Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy

Domino Liver Transplants for Metabolic Disorders:Experience with Familial Amyloidotic Polyneuropathy

Daniel Azoulay, MD, PhD, Didier Samuel, MD, PhD, Denis Castaing, MD, Rene Adam, MD, PhD,David Adams, MD, Gerard Said, MD, Henri Bismuth, MD, FACS (Hon)

Background: Shortage of liver donors means that newmethods of liver procurement must be explored. Indomino transplantation, organs explanted during trans-plantation in one patient are transplanted into a secondpatient. Domino procedures can be performed with liv-ers from patients having transplantion for hepatic met-abolic disorders that cause systemic disease without af-fecting other liver functions. Familial amyloidoticpolyneuropathy (FAP) type I is one of these.

Study Design: We reviewed the Paul Brousse experiencewith a domino liver transplant program for FAP, hopingto extend the approach to other metabolic disorders.

Results: Livers from 10 patients transplanted for FAPtype 1 were used for domino transplants to patients withunresectable primary or metastatic liver cancers. Therewas no perioperative mortality. Neuropathy or cardio-myopathy did not increase the morbidity of the dominoliver explant and transplant procedures. Morbidity for thedomino recipients did not appear to be increased. Varianttransthyretin was detected in the serum in FAP liver recip-ients, with no immediate clinical consequences.

Conclusions: The domino approach is feasible and re-quires careful planning of the surgical procedures forliver explantation, particularly for the nature and site ofvascular anastomoses. Domino transplantation of met-abolically dysfunctional livers creates new categories ofpotential donors and potential recipients. It raises newethical, technical, and societal issues. The domino ap-proach could be used in several genetic or biochemicaldisorders now treated by liver transplantation. It has thepotential to increase the number of liver grafts availablefor transplantation. (J Am Coll Surg 1999;189:

584–593. © 1999 by the American College ofSurgeons)

FAMILIAL AMYLOIDOTICPOLYNEUROPATHY

Liver transplantation for familial amyloidotic poly-neuropathy (FAP) type 1 was first described byHolmgren and associates.1 FAP is an autosomal dom-inant condition in which there is a point mutation intransthyretin (TTR), one of the prealbumins. Methi-onine replaces valine at the 30 position, formingTTR-met 30, and changing its solubility. TTR-met30 precipitates in the extracellular space, formingfibrillary amyloid deposits. The same TTR-met 30mutation is found in FAP patients in Portugal, Swe-den, Brazil, and Japan.2 Other point mutations inTTR also occur, not all of which lead to amyloiddeposition.3 Depending on the type of mutation, thecondition becomes evident in the third decade orlater, with sensorimotor and autonomic neuropathyand amyloid infiltration of viscera and the nervoussystem. The Portuguese variant leads to death 10 to14 years after initial presentation.4

More than 90% of TTR is synthesized in theliver.1 Liver transplantation has become standardtreatment,5 associated with simultaneous kidneytransplantation if amyloid deposition has led to im-paired renal function.6 The neurological declinecaused by deposition of the variant TTR can behalted by transplantation,7 especially in patients withmild neuropathy.8

DOMINO TRANSPLANTATION

In FAP patients, the liver is usually anatomically andfunctionally normal, except for the production ofTTR-met 30.9 Total hepatectomy in such patientsshould produce explants in good condition for organtransplantation. If an FAP patient’s liver is trans-

No competing interests declared.

Received July 14, 1999; Accepted August 19, 1999.From the Centre Hepatobiliaire et Universite Paris-Sud, Hopital Paul Brousse,Villejuif, France (Azoulay, Samuel, Castaing, Adam, Bismuth) and the Depar-tement de Neurologie et Universite Paris-Sud, Hopital Bicetre, Le KremlinBicetre, France (Adams, Said).Correspondence address: Daniel Azoulay, MD, PhD, Centre Hepatobiliaire,Hopital Paul Brousse, 12 avenue Paul Vaillant Couturier, 94800, Villejuif,France.

