J Med Sci Hia et al.

, Correlation between overt hyperthyroid and subclinical hyperthyroid

Volume 44, No. 1, March 2012: 57 - 64
and cognitive impairment in Dr. Sardjito General Hospital, Yogyakarta, Indonesia

Correlation between overt hyperthyroid

and subclinical hyperthyroid and cognitive
impairment in Dr. Sardjito General
Hospital, Yogyakarta, Indonesia
Berkat Hia1* , Pernodjo Dahlan2, Abdul Ghofir 2
1
District Hospital of Gunung Sitoli, Nias, North Sumatra, 2 Department of Neurology,
Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta,
Indonesia

ABSTRACT
Hyperthyroidism is a metabolic imbalance resulting from excessive production of thyroid hormones.
Overt or subclinical hyperthyroid prevalence has reached 20%. The differences in thyroid status
induce apoptosis in adult cerebral cortex. Triiodothyroxine (T3 ) acts directly on the cerebral
cortex mitochondria and induces the release of cytochrome-c which leads to apoptosis. The
increase of hormone levels encountered in hyperthyroidism which is associated with an increase
in necrotic death of neurons and oxidative stress has a negative effect on cognition. Several
studies demonstrated the significant association of hyperthyroidism with cognitive impairment,
despite remaining as controversial results. The study aimed to evaluate the correlation between
overt hyperthyroid and subclinical hyperthyroid and cognitive impairment in hyperthyroidism
patients. This was a cross-sectional study involving 68 patients of hyperthyroidism who were
treated in Endocrine Clinic of Dr. Sardjito General Hospital, Yogyakarta. The inclusion criteria
were hyperthyroidism based on anamnesis, clinical examination and laboratory tests, age of 20-
60 years, symptoms of hyperthyroidism, and minimum education of elementary school. The
relationship of hyperthyroidism and cognitive impairment, and multivariate analysis was analyzed
by Chi-square and logistic regression tests, respectively. The results were considered as statistically
significant if the value of p was <0.05. The results showed that overt hyperthyroidism had
significantly associated with cognitive impairment (p = 0.021). Another variable associated
with cognitive impairment was female gender (p = 0.019). In a multivariate analysis, the variables
of overt hyperthyroidism (p = 0.024) and sex (p = 0.025) had independent association with
cognitive impairment. In conclusion, this study found that overt hyperthyroidism had a significant
association with incidence of cognitive impairment compared to subclinical hyperthyroidism.

ABSTRAK
Hipertiroid adalah suatu gangguan akibat kelebihan produksi hormon tiroid. Prevalensi hipertiroid
jenis subklinik atau klinik (overt) mencapai 20%. Perbedaan pada status tiroid akan mengakibatkan
apoptosis pada korteks cerebri dewasa. Triodotiroksin (T3) berperan secara langsung pada
mitrokondria korteks cerebri dan menginduksi pelepasan sitokrom-c untuk proses apoptosis.
Peningkatan kadar hormon tiroid pada hipertiroid yang berhubungan dengan peningkatan kematian
sel saraf (neuron) dan peningkatan stres oksidatif mempunyai efek negatif pada kognitif. Beberapa
penelitian telah menunjukkan hubungan bermakna antara hipertiroid dengan gangguan kognitif,
meskipun masih diperdebatkan. Penelitian ini bertujuan untuk mengkaji hubungan antara hipertiroid
dan hipertiroid subklinik dengan gangguan kognitif pada pasien hipertiroid. Rancangan penelitian
ini adalah potong lintang yang melibatkan 68 pasien hipertiroid yang berobat di Klinik Endokrin
RSUP Dr. Sardjito Yogyakarta. Kriteria inklusi adalah hipertiroid berdasarkan anamnesis,
pemeriksaan klinik dan laboratorium, usia antara 20-60 tahun, gejala hipertiroid, dan pendidikan

* corresponding author: [email protected]

