HYPOTHYROIDISM CLINICAL FEATURES

    

1.      What are the clinical features of congenital hypothyroidism in a newborn?

The clinical manifestations are commonly subtle in newborns with congenital hypothyroidism (CH).

 

Newborns with CH may be asymptomatic because of presence of maternal T 4 (which contributes to approximately one-third of circulating T 4 in a newborn) and residual functioning thyroid tissue.

 

FEATURES AT BIRTH

 

The classical symptoms of congenital hypothyroidism include

·         lethargy,

·         hoarse cry,

·         feeding difficulty,

·         constipation not responding to treatment, and increased somnolence.

 

The characteristic signs of CH include

·         Prolonged neonatal jaundice,

·         Macroglossia,

·         Umbilical hernia,

·         Wide posterior fontanelle,

·         Hypotonia,

·         Dry skin,

·         Head circumference may be slightly increased d/t myxedema of brain

·         Hypothermia.

·         Hirsute forhead

·         Twenty percent of neonates with CH have history of postmaturity (>42 weeks).

·         Birth length is normal, while birth weight may be >90th percentile.

 

 

v  Presence of goiter points to a clinical diagnosis of thyroid dyshormonogenesis, whereas absence of goiter suggests thyroid dysgenesis; however it does not rule out dyshormonogenesis.

 

v  In addition, oral cavity should also be carefully examined for lingual thyroid.

 

v  Deafness may be present in newborns with CH as an association with congenital hypothyroidism or as a manifestation of Pendred syndrome.

 

v  Delayed bone age is a characteristic feature of CH, as evidenced by the absence of distal femoral and proximal tibial epiphysis in approximately 54 % of neonates at birth.

2.      Are congenital malformations common in newborns with congenital hypothyroidism?

 

·         There is a four-fold higher prevalence of congenital malformations in newborns with congenital hypothyroidism as compared to general population (8.4 % vs.2 %).

 

·         Congenital cardiac malformations are most common, followed by malformations of nervous system and eyes and cleft lip/palate.

 

·         The most common congenital cardiac malformation is ostium secundum atrial septal defect, followed by tetralogy of Fallot and pulmonary stenosis.

 

·         They might present with bradycardia, murmurs, heart failure and cardiomegaly.

                                                                                                     

If CH go unrecognized at birth there will be a delay in the physical and mental development over time and by 3-6 months of age the clinical picture is fully developed.

 

3.      Which type of anemia is present in CH?

Macrocytic hypochromic

 

4.      Can breast feeding help supply adequate thyroid hormones?

Although breast milk contains significant amounts of thyroid hormones particularly T3, it is inadequate to protect the breastfed infant with CH and has no effect in neonatal thyroid screening.

 

5.      What are the radiological manifestations of congenital hypothyroidism?

 

·         Thyroid hormones play an important role in epiphyseal growth and development.

 

·         Thyroid hormone deficiency during intrauterine period may result in absent distal femoral and upper tibial epiphyses (in a term newborn) and wide posterior fontanels.

 

·         Epiphyseal dysgenesis, short long bones, anterior beaking of 12th thoracic, first and second lumbar vertebra, enlarged sella, and delayed bone age are other manifestations of untreated congenital hypothyroidism in a child.

 

 

 

6.      What may be the probable cause of subcutaneous nodules (ossification) in CH?

 

It may indicate the CH d/t of pseudohypoparathyroidism as seen in GNAS mutation.

 

7.      If a CH at birth goes undetected the child may develop following features

FEATURES AFTER 3-6 MONTHS IF UNTREATED

1.      What is Kocher – Debre – Semelaigne syndrome?

·         Kocher–Debre–Semelaigne syndrome refers to pseudohypertrophy of calf muscles as a result of long-standing untreated congenital/juvenile hypothyroidism.

 

·         Pseudo hypertrophy is a result of accumulation of glycogen, glycosaminoglycans,and connective tissue in the muscle as a result of hypothyroidism.

 

·         Male are more prone.

·         These patients are more prone to develop severe and prolonged hypothyroidism.

 

·         H/O of consanguity is often present.

 

·         The level of creatine phosphokinase is mildly elevated and electromyogram shows a myopathic pattern.

·         The counterpart of Kocher–Debre–Semelaigne syndrome in adults is Hoffman’s syndrome.

 

·         Both these disorders are reversible with thyroxine therapy.

 

9.      Can a case of CH present beyond infancy?

 

·         Yes, some cases with mild CH aren’t identified by neonatal screening program.

 

·         This is particularly true in cases of ectopic thyroid where ectopic gland can produce sufficient hormones for certain duration of life.

