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1.  Intelligence quotient in children with congenital hypothyroidism: The effect of diagnostic and treatment variables 
Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan, the intelligence quotient (IQ) of children with CH and the effect of diagnostic and treatment variables on it were investigated during the CH screening program.
Materials and Methods:
A total of 120 children in three studied groups were studied in this comparative study the IQ score, in three subsets of verbal IQ, performance IQ and full scale IQ, of children diagnosed with transient congenital hypothyroidism (TCH) and permanent congenital hypothyroidism (PCH) was measured using revised Wechsler pre-school and primary scale of intelligence and compared with the control group. The relation between IQ score with time of treatment initiation and screening thyroid stimulating hormone (TSH) level was evaluated in all studied groups.
Mean of verbal IQ, performance IQ, and full scale IQ score was significantly higher in the control group than CH patients (both permanent and transient) In PCH patients though it was not significant, there was a negative relationship between verbal IQ, performance IQ and full scale IQ and screening TSH and age of treatment initiation. In TCH patients, there was negative and significant relationship between verbal IQ (r = −0.40) and full scale IQ (r = −0.38) and age of treatment initiation (r = −0.46).
Mean IQ score in both PCH and TCH patients were lower than the control group, which correlates negatively with treatment initiation time. Though CH screening and early treatment has improved the prognosis of patients, but early and high dose of treatment in children with CH is recommended.
PMCID: PMC3810573  PMID: 24174944
Congenital hypothyroidism; intelligence quotient; permanent; transient; Wechsler pre-school and primary scale
2.  Prevalence of transient congenital hypothyroidism in central part of Iran 
Congenital hypothyroidism (CH) considered a common endocrine disorder in Iran. We report the epidemiologic findings of CH screening program in Isfahan, seven years after its development, regarding the prevalence of transient CH (TCH) and its screening properties comparing with permanent CH (PCH).
Materials and Methods:
In this cross-sectional study, children with primary diagnosis of CH were studied. Considering screening and follow-up lab data and the decision of pediatric endocrinologists, the final diagnosis of TCH was determined.
A total of 464,648 neonates were screened. The coverage percent of the CH screening and recall rate was 98.9 and 2.1%, respectively. Out of which, 1,990 neonates were diagnosed with primary CH. TCH was diagnosed in 1,580 neonates. The prevalence of TCH was 1 in 294 live births. 79.4% of patients with primary CH had TCH. Mean of screening (54.7 ± 59.0 in PCH vs 21.8 ± 28.9 in TCH), recall (56.5 ± 58.8 in PCH vs 36.6 ± 45.0 in TCH), and thyroid stimulating hormone (TSH) and mean of TSH before (2.0 ± 2.9 in PCH vs 1.6 ± 1.6 in TCH) and after (37.7 ± 29.5 in PCH vs 4.3 ± 1.9 in TCH) discontinuing treatment at 3 years of age was significantly higher in PCH than TCH (P < 0.0000).
The higher rate of CH in Isfahan is mainly due to the transient form of the disease. Further studies for evaluating the role of other environmental, autoimmune and/or genetic factors in the pathophysiology of the disease is warranted.
PMCID: PMC3872610  PMID: 24379847
Congenital hypothyroidism; permanent; transient
3.  Neonatal Thyroid Function in Seveso 25 Years after Maternal Exposure to Dioxin 
PLoS Medicine  2008;5(7):e161.
Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.
Methods and Findings
Between 1994 and 2005, in individuals exposed to TCDD after the 1976 Seveso accident we conducted: (i) a residence-based population study on 1,014 children born to the 1,772 women of reproductive age in the most contaminated zones (A, very high contamination; B, high contamination), and 1,772 age-matched women from the surrounding noncontaminated area (reference); (ii) a biomarker study on 51 mother–child pairs for whom recent maternal plasma dioxin measurements were available. Neonatal blood thyroid-stimulating hormone (b-TSH) was measured on all children. We performed crude and multivariate analyses adjusting for gender, birth weight, birth order, maternal age, hospital, and type of delivery. Mean neonatal b-TSH was 0.98 μU/ml (95% confidence interval [CI] 0.90–1.08) in the reference area (n = 533), 1.35 μU/ml (95% CI 1.22–1.49) in zone B (n = 425), and 1.66 μU/ml (95% CI 1.19–2.31) in zone A (n = 56) (p < 0.001). The proportion of children with b-TSH > 5 μU/ml was 2.8% in the reference area, 4.9% in zone B, and 16.1% in zone A (p < 0.001). Neonatal b-TSH was correlated with current maternal plasma TCDD (n = 51, β = 0.47, p < 0.001) and plasma toxic equivalents of coplanar dioxin-like compounds (n = 51, β = 0.45, p = 0.005).
Our data indicate that environmental contaminants such as dioxins have a long-lasting capability to modify neonatal thyroid function after the initial exposure.
Andrea Baccarelli and colleagues show that maternal exposure to a dioxin following the industrial accident in Seveso, Italy in 1976 is associated with modified neonatal thyroid function even many years later.
