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Congenitalhypothyroidism.nl
Kempers, M.J.E.
Publication date
2006
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Citation for published version (APA):
Kempers, M. J. E. (2006). Congenitalhypothyroidism.nl.
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GENERALL DISCUSSION
Congenitall hypothyroidism (CH) is known to be notorious because of the serious life-long cognitivee and motor deficits seen before the advent of neonatal CH-screeuing programs (1-5).. The ultimate aim of neonatal screening and early treatment of CH patients is to prevent irreversiblee delay in brain development due to thyroid hormone deficiency in early (postnatal) lifee and to guarantee an outcome, indistinguishable from their peer group. This preventive actionn comprises the complete process of detection, confirmative diagnostics, early and adequatee initial and long-term treatment, careful follow-up and continuous evaluation of thee screening procedure. In this context outcome should be interpreted in a wider sense encompassingg cognitive, motor and socio-emotional outcome, as well as physical well-being andd quality of life.
Inn the chapters 2 to 7 various aspects of prevention, outcome and disease-related features of CHH patients were studied. This chapter presents a conclusive overview of the results of the previouss chapters.
Beforee the nationwide introduction of screening on CH in The Netherlands in 1981, the efficacyy of the method was evaluated in a regional trial. Because the method appeared feasible too detect children with CH and additionally, early treatment provided favorable psychomotor outcome,, the decision to introduce the screening nationwide was made. Although a randomizedd controlled clinical trial would have been the method of choice to evaluate the effectt of early screening and postnatal treatment, ethical motives (not withholding this beneficiall early treatment to any child with CH), amongst others, restrained this not only in Thee Netherlands, but in fact all over the world.
Inn recent years knowledge about the effect of thyroid hormone on brain development has increasedd tremendously. It is well-known that any state of prenatal (cerebral) shortage of thyroid hormonee as in endemic iodine deficiency, maternal hypothyroidism or hypothyroxinemia andd presumably also in MCT8 deficiency and thyroid hormone resistance can lead to cerebral damagee (6-10). Since important thyroid hormone dependent steps in brain development take placee from early gestation till several years after birth, both the pre- and postnatal thyroid hormonee state should be taken into account as important factors for outcome of CHH patients. Informationn on the severity and course of the prenatal thyroid hormone state of CH patients iss usually not available. However, there is evidence that CH patients are subject to some degreee of prenatal thyroid hormone deficiency; maternal-fetal transfer of thyroid hormone in thee second half of pregnancy is not sufficient to fill the gap in fetal T4 production completely ass shown by increased TSH and decreased T4 in cord blood measurements of CH patients (11).. Sporadically performed fetal blood sampling in CH patients have shown decreased FT4 andd increased TSH concentrations (12;13) and skeletal maturation, as determined in the first weekss after birth, is significantly reduced (14-16).
Itt should be kept in mind that neonatal screening is only capable of shortening the postnatal phasee of thyroid hormone deficiency. Its potential to establish normal outcome in CH patients (onn condition that the mother was euthyroid during pregnancy) is dependent on one of two options:: 1) the prenatal hypothyroid state has no irreversible consequences for outcome or 2) thee consequences of a prenatal hypothyroid state are reversible with early adequate thyroid hormonee treatment.
Whilee indeed many studies have shown that early postnatal treatment of hypothyroidism wass highly effective in eradicating serious impairments, it gradually became clear that CH patientss were still vulnerable to persistent cognitive and motor sequela. Under the assumption thatt these impairments were related to non-optimal treatment conditions in the early years afterr the introduction of the screening, many countries, including The Netherlands, have changedd the screening procedure and treatment strategy several times, in order to improve outcomee of CH patients (17;18). By now, the majority of children are treated within 14 days afterr birth with initial T4 doses of 10-15 ug/kg body weight. However, there is an ongoing discussionn as to whether it is reasonable to expect that all CH patients, especially those withoutt any residual thyroid hormone production, can escape from any clinically significant brainn damage, just by restoring thyroid hormone state shortly after birth.
Thee aim of our nationwide study entitled "Effect evaluation of the screening on CH in Thee Netherlands" was to investigate whether the improvements in screening strategy had normalizedd development of CH patients, and if not, whether further improvements would bee feasible. In the design of the study two issues were given highest priority. The first was too avoid an inclusion bias, therefore, all patients born within three selected time periods {1981-82,, 1992-93, 2002-04) were recruited nationwide. The second issue was to avoid a bias byy suboptimal treatment at the time of the assessments. Therefore, all patients of whom dataa were analyzed had their assessments under euthyroid conditions. Furthermore, all cohortss were well characterized in terms of etiology and initial disease characteristics. The specificc years of the cohorts were deliberately chosen; 1981-82 because these patients were bornn the first years after the introduction of national screening, moreover, this cohort was testedd previously at the age of 7.5 and 9.5 years and the patients had reached adult age; 1992-933 because initiation of treatment was significantly different from the 1981-82 cohort, and becausee their results at 10.5 years of age could be compared to the results of previous studies inn the 1981-82 cohort; 2002-04 because this cohort reflected current screening practice, and becausee both initiation of treatment was earlier and initial T4 dose higher as compared to thee other cohorts.
Whatt may be expected for intellectual and motor outcome in CH patients,
integratingg the results of the 'Effect evaluation of the Dutch neonatal CH
screening'' study?