 

·         When the amount of hormones cannot meet the demand particularly during the growing and developing age group of children they manifest the symptoms.

 

 

                Children with trisomy 21 (down ) hav higher incidence of CH.

 

                If an infant has central hypothyroidism, the clinical manifestations are often related to associated deficiencies of other pituitary hormones and include hypoglycemia (growth hormone and adrenocorticotropic hormone), micropenis (growth hormone and/or gonadotropins), undescended testes (gonadotropins), and, least commonly, features of diabetes insipidus (vasopressin). 

 

NEONATAL SCREENING PROGRAM

1.      What are the physiological alterations in thyroid function during the neonatal

period?

 

·         Immediately after birth of a term baby, there is a physiological TSH surge,which can be as high as 80 μIU/ml.

 

·         The elevation of TSH occurs in response to exposure to cold environment after birth.

 

·         The elevated TSH increases free T 4 within 24–48h, which results in induction of non-shivering thermogenesis.

 

·         Thereafter, there is a decline in TSH (which starts after 60 min of birth) and free T 4 levels, and by second week free T 4 normalizes and TSH falls to <10 μIU/ml.

 

5. When to screen for congenital hypothyroidism?

 

·         Screening for congenital hypothyroidism is recommended in a newborn between the second and fifth day of life.

 

·         This is because, immediately after birth, there is a neonatal TSH surge, followed by rapid decline in serum TSH levels during the first 24h of life (serum TSH levels falls to 50 % of peak value by 2h and to

·         20 % by 24h). Thereafter, there is a gradual fall in serum TSH.

 

·         Hence, neonatal screening performed within the fi rst 24h of life frequently yields false-positive

results and is not preferred.

 

·         However, sampling from cord blood is indicated in those neonates whose mother is receiving antithyroid drugs or with history of previous baby with congenital hypothyroidism.

 

6.      How to screen for congenital hypothyroidism  ?

 

·         Sample obtained by heel prick is preferred for neonatal screening of congenital hypothyroidism.

 

·         Following heel prick, blood drop is placed on specially designed fi lter paper (Guthrie’s card), is allowed to dry (for 3h), and is sent to the laboratory.

 

·         The common strategies employed for neonatal screening include “primary TSH” or “primary T 4 –backup TSH.”

 

·         However, the ideal screening strategy is combined estimation of both T 4 and TSH.

 

·         All newborns with abnormal screening results should have a confi rmatory venous sample for FT 4 and TSH.

 

7.      Can cord blood be used for screening of congenital hypothyroidism?

 

·         Sample from umbilical cord can be used for screening of congenital hypothyroidism.

 

·         Cord blood contains mixed blood from both umbilical artery and veins and can be smeared on filter paper (dried blood spot, DBS) or can be used after separation of serum.

 

·         Cord blood sampling is performed immediately after birth (prior to neonatal surge which occurs after 30 min of birth), thereby reducing the number of false positive screening tests as a result of neonatal TSH surge.

 

·         However, cord blood is not recommended for neonatal screening for phenylketonuria (PKU) and congenital adrenal hyperplasia (CAH).

 

·         This is because sampling immediately after birth will result in under-diagnosis of phenylketonuria

and over-diagnosis (false positive) of congenital adrenal hyperplasia in newborns.

 

·         Screening for all these disorders (PKU, CAH, and CH) can be done from a single sample obtained from heel prick after 2–3 days of life.

 

8.      What are the merits and demerits of different strategies in neonatal screening

program for congenital hypothyroidism ?

·         The commonly used strategies for neonatal screening of congenital hypothyroidism include “primary TSH” and “primary T 4 –backup TSH.”

 

·         TSH is the most sensitive test for the diagnosis of primary congenital hypothyroidism; however, a primary TSH strategy will miss central hypothyroidism and neonates with hypothyroxinemia with delayed TSH rise (which is common in newborns with low birth weight).

 

·         In addition, congenital thyroxine-binding globulin deficiency will also be missed which may not be of clinical relevance.

 

·         The primary T4 approach can diagnose secondary hypothyroidism and thyroxine-binding globulin defi ciency; however the primary T 4 strategy will miss compensated hypothyroidism (e.g., in ectopic thyroid tissue) and subclinical hypothyroidism.

 

·         Both these approaches require a recall rate of approximately 0.05 % and may miss 3–5 % patients with congenital hypothyroidism.

 

·         This may be due to improper sample collection, technical difficulties with assays, and immaturity of hypothalamo–pituitary–thyroid axis.