Editors' Summary
The thyroid, a butterfly-shaped gland in the neck, controls the speed at which the human body converts food into the energy and chemicals needed for life. In healthy people, the thyroid makes and releases two hormones (chemical messengers that travel around the body and regulate the activity of specific cells) called thyroxine (T4) and triiodothyronine (T3). The release of T4 and T3 is controlled by thyroid secreting hormone (TSH), which is made by the pituitary gland in response to electrical messages from the brain. If the thyroid stops making enough T4 and T3, a condition called hypothyroidism (an underactive thyroid) develops. Adults with hypothyroidism put on weight, feel the cold, and are often tired; children with hypothyroidism may also have poor growth and mental development. Because even a small reduction in thyroid hormone levels increases TSH production by the pituitary, hypothyroidism is often diagnosed by measuring the amount of TSH in the blood; it is treated with daily doses of the synthetic thyroid hormone levothyroxine.
Why Was This Study Done?
Although hypothyroidism is most common in ageing women, newborn babies sometimes have hypothyroidism. If untreated, “neonatal” hyperthyroidism can cause severe mental and physical retardation so, in many countries, blood TSH levels are measured soon after birth. That way, levothyroxine treatment can be started before thyroid hormone deficiency permanently damages the baby's developing body and brain. But what causes neonatal hypothyroidism? Animal experiments (and some but not all studies in people) suggest that maternal exposure to toxic chemicals called dioxins may be one cause. Dioxins are byproducts of waste incineration that persist in the environment and that accumulate in people. In this study, the researchers investigate whether exposure to dioxin (this name refers to the most toxic of the dioxins—2,3,7,8-Tetrachlorodibenzo-p-dioxin) affects neonatal thyroid function by studying children born near Seveso, Italy between 1994 and 2005. An accident at a chemical factory in 1976 heavily contaminated the region around this town with dioxin and, even now, the local people have high amounts of dioxin in their bodies.
What Did the Researchers Do and Find?
The researchers identified 1,772 women of child-bearing age who were living very near the Seveso factory (the most highly contaminated area, zone A) or slightly further away where the contamination was less but still high (zone B) at the time of the accident or soon after. As controls, they selected 1,772 women living in the surrounding, noncontaminated (reference) area. Altogether, these women had 1,014 babies between 1994 and 2005. The babies born to the mothers living in the reference area had lower neonatal blood TSH levels on average than the babies born to mothers living in zone A; zone B babies had intermediate TSH levels. Zone A babies were 6.6. times more likely to have a TSH level of more than 5 μU/ml than the reference area babies (the threshold TSH level for further investigations is 10 μU/ml; the average TSH level among the reference area babies was 0.98 μU/ml). The researchers also examined the relationship between neonatal TSH measurements and maternal dioxin measurements at delivery (extrapolated from measurements made between 1992 and 1998) in 51 mother–baby pairs. Neonatal TSH levels were highest in the babies whose mothers had the highest blood dioxin levels.
What Do These Findings Mean?
These findings suggest that maternal dioxin exposure has a long-lasting, deleterious effect on neonatal thyroid function. Because the long-term progress of the children in this study was not examined, it is not known whether the increases in neonatal TSH measurements associated with dioxin exposure caused any developmental problems. However, in regions where there is a mild iodine deficiency (the only environmental exposure consistently associated with reduced human neonatal thyroid function), TSH levels are increased to a similar extent and there is evidence of reduced intellectual and physical development. Future investigations on the progress of this group of children should show whether the long-term legacy of the Seveso accident (and of the high environmental levels of dioxin elsewhere) includes any effects on children's growth and development.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia provides information about hypothyroidism and neonatal hypothyroidism; MedlinePlus provides links to additional information on thyroid diseases (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on hypothyroidism
The Nemours Foundation's KidsHealth site has information written for children about thyroid disorders
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to dioxins (in English and Spanish)
More information about dioxins is provided by the US Environmental Protection Agency and by the US Food and Drug Administration
Wikipedia has a page on the Seveso disaster (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2488197  PMID: 18666825
4.  Does Congenital Hypothyroidism Have Different Etiologies in Iran? 
Iranian Journal of Pediatrics  2011;21(2):188-192.
To determine the prevalence of congenital hypothyroidism (CH), permanent and transient CH.
From November 2006 to September 2007, 63031 newborns were screened by measuring serum TSH obtained by heel prick. The neonates who had a TSH≥5mU/L were recalled for measurement of serum T4, thyroid stimulating hormone (TSH) and TSH receptor blocking antibodies (TRBAb) in venous samples. In 43 primarily diagnosed as cases of CH, treatment was discontinued at age 2–3 years for 4 weeks and T4 and TSH were measured again. Permanent or transient CH was determined from the results of these tests and radiologic evaluation.
The incidence of congenital hypothyroidism was found to be 1:1465 with a female to male ratio of 1.19:1. The most common clinical findings were prolonged jaundice (73%), large anterior fontanel (56%) and wide posterior fontanel (55%). In 43 patients with CH, prevalence of permanent and transient form of the disorder was 53.6% and 46.4% respectively. Permanent CH was associated with higher initial TSH level than transient hypothyroidism (P<0.001). The most common etiology of permanent CH was dyshormonogenesis (57%). TRBAb was found in 6.8% of the total 43 cases.
Congenital hypothyroidism in Iran may have different etiologies. Due to higher rate of transient CH than other similar researches, it is reasonable to follow these patients for a longer period to rule out the possibility of permanent hypothyroidism.