Beforee the results of the three cohorts can be integrated, some comments need to be made. In thee study design patients born in the 2002-04 cohort are tested at 1 and 2 years of age. Because thee 2 years results were not yet available when this thesis was written, only the preliminary resultss at 1 year of age can be presented. These results ought to be interpreted cautiously. First,, the recently established Dutch norms of the Bayley Scales of Infant DevelopmentTI att 1 year of age seem to differ substantially from the American norms, at least when used inn premature born children, while the Dutch and American norms at 2 years of age are comparablee (19). Testing of a young child is in many aspects difficult and the predictability of eventuall outcome increases with age. With this in mind the developmental quotients should nott be considered the exact equivalent of the intellectual and motor quotients obtained in thee other cohorts.
Inn Table 1 the results of IQ scores obtained in the 1992-93 and 1981-82 cohorts and the mentall developmental index (MDI) scores of the 2002-04 cohort are presented, for the total groupp and the severity subgroups, of patients with thyroidal CH. Because of the differences inn norm scores for the tests used to assess motor development between the cohorts, these dataa are not presented in a table, but in the text.
Thee effect evaluation of the Dutch neonatal CH screening study showed that:
DeficitsDeficits persist into adulthood
Thee study presented in Chapter 5.1 is the second one worldwide to report on outcome of adult patientss with thyroidal CH. In adult CH patients born in 1981-82, and in whom treatment startedd at a median age of 28 days, IQ and motor performance were significantly lower than in thee norm population, especially in patients with severe CH. IQ scores correlated significantly too those obtained at 9.5 years of age.
Thee other paper, from Norway, also showed persisting cognitive and motor deficits (20). A shortcomingg of this study is that at the time of testing the mean TSH concentration of the patientt group was 12.2 mU/1. This is a potential bias because the suboptimal treatment, at leastt in part of the CH patients, might have affected their cognitive functioning (i.e. attention, speedd of processing etc.) (21;22). Besides, because a subdivision according to severity of CH wass lacking, the effect of severity on outcome in their patient group could not be analyzed.
PatientsPatients suffer most, in terms of intellectual deficits, when CH is severe and treatment is delayed delayed
Patientss with severe thyroidal CH, born in 1992-93, and in whom treatment started at a mean agee of 19 days, had lower IQ scores at the age of 10.5 years (mean IQ score 93.7), than the normm population. In patients with moderate and mild thyroidal CH no significant differences inn IQ scores as compared to the norm population were observed. So, the significant reduction inn timing of treatment (the initial dose did not differ significantly) in patients with severe thyroidall CH from mean 29 (in 1981-82) to 19 days (in 1992-93) did not result in improved intellectuall outcome at the age of 10 years. Patients born in 2002-04 had at the age of 1 year, aa mental developmental index score (MDI 101.2) comparable with the norm population. Also inn patients with severe thyroidal CH whose mean age at start of treatment was 9 days, no deficitss in mental scores (MDI 100.8) could be demonstrated. This might indicate a protective rolee of maternally derived T4 extending up till the first days after birth, at least when mental developmentall index is concerned.
InIn all three cohorts motor scores were worse than in the norm population
Wee have to keep in mind that the tests used to assess motor development in the three cohortss were different. Substantial motor problems were observed in the 1981-82 and 1992-933 cohorts, and even in the 2002-04 cohort, with the earliest treatment and highest initial T44 dose, psychomotor developmental index (PDI) scores were still significantly lower than thee population mean, with no differences between the severity subgroups. Apparently, motor deficitss persisted despite a substantial advancement of initiation of T4 supplementation. Inn none of the three cohorts a correlation could be demonstrated between motor scores or psychomotorr developmental index score and day of initiation of treatment.
Tablee 1. Full scale 1Q score in the 1992-93 and 1981-82 cohort and mental developomental index score in the
2002-044 cohort of patients with thyroidal CH
Cohortt 2 0 0 2 - 0 4 Cohort 1992-93 Cohort 1981-82
1.11 years 10.5 years 21.5 years [1.04.4]] [9.6-11.4] [21.0-22.3] Age e
[range] ]
Severee thyroidal CH n = 3 4 ,, 41 and 35*
Meann age at start of T4 supplementation inn udV.s
Meann initial T4 dose inn pg/kg
Moderatee thyroidal CH n = 3 2 ,, 19 and 16*
Meann age at start of T4 supplementationn in days Meann initial 4 4 dose inn ng/kg
Mildd thyroidal CH n = 5 3 ,, 2 2 and 19*
Meann age at start of T4 supplementation inn days
Meann initial 4 4 dose inn pg/kg
Totall group with thyroidal CH n=119,, 8 2 and 70*
Meann (median) age at start of'T4 supplementationn in days [range] Meann (median) initial 74 dose inn pg/kg [range] 100.8 8 (96.7-104.9) ) 9 9 12.0 0 103.2 2 (98.7-107.7) ) 10 0 11.5 5 100.4 4 (97.1-103.7) ) 13 3 10.5 5 93.7 7 (89.5-97.9) ) 19 9 7.0 0 9 6 . 2 2 (88.9-103.5) ) 19 9 66 6 105.0 0 (99.5-110.4) ) 31 1 5.0 0 91.3 3 (86.3-96.3) ) 27 7 99.1 1 (91.1-107.1) ) 27 7 7.1 1 101.3 3 (95.7-106.9) ) 74 4 101.2 2 (99.1-103.4) ) 11(9) ) [2-34] ] 11.22 (10.4) [5.4-20.1] ] 97.3 3 (94.2-100.4) ) 23(20) ) [2-73] ] 6.55 (6.0) [2.8-12.9] ] 9 5 . 8 8 (92.3-99.2) ) 400 (28) [4-293] ] 5.77 (5.8) [2.5-10.71 1 '' X'umber of patients in the 2002-04, 1992-93, 1982- 82 cohort respectively
Fulll scale 1Q score and mental developmental index score are expressed as mean with V.V', CI between parentheses s
Doo the results of intellectual and motor outcome urge to advance initiation
off treatment?
