Influence of Liver Transplantation on Neuropsychiatric Manifestations
of Wilson Disease
M.A. Yagci*, A. Tardu, S. Karagul, I. Ertugrul, V. Ince, S. Kirmizi, B. Unal, B. Isik, C. Kayaalp, and S. Yilmaz
Department of Surgery, Turgut Ozal Medical Center, Inonu University, Malatya, Turkey
neuropsychological manifestations of Wilson disease.
Materials and Methods.
symptoms before liver transplantation. They were 7 male and 2 female subjects with a
median age of 19 years (range 10 to 25). They were analyzed for their preoperative and
postoperative hepatic, neurological, and psychological scores described by the Unified
Wilson Disease Rating Scale after a mean 36.6 months of follow-up.
Preoperative mean Model for End-Stage Liver Disease and Child-Pugh scores
were 18.3 (range 15 to 26) and 8.9 (range 6 to 12), respectively. One patient had acute
postoperative ischemic stroke unrelated to Wilson disease and was excluded from the
psychological scores of the remaining 8 patients were 7.4 ? 2.3 vs 2.4 ? 1.3 (P ¼ .0005),
17.7 ? 11.7 vs 12.7 ? 12.5 (P ¼ .055), and 9.0 ? 1.7 vs 7.0 ? 2.1 (P ¼ .033).
Liver transplantation for Wilson disease can provide some improvement of
the neuropsychological symptoms in addition to the hepatic recovery.
This study sought to evaluate the effect of liver transplantation on the
Nine of 42 Wilson disease patients had neuropsychological
gene, with resultant impairment of biliary excretion of
copper. It has a prevalence of 1 per 30,000 in the general
population . The accumulation of copper in different
organs is due to a reduced excretion of copper via the
bile, leading to hepatic and neuropsychiatric manifesta-
Copper chelating agents such as D-penicillamine and
trientine hydrochloride, as well as copper absorption
blockers such as zinc salts, are effective and have mark-
edly improved the prognosis of WD [1,2]. Nevertheless,
WD is an indication for liver transplantation (LT) in
cases of decompensate liver disease or fulminant liver
failure when medical treatment options fail . However,
its use for treatment of progressive neurological deteri-
oration is still controversial [4e6]. Because few data are
available in the field, the aim of the present study was to
evaluate the effect of LT on outcomes of hepatic and
especially neuropsychiatric manifestations in patients
ILSON DISEASE (WD) is an autosomal-recessive
disorder caused by a mutation in the ATP7B
MATERIALS AND METHODS
Data were derived from a prospectively collected database at the
Turgut Ozal Medical Center of Inonu University from March 2002
to August 2014. We performed 1042 living donor liver trans-
plantations (LDLTs) and 282 deceased donor liver transplantations
in patients with end-stage liver disease at our center. We investi-
gated the pretransplantation characteristics of patients who were
diagnosed with WD with neuropsychiatric manifestations (9 of 42
WD patients who underwent LT), including Model for End-Stage
Liver Disease (MELD) and Child-Pugh score and the donors’
relationships to their respective patients. Other examined features
consisted of operation time, graft type, graft weight, actual graft-to-
recipient weight ratio (GRWR, %), postoperative complications,
and survival outcomes. Table 1 shows the patient characteristics.
Nine patients, including 5 adults and 4 children (7 male, 2 female),
underwent LT. The diagnosis of WD was based on the presence of
liver disease associated with at least 2 of the following criteria:
*Address correspondence to Mehmet Ali Yagci, MD, Depart-
ment of Surgery, Turgut Ozal Medical Center, Inonu University,
Malatya, 44315, Turkey. E-mail: firstname.lastname@example.org
ª 2015 by Elsevier Inc. All rights reserved.