584© 1999 by the American College of Surgeons ISSN 1072-7515/99/$21.00Published by Elsevier Science Inc. PII S1072-7515(99)00208-2

planted to a patient without FAP and the rate ofproduction of TTR-met 30 does not change, the de-lay before amyloid deposition becomes symptomaticwould be the same as for FAP patients, ie, 20 yearsor so.10

The shortage of cadaver grafts leads effectively tothe exclusion of some potential recipients, for exam-ple, those who have a high risk of recurrence of ma-lignant disease in the graft. The explanted livers ofFAP patients, although metabolically deficient, canbe used for such recipients in sequential, or “domi-no,” transplants. Several centers have reported pro-cedures using this approach.9-14 Indications for re-ceiving a domino FAP liver transplant in our centerinclude some primary liver tumors, special cases ofunresectable metastatic tumors with no extrahepaticspread, and cases of severe cirrhosis in patients withrare blood groups.

This article summarizes our experience of 10domino liver transplants at the Paul Brousse Hospi-tal, with an emphasis on the surgical techniques andoutcomes and with a view to expanding the dominoapproach in FAP and other metabolic disorders.

METHODS

Between September 30, 1997 and May 6, 1999, 145transplants were performed with cadaver livers, ofwhich 16 were performed in FAP patients. Ten weredomino procedures. The cadaver organ donors (6men and 4 women) were all local, aged from 22 to 47years (median age 36 years). Each was matched foridentical blood groups. Specific ethical aspects of thedomino transplantation program are reviewed in theDiscussion section of this article. The domino do-nors (recipients of the cadaver livers) receiving trans-plants for FAP were all of Portuguese origin, withmedian age 35 years (range 29 to 69 years). Thesurgical characteristics of these patients (identified as

A to J) are given in Table 1. One patient underwentsimultaneous hepatic and renal transplantation. Me-dian waiting time on the waiting list for transplanta-tion was 108 days (range 20 to 381 days).

The domino recipients (of the FAP liver explant;identified as patients a to j) were selected mainly frompatients (8 of 10 patients) with hepatocellular carci-noma on a cirrhotic liver, who had been assessed butexcluded from cadaver organ transplantation accord-ing to our selection criteria.15,16 The tumors werestrictly confined to the liver, with more than threenodules, at least one of which was larger than 3 cm indiameter. Such patients are usually excluded fromcadaver transplantation programs because their3-year survival is less than 44%,15 too low to accept inthe context of graft shortage when patients withother liver transplantation indications have greaterpotential for survival. Domino recipient b (Table 2)was selected because the hemangiopericytoma metas-tases were strictly limited to the liver and had ap-peared a long time after nephrectomy (12 years). Re-cipient g was selected for a domino procedurebecause of severe cirrhosis associated with a rareblood group (blood group AB) after an initial periodof 12 months on the waiting list.

Table 2 summarizes the clinical situations ofthese patients (identified as a to j) before transplan-tation. Median waiting time for domino recipientswas 54 days (range 8 to 420 days). For patients re-ceiving transplants for cancer, a preoperative assess-ment is made to check that there is no extrahepaticspread (brain scan, thoracic and abdominal scans,bone scintigraphy). This is repeated every 3 monthsduring the waiting period.

Surgical proceduresThree surgical teams are needed—including one forcadaveric liver harvesting, working in parallel, inoverlapping operations—to minimize the cold isch-

Table 1. Characteristics of Domino Donors (Cadaver Liver Recipients)

Donor characteristics

Domino donors

A B C D E F G H I J

Gender Female Female Male Male Female Female Female Female Female MaleAge (y) 31 54 29 39 35 34 69 40 33 32Body weight (kg) 57 55 75 53 50 45 61 44 70 50Graft weight (kg) 1.340 1.140 1.580 1.220 0.980 1.420 2.420 1.020 2.320 1.580Graft/body weight ratio (%) 2.35 2.55 2.11 2.30 1.96 3.16 3.96 4.31 3.31 3.16Native liver weight (kg) 1.180 1.100 1.200 0.960 1.000 0.980 1.340 1.220 1.700 1.060Blood group A O AB O A A B O A ADays on waiting list 32 20 381 115 180 150 108 107 69 85

585Vol. 189, No. 6, December 1999 Azoulay et al Domino Liver Transplants

Tab

le2.