Forr t h e different b r a i n regions, t h e p e r i o d w h e n t h y r o i d h o r m o n e is essential for t h e i r d e v e l o p m e n tt differs, so deficits may v a r y d e p e n d i n g on t h e t i m i n g , d u r a t i o n a n d severity off h y p o t h y r o i d i s m (23;24). W h e n after b i r t h , in p a r t i c u l a r in p a t i e n t s w i t h severe C H , T4-c o n T4-c e n t r a t i o n ss rapidly d e T4-c l i n e t h i s is u n d o u b t e d l y a d a n g e r o u s T4-c o n d i t i o n w i t h r e s p e T4-c t to t h y r o i dd h o r m o n e d e p e n d e n t b r a i n d e v e l o p m e n t .
O u rr effect evaluation s t u d y s h o w e d t h a t w i t h t h e p r e s e n t s c r e e n i n g p r o c e d u r e a n d t r e a t m e n t s t r a t e g yy m e n t a l d e v e l o p m e n t a l o u t c o m e ( m e a s u r e d with the Bayley Scales of Infant D e v e l o p m e n t !! I-\TL) in 1 year old C H p a t i e n t s b o r n in 2 0 0 2 - 0 4 e q u a l s t h e n o r m p o p u l a t i o n . P s y c h o m o t o rr d e v e l o p m e n t a l o u t c o m e in t h e y o u n g e s t c o h o r t , however, w a s lower t h a n c o n t r o l s .. Remarkably, t h e r e w a s no c o r r e l a t i o n w i t h the s t a r t i n g day o f ' t r e a t m e n t . The lack off an effect of t h e s u b s t a n t i a l a d v a n c e m e n t of t r e a t m e n t suggests t h a t t h e d o m a i n ' m o t o r o u t c o m e '' m u s t be p r e d o m i n a n t l y d e t e r m i n e d by p r e n a t a l factors related to C H . 'This is
supportedd by the observation that healthy children born to healthy mothers with a FT4 beloww the 10th percentile of the reference range at 12 weeks of gestation, had significantly lowerr mental and especially motor function at the age of 2 years than those born to mothers withh a FT4 between the 50th and 90t h percentile (25).
Mostt intriguingly, we found that in the 2002-04 cohort, the psychomotor developmental indexx score was highest in children with central CH at birth, who were presumably exposed too a hyperthyroid environment during gestation because of inadequately treated maternal Graves'' disease (PDI 97.3 in 10 patients with this type of central CH, as compared to PDI 89.1 inn 119 patients with thyroidal CH), [Chapter 5.3].
Certainly,, the 2002-04 cohort was very young at the time of this first effect evaluation, and definitee conclusions about their cognitive and motor capabilities require retesting these childrenn after at least another decade. Nevertheless, especially the mental developmental scoress do justify optimism, since the current screening practice meets its obligation. On thee other hand, no substantial beneficial effect on psychomotor outcome was seen, even afterr shortening the postnatal phase of thyroid hormone deficiency, making it unlikely that advancingg the start of treatment with another few days will be able to improve motor outcome inn later life. This is in view with our hypothesis that motor problems are predominantly determinedd before birth. Taking these (partly preliminary) results together, there is for the momentt no compelling reason to modify the day of heel puncture sampling.
Shouldd the treatment strategy be further optimized?
Inn evaluating treatment adequacy in relation to outcome of CH patients three aspects of treatmentt are most important: 1) the time needed to establish FT4 within the reference range afterr the initiation of treatment, 2) thyroid hormone determinants during follow-up and 3) thyroidd hormone determinants at the time cognitive and motor assessments are being done.
InitialInitial T4 dose
Anyy effect of (initial) T4-supplementation on cerebral development is ultimately mediated byy the intracellular thyroid hormone receptor occupation, via the established plasma FT4 concentration.. In Chapter 4.1 it is shown that after the initiation of T4 supplementation plasmaa T3 concentrations level off when plasma total T4 concentration is around 75-100 nmol/1.. Already after 3 days plasma FT4 reaches the lower limit of the reference range, whereass it takes around 3 to 4 weeks for plasma TSH to reach its reference range. The initial T44 dose in the studied patients varied considerably (4.8 to 11.1 ug/kg per day). Nevertheless, noo solid correlation could be observed between the height of the initial T4-dose and the 50% TSHH reduction time, nor with the time needed to establish a FT4 concentration within the referencee range (26).
Despitee more than 30 years of experience worldwide, the effect of the initial dose on (long-term)) outcome is still unclear. Also recent reports give conflicting results: e.g. a dose of 10-11 ug/kgg per day was considered low and related to worse outcome by Selva et al. (27), whereas a similarr dose of 10-11 ug/kg per day was considered to be high by Bongers et al.; the high dose wass found to be related to above normal outcome at the age of 11-30 months but no clear effectt could be demonstrated at the age of 5.5-7 years (28;29).
Withinn the ranges of initial T4 doses used in the present effect evaluation study, no beneficial effectt was seen of higher versus lower initial T4 doses on outcome.
LongLong term treatment strategy
Ass outlined above thyroid function determinants during follow-up and at the time of cognitive andd motor assessments are important factors evaluating treatment adequacy. However, for severall reasons it is difficult to assess treatment adequacy solely based on intermittently measuredd FT4 and TSH concentrations.