PMCID: PMC3446167  PMID: 23056786
Congenital Hypothyroidism; TSH Receptor; Dyshormonogenesis; Thyroid Dysgenesis
5.  The effect of glucocorticoids on thyrotropin secretion 
Journal of Clinical Investigation  1969;48(11):2096-2103.
The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.
TSH responses to steroid were also studied in rats. In hypothyroid rats given dexamethasone intravenously, plasma TSH fell to 63% of control in 30-90 min and then returned to normal or above in 3-4 hr. Dexamethasone also reduced plasma TSH concentrations in normal rats but no rebound was observed in these animals. Dexamethasone did not block the increase in plasma TSH produced by thyrotropin releasing factor (TRF) administration in vivo. Neither basal nor TRF-mediated TSH release from hemipituitaries in vitro was reduced by dexamethasone or corticosterone. These studies indicate that glucocorticoids reduce TSH secretion and suggest that this effect occurs at a suprahypophyseal level.
PMCID: PMC297463  PMID: 4980930
6.  Audit of screening programme for congenital hypothyroidism in Scotland 1979-93 
Archives of Disease in Childhood  1997;76(5):411-415.
Accepted 30 January 1997

OBJECTIVE—To evaluate the efficiency of the screening programme for congenital hypothyroidism in Scotland and to determine the outcome in the cohort of children with positive testing for thyroid stimulating hormone (TSH).
DESIGN—Establishment of comprehensive database for all Scottish infants with high TSH, detected on Guthrie screening.
SUBJECTS—344 infants born between August 1979 and December 1993 with TSH greater than 40 mU/l on initial Guthrie, or 15-40 mU/l on repeat Guthrie.
MAIN OUTCOME MEASURES—Ages at time of: (a) Guthrie collection, (b) notification of positive result by laboratory, and (c) start of treatment; audit of late diagnosis/missed cases; categorisation of positive cases into definite and probable congenital hypothyroidism, transient TSH elevation, and uncertain status; educational status of children with definite and probable congenital hypothyroidism.
RESULTS—344 positive cases were categorised as having definite (224) and probable (11) congenital hypothyroidism, transient TSH elevation (88), and status uncertain (21). The overall incidence of definite/probable congenital hypothyroidism was 1 in 4400 live births. For the definite/probable groups median age of Guthrie collection was consistently between 6 and 7 days from 1983 onwards but for the whole cohort was later than 10 days in 10.5%. Median age of notification fell from 14days in 1980 to 11 days in 1993. Median age of starting treatment ranged between 11 and 15 days from 1983 onwards. Treatment was delayed in four cases, three due to failed or late Guthrie card submission. Of 149 children with definite/probable congenital hypothyroidism who were of school age, educational status was ascertained in 139 (93%). Only two children (1.4%) were attending special school, one of whom was known to have mild hypothyroidism. Sixteen children (11.5%) were receiving extra help in mainstream education compared with 18% of control children in the Scottish very low birth weight study.
CONCLUSION—The current screening programme is working well, but efficiency could be increased by earlier and more reliable Guthrie collection. A substantial proportion of children picked up on the screening programme have a transient rise in TSH rather than true congenital hypothyroidism. The incidence of special education and learning support in Scottish children with congenital hypothyroidism appears to be no different to that of the general population.

PMCID: PMC1717190  PMID: 9196355
7.  The relation between serum and filter paper TSH level in neonates with congenital hypothyroidism 
the aim of this study was to determine the relation between serum and filter paper thyroid-stimulating hormone (TSH) levels in neonates with congenital hypothyroidism (CH). We also tried to determine an appropriate cutoff point of filter TSH for recalling screened neonates.
Materials and Methods:
in this descriptive-analytic study, records of 2283 neonates who had been recalled during CH screening program in Isfahan (Iran) were studied. The relation between serum and filter paper TSH levels in the studied neonates was assessed and the best cutoff point of filter TSH and its sensitivity and specificity for proper diagnosis of CH were determined.
among the studied neonates, 103 (4.5%) were diagnosed with CH. Using receiver operating characteristic (ROC) curve, the best cutoff point for diagnosing CH was 7.5 with a sensitivity of 74.8% and specificity of 71.3%. The rates of false positive and false negative diagnoses at this cutoff point were28.7% and 25.2%, respectively. There was a significant relationship between serum and filter paper TSH levels.
the cutoff point for recall should be changed to 7.5 for appropriate screening outcome. On the other hand, considering the low cost of filter paper and importance of missing any case of CH, changing the cutoff point is not necessary. However, further studies in different parts of Iran are required to obtain more accurate results and consider all related factors.
PMCID: PMC3928837  PMID: 24592370
Congenital hypothyroidism; filter paper; thyroid-stimulating hormone
8.  Newborn Screening for Congenital Hypothyroidism 
Newborn screening (NS) for congenital hypothyroidism (CH) is one of the major achievements in preventive medicine. Most neonates born with CH have normal appearance and no detectable physical signs. Hypothyroidism in the newborn period is almost always overlooked, and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of NS. Blood spot thyroid stimulating hormone (TSH) or thyroxine (T4) or both can be used for CH screening. The latter is more sensitive but not cost-effective, so screening by TSH or T4 is used in different programs around the world. TSH screening was shown to be more specific in the diagnosis of CH. T4 screening is more sensitive in detecting especially those newborns with rare hypothalamic-pituitary-hypothyroidism, but it is less specific with a high frequency of false positives mainly in low birth weight and premature infants. The time at which the sample is taken may vary. In the majority of the centers, blood is obtained from a heel prick after 24 hours of age to minimize the false positive high TSH due to the physiological neonatal TSH surge that elevates TSH levels and causes dynamic T4 and T3 changes in the first 1 or 2 days after birth. Early discharge of mothers postpartum has increased the ratio of false positive TSH elevations. Although transient hypothyroidism may occur frequently, all these infants should be treated as having CH for the first 3 years of life, taking into account the risk of mental retardation. A reevaluation after 3 years is needed in such patients. The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as rapidly as possible.