Cha

ract

eris

tics

ofD

omin

oR

ecip

ient

s(F

amili

alA

myl

oido

tic

Poly

neur

opat

hyLi

ver

Rec

ipie

nts)

Rec

ipie

ntch

arac

teri

stic

s

Dom

ino

reci

pien

ts

ab

cd

ef

gh

ij

Gen

der

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ale

Mal

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ale

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ale

Mal

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ale

Mal

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ale

Age

(y)

5548

5055

6355

4460

5669

Bod

yw

eigh

t(kg

)87

7878

104

6284

7285

8073

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ft/b

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ght

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o(%

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361.

411.

540.

921.

611.

161.

861.

432.

121.

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C*

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sis

hem

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cirr

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s.

586 Azoulay et al Domino Liver Transplants J Am Coll Surg

emic time for the organs being transplanted. Whenthe harvesting team is sure that the cadaver organ canbe transplanted, the domino donor is operated on bya second team. The third team operates on the dom-ino recipient when the second one confirms that theFAP liver can be used as a graft. In the event thatextrahepatic spread is found in the domino recipientat the time of the intended liver transplantation, theFAP liver can be offered to a second potential recip-ient who has been put on standby. So far this has nothappened.

Hepatectomy in the domino donor. Our generalapproach to hepatectomy is to:

1. Minimally dissect the hepatic pedicle to preservetissue viability. Section the main bile duct, with-out dissection, at the middle part of the hepaticpedicle. Open the gallbladder and wash withsaline.

2. Free the entire liver. Open up the diaphragmaticorifice of the vena cava. The adequacy of stumplength is the single most important technical is-sue. The ligature and section of any diaphrag-matic veins allow an adequate vena cava stump tobe maintained on both sides. If needed the peri-cardium may be opened to lengthen the cavastumps.

3. Test the hemodynamic and splanchnic toleranceto clamping the pedicle and the infrahepatic venacava. Install extracorporeal veno-venous bypass ifneeded.

4. Perform rapid total hepatectomy. Section the por-tal vein 1 cm below the portal bifurcation. Sectionthe hepatic artery as appropriate to the anatomi-cal variations found in the individual patient, tobe able to perform a single arterial anastomosis inthe recipient of the explanted liver. Flush arterywith heparin.

Explant preparation is performed on the back table,as usual. Vascular grafts (arterial and venous) fromthe cadaver donor are prepared if necessary.

Transplantation of the FAP patient (domino do-nor) is performed according to the usual technique oforthotopic liver transplantation.

Transplantation of the domino recipient is a se-quential process:

1. Perform an initial exploratory laparotomy for pa-tients with cancer. Systematic biopsies of lymphnodes in the celiac axis and hepatic pedicle areperformed, with rapid frozen-section histology.

Each suspect lymph node is sent for later histo-logic analysis. (If the frozen section indicates ex-trahepatic spread, the standby recipient isprepared).

2. Assess the need for veno-venous bypass.3. Perform the usual transplantation procedure.

Postoperative neurological monitoring of dom-ino recipients. Clinical monitoring of domino recip-ients was the same as for FAP patients. This wasperformed at 6-month intervals using a score basedon a questionnaire related to autonomic dysfunc-tion,17 and clinical motor scores by assessment ofmultiple muscle functions according to the MedicalResearch Council 5-point scale. Light touch, pin-prick, vibration, temperature sensation at 14°C and140°C, and position sense were tested. Autonomicfunctions were assessed by studying variations inblood pressure and pulse rate in recumbent andstanding positions, and in heart rate responses topostural change, the Valsalva maneuver, and deepbreathing.

Electrophysiologic monitoring was performedby measurement of sensory nerve action potentials insural, ulnar, and median nerves. Compound muscleaction potentials, were measured in median, ulnar,peroneal, and popliteal nerves. Motor and sensoryelectrophysiologic scores were derived by adding theamplitudes of sensory nerve action potentials andcompound muscle action potentials.

