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R.Madhuri, Roll no: 5, Pharm D Intern, SVCP.

SEMINAR

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Function of THYROID GLAND The gland has two primary functions:

Secrete the thyroid hormones, which maintain the level of metabolism in the tissues that is optimal for their normal function.

Secretes calcitonin, a hormone that regulates circulating levels of calcium.

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ACTIONS OF THYROID HORMONES:T3 and T4• Increase BMR, the rate of oxygen consumption under standard or basal

conditions (awake, at rest, and fasting), by stimulating the use of cellular oxygen to produce ATP

• Maintenance of normal body temperature

• Stimulate protein synthesis and increase the use of glucose and fatty acids for ATP production

• Increase lipolysis. Enhance cholesterol excretion, thus reducing blood cholesterol level.

• Enhance some actions of the norepinephrine and epinephrine because they up-regulate beta receptors

• Together with human growth hormone and insulin, thyroid hormones accelerate body growth, particularly the growth of the nervous and skeletal systems.

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Iodide transport across the thyrocyte.

Iodine is an essential raw material for thyroid hormone synthesis.

Dietary iodide is absorbed by the intestine and enters the circulation.

The basolateralmembrane of thyrocytes facing the capillaries contain Na+/ I–symporter(NIS) that transports two Na + ions and one I–ion into the cell with each cycle, against the electrochemical gradient

The process involved is secondary active transport, with the energy provided by Na+K+ATPase.

Cl –/ I –exchanger known as Pendrin is present on the apical membrane of thyrocytes.

It mediates transport of iodide out of thyrocyte into the lumen, where colloid (Thyroglobulin -TG) is located.

THYROID HORMONE SYNTHESIS:

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Synthesis & secretion of thyroid hormone

As soon as iodide reaches apical membrane of thyrocyte, it undergoes a two step process called organification.

First, it is oxidized to iodine.

DUOX2 (Dual Oxidase-2) located in the apical membrane generates H2O2, which utilized by thyroid peroxidase (TPO) for oxidation of iodide into iodine.

Thyroid peroxidase (TPO) also catalyzes incorporation of iodine into tyrosine residues of thyroglobulin.

Next step is incorporation of iodine into tyrosine residues of thyroglobulin.

The thyroid hormones so produced remain part of the thyroglobulin molecule (colloid) until needed.

Colloid represents a reservoir of thyroid hormones, which can serve body requirements up to 2 months.

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Synthesis & secretion of thyroid hormones

During incorporation of iodine into Tyrosine residues of Thyroglobulin, following molecules are formed:

3-iodo tyrosine –Monoiodotyrosine(MIT) 3,5-di-iodo tyrosine –Diiodotyrosine(DIT)

Condensation of two DITs -3,5,3',5'-Tetraiodothyronine (T4) Condensation of MIT with DIT-3,5,3'-Triodothyronine (T3) Condensation of DIT with MIT-3,3',5'-Triodothyronine (RT3)

Whenever is a need for thyroid hormone secretion, colloid is internalized by endocytosis. Lysosomal degradation of thyroglobulin occurs.

T4 (80 μg/day), T3(4μg/day) & RT3(2 μg/day) are secreted into circulation.

MIT and DIT are not secreted, they are deiodinated by a microsomal iodotyrosine deiodinase and are reutilized.

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T4 and T3 are relatively lipophilic, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma.

Protein binding:•Maintains large pool of hormone that can readily be mobilized as needed.•Prevents excess uptake by the first cells encountered and promotes uniform tissue distribution

The plasma proteins that bind thyroid hormones are •Albumin, •Transthyretin (Thyroxine-binding Prealbumin) and •TBG.

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T3 is 3-5 times more potent than T4.

•Deiodinationof T4occurs at tissue level by Selenocysteine containing enzyme Deiodinase (D1, D2 & D3 isoforms) to produce T3 .

•Deiodinase activity varies among different tissues & at different periods.

•Cerebral cortex and pitutary gland have maximal Deiodinase activity resulting in maximum T3/T4 ratio in them.

•Thyroid hormones enter cells and act by binding to nuclear receptors.

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Effects of thyroid hormones

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CONGENITAL HYPOTHYROIDISM Thyroid hormone deficiency present at birth. Most common preventable cause of mental retardation. Prevalence 1:3000-4000 Worldwide, 1:2500-2800 in India. Twice common in girls compared to boys.

Till 18-20 weeks, the fetus is dependent on trans-placental passage of maternal hormones.