Conflict of interest:None declared.
PMCID: PMC3608007  PMID: 23154158
Neonatal screening; congenital hypothyroidism; iodine deficiency
9.  Current Loss-of-Function Mutations in the Thyrotropin Receptor Gene: When to Investigate, Clinical Effects, and Treatment 
Thyroid-stimulating hormone receptor (TSHR) loss-of-function (LOF) mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism (CH) to mild euthyroid hyperthyrotropinemia. The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles In this review data about genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed. Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening. Partial forms of TSH resistance show a more heterogeneous hormonal and clinical pattern . In these cases TSH serum levels are above the upper limit of normal range for the age but with a very variable pattern, free thyroxine (T4) concentrations are within the normal range and thyroid size can be normal or hypoplastic at ultrasound scan. An early substitutive treatment with L-T4 must be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening. The usefulness of substitutive treatment appears much more controversial in patients with subclinical hypothyroidism due to partial TSH resistance in whom the increased TSH concentration should be able to compensate the mild functional impairment of the mutant receptor. Together with standard criteria we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation.
Conflict of interest:None declared.
PMCID: PMC3608004  PMID: 23154162
Thyrotropin receptor gene mutations; congenital hypothyroidism; Neonatal screening; Subclinical hypothyroidism
10.  Serum TSH Level in Healthy Koreans and the Association of TSH with Serum Lipid Concentration and Metabolic Syndrome 
The proper treatment of subclinical hypothyroidism and the normal range of serum thyroid stimulating hormone (TSH) concentration are intensely debated. However, few reports have investigated TSH concentrations in Asian ethnic groups. Therefore, the present study was designed to define the TSH reference range in a Korean population and to investigate the metabolic significance of TSH concentration.
We enrolled patients who underwent medical examination at the CHA Bundang Medical Center. Anthropometric data were evaluated, and serum TSH, free T4, and lipid profiles were assayed.
A total of 7,270 subjects were included. Mean TSH concentration of the study population was 1.82 ± 0.95 mU/L, and we observed a sex-related difference in TSH concentration (male, 1.67 ± 0.87 mU/L; female, 2.02 ± 1.01 mU/L; p < 0.01). When the 2.5 and 97.5 percentiles were calculated, 95% TSH reference limits were 0.52-4.29 mU/L. TSH concentration was higher in elderly subjects, during winter, in postmenopausal women, and in obese males. Moreover, TSH showed significantly positive correlations with serum total cholesterol, triglyceride, and low density lipoprotein cholesterol regardless of sex, age, season, obesity, or menopausal status (all p < 0.01). Finally, TSH concentration was positively related to the prevalence of metabolic syndrome.
We demonstrated the association between TSH concentration within the normal reference range and serum lipid levels. TSH concentration varies according to sex, age, season, and body mass index (only in males). Moreover, high normal TSH levels were significantly associated with an increased prevalence of metabolic syndrome, which may be of importance when evaluating subjects with high normal TSH concentration.
PMCID: PMC3245392  PMID: 22205844
Thyroid function tests; Thyrotropin; Metabolic syndrome
11.  Hearing Impairment in Congenitally Hypothyroid Patients 
Iranian Journal of Pediatrics  2012;22(1):92-96.
Thyroid hormone is necessary for normal development of the auditory system. The aim of this study was to investigate the rate of hearing impairment in congenitally hypothyroid (CH) patients, and its relation with factors such as CH severity and age at starting treatment, during CH screening program in Isfahan.
Hearing acuity was assessed in two groups of children with (94 patients aged 4 months – 3 years) and without CH (450), between 2000-2006. Otoacostic emission (OAE) was performed by a two step method. After two tests without OAE signals bilaterally, they were referred for auditory brainstem response (ABR) test. Subjects with both OAE and ABR abnormal test results were considered to have hearing problem. Obtained data was compared in case and control group and also CH patients with and without hearing impairment.
Three (3.2%) of patients and 1 of control group (0.2%) were diagnosed with sensorineural hearing loss. The rate of hearing loss was not different significantly in two studied groups (P>0.05). There was no difference between age of starting treatment and first T4 and TSH level in CH patients with and without hearing loss (P>0.05). CH neonates with hearing impairment had thyroid dyshormonogenesis according to the follow up results.
The rate of hearing loss was low among our studied CH patients. It may be due to proper management of CH patients. In view of the fact that all CH neonates were dyshormonogentic and considering the relation between certain gene mutations and hearing impairment in CH patients, further studies with larger sample size, with regard to different etiologies of CH should be investigated to indicate the possible gene mutations related to hearing loss in CH.
PMCID: PMC3448222  PMID: 23056865
Hearing impairment; Auditory Brain Stem Response; ABR; Oto Acostic Emission; OAE
12.  Thyroid screening in pregnancy — A study of 82 women 
To create awareness, lay down a new criterion to pick up probable cases, and draw a proper management protocol for hypothyroidism in pregnancy.
