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The Journal of Clinical Endocrinology & Metabolism 86(12):5848 –5853
Copyright © 2001 by The Endocrine Society
Food Choice in Hyperthyroidism: Potential Influence of
the Autonomic Nervous System and Brain Serotonin
Precursor Availability
H. PIJL, P. H. E. M. DE MEIJER, J. LANGIUS, C. I. G. M. COENEGRACHT, A. H. M. VAN DEN BERK,
P. K. CHANDIE SHAW, H. BOOM, R. C. SCHOEMAKER, A. F. COHEN, J. BURGGRAAF, AND
A. E. MEINDERS
Department of General Internal Medicine (H.P., P.H.E.M.d.M., P.K.C.S., H.B., A.E.M.), Dietetics (J.L., C.I.G.M.C.), and
Centre for Human Drug Research (A.H.M.v.d.B., R.C.S., A.F.C., J.B.), Leiden University Medical Center, Leiden 2300 RC,
The Netherlands
We explored energy and macronutrient intake in patients
with Graves’ hyperthyroidism. We specifically hypothesized
that hyperthyroidism is associated with increased appetite
for carbohydrates, because of enhanced sympathetic tone and
diminished serotonin mediated neurotransmission in the
brain. To test this hypothesis, we measured food intake by
dietary history and food selected for lunch in the laboratory
in 14 patients with Graves’ hyperthyroidism. Twenty-fourhour catecholamine excretion was used as a measure of activity of the sympathetic nervous system (SNS) and the plasma
[Trp]/[NAA] ratio was measured to estimate (rate limiting)
precursor availability for brain 5-hydroxytryptamine synthesis. All measurements were repeated after the subjects had
been treated to establish euthyroidism. In addition, the effects
of nonselective ␤-adrenoceptor blockade upon these parameters were studied to evaluate the influence of ␤-adrenergic
M
OST MEDICAL textbooks consider a voracious appetite to be one of the clinical features of hyperthyroidism. However, as far as we are aware, food intake has
never been measured in hyperthyroid humans. Moreover,
the mechanism underlying this presumed need for food is
unclear.
Appetite is governed by extremely complex interactions
between neurotransmitter systems in specific brain nuclei
(1). Serotonin (5-hydroxytryptamine, 5-HT) mediated neurotransmission appears to play an important role. Stimulation of postsynaptic 5-HT receptors specifically inhibits
carbohydrate consumption in rats (2, 3). More vigorous stimulation reduces total calorie intake as well. In humans, serotoninergic drugs exert a similar influence upon food intake
(4, 5). Conversely, low 5-HT levels in the brain are associated
with enhanced appetite (3). Brain 5-HT is produced locally
in serotoninergic neurons. 5-HT synthesis is critically dependent on the availability of its precursor amino acid tryptophan (Trp). Because transport of Trp across the blood brain
barrier is competitive with transport of other neutral amino
acids (NAA), e.g. isoleucine, leucine, valine, phenylalanine
and tyrosine, its brain concentration is largely determined by
the plasma ratio of Trp to other NAA (6, 7). A reduced plasma
Abbreviations: AUC, Areas under curve; CV, coefficient of variation;
fT4, free T4; 5-HT, 5-hydroxytryptamine; NAA, neutral amino acids; NE,
norepinephrine; SNS, sympathetic nervous system; Trp, tryptophan.
hyperactivity on food intake. Hyperthyroidism was marked
by increased SNS activity and reduced plasma [Trp]/[NAA]
ratio. Accordingly, energy intake was considerably and significantly increased in hyper vs. euthyroidism, which was
fully attributable to enhanced carbohydrate consumption, as
protein and fat intake were not affected. These results suggest
that hyperthyroidism alters the neurophysiology of food intake regulation. Increased SNS activity and reduced Trp precursor availability for 5-hydroxytryptamine synthesis in the
brain may drive the marked hyperphagia and craving for carbohydrates that appears to characterize hyperthyroid patients. Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food
intake might be mediated by ␣-adrenoceptors. (J Clin Endocrinol Metab 86: 5848 –5853, 2001)
[Trp]/[NAA] ratio hampers transport of Trp into brain tissue
and thereby diminishes 5-HT synthesis in the brain. This
potentially stimulates appetite and energy (carbohydrate)
intake.
