Wilson Disease Wilson Disease and Liver and Liver

TransplantationTransplantationCatherine Frenette, M.D.Catherine Frenette, M.D.

Department of Transplantation and Department of Transplantation and HepatologyHepatology

California Pacific Medical CenterCalifornia Pacific Medical Center

Liver Transplantation in Liver Transplantation in the USthe US

Since 1988, 95,985 patients transplanted Since 1988, 95,985 patients transplanted in USin US

Current liver transplant listings: 15,859Current liver transplant listings: 15,859 2008: 6,318 patients transplanted2008: 6,318 patients transplanted

249 living donor249 living donor 6069 deceased donor6069 deceased donor

914 OLTs in 2008 in region 5914 OLTs in 2008 in region 5 871 deceased donor871 deceased donor 43 living donor43 living donor

www.UNOS.org

Liver Transplantation for Liver Transplantation for Wilson DiseaseWilson Disease

1971: first successful transplant for 1971: first successful transplant for Wilson diseaseWilson disease

1.4% of current patients listed are 1.4% of current patients listed are listed for “metabolic disease”listed for “metabolic disease”

577 transplants to date for Wilson 577 transplants to date for Wilson diseasedisease 34 transplants in 200834 transplants in 2008

4 transplants in Region 54 transplants in Region 5

Indications for Liver Indications for Liver TransplantTransplant

Acute liver failure: onset of Acute liver failure: onset of coagulopathy and encephalopathy coagulopathy and encephalopathy within 8 weeks of presentationwithin 8 weeks of presentation

End stage liver disease: cirrhosis End stage liver disease: cirrhosis with complicationswith complications EncephalopathyEncephalopathy AscitesAscites Portal hypertensive bleedingPortal hypertensive bleeding Liver cancerLiver cancer

Indications for Liver Indications for Liver Transplant:Transplant:

Wilson DiseaseWilson Disease Acute liver failureAcute liver failure

Can be seen as initial presentation of Wilson Can be seen as initial presentation of Wilson diseasedisease

Can occur when chelating medications are Can occur when chelating medications are stoppedstopped

End stage liver diseaseEnd stage liver disease Wilson disease unresponsive to chelating Wilson disease unresponsive to chelating

medications or patients intolerant of medications or patients intolerant of medicationsmedications

?Neurologic Symptoms?Neurologic Symptoms Controversial whether patients should Controversial whether patients should

undergo transplant for this undergo transplant for this

Liver Transplantation Liver Transplantation ContraindicationsContraindications

Severe cardiopulmonary diseaseSevere cardiopulmonary disease Infections or malignancies outside of the Infections or malignancies outside of the

liverliver Hepatoma > 6.5 cm or multifocal (>5 Hepatoma > 6.5 cm or multifocal (>5

lesions)lesions) Age > 70 years: relative contraindication Age > 70 years: relative contraindication

onlyonly Active substance abuse (w/in past 6 months)Active substance abuse (w/in past 6 months) Inadequate support or coping mechanismsInadequate support or coping mechanisms Non-complianceNon-compliance

MELD ScoreMELD Score

MELD = Model for Endstage Liver MELD = Model for Endstage Liver DiseaseDisease (0.957 x LN(creatinine) + 0.378 x (0.957 x LN(creatinine) + 0.378 x

LN(bilirubin) +1.12 x LN(PT-INR) +0.643) x LN(bilirubin) +1.12 x LN(PT-INR) +0.643) x 10 10 Range 6 - 40*Range 6 - 40*

Predictive of 3 months and 12 months Predictive of 3 months and 12 months survivalsurvival

Utilized as a disease severity index to Utilized as a disease severity index to prioritize patients listed for liver prioritize patients listed for liver transplantation transplantation

www.UNOS.org

0

10

20

30

40

50

60

70

80

90

< 9 10 to 19 20 to 29 30 to 39 > 40

% M

orta

lity

MELD Score

n=124 n=1800 n=1038 n=295 n=126

2.97.7

23.5

60

81

3-Month Mortality based 3-Month Mortality based on Listing MELD Scoreon Listing MELD Score

