INTRODUCTION

1. INTRODUCTION • Thyroid Disease is the Most Common EndocrinopathyObserved in Children • Incidences, Presentations, and Clinical Consequences Differ Markedly than in adults • Failure to Diagnose and Treat Promptly may Lead to Irreversible Neurologic Damage

2. THYROID GLAND • Derived from pharyngeal endoderm at 4/40 • Migrate from base of the tongue to cover the 2&3 tracheal rings. • Blood supply from ext. carotid & subclavian and blood flow is twice as renal blood flow/g tissue. • Starts producing thyroxin at 14/40.

3. Thyroid Development • Orignatesfrom thyroid diverticulum and ultimobranchial bodies • Ontogeny influenced by several transcription factors (TTF, PAX8, HOX3) • Largely complete by 10-12 weeks • Gradual Maturation in Hypothalamic-Pituitary-Thyroid Axis

4. Fetal Thyroid Maturation: • TSH detectable by 12 wks • Feedback mechanisms established by 20 wks • T3 levels remain low • Reverse T3 levels high

5. Placental and Fetal ThyroidMetabolism • Maternal and fetal glands are independent • Little T4 transplacental transfer • TSH does not cross the placenta although it is permeable to TRH, IgG, and thionamides • Fetal brain converts T4 to T3 efficiently • Effect of maternal hypothyroidism is most important in first trimester

6. Thyroid Changes at Birth • Cord Blood Thyroid Levels are Influenced by gestational age withProgressive increase with approach to term. • TSH surge at birth followed by T4 and T3 rise to approximates maternal level but increases rapidly during the first week of life. • Lower rise in preterm Infants • High TSH in the first 5 days of life can give false positive neonatal screening

7. THYROID HORMONES • Iodine & tyrosine form both T3 & T4 under TSH stimulation. • 10% of T4 production is autonomous and is present in patients with central hypothyroidism. • Less than 1% of T4 & T3 is free in plasma. • T4 is deiodinated in the tissues to either T3 (active) or reverse T3 (inactive). • When released into circulation T4 binds to: • Globulin TBG 75% • Prealbumin TBPA 20% • Albumin TBA 5%

8. TSH • Is a Glico-protein with Molecular Wt of 28000 • Secreted by the anterior pituitary under influence of TRH • It stimulates iodine trapping,oxidation,organification, coupling and proteolysis of T4 & T3 • It also has trophic effect on thyroid gland

9. T4 & T3 are feed-back regulators of TSH • TSH is stimulated by a-adrenergic agonists • TSH secretion is inhibited by: • Dopamine • Bromocreptine • Somatostatin • Corticosteroids

10. THYROXINE (T4) • Conversion of T4 to T3 is decreased by: • Acute & chronic illnesses • b-adrenergic receptor blockers • Starvation & severe PEM • Corticosteroids • Propylthiouracil • High iodine intake (Wolff-Chaikoff effect

11. Total T4 level is decreased in: • Premature infants • Hypopituitarism • Nephrotic syndrome • Liver cirrhosis • PEM • Protein losing entropathy

12. Total T4 is decreased with the following drugs : • Steroids • Phenytoin • Salicylates • Sulfonamides • Testosterone • Maternal TBII

13. Total T4 is increased with: • Acute thyroiditis • Acute hepatitis • Estrogen therapy • Clofibrate • iodides • Pregnancy • Maternal TSI

14. Thyroid hormones are essential for: • Linear growth & pubertal development • Normal brain development & function • Energy production • Calcium mobilization from bone • Increasing sensitivity of b-adrenergic receptors to catecholeamines

15. Hypothyroidism •Congenital • Acquired • – Primary • Surgery • Radiation • Autoimmune • Iodine Deficiency • – Secondary • Surgery • Radiation • Infiltrative • Tumor • – Primary • Thryoid Agenesis, Hypoplasia & mal-descent • Dyshormonogenesis • Iodine Deficiency • – Secondary • Hypopituitarism • Intake of goitrogens during pregnancy • Idiopathic