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J Med Sci, Volume 44, No. 1, March 2012: 57 - 64

minimal sekolah dasar. Hubungan antara hipertiroid dan gangguan kognitif, dan multivariat
dianalisis dengan test Chi Square dan regresi logistik. Hasil analisis dinyatakan bermakna secara
statistik apabila nilai p<0.05. Hasil penelitian menunjukkan bahwa hipertiroid secara klinik
mempunyai hubungan bermakna dengan gangguan kognitif (p=0,021). Variabel lain yang
mempunyai hubungan dengan gangguan kognitif adalah jenis kelamin perempuan (p=0,019).
Pada analisis multivariat, hipertiroid klinik (p=0,024) dan jenis kelamin (p=0,025) mempunyai
hubungan independen dengan gangguan kognitif. Dari penelitian ini dapat disimpulkan bahwa
hipertiroid klinik mempunyai hubungan bermakna dengan gangguan kognitif dibanding dengan
hipertiroid subklinik.

Keywords: hyperthyroidism - overt - subclinical - cognitive - mini-mental state examination

INTRODUCTION decrease of MMSE (mini-mental state exami-

Hyperthiroidism is a syndrome resulting nation) score. The cognitive impairment resulting
from the increased level of free thyroid from hyperthyroid was 2.26 times higher than
hormones in the body due to the impairment of eutiroid. Hyperthyroid with the higher levels of
some organ systems signified by the increased T 4 is associated with the increased risk of dementia
levels of free thyroxine (fT 4 or T 4 ), free and Alzeimer diseases. It was showed that the
triiodothyronine (fT3 or T 3) and the decrease of higher level of T 4 was associated with large
thyroid stimulating hormone (TSH). 1,2 amount of plaque neuritic (PN) and neuro
Hypertiroidism may be caused by some factors. fibrillary tangle (NFT) in the cortex (girus
Graves’ disease is the most common cause and frontalis media, inferior parietal lobes,
an autoimmune impairment related to the temporal media and occipital cortex). 5 Singh et
antibody. Single or multiple thyroids that al. 6 showed that the thyroid status differences
produce thyroid hormone may also cause induced apoptosis in adult cerebral cortex,
hyperthyroidism. Some studies showed that the where T3 was expected to play a role directly
changes of thyroid function affect brain in the mitochondrial cerebral cortex and induced
metabolism and may cause cognitive impairment the release of sitokrom-C to induce apoptosis.
at different levels of severity, and even In neurogenesis the role of mitochondria is very
dementia. This involves primary neuro- important for brain development.
transmitters of acetylcholine, dopamine,
norepinephrine, serotonin, and aminobutyric MATERIALS AND METHODS
acid. This alteration involves the axis of This cross-sectional study involved 68
pituitary-tiroid hypotalamus resulting in patients of hyperthyroid as the subjects. The
cognitive and affective impairments. 3 subjects were collected from the Endocryne
Subclinical hyperthyroid is more prevalent Outpatient Installation of Dr. Sardjito General
than overt hyperthyroid which is related with Hospital, Yogyakarta from May to September
cognitive impairment. Caresini et al.4 2011. The protocol of the study has been approved
demonstrated that among 1453 patients with by the Medical and Health Research Ethics
thyroid function impairment, about 7.8% of them Committee, Faculty of Medicine, Universitas
were subclinical hyperthyroid and about 2% Gadjah Mada.
were overt hyperthyroid. Both types of The subjects were then collected conse-
hyperthyroid showed statistical significance for cutively from the accessible population of the
cognitive impairment as signified by the hyperthyroid patients with the inclusion criteria

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 Hia et al., Correlation between overt hyperthyroid and subclinical hyperthyroid
and cognitive impairment in Dr. Sardjito General Hospital, Yogyakarta, Indonesia

as follow 1) hyperthyroid patients with level of The independent variables of the study were
TSH < 0,3 mIU/L; 2) age of 20-60 years; 3) age, gender, hyperthyroid type, marital status,
minimum education of elementary school; and 4) history of hyperthyroid medication, occupation,
consent of participation. The exclusion criteria and length of medication. The dependent
were patients with history of 1) hypertension; 2) variable was MMSE category. The association
cerebrovascular disease; 3) capitis trauma; 4) of hyperthyroid category and MMSE was
diabetes; 5) brain infection; 6) hypothyroid; 7) analyzed in two phases: bivariate analysis using
dislipidemia; 8) smoking; 9) heart disease; 10) Chi square test, and multivariate analysis using
malignancy/tumor; 11) parkinson. logistic regression.