T44 supplementation requires a strict once-a-day administration of T4. Treatment control, byy measuring the plasma TSH and FT4 concentrations, and adjustment of the T4 dose accordingly,, should anticipate on the increasing body weight and the gradually decreasing needd of T4 per kg body weight. In general, with an initial frequency of testing TSH and FT4 twicee a week for neonates, gradually liberalized via monthly to two-monthly testing for infantss and three to four times per year during childhood, to finally once or twice yearly for adolescents,, it is possible to prevent significant under- or overtreatment, as long as treatment compliancee is warranted. Even such a frequent control schedule is unsuitable to disclose andd quantify incidental lack of compliance of the parents, and later on of the patients themselves. .
Ourr data on FT4 and TSH concentrations during follow-up of the patients from the 1981-822 and 1992-93 cohort were not complete, which was mainly due to the fact that it was a retrospectivee study and that patients were treated by many pediatricians all over the country. Onee could speculate that the IQ deficits seen in these two cohorts were related to inadequate longg term treatment. In our study, all CH patients, regardless of severity, were treated with T44 according to criteria of Good Clinical Practice, by pediatricians who followed the Dutch nationall guidelines, published in three editions (1980,1986, 1997). In the 1981-82 and 1992-93 cohortss patients with moderate or mild CH had IQ scores indistinguishable from the normal population,, indicating implicitly that even if patients had experienced phases of insufficient treatment,, these had no consequences for intellectual outcome at adult age, respectively 10 vearss of age. This makes it unlikely that IQ deficits as observed in patients with severe CH hadd something to do with long-term treatment insufficiency.
Ann important issue in evaluating treatment adequacy is that 'euthyroidism' requires an etiologyy specific definition as described in Chapter 4.2. in practice, reference ranges obtained fromm healthy individuals are used to evaluate '14 supplementation adequacy in patients treatedd for a thyroid disease. Chapter 4.2 shows that when TSH was within the reference range,, FT4 concentrations of patients with thyroidal CH, were shifted upwards compared too patients with auto-immune thyroid disease and type I diabetes mellitus; the fact that theyy were normally distributed suggests that the setpomt shift in thyroidal CH is a group phenomenon.. So, under identical treatment conditions, children with thyroidal CH had substantiallyy higher steady state FT4 concentrations than children with acquired thyroidal hvpothvroidismm due to auto-immune thyroid disease. 'Ihe only relevant difference between thesee two groups is the phase of onset of the hypothyroid state (prenatally vs. postnatally). Duringg fetal life the hypothalamus-pituitary-thyroid feedback system seems to operate at aa different setpoint from that in postnatal life because prenatally T4, TBG, TSH and FT4 concentrationss increase with gestational age (3();31). By comparing FT4 and TSH in cord
seraa of newborns from various gestational ages to those of 2 month old children, it has been suggestedd that the negative feedback control of TSH secretion is changing between 26 weeks gestationall age and 2 months of life (32). Apparently, the prenatal onset of hypothyroidism inducedd a state of pituitary hyporesponsiveness to thyroid hormone, lasting at least for the firstt 20 years of life.
Studiess in the rat have shown that dynamic changes in the maturation of TSH release occurred (33),, and that exposure to hypothyroidism in the perinatal period in rats led to permanent alterations,, whereas exposure in the young and adult rats failed to produce permanent alterations.. The alterations observed were persistently enlarged pituitary gland and higher serumm TSH concentrations (34). Different genes involved in pituitary TSH expression (TSH Beta,, Dl, D2 and the 4 main TR subtypes) have a distinct expression pattern during fetal andd neonatal development and react upon changes in thyroid hormone state (35). 'Ihese observationss suggest that alterations in the thyroid hormone state during a critical phase of totall programming might induce permanent changes in the thyroid hormone setpoint for TSHH secretion.
Remarkably,, we did not find a relation between the setpoint shift and severity of CH. 'This mightt indicate that differences between severe and mild CH are less distinct in the prenatal phasee than post natal ly, According to term cord plasma 'Pi-concentrations, the prenatal thyroidd hormone state in fetuses without (functioning) thyroid tissue is comparable to the postnatall thyroid hormone state in neonates with moderate CH. This must be the effect of thee substantial but limited maternal-fetal transfer of'T4 (36).
Ourr study described in Chapter 4.2 does not allow a conclusion as to whether the hyporesponsivenesss to thyroid hormone is restricted to the pituitary or whether also brain andd other target tissues are involved. When treated according to international guidelines [i.e.. to establish 4'SH within the reference range (37)], the relatively high FT4 concentrations neededd to reach a TSH concentration within the reference range might be unfavorable or evenn harmful if other tissues, including the brain, are not hyporesponsive.
Inn Chapter 6 the influence of long-term 44 supplementation on bone mineral density in adult femalee patients with thyroidal CH was investigated. Although bone mineral density in these patientss was slightly lower as compared to controls, all scores were within the reference range.. In addition, adult height and body mass index were not different from the control group.. These observations, and our personal experience that patients are in a normal clinical andd mental condition when TSH is within the reference range, do not support the hypothesis thatt the upwards shifted plasma FT4 concentrations in T4 supplemented patients with congenitall hypothyroidism are harmful for development.