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Congenital Hypothyroidism -Terminology Primary hypothyroidism: Deficient production of thyroid hormones, either due to structural

(dysgenesis) or functional (dyshormonogenesis) causes.

Secondary or central hypothyroidism: Deficiency of TSH

Peripheral hypothyroidism: Results from defects of thyroid hormone transport, metabolism, or action at

the target site.

Permanent congenital hypothyroidism: Persistent deficiency of thyroid hormone that requires life-long treatment.

Transient congenital hypothyroidism temporary deficiency of thyroid hormone, discovered at birth, but then

recovering to normal thyroid hormone production.

Syndromic hypothyroidism: Some forms of CH are associated with defects in other organ systems.

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Congenital Hypothyroidism –Two scenarios

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Clinical features of Congenital Hypothyroidism

Most infants with congenital hypothyroidism are asymptomatic at birth to the trans-placental passage of maternal T4.

Post maturity (In 20%, gestation extends beyond 42 weeks) Birth weight and length are normal. Head size may be slightly increased because of myxedema of the brain. Wide posterior fontanelle Prolongation of physiologic jaundice. Sluggishness, cry little Poor appetite -feeding difficulties Lack of interest, Somnolence Protruberent abdomen, umbilical hernia Macroglossia Cold or mottled skin Hypotonia

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By 3-6 months of age the clinical picture is fully developed, if untreated.The child’s growth will be stunted, the extremities are short, and the head size is normal or even increased.

Coarse facial features: o The eyes appear far apart.o The bridge of the broad nose is depressed. o The palpebral fissures are narrow and the eyelids are swollen. o The mouth is kept open, and the thick, broad tongue protrudes. o Dentition will be delayed. o The neck is short and thick, and there may be deposits of fat above the

clavicles and between the neck and shoulders.o The hands are broad and the fingers are short. o The skin is dry and scaly.o The scalp is thickened, and the hair is coarse, brittle, and scanty. The

hairline reaches far down on the forehead.

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o Myxedema is manifested, particularly in the skin of the eyelids, the back of the hands, and the external genitals.

o Carotenemia can cause a yellow discoloration of the skin, but the sclerae remain white.

o Development is delayed. o Voice is hoarse.o Sexual maturation may be delayed.

Infants Children and Adolescents

Hypothermia Growth failure Poor feeding Markedly delayed bone maturationBradycardia Delayed eruption of permanent teeth

Jaundice Muscle pseudohypertrophy

Enlarged posterior fontanel Delayed or precocious puberty Umbilical hernia Pituitary enlargement

Galactorrhoea

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Post natal changes in Thyroid hormones

TSH•Within 30-60 min after delivery, there is an early post natal surge upto 60-80 mU/L in response to cold in utero environment.•Rapid fall to 20 mU/L in 24 hours.•Falls to 10 mU/L by one week.

T4•Peaks to 17 μg/dL at 24-36 hours.•Gradual decline over 4-5 weeks.Pre-terms exhibit similar but blunted response.

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Screening for Congenital Hypothyroidism

Ideal is screening at 3-4 days of age.

Newborns with following indications must be screened:

1.Having clinical features of congenital hypothyroidism or family history.2.History of thyroid disease or anti-thyroid medication intake in mother.3.Presence of other conditions like • Down’s syndrome• Trisomy 18• Neural tube defects• Congenital heart disease• Metabolic disorders• Familial autoimmune disorders• Pierre-robin syndrome

which are associated with higher prevalence of congenital hypothyroidism.

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Quebec Clinical Scoring for Congenital Hypothyroidism

If the score is > 4 / 13, hypothyroidism is suspected and the child is investigated accordingly.

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Antenatal Diagnosis

o Majority of cases of congenital hypothyroidism are sporadic, not heritable.

Women who are at high risk for fetal hypothyroidism are:

Previous infant with congenital hypothyroidism (resulting from dyshormonogenesis or maternal TRB-Ab)

Pregnant woman with Graves’ disease and treated with anti-thyroid drugs

Iodide exposure during pregnancy, treatment with radioactive iodine (RAI) after 8-10 weeks gestation.

o Hypothyroidism is suspected if there is fetal goiter, increased amniotic fluid and fetal bradycardia.

o Measurement of amniotic fluid TSH or thyroid hormone levels are not reliable, and fetal umbilical cord blood levels are necessary to diagnose fetal hypothyroidism.

o Genetic testing on fetal cells obtained by amniocentesis confirms the diagnosis.

