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REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 64-70

Congenital hypothyroidism: Screening, diagnosis, management, and outcome


King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia

Date of Web Publication13-Apr-2017

Correspondence Address:
Noman Ahmad
King Faisal Specialist Hospital and Research Centre, Jeddah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_5_17

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  Abstract 

Congenital hypothyroidism (CH) is one of the most common causes of preventable mental retardation. Thyroid hormone has an essential role in the brain development during the first 2–3 years of life. Incidence of CH is 1:3000–1:4000 live births, but there is evidence that its incidence is increasing. Majority of newborn babies do not exhibit obvious clinical signs and symptoms until the age of 3 months due to either some residual thyroid function or transplacental passage of maternal thyroid hormone. Common clinical symptoms include lethargy, sleepiness, poor feeding, constipation, and prolonged jaundice. Other common findings on clinical examination include macroglossia, large fontanels, umbilical hernia, and hypotonia. Neonatal screening for CH is practiced in the developed countries for the last three decades, and various studies show that normal cognitive function is attainable with early detection and treatment. This review discusses different protocols being used for screening. It highlights recent recommendation of screening and retesting cutoffs. Thyroid imaging can help in differentiating underlying etiology, either thyroid dysgenesis or dyshormonogenesis. Treatment with levothyroxine (L-T4) 10–15 mcg/kg should be started immediately after diagnosis without delaying for imaging purposes. Frequent and vigilant monitoring with L-T4 dose adjustment is mandatory in infancy and childhood to achieve normal physical growth and neurodevelopment. Children with CH are followed by different pediatric specialties including general pediatricians, neonatologists, developmental pediatricians, and endocrinologists and in primary care; therefore, it is essential to increase the awareness of monitoring protocols among all physicians.

Keywords: Dyshormonogenesis, newborn screening, thyroid dysgenesis, thyroid scintigraphy


How to cite this article:
Ahmad N, Irfan A, Al Saedi SA. Congenital hypothyroidism: Screening, diagnosis, management, and outcome. J Clin Neonatol 2017;6:64-70

How to cite this URL:
Ahmad N, Irfan A, Al Saedi SA. Congenital hypothyroidism: Screening, diagnosis, management, and outcome. J Clin Neonatol [serial online] 2017 [cited 2017 Jun 25];6:64-70. Available from: http://www.jcnonweb.com/text.asp?2017/6/2/64/204513


  Introduction Top


Congenital hypothyroidism (CH) is one of the most common causes of preventable mental retardation. Thyroid hormone has an essential role in the brain development during the first 2–3 years of life.[1],[2] Majority of newborn babies do not exhibit obvious clinical signs and symptoms until the age of 3 months due to either some residual thyroid function or transplacental passage of maternal thyroid hormone.[3] Clinical features [Table 1] become evident if diagnosis is missed or treatment is delayed or suboptimal. Neonatal screening for CH is practiced in the developed countries for the last three decades, and various studies show that normal cognitive function is attainable with early detection and treatment.[4] Children with CH are followed by different pediatric specialties including general pediatricians, neonatologists, developmental pediatricians, and endocrinologists and in primary care; therefore, it is essential to increase the awareness of monitoring protocols among the physicians.
Table 1: Clinical features of congenital hypothyroidism

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  Epidemiology Top


The incidence of CH has significantly increased after the initiation of newborn screening (NBS) programs. Before NBS, the incidence of CH was approximately 1:7000–1:10,000 live births usually diagnosed based on the appearance of clinical manifestations.[5] The incidence of CH reported after the introduction of NBS has been 1:3000–1:4000 live births.[6] This increase in incidence is probably explained by early detection of cases, including the diagnosis of mild and transient cases.[7] There is doubling of incidence reported from the United States in 2007, increasing from 1:3985 (1987) to 1:2273 (2002) and 1:1415 (2005).[8] The rise in incidence could not be attributed solely to one reason, but it is accounted by the change in demographics, such as rise in Hispanic and Asian births, increase in preterm and twin births, infants born to advanced age mothers, and lower cutoff values on screening tests. A similar rise in incidence is reported from New Zealand in 2010 associated with two-fold increase in Asian births.[9]

CH is classified into two main types: transient and permanent types.[10] Permanent CH requires lifelong monitoring and treatment, whereas transient CH shows normal thyroid hormone production after first few months of life. Transient CH can be secondary to maternal antithyroid medications, endemic iodine deficiency, or iodine excess.