Biochemical monitoring of TTR-met was madeby radioimmunoassay18 on serum collected beforetransplantation and at subsequent followup visits.

RESULTS

Morbidity and mortality within60 days of transplantation

Domino donors. The intraoperative status andpostoperative status of the FAP patients were notdifferent from those of FAP patients undergoing nor-mal transplantation procedures. Median cold isch-emia time was 461 minutes (range 405 to 730 min-utes), and median transfusion was 4.5 units of blood(range 0 to 8 units). There were no vascular difficul-ties, immediate postoperative hemoperitoneum, orbiliary complications. The patients remained in theICU for 9 to 19 days (median 10 days). The patientwho had a simultaneous kidney transplant developedtransient anuria. Two other patients, one with a his-tory of recurrent urinary tract infections and neuro-logical bladder dysfunction, also developed postop-


Tab

le3.

Surg

ical

Out

com

esin

Dom

ino

Rec

ipie

nts

(Fam

ilial

Am

yloi

doti

cPo

lyne

urop

athy

Exp

lant

Rec

ipie

nts)

Out

com

escr

iter

ia

Dom

ino

reci

pien

ts

ab

cd

ef

gh

ij

Day

sin

ICU

228

1211

1410

911

118

Tot

alda

ysin

hosp

ital

4821

3931

3230

2432

2532

Intr

aope

rati

veev

ents

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pass

Non

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iffic

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tom

osis

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icul

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one

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o-v

enou

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pass

Ven

o-v

enou

sby

pass

Non

eN

one

Col

dis

chem

iati

me

(h)

516

405

443

368

420

650

255

225

599

153

Blo

odtr

ansf

usio

n(U

)16

50

139

42

67

0Po

stop

erat

ive

even

tsT

empo

rary

rena

lin

suff

icie

ncy

CM

Vpn

eum

opat

hy

Non

eN

one

Asc

ites

CM

Vpn

eum

opat

hyN

one

Non

eN

one

Non

eT

rans

ient

conf

usio

n

Gra

ftre

ject

ion

Non

eM

ild reje

ctio

nda

y9

Non

eN

one

Non

eN

one

Non

eN

one

Non

eN

one

Mon

ths

offo

llow

up22

1616

1412

95

33

2G

raft

func

tion

Nor

mal

Nor

mal

Fulm

inan

the

pati

tis

B:

liver

failu

re,

seps

is,de

ath

Nor

mal

Nor

mal

Nor

mal

Nor

mal

Nor

mal

Nor

mal

Nor

mal

Can

cer

recu

rren

ceC

hem

oem

boliz

atio

nfo

llow

edby

segm

ente

ctom

yV

IIfo

rre

curr

ence

at15

mon

ths;

radi

othe

rapy

tofe

mor

alhe

adm

etas

tasi

s

Non

eN

one

Non

eN

one

Non

eN

otu

mor

atLT

Non

eN

one

Non

e

CM

V,cy

tom

egal

ovir

us;L

T,liv

ertr

ansp

lant

atio

n.


erative urinary tract infections. There were nodeaths. All domino donors were discharged from thehospital at 20 to 93 days (median 28 days)posttransplantation.

Domino recipients. Surgical outcomes of thesepatients are summarized in Table 3. The IVC waspreserved in five patients and cavo-caval anastomosiswas straightforward in all of them. The IVC couldnot be preserved because of technical difficulties infive patients, and the upper cavo-caval anastomosiswas difficult in two of them, in whom the cavalstump was short. There were no deaths in the post-operative period. Domino recipients were dischargedat 21 to 48 days (median 31 days) posttransplant.