One of the other neurotransmitters involved in the complex regulation of food intake is norepinephrine (NE). Injection of NE in the paraventricular nucleus specifically stimulates carbohydrate intake (8, 9) and a spontaneous increase
of brain NE levels precedes carbohydrate consumption in
rats (10).
The activity of the sympathetic component of the autonomic nervous system (SNS) is enhanced in hyperthyroidism
(11). Moreover, the plasma [Trp]/[NAA] ratio appears to be
reduced in experimental hyperthyroidism in rodents. Several mechanisms may underlie this phenomenon. Firstly,
thyroid hormones are proteolytic and promote NAA release
from muscle tissue (12), and secondly, tissue uptake of NAA
is hampered, because their transport across cell membranes
competes with thyroid hormones (13, 14). Finally, hyperthyroidism is associated with insulin resistance (15, 16), which
may contribute to the diminution of the plasma [Trp]/[NAA]
ratio (7, 17, 18).
Both neuroendocrine changes potentially stimulate energy
(carbohydrate) consumption. A reduction of the plasma
[Trp]/[NAA] ratio can diminish brain 5-HT synthesis and
thereby enhance appetite for carbohydrates. Increased sym-
5848
Pijl et al. • Food Choice in Hyperthyroidism
pathetic tone in hyperthyroidism may stimulate carbohydrate intake directly by activation of postsynaptic adrenergic
receptors in the brain.
We hypothesized that food choice in hyperthyroidism is
characterized by high energy intake and a preference for
carbohydrate-rich food items because of increased SNS tone
and reduced precursor availability for brain 5-HT synthesis.
To test this hypothesis, we measured food intake and neuroendocrine parameters in patients with Graves’ hyperthyroidism and compared the results with those of the same
patients in the euthyroid state. We reasoned that this design
allows optimal evaluation of the effects of hyperthyroidism
on neuroendocrine systems and food intake within an individual patient. 24-h catecholamine excretion in urine was
used as a measure of activity of the SNS and the plasma
[Trp]/[NAA] ratio was measured to estimate precursor
availability for brain 5-HT synthesis. In addition, the effects
of nonselective ␤-adrenergic receptor blockade upon these
parameters were studied to evaluate the influence of ␤adrenergic hyperactivity on food intake.
Subjects and Methods
Subjects
Newly diagnosed, untreated hyperthyroid patients (HT) were recruited from the outpatient clinic of the department of Internal Medicine
of Leiden University Medical Center. The diagnosis of Graves’ disease
was established on the basis of clinical, biochemical and immunological
data in all patients. Severe Graves’ opthalmopathy, any serious concomitant disease, the use of medication (except oral contraceptives) or
diet and pregnancy were exclusion criteria. The Ethics Committee of
Leiden University Medical Center approved the study protocol and all
subjects gave written informed consent. The study was conducted according to the principles of the Helsinki declaration.
Study design
Hyperthyroid patients were studied on three occasions in this open
study. The first occasion took place at the time of diagnosis. Subsequently, treatment with propranolol (10 mg orally qid) was initiated. The
second occasion took place after 1 wk of propranolol treatment. Thereafter, the subjects started using thiamazol (Strumazol; 10 mg orally tid)
to completely suppress thyroid function. l-thyroxine (Thyrax; 100 ␮g
starting dose, rising up to 2 ␮g/kg body weight) was added to establish
clinical and biochemical euthyroidism. Propranolol treatment was continued for several weeks until most clinical symptoms had vanished. The
third occasion, which was required to be at least one month after the last
dose of propranolol, took place in a stable euthyroid state, which was
between 3–10 months after treatment initialization.
Study days
After an overnight fast, the subjects were admitted to the clinical
research unit, where they handed in the urine collected over the previous
24 h. Blood samples for determination of plasma glucose, insulin, valine,
isoleucine, leucine, phenylalanine, tyrosine and tryptophan, T3, T4, and
TSH concentrations were collected. Subsequently, the subjects received
a pure carbohydrate solution (75 g of glucose in 200 ml water). Blood
samples for measurement of serum glucose and insulin concentrations
were collected 30, 60, 90, and 120 min after glucose ingestion. Blood
sampling for determination of amino acid levels was repeated at 120 min
after the glucose load. The subjects were not allowed to eat or drink
anything until lunch at 180 min after glucose ingestion. Spontaneous
food choice was determined by offering the subjects a lunch buffet
comprising 29 different food items of known macronutrient content and
weight (19). All items were commercially available and known to the
subjects. The subjects were asked to select their lunch from these items.