Subclinical hyperthyroid
(34)

FIGURE 1. The scheme of the study

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RESULTS Sardjito General Hospital, Yogyakarta. The

Sixty eight hyperthyroid patients consisted characteristics of subjects are presented in
of 34 overt hyperthyroid patients and 34 TABLE 1. There was no significant difference
subclinical hyperthyroid patients participated of subjects’ characteristics between overt
in this study. All subjects were taking the hyperthyroid and subclinical hyperthyroid
medication at the Endocryne Polyclinic of Dr. patients observed in this study (p > 0.05).

TABLE 1. Characteristics of subjects

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 Hia et al., Correlation between overt hyperthyroid and subclinical hyperthyroid
and cognitive impairment in Dr. Sardjito General Hospital, Yogyakarta, Indonesia

To identify the correlation between other 0.933-3.832; p=0.019). The female patients with
variables and MMSE category (cognitive hyperthyroid had the cognitive impairment
impairment) bivariate analysis was performed ration of 1.891 times higher than subclinical
as presented in TABLE 2. Among variables hyperthyroid patients. Other variables such as
evaluated, the female was significantly age, education, marital status, duration of
associated with cognitive impairment in hyperthyroid medication were not associated
hyperthyroid patients (RP= 1.891; 95%CI= with cognitive impairment.

TABLE 2. Bivariate analysis of the association of other variables and MMSE category

NA: not applicable

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J Med Sci, Volume 44, No. 1, March 2012: 57 - 64

The result of the analysis of hyperthyroid It was indicated that the patients with overt
category variable on MMSE category showed hyperthyroid had the ratio of cognitive
statistically significant difference (RP= 1.50; impairment prevalence of 1.50 times higher than
95% CI= 1.046-2.150; p = 0.021) (TABLE 3). the patients of subclinical hyperthyroid.

TABLE 3. Bivariate analysis of the association of hyperthyroid category and MMSE category

Multivariate analysis was performed for the 4). The results of multivariate analysis suggested
sex category variable and overt hyperthyroid that female sex and overt hyperthyroid had
showed that it had significant bivariate independent association with cognitive
association with cognitive impairment (TABLE impairment.

TABLE 4. Multivariate analysis of the association of female sex variable with overt
hyperthyroid and cognitive impairment.

DISCUSSION (25 patients or 36.8%) with the average age of

Among 68 patients of hyperthyroid 41 ± 10.6 years (TABLE 1). The most
involved in this study, the percentage of male prevalence based on the age in this study was
patients was 19.1% (13 patients) and 80.9% comparable also with some other studies. Vogel
(55 patients) for female patients. The percentage et al. 8 reported that the average age of
of patients were comparable with some others subclinical or overt hyperthyroid was 35.2 ±
studies. Vadivelo et al.1 involved 2024 patients 9.8 years, whereas Canaris et al.9 showed that
in their study consisting 22.6% of male patients the most prevalent age of hyperthyroid was 45-
and 77.4% of female patients, whereas Aryal 55 years.
et al. 7 reported that among patients who were Twenty nine subjects were senior high
recruited in their study, 27.7% were male school students (42.6%) while there were 27
patients and 72.3% were female patients. (39.7%) subjects of those with higher education.
It was found in this study that hyperthyroid This finding supported the study of Ceresini et
was the most prevalent at the age of 40-49 year al.4 who showed that the average length of study

