2008 Wiley Periodicals, Inc.

Clin Transplant 2008 DOI: 10.1111/j.1399-0012.2008.00935.x

Case Report

Domino liver transplantation using

a graft from a donor with familial
hypercholesterolemia: seven-yr follow-up
Popescu I, Habib N, Dima S, Hancu N, Gheorghe L, Iacob S, Mihaila M,
Dorobantu B, Matei E, Botea F. Domino liver transplantation using a graft
from a donor with familial hypercholesterolemia: seven-yr follow-up.
Clin Transplant 2008 DOI: 10.1111/j.1399-0012.2008.00935.x
2008 Wiley Periodicals, Inc.
Abstract: A 46-yr-old female with hepatocellular carcinoma and severe
hepatitis B-related liver cirrhosis received a domino liver graft from a
25-yr-old female with homozygous familial hypercholesterolemia (HFHC)
in September 2001. Hypercholesterolemia occurred in the graft recipient
within one yr after transplantation and was partially controlled by
atorvastatin. Three yr after transplantation, an autologous CD34+ cell
transplantation was performed in order to better control the hypercholesterolemia. Only preliminary results of this domino liver transplantation
(DLT) were published in 2003, without a long-term analysis of the hypercholesterolemic eects in recipient. Subsequent to DLT, the average plasma
cholesterol level in the domino donor rapidly normalized and seven yr after
had a value of 182 mg/dL. After seven-yr follow-up, the domino recipient
has no hepatocarcinoma recurrence. Moreover, no signs of cardiovascular
or atherosclerotic lesions were noted despite an elevated plasma cholesterol
level (339 mg/dL after seven yr of follow-up) resistant to drug therapy and
stem cell autotransplantation. In conclusion, DLT using a liver graft from a
patient with HFHC provides a viable option for marginal recipients.

Irinel Popescua, Nagy Habibb,

Simona Dimaa, Nicolae Hancuc,
Liana Gheorghed, Speranta Iacobd,
Mariana Mihailae, Bogdan
Dorobantua, Emil Mateia and
Florin Boteaf
a
Center of General Surgery and Liver
Transplantation, Fundeni Clinical Institute,
Bucharest, Romania , bDepartments of Surgery,
Hepatology, Haematology, and Radiology at
Hammersmith Campus, Imperial College,
London, UK, cClinical Center of Diabetes,
Nutrition, Metabolic Diseases, Iuliu Hatieganu
University of Medicine and Pharmacy,
Cluj-Napoca, Romania, dCenter of
Gastroenterology and Hepatology, Fundeni
Clinical Institute, Bucharest, Romania,
e
Department of Internal Medicine, Fundeni
Clinical Institute, Bucharest, Romania and
f
Department of Liver Surgery, Humanitas Clinical
Institute IRCCS, Rozzano, Milan, Italy

Key words: domino procedure hepatocellular

carcinoma homozygous familial
hypercholesterolemia liver transplantation
stem cell autotransplantation
Corresponding author: Irinel Popescu, MD, PhD,
Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni
258, sector 2, 022328, Bucharest, Romania.
Tel: +40 21 3180417; fax: +40 21 3180417;
e-mail: irinel.popescu@icfundeni.ro
Accepted for publication 14 October 2008

Limited organ availability and the signicant

percentage of drop-outs from the waiting list
because of cirrhosis and/or tumor progression still
represent major drawbacks for transplantation
strategies. Because of these drawbacks, not all

patients initially eligible for transplantation eventually benet from it (1). As a result, novel
strategies, such as increased use of marginal
donors, living donor liver grafts, split liver grafts
from deceased donors, and so-called domino liver

Popescu et al.