Inn patients with central CH 44 treatment evaluation is even more complex. Plasma 4'SH concentrationss were found to be extremely low when FT4 was within its reference range. F.venn when 4'SH concentrations were <().03 mU/1 FT4 concentrations were significantly lower thann in patients with thyroidal CH, but still higher than in patients with T1DM and AIT'D. Moreover,, with 'FSH concentrations <0.03 mL'/l, we observed that the F"I'4 concentrations off patients with central CH perfectly matched a Gaussian distribution, quite similar with thee one of'healthy children. Obviously, the 4'SH reference range for the healthy population cannott be used as a guideline for treatment adequacy in patients with central CH. The
difficultyy is that by measuring exclusively FT4 and aiming at a FT4 concentration within the (wide)) reference range (10-23 pmol/1), it is hard to tell which FT4 is adequate and the best approachh of the patients' individual setpoint.
Inn patients with thyroidal hypothyroidism measurement of TSH in addition to FT4 gives aa more specified impression what the patient's individual setpoint is, being shifted or not. Still,, measurement of TSH in addition to FT4 in patients with central CH might be helpful iff TSH is still responsive to changes in FT4 concentration. Whenever extremely sensitive TSHH assays become available, it is worthwhile to investigate whether in central CH, TSH still correlatess with FT4 according to a negative feedback system.
Whilee timing of the current screening procedure is considered satisfactory,
whatt about other aspects of the screening procedure?
Thee Dutch screening method distinguishes itself in particular by a unique approach measuring T4,, TSH and TBG. An important concern in every screening program are the numbers of false-positivee and false-negative cases. In chapter 2 we have evaluated the Dutch neonatal CHH screening method, based on data obtained from the 2002-04 cohort; the sensitivity and specificityy of the Dutch screening approach were 95.8% and 99.9%, respectively. There was aa remarkable reduction in the percentage of patients with transient CH when the 2002-04 cohortt (38) was compared to the 1981-82 cohort (39), probably as a result of reduced perinatal usee of iodine in recent years. However, it should be noticed that the evaluation period in the 2002-044 cohort was rather short. Some patients classified as permanent CH in the neonatal period,, might turn out to be transient cases (40).
False-positives False-positives
Whenn T4 is <-1.6 SD, both TSH and TBG are measured. From the T4 (expressed in SD) and thee TBG (in nmol/1) the ratio is calculated, reflecting the free T4 concentration. In patients withh a moderately decreased T4 concentration TBG measurement aims to discriminate thosee patients at risk for hypothyroidism (with a low T4/TBG ratio), in whom referral is warranted,, from those not at risk for hypothyroidism (with a normal T4/TBG ratio). Ideally, thee TBG measurement in the screening procedure prevents referral of children with TBG-deficiency.. Nevertheless, we did encounter children with (total and partial) TBG-deficiency. Partt of these children had extremely low T4 (i.e. <-3.0 SD). Although their referral can be preventedd by awaiting their heel puncture TSH and TBG concentrations, this will also delay referrall in those children at risk of severe hypothyroidism. The remaining group of children hadd moderately decreased T4, in combination with normal TSH but decreased T4/TBG ratio. Theirr referral can be prevented by lowering the T4/TBG ratio cut-off' for referral (from 8.5 too e.g. 6.5). However, lowering the cut-off implies that patients with central CH may not be detectedd by neonatal screening.
Thee other major group, in whom none of the classical types of CH could be diagnosed consisted off severely ill neonates hospitalized in intensive care units at the time of heel puncture sampling.. In the majority of this group referral could have been avoided if only children withh elevated TSH would have been referred, as is done for preterm children. However, such adaptedd referral criteria will hamper timely detection of central CH by screening. Besides, beforee preventing their referral we ought to be certain that their decreased heel puncture '14 concentrationss are not a risk factor for impaired brain development.
Larsonn et al. have shown that a substantial amount of children with very low birth weight orr cardiac disease were missed by neonatal CH screening at 2 to 3 days, which led these authorss to advocate the routine performance of a second screening in the subgroup of neonatess hospitalized on an intensive care unit (41). This implies that if (in future research) T44 supplementation is found to be beneficial in severely ill children, the neonatal screening resultt should not be awaited, because some of these patients might escape detection.
False-negatives False-negatives
Forr the 2002-04 cohort, we are aware of 10 false-negative cases of whom 8 had central CH. Inn 5 of the false-negative cases CH was too mild for detection by screening. The number of false-negativess can be diminished by changing the cut-off criteria, but this also increases thee number of false-positive referrals. An alternative approach would be to measure T4, TSHH and TBG in all heel puncture samples. This costly approach will enable detection of childrenn with normal T4 concentrations and elevated TSH and children with normal T4 concentrationss but low T4/TBG ratio. However, also with this approach, some cases might bee missed, dependent on the cut-off criteria used.
Masss screening programs are almost inevitably confronted with false-negative cases. In a primaryy T4 screening program patients with normal T4 and elevated TSH will be missed, whereass in a primary TSH screening program, especially patients with central CH will be missed.. Considering that the aim of screening is to prevent thyroid hormone dependent risk off brain development the Dutch T4-based approach is in our opinion the best choice.
Incidence Incidence
Overall,, the incidence figures of CH in the screening era (frequently reported to be around 1:3,000)) are higher than in the prescreening era (around 1:6,000), probably due to improved detectionn of milder cases, previously missed because of lack of specific symptoms (42-44). Thee Dutch CH incidence figures we calculated are among the highest worldwide. This demonstratess that the Dutch screening approach is an efficiënt method to detect CH of variablee etiology and severity.
Thee Dutch screening method is, compared to other screening methods which measure only TSHH or T4 and TSH, most suitable to detect children with central CH and those with mild thyroidall CH (38;45;46). Early detection via screening and immediate supplementation of multiplee hormone deficiencies in patients with central CH has a high priority in terms of reducingg morbidity and mortality.
