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Congenitalhypothyroidism.nl
Kempers, M.J.E.
Publication date
2006
Link to publication
Citation for published version (APA):
Kempers, M. J. E. (2006). Congenitalhypothyroidism.nl.
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ABSTRACT T
Objective e
Normalizationn of plasma thyrotropin in T4-supplemented patients with thyroidal congenital hypothyroidismm (CH), requires elevated plasma FT4-concentrations as compared to patients withh acquired thyroidal hypothyroidism. Therefore, bone mineral density (BMD) in patients withh CH was investigated.
Subjects s
Inn 14 adult women with thyroidal CH and 9 age-matched female controls BMD was measured. .
Results s
Theree were no significant differences between patients and controls for femoral neck bone minerall content (38.6 vs. 37.6gram), BMD (0.98 vs. 1.01g/cm2), T-score (0.1 vs. 0.3SD) and Z-scoree (0.1 vs. 0.3SD) and for spine bone mineral content (63.1 vs. 71.9gram). The difference inn spine BMD (0.97 vs. 1.09g/crrr), T-score (-0.7 vs. 0.4SD) and Z-score (-0.5 vs. 0.6SD) was significantt (p=0.025, p=0.023, p=0.021 respectively).
Conclusions s
Althoughh BMD in patients with CH was slightly lower compared to controls, all scores were withinn the reference range. This does not support the hypothesis that the upwards shifted plasmaa FT4-concentrations in patients treated for CH have a deleterious effect on BMD.
INTRODUCTION N
Thyroidd hormone is involved in the process of bone remodelling and has an important role inn the development and maintenance of bone mass. In case of thyroid hormone excess the remodellingg cycle is shortened and an imbalance between bone resorption and formation occurss leading to a net loss of mineralized bone and increased fracture risk (1,2). Studies on bonee mineral density (BMD) in hyperthyroid subjects have shown a decrease in BMD (3). Besides,, also in patients with thyroid cancer who receive suppressive T4 doses, decreased BMDD has been observed (4).
Inn general, in T'4 supplemented patients, the adequacy of treatment is monitored by measuringg the plasma TSH concentration, being considered the most sensitive indicator of thee thyroid hormone state (5). However, when in T4 supplemented patients with thyroidal congenitall hypothyroidism (CH) plasma TSH concentrations are established within the referencee range, plasma FT4 concentrations are substantially higher (mean 21.2 pmol/1) than inn T4 supplemented patients with acquired hypothyroidism (mean 14.8 pmol/1) or in controls (meann 13.9 pmol/1) (6). So, T4 supplemented patients with CH, especially those diagnosed by neonatall screening, experience an upward shift in FT4 concentrations from early childhood on,, compared to patients with acquired hypothyroidism or controls.
Childhoodd is an important phase determining bone quality in later life. During childhood bonee mineralization increases with age, until the peak bone mass is achieved in early adulthood.. BMD in late adulthood is, among others, dependent on the height of the peak bonee mass achieved in early adulthood and the subsequent bone loss.
AA few studies have investigated BMD in CH children (7,8), up to the age of 19 years (9). In thesee studies BMD of CH children was not different from controls. However, information on BMDD in adult patients with CH is lacking.
Thee aim of this study was to investigate BMD in young adult CH patients, who had been treatedd with T4 since the first month of life. Since CH patients are known to have substantial motorr problems, due to thyroid hormone deficiency in the pre- and early postnatal period (10),, this might have negatively influenced their physical activity, which in turn, might have influencedd BMD (11). Therefore, we evaluated the influence of patterns of physical activity onn BMD as well.
PATIENTSS AND METHODS
Patients s
Thee original cohort of patients with CH born in 1981 and 1982 in The Netherlands and detectedd by neonatal screening consists of 90 female and 46 male patients (12). Of this cohort 200 females with severe CH (defined as an initial T4 concentration <30 nmol/I) were invited too participate in the study; of all patients adult height was within 2 SD of the mean of the referencee population; in none of the patients menarcheal age was reported as abnormal. Fourteenn patients with CH were willing to participate. Thirteen patients had thyroid agenesiss and one patient had a total iodide organification defect. The etiological classification wass based on thyroid function determinants and thyroid imaging. All patients received
T44 supplementation from a few weeks after birth onwards (mean age at initiation of T4 supplementationn 21 days, range 16-26 days). The T4 dosage was adjusted in accordance to the Europeann treatment guidelines, i.e. to normalize TSH and accept FT4 in the upper normal rangee (13).