Inclusion criteria — All normal pregnant women and those with thyroid problems were included in the study. Exclusion criteria — All others who had diabetes, collagen disease, heart disease with pregnancy were excluded from the study. Eighty two women were screened for hypothyroidism in pregnancy using T3, T4, TSH and FT4. A new screening criterion was followed [TSH value — 0.5–1.5 mIU/ml i.e biological range]. Women with TSH in pregnancy were followed up. Women with TSH value above 3mIU/ml, were considered hypothyroid and received treatment with L-Thyroxin. The group with a TSH value 2–3 mIU/ml was assessed with FT4. Those with low values or those with increasing TSH value on subsequent follow up received treatment.
Study group consisted of 62 Primigravidae and 20 multigravidae. A. 40[32P + 8M] > 3 TSH value, these women received treatment with L-Thyroxin B. 24[16P + 8M] 2–3 TSH value, C. 18[14P + 4M] <2 TSH value. According to thyroid status, they were categorized into euthyroid — [27 true euthyroid + 4 potential hypothyroid] and overt hypothyroid — [43 adequately treated and 6 inadequately treated], two were untreated. Inadequately treated and potential hypothyroid pregnant women landed with miscarriages or pregnancy inducted hypertension, oligohydramnios and IUGR.
Potential and inadequately treated hypothyroid patients present with problems in pregnancy, while adequately treated hypothyroid and true euthyroid women get normal ongoing pregnancies. So to identify these potential or overt hypothyroid women, thyroid screening with T3, T4, TSH and FT4 must be done during prenatal period, at first booking, and repeated at 8 weeks interval thereafter, in pregnancy. TSH value should be kept below 2mIU/ml to get adequate control.
PMCID: PMC3394518
screening in pregnancy; thyroid and pregnancy; hypothyroidism
13.  Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine. 
Archives of Disease in Childhood  1993;69(5):555-558.
Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.
PMCID: PMC1029617  PMID: 8257174
14.  Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women 
Thyroid Research  2012;5:13.
Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes.
We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism.
We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/− 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels.
All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels.
Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.
PMCID: PMC3520819  PMID: 23111240
TSH; Free T3; Free T4; Cortisol; Subclinical hypothyroidism
15.  Improvement in screening performance and diagnosis of congenital hypothyroidism in Scotland 1979–2003 
Archives of Disease in Childhood  2006;91(8):680-685.
To assess the Scottish newborn screening programme for congenital hypothyroidism from 1994 to 2003 (period 2) for performance and compare with an initial audit covering 1979 to 1993 (period 1).
Performance data—age at blood spot sampling, notification by screening laboratory, start of treatment, and the prevalence of late testing, notification or treatment—were compared, together with the incidence of congenital hypothyroidism.
Comparing data for period 2 with period 1, the mean annual incidence of true congenital hypothyroidism was 1:3655 live births v 1:4363. Median age for Guthrie sampling (all referrals) was 6 v 7 days (p<0.0001). Late sampling (>10 days) had fallen from 10.7% to 7%. For infants requiring repeat sampling before notification, the median (range) interval between initial and final repeat samples was 11 (1 to 52) compared with 14 (3 to 73) days. Median age at notification for true congenital hypothyroidism was 10 v 12 days (p <0.0001). Late notification (>15 days) was justifiable (mild TSH elevation) in 10 of 13 patients in period 2. Median age at start of treatment for true congenital hypothyroidism had improved to 11 days from 13.5 days. For true congenital hypothyroidism, late treatment (>16 days) occurred in 7% of patients compared with 19% (p<0.0001).
There has been an improvement in performance measures for the congenital hypothyroidism screening programme in Scotland. However, late sampling, occurring primarily in inpatients and which is never justified, remains a problem, while the interval between initial and recall sampling is a further source of delay.
PMCID: PMC2083034  PMID: 16595645
congenital hypothyroidism; screening
16.  Prevalence of thyroid dysfunction in patients with diabetes mellitus 
Diabetes mellitus (DM) and thyroid dysfunction (TD) are the two most common endocrine disorders in clinical practice. The unrecognized TD may adversely affect the metabolic control and add more risk to an already predisposing scenario for cardiovascular diseases. The objective of this study was to investigate the prevalence of TD in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM).
This is an observational cross-sectional study. Three hundred eighty-six (386) patients with T1DM or T2DM that regularly attended the outpatient clinic of the Diabetes unit, Hospital Universitário Pedro Ernesto, participated in the study. All patients underwent a clinical and laboratory evaluation. Thyroid dysfunction was classified as clinical hypothyroidism (C-Hypo) if TSH > 4.20 μUI/mL and FT4 < 0.93 ng/dL; Subclinical hypothyroidism (SC-Hypo) if TSH > 4.20 μUI/ml and FT4 ranged from 0.93 to 1.7 ng/dL; Subclinical hyperthyroidism (SC-Hyper) if TSH < 0.27 μUI/ml and FT4 in the normal range (0.93 and 1.7 ng/dL) and Clinical hyperthyroidism (C-Hyper) if TSH < 0.27 μUI/ml and FT4 > 1.7 μUI/mL. Autoimmunity were diagnosed when anti-TPO levels were greater than 34 IU/mL. The positive autoimmunity was not considered as a criterion of thyroid dysfunction.