360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 1469e1473 (2015)1469
positive family history, low serum ceruloplasmin (<20 mg/dL),
presence of Kayser-Fleischer rings, elevated 24-hour urinary copper
excretion (>50 mg/d), Coombs-negative hemolytic anemia, or
presence of elevated liver copper (>250 mg/g) . The median age
was 19 years old; patient ages ranged from 10 to 25 years. The
patients were monitored until August 2014, and their medical re-
cords were retrospectively reviewed. The patients with or without
parents were asked to complete a questionnaire about their pre-
operative and postoperative hepatic, neurological, and neuropsy-
chiatric symptoms at follow-up examinations. The questionnaire
was completed by all patients, and a score was developed to
describe the evolution of hepatic, neurological, and neuropsycho-
logical symptoms. The parameters included in the scoring system
are shown in Table 2. The score range for hepatic symptoms was
0 to 17 points (0 ¼ no symptoms), for neurological symptoms was 12
to 60 points (12 ¼ no symptoms), and for neuropsychological
symptoms was 0 to 19 points (0 ¼ no symptoms). The items of the
scores correspond in part to items selected by the EuroWilson
registry and in part to items used by neurological evaluation scales
for WD (Unified Wilson Disease Rating Scale) [6e9].
Donor relationship was familial for 7 donors (3 fathers, 1
mothers, 2 sister, 1 cousin) who underwent LDLT, and unrelated
for 2 donors (2 deceased) who underwent deceased donor liver
transplantations. Blood types were compatible in all cases. Dona-
tions were voluntary and altruistic in all cases, written informed
consent had been obtained from both donor and recipient before
surgery, and all LTs were approved by the Ethics Committee of
Turgut Ozal Medical Center.
Preoperative radiographic assessment was done by ultrasound
(US) and computed tomography (CT). Magnetic resonance imaging
(MRI) was not used at preoperative evaluation routinely. Piggy-
back technique was used in all patients. The details of our surgi-
cal technique have been described previously . Standard
immunosuppressive therapy was used with low-dose corticosteroids,
mycophenolate mofetil, and tacrolimus. Cyclosporine A was
preferred to tacrolimus in children and patients with diabetes
mellitus. Induction therapy with basiliximab was administered in
patients with a creatinine value over normal. Doppler US was used
at the early postoperative period, and CT scan was used on post-
operative day 10 to confirm patency of the hepatic vasculature.
Statistical analyses were performed using SPSS for Windows,
version 13.0 (SPSS Inc., Chicago, Illinois, United States). Cate-
gorical data are defined as percentage and numbers, and measur-
able data are defined by median or mean ? standard deviation.
Paired Student t test was used for statistical analysis. Survival
analysis was performed by the life table method. A value of P ? .05
was considered significant.
Preoperative mean MELD and Child-Pugh scores were 18.3
(range 15 to 26) and 8.9 (range 6 to 12), respectively. The
Table 1. Patient Characteristics
Index MELD Child-Pugh
Abbreviation: MELD, Model for End-Stage Liver Disease.
Table 2. Items on the Patient Questionnaire
Hepatic ScorePsychiatric ScoreNeurological Score
Points per item Symptom present, 1 point
Symptom absent, 0 point
ItemsFeeling of general ill health
Lower limb edema
Other cutaneous signs of liver disease Eating disorder
Symptom present, 1 point
Symptom absent, 0 point
Change in mood
Change in mood noticed by patient
Deteriorating cognitive performance
Needing more time to complete work
Loss of interpersonal skills
Loss of interest in previous leisure pursuits
Range from 1 point (symptom absent)
to 5 points (most severe affection)
Tremor at rest
Change in speech
Salivation or drooling
Change in handwriting
Oromandibular or cervical
Deteriorating standard of personal hygiene
Change in sexual behavior or preferences
Abuse of alcohol or other recreational drugs
1470 YAGCI, TARDU, KARAGUL ET AL
median body mass index was 18.6 (range 15.1 to 30.8). Right
lobe grafts in 7 patients (split graft in 1 patient), left lobe
graft in 1 patient, and whole liver graft in 1 patient were
transplanted. Average GRWR was 1.98% (range 1% to
5.2%). Multiple bile duct orifices had to be reconstructed in
one of the grafts (11.1%). Biliary reconstructions in all pa-
tients were duct-to-duct anastomosis. Hepatic veins of all
grafts with LDLT were enveloped like a circumferential
fence by autologous saphenous vein. Hepatic artery anas-
tomosis was made with a surgical telescope (4.5 or 8
magnification). The mean operative time was 350 minutes
(range 265 to 410). The cold ischemia duration was less than
60 minutes in all patients. The median hospital stay was 20
days (range 15 to 114 days).