Weisner et al, 2003

MELDMELD

MELD 21-30: MELD 21-30: Mean time to OLT, 128 daysMean time to OLT, 128 days

MELD 31-40: MELD 31-40: Mean time to OLT, 29 daysMean time to OLT, 29 days

Status 1 (acute liver failure): Status 1 (acute liver failure): Mean time to OLT, 11 daysMean time to OLT, 11 days

Wilson Disease Wilson Disease and Acute Liver and Acute Liver

FailureFailure

Acute Liver Failure: Wilson Acute Liver Failure: Wilson DiseaseDisease

Wilson disease accounts for 4-6% of Wilson disease accounts for 4-6% of all liver transplants in US done for all liver transplants in US done for acute liver failureacute liver failure

Female preponderance for acute Female preponderance for acute liver failure and Wilson diseaseliver failure and Wilson disease ?role of hormonal factors?role of hormonal factors

5% of all Wilson patients present 5% of all Wilson patients present with acute liver failurewith acute liver failure

Acute Liver Failure: Wilson Acute Liver Failure: Wilson DiseaseDisease

Often with underlying Often with underlying cirrhosis/advanced fibrosiscirrhosis/advanced fibrosis

Can occur as initial presentation or in Can occur as initial presentation or in a known Wilson patient with a known Wilson patient with medication non-adherence or medication non-adherence or treatment failuretreatment failure

Near 100% mortality without Near 100% mortality without emergency liver transplantemergency liver transplant Early identification is key!Early identification is key!

1 year survival after OLT 79-87%1 year survival after OLT 79-87%Kormen et al Hepatology 2008

ALF and Wilson diseaseALF and Wilson disease Relatively low transaminasesRelatively low transaminases Low alkaline phosphatase (alk phos/bili)Low alkaline phosphatase (alk phos/bili) Coombs negative hemolysisCoombs negative hemolysis Elevated urine and serum copperElevated urine and serum copper KF in 50%KF in 50% Ceruloplasmin not always helpful*Ceruloplasmin not always helpful*

*ALFSG data *ALFSG data

Hemolysis

Liver Injury

Copper accumulationLoss of antioxidant potential

Copper releaseRelease of Heme iron

Renal Injury

Diagnosis of Acute Wilson Diagnosis of Acute Wilson DiseaseDisease

AP:TB <4AP:TB <4AST:ALT >2.2AST:ALT >2.2

Kormen et al Hepatology 2008

Revised King’s Score for Revised King’s Score for Liver TransplantationLiver Transplantation

ScorScore e

BilirubiBilirubin n µmoleµmole

INRINR ASTAST WCCWCC AlbumAlbuminin

00 0-1000-100 0-0-1.291.29

0-1000-100 0-6.70-6.7 >45>45

11 101-101-150150

1.3-1.3-1.61.6

101-101-150150

6.8-6.8-8.38.3

35-4435-44

22 151-151-200200

1.7-1.7-1.91.9

151-151-300300

8.4-8.4-10.310.3

25-3325-33

33 201-201-300300

2-2.42-2.4 301-301-400400

10.4-10.4-15.315.3

21-2421-24

44 >301>301 >2.5>2.5 >401>401 >15.4>15.4 <20<20

Dhawan et al Liver Transpl 2005

Prospective Application of Scoring System

Dhawan et al Liver Transpl 2005

Supportive Measures Awaiting Supportive Measures Awaiting Liver Transplant for Acute Liver Liver Transplant for Acute Liver

Failure Failure Plasma Plasma

exchange/treatmentexchange/treatment

Exchange transfusion Exchange transfusion PlasmapheresisPlasmapheresis

MARSMARS

Albumin dialysisAlbumin dialysis Early institution of renal Early institution of renal

replacement therapyreplacement therapy

Neurologic Neurologic Disease and Disease and

TransplantationTransplantation

Neurological Neurological Manifestations and Manifestations and

TransplantationTransplantation OLT reverses neurological OLT reverses neurological

deterioration in many Wilson deterioration in many Wilson patientspatients ~80% of patients improve or stabilize~80% of patients improve or stabilize

