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Creutzfeldt-Jakob disease after liver transplantation.

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modes of inheritance, age at onset, and ethnic origin,
the clinical heterogeneity of the disease and its clinicopathological overlap with other hereditary distal myopathies or oculopharyngeal dystrophy with rimmed vacuoles and amyloid deposits (31 suggests that mutations
in exons 16 and 1 7 of this gene should be also searched
in families with these disorders.
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in exon 17 of amyloid precursor protein in Japanese familial
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(Abstract)
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Creutzfeldt-Jakob Disease
atter Liver
Transplantation
Alain Crkange, MD," Franqoise Gray, MD, PhD,"
Pierre Cesaro, MD, PhD," Homa Adle-Biassette, MD,"
Christophe Duvoux, MD,t Daniel Cherqui, MD,t
Jeanne Bell, MD,S Piero Parchi, MD,$
Pierluigi Gambetti, MD,Qand Jean-Denis Degos, MD"
We report a 57-year-old woman who died from Creutzfeldt-Jakob disease 2 years after a liver transplantation.
The liver donor had no history of neurological disease.
In one albumin donor, possible Creutzfeldt-Jakob disease developed 3 years later. The patient initially had
cerebellar symptoms. Neuropathology included "Kurutype" plaques and prion protein (PrP) deposits involving
the cerebellum predominantly. The patient was homozygote valine at codon 129 of the PrP gene while the liver
was homozygote methionine. This observation raises the
possibility of transmission of Creutzfeldt-Jakob disease
by the graft itself or the associated albumin transfusions
and, on a wider extent, by nonneural tissue.
Crkange A, Gray F, Cesaro P, Adle-Biassette H,
Duvoux C, Cherqui D, Bell J, Parchi P, Gambetti P,
Degos J-D. Creuttfeldt-Jakob disease after liver
transplantation. Ann Neurol 1995;38:269-272
Since the first report of a corneal transplant transmission of Creutzfeldt-Jakob disease CCJD), the threat of
iatrogenic transmission of CJD has been emphasized
repeatedly. Neurosurgery, stereotaxic electroencephalography (EEG), corneal transplantation, dura mater
implantation, tympanic membrane grafting, and in jection of growth hormone or gonadotropin hormone extracted from cadaveric pituitary glands have been described as possible roures for prion transmission [ 1-31.
More recently, blood transfusions also have been suspected [4].We report a case of CJD occurring 2 years
after a liver transplantation (LT),raising the possibility
of a new route for iatrogenic CJD.
From rhe "Departement de Neurosciences and the t u n i t 6 de Transplantation Hepatique, Centre Hospitalier Universitaire Henri
Mondor, CrCreil, France; the fNeuropathology Laboratory, Western
General Hospital, The University of Edinburgh, United Kingdom;
and the §Division of Neuropathology, Institute of Pathology, Case
Western Reserve University. Cleveland, OH.
Received Jan 12. 1995, and in revised form Mar 23. Accepted for
publication Mar 24, 1995.
Address correspondence to D r Creange. Service de Neurologie,
Centre Hospitalier Universitaire Henri Mondor, 94010 Cr6teil
Cedex, France.
Copyright 0 1995 by the American Neurological Association
269
Patient History
A 57-year-old woman was referred for a 1-month history of
gait disturbances. She had a history of sclerosing cholangitis
and ulcerative colitis complica.ted by a cholangiocarcinoma
that required LT in November 1991. During and in the days
following grafting, 6.3 liters of blood, 7.5 liters of plasma,
660 gm of albumin, and 3 7 3 gm of anticytomegalovirus
(CMV) immunoglobulins were transfused. Histological examination of the transplanted liver at the time of transplantation showed mild centrolobular fatty change and hepatocellular necrosis. After transplantation, the patient was treated
with cyclosporine. The liver donor was a 42-year-old man
with a history of alcoholism with abstinence for 4 years and
no history of neurological disease. His family history was not
known. H e had died from rupture of a cerebral aneurysm.