Too compare the measurements with healthy controls, nine healthy age and sex matched subjectss without any known thyroid problem were recruited.
Thee study protocol was approved by our institutional review board. All study subjects gave theirr written informed consent before participation.
Methods s
Alll study participants visited the outpatient clinic of the Emma Children's Hospital AMC once.. During this visit 1) BMD was measured, 2) history of bone fractures in the past and informationn on physical activity, diet, cigarette and alcohol consumption was obtained and 3)) height and weight of the subjects were measured.
BoneBone mineral density assessment
'Thee bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spinee vertebrae (L1-L4), and the left femoral neck were assessed with dual energy X-rayy absorptiometry (DXA) using a Hologic scanner (QDR 4500 W, Hologic, Waltham, MA,, United States of America). Daily phantom scanning during a 1-year period yielded a coefficientt of variation for BMD of 0.42%.
Thee BMD (g/ctrr) was also expressed as T- and Z-scores. The T-score is obtained by comparingg the measured BMD to mean BMD of 20-year-old, sex-matched healthy individuals (peakk BMD) and expressed as standard deviation from this peak BMD. Z-score is obtained byy comparing the measured BMD to mean BMD of age and sex-matched healthy individuals andd expressed as standard deviation from this mean BMD. Osteopenia was defined according thee World Health Organization (WHO) recommendation as a T-score of more than 1.0 SD beloww the mean and osteoporosis as a 'E-score more than 2.5 SD below the mean. Since there aree no Dutch nomograms available, the BMD nomograms as provided by the manufacturer off the DXA scanner were used.
PhysicalPhysical activity questionnaire
Thee questionnaire was adapted from a course of life questionnaire (14). The participants were askedd whether they had joined a sports club during primary school and secondary school andd whether they participated in sports activities at present and if yes, the frequency of the presentt sports activities (in times per month).
MotorMotor skills
Thee CH patients formerly participated in a study on cognitive and motor development. Motor skillss were assessed with the Movement Assessment Battery for Children (MABC) (15,16). Thee test results are expressed in terms of a Total Motor Impairment score (ranging from 0 too 40), a Manual Dexterity score (0-15), a Ball Skills score (0-10) and a Balance score (0-15); higherr scores indicate more motor problems. A Total Motor Impairment score >9.5 indicates motorr problems (which is seen in 15% of the normative population).
Thee results of motor assessments were analyzed in relation to the results of BMD assessments andd whether fractures in the past had been reported.
Statisticall analysis
Dataa are expressed as mean and 95% confidence intervals (95% CI). The Mann-Whitney U test,, Chi-square test and non-parametric binomial test were performed where appropriate. Spearmann correlation coefficient was used for correlation analysis (SPSS 11.5, Chicago IL USA).. A p-value of <0.05 was considered statistically significant.
RESULTS S
Tablee 1 displays characteristics of the CH patients and controls. There was no significant differencee between CH patients and controls in age (22.5 vs. 22.3 years, p=0.186), height (172.33 vs. 174.2 cm, p=0.395) or in body mass index (23.4 vs. 23.0 kg/cm2, p=0.378). The sixx non-participating patients did not differ from the participating group. Especially no differencess were found in attained adult height and weight. None of the patients or controls wass on a special diet. All patients used thyroxine, mean dose 170 ug/day (range 125-212.5 ug/ day).. At the latest measurement before the study their mean FT4 concentration was 1.7 ng/ dLL (22.3 pmol/1), range 1.4-2.2 ng/dL (18.0-27.9 pmol/1) and their mean TSH concentration wass 1.5 mU/1, range 0.5-3.7 mU/1.
Tablee 1. Characteristics of patients and controls
CHH patients Controls p n=144 n=9 Agee (years) Heightt (cm) BMII (kg/cm2) %% participating in sports activitiess during primary school %% participating in sports
activitiess during secondary school %% participating in sports
activitiess at present
Numberr of sports activities at present perr month (range)
%% drinking 2-10 alcoholicbeverages/week* %% smoking cigarettes
%% of subjects with fractures in the past
Age,, height and BMI are expressed as mean, with 95% confidence interval between brackets.