The surgical complications and outcomes of the individ-
ual patients are summarized in Table 3. One patient
developed major biliary leakage, which was treated with
repeat laparotomy. There was only 1 case with biliary
stricture in the long term. A biliary stent was inserted
percutaneously after balloon dilatation in this case. Hepatic
artery thrombosis was seen in 1 patient at postoperative day
2 and was treated with cadaveric retransplantation. One
patient developed hepatic outflow obstruction at 22 days
after LDLT. Graft failure developed at postoperative day 80
after failed balloon dilatation and interventional throm-
bectomy, and cadaveric retransplantation was performed.
Acute ischemic stroke occurred after retransplantation and
was resolved with medical treatment. This patient was
excluded from the statistical analysis because of confused
neurological symptoms due to WD and stroke.
The hepatic symptom score obtained from the patients’
questionnaires showed a decrease after LT. The individual
hepatic symptom scores of 8 patients are shown in Fig 1. All
patients underwent transplantation for chronic liver disease.
The mean hepatic scores for the preoperative and post-
operative period were 7.4 ? 2.3 vs 2.4 ? 1.3 (P ¼ .0005).
The mean neurological symptom scores for the preop-
erative and postoperative period were 17.7 ? 11.7 vs
12.7 ? 12.5 (P ¼ .055). Only 1 patient’s neurological
symptoms progressed during posttransplantation follow-
up. The mean psychiatric symptom scores for the preop-
erative and postoperative period were 9.0 ? 1.7 vs 7.0 ?
2.1 (P ¼ .033). One patient’s psychiatric symptoms pro-
gressed during transplantation follow-up and in 2 patients
stayed the same, whereas the remaining patients had some
improvement. As a result, although hepatic symptoms
improved in all patients (100%), neurological and psychi-
atric symptoms improved in 7 patients (87.5%) and in 5
patients (62.5%), respectively.
In-hospital mortality, which was defined as any death
within the same hospital admission for LT, regardless of the
number of days after LT, did not occur. All patients are still
alive at a mean follow-up of 36.6 months (range 6 to 81
months). All patients followed up as outpatients had good
Since the first success with transplant surgery in 1969, many
reports in the literature have considered WD an excellent
indication for transplantation in cases that were unrespon-
sive to drug therapy or that were too severe. This treatment
can reverse biochemical and clinical signs and offer long-
term survival [3,11e13]. The neurological aspects of WD
and its indication for LT is a topic that evokes much dis-
cussion among specialists.
analyzed WD patients who underwent transplantation,
describing their clinical features before and after LT. Our
results clearly confirm that WD is a rare indication for LT,
but this surgery can achieve a very good long-term outcome
even in cases of liver failure with neurological manifesta-
tions. Also, LT for WD can provide some improvements on
neuropsychological symptoms, in addition to the hepatic
We performed more than 1300 liver transplantations, and
there were only 42 WD patients (3.2%). Therefore, WD is
an uncommon indication for liver transplantation, and
neurological manifestations are rare. This can be explained
by successful medical treatment, which contains copper
chelating agents to promote copper excretion from the
body, or zinc to reduce copper absorption, or both.
The effect of LT on neurological manifestations is still
controversial. There are only a few studies in the literature
[14,15]. Wang et al.  showed neurological improvements
Table 3. Surgical Details and Outcomes
PatientsOperating Time (min)Liver GraftGRWR (%)LOS (d)Outcome Follow-Up (mos) Complications and Management
Biliary stricture (biliary stent)
Biliary leakage (repeat laparotomy)
Hepatic artery thrombosis (cadaveric re-transplantation)
Cerebrovascular accident (resolved over time)
Hepatic venous outflow obstruction (vascular stent)
Graft failure (cadaveric re-transplantation)
Abbreviations: RL, right lobe; LL, left lobe.