 

·         “Simultaneous T 4 and TSH”-based neonatal screening is the ideal screening strategy; however, the cost- effectiveness of this approach has not been proven.

 

 

 

9.      What are the investigations required to establish an etiological diagnosis in a

newborn with confi rmed congenital hypothyroidism ?

In newborns with primary hypothyroidism, these include

·         Ultrasonography of neck,

·         Radionuclide

·         Thyroid scan ( 99m Tc pertechnetate/ 123 I scan),

·         Serum thyroglobulin, TRAbs, and

·         Urinary iodine levels.

 

In newborns with secondary hypothyroidism,

·         MRI sella,       

·         Other pituitary hormones, and

·         Ophthalmological evaluation for optic nerve hypoplasia should be performed.

 

10.  What are the causes of negative 99m Tc pertechnetate scan in a neonate with

congenital hypothyroidism ?

 

Absence of tracer uptake in a neonate with congenital hypothyroidism usually suggests a diagnosis of thyroid agenesis.

 

However, thyroid uptake may be absent even in the presence of eutopic thyroid gland in conditions like

·         Antenatal maternal iodine exposure,

·         Transplacental transfer of TSH receptor-blocking antibodies,

·         TSH suppression from L-thyroxine treatment, TSH receptor- inactivating mutations,and Dyshormonogenesis due to sodium–iodide symporter (NIS) defect.

 

Therefore, ultrasonography of the thyroid and estimation of thyroglobulin shouldbe performed to establish the diagnosis of thyroid aplasia.

 

 

 

 

11.  How to approach a newborn with congenital hypothyroidism?

 

·         Thyroid radionuclide uptake and scan ( 99m Tc pertechnetate/ 123 I scan) is the preferred first-line investigation in a newborn with primary CH, and this can be done even within a week after initiation of L-thyroxine therapy.

 

·         An approach to newborn with congenital hypothyroidism is shown in the figure

given below.

 

·         If a child was not evaluated for the etiology of congenital hypothyroidism before initiation of therapy, L-thyroxine should not be discontinued, and the child may be reevaluated after 3 years of age.

 

 

12.  How to treat congenital hypothyroidism?

·         The goal of therapy in congenital hypothyroidism is normalization of T 4 /FT 4 and TSH as rapidly as possible (T 4 /FT 4 within 2 weeks and TSH within a month) for normal growth and development. Oral

 

·         L-thyroxine (L-T 4 ) is the therapy of choice for congenital hypothyroidism.

 

·         Although T3 is required for neuronal growth and development, T 3 in brain is predominantly derived from local deiodination of circulating T 4 ; hence therapy with T 3 is not recommended.

 

·         L-thyroxine should be initiated at a dose of 10–15 μg/Kg/day for infants aged 0–3 months, 8–10 μg/Kg/day for 4–6 months, and 6–8 μg/Kg/day for infants of 7–12 months.

 

·         The tablet must be crushed and mixed with breast milk/formula feed/water before administration.

 

·         L-thyroxine tablet should not be mixed with preparations containing iron/calcium/soya as they interfere with the absorption of L-T 4.

 

·         L-thyroxine tablet should be ideally taken in empty stomach and food should be avoided for 30 -60min which is practically impossible in infants.

 

13.  How to monitor a newborn with congenital hypothyroidism on L – thyroxine therapy?

·         After initiation of therapy, infants should be closely followed up with estimation

of T 4 /FT 4 and TSH every 1-2 months for first 6 months of life and then 2-4 monthly between 6 months and 3 years.

 

·         Sample for thyroid profile can be taken either before the administration of next dose or at least 4h after intake of L-thyroxine.

·         TSH should be maintained in the age-specific normal range and T 4 /FT 4 in the upper half of age-specific normal range.

.

·         However, it should be noted that some infants may have TSH above the reference

range, despite having T 4 /FT 4 above age-specifi c normal range. This is possibly because of resetting of hypothalamo–pituitary–thyroid axis as a result of long-standing hypothyroidism during intrauterine life.

 

·         Linear growth and milestones should be regularly monitored in children with congenital hypothyroidism on therapy.

 

·         In addition, periodic assessment for hearing is also essential in these children.

 

 

14.  What is the neurological outcome of newborns with congenital hypothyroidism?

 

·         It is important to initiate therapy as early as possible (preferably within 2 weeks of birth)in newborns with congenital hypothyroidism for optimal neurocognitive development.

 

·         It has been shown that early therapy is associated with near normal intellectual outcome.