During the meal, the subjects were allowed to take additional propor-
J Clin Endocrinol Metab, December 2001, 86(12):5848 –5853 5849
tions of any product. They were instructed to eat to satiety. Remaining
food was weighed and subtracted from the records.
Daily food consumption in free living conditions was determined
using the dietary history with a food frequency list as cross-check (20).
Patients were interviewed by a dietician about their dietary history at
occasion 1 and 3. Macronutrient composition and daily caloric intake
were calculated with the use of food composition tables (21).
Assays
All measurements were performed using standardized routine methodology. Free T4 (fT4) was measured on an IMx [Abbott, Abbott Park,
IL; interassay coefficient of variation (CV), 3.8 –7.1% at different levels].
T3 was measured by RIABEAD of the same company (interassay CVs of
2.0 – 4.4%). TSH was determined with an immunofluorometric assay
(Wallac, Inc., Turku, Finland, interassay CVs: 2.4 –5.9%). Serum insulin
was measured by RIA (Medgenix, Fleurus, Belgium) and glucose was
measured by a fully automated Hitachi system. NE, dopamine, and
vanillylmandelic acid in urine were determined by HPLC.
Blood for amino acid measurements was collected in EDTA containing tubes. Plasma was deproteinized using an equal volume of 5%
(wt/vol) sulfosalicylic acid in water and analyzed for amino acid concentrations by ion-exchange chromatography and ninhydrin derivatization on an LKB 4151 ALPHA PLUS automated amino acid analyzer
(LKB Biochrom, Cambridge, UK) using standard conditions. For tryptophan the sum of albumin-bound and free plasma concentrations was
determined using a standard addition calibration curve. All assays were
performed at the clinical chemistry laboratories of Leiden University
Medical Center.
Calculations and statistics
Insulin resistance was calculated by the HOMA index described by
Matthews et al. (22): IRI ⫽ I/22.5䡠e⫺InG, where IRI ⫽ insulin resistance
index, I ⫽ fasting serum insulin concentration, and G ⫽ fasting serum
glucose concentration. The time-integrated glucose and insulin response
to the breakfast was calculated as AUC.
Paired t tests were used to detect differences within groups. Correlation between variables was established by Pearson’s statistic. All calculations were carried out using SPSS for Windows (SPSS, Inc., Chicago,
IL). Results are reported as mean (⫾sd).
Results
Subjects characteristics
Fifteen patients were included. The data from 1 subject
were not used in the analysis. This patient completed only
the first occasion. Another patient withdrew from the study
before the third occasion. The available data from this subject
were used in the analysis. Thus, the data represent 14 patients
(13F/1M). At inclusion they were 38.9 ⫾ 9.7 (mean ⫾ sd;
range 21–56) yr; body mass index, 23.1 ⫾ 4.4 (16.2–30.0)
kg/m2.
Thyroid hormone concentrations
Thyroid hormone levels are summarized in Table 1. TSH
and fT4 concentrations were frequently lower, respectively
higher than the limit of detection in untreated patients and
propranolol-treated patients. In these cases, the limit of detection for TSH (0.06 mU/liter) or the valid upper range
value for fT4 (77.2 pmol/liter) was used. fT4 concentrations
exceeded the valid upper range value in so many cases for
the untreated (8 cases) and propranolol-treated (10 cases)
patients that statistical analysis on these parameters was not
performed. Propranolol had no major influence on TSH and
fT4 levels but reduced T3 levels by 0.74 nmol/liter. The eu-
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J Clin Endocrinol Metab, December 2001, 86(12):5848 –5853
Pijl et al. • Food Choice in Hyperthyroidism
thyroid state was adequately established by the use of thiamazol and l-thyroxine in all patients.
