Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls.

CONTEXT: The Dutch T(4)-TSH-TBG-based neonatal screening program detects patients with congenital hypothyroidism (CH) of thyroidal (CH-T) as well as central (CH-C) origin. The numbers and characteristics of true-positive and false-positive referrals will differ from other, predominantly TSH-based, screening methods. OBJECTIVE: The present study describes the characteristics of the referred neonates, both CH patients and false positives, and of the reported CH patients with a false-negative screening result born in the study period. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: For each referred child born between April 1, 2002, and May 31, 2004, screening results and first venous sample results were recorded and classified as transient or permanent CH-T or CH-C or as no CH. RESULTS: In the study period, 430,764 children were screened. Of the 772 children with abnormal screening results, 224 (29%) had CH; another 13 CH patients did not have abnormal screening results, giving an overall CH incidence of 1:1800. Incidences of permanent CH, permanent CH-T, permanent CH-C, and transient CH were 1:2200, 1:2500, 1:21,000, and 1:12,000, respectively. The most frequent explanations for the 548 false-positive referrals (71% of the referred cohort) were severe illness and TBG deficiency (occurring in 198 and 200 children, respectively). CONCLUSIONS: The Dutch incidence figures for CH belong to the highest worldwide, suggesting that the T(4)-TSH-TBG screening program is an efficient method to detect CH of variable etiology and severity. Still, a small percentage of children with CH escaped detection via this screening approach. Severe illness and TBG deficiency appear to be responsible for the majority of false-positive referrals.

Endocrine intervention during irradiation does not prevent damage to the thyroid gland.

Radiation to the head-neck region may damage the thyroid gland, leading to hypothyroidism or thyroid carcinoma. Outcomes of radiation protection by lowering plasma thyroid-stimulating hormone (TSH) have thus far been ambiguous. Our aim was to evaluate the radioprotective effect of inhibiting the thyroid gland's activity during x-radiation. For this purpose, of 80 5-week old Wistar rats, 64 received cervical irradiation with 15 Gy (single dose). During irradiation, endocrine intervention was done, using thyroxine (T(4)), T(4) plus iodine, or iodine alone compared to placebo. During the endocrine interventions and follow-up, TSH and T(4) concentrations were measured periodically. Histologic examination of thyroid, pituitary gland, or the hypothalamus and any suspect lymph nodes, lungs, and liver was performed after 6 and 54 weeks. It was found that during the endocrine intervention, plasma levels of TSH were lower in rats given T(4) and higher in rats given iodine. After 6 and 54 weeks, no significant reduction in hypothyroidism or thyroid carcinoma was found between the different groups of rats given any endocrine intervention or no intervention. In conclusion, the administration of T(4), iodine or the combination during x-irradiation does not protect against radiation-induced thyroid damage.

Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening.

CONTEXT: Long-term follow-up data on cognitive and motor functioning in adult patients with congenital hypothyroidism, diagnosed by neonatal screening, are scarce. Hence, it is still unclear whether the frequently reported cognitive and motor deficits observed during childhood persist in adulthood. OBJECTIVE: The objective of this study was to examine cognitive and motor functioning in young adults with congenital hypothyroidism, born in the first 2 yr after the introduction of the Dutch neonatal screening program. DESIGN/SETTING/PATIENTS: Seventy patients were tested (mean age, 21.5 yr); 49 of them were previously tested at 9.5 yr. The median age at the start of treatment was 28 d (range, 4-293 d). Congenital hypothyroidism was classified as severe, moderate, or mild, according to pretreatment T(4) concentrations. MAIN OUTCOME MEASUREMENT: The main outcome measurement was the influence of the severity of congenital hypothyroidism and age at which T(4) supplementation was started on cognitive and motor outcome. RESULTS: Patients, particularly those with severe congenital hypothyroidism, had significantly higher (i.e. worse) motor scores (total score, 7.8; ball skills, 2.0; balance, 4.1) compared with controls (total score, 3.2; ball skills, 0.7; balance, 1.1), and lower full-scale (95.8), verbal (96.4), and performance (95.6) intelligence quotient (IQ) scores than the normal population. No significant change in IQ from childhood to adulthood was found, and for the majority of patients, motor score classification remained the same. The severity of congenital hypothyroidism, but not the starting day of treatment, was correlated with IQ and motor scores. CONCLUSIONS: It is concluded that the severity of congenital hypothyroidism, but not the timing of treatment initiation, is an important factor determining long-term cognitive and motor outcome. Clearly, detrimental effects on developmental outcome in patients with congenital hypothyroidism persist over time.

The effect of life-long thyroxine treatment and physical activity on bone mineral density in young adult women with congenital hypothyroidism.

OBJECTIVE: Normalization of plasma thyrotropin in T4-supplemented patients with thyroidal congenital hypothyroidism (CH) requires elevated plasma FT4-concentrations compared to patients with acquired thyroidal hypothyroidism. We investigated bone mineral density (BMD) in patients with CH. PATIENTS AND METHODS: BMD was measured in 14 adult women with thyroidal CH and nine age-matched female controls. RESULTS: There were no significant differences between patients and controls for femoral neck bone mineral content (BMC) (38.6 vs 37.6 g), BMD (0.98 vs 1.01 g/cm(2)), T-score (0.1 vs 0.3 SD) and z-score (0.1 vs 0.3 SD) and for spine BMC (63.1 vs 71.9 g). The differences in spine BMD (0.97 vs 1.09 g/cm(2)), T-score (-0.7 vs 0.4 SD) and z-score (-0.5 vs 0.6 SD) were significant (p = 0.025, p = 0.023, and p = 0.021, respectively). CONCLUSIONS: Although BMD in patients with CH was slightly lower compared to controls, all scores were within the reference range. This does not support the hypothesis that the upwards shifted plasma FT4-concentrations in patients treated for CH have a deleterious effect on BMD.

Disseminated medullary thyroid carcinoma despite early thyroid surgery in the multiple endocrine neoplasia-2A syndrome.

A 51/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly elevated, plasma carcinoembryonic antigen (CEA) was normal. Within a year both tumor markers increased and total thyroidectomy was performed. Histologic examination did not show MTC. In the following years, both tumor markers increased progressively but despite the use of multiple imaging techniques no metastases were localized. After 6 years, biopsy of a palpable lymph node showed MTC. The boy was treated with total cervical, suprahyoidal, and mediastinal lymph node dissection, showing MTC in almost all nodes. Again, the tumor markers remained high. At this point in time, the disadvantages of further medical interventions were outweighed against the chance for cure and it was decided to shift the goal of treatment toward palliation rather than cure. At the last visit the boy was clinically well with persistent extremely high levels of plasma CEA and CT. In conclusion, when prophylactic thyroidectomy in the MEN-2A syndrome has failed, it may be best to withdraw from further interventions to prevent more damage.

The effect of cervical X-irradiation on activity index of thyrocytes and plasma TSH: a pre-clinical model for radiation-induced thyroid damage.

Because radiotherapy in the head and neck region is necessary in the treatment of childhood cancer, possibilities to prevent damage to the thyroid gland must be explored. We developed a model in which radiation-induced effects can be investigated in a way that these effects can be quantified, using thyroid dysmorphology and plasma TSH. Thirty-five Wistar rats, 5 weeks old, were X-irradiated on the cervical region, with a single dose varying from 0 to 20 Gy. After 6 weeks, TSH, T4 and T3 were determined, and thyroid glands were processed for histological examination by two independent pathologists. A histological classification scale was developed, using follicular size, colloid density and cell height of thyrocytes to measure hyperplasia and hypertrophy. By the sum of these scores, a cell-activity index was calculated, which was related to plasma TSH concentration. Numbers of PAS-positive droplets and epithelial desquamation were also counted. Inter-observer reliability was assessed. Good to very good reliability was found for scores of follicular size, colloid density and cell height. Significant increase of cell-activity index was found after 10, 15 and 20 Gy. The plasma TSH concentration was positively correlated to the cell-activity index, increasing with radiation-doses up to 15 Gy. The number of desquamated cells was significantly increased after radiation doses >10 Gy, with moderate reliability. In conclusion, this model using cell-activity index of thyrocytes together with plasma thyrotropin concentrations and desquamation of cells can be used for interpretation and future (pre-clinical) studies of prevention of radiation-induced thyroid damage.

Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism.