N'umberr of sports activities at present per month is expressed as mean, with the range between brackets. ** none of the subjects used >10 alcoholic beverat^es'week
22.55 (22.2-22.9) 72.3(168.2-176.4) ) 23.4(21.6-25.2) ) 57% % 43% % 43% % 3.88 (0-15) 50% % 57% % 43% % 22.33 (20.7-23.9) 174.22 (168.9-179.4) 23.00 (20.3-25.7) 89% % 67% % 89% % 6.11 (0-12) 89% % 44% % 22% % 0.186 6 0.395 5 0.378 8 0.106 6 0.265 5 0.027 7 0.152 2 0.056 6 0.552 2 0.311 1
Duringg primary and secondary school there was no significant difference in the percentage off patients and controls participating in sports activity (p-0.106 and p=0.265 respectively). Att the time of BMD evaluation, a significantly smaller percentage of CH patients participated inn sports activity compared to controls (p=0.027). CH patients sported less frequent per monthh compared to controls but this difference was not significant (p=0.152). There was noo significant difference between CH patients and controls in alcohol consumption or the percentagee of smokers and non-smokers (p=0.056 and p=0.552). Although CH patients reportedd to have had more fractures in the past than controls (43% vs. 22%) the difference wass not significant (p=0.311).
Bonee mineral assessment of the left femoral neck
Figuree 1A and IB show BMD and T-score of the femoral neck. There were no statistically significantt differences between CH patients and controls for femoral neck BMC (38.6 vs. 37.66 gram, p=0.753), BMD (0.98 vs. 1.01 g/cm2, p=0.361), T-score (0.1 vs. 0.3 SD, p=0.429) andd Z-score (0.1 vs. 0.3 SD, p=0.448) (Table 2). Neither in the CH-group, nor in the control groupp was the T-score or Z-score significantly different compared to the population mean (p=0.821,, p=0.784 respectively).
Inn the patient group 29% had a T-score or Z-score below -1.0 SD, whereas in the norm population,, by definition, 16% has a score below -1.0 SD. None of the controls had a T-score orr Z-score <-1.0 SD. The differences in percentages between patients and controls were nott significant (p=0.078 for both T- and Z-score), neither between patients and the norm populationn (p-0.174 for both T- and score). None of the CH-patients had a T-score or Z-scoree below -2.0 SD.
Bonee mineral assessment of the lumbar spine
Figuree 1A and IB show BMD and T-score of the lumbar spine. In one CH-patient BMC and BMDD of the spine could not accurately be measured (her umbilical piercing could not be removed).. The difference between CH patients (n=13) and controls for spine BMC (63.1 vs. 71.99 gram) was not significant (p=0.116). For spine BMD (0.97 vs. 1.09 g/cm2), T-score (-0.7 vs.. 0.4 SD) and Z-score (-0.5 vs. 0.6 SD) differences between the CH-group and controls weree significant (Table 2, p=0.025, p=0.023, p=0.021 respectively). When compared to the populationn mean, the T-score and Z-score were significantly lower in CH patients (p=0.003, p=0.0177 respectively). Although the percentage of patients with a T-score below -1.0 SD (31%) wass higher than the percentage of controls (0%) or the norm population (16% by definition) thee differences were not significant (p=0.066, p=0.141 respectively). None of the CH patients hadd a T-score or Z-score below -2.0 SD.
Influencee of physical activity and motor skills
Inn the CH-group 4 patients never participated in any sports activities. Although the mean femorall neck T-score and mean femoral neck Z-score of these patients (T-score -0.5 SD, Z-scoree -0.4 SD) were lower than in the patients and controls who did participate in sports activity,, at any time during life (T-score 0.3 SD, Z-score 0.3 SD), the differences were statisticallyy not significant (p=0.193 and p=0.179 respectively). Also the spine T-score and Z-scoree of these 4 patients (T-score -0.2 SD, Z-score 0.0 SD) were not different from patients
Bonee mineral densit) BMDD in femoral neck and lumbar spine
Figuree 1A. BMD of left femoral neck and lumbar spine. Femorall neck is presented as an open square, lumbar spinee is presented as a closed triangle.
CHH Controls T-scoree of femoral neck and lumbar spine
2,5 5 2 2 1,5 5 1 1 0,5 5
o o
0,5 5 -1 1 1,5 5 0 0 D DB B
a aB B
D Dt t
A A A A A At t
A A A A a a D D D DB B
a a D D A At t
A A A A A AÉ É
Figuree IB. T-score of left femoral neck and lumbar spine.
