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Common Endocrine Problem I

Overviews and objectives. Thyroid disorder- Congenital hypothyroidism/ neonatal screening- Acquire hypo/hyperthyroidism/euthyroid goiterGrowth disorders- Definition of short stature- Etiology- Growth chart interpretationAdrenocortical insufficiency- Definition of adrenocortical insufficiency- Congenital adrenal hyperplasia.

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Common Endocrine Problem I

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    1. Common Endocrine Problem I Nattakarn Wongjitrat Endocrine unit Department of Pediatric Faculty of Medicine Srinakharinwirot University

    2. Overviews and objectives Thyroid disorder - Congenital hypothyroidism/ neonatal screening - Acquire hypo/hyperthyroidism/euthyroid goiter Growth disorders - Definition of short stature - Etiology - Growth chart interpretation Adrenocortical insufficiency - Definition of adrenocortical insufficiency - Congenital adrenal hyperplasia

    3. Endocrine organ

    4. What is hormone ? Hormones: cell to cell communication molecules Made in gland(s) or cells Transported by blood / extracellular fluids Distant / local target tissue receptors Activates physiological response

    5. General Functions of Hormone Energy production, utilization and storage Reproduction Growth and development Internal balance of body systems Response to surrounding stress and injury

    6. Thyroid Disorders

    7. Thyroid hormone synthesis

    8. Thyroid hormone metabolism

    9. Thyroid hormone action

    10. Thyroid disorders 1. Hypothyroidism Congenital hypothyroidism Acquired hypothyroidism 2. Hyperthyroidism Graves' disease 3. Euthyroid goiter Simple goiter Autoimmune thyroiditis Acute suppurative thyroiditis Thyroid tumor

    11. Hypothyroidism

    12. Hypothyroidism Congenital hypothyroidism Acquired hypothyroidism

    13. 1. Congenital hypothyroidism Most common cause is Permanent hypothyroidism (90%) Thyroid dysgenesis; Incidence = 1:4,000 Clinical presentation Vary Depend on age group, cause of disease and severity

    14. Etiology Permanent hypothyroidism (90%) Thyroid dysgenesis: agenesis, hypoplasia, ectopic Familial thyroid dyshormonogenesis: autosomal recessive (AR) inborn errors of thyroid hormone synthesis, secretion, or uptake Iodine deficiency Hypopituitarism Transient hypothyroidism (10%) Transplacental passage of maternal TSH-binding inhibitory antibodies Maternal exposure to radioiodine Iodine deficiency Goitrogens Transient hyperthyrotropinemia: Down syndrome

    15. Clinical findings of congenital hypothyroidism Early neonate Prolonged jaundice > 7 days Edema Poor feeding Hypothermia Abdominal distention Large posterior fontanel (> 5 mm.) During the first month of age Peripheral cyanosis and mottling Respiratory distress Failure to gain weight and poor suckling ability Decreased stool frequency Decreased activity and lethargy During the first 3 month of age Umbilical hernia Constipation Dry skin Macroglossia Generalized myxedema Hoarse cry Anemia (normocytic, normochromic)

    16. Diagnosis Mostly asymptomatic or nonspecific symptoms during the neonatal period (95%). Neonatal screening would be the best intervention for congenital hypothyroidism. TSH screening: perform in Japan, Europe & Thailand - If TSH > 25 mU/L ? Check T4 & TSH level - Best period = 2 – 6 days of age or before discharging from hospital

    17. Management of CH

    18. 2. Acquired hypothyroidism Autoimmune CLT (Chronic lymphocytic thyroiditis, Hashimoto thyroiditis) Subacute thyroiditis Goitrogen ingestion Endemic goiter Euthyroid sick syndrome (non-thyroidal illness) Irradiation of the thyroid gland Infiltrative and storage disorders of the thyroid gland (histiocytosis X and cystinosis) Surgical excision

    19. Thyroiditis Acute suppurative thyroiditis Subacute nonsuppurative thyroiditis Chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis)

    20. Chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) Most common cause of goiter and hypothyroid in childhood Peak age group: 8 – 15 years old Female:male = 4:1 Cause: Autoimmune attack on thyroid gland Thyroid antibodies was found 80 – 95% Thyrotropin receptor antibodies may be found Pathology: lymphocytes infiltrate between thyroid follicles

    21. Course of diseases : can be found in 3 types 1. Euthyroid Hashimoto thyroiditis 2. Subclinical hypothyroidism (compensated hypothyroidism) 3. Overt hypothyroiditis Clinical findings - Depend on each stage of disease - Insidious onset - Diffuse goiter, firm, freely movable, nontender, pebbly consistency - Sensation of tracheal compression, hoarseness, dysphagia - No local signs of inflammation - No evidence of systemic infection