16. CONGENITAL HYPOTHYROIDISM

17. Epidemiology: • Incidence 1:4000 – Slightly higher in female infants – Higher in Asian babies – Lower in Black babies • Overt symptoms may not be present at birth • Profound effects on brain development, thus it is The most common cause of preventable mental retardation in children • Reliable testing available (T4 and/or TSH) • No sequelae if treatment initiated by 4 wks– 10-15 mcg/kg/d

18. Principles of NewbornScreening • Relatively High Prevalence • Deleterious Consequence of Delayed Diagnosis • Difficult ClinicalRecognition • Reliable Method of Screening (sensitive & specific) • Safe, Effective Treatment available

19. Etiology of Congenital Hypothryoidism: • Extensive testing for precise etiology is generally not necessary (will not change immediate care plans) • May allow assessment of risk in future pregnancies • May allow early determination of transient vs permanent disease

20. Transient Congenital Hypothyroidism: • Defined as abnormal newborn screen with • abnormal confirmatory labs • 75-80% of abnormal screens due to false + • Incidence estimated to be ~10% of cases • Most common in premature infants • Causes: – Iodine deficiency or excess – Maternal antithyroid medication – Maternal TSH receptor blocking antibodies

21. Maternal TSH receptor blocking antibodies: • Incidence estimated at 1:180,000 • Often history of treated Graves in mom • Mothers may have unrecognized hypothryoidism • Infant will not have goiter • Difficult to distinguish from thyroid dysgenesisMay have permanent neurocognitive deficit if present in utero • Resolves in 2-3 months as antibody clears

22. Cretinism is : • A condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroidhormones (congenital hypothyroidism)

25. Symptoms and Signs: • Gestational age > 42 weeks • Birth weight > 4 kg • Open posterior fontanel • Nasal stuffiness & discharge • Macroglossia • Constipation & abdominal distension • Feeding problems & vomiting

26. Non pitting edema of lower limbs & feet • Coarse features • Umbilical hernia • Hoarseness of voice • Anemia • Decreased physical activity • Prolonged (>2/52) neonatal jaundice

27. Dry, pale & mottled skin • Low hair line & dry, scanty hair • Hypothermia & peripheral cyanosis • Hypercarotenemia • Growth failure • Retarded bone age • Stumpy fingers & broad hands

28. Skeletal abnormalities: • Infantile proportions • Hip & knee flexion • Exaggerated lumbar lordosis • Delayed teeth eruption • Under developed mandible • Delayed closure of anterior fontanel

29. Neurological manifestations • Hypotonia& later spasticity • Lethargy • Ataxia • Deafness +Mutism • Mental retardation • Slow relaxation of deep tendon jerks

30. OCCASIONAL FEATURES • Overt obesity • Myopathy & rheumatic pains • Speech disorder • Impaired night vision • Sleep apnea (central & obstructive) • Anasarca • Achlorhydria & low intrinsic factor • Decreased bone turnover • Decreased VIII, IX & platelets adhesion • Decreased GFR & hyponatremia • Hypertension • Increased levels of CK, LDH & AST • Abnormal EEG & high CSF protein • Psychiatric manifestations

33. ASSOCIATIONS • Autoimmune diseases (Diabetes Mellitus) • Cardiomyopathy & CHD • Galactorrhoea • Muscular dystrophy + pseudohypertrophy (Kocher-Debre-Semelaigne)

34. Hashimoto thyroiditis • Most common cause of aquired hypothyroidism • Female: male ratio 3:1 • Most children presents with asymptomatic goiter or non specific Symptoms • Most frequent in Down and turner syndromes

35. DIAGNOSIS • Early detection by neonatal screening • High index of suspicion in all infants with increased risk • Overt clinical presentation • Confirm diagnosis by appropriate lab and radiological tests

36. LABROTARY FINDINGS • Low (T4, RI uptake & T3 resin uptake) • High TSH in primary hypothyroidism • High serum cholesterol & carotene levels • Anaemia (normo, micro or macrocytic) • High urinary creatinine/hydroxyproline ratio • CXR: cardiomegaly • ECG: low voltage & bradycardia

37. IMAGING TESTS • X-ray films can show: • Delayed bone age or epiphyseal dysgenesis • Anterior peaking of vertebrae • Coxavara & coxaplana • Thyroid radio-isotope scan • Thyroid ultrasound • CT or MRI