Permanent CH is mainly due to primary hypothyroidism presented with elevated thyroid-stimulating hormone (TSH) levels. Secondary or central hypothyroidism is very rare (incidence of 1:25,000) which may present with isolated TSH deficiency or as a part of panhypopituitarism. Primary CH cases are 80% due to thyroid dysgenesis and 20% due to thyroid dyshormonogenesis. Isolated thyroid dysgenesis is generally sporadic, but thyroid dyshormonogenesis is associated with hormone synthesis protein genes mutations.[11]


  Newborn Screening Top


The first pilot program for NBS for CH was started in Quebec, Canada, in 1972.[12] New York State made it mandatory in 1978, and currently, it is a routine practice in developed countries.[13] NBS brought a revolutionary advancement in the preventive medicine and showed promising result in preventing the cognitive dysfunction secondary to CH; however, unfortunately, 71% of babies currently born worldwide are in those areas where there is no established NBS program.[14]

Saudi Arabia is one of the countries where incidence of CH is relatively higher 1:2500.[15] The Ministry of Health established a national screening program in 1989.[16] The majority of babies in the Kingdom are born in hospital, but most of the mothers and babies are discharged within 24 h of delivery. Advisory committee for CH screening agreed to measure TSH in cord blood as a primary screening test. TSH concentration >60 mU/L is considered highly suspicious for CH and advised for infant examination and repeat testing. Cord blood TSH 30–60 mU/L initiates testing of T4 in same sample; if T4 level is <80 nmol/L, infant is recalled for examination and testing. We did not find any specific recommendation for cord TSH 30–60 mU/L and T4 >80 nmol/L; we suggest repeat testing and follow-up with primary pediatrician. Cord blood TSH <30 mU/L is considered as normal.[16],[17]

Three major strategies for NBS [Table 2] are in practice worldwide.[14] The majority of babies with CH would be detected and later diagnosed with anyone of these strategies. Measuring T4 with follow-up TSH would detect central/secondary CH and also late rise of TSH in cases of primary CH. Initial TSH measurement would not detect central/secondary CH but would detect primary CH and also subclinical, mild, and transient cases of primary CH.[10] NBS strategies changed in the last three decades. In 1990, majority of US programs used initial T4 with follow-up TSH measurement, and currently (2010), majority is using initial TSH measurement and some are measuring T4 and TSH simultaneously.[14] Changes in screening program strategy resulted in increased incidence of CH.[8] The most sensitive screening test for primary hypothyroidism is initial measurement of TSH. Sample can be collected from cord blood or after the age of 24 h, but best window period is 48–72 h.[11] Blood sample is usually collected by heel prick, spotted on filter paper, then dried, and send for TSH analysis.
Table 2: Newborn screening strategies

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Second screening is recommended for certain group of babies; sick babies may have TSH suppression due to effect of drugs such as steroids, dopamine, and iodine [18] or because of hypothalamic–pituitary immaturity.[19] Fetal blood mixing in multiple pregnancies can mask TSH level.[20] The European Society for Pediatric endocrinology (ESPE) guidelines (2014) advised repeat screening in preterm neonates with gestational age <37 weeks, low birth weight and very low birth weight neonates, ill neonates admitted to the Neonatal Intensive Care Unit, multiple births, and in babies whom sample is collected in first 24 h. The second screening sample should be collected at 2 weeks of age or after 2 weeks of first sample.[11] All specimens' results should be considered to interpret the result of screening.

There is large variability in defining the cutoff values between the NBS programs. This largely depends on timings of sample collection to define cutoffs. Specimen collected in the first 24 h may have TSH cutoff of >60 mU/L, whereas sample taken at 72 h has a cutoff of >15 mU/L.[21] Most of programs use the cutoff value of 20 mU/L of whole blood on dried blood spot (DBS).[14] The ESPE guidelines 2014 have given following advice.[11]

  • TSH ≥40 mU/L of whole blood on DBS; start treatment immediately
  • TSH <40 mU/L of whole blood treatment can be postponed for 1–2 days to get venous sample result
  • TSH >20 mU/L on venous sample requires treatment, irrespective of FT4 levels
  • Low serum FT4 regardless of TSH level should be treated immediately
  • TSH of 6–20 mU/L on venous sample with normal FT4 is a gray area; if TSH level remains high for 3–4 weeks or imaging results are suggestive of thyroid dysgenesis, treatment should be started immediately.