    22. Lab investigations Variable, depend on each stage of disease TFT is usually normal In subclinical hypothyroidism; T4 & T3 are normal, elevated TSH In overt hypothyroidism; T4 & T3 are decreased, elevated TSH Thyroid antibodies (antithyroglobulin, antithyroid peroxidase): usually present Thyroid scan; diffuse or patchy pattern, cold nodules

    23. Thyroid Antibodies Thyrotropin receptor antibodies - TR blocking Ab (TRBAB) - TR stimulating AB (TRSAB) 2. TPO antibodies (anti microsomal ) 3. Antithyroglobulin

    24. Treatment Depend on the stage of thyroiditis Euthyroid stage; F/U TFT (T4 & TSH) q 6 – 12 mo Subclinical hypothyroidism; F/U q 3 – 6 mo - Evaluate thyroid gland’s size, growth and puberty - Evaluate TFT (T4 & TSH) - No need for any treatment Overt hypothyroidism; - L-thyroxin (Eltroxin) - Help in decreasing the size of goiter in 3 months

    25. Hyperthyroidism

    26. Etiology 1. Overactivity of thyroid gland (hyperthyroidism) 1.1 Graves' disease 1.2 Neonatal Graves' disease 1.3 Autoimmune functional nodule Toxic adenoma Hyperfunctioning papillary or Follicular carcinoma McCune-Albright syndrome 1.4 TSH-induced hyperthyroidism Thyrotropin (TSH) – producing pituitary adenoma Pituitary resistance to thyroid hormone 1.5 Tumor-produced thyroid stimulators Human chorionic gonadotropin – secreting tumors Choriocarcinoma 1.6 Iodine-induced thyrotoxicosis (Jod-Basedow) 2. Receiving exogenous thyroid hormone

    27. The vast majority of cases in children are caused by “Graves' disease”

    28. Graves' disease Multisystem autoimmune disorders Classic triad - Hyperthyroidism (goiter) - Exophthalmos - Dermopathy (rare in children) Incidence: 10 – 15% in childhood thyroid disorders Increases with age (peak in adolescence) and family history Male:female = 1:4-5

    29. Clinical findings History Nervousness, irritability, emotional lability Tremor Excessive appetite, weight loss Smooth, moist, warm skin and flushed face Heat tolerance Deterioration in school performance Weakness, dyspnea Amenorrhea

    30. Physical exam Goiter (diffuse, firm, may present bruit) Exophthalmos and proptosis (lid lag, lid retraction) Tachycardia Systolic ejection murmur Widened pulse pressure (systolic hypertension) Fine tremor Accelerated growth and advanced bone age In neonatal hyperthyroidism; hepatosplenomegaly and thrombocytopenia

    31. Lab investigations 1. Thyroid function test Increased T4, T3, Free T4, Free T3 T3 increased more than T4 T3 thyrotoxicosis (10 – 20%) TSH level : very low 2. Positive autoantibodies; Thyroid stimulating immunoglobulin (TSI); 87% Antithyroglobulin & antimicrosomal antibodies; 70% 3. Radioiodine uptake : elevated

    32. Thyroid Antibodies Thyrotropin receptor antibodies - TR blocking Ab (TRBAB) - TR stimulating AB (TRSAB) 2. TPO antibodies (anti microsomal ) 3. Antithyroglobulin

    33. Treatment 1. Medical treatment Antithyroid medication (Thiourea derivatives) Propylthiouracil: 5 – 7 mg/kg/day, tid Methimazole: 0.5 – 0.7 mg/kg/day, OD-bid F/U TFT (T4, T3, TSH) ? maintainance dose (at least 2 yr) ?-blocker (control sympathomimetic symptoms) Propanolol or atenolol Continue until T4 / T3 are under control 2. Radiation Therapy - Radioactive iodide (131I) ablation of thyroid gland - Definite therapy (90 – 100% effective); if.. Failure of medical treatment and non compliance Remission does not achieve in 2 yr.

    34. Surgical treatment Subtotal thyroidectomy (80 – 100% effective) Indication Large thyroid gland with thyrotoxicosis Severe adverse drug reaction from antithyroid medication Failure of medical treatment and non complicance Complication Permanent hypothyroidism; lifelong thyroxine replacement needed Recurrent laryngeal nerve injury and paralysis

    35. Short stature

    36. Pituitary hormone

    37. GH action

    38. Growth with growth hormone

    39. Definitions of growth failure Height below third percentile or -2SDS for age and gender Height significantly below genetic potential Abnormally slow growth velocity Downwardly crossing percentile channels on growth chart after the age of 18 months

    40. Etiology

    41. Diagnosis of short stature History – History of growth problem – Pre- and peri-natal events – Medical Hx – Psychosocial Hx – Family Hx • Examination – Measurements: wt, ht, sitting ht, head circumference, HV – PE: puberty, body proportion, dysmorphism, specific signs (Turner, Noonan, GHD, Cushingoid, septo-optic dysplasia, etc)

