis
• Polycystic liver and kidney disease
• Heart/Lung/Liver Tx
• Familial hypercholesterolemia
• Cystic Fibrosis
• Bone Marrow/Liver Tx
• ?Gauchers Disease

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Advances in Medical Therapy Affecting Liver
Transplantation

• New Treatment
• - Tyrosinaemia Type I
• NTBC
• - Haemochromatosis
• Antioxidant cocktail/Immunoglobulin infusion
• - Inborn errors of bile salt metabolism
• - cholic acid /- ursodeoxycholic acid

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Non-Transplant Options for Metabolic Disease

• Tyrosinaemia Type I
• NTBC reverses metabolic effects
• ?Prevents hepatic cancer
• Neonatal Haemochromatosis
• Anti-oxidant cocktail
• Wilsons Disease
• Penicillamine/Zinc
• PFIC Disease
• Biliary diversion
• Defects in bile acid synthesis
• Oral bile acids

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Results of Liver Transplantation for Metabolic
Liver Disease

• Liver Disease
• Phenotypic and functional cure
• - Alpha-1-antitrypsin deficiency
• - Wilsons disease
• - PFIC disease
• - Neonatal haemochromatosis

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Transplantation for Metabolic Liver Disease

• Functional and Phenotypic Cure
• Wilsons Disease
• - Reversal of abnormal copper metabolism
• - Improved Kayser-Fleisher Rings
• Neurological disease
• Neonatal Haemochromatosis
• Reversal of iron storage
• No recurrence of extrahepatic iron

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Results of Metabolic Liver Transplantation

• Tyrosinaemia Type I
• - Cures Liver failure
• Hepatic cancer
• but kidney produces succinylacetone
• Primary Oxalosis
• - Cures metabolic defect
• - Prognosis Extent of systemic oxalosis

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Liver Transplantation for Metabolic Disease

• Operative Techniques
• Orthotopic whole graft
• Reduction hepatectomy
• Split liver graft
• Living related donation
• Auxiliary liver transplantation
• Combined Transplantation
• Liver/Kidney
• Heart/Liver /Lung

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Liver Transplantation for Metabolic Liver Disease
Birmingham Paediatric Liver Transplant Programme
1983-2005

• Extra Hepatic Disease
• Tx Alive ()
• Crigler-Najjar 1 1 (100)
• Oxalosis 12 10 (83)
• Propionic acidemia 7 2 (29)
• Methylmalonic acidemia 2 0 (0)

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Actuarial survival in metabolic patients post
Liver TransplantBirmingham Paediatric Liver
Transplant Programme 1983 - 2005
1.0
0.8
Non organic acidaemias (n 116)
Cumulative survival
0.6
0.4
0.2
Organic acidaemias (n9)
0.0
0.00
5.00
10.00
15.00
20.00
Kaplan Meier Curve
Survival post transplant (years)
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Results of Liver Transplantation for Metabolic
Liver Disease

• Complete correction of Metabolic Defect
• - Crigler-Najjar Type I
• - Urea cycle defect
• - Primary oxalosis
• - Familial hypercholesterolemia

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Liver Transplantation for Metabolic Liver Disease
Birmingham Paediatric Liver Transplant Programme
1983-2005

• Liver Disease Tx Alive ()
• - Cholestatic ?1AT 30 22 (73)
• PFIC 9 5 (56)
• - Cirrhosis CF 17 14 (82)
• Tyr 10 8 (80)
• - ALF N Haem 5 3 (60)
• Wilsons 18 17 (94)
• Alpers/MD 2 -

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Results of Liver Transplantation for Metabolic
Liver Disease

• Partial correction of metabolic defect
• Tyrosinaemia Type I
• - resolution of cardiac/neurological/hepatic
• - renal production of succinyl acetone
• - renal dysfunction
• Organic acidemia
• - ?sufficient hepatic enzyme
• - metabolic crises during intercurrent
  illness