Effects of propranolol on food intake, hormones, and
metabolites in hyperthyroidism
Food intake, hormones, and metabolites in hyperthyroid vs.
euthyroid patients
Propranolol did not significantly affect food selection at
lunch (Table 2), the plasma glucose or insulin concentrations
in fasting conditions or in response to glucose ingestion (Fig.
2), the plasma [Trp]/[NAA] ratio (Table 3), or urinary catecholamine excretion (Table 4).
Total daily energy intake in free living conditions was
significantly increased in hyperthyroidism, whereas energy
intake for lunch was not affected (Table 2). The increase of
daily energy intake was fully attributable to an increase of
carbohydrate consumption because protein and fat intake
were not affected (Fig. 1). Thus, the percentage of carbohydrate consumption was significantly increased, whereas the
percentage protein intake was significantly reduced and percentage fat intake not affected in hyperthyroid compared
with euthyroid subjects, both in free living conditions and for
lunch (Table 2). The percentage carbohydrate, fat, and protein that was chosen at lunch correlated with dietary history
data in hyper as well as in euthyroid conditions (Pearson’s
r ⫽ 0.46 – 0.87 (except for protein intake in euthyroid conditions: r ⫽ 0.04), data not shown), which underscores the
reliability of our food intake data.
Plasma glucose and insulin levels in fasting conditions and
in response to glucose ingestion were significantly increased
in the hyper vs. the euthyroid state (Fig. 2). Also, IRI was
increased in hyperthroidism (Fig. 3).
The plasma [Trp]/[NAA] ratio was significantly reduced
in hyper vs. euthyroidism (Table 3). The percentage change
of this ratio in response to glucose ingestion was not affected
by hyperthyroidism (Table 3).
Catecholamine excretion in urine was significantly higher
in hyperthyroidism (Table 4).
Discussion
We explored energy and macronutrient intake in patients
with Graves’ hyperthyroidism. Many medical textbooks
(and our clinical impressions) consider hyperphagia to be an
important feature of hyperthyroidism. We specifically hypothesized that hyperthyroidism is associated with increased appetite for carbohydrates because enhanced sympathetic tone and a decreased plasma [Trp]/[NAA] ratio
potentially promote carbohydrate consumption.
The results of our work suggest that hyperthyroidism
profoundly changes the neuroendocrine milieu that governs
food intake. Specifically, the plasma [Trp]/[NAA] ratio was
significantly reduced and SNS activity increased in hyperthyroid vs. euthyroid conditions. These neuroendocrine
changes potentially hamper 5-HT synthesis and activate adrenoceptors in the brain respectively. Accordingly, energy
intake was considerably and significantly higher in the hyperthyroid state, which was fully attributable to an increase
of carbohydrate consumption. Protein and fat intake were
not affected by hyperthyroidism.
Hyperthyroidism was marked by a reduction of the
plasma [Trp]/[NAA] ratio compared with the euthyroid
state, probably because thyroid hormones promote the re-
TABLE 1. Plasma concentrations of thyroid hormones
Untreated
Propranolol
Euthyroid
TSHa
(mU/liter)
T3
(nmol/liter)
fT4b
(pmol/liter)
0.15 ⫾ 0.28
0.17 ⫾ 0.32
1.37 ⫾ 1.91c
5.27 ⫾ 2.22
4.53 ⫾ 2.12d
1.51 ⫾ 0.28e
64.0 ⫾ 19.3
70.1 ⫾ 15.8
21.3 ⫾ 16.5
Normal values: TSH, 0.3– 4.8 mU/liter; T3, 1.1–3.1 nmol/liter; T4,
70 –160 nmol/liter; fT4, 10 –24 pmol/liter). TSHa and fT4b, TSH, and
fT4 concentrations were frequently lower, respectively, higher than
the limit of detection in untreated patients and propranolol-treated
patients. In these cases, the limit of detection for TSH or the valid
upper range value for fT4 was used. Values are mean (SD). c P ⬍ 0.05
vs. untreated; d P ⬍ 0.01 vs. untreated; e P ⬍ 0.001 vs. untreated.
FIG. 1. Daily macronutrient consumption in hyper and euthyroid
patients as determined by dietary history with food frequency list as
cross-check.