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Most cases are sporadic.

Dyshormonogenesis,

Maternal antithyroid drugs and iodide usage,

Endemic iodine deficiency and

Neonatal graves’ disease

CONGENITAL GOITRE

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Treatment of fetal hypothyroidism

• Significant enlargement of the thyroid at birth may lead to respiratory distress and can even cause death. Partial thyroidectomy may be needed in such cases.

• Hypothyroidism diagnosed antenatally is treated with weekly intra-amniotic injections of L-thyroxine.

• Initial dose is 250 mcg of L-thyroxine per week(range 250 to 600 mcg).

• Subsequent dosing is based on the treatment effect in reducing the size of the fetal and on repeat fetal cord blood thyroid tests.

• Main aim of antenatal therapy is to shrink the goiter. Role in long term neuro cognitive outcome is questionable.

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Treatment of congenital hypothyroidism

o Infants with low T4 and elevated TSH should be started on L-Thyroxine as soon as the diagnosis is made.

o Initial dose of L-Thyroxine is 10-15 μg/Kg/day.

o Infants with severe hypothyroidism (very low T4, very high TSH and absence of distal femoral and proximal tibial epiphyses on radiograph of knee) should be started with the highest dose of 15μg/Kg/day.

o Preferred preparation is Sodium Levothyroxine. It has uniform potency, reliable absorption and good bioavailability.

o Daily dose should be crushed and placed directly on the tongue in the morning.

o Iron and Calcium preparations interfere with its absorption.

o If a dose is missed, then double dose should be given on the next day.

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Treatment of congenital hypothyroidism

Goal of therapy:• T4 should be kept in the upper half of normal range (10-16 μg/dL) or• free T4 in the 1.4-2.3 ng/dl range with TSH in normal range.• It takes less than a week for T4 to raise and 4-5 weeks for TSH to

normalize.

Monitoring:Free T4 is a more robust marker, as it represents the bioavailable fraction of T4.Low total T4 and normal TSH: a)If free T4 is normal >>> Congenital complete or partial TBG deficiency.b)If free T4 is low >>> Suspect central hypothyroidism.

T4 and TSH should be monitored according to following schedule.

Growth and development of infant should be monitored.

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Transient hypothyroidism

Presumed to be due to maternal goitrogenic drugs:

o It needs to be treated, if low T4and high TSH. o Therapy can be discontinued after 8-12 weeks, if values return to

normal.

Presumed to be due to maternal autoimmune thyroiditis:

o If TBII (Thyroxine Binding Inhibitory Immunoglobulin) are documented in infant, treatment should be started if T4 is low and continued for 3-6 months.

o If it is not possible to document TBII, continue treatment till the age of 3 years and then give a trial off therapy for 6 weeks followed by retesting of T4 and TSH to determine the need for continuation of therapy. If they are normal, monitor TSH annually.

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Prognosis•It depends on age of onset of treatment, starting dose of L-Thyroxine & severity of hypothyroidism.

•Age of onset of treatment: In infants in whom treatment was started between birth and 3 months of age, the mean IQ was 89; between 3 and 6 months of age, the mean IQ was 71; while if treatment did not start until after 6 months of age, the mean IQ dropped to 54.

•Starting dose of L-Thyroxine: Outcome is better in children on “high” dose 10.1-15 mcg/kg/day than “low” dose 6-8 mcg/kg/day and “intermediate” dose 8.1-10.0 mcg/kg/day.

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CONCLUSION:

• Congenital hypothyroidism is quite common in Indians and is the most common reversible congenital cause of mental retardation.

• Early identification and intervention is important as Thyroid dependent brain development is complete by 3 years of age.

• Serum Thyroid hormone levels are of primary importance in diagnosing and managing this condition, other investigations are ancillary.

• Age based reference values must be followed in interpreting the results.

• Timely monitoring (serum hormone levels, compliance, growth & development) and adequate counseling of care givers are key in managing this condition.

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REFERENCE:• American Academy of Pediatrics Newborn Screening for Congenital

Hypothyroidism: Recommended guidelines. Pediatrics 1993; 91: 1203 - 8.

• Maynika V Rastogi, Stephen H LaFranchi. Congenital hypothyroidism, Rastogi and LaFranchi Orphanet Journal of Rare Diseases 2010, 5:17 http://www.ojrd.com/content/5/1/17

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