Autopsy was not performed. He was CMV positive. His
heart was transplanted but the recipient died 18 days after
the operation. His right kidney was transplanted and then
removed 2 months later. The kidney recipient is still in good
health. No blood donor was known to have CJD. However,
one albumin donor had died 3 years later from a rapidly
progressive dementia with myoclonus, extrapyramidal signs,
and periodic short-wave complexes on EEG. Only 0.17% of
220 gm of albumin injected was potentially contaminated
with respect to the techniques of production of blood products from thousands of units of plasma.
In November 1993, the patient presented with dizziness
and gait disturbance: Clinical examination showed a static
cerebellar syndrome, distal postural tremor of the upper
limbs with few irregular myoclonic jerks, horizontal diplopia,
and nystagmus with left gaze. Laboratory test results were
unremarkable except for raised gamma-glutamyltransferase
levels (243 unitdliter; normal -<65).Cerebrospinal fluid contained 2 white blood cells/mm3 and 78 mg/dl of protein.
Anti-hepatitis C virus antibodies were undetectable using a
second-generation assay. Extractable nuclear antigens were
negative. Computed tomography scans and cerebral magnetic
resonance images appeared normal. Cyclosporine treatment
was continued. H e r condition worsened rapidly. Ten weeks
later, the patient was mute and confined to bed, with diffuse
myoclonic jerks exaggerated by touch, bilateral extrapyramidal rigidity, and severe static and kinetic cerebellar symptoms. The first EEG showed a nonreactive rhythm at 7 to 8
Hz. Subsequent EEGs showed temporal and frontal delta
waves. The patient died on March 24, 1994, 5 months after
onset of the neurological signs.
Pathological Findings
Postmortem examination was performed 12 hours
after death and was limited to the brain, liver, and
spleen. Gross examination of the brain showed only
cerebellar atrophy involving predominantly the vermis.
Microscopic examination showed characteristic spongiosis and gliosis of the gray matter. It was diffuse but
mild in the cerebral cortex except in the subiculum
where there was severe spongiosis. Ammon’s horn was
spared. Spongiosis and reactive gliosis were more
marked in the caudate nuclei, thalamus, and substantia
nigra. The most severe changes involved the cerebel-
270 Annals of Neurology
Vol 38 N o 2
August 1995
lum, which showed marked granule atrophy with reactive astrocytosis. The molecular layer also showed
spongiosis and gliosis.
Immunocytochemistry for the proteinase Kresistant isoform of prion protein (PrP), PrP”’, was performed according to Hayward and colleagues [ 5 } . It
showed intense positivity in areas of confluent spongiosis in the subiculum. In the cerebellum, there were
a number of parenchymal deposits forming “plaques”
in the granule layer, in the molecular layer, and between Purkinje cells (Fig 1). Immunoblot analysis was
performed as previously described [b}. PrPS‘ was more
abundant in the cerebellum than in the frontal cortex;
no PrPS‘ could be detected in the liver or in the spleen
(Fig 2). For molecular genetic study, genomic D N A
was purified from peripheral blood leukocytes. The
PrP coding region was screened for sequence variations using polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE). Oligonucleotide primers and conditions were as previously
described [7]. D N A analysis using PCR and DGGE
revealed a valine homozygosity at codon 129 of the
PrP gene in blood. None of the known pathogenic
mutation was detected in the PrP gene coding sequence, even in the D N A extracted from the grafted
liver. Methionine homotygosity at codon 129 of the
PrP gene was found in the donor’s liver.
Discussion
The occurrence of a pathologically and biochemically
proved CJD, 2 years after a LT, raises the question of
the role of the graft in the development of CJD. The
hypothesis that immunosuppressive therapy may have
Fig 1 . lmmunostaining of the proteilzase K-resistant isoform of
p i o n protein ( P P ) in the cerebellar cortex s h w i n g abundant
PrP” deposits forming “kuru-type”plaques (arrowheads) or
multicentric plaques (arrows) in the granule layer. Most granule cells have disappeared and there is a marked Purkinje cell
loss with proljferation of Bergmann glia. (PrP” antibody: 1A8,
Dr Hope, Edinburgh Neuropathogenesis U n i t ) . ( x 100 before
19% reduction.)
Fig 2. Western blot analysis of brain samples before (lanes 1 , 3.
and and after proteinase K digestion (lanes 2. 4. 6 , and 7 ) .