The prevalence of TD in all diabetic patients was 14,7%. In patients who had not or denied prior TD the frequency of TD was 13%. The most frequently TD was subclinical hypothyroidism, in 13% of patients with T1DM and in 12% of patients with T2DM. The prevalence of anti-TPO antibodies was 10.8%. Forty-four (11.2%) new cases of TD were diagnosed during the clinical evaluation. The forty-nine patients with prior TD, 50% with T1DM and 76% with T2DM were with normal TSH levels.
We conclude that screening for thyroid disease among patients with diabetes mellitus should be routinely performed considering the prevalence of new cases diagnosed and the possible aggravation the classical risk factors such as hypertension and dyslipidemia, arising from an undiagnosed thyroid dysfunction.
PMCID: PMC3852595  PMID: 24499529
Thyroid dysfunction; Prevalence; Diabetes mellitus
17.  Vertical Transmission of Hypopituitarism: Critical Importance of Appropriate Interpretation of Thyroid Function Tests and Levothyroxine Therapy During Pregnancy 
Thyroid  2013;23(7):892-897.
Typically, newborns with congenital hypothyroidism are asymptomatic at birth, having been exposed to euthyroid mothers. However, hypopituitarism may be associated with central hypothyroidism, preserved fertility, and autosomal dominant inheritance, requiring increased attention to thyroid management during pregnancy.
Patient Findings
A woman with a history of growth hormone deficiency and central hypothyroidism gave birth to a term male neonate appropriate for gestational age. Due to low thyrotropin (TSH) in the second trimester, the levothyroxine dose was decreased by the obstetrician, and free T4 was low throughout the latter half of pregnancy. The neonatal laboratory evaluation showed central hypothyroidism with a low T4 of 2.1 μg/dL (4.5–11.5) and an inappropriately normal TSH of 0.98 uIU/mL (0.5–4.5); undetectable growth hormone, IGF-I, and IGFBP3; a normal cortisol level; and a normal gonadotropin surge. After initiation of levothyroxine in the first week, both tone and feeding tolerance improved. However, the patient was found to have hearing loss, gross motor delay, and speech delay.
In this report, we review a case of vertical transmission of a dominant negative POU1F1 mutation in which fetal abnormalities due to the hypothyroxinemic state during gestation may have been exacerbated by a decrease in the mother's levothyroxine dose based on a low TSH in early gestation. Both mother and fetus were unable to synthesize sufficient thyroid hormone, which may be responsible for the patient's clinical presentation.
This case underscores several important points in the management of women with hypopituitarism. First, it is important that patients and clinicians are both aware of the differences in etiology, as well as appropriate screening and treatment, of primary versus central hypothyroidism. Second, it is necessary to monitor the thyroid hormone status closely during pregnancy to prevent fetal sequelae of maternal hypothyroidism. Third, genetic screening of patients with combined pituitary hormone deficiency is necessary, so that prenatal genetic counseling may be an option for expecting parents.
PMCID: PMC3704046  PMID: 23397938
18.  Hypothyroidism in the elderly: diagnosis and management 
Thyroid disorders are highly prevalent, occurring most frequently in aging women. Thyroid-associated symptoms are very similar to symptoms of the aging process; thus, improved methods for diagnosing overt and subclinical hypothyroidism in elderly people are crucial. Thyrotropin measurement is considered to be the main test for detecting hypothyroidism. Combined evaluations of thyroid stimulating hormone (TSH) and free-thyroxine can detect overt hypothyroidism (high TSH with low free-thyroxine levels) and subclinical hypothyroidism (high TSH with normal free-thyroxine levels). It is difficult to confirm the diagnosis of thyroid diseases based only on symptoms, but presence of symptoms could be an indicator of who should be evaluated for thyroid function. The most important reasons to treat overt hypothyroidism are to relieve symptoms and avoid progression to myxedema. Overt hypothyroidism is classically treated using L-thyroxine; elderly patients require a low initial dose that is increased every 4 to 6 weeks until normalization of TSH levels. After stabilization, TSH levels are monitored yearly. There is no doubt about the indication for treatment of overt hypothyroidism, but indications for treatment of subclinical disease are controversial. Although treatment of subclinical hypothyroidism may result in lipid profile improvement, there is no evidence that this improvement is associated with decreased cardiovascular or all-cause mortality in elderly patients. In patients with a high risk of progression from subclinical to overt disease, close monitoring of thyroid function could be the best option.
PMCID: PMC3340110  PMID: 22573936
overt hypothyroidism; subclinical hypothyroidism; diagnosis; treatment; elderly
19.  Permanent and Transient Congenital Hypothyroidism in Fayoum, Egypt: A Descriptive Retrospective Study 
PLoS ONE  2013;8(6):e68048.
Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation. One important challenge in understanding the epidemiology of CH is that some newborns will have transient CH, a temporary depression of thyroid hormone concentrations that can last from several days to several months. Studies from other countries have reported that 10 to 15% of children treated for CH ultimately prove not to need treatment past 3 years of age to maintain normal hormone concentrations, and thus have transient hypothyroidism. The purpose of this study was to determine the prevalence of permanent and transient congenital hypothyroidism in Fayoum, Egypt.