Femorall neck is presented as an open square, lumbar spinee is presented as a closed triangle
CH H Controls s Tablee 2. Results of BMD assessment
Femorall neck total BMC (g) Femorall neck total BMD (g/cm2)
Femorall neck total T-score %% (n) with T-score < -1SD Femorall neck total Z-score %% (n) with Z-score < -1SD
Spinee total BMC (g) Spinee total BMD (g/cm.2) Spinee total T-score %% (n) with T-score < -1SD Spinee total Z-score %% (n) with Z-score < -1SD CHH patients n=14 4 38.66 (31.7 to 45.4) 0.988 (0.90 to 1.06) 0.11 (-0.6 to+0.7) 29%% (4) 0.11 (-0.6 to+0.7) 29%% (4) CHH patients n=13 3 63.11 (59.3 to 66.9) 0.977 (0.93 to 1.02) -0.77 (-1.1 to-0.3) 31%% (4) -0.55 (-0.9 to-0.1) 15%% (2) Controls s n=9 9 37.66 (33.8 to 41.5) 1.011 (0.94 to 1.07) 0.33 (-0.2 to +0.9) 0%% (0) 0.33 (-0.2 to+0.9) 0%% (0) Controls s n=9 9 71.9(62.11 to 81.6) 1.099 (1.00 to 1.19) 0.44 (-0.4 to +1.3 ) 0%% (0) 0.66 (-0.3 to+1.5) 0%% (0) P P 0.753 3 0.361 1 0.429 9 0.078 8 0.448 8 0.078 8 P P 0.116 6 0.025 5 0.023 3 0.066 6 0.021 1 0.217 7 Resultss of BMC, BMD, T-score and
brackets. .
andd controls (T-score -0.2 SD, Z-score -0.1 SD) who did, at any time during life, exhibit sportss activity (p=0.831 and p=0.798 respectively). Neither were BMD, BMC, T-score and Z-scoree of the femoral neck and spine significantly different between the patients and controls whoo participated in sports activity at the time of BMD evaluation (regardless of any sports activityy in the past) and those who did not (all p-values >0.05).
Theree was a weak correlation between the frequency of sports activities per month and thee BMD, T-score and Z-score of the femoral neck (r=0.417, p=0.048; r=0.432, p=0.040 andd r=0.430, p=0.040, respectively). No significant correlations were found between the frequencyy of sports activities and BMD, T-score and Z-score of the lumbar spine (p=0.348, p=0.367,, p=0.351 respectively).
Inn the CH group 8 patients had a Total Motor Impairment score <9.5, indicating normal motorr performance and 6 patients had a Total Motor Impairment score >9.5 indicating poorr motor performance. Femoral neck T-score (-0.4 SD) and lumbar spine T-score (-0.9 SD)) of the patients with poor motor performance were slightly but not significantly lower thann femoral neck (0.2 SD) and lumbar spine (-0.5 SD) T-score of the patients with normal motorr performance (p=0.241 for femoral neck, p=0.099 for lumbar spine). The Total Motor Impairmentt score of patients who had fractures in the past was poorer (10.3) than of patients withoutt any fractures (5.0), the difference was not significant (p-0.154).
DISCUSSION N
Sincee the first patients with CH, diagnosed by neonatal screening programmes, have reached adulthood,, we are starting to learn about the long-term prognosis of early and adequately treatedd CH-patients. Cognitive and motor development of young adult CH patients seems subnormall (17), attributed to (the severity of) hypothyroidism in early life (10) and final height iss reported to be within the normal range (18). When treated according to international guideliness (i.e. to establish TSH within the reference range), patients with thyroidal CH experiencee upwards shifted FT4 concentrations as compared to e.g. T4 supplemented patients withh acquired thyroidal hypothyroidism (6). The aim of this study was to investigate the influencee of long-term T4 supplementation and subtle motor impairments on bone mineral densityy in adult patients with thyroidal congenital hypothyroidism.
Althoughh the studied patient group was relatively small, the group was homogeneous i.e. allall patients had severe thyroidal congenital hypothyroidism at birth and were treated from earlyy life on. To further improve the homogeneity of the small study cohort only females with CHH were selected. Their final height and body mass index were not different from controls. Theirr mean BMD of the left femoral neck was comparable to controls and to the population mean.. Their mean BMD of the lumbar spine was significantly lower compared to controls, althoughh the T-score of most of them was above -1 SD. None of the patients had a score <-2.55 SD, which is considered to indicate osteoporosis. Apparently in our patient group, the lifelongg relatively high FT4 concentrations had no deleterious effect on bone formation or physicall growth.