Morbidity and mortality in followupbeyond 60 days of transplantation

Domino donors. At present, with followup from2 to 22 months (median 10.5 months), all patientshave normal liver function. The combined liver-kidney transplant patient has an anicteric cholestasis.Serum TTR-met 30 levels in these patients (data notshown) declined after liver transplantation at a rateconsistent with the published 2.1-day half-life of theprotein.19

Domino recipients. Surgical outcomes in thesepatients are summarized in Table 3. Nine patientshave normal liver function at followup. Seven of ninepatients receiving transplants for cancer are alive withno sign of recurrence. Recipient a developed one liver

nodule of recurrent hepatocellular carcinoma 2.1 cmin diameter at 9 months posttransplant, with an ele-vation of serum alpha-foetoprotein from 3 to 13mg/L. One session of intraarterial chemoemboliza-tion20 has been undertaken. Severe hepatitis B re-curred at 13 months and was treated with lamivu-dine. Bone metastases in the upper femur wererecognized and treated by radiation. The liver nodulewas resected by removal of segment 8 at 14 monthsposttransplant, with normal liver function 8 monthslater. One patient, 3 months posttransplant, withpreviously normal liver function, developed fulmi-nant hepatitis B, dying from liver failure and sepsiswithout evidence of recurrent malignant disease. Au-topsy permission was not granted.

TTR-met 30 analyses available in four patientsshowed the presence of the variant protein in theimmediate postoperative period, rising to plateaulevels 3 to 4 weeks after transplantation (Fig. 1). Thislevel has been maintained in one patient for 10months posttransplant. TTR-met 30 levels on theday of death in the patient with fulminant hepatitis(domino recipient c) had fallen to below 1 mg/dL,consistent with hepatic failure.

Nine patients were available for neurologic ex-aminations and electrophysiologic studies (see Meth-ods section for details) after transplantation. Nonehad symptoms of autonomic dysfunction. Two pa-tients complained of paresthesia immediately after

Figure 1. Posttransplant serum TTR-met 30 levels in four domino recipients of familial amyloidotic polyneuropathylivers. a, patient a; b, patient b; c, patient c; d, patient d; e, patient e; TTR-met, transthyretin-methionine.


operation. On examination, two had hypoesthesia.In one patient, this was considered secondary toknown pretransplant alcohol abuse, and in the otherto entrapment neuropathy favored by prolonged op-erative immobilization. Cardiocirculatory auto-nomic tests and sensory electrophysiologic studieswere normal in all patients, although preexistingheart block and antihypertensive therapy precludedassessments based on heart rate in two patients.

DISCUSSION

No perioperative fatalities have been reported in theliterature concerning the domino procedure. Thisseries confirms the safety in terms of mortality, anddoes not show any excess morbidity induced by sur-gical techniques.

Ethics and informed consentA domino transplantation program for metabolicdisorders involves specific ethical issues. For the FAPpatient, these concern timing and technique. When adecision is made to perform transplantation on anFAP patient, the priority should be a function of thatpatient’s clinical need, and not that of a potentialrecipient of the explanted organ. The surgical tech-nique for explanting a domino donor is differentfrom recipient organ removal but carries no addi-tional risk. The procedure has to optimize the ease oftransplanting the cadaver organ in the FAP patient,and of the explanted FAP patient’s liver into thedomino recipient. This has to be carefully explainedto the FAP patient. Others have likened the informedconsent discussion to that for living donor consent.9

But the domino donor is quite different from a livingdonor, because the primary objective of the surgery istherapeutic transplantation, not harvesting part of aliver. In essence, the FAP liver is surgical waste fromthe transplantation.

For the domino recipient, the ethical issues con-cern the risk of developing the disease caused by themetabolic defect in the transplanted liver. Amyloiddeposition is asymptomatic for many years in FAP.Experience to date with domino recipients of FAPlivers does not allow a definitive assessment of therisk of developing amyloidotic neuropathy. Theprognosis for the patient without the transplant isusually better known. Consequently, the risks of sur-gery and amyloidotic complications could be justifi-able in patients whose survival is likely to be for aperiod of time that is less than that over which amy-loidotic symptoms might develop. In our program

we discuss retransplantation with a normal cadavergraft if the recipient survives for more than 5 years,provided there is no recurrence of the malignant dis-ease for those patients transplanted for cancer.

Origin of donors and patientsThe cadaver donors in this series are representative ofthose seen at our center. The patients with FAP are allof Portuguese origin, consistent with the genetic ba-sis of the condition, and with the population in thegeographic area served by the hospitals.