Theree is one report with an exceptionally high incidence of CH (no distinction was made for permanentt or transient CH) in Iran being 1:350 using a combined TSH and T4 screening initially,, which was changed by TSH only in 2003 (47). Whereas it might be that their high incidencee is caused by detection of a large amount of children with normal T4 and high TSH, nott detected by a T4 based approach, other countries with a TSH based screening approach foundd much lower incidence figures (48;49). Therefore, it is more likely that the high incidence inn the Iranian population is related to ethnic differences, high level of consanguinity (38.9% inn their study), or unrecognized false-positives.
Whatt are additional features of the Dutch screening?
Inn chapter 2 it was shown that in the 2002-04 cohort among the 34 children diagnosed withh central CH 13 (38%) had a mother with Graves' disease inadequately treated during pregnane}'.. The incidence of this subtype of central CH was calculated to be at least 1:33,000. Inn chapter 34 we have shown that in 7 of 18 children (39%) with central CH the abnormal CH screeningg result was the first clue to maternal Graves' disease. This illustrates another unique featuree of the Dutch neonatal screening, i.e. to detect previously neglected or inadequately treatedd maternal Graves' disease.
Despitee the rather high incidence of this type of central CH, endocrinology textbooks generallyy do not mention central CH as a consequence of maternal Graves' disease. Especially becausee some of the neonates can become severely hypothyroid (50), it is important to detect thiss type of CH as soon as possible.
Alll women described in Chapter 3.1 were inadequately treated during pregnane}'; in some off them because Graves' disease was diagnosed after or in late pregnancy in others because treatmentt was inadequate throughout pregnancy, despite diagnosis of Graves' disease before or inn earlv pregnane}'. Because in our population of patients with central CH we did notencounter an}'' mother who was adequately treated we postulated that it was the maternal gestational hyperthyroidismm that caused central CH in the child. So, in the children there is a complex situationn of likely but not proven fetal hyperthyroidism which pre- or postnatally evolves to hypothyroidism.. Both conditions may be considered harmful for the developing brain.
Twoo recent publications support the hypothesis that the central hypothyroidism was due too excess thyroid hormone in the fetal period. 'Ihe first one by Anselmo et al., reported on outcomee of children born in families with thyroid hormone resistance, due to a mutation in thee thyroid hormone receptor (TRp1 . 'These authors showed that the maternal
hyperthyroxinemiaa (to which children without a mutation born to mothers with a mutation weree exposed) led to insufficient fetal TSH secretion (51). The other one by Hernandez et al. showedd that D3-knockout mice, who were thyrotoxic in the fetal and early postnatal period, hadd markedly elevated serum T3 concentrations and decreased TSH concentrations. 'The micee were central hypothyroid from the late postnatal period up to adulthood. 'Ihe authors concludedd that central hypothyroidism was probably induced by overexposure to T3 during aa critical period of thyroid regulatory axis development (52).
Alsoo other animal studies have shown that excess thyroid hormone in the perinatal period cann induce permanent alterations in the regulation of thyroid hormone production by thee hypothalamus-pituitary-thyroid axis (53;54). Eayrs et al. have shown that exposure too hyperthyroidism during the first 24 days of life resulted in reduced adult thyroidal and pituitaryy size, while hyperthyroidism induced later did not produce these persistent effects (55).. These observations suggest the existence of a critical period in which the regulatory systemm is programmed.
Inn literature the condition of central CH, related to maternal Graves' disease is supposed too be transient because plasma concentrations of FI'4 and TSH remained within their referencee ranges when T4-supplementation was withdrawn and because the TSH response afterr TRH administration recovered. In the children with this type of central CH, known att our department, T4 supplementation was initiated in nearly all because of persistently and/orr extremely low FT4 concentrations; in 1 child T'4 treatment was not initiated because
off a spontaneous increase of plasma FT4 concentration. In 13 children we evaluated thyroid functionn after withdrawal of T4 supplementation; persistent thyroidal hypothyroidism was observedd in 5 of them. Most intriguingly their thyroid ultrasound showed images suspect off thyroid damage. Neither this complication, nor the transition from central to thyroidal hypothyroidismm in the offspring of mothers with Graves' disease has been described before. Inn search for the pathogenesis of this novel finding we also investigated thyroid function andd structure in children born to mothers with adequately treated Graves' disease during pregnancyy and in children with central congenital hypothyroidism as part of multiple pituitaryy hormone deficiencies. In the first group thyroid function was normal (in the neonatall period as well as at the time of this study), as well as their thyroid ultrasound images. However,, in patients with multiple pituitary hormone deficiencies, in whom adequate T4-supplementationn invariably causes longstanding extremely low TSH concentrations (56), very smalll thyroid volumes were observed. Although our results do not allow exclusion of the role off antibodies as a causal factor, the fact that only children born to mothers with inadequately treatedd Graves' disease were affected, strongly suggests that the maternal hyperthyroid state (whichh distinguishes the inadequately from the adequately treated mothers) and excessive placentall T4 transfer is the major pathologic mechanism. This led us to the hypothesis that insufficientt TSH secretion due to excessively high maternally derived thyroid hormone concentrations,, inhibited physiological thyroid growth and development and resulted in loss off thyroid integrity in terms of thyroid morphology and function.