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 Hia et al., Correlation between overt hyperthyroid and subclinical hyperthyroid
and cognitive impairment in Dr. Sardjito General Hospital, Yogyakarta, Indonesia

was 11.6±5.36 years for overt hyperthyroid and Braathen et al.14 found that Poly Chlorinated
7.8 ±3.56 years for subclinical hyperthyroid. Biphenyls (PCBs) had effect on five variables
Regarding to the occupation, 20 (29.4%) of thyroid hormones of TT 4 , fT4 , TT3 , fT3 ,
were housewives. This finding was in TT 4:TT3 in women but in men only affected two
accordance with the Indonesian demography as variables of fT4 and fT3. This higher exposure
reported by the National Statistic Bureau (BPS) had resulted in the difference between women
in 2004 that there was 52.7% of married women and men. The difference affects cognitive
in rural and 63.3% in urban areas. 10 Concerning impairment based on gender.14 It has been
the marital status, 63 (92.6%) were married. reported that female production hormone on
This proportion is in line with the National immunology was also affected by the low
Report of Basic Health Research (RIKESDAS) androgen hormone that might protect
in 2010 which suggested that in the productive autoimmune disease in hyperthyroid patients.15
age of 15-49 years in Indonesia, 50.4% were The result of multivariate analysis suggested
married. 11 About the category of length of that the variable of overt hyperthyroid is
hyperthyroid, the number of those who had been associated independently with cognitive
suffering from hyperthyroid of more than 2 years impairment. Hogervorst et al.12 in their study
was 39.7% and those with less than 2 years of found that the risk of cognitive impairment in
hyperthyroid was 60.3%. Meanwhile 89.7% overt hyperthyroid patients were twice higher
had had treatment since the recognition of than those with subclinical hyperthyroid after
hyperthyroid. the follow up of 2 years. Similar finding was
The variable-associated cognitive also reported by Ceresini et al.4 which stated
impairment was hyperthyroid category with the that a negative correlation between hyperthyroid
RP of 1.500 (95%CI = 1.046-2.150; p = 0.021). and cognitive impairment was twice higher than
Meanwhile for female the RP was 1.891 (95% eutiroid. This risk was due to the increased level
CI= 0.933-3.832; p = 0,019). This result showed of thyroid hormone with the effect on neuron
that female patients of hyperthyroid and overt damage and because it destroyed the release of
hyperthyroid had the risk of cognitive acetylcholine. The increase of thyroid hormone
impairment of 1.5 and 1.891 respectively, level will increase oxidative stress that leads
higher than male patients and subclinical to apoptosis that can damage or even cause the
hyperthyroid. Hyperthyroid is characterized by death of neuron.4
high fT 4 and low TSH and can arouse oxidative The cross sectional method with once risk
stress with the negative effect on cognition. 12 factor measurement in this study had made it
Van Osch et al.13 suggested that hyperthyroid difficult to measure natural discourse of the
with low level of TSH results in neuron damage disease. Cohort study is a better method to
could lead to the decreased secretion of TRH identify the causal relationship between risk
or decreased response from pituitary. TSH and factors and the commorbidity.16 In this study,
TRH were analogues with the increased consecutive sampling method was employed,
synthesis of acetylcholine in rats, while the using the minimal number of sample. Another
increased level of hormones found in limitation was that the possible selection might
hyperthyroid was associated with the increase be biased because this study was hospital based
of necrotic neuron death and oxidative stress.13 and based on reference pattern of the patients.

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CONCLUSION 6. Singh R, Upadhyay G, Godbole MM.

Hypothyroidism alters mitochondrial morphology
The study demonstrates that patients with and induces release of apoptogenic proteins during
overt hyperthyroid have more significant rat cerebellar development. J Endocrinol
association with cognitive impairment than with 2003;176:321–9.
patients with subclinical hyperthyroid. 7. Aryal M, Gyawali P, Rajbhandari N, Aryal P,
Pandeya DR. A prevalence of thyroid dysfunction
in Kathmandu University Hospital. Nepal Biomed
ACKNOWLEDGEMENTS Res 2010; 21(4): 411-5.
Authors would like to thank all subjects 8. Vogel A, Elberling TV, Hording M, Dock J,
Waldemar G. Affective symptoms and cognitive
who participated in this study. We also thank functions in the acute phase of Graves’
the Head of Endocryne Polyclinic of Dr. thyrotoxicosis. Psychoneuroendocrinology
Sardjito General Hospital, Yogyakarta who has 2007;32: 36–43.
provided permission and facilities during this 9. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC.
study. The Colorado thyroid disease Prevalence study.
Arch Intern Med 2000;160:526-534.
10. Anonim. Status ibu rumah tangga. Jakarta: Badan
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