  Radiological Workup Top


The imaging modalities such as ultrasound and scintigraphy can help in defining the etiology of CH and also predict whether it is transient or permanent type of CH. Transient CH requires a reassessment with cessation of therapy with thyroxin treatment at the age of 3 years. Infants with elevated TSH on NBS should have both ultrasound and scintigraphy; treatment should not be delayed to perform the imaging. The scintigraphy after the initiation of treatment may give false negative result due to suppressed TSH level and poor tracer uptake. The optimal results of scintigraphy can be achieved when it is done within 7–10 days of treatment.[11],[22] Combined ultrasound and scintigraphy can give correct diagnosis in 80% of CH patients presenting with elevated TSH.[18]

The technetium-99m (99m Tc) or iodine-123 (123 I) can be used to carry out scintigraphy.123 I is specifically taken up by the thyroid gland and gives better scan than 99m Tc.[23] Babies should be fed before scanning to empty salivary glands; otherwise, tracer uptake in the salivary glands can give false interpretation.[11] TSH levels measured at time of scan would help in interpreting the results.[18] Eutopic glands may not have tracer uptake if TSH is suppressed due to thyroxin treatment, excess iodine intake, maternal TSH receptor-blocking antibodies, inactivating mutations in TSH receptor, and the sodium-iodide symporter.[24],[25]

The ultrasound imaging can investigate the absence or presence of thyroid gland; it may also suggest size, texture, and structure. This modality is, unfortunately, highly observer dependent and not very sensitive in detecting ectopic (lingual and sublingual) thyroid gland.[26]

Ami De Silva defined five major categories of scintigram findings in babies with primary CH; (1) normal site, normal uptake, (2) normal site, increased uptake, (3) normal site, decreased uptake, (4) no uptake, and (5) ectopic uptake [Figure 1].[27] Highest predictive value (100%) is seen in ectopic gland for permanent primary hypothyroidism. The scintigram uptake can help in diagnosing the underlying etiology of CH. Majority of primary CH cases are sporadic and secondary to thyroid dysgenesis, but small percentage is due to dyshormonogenesis; therefore, prediction of underlying cause would suggest genetic testing and counseling.
Figure 1: The technetium-99m or iodine - scintigraphy findings in congenital hypothyroidism

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Long bones epiphysis X-ray gives an indication for the severity of CH. Absent epiphysis on X-ray is associated with significant in utero compromise due to severe CH [Figure 2].[10]
Figure 2: The left lower extremity of two infants; absent distal femoral epiphysis on left while in the normal infant on the right the distal femoral epiphysis is present

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  Genetic Mutation Analysis Top


A careful family history and thyroid morphology on imaging may indicate genetic mutation and risk of recurrence. Each family with a baby born with primary CH deserves genetic counseling from an expert and specially those who have goiter or abnormal thyroid morphology suggestive of dyshormonogenesis. Thyroid dyshormonogenesis gene mutations are autosomal recessive in inheritance; these include SCL5A5/NIS iodide transporter defect, SCL26A4/PDS pendrin (Pendred syndrome), thyroglobulin, thyroid peroxidase, dual oxidase 2 (DUOX2), and iodotyrosine deiodinase.[28]

There is some evidence that sporadic thyroid dysgenesis resulting in primary CH may also have a genetic basis. The observations suggesting this association are >15 times higher rate of familial cases than by chance alone; minor morphological abnormalities in euthyroid first-degree relatives and increase incidence of extrathyroidal malformations.[29],[30]


  Treatment Top


The prevention of mental and growth retardation associated with CH is only possible with prompt treatment and vigilant monitoring throughout childhood and adolescence. The treatment should be commenced immediately after confirmation of diagnosis based on NBS or follow-up blood test. The initiation of treatment within first 2 weeks of life is crucial for the normal neurodevelopment.[31]


  Dosing Top


Levothyroxine (L-T4) is the only recommended treatment for replacement therapy. Triiodothyronine (T3) is biologically active hormone but it is efficiently formed by endogenous deiodination of L-T4. The treatment with combination of L-T4 and T3 has not shown any extra benefit than treatment with L-T4 alone in terms of neurodevelopment.[32],[33] L-T4-recommended dose is 10–15 μg/kg/day as a single dose. High dose can be started in severe cases of CH, defined by very low FT4 (<5 pmol/L), and delayed bone age. The lower dose can be given in mild (FT4 5–10 pmol/L) and moderate (FT4 10–15 pmol/L) cases.[11]