TABLE 2. Food selection in free living conditions and at lunch
Lunch choice
Untreated
Propranolol
Euthyroid
Dietary history
Total energy
(KJ)
CHO
(energy %)
Fat
(energy %)
Protein
(energy %)
Total daily
energy (KJ)
CHO
(energy %)
Fat
(energy %)
Protein
(energy %)
3182 (1784)
3326 (1614)
3152 (1352)
49 (10)
51 (8)
44 (9)a
34 (10)
31 (8)
37 (9)
17 (3)
19 (3)
20 (4)a
9367 (3496)
49 (7)
34 (6)
15 (3)
7754 (2420)b
44 (8)b
36 (6)a
17 (4)a
Energy %, Energy percentage of total energy intake; CHO, carbohydrates. Data are mean (SD).
a
P ⬍ 0.05 vs. untreated.
b
P ⬍ 0.01 vs. untreated.
Pijl et al. • Food Choice in Hyperthyroidism
J Clin Endocrinol Metab, December 2001, 86(12):5848 –5853 5851
FIG. 2. AUC and fasting plasma glucose and insulin concentrations in response to a 75-g oral glucose load in
hyper- and euthyroid patients. The
middle bar in each panel represents
values obtained during propranolol
treatment of hyperthyroid patients. *,
P ⬍ 0.05 vs. untreated. †, P ⬍ 0.01 vs.
untreated.
lease of NAA from protein depots (12) and hamper uptake
of NAA by peripheral tissues (13), whereas Trp metabolism
remains relatively unaffected (14). Moreover, hyperthyroidism was associated with insulin resistance, as was consistently demonstrated by the fasting glucose and insulin levels,
the response to glucose ingestion and by the IRI. These findings are in keeping with previous work by other authors (15,
16). Insulin increases the plasma [Trp]/[NAA] ratio because
it promotes uptake of NAA in muscle tissue, whereas Trp
uptake is hampered by its chemical bond to albumin in
plasma (7, 17, 18). This mechanism was sustained by our
observations of the plasma [Trp]/[NAA] ratio in response to
glucose ingestion. Therefore, insulin resistance may reduce
the plasma [Trp]/[NAA] ratio. However, the change of the
plasma [Trp]/[NAA] ratio in response to glucose ingestion
was not different in the hyper vs. the euthyroid state, suggesting that insulin resistance did not significantly affect the
ratio in hyperthyroidism. This probably reflects the fact that
the protein sparing effects of insulin are preserved in the hyperthyroid state, which may serve to counteract the proteolytic effects of thyroid hormones (12). Thus, compensatory hyperinsulinemia presumably mitigates the thyroid
hormone-induced increase of plasma NAA levels in
hyperthyroidism.
Catecholamine excretion in urine was considerably increased in the hyperthyroid state. This finding suggests that
sympathetic tone is enhanced in hyperthyroidism, which is
underscored by spectral analysis of heart rate fluctuations in
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J Clin Endocrinol Metab, December 2001, 86(12):5848 –5853
Pijl et al. • Food Choice in Hyperthyroidism
hyperthyroid patients (11). However, it is in apparent contrast to earlier papers reporting normal or even reduced
sympathetic activity in hyperthyroidism (23–26). Importantly, these reports are generally based on plasma norepinephrine concentrations in single samples of venous forearm
blood (25, 26) or whole body catecholamine turnover rates,
calculated from specific activities of radiolabeled catecholamines in venous plasma (23, 24). It is now known that
catecholamine levels are more appropriately determined in
arterial(ized) blood, inasmuch as extraction from venous circulation occurs across various organs (27, 28). Urinary excretion of catecholamines and their metabolites also appears
to be a reliable tool to estimate their plasma concentration
and whole body turnover (28, 29).
Nonselective ␤-adrenergic receptor blockade did not affect
food intake in hyperthyroid patients. This finding corroborates observations in rats, which show that the ␣-adreno-
FIG. 3. Homeostatic model assessment estimate of insulin resistance
in hyper and euthyroid subjects. The middle bar represents values
obtained during propranolol treatment of hyperthyroid patients.
ceptor antagonist phentolamine, but not propranolol, blocks
NE-induced feeding (30). More recent data indicate that the
stimulatory action of NE on eating is specifically linked to
activation of ␣2-adrenoceptors in the paraventricular nucleus
(31, 32). Thus, the fact that propranolol did not affect food
intake in hyperthyroid patients does not discard the possibility that hyperactivity of adrenoceptors stimulates appetite
for carbohydrates in hyperthyroidism. It seems important to
emphasize that our data do not prove a causal relationship
between enhanced sympathetic tone or reduced brain 5-HT
synthesis and food intake in hyperthyroid patients. Our inferences in this context are based on data from animal experiments (10, 33). In fact, the positive association between
catecholamine excretion in urine and carbohydrate intake
did not attain statistical significance (P ⫽ 0.1) in our study.