'Thee effect of (elevated) thyroid hormone concentrations on BMD has been studied in various patientt groups. Studies on BMD in T4 supplemented CH patients have been consistent in
theirr results. In prepubertal children with CH, tested at the age of 8.5 years, no differences weree found between patients and controls (7,8). Similarly, spinal Z-score of CH patients (-0.3SD)) tested at late adolescence (17.8 years) was within the normal range (9). Our results confirmm these findings and show that also at the time the peak bone mass should be achieved inn early adulthood, BMD of CH patients is within the normal range.
Studiess on patients with auto-immune hyperthyroidism and patients receiving TSH-suppressivee T4 doses for goitre or thyroid malignancy have revealed conflicting results. Some studiess have found a reduction in BMD in patients with hyperthyroidism (3,19), whereas otherss did not (20). In patients receiving T4 supplementation in order to suppress TSH concentrationss for goitre or after thyroidectomy because of thyroid malignancy, reduced (4,21)) but also normal (22) BMD has been reported. These data are difficult to extrapolate to thee CH patient group because of the co-existence of auto-immunity or cancer and because elevatedd (F)7"4 concentrations are not present from birth on. Besides, in patients with CH plasmaa T3 concentrations are known to remain within the reference range, despite upwards shiftedd (F)T4 concentrations (6,23), whereas in patients with auto-immune hyperthyroidism T33 concentrations are frequently elevated. Since the effect of thyroid hormone on bone is knownn to be mediated via nuclear T3 receptors the risk of decreased BMD might be confined too those patients in whom T4 treatment or the thyroid disease itself results in elevated plasma (F)T33 concentrations.
Furthermore,, recent studies have shown that also TSH has a direct effect on bone remodelling (24).. A 50% reduction in TSH receptor expression produced profound osteoporosis in mice.. In these mice, unable to respond to TSH, there was a high turnover state in which bonee resorption outpaced bone formation. If indeed, reduced TSH concentrations have a deleteriouss effect on bone mineral density, those patients in whom TSH is suppressed due too auto-immune hyperthyroidism or due to TSH suppressive T4 treatment, are at risk of aa decrease in BMD after long-term treatment. This might imply that in CH patients T4 treatmentt is not harmful for BMD as long as the treatment goal, i.e. establishing plasma TSH concentrationss within the reference range, is achieved.
Sincee physical activity is known to have a positive influence on bone quality, we also tested whetherr BMD was related to the frequency of sports activities. In general, CH patients aree known to have more motor problems such as clumsiness (10) which was probably also reflectedd by a slightly higher occurrence of bone fractures in the past in our patient group. Patientss with fractures in the past had poorer motor scores than patients without any fractures.. Besides, patients with poorer motor skills had lower T-scores for both spine and femorall neck than those with normal motor skills. The motor problems might have reduced theirr level of physical activity, which in turn might have negatively influenced their BMD. We foundd a weak correlation between the femoral neck BMD scores and the number of sports activitiess per month. However, despite a lower percentage of patients participating in sports activitiess during childhood, adolescence and at the time of the study, the femoral neck BMD scoress of CH patients were not different from controls.
Inn congenital hypothyroidism, both the early initiation of T4 treatment as well as maintaining adequatee thyroid hormone concentrations in the long term are important factors determining psychomotorr development and maintaining an adequate physical health. The results of this studyy do not support the hypothesis that the upwards shifted plasma FT4 concentrations inn T4 supplemented CH patients have a deleterious effect on BMD. However, the reduced
physicall activity of C H p a t i e n t s m i g h t have had s o m e negative influence on B M D . In light off o u r findings t h e r e is no r e a s o n to c h a n g e t h e c u r r e n t t r e a t m e n t s t r a t e g y of e s t a b l i s h i n g p l a s m aa T S H w i t h i n t h e reference r a n g e a n d accept the s u b s e q u e n t u p w a r d shift of p l a s m a F'I'4 c o n c e n t r a t i o n s .. However, it still n e e d s to be e s t a b l i s h e d w h e t h e r also after t h e a t t a i n m e n t of t h ee peak b o n e m a s s in early a d u l t h o o d , the s u b s e q u e n t physiological b o n e loss is not different inn C H p a t i e n t s , c o m p a r e d to c o n t r o l s .
Acknowledgements s
W ee are i n d e b t e d t o t h e p a t i e n t s a n d c o n t r o l s w h o p a r t i c i p a t e d in t h i s study.
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