grafts from patients with metabolic liver disease,

have been explored to expand the pool of hepatic
allograft. The last method was applied by several
authors using as donors for domino liver transplantation (DLT) the following subjects: patients
with familial amyloid polyneuropathy (2), maple
syrup urine disease (3), or primary hyperoxaluria
(4). Grafts from these donors were received by
patients with advanced stage hepatocellular carcinoma (HCC) (5) with low priority on the waiting
list and/or unlikely to survive until standard liver
transplantation, or by tumor free cirrhotic domino
receptors, sporadic cases of metabolic fulminant
liver failure (6), and retransplants (7, 8).
In 2001, we performed a combination of splitliver and DLT procedures (9). A 25-yr-old female
patient with homozygous familial hypercholesterolemia (HFHC) received the right liver along with
segment I from a cadaveric donor (segments II and
III from that donor were allocated to a child with
type I glycogenosis). Subsequently, the liver from
the patient with HFHC was grafted into a 46-yrold female patient with a 5-cm-diameter HCC with
a high alpha fetoprotein (AFP) value of 500 ng/mL
and unresponsive to repeated chemoembolization,
and hepatitis B virus (HBV) Child Pugh class B
liver cirrhosis associated with repeated episodes of
encephalopathy. The severe shortage of liver grafts
in Romania represented additional arguments in
favor of DLT in this particular case. No other
similar cases have been reported in the literature.
We concluded at that time that serum cholesterol
levels in the domino recipient could be maintained
within an acceptable range by extrahepatic LDL
receptors (LDL-Rs), such as those on monocytes
and broblasts (9). Since in 2003, we published
only preliminary results of DLT in HFHC without
a long-term analysis of the eects of hypercholesterolemia, we consider the seven-yr follow-up
results of this procedure to be relevant to report.

transplantation. The transplantation procedure

and follow-up protocol were reviewed and
approved by our institutional ethics board and
conducted according to good clinical practices.
Written informed consent was obtained prior to
any intervention.

Case report

Domino transplant recipient

This study analyzed the seven-yr outcome of DLT.

Presently, both transplanted patients are alive and
show normal graft function. The details of the
cases involved in the present study have been
previously reported (9).
Possible systemic atherosclerosis was investigated by laboratory tests [total cholesterol, triglyceride (TG), HDL-C, and LDL-C] in both the
domino transplant donor (DTD) and domino
transplant recipient (DTR). Additionally, the
DTD was monitored by cardiac ultrasound and
the DTR investigated by coronary angiography
with the Seldinger technique seven yr after

Six wk after liver transplantation, plasma cholesterol value increased and therapy with simvastatin

Domino transplant donor

Total cholesterol rapidly normalized after liver

transplantation. A right coronary artery stenosis
was diagnosed by angiography at the time of liver
transplantation. This stenosis necessitated two
consecutive stent placements one and two yr after
transplantation. The post-transplantation course
was complicated by a decline of renal function and
dialysis-dependent end-stage renal disease occurred
in 2003. Consequently, the patient underwent
kidney transplantation in January 2004 at the
Clinical Institute of Urology and Renal Transplantation in Cluj-Napoca (Romania).
The characteristics of the domino donor during
a screening for alterations of the lipid metabolism
are shown in Table 1. The plasma cholesterol level
before and six yr after transplantation were
500 mg/dL and 182 mg/dL, respectively; the
LDL-C values for the same time points were 286
and 98 mg/dL. The patient was metabolically
stable and showed no signs of lipid imbalance.
The last cardiac ultrasonography showed a mild
aortic systolic ejection murmur; there was nodular
calcication on the posterior part of the mitral
valve ring, but left ventricular contractions and the
ejection fraction were normal. Currently, the
immune suppression consists of tacrolimus
(Astellas Pharma US, Inc., Deereld, IL, USA),
mycophenolate mofetil (CellCept; Roche Pharmaceuticals, Indianapolis, IN, USA), and prednisolone (Medrol; Pharmacia & Upjohn N.V./S.A.,
Puurs, Belgium).

Table 1. Plasma lipid profile of the DTD

TC (mg/dL)
TG (mg/dL)
LDL-C (mg/dL)

Before
transplantation

Seven yr
after
transplantation

500
80
286

182
102
98

TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein; DTD,

domino transplant donor.