 

·         However, newborns with severe congenital hypothyroidism (as evidenced by athyreosis, absent distal femoral epiphysis,FT 4 <0.38 ng/dl, and significantly elevated TSH), delay in initiation of L-T4 therapy (>6 weeks) and those with poor compliance to therapy may have subnormal IQ and cognitive score.

 

 

15.  What is cretinism?

·         Cretinism is a disorder characterized by irreversible mental disability and

poor linear growth due to severe thyroid hormone defi ciency during pre- and/

or early postnatal period (<3 years of age).

 

·         Cretinism can be endemic or sporadic.

 

 

16.  What are the differences between endemic cretinism and sporadic congenital

hypothyroidism?

·         The differences between endemic cretinism and sporadic congenital hypothyroidism are summarized in the table given below.

 

 

 

17.  What is endemic cretinism?

·         Endemic cretinism is characterized by irreversible mental disability in individuals born in endemic iodine-deficient regions and exhibit some or all of thefollowing features including;

§  neuromuscular dysfunction (spasticity, motor inco-ordination, and squint),

§  deaf–mutism,

§  impaired linear growth, and

§  hypothyroidism with or without goiter.

 

·         Endemic cretinism occurs in regions where intake of iodine is <25 μg/day.

 

 

18.  What are the differences between neurological and myxedematous cretin?

·         Endemic cretinism can manifest as either neurological or myxedematous

cretinism. The differences between the two are summarized in the table given below.

 

 

19.  Why do some individuals with severe iodine deficiency develop myxedematous cretinism, while others develop neurological cretinism?

·         Severe maternal and fetal iodine deficiency results in endemic cretinism and

·         may manifest as neurological or myxedematous cretin.

 

·         The exact cause for variation in the presentation of endemic cretinism is not known; however, it is

·         thought that clinical manifestation of endemic cretinism is the result of two pathophysiologic events.

 

·         Severe thyroid hormone deficiency (as a consequence of severe maternal and fetal iodine deficiency) during early intrauterine period results in impaired brain development and, consequently, irreversible neuronal damage. This occurs in both variants of endemic cretinism.

 

·         Subsequent manifestation as either neurological or myxedematous cretinism depends on the

·         response of thyroid gland to severe iodine deficiency, i.e., either goiter or atrophy.

 

·         Those who develop goiter (and consequently compensated euthyroxinemia) manifest as neurological cretins, whereas those with thyroid gland atrophy (and consequently severe and persistent hypothyroxinemia) manifest as myxedematous cretins.

 

·         It is speculated that environmental factors like selenium deficiency and exposure to thiocyanate may modulate thyroid gland response to iodine defi ciency.

 

·         However, it should be noted that some individuals have features of both neurologic and myxedematous cretinism (mixed cretin).

 

20.  How does selenium deficiency and exposure to thiocyanate cause thyroid gland

atrophy in endemic iodine - deficient areas ?

·         Iodine defi ciency results in hypothyroxinemia and consequent increased TSH

·         drive leads to increased intrathyroidal hydrogen peroxide H₂O₂ production.

 

·         Glutathione peroxidase, a selenoprotein, protects thyroid gland from H₂O₂-mediated injury to thyroid follicular cells.

 

·         In the presence of selenium deficiency, there is accumulation of intrathyroidal H₂O₂ which results in follicular cell damage and f brosis.

 

·         Thiocyanate not only competes with iodine for sodium–iodide symporter in the thyroid gland but has also been shown to induce follicular cell necrosis.

 

 

21.  What is the treatment for endemic cretinism?

·         Endemic cretinism is a preventable disorder and optimal iodine supplementation prior to conception prevents the development of cretinism. Therefore,effective strategies for iodine supplementation should be implemented in iodine-defi cient areas.

 

·         In myxedematous cretins, iodine therapy has been shown to improve myxedematous features when initiated prior to the age of 3–4 years; however L-thyroxine should be preferred in children with myxedematous cretin.

 

·         Neurocognitive deficits do not improve either with iodine or L-thyroxine therapy in myxedematous cretins. Rehabilitation is the mainstay of therapy in neurological cretins.

 

22.  What are the precautions required for the optimal delivery of iodine from iodized salt ?

The following precautions should be observed while using iodized salt.

 

·         Salt should be purchased within 3 months from the date of manufacture and at the

time of purchase it should be crystal clear and white.

 

·         It must be stored in a dry airtight container along with plastic-pack and kept away from the furnace.

 

·         Once the pack is opened, it has to be consumed within 4 weeks.

 

·         Salt should preferably be added on table rather than during cooking, as iodine quickly sublimates

·         on exposure to heat.

        Thank You

Dr Nischal Neupane