38. Treatment Guidelines • Confirm all abnormal newborn screens with laboratory TSH and free T4 • Borderline results may require repeat testing in 2-4 Wks • If repeat labs abnormal, begin thryoxine (25-37.5 mcg/day) • Goal is to start treatment within first month of life • Recheck q 2-3 months and adjust dose if Necessary • If no need to increase dose by 2 ½ -3 yrs, give 4 wktrial off of thyroxine

39. TREATMENT • Life-long replacement therapy • 5 types of preparations are available: • L-thyroxin (T4) • Triiodothyronine (T3) • Synthetic mixture T4/T3 in 4:1 ratio • Desiccated thyroid (38mg T4 & 9mg T3/grain) • Thyroglobulin (36mg T4 & 12mg T3/grain)

40. L-Thyroxin is the drug of choice. Start with small dose to avoid cardiac strain. • Dose is 10 mg/kg/day in infancy. In older children start with 25 mg/day and increase by 25 mg every 2 weeks till required dose. • Monitor clinical progress & hormones level

41. PROGNOSIS • Is good for linear growth & physical features even if treatment is delayed • for mental and intellectual development early treatment is crucial. • Sometimes early treatment may fail to prevent mental subnormality due to severe intra-uterine deficiency of thyroid hormones

42. Goiter: Differential Diagnosis • • Congenital • – Dyshormonogenesis • – Maternal Antibodies • • Blocking • • Stimulating • – Maternal Antithyroid drug • PTU, methimazole • – TSH receptor Activating • Mutation • – McCune Albright Syndrome • – Thyroid Tumor • • Acquired • – Inflammation • – Colloid • – Iodine Deficiency • – Goiterogen • – Infiltrative disease • – Toxic goiter • – Thyroglossal duct • cyst • – Adenoma • – Carcinoma

43. Endemic Goiter: • • Usually euthryoid • • Diffuse gland enlargement • • Rare in US (iodized salt provides adequate iodine • source) • • Rule out autoimmune thyroiditis • • Treament Doses in Children (6-12 months) • – Infants 100 mcg/d • – Children 200 mcg/day • – Adolescents 200-300 mcg/d

44. Hyperthyroidism: • • Graves Disease (>95% of Cases) • – Relatively rare in children • – Incidence increases with puberty • – Female:Male (3-5:1) • • Neonatal Graves; Transplacental Antibodies • • Hashitoxicosis • • TSH receptor mutations (gain of function); McCune Albright syndrome • • Subacute Thyroiditis • • Exogenous thyroxine Exposure

45. Neonatal Hyperthyroidism • • Almost always transient • • Usually associated with maternal Graves: • – Transplacental passage of TSI • – Blocking and stimulating Abs may coexist • • Incidence ~1:50,000 infants • – 1-2% of moms with Graves disease • • Often presents in first week of life • – Emerges with clearance of maternal thionamide

46. • Treatment: • – PTU or Methimazole • – SSKI (If severe symptoms) • – Propranolol (If significant sympathetic symptoms (HR>160)

47. Signs of Hyperthyroidism in Children • • Change in School Performance • • Insomnia • • Restlessness and Irritability • • Nocturia • • Bone age advancement • • Infants: Premature birth, Craniosynostosis, Poor feeding, Failure to Thrive

48. • Other classic signs: • – Weight Loss, Polyphagia, Tachycardia, Increased Pulse • Pressure, Heat Intolerance, Diarrhea, Tremor

49. Grave’s Disease: Diagnosis • • Suppressed TSH • • Elevated T4, Free T4, T3 levels • • Positive Thyroid Stimulating Antibodies: • (May be helpful if exophthalmos absent) • – Thyroid Peroxidase • – Thyroglobulin • – Thyroid Stimulating Immunoglobulin

50. Treatment of Graves’ Disease • • Radioactive Iodine • – Preferred treatment in older children and adolescents • – Theoretical risk of radiation not established • – Possible increased risk of thryoid cancer (<5yrs) • • Thionamides (methimazole, PTU) • – Agranulocytosis, hepatitis, rash • – Poor long term remission rates • – Difficult to titrate dose, frequent monitoring • – Poor compliance in adolescents • • Surgical Thyroidectomy; Rarely indicated