Haemochromatosis and dementia
z Case notes
Haemochromatosis and dementia:
cause or contributor?
Bheemraya Hanmanthraya MRCPsych, Andrew Byrne MRCPsych, MMedSc
Haematological conditions, including haemochromatosis, have been reported as
predictors of cognitive decline in their own right. Here, the authors describe a case of
accelerated cognitive decline in a patient newly diagnosed with Alzheimer’s dementia
and the possible effect of haemochromatosis on the patient’s dementia progression.
H
aemochromatosis is a
c o m p l e x
genetic disease
where there is
primar y iron
overload.
Hereditary haemochromatosis is
common, particularly in people of
northern European extraction,
and has an autosomal recessive
mode of inheritance.1 Prevalence
is estimated at 1 in 200 to 1 in 400.2
Early diagnosis of individuals at risk
of the development of haemochromatosis is important, because survival and morbidity are improved.1
The clinical manifestations are the
result of the specific pattern of
organs affected, and most often
seen are weakness and weight loss,
arthralgia, abdominal pain, skin
pigmentation,
hepatomegaly,
hepatic cirrhosis, diabetes mellitus,
arthropathy, cardiac manifestations
and hypogonadism. The most common laboratory abnormalities are
raised percentage saturation of
transferrin and serum ferritin
concentration, increased amounts
of stainable iron in hepatocytes
and an increased hepatic iron
concentration.3
Haemochromatosis rarely presents with CNS manifestations.4,5
However, there have been several
cases reported in recent literature.
One such case report discussed
cognitive decline in association
with haemochromatosis.6 Further
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case reports described patients
developing dementia associated
with haemochromatosis. 7,8 Two
cases have been described where
there has been a presentation of
dementia and ataxia.9 In both cases
the patients died within two years of
the onset of neurological symptoms.
In this case, we describe a
female patient in her 70s with a history of haemochromatosis who was
diagnosed with dementia and who
presented with a very rapid decline
in her cognitive functioning.
Case presentation
A lady in her early 70s who lived at
home with her husband presented
with a one-year histor y of rapid,
non-fluctuating, moderate cognitive impairment. At initial assessment her Addenbrooke’s Cognitive
Examination-Revised (ACE-R)
score was 50 out of 100 with a MiniMental State Examination (MMSE)
score of 15 out of 30.
She had been diagnosed with
hereditary hemochromatosis ten
years prior and received regular
venesection. She had developed
liver cirrhosis two years following
her diagnosis of haemochromatosis.
She was closely monitored by her
haematologist and her haemachromatosis was well controlled. At the
time of our initial assessment, ferritin was normal at 38ug/L.
Haemoglobin was within normal
range, haematocrit was low at
0.334L/L and mean corpuscular
haemoglobin was high at 32.3pg.
Gamma glutamyl transferase was
raised at 101U/L and all other
liver function tests were normal.
Er ythrocyte sedimentation rate
and C-reactive protein were normal. There had been no episodes of
delirium or hepatic encephalopathy. Several years prior to the onset
of cognitive impairment, she developed hypothyroidism, which was satisfactorily treated. There was no
histor y of alcohol-related problems. Of note, she had no family
history of cognitive impairment,
dementia or other significant
relevant medical condition.
It was apparent that neurological signs and symptoms were evident early in the course of her
cognitive decline. She initially displayed more significant receptive
and expressive dysphasia than
would be expected at her stage of
dementia. She had additional
symptoms of visuo-spatial disorientation. At times, she presented with
motor disturbances leading to gait
ataxia and repeated falls. She had
episodes of urinary incontinence
several times per week. Significant
behavioural and psychological
symptoms developed, including
irritability and hostility directed at
her husband and bouts of agitation. She also presented with infrequent auditor y hallucinations
associated with distress but no
visual hallucinations. There were
no parkinsonian symptoms. In
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Case notes z
Haemochromatosis and dementia
terms of functioning, she was initially able to attend to some basic
personal activities of daily living
with supervision and help. Socially,
she had excellent support from
her husband and children.
Given her unresponsiveness to
behavioural and psychological
management of her distressing
behavioural and psychological
symptoms, risperidone 0.5mg at
night was required in the first two
weeks of initial assessment. This
resulted in a significant improvement in her behavioural and psychological symptoms. She was
closely monitored for any adverse
effects of risperidone treatment,
of which there were none.
Risperidone treatment was
subsequently discontinued.
During her assessment, dementia screening investigations, including relevant blood tests (apart
from the above mentioned blood
tests) were within normal limits.
Her CT head scan showed both
atrophic and periventricular
ischaemic changes. Further neuroradiological investigations (eg
MRI, DaTSCAN) were considered
not feasible due to her mental
state. Lewy body dementia was clinically excluded. She was diagnosed
with probable Alzheimer’s dementia (AD) and commenced on
donepezil treatment, which was
titrated up to 10mg daily and was
well tolerated.