Fetall thyroid size, as measured by ultrasound, is increasing with gestational age (57). Besides, inn patients with TSH receptor mutations hypoplastic thyroid glands have been observed (58). Inn a rat model Eayrs showed that in rats exposed to neonatal hyperthyroidism adult thyroid andd pituitary size were significantly reduced, and that the relative proportion of pituitary mucoidd cells (both thyrotropic and gonadotropic type) was higher than in controls (55). Ann intriguing diagnostic (and therapeutic) dilemma evolves, observing the ultrasound featuress of substantial thyroid damage, in patients without elevated TSH concentrations. An explanationn is that the thyroid was still able to meet the need for T4. However, especially inn the presence of low or low-normal FT4 concentrations, this might indicate that central hypothyroidismm persisted, and prevented an adequate TSH response. In theory, a TRH-test iss not helpful as a diagnostic tool, because the TSH response might appear normal when thyroidall and central dysfunction co-exist.
Thee observation that some of the patients with normal TSH after T4-withdrawal showed a tendencyy to lower FT4 concentrations, can also be explained by a shift in the pituitary's setpoint forr TSH secretion to slightly lower FT4 concentrations, due to the fetal hyperthyroidism to whichh our patients were exposed. Such a setpoint shift, yet in the opposite direction, is a commonn feature in children with thyroidal CH exposed to fetal or perinatal hypothyroidism (56).. Bakke et al. found that rats exposed to hyperthyroidism in the neonatal period (comparablee with the fetal phase in humans), responded with lower TSH concentrations on ann antithyroid drug challenge at adult age than control rats, which suggests that permanent alterationss in the setpoint for TSH secretion can be induced (59).
Inn recent years the influence of (even subtle) changes in the maternal thyroid hormone state onn the child's brain development has been a subject of major interest. Although attention iss mainly focused towards maternal hypothyroidism or hypothyroxinemia, the other side off the spectrum, i.e. hyperthyroidism or hyperthyroxinemia might be equally important.
Properr detection and early treatment of hypothyroidism of thyroidal as well as central origin iss necessary to minimize the risk of damage to the developing brain, but naturally, primary preventionn is -if possible- the first choice.
Thee fact that many of the mothers and/or fathers involved, were not natively Dutch is troublesomee because apparently even in The Netherlands, with high standards for health care,, women with high risk pregnancies in terms of child health may escape from proper medicall attention.
RECOMMENDATIONSS AND FUTURE PERSPECTIVES
Neonatall screening
Withh the referral criteria as used in the 2002-04 cohort around 350 children are referred eachh year in The Netherlands, of whom 29% are found to have CH. In all referred children thyroidd function determinants are measured in venous blood samples and compared to their referencee ranges. A major issue in pediatric thyroidology is the lack of age-specific reference ranges.. Reference ranges should be obtained, in order to adequately discriminate the true-fromm the false-positives.
Ass yet, neonatal screening has no referral criterion for elevated T4, so neonatal hyperthyroidism andd resistance to thyroid hormone are missed by screening. Among 101 children (from a totall group of 241 with T4>3.0SD) 17 had persistently elevated T4, attributed to abnormal T44 binding and thyroid hormone resistance, but none had neonatal Graves' disease (60). Consideringg the high mortality and morbidity rates in children with hyperthyroidism and becausee we have shown that a substantial part of maternal Graves' disease is not recognized untill after neonatal screening for thyroid dysfunction, its implementation might be beneficial forr both child and mother.
Inn Chapter 3 it is shown that neonatal screening is able to detect a specific type of central CH relatedd to inadequately treated maternal Graves' disease; in fact neonatal screening was the firstt clue to maternal thyroid disease in nearly half of the patients. It is also shown that some patientss have thyroidal CH after T4 supplementation withdrawal characterized by persistent TSHH elevation and disintegrated thyroid glands on ultrasound imaging. So, central CH as welll as persistent thyroidal dysfunction should be considered risk factors of (inadequately treated)) maternal Graves' disease. The incidence, specific diagnostic features and long-termm consequences of this type of central CH and the subsequent thyroid disintegration remainn to be elucidated. It will be challenging to find the optimal treatment strategy for thiss condition, especially because central and thyroidal CH co-exist and as was speculated, maternall gestational hyperthyroidism might have caused a setpoint shift in the TSH secretion [Chapterr 3.2].
AA suppressed TSH in the first days to weeks after birth should increase suspicion that the child'ss thyroid's regulatory system had been overexposed to thyroid hormone. Especially whenn maternal Graves' disease was inadequately treated, follow up of their children should bee extended up to several months after birth. If there is any doubt about the sufficiency of thyroidd function determinants, T4 supplementation should be initiated. Notwithstanding thee capability of neonatal screening to detect these children (and their mothers), we have to keepp in mind that some children might remain undetected especially in case of premature birth,, when the mother is not diagnosed or when she is non-compliant.
Neitherr in our study cohort, nor in literature, this type of CH (both the initial central type ass well as the subsequently disclosed thyroidal type) has been observed in children born to womenn with Graves' disease, adequately treated during pregnancy. Therefore, it is likely that preservingg euthyroidism in these women throughout pregnancy will prevent the occurrence off this type of CH in their children. Therefore, health care professionals involved in the care off pregnant patients with Graves' disease have an important task to preserve euthyroidism.
Thiss implies that the discussion on whether pregnant woman should be screened for hypothyroidismm should be extended to a screening for hyperthyroidism as well. Still, it shouldd be kept in mind that women who escape from medical attention during pregnancy mightt also escape from participation in mass-screening programs.