  Administration Top


The L-T4 is available in tablet form worldwide and is recommended to be used in tablet form by crushing and mixing in few milliliters of water or breast milk immediately before administration. Suspensions prepared by pharmacies are unreliable in dosing.[10] The L-T4 is available in liquid form in Europe which is produced pharmaceutically and licensed for use. This liquid form is reliable in dosing and convenient for infants.[34],[35]

Oral forms can be given either before feeding or with food; bioavailability can be influenced by the presence of some food or minerals.[11] Food and drugs which interfere with absorption are soy protein formulas, concentrated iron, calcium, aluminum hydroxide, cholestyramine and other resins, fiber supplements, and sucralfate.[10]


  Monitoring Top


Normalization of TSH within the first 2 weeks and maintaining FT4 in the upper half of normal range results in better intellectual outcome.[36] Treatment should be monitored and adjusted by measuring TSH and FT4 serum or plasma concentrations. ESPE consensus guidelines [11] recommended frequent monitoring in infancy and childhood for TSH and FT4 [Table 3]. Monitoring may be performed more frequent if results are abnormal or there are concerns regarding compliance. Changes in dose or formulation of L-T4 should be followed with laboratory evaluation after 4–6 weeks.
Table 3: Monitoring recommendation in infancy and childhood

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The reevaluation may be considered in those patients who do not have definite diagnosis in the neonatal period. The central nervous system myelination is completed by the age of 36–40 months;[37] therefore, it would be safe to do reevaluation at the age of 3 years when children are also more cooperative for imaging of thyroid gland. Reevaluation is not necessary in those who have definite diagnosis of thyroid agenesis, ectopic thyroid, and dyshormonogenesis with DUOX2 mutation or Pandered syndrome. The rising TSH with age due to insufficient dose or poor compliance also rules out the need of reassessment. The L-T4 therapy should be discontinued for 4–6 weeks, followed with measurement of TSH and FT4, and if biochemical profile confirms hypothyroidism, repeat thyroid imaging will be performed.[11]


  Intellectual Disability and Neurodevelopmental Outcome Top


The early detection and appropriate treatment of CH is associated with normal neurodevelopment. Universal NBS in developed countries has shown disappearance of intellectual disability (IQ <70) in treated patients with CH.[4] Children with CH should have regular monitoring of psychomotor and language development. School progress needs to be monitored and recorded.[11]

The earlier data estimated that 35%–40% cases diagnosed clinically before the introduction of NBS experienced overt disability.[38],[39] The analysis of current data suggests that it is more reasonable to conclude that approximately 25% children born with clinically diagnosed CH (1 in 25000 births) may have experienced overt disability before introduction of NBS. Despite an overestimation of intellectual disability, studies with long-term follow-up have proven excellent neurodevelopmental outcome in children with CH diagnosed and treated soon after birth.[40],[41],[42]

Children born with mild CH are treated routinely, but there is lack of good evidence that treatment affects long-term neurodevelopment.[4] The long-term studied cohorts who were screened for CH suggest that children with severe CH based on very low FT4 at diagnosis and delayed bone maturation are at risk to have lower IQ.[43],[44] However, rapid normalization of TSH and FT4 in upper normal range, vigilant monitoring with appropriate dose adjustment would result in normal intelligence.


  Conclusion Top


The NBS program is a major success to prevent CH-related neurodisability. The majority of cases can be diagnosed by any of NBS strategies [Table 2]. Immediate treatment is necessary after establishing the diagnosis. Frequent monitoring can avoid over- or under-treatment. TSH is a highly sensitive test but needs further studies to define the cutoff and to avoid false positive cases. Further studies are also needed to identify transient cases. Families and caregivers need detailed counseling about diagnosis, drug administration method, compliance, and consequences of poor treatment.

Practical points

  • Start treatment with L-T4 10-15 mcg/kg single daily dose without any delay
  • Only pharmaceutically produced liquid formulation should be used if available
  • Maintain TSH in age-specific range with FT4 in high normal range
  • Treatment should not be delayed for imaging purposes
  • Screening should be repeated in preterm, low birth weight, multiple birth, and sick babies requiring NICU admission
  • Reevaluate TSH and FT4 in 4–6 weeks if change of dose is required
  • There is no evidence for combination therapy of LT3 and LT4
  • There is no evidence for treating mildly elevated TSH with normal FT4
  • Off therapy trial should be considered after the age of 3 years.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Introduction
Epidemiology
Newborn Screening
Radiological Workup
Genetic Mutation...
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Dosing
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Intellectual Dis...
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