Blood group compatibilityThe potential domino recipients with relatively rareblood groups could wait many months for the avail-ability of a matched organ. Also, for liver donors whoare group O, there are proportionately more poten-tial recipients. Delays in graft availability couldworsen the prognosis of their disease. For this reason,transplantation is made with major group compati-bility, as demonstrated by the domino pairs (B,b),(D,d), (G,g), and (H,h) (Tables 1 and 2).

Surgical techniqueBefore inclusion on the registry for transplantation,both domino donors and recipients receive the usualpretransplantation evaluation in our center, includ-ing hepatic arteriography. Arteriography is helpful inplanning the nature of the surgical intervention andto anticipate the use of special items, such as thetissue bank arterial graft in the domino recipient inprocedure (A,a). Arteriography is also essential toidentify the anatomic variants of the hepatic bloodsupply in the domino donors, although the preoper-ative assessment did not detect the presence of a lefthepatic artery in one patient. Arteriography can alsoinfluence the choice of position and type of anasto-mosis in the domino recipients with arterial throm-bosis caused by preoperative intrarterial chemoem-bolization,21 or related interventions in primary orsecondary liver cancers.

FAP donors are generally relatively young andslim, with easy access to vessels. But amyloidotic neu-ropathy can lead to autonomic nervous system dys-function, with intraoperative circulatory instability.22

Conduction defects had been diagnosed before oper-ation in three patients, including one with a cardiacpacemaker, but no intraoperative anomalies of car-diac rhythm or of severe hypotension were noted.

The principal technical issue in removing an FAPliver for domino transplantation is in the sectioningof the suprahepatic vena cava. The challenge is to


ensure an adequate cuff for the donor and to have anadequate cuff on the liver. Even though the diaphrag-matic orifice of the inferior vena cava was opened toallow clamping of the vena cava above the liver andunder the pericardium above the diaphragm,9 thecaval stump proved to be short in two patients. Wehave identified the option of prolonging the venacava above the domino liver by a vein graft from atissue bank, but so far we have not yet needed thiscontingency.

Standardization of resection technique and of theuse of vein grafts will be necessary if domino proce-dures are to be performed by surgical teams in differ-ent centers. Techniques for vena cava preservationand face-to-face anastomosis in the dominorecipient23-25 can facilitate the use of FAP livers.

Selection of domino recipientsOur program offers domino livers mainly to patientswho may be cured of their disease by liver transplan-tation, and who are not candidates for cadaver liversbecause of the shortage of grafts. This is the case withpatients with hepatocellular carcinoma who are notin the group with good expected survival.15 Thatmeans that patients with extrahepatic disease inwhom the risk of recurrence is 100% are excludedeven from our domino program. It is the same formetastatic liver disease, which commonly recurs afterliver transplantation. Domino transplantation maybe offered to some special patients, as our patients band g. In the future, domino transplantation may beoffered to other categories of patients, namely, pa-tients with AIDS, with active replication of virus Bnot controlled by antiviral therapy before transplan-tation. A second category could be patients olderthan 70 years, with a relatively short life expectancy.Until now, FAP livers have not been proposed for theusual candidates for liver transplantation.

Theoretical risks in the domino recipientIt is currently known that the TTR-met 30 produc-tion in the domino recipient continues after trans-plantation,14 as in the FAP patient.9 Little has beenpublished concerning the influence of immunosup-pression on TTR production, or on the influence onamyloid deposition in the recipient since the descrip-tion by Holmgren and associate’s1 two patients. Thedomino recipient’s previous diagnosis, clinical status,immunosuppressive therapy, and postoperativeprogress can all influence TTR-met 30 production,but in opposing ways; TTR levels are indicators of

liver function and nutritional status.26 Animal stud-ies have shown serum TTR levels to be negativemarkers of surgical stress,27 and TTR production byisolated hepatocytes can be reduced by interleukin 8,a mediator of the acute-phase response.28 Liver cir-rhosis appears to accelerate peripheral degradation ofTTR in muscle29 in a rat model.