Domino liver transplantation

(a progressively increased dose from 10 to 60 mg/d)
was introduced. During the follow-up of the
recipient, the lipid lowering drug protocol was
modied and simvastatin therapy switched to
atorvastatin (Sortis at 60 mg/d; Pzer, Vienna,
Austria).
Autologous stem cell transplantation. Three yr after
the domino procedure, an autologous CD34+ cell
transplantation was performed in order to better
control the hypercholesterolemia. The rationale for
using granulocyte colony-stimulating factor
(G-CSF) mobilized peripheral blood stem cells
was that these cells could repopulate the liver
parenchyma and could be reprogrammed to contribute in restoring the liver function after fusing
with defective hepatocytes.
After daily subcutaneous administration of GCSF (G-CSF 10 lg/kg of body weight, Neupogen; Amgen Manufacturing, Thousand Oaks,
CA, USA), leukapheresis (Haemonetics MCS Plus;
Haemonetics Corp., Braintree, MA, USA) was
performed on day 5 when the level of CD34+
reached a value of 17 106/kg. The leukapheresis
product was transferred to the Cambridge Laboratory of Cellular Therapy, where CD34+ cells
were immunoselected using the CliniMacs device
(Miltenyi Biotech GmbH, Bergisch Gladbach,
Germany) and then ex-vivo expanded. The stem
cells were then infused into the patient via the
hepatic artery in the Department of Interventional
Radiology and Angiography in the CC Iliescu
Institute of Cardiology, Bucharest, Romania. The
nal leukapheresis product had a volume of
130 mL and consisted of a mononuclear cell
concentrate with a hematocrit level of 5.2%,
viability of 97%, and CD34+ stem cell proportion
of 45.4% (the actual number of stem cells
was 91.86 106). The injected product had
a hematocrit level of 0.1%, CD34+ and CD45)
cell proportion of 58%, and an actual CD34+ cell
number of 103.95 106. The autologous stem cell
transplantation was well tolerated, and no procedure-related complications were observed. The
procedure did not reduce the plasma cholesterol
levels in DTR.
The characteristics of the DTR during a screening for alterations of lipid metabolism are shown in
Fig. 1. The lipid metabolism parameters studied
included cholesterol (mean 336.4 79.7 mg/dL,
range 112478) (Fig. 1A), LDL-C (mean 271.6
79.1 mg/dL, range 70421) (Fig. 1B), HDL-C
(mean 39.4 9 mg/dL, range 2863) (Fig. 1C),
and TG (mean 135.5 50.3 mg/dL, range 50
266). The values for apolipoprotein A and B levels
were within the normal range (109 and 107 mg/dL,

Fig. 1. Post-liver transplantation variation in the principal

parameters of lipid metabolism in the domino transplantation
recipient (DTR). (A) Plasma cholesterol (mg/dL); (B) high
density lipoprotein (HDL-C) (mg/dL); (C) low density lipoprotein (LDL-C) (mg/dL). Continued lines = values recorded
during follow-up; dotted lines = trend line.

respectively). The acquired hypercholesterolemia

is currently well managed with two cholesterol
lowering agents: atorvastatin (Sortis 60 mg/d;
Pzer) and the cholesterol absorption inhibitor
ezetimibe (Ezetrol 10 mg/d; Merck Sharp &
Dohme, Whitehouse Station, NJ, USA).
The patient currently exhibits no HCC recurrence. Her AFP and CA 199 levels are within
normal range, and computed tomography is negative. No signs of cardiovascular or atherosclerotic
lesions were noted at an angiography performed in

Popescu et al.

Fig. 2. Normal coronary angiography with the Seldinger technique in the domino transplantation recipient (DTR) (six years after
transplantation).

January 2008 (Fig. 2). Currently, the immunosuppression regime consists only of tacrolimus
(Astellas Pharma US, Inc.).
Discussion