LT ON NEUROPSYCHIATRIC MANIFESTATIONS OF WD1471
in 8 of 9 patients (88.9%) who underwent LDLT for
neurological complications. In a review of 41 neurologically
affected patients with WD, LT reversed neurological dete-
rioration in 78% of patients, whereas the remaining patients
did not present any change in their neurological status .
According to Eghtesad et al. , neurological improve-
ment (58%) can be obtained in patients with liver failure
and neurological manifestations. Similarly in our series,
neurological improvement was seen in 7 of 8 patients
(87.5%) who received LT for hepatic failure with neuro-
Neurological deterioration was detected after the LT in 2
patients. Although 1 of them had acute ischemic stroke and
confused neurological symptoms due to WD and stroke,
neurological improvement cannot be obtained in all patients
and therefore careful patient selection and timing of LT are
important for those affected by neurological symptoms as
well as liver disease. Geissler et al.  reported that 2 of 6
WD patients with mixed hepatic and neurological symptoms
fully recovered after LT. They suggested that in such cases
an early decision for LT is justified because neurological
deficits may become irreversible. Likewise, Eghtesad et al.
 indicated the benefit and importance of performing
transplantation before neurological impairment becomes
Another debate is whether progressive neurological dis-
ease due to WD without liver failure is an indication for
liver transplantation. Bax et al.  reported the case of a
15-year-old patient with neurological manifestations due to
WD without liver failure who returned almost to normal
after LT. In a multicenter French study with 121 WD pa-
tients , 94% of patients underwent transplantation for
predominant liver disease, whereas 6% received LT because
of a purely neurological indication. Unlike in the study by
Bax et al., they advocated that patients with purely neuro-
logical symptoms also seemed to have a significantly worse
prognosis after LT when compared with hepatic patients.
Also, the same study reported that all 3 patients with severe
axial Parkinson syndrome died (of infection) with a func-
tional graft but without any neurological improvement.
Likewise, in a recent report summarizing the experience of a
consortium of Italian centers, individuals with both neuro-
psychiatric and hepatic dysfunction had a lower mean sur-
vival rate than patients with hepatic dysfunction alone .
Unlike the previously reported studies, in our series we did
not observe hospital mortality in any patients, and also all
patients are still alive with an acceptable morbidity rate at a
meanfollow-up of36.6 months.
improvement in all patients (100%), neurological improve-
ment in 7 of 8 patients (87.5%), and psychiatric improve-
ment in 5 of 8 (67.5%) patients were achieved with an
excellent survival rate. This can be explained by our
approach in WD patients with mixed hepatic and neuro-
logical involvement, which includes a complete hepatic and
neurological evaluation and an early decision for LT.
Therefore, in this series, the patient’s mean MELD score
was significantly lower compared with results from our first
304 LDLTs . However, the number of patients is not
high enough to shed light on this area.
Although it is clearly difficult to evaluate psychiatric
outcomes due to the complexity of the presenting signs and
the variety of factors potentially influencing clinical out-
comes, such as immunosuppressive therapy, WD itself, and
major surgery, moderate psychiatric improvement was
observed in our series. Generally, the presence of psychi-
atric symptoms has been accepted as a partial contraindi-
cation for LT . However, our data showed that even
WD-related psychiatric symptoms can be treated with LT.
Therefore, close collaboration with psychiatrists and neu-
rologists is essential for an accurate decision.
In conclusion, LT is an effective and safe therapy for WD
patients with end-stage liver disease, even in the presence of
neuropsychiatric involvement. WD patients with mixed he-
patic and neurological manifestations must be considered
carefully, and a decision should be made without delay
based on the stage of the neurological damage and its
irreversibility to achieve significant hepatic and neurological
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LT ON NEUROPSYCHIATRIC MANIFESTATIONS OF WD1473