The results show that TTR-met 30 productioncontinues in the transplanted FAP liver, with plasmalevels rising to a plateau at 3 to 4 weeks after trans-plantation (Fig. 1). In one patient with a followupresult at 10 months, the TTR-met 30 level is similarto that at 1 month. TTR-met 30 levels in recipients aand e show some fluctuation in the first 30 days. Inpatient c, TTR fell dramatically to 0.4 mg/mL at thetime of developing liver failure, reflecting the severityof liver function impairment. A systematic biochem-ical and neurologic followup of recipients of FAPlivers is necessary to monitor graft function and todetect early signs of development of amyloidotic de-posits and neuropathy.

Domino transplantation frompatients with metabolic disordersThe concept of domino transplantation as an appro-priate means of augmenting the donor pool has beenused successfully in the transplant of thoracic or-gans.30,31 Patient survival after domino transplanta-tion is comparable to that of conventional orthotopiccardiac transplantation. There does not seem to be anincreased risk of early graft failure, rejection, or in-fection. But we must admit that, in heart transplants,the domino heart is considered an absolutely normalorgan without any potential future additional risk forthe recipient. More FAP livers can be expected tobecome available as the use of transplantation in-creases. Some 200 FAP transplants have been identi-fied in the medical literature.9

The domino approach to transplantation in pa-tients with FAP can yield a small, but nonnegligiblenumber of transplantable organs. Furtado and col-leagues10 have estimated some 50 per year in Portu-gal, with a fair allocation of cadaver grafts to FAPpatients. In our department, 36 FAP patients hadtransplants before the start of our domino program.There were 16 patients in the period under study,and only 10 were used in domino procedures becausethere were no local recipients at the time of livertransplantation in the others.

The approach could also be extended to dominodonors with other metabolic disorders in which slow-


onset systemic pathologic effects result from a meta-bolic or functional deficiency in the liver, which isotherwise not affected. Some examples are primaryhyperoxaluria, urea cycle disorders (including orni-thine transcarbylamase deficiency) or protein C de-ficiency. These are rare conditions, but some are be-ginning to be treated with liver transplantationbecause the morbidity and mortality of this proce-dure continue to improve. Primary hyperoxaluria isthe best-known example.

Combined hepatic and renal transplants havebeen reported from 30 European centers, with 80patients transplanted over a 3-year period being fol-lowed up.32 One case of domino liver transplantationfrom a late case of hereditary oxalosis is known to us(Dr G Mentha, Geneva, Switzerland, personal com-munication), and we have recently performed asecond.

The European Liver Transplant Registry identi-fied 958 transplants for metabolic disorders in theperiod January 1988 to December 1997.33 The pro-portion of these patients with metabolic disorders forwhich domino transplantation could be planned isnot certain, because until 1998 the full diagnosis wasnot recorded.

Ethical issues for the recipients of a metabolicallydefective liver remain the same as for FAP. They con-cern the balance between the patient’s risk, particu-larly mortality from the existing condition, the risksinvolved in the surgery, and risks from the metabolicdefect acquired from the transplanted liver. The risksfor each metabolic disorder have to be assessed in thecontext of the individual recipient’s clinical statusand prognosis.

In conclusion, the opportunities for domino livertransplantation exist, but are sporadic and relativelyinfrequent. Domino procedures do not create addi-tional risk for the domino donor. The prognosis ofthe domino recipient with cancer can be greatlyimproved. Part of the ethical justification in thesepatients for proposing an initial transplant with ametabolically deficient liver involves possible re-transplantation with a cadaver graft after a period ofrecurrence-free survival chosen to be less than theperiod beyond which the metabolic deficiency couldbe harmful.

The safety of the donor explant and the recipienttransplant are largely dependent on surgical tech-nique, particularly concerning the upper vena cavalsectioning and anastomoses. Diffusion of informa-tion on the domino approach and standardization of

the techniques of preoperative assessment and thoseused during surgery may make it possible to performmore domino procedures, with collaboration betweencenters as in conventional transplantation.

Acknowledgment: We thank Professor MasamitsuNakazato, Third Department of Internal Medicine,Miyazaki Medical College, Miyazaki, Japan, for theradioimmunoassay measurements of TTR-met 30.

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Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy