Search

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

Background: Long-term consequences of mild subclinical hypothyroidism (SH) in children are still unclear, and the need for levothyroxine (L-T4) supplementation remains controversial. We designed a 2-year, case-control, prospective study of a cohort of children with SH to evaluate the effects of L-T4 therapy on neurocognitive outcome., Methods: Thirty-four children, age 9.1 ± 2.6 years, with long-lasting, idiopathic, and mild SH, and 34 healthy matched controls, were enrolled. Twenty SH children underwent a 2-year L-T4 treatment (group A), whereas 14 refused treatment and were reevaluated after a 2-year-follow-up (group B). IQ and specific cognitive domains were evaluated in all children at study entry and after 2 years of therapy (group A) or observation (group B) in SH individuals., Results: In SH children baseline IQ scores were normal and comparable to controls (full-scale IQ [FSIQ] 100.4 ± 11.3 vs 101.8 ± 14.2, verbal IQ [VIQ] 99.7 ± 13.7 vs 98.3 ± 14.9 and performance IQ [PIQ] 101.2 ± 10.4 vs 105 ± 10.4).In group A, L-T4 treatment was associated with normalization of thyrotropin (6.3 ± 1.0 mIU/L at baseline vs 2.8 ± 1.4 mIU/L at 2 years, P < .001). However, 2-year L-T4 therapy was not associated with a change in IQ scores (FSIQ 104.4 ± 13.8 vs 102.7 ± 11.0; VIQ 101.8 ± 14.9 vs 102.3 ± 11.9; and PIQ 106.5 ± 13.9 vs 102.7 ± 10.7) or in verbal or performance subtest scores. No significant differences were found in IQ scores after 2 years of treatment in group A compared to group B after a 2-year follow-up., Conclusions: Our data suggest neurocognitive function in children is not impaired by persistent, mild, untreated SH and is not significantly modified by 2-year L-T4 supplementation., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Subclinical hypothyroidism is defined as serum levels of TSH above the upper limit of the reference range, in the presence of normal concentrations of total T 4 or free T 4 . This biochemical profile might be an indication of mild hypothyroidism, with a potential increased risk of metabolic abnormalities and cardiovascular disease recorded among adults. Whether subclinical hypothyroidism results in adverse health outcomes among children is a matter of debate and so management of this condition remains challenging. Mild forms of untreated subclinical hypothyroidism do not seem to be associated with impairments in growth, bone health or neurocognitive outcome. However, ongoing scientific investigations have highlighted the presence of subtle proatherogenic abnormalities among children with modest elevations in their TSH levels. Although current findings are insufficient to recommend levothyroxine treatment for all children with mild asymptomatic forms of subclinical hypothyroidism, they highlight the potential need for assessment of cardiovascular risk among children with this condition. Increased understanding of the early metabolic risk factors associated with subclinical hypothyroidism in childhood will help to improve the management of affected individuals.

Objective: To investigate the effect of levothyroxine (L-T4) treatment on early markers of atherosclerotic disease in children with mild idiopathic subclinical hypothyroidism (SH)., Design: Two-year, open, case-control prospective study., Methods: A total of 39 children, aged 9.18±3.56 years, with SH and 39 healthy controls were enrolled in the study. Waist-to-height ratio (WHtR), blood pressure, triglycerides, total cholesterol (total-C), HDL-C, LDL-C, non-HDL-C, triglycerides/HDL-C, atherogenic index (AI), homocysteine (Hcy), asymmetric dimethylarginine (ADMA), flow-mediated dilation (FMD) and intima-media thickness (IMT) were evaluated at baseline and after 2 years of L-T4 treatment in SH children and after 2 years of follow-up in controls., Results: At study entry WHtR was higher in SH subjects compared with controls (0.56±0.08 vs 0.49±0.07, P=0.04) and significantly decreased after 2 years of treatment (0.50±0.06, P<0.0001). Mean HDL-C levels (50.47±11.43 vs 61.06±13.83mg/dL, P=0.002) were lower, while triglycerides/HDL-C (1.63±1.07 vs 1.19±0.69, P=0.05), AI (3.32±0.90 vs 2.78±0.68, P=0.005), and Hcy (9.35±2.61 vs 7.71±1.94μmol/L, P=0.01) were higher in SH subjects compared with controls and improved after 2 years of treatment (HDL-C 56.26±13.76mg/dL, P<0.0001; triglycerides/HDL-C 1.23±0.78, P=0.006; AI 2.82±0.68, P<0.0001; and Hcy 8.25±2.09μmol/L, P=0.06). ADMA concentrations at baseline were higher in SH subjects compared with controls (0.77±0.21 vs 0.60±0.16μmol/L, P=0.001) and decreased after therapy (0.58±0.13μmol/L, P<0.0001). FMD, IMT and other metabolic parameters were not different among SH subjects and controls at baseline and after 2 years., Conclusions: Children with SH may have subtle pro-atherogenic abnormalities. Although L-T4 treatment exerts some beneficial effects, the long-term impact of therapy on metabolic outcomes in SH children still remains unclear., (© 2016 European Society of Endocrinology.)

Aim: To follow-up for 5 years thyroid status evolution in 127 girls with mild (TSH 5-10 mU/l) subclinical hypothyroidism (SH) of different etiologies., Patients: The population was divided into two age-matched groups of 42 and 85 girls with either idiopathic (group A) or Hashimoto's thyroiditis (HT)-related SH (group B). Group B was in turn divided into three subgroups, according to whether SH was either isolated or associated with Turner syndrome (TS) or Down syndrome (DS)., Results: At the end of follow-up the rate of girls who became euthyroid was higher in group A (61.9% vs 10.6%), whereas the rates of patients who remained SH (55.3% vs 26.2%), became overtly hypothyroid (30.6% vs 11.9%) or required levothyroxine (l-T4) therapy (63.5% vs 23.8%) were higher in group B. Among the girls of group B, the risk of remaining SH or developing overt hypothyroidism was higher in the subgroups with TS or DS than in those with isolated HT., Conclusions: Long-term prognosis of mild and idiopathic SH is frequently benign, even though a l-T4 treatment may be needed throughout follow-up in almost a quarter of cases; long-term prognosis is different in the girls with either idiopathic or HT-related SH; and the association with either TS or DS impairs the outcome of HT-related SH., (© 2015 European Society of Endocrinology.)

Context: Subclinical hypothyroidism (SH), defined as increased TSH serum levels and normal serum free T4 concentrations, has been associated with an increased risk of coronary heart disease in adults. Data in children and adolescents are scanty., Objective: The objective of the study was to investigate the clinical and biochemical cardiovascular risk factors in children with mild SH (serum TSH concentrations 4.5-10 mU/L)., Design and Setting: This is a cross-sectional and controlled study conducted at a tertiary referral center on patients with persistent idiopathic long-standing (3.2 ± 0.4 y) mild SH. At study entry patients and controls underwent a clinical and biochemical assessment for cardiovascular risk., Participants: Forty-nine children aged 8.5 ± 0.5 years with SH and 49 controls were enrolled in the study., Main Outcome Measure: Systolic and diastolic blood pressure, body mass index (BMI), waist to height ratio, lipid profile, homocysteine, high-sensitivity serum C-reactive protein, fibrinogen, adiponectin, insulin, and homeostasis model assessment index were measured., Results: Waist to height ratio (P < .0001), atherogenic index (P = .001), triglycerides to high-density lipoprotein-cholesterol ratio (P = .01), and homocysteine levels (P = .002) were significantly higher and high-density lipoprotein-cholesterol significantly lower (P = .003) in SH subjects compared with controls. No significant differences were found in the other clinical and biochemical cardiovascular risk factors analyzed. Multivariate regression model revealed that BMI and thyroid status were the main independent factors affecting dependent variables. Even after an adjustment for BMI, most of the variables still remained significantly associated with mean TSH levels or SH duration., Conclusions: Mild long-lasting untreated idiopathic SH may be associated with subtle proatherogenic abnormalities. Although it is difficult to establish whether these mild abnormalities represent the early steps in the initiation of atherogenesis, these children need to be carefully monitored for metabolic complications.

Background: Subclinical hypothyroidism (SH) is a relatively common condition characterized by a mild persistent thyroid failure. The management of children with SH is still a controversial issue and the decision to treat with L-thyroxine represents a clinical dilemma. Thyroid hormone and TSH play an important role in skeletal growth and bone mineral homeostasis., Aim: To evaluate whether untreated idiopathic SH may affect bone health in childhood and to compare two different diagnostic tools such as dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS)., Patients and Methods: Twenty-five children and adolescents (11 males) aged 9.8 ± 3.5 years (range 4.2-18.7) with untreated idiopathic SH were enrolled in the study. SH was diagnosed on the basis of normal FT4 levels with TSH concentrations between 4.2 and 10 mU/l. Children have been followed for 3.3 ± 0.3 years from the time of SH diagnosis. Twenty-five healthy children, age- and sex-matched, were enrolled as controls. Patients and controls underwent DXA to evaluate lumbar spine bone mineral density (BMD) and QUS at proximal phalanges of the non-dominant hand to assess bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) and bone transmission time (BTT)., Results: Mean BMD Z-score was -0.4 ± 1.36 in patients and -0.2 ± 1.2 in controls. Mean Ad-SoS Z-score was 0.01 ± 1.0 in patients and 0.1 ± 1.2 in controls and mean BTT Z-score was -0.03 ± 0.8 and 0.04 ± 1.1 respectively. All values were within the normal range, both in patients and in controls. There were no statistically significant differences between the two groups., Conclusion: Bone health, evaluated by lumbar spine DXA and phalangeal QUS, is not impaired in our children, despite long-term duration of idiopathic SH. Data about bone status provided by QUS are comparable to those provided by DXA. Therefore, QUS may represent a good, cheaper and safe screening test for bone evaluation in children with SH.

Objective: The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine., Design and Methods: Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4-18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0-9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls., Results: At study entry, height (-0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI -0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (-0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (-0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH., Conclusions: Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.

Objective: To prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH., Design: Clinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1+/-3.0 years) with idiopathic SH., Results: During the study, mean TSH levels showed a trend toward a progressive decrease while FT(4) levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT(4) levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT(4) at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period., Conclusions: (a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT(4) values or clinical status or auxological parameters.

Objective: To evaluate whether long-term L-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD)., Design: Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied., Methods: Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated., Results: Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or L-thyroxine dosages at the time of the study or during the pubertal period., Conclusions: The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged L-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.

To evaluate the effect of different initial levothyroxine (LT4) replacement doses on growth and intellectual outcome in patients with congenital hypothyroidism (CH) detected by neonatal screening program, the longitudinal growth and intelligence quotient (IQ) were assessed and compared at 4 years of age in 83 patients with CH. The patients were divided into three groups according to the initial LT4 dose used: (1) group 1 (n = 42) received the previously recommended dose of 6.0-8.0 microg/kg per day; (2) group 2 (n = 21) received a dose of 8.1-10.0 microg/kg per day; (3) Group 3 (n = 20) a dose of 10.1-15.0 microg/kg per day. The IQ, evaluated by the Wechsler Preschool and Primary Scale of Intelligence test at 4 years of age, was significantly higher in group 3 (IQ 98 +/- 9) compared to group 1 (IQ 88 +/- 13; p < 0.05) but not compared to group 2 (IQ 94 +/- 13). However, the IQs were below the normal range (< 85) in six patients from group 2 (28%), but in none of the patients from group 3 (p = 0.03). Patients from group 3, with severe CH at diagnosis, had an IQ (97 +/- 9) at 4 years of age, which was not different from that of patients from the same group with moderate CH at diagnosis (IQ 99 +/- 9). Similar results were also observed in patients from group 2 however, mean IQ scores in these patients (93 +/- 12) were several points lower than those observed in patients from group 3 (95 +/- 15). After the first month of treatment, optimal serum levels of thyroxine (T4) and free thyroxine (FT4) were achieved in all groups, however, only patients from group 3 were able to normalize thyrotropin (TSH) (group 1, 16.0 +/- 12.0; group 2, 9.2 +/- 10.0; and group 3, 2.4 +/- 3.3 mU/L; p < 0.0001). Twelve patients from group 2 treated with an initial LT4 dose above 9 microg/kg per day were able to normalize TSH levels within the first 3 months of life and this resulted in a better IQ (97 +/- 16) compared to the remaining patients from the same group (IQ 90 +/- 9). In the whole group of 83 patients the IQ at 4 years of age was positively correlated to both initial LT4 dosage (r = 0.27, p < 0.02) and FT4 concentrations after the first month of treatment (r = 0.29, p < 0.02), and negatively correlated to TSH concentrations after the first month of treatment (r = -0.27, p < 0.02). No significant differences were observed in height, weight, head circumference, and bone age maturation among the three groups of patients. No clinical signs or symptoms of overtreatment were observed during follow-up in patients receiving the higher LT4 dosage. Our results indicate that high LT4 starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age, even in patients with severe CH at diagnosis. Growth and bone age maturation are not affected by such a high dose.

Objective: To evaluate longitudinal growth, pubertal development and final height in patients with congenital hypothyroidism (CH) detected by a neonatal screening programme, and to identify factors potentially affecting growth outcome., Patients: Fifty-five patients (41 females) detected by neonatal screening and followed longitudinally from the time of diagnosis and treatment (25+/-5 days) up to the age of 17+/-0.5 years were evaluated retrospectively., Results: Pubertal development began and progressed normally in both males and females. In boys, a testicular volume of 4 ml was reached at 11.3+/-1.0 years. In girls breast enlargement (B2) occurred at a mean age of 10.3+/-1.2 years and the mean age of menarche was 12.5+/-1.2 years. The onset and the progression of puberty were independent of the aetiology, the severity of CH and the timing of the beginning of treatment. Girls treated with an initial amount of L-thyroxine (L-T4) greater than 8 microg/kg per day showed an earlier onset of puberty (B2 9.4+/-0.9 years; menarche 11.5+/-0.8 years) compared with girls treated with a lower initial dose of L-T4 (B2 10.5+/-1.2 years; menarche 12.6+/-1.2 years; P<0.02). However, both groups attained a similar final height (-0.1+/-1.0 SDS and 0.4+/-1.0 SDS, respectively), which in both cases was above the target height (P=0.03). All the patients in the study attained a mean final height (0.1+/-1.1 SDS) within the normal range for the reference population and above the target height (-0.9+/-0.9 SDS, P<0.0001). No significant relationship was found between final height and severity of CH at diagnosis, initial L-T4 dosage or aetiology of the defect. Patients with ectopic gland, thyroid aplasia or in situ gland attained a similar mean final height (0.1+/-1.1 SDS, 0.5+/-1.0 SDS and -0.5+/-1.0 SDS, respectively), which was in all cases greater than target height (-1.0+/-0.9, -0.6+/-0.8, -0.9+/-0.8 respectively; P<0.05)., Conclusions: Our results suggest that conventional management of children with CH detected by neonatal screening leads to normal sexual development and normal adult height, and that the major factor determining height in these children is familial genetic growth potential.