This study examined the long-term results after

DLT using a donor (DTD) with HFHC and a
recipient (DTR) with HCC and HBV-related Child
B cirrhosis.
The general shortage of cadaveric organs has led
to a search for alternative methods for expanding
the donor pool. The Domino Liver World Transplant Registry (http://www.fapwtr.org) was established in 1999 and 579 domino transplantations
have been performed by December 2007 (7). DLT
was rst carried out in Portugal in 1995 (10)
followed by a considerable number of DLT for
familial amyloidotic polyneuropathy (FAP) (8).
Current treatment options for HFHC patients
include LDL apheresis (11) and liver transplantation (12). The rst liver transplantation as a
treatment for HFHC was performed in 1984 by
Starzl et al. (13). Liver transplantation, in which a
liver with normal LDL receptors is substituted for
one that is decient in these receptors (14), is the
most eective curative method (15). The timing of
surgery can be dicult, but surgery should be
considered if there is evidence of atheromatous
disease even in the absence of the cardiovascular
symptoms (16). We underline the fact that our
patient already had a right coronary artery stenosis
at the time of liver transplantation. A LDL
apheresis procedure can transiently reduce LDL
cholesterol levels by more than 50% (17) and may
delay the onset of atherosclerosis (18). Neverthe-

less, it must be frequently repeated (every one to

two wk) and is both costly and not widely
available.
In our DTD, liver transplantation normalized
cholesterol concentrations. This fact conrms that
liver transplantation provides the patient with
enough LDL receptors to prevent the onset of
clinical disease. Furthermore, the good results
recorded in the DTD argue in favor of DLT as a
treatment for patients with HFHC.
According to the Milan criteria, liver transplantation is recommended as a therapeutic option for
cirrhotic patients with a single tumor of 5 cm or less
in diameter and in patients with multiple tumors
with no more than three tumor nodules, each 3 cm
or less in diameter (19). The Barcelona Clinic Liver
Cancer Group (BCLC) recommends the transplantation in Child-Pugh AB cirrhotic patients with
one hepatocarcinoma or with up to three nodules of
no more than 3 cm in diameter each (20). Indeed,
our DTR had a 5-cm-diameter HCC that was nonresponsive to repeated chemoembolization, with a
high AFP value of 500 ng/mL, associated with
repeated episodes of encephalopathy.
Seven yr after the transplantation, the domino
recipient currently shows a good graft function, no
recurrence of HCC, and no signs of coronary
disease, atheromatosis, or peripheral deposits of
cholesterol (xantoma or xantelasma), despite her
high cholesterol level (currently 339 mg/dL). An
important concern with regard to DLT from
patients with genetically altered organ is the
development of acquired hypercholesterolemia in
the DTR. Acquired hypercholesterolemia may lead
to a poor long-term prognosis because of cardiovascular complications. Some authors suggest that

Domino liver transplantation

livers explanted from patients with HFHC do not
represent suitable organs for DLT, because raising
plasma LDL-cholesterol levels in subjects who may
already have pre-existing atherosclerotic lesions
could be detrimental (21). However, cirrhotic
patients have a low prevalence of coronary atherosclerosis and the risk of cardiovascular disease
decreases as severity of liver cirrhosis increases
through hypotension and hyperbilirubinemia (22).
In our case, the acquired hypercholesterolemia in the DTR is well managed with two
cholesterol lowering treatments: atorvastatin
(Sortis 60 mg/d; Pzer) and the cholesterol
absorption inhibitor ezetimibe (Ezetrol 10 mg/d;
Merck Sharp & Dohme).
Stem cell autotransplantation did not reduce
plasma cholesterol levels as expected. More
studies examining the potential use of stem cell
transplantation in metabolic disease are needed.
To date, there are 11 published human clinical
studies investigating the eects of BMSC therapy
in patients with liver disease (23). Some studies
have reported adult hematopoietic stem cellbased therapies in liver disease: liver insuciency
(24), alcoholic liver cirrhosis (25). Previous studies have shown conversion of HSC to hepatocytes
through cell fusion (26) or by transdierentiation
(27).
Our results after seven yr of follow-up of the
DTR support our initial conclusions that livers
from patients with HFHC may be used for DLT
(9). The risks must be assessed for each recipient
according to their clinical status and prognosis.
In conclusion, the long follow-up period for our
presented cases allows us to propose DLT using
liver grafts from patients with HFHC as a viable
option for marginal recipients faced with a donor
shortage and associated waiting list mortality.
Financial support
No form of support was received by any of the authors for
this study.

Conflict of interest
None.

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