BACKGROUND: During T(4) supplementation of patients with thyroidal (primary) congenital hypothyroidism (CH) TSH concentrations are frequently elevated despite free T(4) (FT(4)) concentrations being well within the reference range. To examine the thyroid's regulatory system, we analyzed thyroid function determinants in children with congenital and acquired thyroid disorders and in controls. METHODS: Retrospectively, plasma FT(4), TSH, and T(3) concentrations were analyzed in T(4)-supplemented children aged 0.5-20.0 yr with thyroidal CH, central (secondary or tertiary) CH, or autoimmune thyroid disease and in control children with type 1 diabetes mellitus. RESULTS: When TSH was within the reference range (0.4-4.0 mU/liter), mean FT(4) in thyroidal CH [1.65 ng/dl; 95% confidence interval (CI), 1.62-1.67] was significantly higher than in autoimmune thyroid disease (1.15 ng/dl; 95% CI, 1.11-1.19) and diabetes (1.08 ng/dl; 95% CI, 1.06-1.10). In central CH, when TSH was less than or equal to 0.02 mU/liter, mean FT(4) was 1.27 ng/dl (95% CI, 1.24-1.29). When FT(4) was within the reference range (0.78-1.79 ng/dl), 43% of the TSH measurements in thyroidal CH were more than 4.0 mU/liter, compared with 18% in autoimmune thyroid disease and 0% in type 1 diabetes mellitus; in central CH, 95% of TSH measurements were less than 0.4 mU/liter. CONCLUSIONS: In T(4)-supplemented patients with thyroidal CH, when TSH concentrations are established within the reference range, FT(4) concentrations tend to be elevated, and vice versa. Because this phenomenon could not be observed in acquired thyroidal hypothyroidism, we hypothesize that a pre- and/or perinatal hypothyroid state shifts the setpoint of the thyroid's regulatory system. In central CH, when FT(4) concentrations are established within the reference range, the pituitary secretes only minute amounts of TSH. For monitoring T(4) supplementation, reference ranges for FT(4) and TSH should be adapted to the etiology of hypothyroidism.

Frequent adverse events after treatment for childhood-onset differentiated thyroid carcinoma: a single institute experience.

Since the mortality rate for childhood differentiated thyroid carcinoma is nearly zero, the focus must be to minimise morbidity following treatment. Our aim was to analyse early and late adverse events. Twenty-five of 26 children treated between 1962 and 2002 were evaluated. Median follow-up was 14.2 years (range 0.9-39.4 years). All underwent total thyroidectomy, 15 (60%) with lymph node dissection and 15 (60%) with adjuvant radio-iodide therapy. Mortality was zero. Seven developed recurrent disease, two developed a third recurrence. Twenty-one (84%) had > or =1 adverse event. Eight had permanent hypoparathyroidism (PH), six permanent recurrent nerve paralysis (PRNP) and two Horner's syndrome. Risk factors for PH and PRNP were total thyroidectomy with lymph node dissection (RR: 6.45, P = 0.015) and recurrent nerve tumour encasement (RR: 8.00, P = 0.001), respectively. Other adverse events were fatigue (n = 5), scar problems (n = 4) and chronic myeloid leukaemia (n = 1). These results emphasise the need to improve treatment strategies.

Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas.

Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.

Lower neonatal screening thyroxine concentrations in down syndrome newborns.

There is an unexplained higher incidence of congenital hypothyroidism (CH) detected by T(4)-based neonatal screening programs and a very high prevalence of (mild) plasma TSH elevation in young children with Down syndrome (DS). To determine whether newborns with DS have decreased blood T(4) concentrations at the time of the neonatal screening, we conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. CH screening results (T(4), TSH, and T(4)-binding globulin concentrations) were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T(4) concentration of the studied children with DS (n = 284) was significantly decreased. The individual T(4) concentrations were normally (Gaussian) distributed but shifted to lower concentrations. This could not be explained by prematurity, nonthyroidal illness, or iodine exposure. Mean TSH and T(4)-binding globulin concentrations were significantly increased and normal, respectively. The decreased T(4) concentration, left-shifted normal distribution, and mildly elevated TSH concentrations point to a mild hypothyroid state in newborns with DS and support the existence of a DS-specific thyroid (regulation) disorder. The question remains whether this contributes to the brain maldevelopment.