Lanes 1 and 2: frontal cortex fmm a normal age-matched hum a n brain; lanes 3 and 4: frontal cortex from the patient; lanes
5 and 6: cerebellum from the patient; lane 7:frontal cortex from
the patient loaded fiiie times more than in lane 4 (lanes 1-6 =
loading equizfalentt o 0.3 mg of wet tissue; lane 7 = loading
equicalent of 1.5 mg of wet tissue). The amount of the proteinase K (PIC)-resistant iJ-oform of prion protein is much higher in
the cerebellum than in the frontal cortex in this patient even
when the sample from the cerebral cortex is ozierloaded five times
(lane 7).
favored the onset of CJD is very unlikely as, to our
knowledge, prion diseases have never been documented in immunocompromised patients.
A random association of two very rare conditions
remains the most likely possibility. Indeed, the patient
was at the peak of onset of sporadic CJD, and clinical,
neuropathological, and genetic features observed in the
patient may be found in spontaneous CJD [8, 93.
However some features suggest the possibility of a
graft-transmitted CJD. Unlike sporadic CJD and iatrogenic central inoculation with electrodes, instruments,
or transplants in which mental deterioration usually
represents the initial symptom, peripheral iatrogenic
transmission, as kuru, presents mainly with cerebellar
ataxia 121. Neuropathology and Western blot analysis
confirmed the clinical features with predominant
involvement of the cerebellum and basal ganglia and
“kuru-type” plaques, which also have been described
in patients with iatrogenic CJD following growth hormone injection [lo]. V a h e homozygosity at codon
129 of the PrP gene, although nonpathognomonic, is
overrepresented in patients with peripheral iatrogenic
infection compared to sporadic CJD [8, 111. Methionine homozygosity, as found in the donor genotype, is
also the most prevalent genotype in sporadic CJD [ 111.
Incubation periods after cerebral prion inoculation last
several months (16-120 months), compared to years
after peripheral inoculation (4-30 years) [2]. However, in this patient, the shorter incubation period (2
years) may reflect the differences in infectivity and
greater transmissibility 181 of a hepatic graft. Indeed
organ transplantation is a unique route of transmission
that might cause a persistent exposure of the host, very
different from repeated injections of small amounts of
pituitary hormones. Iatrogenic human CJD has never
been unequivocally related to inoculation of tissue
other than nervous tissue or tissue in contact with nervous tissue (dura mater, pituitary extracts, or cornea).
PrPSChas never been detected in liver. However, liver,
lung, kidney, spleen, lymph node, cerebrospinal fluid,
and central nervous system tissue of patients with subacute spongiform encephalopathy (SSE) have transmitted disease to primates through intracerebral, intrathecal, and subcutaneous routes 181. Thus, grafted liver
has an infective potential despite the absence of demonstrable PrPSC.
The possible issue of administration of potentially
contaminated albumin during surgery and in the following days needs to be discussed. The very small
amount of potentially infected albumin administered
does not seem consistent with the short incubation period in our patient t2). However, growth hormonerelated CJD results from very small amounts of contaminated hormone. It is noteworthy that similar
techniques are used in the production of human blood
products and human growth hormone. The growth
hormone was purified from thousands of pituitaries
and thousands of units of plasma are processed to produce purified blood fractions. Transmission of CJD by
blood transfusion in humans is thus far only speculative
[4]. However, transmission to animals from human
blood has been reported in exceptional cases [ 12-14]
and blood has been shown to be infectious during the
incubation period and clinical phase of SSE in experimental animals [IS, 161.
Although no definitive criteria other than PrP gene
mutation differentiates iatrogenic CJD from sporadic
CJD, some of the clinical, neuropathological, and genetic data are compatible with iatrogenic CJD. Considering that CJD in this patient might have been secondary to liver transplantation including albumin infusion,
particular attention should be paid to the prevalence
of CJD among organ transplant recipients in order to
assess the risk of prion disease transmission through
this procedure.
The authors wish to thank Drs J. L. Laplanche and P. Beaudry for
molecular genetic data and helpful discussion, and Drs P. Bierling
and J . Tanzer (Agence Francaise du Sang) for blood transfusion data.
Supported by a concerted action of the EU
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