Treatment t
Too date it is unknown what the most adequate dose and plasma FT4 concentration would bee to ascertain normal brain development. It seems reasonable to maintain our current initiall strategy, in accordance with international guidelines i.e. to start with an initial T4-dosee of 10 |ag/kg per day. This should be followed by frequent evaluation of thyroid function determinantss (every 2 to 3 days, in the first 1 to 2 weeks, gradually liberated to once a month inn the first year), in order to make dose adjustments when necessary. Because TSH is not a reliablee determinant in the first 2-4 weeks of treatment, initially, FT4 is the determinant of choice. .
Randomizedd controlled clinical trials evaluating outcome in relation to the established plasmaa FT4 concentration are necessary to further optimize treatment strategy. This howeverr requires large groups of CH patients with well defined etiologies, as well as long-termm follow-up. An additional problem is that adequacy of treatment is difficult to evaluate inn a prospective trial because, for reasons of Good Clinical Practice, adequate patient care requiress an individualized and not a standardized treatment approach. In terms of research thee variability in approaches hampers the interpretation of data.
Monitoringg adequacy of treatment in patients with hypothyroidism requires etiology based referencee ranges. For the group of patients with thyroidal CH TSH concentrations within thee reference range can only be established when FT4 concentrations are shifted upwards as comparedd to the reference range. At present, no long term adverse effects of the treatment strategyy in thyroidal CH patients to establish TSH within the reference range are known. For patientss with central CH the determinant of choice to monitor treatment adequacy should be FT4,, since TSH concentrations are well below their reference range when T4 supplementation establishess FT4 concentrations within the reference range.
Furtherr research is needed to elucidate the optimal long-term treatment strategy for CH patients.. Furthermore, establishing hypothyroidism at different pre- and postnatal periods in ann animal model and investigating the effect on adult pituitary and thyroid morphology and genee expression, may elucidate which components of the hypothalamus-pituitary-thyroid axiss are involved in the establishment of the (shifted) setpoint.
Thee goal of neonatal screening on CH is to detect patients who benefit from early treatment. Earlyy treatment is of special importance for patients with severe thyroidal CH, who, in thee absence of own thyroid hormone production, are completely dependent on maternally derivedd thyroid hormone.
Forr the specific subgroup of patients born at term with serious illness and low thyroid hormone concentrationn it is as yet unknown whether they might benefit from T4 supplementation. As (partt of) these patients are inevitably detected in a T4-based screening program, it should bee investigated whether this subgroup might benefit from treatment in terms of reducing morbidity. .
Chapterr 2 showed that some patients with mild CH escaped detection by neonatal screening. Patientss with trisomy 21 have a mild type of thyroidal CH (61), which is in the vast majority tooo mild to detect by neonatal screening (38;62). Yet, early started T4 supplementation subtly improvess their early motor development and growth (63). It needs to be established whether alsoo other types of mild CH in non-Down-syndrome children are unfavorable for brain development,, and whether these children might benefit from early T4 supplementation, whichh warrants their detection by screening.
Outcome e
Inn this thesis, Chapter 5, cognitive and motor outcome as investigated in the effect evaluation studyy is presented. This study also investigated outcome at 2 years of age in the 2002-04 cohort,, and various other relevant aspects in all three cohorts such as education, social andd emotional functioning, as well as behavior of young children with CH, and choice of professionn and self-esteem in adult patients. At present, these data are being worked out. This informationn will be important to inform patients and parents of children on short and long-termm outcome and to advice them on the possibilities of e.g. physiotherapy, speech-training, andd other types of adjuvant care.
Althoughh the aim of neonatal screening on CH is to establish normal outcome in CH patients,, no routine evaluation is coupled to the screening procedure to evaluate its effect. Ourr evaluation study of the Dutch screening was done on research basis to investigate the potentialss of neonatal CH screening to establish normal outcome. Large-scaled prevention programss should not be performed without feedback with regard to the results, especially in a timee when Evidence Based Medicine is obligatory for accurate curative and preventive patient care.. So, we plead for routine evaluation of outcome as a result of neonatal screening. Inn particular also for the multi-screening approach starting from January 1, 2007 in The Netherlands,, routine evaluation should investigate whether and to what extent patients benefit fromm neonatal screening, whether outcome of patients in relation to disease characteristics andd treatment strategy at various ages is comparable to the norm population, and whether thee screening procedure or treatment strategy should and could be improved.
Finally... .
Thee efforts concerning screening and early treatment of CH aim at prevention of brain damage duee to thyroid hormone deficiency. Many reports in literature, including those presented in thiss thesis show that in CH both the prenatal and (duration of the) postnatal hypothyroid statee appear to be important factors determining outcome. It should be noted however, thatt impaired brain development might not only be the consequence of (pre- or perinatal) thyroidd hormone deficiency. In recent years it has become clear that a number of genes (such ass TITF1, PAX8 and FOXE1) are expressed in the developing thyroid as well as in selected areass of the (developing) central nervous system (58). In patients harbouring a mutation in anyy of these genes, the phenotype usually involves CH in combination with other features suchh as impaired neurological development resulting in cognitive and motor deficits. In this perspective,, the phenotype of patients with mutations in ITTF1, characterized by CH and choreoathetosis,, is most illustrative (64).
Upp till now, only in a minority of patients with thyroid dysgenesis mutations have been found. Inn Chapter 7 we have shown that a thorough physical examination in a large group of CH patientss revealed the occurrence of specific phenotype abnormalities. Some of the observed abnormalitiess seemed to be restricted to one subtype of CH e.g. oligodontia in patients with dystopicc thyroid remnants. These observations might be helpful in the search for novel genes involvedd in thyroid development and to elucidate the whole spectrum of the CH phenotype, whichh eventually will ensure adequate care and counselling for these patients.
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