It was very evident that the
patient began to quickly decline,
with a marked deterioration in cognitive skills and daily functioning
over the following six months. At
eight months her MMSE score was 8
out of 30. She continued to receive
venesection treatment for her
haemochromatosis. However, she
further declined rapidly without
additional medical comorbidities
and soon required 24-hour elderly
and mentally ill nursing care after
one year from initial presentation.
6
Discussion
There is a need to explore in more
detail the effect of iron deposition
and disorders such as hereditary
haemochromatosis
causing
increased cerebral iron in conditions such as AD. This is especially
important, as hereditar y haemo
chromatosis is relatively common.
Clinical cases such as the one
described above prompt the question of how significant iron deposition is in the progression of
common conditions such as AD. In
the case described, there was an
unusually rapid clinical deterioration with significant neurological
symptoms evident. The overall
presentation and progression was
not entirely typical of AD. So, how
important clinically is abnormal
iron deposition in this presentation and progression?
Though iron deposition has
been obser ved in the brain with
normal ageing, increased iron has
also been shown in many chronic
neurological disorders including
AD, Parkinson’s disease (PD), and
multiple sclerosis.3 It has also been
postulated that hemochromatosis
gene mutations may be risk factors
for, or modulators of AD.8,10
Interesting case reports have
described a combination of cognitive and neurological symptoms
where haemochromatosis has been
present. In one such case report,
two patients were described with
haemochromatosis and a syndrome of ataxia, rigidity, myoclonic
jerks, and dementia.7 Other associated symptoms due to haemochromatosis may include, for example,
diminished libido, decreased hearing, peripheral neuropathy, and
large joint disease.7
However, the link between
brain iron deposition and pathology underlying diseases of the
brain is poorly understood. One
study in particular emphasised
the link between brain iron
Progress in Neurology and Psychiatry May/June 2015
dysregulation and the development of white matter lesions,
which may cause impairment in
cognitive functioning.11 Iron deposition is being examined further
as a contributor y factor in the
pathogenesis of AD. It has been
seen that the iron content in the
brain tends to increase with age, in
particular at the sites of the typical
lesions of AD and PD. 12 One
hypothesis put forward to explain
the link between haemochromatosis and AD and PD suggests that
changes in the genes regulating
iron metabolism act together with
acquired endogenous and environmental (toxins) factors in the
aetiopathogenesis of sporadic
cases of AD and PD.13
Studies have examined the
mechanism by which excessive
iron may cause cognitive decline.
These in vitro studies have demonstrated that excessive iron can lead
to free radical production, which
can promote neurotoxicity.14 In
fact, animal models, pathological
studies, and MRI imaging studies
have linked iron to AD. 15,16
Increased iron deposition has
been found, especially in the hippocampus, in some cases of AD.17
Post-mortem studies have indicated that the brain stores more
iron as it ages and imaging studies
by Bartzokis and others have
shown increased levels of iron in
the hippocampus and basal ganglia of patients with AD, PD and
Huntington’s disease.18 The very
rapid cognitive decline in our case
could be linked with iron deposition. Similarly, the atypical and
prominent neurological signs
could be explained by increased
basal ganglia iron deposits.
We sought to consider whether
haemochromatosis accelerated the
pre-existing cognitive decline in
this case as well as considering
haemochromatosis as a standalone cause for dementia. Other
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Case notes z
Haemochromatosis and dementia
case reports have shown that people
presenting with cognitive decline
who are later diagnosed and treated
for haemachromatosis subsequently
improve in their cognitive functioning.19 This suggests that haemochromatosis itself may cause cognitive
decline. We postulate that in our
described case, haemochromatosis
may have accelerated the patient’s
cognitive decline.
It is clear that when haemo
chromatosis co-exists with cognitive decline, haemochromatosis
should be closely monitored and
adequately treated to minimise the
extent and rapidity of the cognitive
decline. In addition, there is a
need for increased awareness of
the potential link between
haemochromatosis and cognitive
impairment, particularly in primar y care but also in secondar y
care. As symptoms of haemochromatosis can be reversed by phlebotomy, appropriate laborator y
studies should be considered
where haemochromatosis is suspected in any patient with unexplained cognitive impairment,
encephalopathy, and/or gait
ataxia.7 Reflecting on this case, the
authors suggest that haemochromatosis should be considered as
part of the differential diagnosis or
as a possible contributor where
prominent neurological symptoms
accompany rapid, atypical and
unexplained cognitive deterioration as part of a dementia
syndrome.
The case report highlights the
need for further studies exploring
the effect of haemochromatosis on
cognitive decline in dementia.
Declaration of interests
No conflicts of interest were
declared.
Dr Hanmanthraya is an ST5 in Old
Age Psychiatry at Bensham Hospital,
Gateshead and Dr Byrne is a
Consultant Old Age Psychiatrist at St
George’s Park, Morpeth
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