It seems important to emphasize that other neuroendocrine systems may affect food intake in hyperthyroidism in
addition to the autonomic nervous system and 5-HT mediated pathways. Complex interactive neural routes in various
brain nuclei orchestrate food intake and macronutrient selection. Numerous neuropeptides and neuramines are involved (1). Several investigators have hypothesized that alterations of leptin secretion might disrupt energy balance in
hyperthyroidism. However, most experiments have refuted
this thesis (34 –37). Interestingly, it was recently reported that
T3 down-regulates expression of the tub gene, encoding the
tubby protein, in the ventral and dorsomedial hypothalamus
in rodents (38). Tubby and tubby-like proteins have been
implicated as transcription factors with potentially broad
biological function (39). Targeted deletion of the tub gene
induces hyperphagia and maturity onset obesity in mice (40).
Thus, although the (neurobehavioral) actions of tubby proteins in humans are not known, it is conceivable that hyperthyroidism modulates energy balance via down-regulation
of tub gene expression in man. The effects of thyroid hormones on other neurotransmitter systems involved in the
regulation of energy balance remain to be established.
TABLE 3. Plasma concentrations of Trp, sum of NAAs, and [Trp]/[NAA] ratio
Fasting
Untreated
Propranolol
Euthyroid
120 min
Trp (␮M)
NAA (␮M)
Ratio
Trp
(% change)
NAA
(% change)
Ratio
(% change)
54.1 (11.8)
59.2 (12.1)
52.7 (9.1)
554 (74)
605 (103)a
490 (75)a
0.098 (0.019)
0.100 (0.026)
0.110 (0.024)a
⫺11.6 (19.0)
⫺19.1 (18.9)
⫺10.2 (14.0)
⫺31.1 (4.5)
⫺35.2 (9.1)
⫺27.5 (8.3)
27.9 (23.8)
26.0 (27.2)
25.1 (23.4)
% change, Percentage change at 120 min after the carbohydrate challenge.
Data are mean (SD).
a
P ⬍ 0.01 vs. untreated.
TABLE 4. Twenty-four-hour urinary catecholamine (normalised for creatinine) and creatinine excretion
Untreated
Propranolol
Euthyroid
Data are mean (SD).
a
P ⬍ 0.05 vs. untreated.
b
P ⬍ 0.001 vs. untreated.
Norepinephrine
(mmol/24 h)
Dopamine
(mmol/24 h)
VMA
(mmol/24 h)
Creatinine
(mmol/24 h)
27.5 (11.1)
30.1 (10.1)
19.5 (9.4)a
0.305 (0.100)
0.314 (0.097)
0.168 (0.095)b
1.70 (0.37)
1.77 (0.40)
1.36 (0.27)b
7.30 (3.01)
7.06 (3.33)
8.60 (4.43)
Pijl et al. • Food Choice in Hyperthyroidism
What picture of the neurophysiology of food intake regulation in hyperthyroidism emerges from our data? It appears that hyperthyroid patients are hyperphagic and specifically crave for carbohydrate rich foods. Increased activity
of the sympathetic nervous system and reduced availability
of Trp for brain 5-HT synthesis may be involved in the
pathogenesis of aberrant eating behavior in these patients.
Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food intake
might be mediated by ␣-adrenoceptors.
J Clin Endocrinol Metab, December 2001, 86(12):5848 –5853 5853
17.
18.
19.
20.
21.
22.
Acknowledgments
Received May 16, 2001. Accepted September 6, 2001.
Address all correspondence and requests for reprints to: Dr. H. Pijl,
M.D., Leiden University Medical Center, Department of Internal Medicine, C1-R39, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail:
[email protected].
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