Combined hepatic and neurological Combined hepatic and neurological disease must be carefully assessed disease must be carefully assessed to determine severity of neurological to determine severity of neurological diseasedisease

Medici et al Liver Transpl 2005; Stracciari et al, Arch Neurol 2000

Neurological Neurological Manifestations and Manifestations and

TransplantationTransplantation Isolated neuropsychiatric symptoms Isolated neuropsychiatric symptoms

is considered by some experts to be is considered by some experts to be a contraindication for OLTa contraindication for OLT May improve with medical therapyMay improve with medical therapy May worsen compliance with post May worsen compliance with post

transplant care and medicationstransplant care and medications Should not expose patients to risk of Should not expose patients to risk of

OLT when it may not improve symptomsOLT when it may not improve symptoms

Neurological Neurological Manifestations and Manifestations and

TransplantationTransplantation

Medici et al Liver Transpl 2005

Transplant OptionsTransplant Options

DDLT: deceased donor liver DDLT: deceased donor liver transplanttransplant

LDLT: living donor liver transplantLDLT: living donor liver transplant 60% of liver taken from healthy person 60% of liver taken from healthy person

to transplant into recipientto transplant into recipient Can occur from relations who are Can occur from relations who are

heterozygous for Wilson mutationheterozygous for Wilson mutation Slower normalization of copper Slower normalization of copper

metabolismmetabolism

Transplant Outcomes in Transplant Outcomes in Wilson DzWilson Dz

Copper metabolism normalizes Copper metabolism normalizes quickly after transplantquickly after transplant

Copper overload slowly resolves in Copper overload slowly resolves in extrahepatic organsextrahepatic organs Within 2-3 months with DDLTWithin 2-3 months with DDLT Within 6 months with LDLTWithin 6 months with LDLT

Changes in Urine Copper Changes in Urine Copper Post OLTPost OLT

Wang et al W J Gastro 2003

Copper Changes after Copper Changes after TransplantTransplant

Stracciari et al, Arch Neurol 2000

Survival Post Survival Post TransplantationTransplantation

Three month survival ~88-90%Three month survival ~88-90% Peri-operative complicationsPeri-operative complications Post-operative infectionPost-operative infection

One year survival ~80-84%One year survival ~80-84% Three year survival ~67-75%Three year survival ~67-75% Five year survival ~60-70%Five year survival ~60-70%

* Depends on age, underlying diagnosis, * Depends on age, underlying diagnosis, disease recurrence, other medical disease recurrence, other medical problemsproblems

OLT outcomes in Wilson OLT outcomes in Wilson DiseaseDisease

Medici et al Liver Transpl 2005

ConclusionsConclusions

Wilson disease can be cured with liver Wilson disease can be cured with liver transplantationtransplantation Copper metabolism normalizesCopper metabolism normalizes Neurological symptoms can improveNeurological symptoms can improve

Wilson patients do just as well as other Wilson patients do just as well as other patients with liver transplantationpatients with liver transplantation

Compliance with chelating medications Compliance with chelating medications is key to avoid transplantationis key to avoid transplantation

CPMC Liver CPMC Liver TransplantationTransplantation

www.cpmc.org/advanced/www.cpmc.org/advanced/liverliver

Birth Death

Hepatic Inflammation Cirrhosis Liver Failure

Complications of portal HTNascitesvariceal bleedingencephalopathy

Non-specific symptoms of liver disease

Neuropsychiatric symptoms

Natural History of Wilson Disease

Birth Death

Hepatic Inflammation

Acute Liver Failure

Advanced fibrosisCirrhosis

Hemolytic anemiaJaundiceAscitesRenal Failure