Cases detected by Fayoum neonatal screening program (NSP) between January 2003 and December 2011, and followed up at health insurance center were included. Permanent or transient CH was determined using results of thyroid function tests.
Of the 248 patients diagnosed primarily with CH by NSP; 204 (82.3%) patients were diagnosed to have permanent CH (prevalence 1/3587 live birth), and 44 (17.7%) patients were diagnosed to have transient CH (prevalence 1/16667 live birth). Initial TSH levels were higher in permanent CH cases than transient cases (p<0.004). Female to male ratio was 0.8 and 0.7 in permanent and transient CH respectively. 161 (65%) patients had thyroid dysgenesis (107 ectopic thyroid gland, 28 athyreosis and 26 thyroid hypoplasia). 87 (35%) patients had intact gland in thyroid scan and were considered to have dyshormonogenesis. Of these 87 patients 44 proved to have transient CH and 43 had permanent CH.
The preliminary data from our study revealed that the incidences of CH as well as the permanent form were similar to worldwide reports. Although the high incidence of transient CH in our study could be explained by iodine deficiency further studies are needed to confirm the etiology and plan the treatment strategies.
PMCID: PMC3695950  PMID: 23840807
20.  TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism 
Thyroid  2010;20(11):1215-1228.
Thyrotropin (TSH) changes in extreme primary hypothyroidism include increased secretion, slowed degradation, and diminished or absent TSH circadian rhythms. Diminished rhythms are also observed in central hypothyroid patients and have been speculated to be a cause of central hypothyroidism. We examined whether TSH secretion saturation, previously suggested in extreme primary hypothyroidism, might explain diminished circadian rhythms in both disorders.
We augmented and extended the range of our published feedback control system model to reflect nonlinear changes in extreme primary hypothyroidism, including putative TSH secretion saturation, and quantified and validated it using multiple clinical datasets ranging from euthyroid to extreme hypothyroid (postthyroidectomy). We simulated central hypothyroidism by reducing overall TSH secretion and also simulated normal TSH secretion without circadian oscillation, maintaining plasma TSH at constant normal levels. We also utilized the validated model to explore thyroid hormone withdrawal protocols used to prepare remnant ablation in thyroid cancer patients postthyroidectomy.
Both central and extreme primary hypothyroidism simulations yielded low thyroid hormone levels and reduced circadian rhythms, with simulated daytime TSH levels low-to-normal for central hypothyroidism and increased in primary hypothyroidism. Simulated plasma TSH showed a rapid rise immediately following triiodothyronine (T3) withdrawal postthyroidectomy, compared with a slower rise after thyroxine withdrawal or postthyroidectomy without replacement.
Diminished circadian rhythms in central and extreme primary hypothyroidism can both be explained by pituitary TSH secretion reaching maximum capacity. In simulated remnant ablation protocols using the extended model, TSH shows a more rapid rise after T3 withdrawal than after thyroxine withdrawal postthyroidectomy, supporting the use of replacement with T3 prior to 131I treatment.
PMCID: PMC2974848  PMID: 21062194
21.  Factors involved in the rate of fall of thyroid stimulating hormone in treated hypothyroidism 
Archives of Disease in Childhood  1997;77(6):526-527.

The rate of fall of serum thyroid stimulating hormone (TSH) concentrations in 32 hypothyroid infants (11 boys, 21 girls) was studied after starting treatment with thyroxine to determine whether it was influenced by initial TSH concentration or the cause of the hypothyroidism. Of 27 patients who had isotope scans before treatment was started, 11 (40%) were athyrotic, 10 (38%) had an ectopic gland, and six (22%) probably had dyshormonogenesis. Treatment was started with thyroxine at 100 µg/m2/24 hours at a mean age of 26 days (range 14-45). Serum TSH concentrations remained increased in 26 (81%) at 3 months, 20 (62.5%) at 6 months, and nine (28%) at 1 year and beyond. The mean age for serum TSH to reach the normal range was 0.79 years (range 0.15-2.1 years). Diagnosis (in 27 patients) and initial results (in 32) made no difference to the rate of fall. 

PMCID: PMC1717416  PMID: 9496191
22.  Congenital Hypothyroidism Due To Maternal Radioactive Iodine Exposure During Pregnancy 
Radioactive iodine (RAI) is used effectively in the treatment of hyperthyroidism and thyroid cancer, but it is contraindicated during pregnancy. RAI treatment during pregnancy can lead to fetal hypothyroidism, mental retardation and increased malignancy risk in the infant. Pregnancy tests must be performed before treatment in all women of reproductive age. However, at times, RAI is being used before ruling out pregnancy.
We herein present a male newborn infant with congenital hypothyroidism whose mother was given a three-week course of methimazole therapy for her multiple hyperactive nodules and subsequently received 20 mCi RAI during the 12th week of her pregnancy. The patient was referred to our neonatology unit at age two weeks when his thyrotropin (TSH) level was reported to be high in the neonatal screening test. Physical examination was normal. Laboratory investigations revealed hypothyroidism (free triiodothyronine 1.55 pg/mL, free thyroxine 2.9 pg/mL, TSH 452 mU/L, thyroglobulin 20.1 ng/mL). The thyroid gland could not be visualized by ultrasonography. L-thyroxine treatment was initiated.
Conflict of interest:None declared.
PMCID: PMC3386771  PMID: 22672871
Pregnancy; Hyperthyroidism; radioactive iodine; fetal hypothyroidism
23.  Screening for Congenital Hypothyroidism in Newborns Transferred to Neonatal Intensive Care 
To evaluate the effectiveness of four screening protocols for congenital hypothyroidism (CH) in newborns transferred to the NICU. Determine an evidence base for the Center for Laboratory Standards Institute’s Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns Approved Guideline by evaluating a nearly identical protocol.
Design, Setting & Patients
Michigan newborns transferred to the NICU from 1998–2011 and screened for CH are included in this population-based retrospective cohort study.
Main Outcome Measures
Screening performance metrics are computed and logistic regression is used to test for differences in the likelihood of detection across four periods characterized by different testing protocols.
Primary TSH plus retest at 30 days of life or discharge achieved the greatest detection rate (2.6: 1,000 births screened). The odds of detection was also significantly greater in this period compared to the tandem T4 and TSH testing period and separately compared to TSH testing alone, adjusted for birth weight, sex and race (aOR 1.5; CI 1.0–2.2; p=0.046, and aOR 2.2; CI 1.5–3.4, respectively). Approximately half of the cases detected during primary TSH plus serial testing periods were identified by retest.
Primary TSH testing programs that do not incorporate serial screening may fail to identify approximately half of newborns with congenital thyroid hormone deficiency transferred to the NICU. Tandem T4 and TSH testing programs also likely miss cases who otherwise would receive treatment if serial testing were conducted. Further research is necessary to determine the optimal NBS protocol for CH; strategies combining tandem T4 and TSH with serial testing conditional on birthweight may be useful.
PMCID: PMC4136805  PMID: 23183553
Newborn Screening; Performance Evaluation; Congenital Hypothyroidism; Repeat Testing
24.  School based screening for hypothyroidism in Down's syndrome by dried blood spot TSH measurement 
OBJECTIVE—To determine the feasibility of annual hypothyroid screening of children with Down's syndrome by measuring thyroid stimulating hormone (TSH) on dried blood spots at school, and to describe the outcome in positive children.
DESIGN—Establishment of a register of school children with Down's syndrome, and procedures for obtaining permission from parents, annual capillary blood samples, TSH measurement, and clinical assessment of children with TSH values > 10 mU/litre.
SUBJECTS—All school age children with Down's syndrome within Lanarkshire and Glasgow Health Boards during 1996-7 and 1997-8.
RESULTS—200 of 214 school children with Down's syndrome were screened. Four of the unscreened children were receiving thyroxine treatment, and only 5 remained unscreened by default. 15 of the 200 children had capillary TSH > 10 mU/litre, and all but 1 had evidence of Hashimoto's thyroiditis. Seven of the 15 children started thyroxine treatment immediately, 6 with a pronounced rise in venous TSH and subnormal free thyroxine (fT4), and one with mildly raised TSH and normal fT4 but symptoms suggesting hypothyroidism. Eight children with mildly raised venous TSH and normal fT4 were left untreated; 1 year after testing positive, fT4 remained > 9 pmol/litre in all cases, but 4 children were started on thyroxine because of a rise in TSH. TSH fell in 3 of the 4 remaining children and there was a marginal rise in 1; all remain untreated. The prevalence of thyroid disease in this population is ⩾ 8.9%.
CONCLUSION—Dried blood spot TSH measurement is effective for detecting hypothyroidism in Down's syndrome and capillary sampling is easily performed at school. The existing programme could be extended to the whole of Scotland within a few years.

PMCID: PMC1718179  PMID: 10630906
25.  Hypothyroidism Due to Hepatic Hemangioendothelioma: A Case Report 
Although hemangioendothelioma (HHE) is a commonly encountered hepatic tumor during infancy, HHE−related hypothyroidism is rare. We present a patient who developed HHE−related hypothyroidism during the neonatal period and showed marked improvement in hypothyroidism by regression of HHE. A 28−day−old boy with TSH level of 77 mIU/mL on neonatal screening and diagnosed as congenital hypothyroidism was started on L−thyroxine (L−T4) (11 μg/kg/day) therapy on the 21th day of life. On physical examination, the liver was palpable 5 cm below the right costal margin, and the thyroid gland was nonpalpable. Thyroid ultrasonography was normal. Although L−T4 dose was increased to 15 μg/kg/day, TSH was not suppressed and free T3 level remained low. HHE in both lobes of the liver was detected by abdominal ultrasonography and magnetic resonance imaging. Treatment was started with prednisolone 2 mg/kg/day and alpha−interferon 3 million U/m2/3 times per week. Thyroid dysfunction was thought to be due to type 3 iodothyronine deiodinase activity expressed by HHE. L−T4 therapy was changed to Bitiron® tablet, which includes both T4 and T3, and euthyroidism was attained within 1 month. Thyroid hormone requirement was reduced and treatment was discontinued after regression of the HHE. At the most recent visit, the patient was 21 months old and off treatment. His growth and neurological development were normal for age and he was euthyroid. HHE should be considered in cases with severe hypothyroidism resistant to high−dose thyroid hormone replacement. The treatment of HHE in combination with T4 and T3 therapy results in euthyroidism.
Conflict of interest:None declared.
PMCID: PMC3005683  PMID: 21274327
Hepatic hemangioendothelioma; consumptive hypothyroidism; type 3 iodothyronine deiodinase

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