    42. Diagnosis of short stature Laboratory – Chemistry – Hormone • GH • IGF-1 • IGFBP-3 • Free T4/TSH – Chromosome / Molecular – Radiology: BA – MRI: sella

    43. Growth chart interpretation

    47. Genetic factors

    49. Congenital adrenal hyperplasia Adrenal insufficiency

    51. Adrenal steroidogenesis

    52. Feedback regulation : Hypothalamic-pituitary-adrenal axis

    53. Feedback regulation : Renin-angiotensin-aldosterone system

    54. Functional of steroid hormones Glucocorticoids  Regulate glucose (blood sugar) levels Increase fat in the body Help to defend the body against infection Help the body respond to stress Mineralocorticoids  Regulate the Body's sodium and potassium levels, Blood volume, and blood pressure.

    55. Functional of steroid hormones In women promote the development of secondary sex characteristics In men most androgens are produced in the testes. Androgens made by the adrenal glands are not as important for normal sexual function.

    56. Cause of Adrenal Insufficiency

    57. Primary adrenal insufficiency Congenital adrenal hyperplasia Congenital adrenal aplasia/hypoplasia Congenital adrenal aplasia X-linked adrenal hypoplasia Mutations of steroidogenetic factor 1 transcription factor IMAGe association Autoimmune AD Isolated autoimmune AD APS type1 APS type 2 Metabolic lipid disorders Adrenoleukodystrophy (ABCD gene) Zellweger syndrome (PEX-1 gene) Wolman syndrome (Acid lipase deficiency) Massive bilateral adrenal hemorrhage Adrenal hemorrhage of the newborn Adrenal hemorrhage of acute infection (Waterhouse-Friderichsen syndrome) Thrombocytopenia and heparine therapy Infectious disorders Tuberculosis Fungal infection (histioplasmosis coccidiomycosis) Viral (HIV) Noninfectious disorders and adrenal tumors Amyloidosis Histiocytosis X Sarcoidosis Tumors (some related to p53 mutation) Congenital Forms Acquired Forms

    58. - Primary abnormal at adrenal gland - Lack of glucocorticoid & mineralocorticoid - Lack of cortisol no negative feedback CRH, ACTH, pro-opiomelanocortin (POMC) pigmentation - aldosterone renal excreation K ,H renal reabsortion Na

    59. Secondary adrenal insufficiency Hypothalamic disorder Pituitary disorder Cessation of glucocorticoid therapy Infants born to mothers treated with glucocorticoid

    60. - Primary abnormal at pituitary gl/hypothalamus ACTH/CRH cortisol - Normal aldosterone level - No skin hyperpigmentation

    61. Clinical manifestations of AI Glucocorticoid def fasting hypoglycemia increased insulin sensitivity decreased gastric acidity GI symptoms (nausea, vomiting) fatique muscle weakness

    62. Laboratory findings

    63. Congenital adrenal hyperplasia

    64. Congenital adrenal hyperplasia There are 5 major forms of CAH Each caused by a mutation of one of the five enzymes required for the biosynthesis of cortisol Autosomal recessive traits 70-75% of all cases of primary hypoadrenocorticism. 21-hydroxylase deficiency : 90% of all CAH

    65. Type of CAH 21 OH deficiency 11 ßOH defiency 3 ß hydroxysteroid dehydrogenase deficiency 17 a hydroxylase deficiency Steroidogenic acute regulatory protein deficiency ( STAR protein)

    66. 21- OHD Most common type 2 forms classic form salt wasting simple virilization non-classic form

    68. Classic salt wasting 21 OHD Cortisol deficiency - HPA axis ? ACTH increase ? hyperpigmentation - 17 OHP increase ? androgen production 46 XX ?ambiguous genitalia 46 XY ?precocious puberty - Hypoglycemia Aldosterone deficiency - Renal loss Na - Hyponatremia hyperkalemia with metabolic acidosis - Present 1-2 wk after birth

    69. Sign & symptom Ambiguous genitalia in 46XX Skin hyperpigmentation Failure to thrive and weight loss Vomiting and diarrhea Alteration of consciousness and seizure

    70. Ambiguous genitalia

    71. Laboratory Electrolyte hyponatremia,hyperkalemia with metabolic acidosis BUN and Cr prerenal renal failure Blood sugar Cortisol and ACTH 17 OHP Plasma renin activity Testosterone Chromosome study

    72. Adrenal crisis Fluid resuscitation NSS 20 cc/kg hr Hyponatremia + convulsion 3% NaCl Hyperkalemia - 10% calcium gluconate - 7.5% NaHCO3 - Glucose + insulin - Kayexalate Hydrocortisone 100 mg /m2 IV then 100 mg /m2 /day in 24 hr Precipitating conditions ??

    73. Long term treatment Glucocorticoid 10-15 mg of hydrocortisone /m2/day lifelong Mineralocorticoid 9 alpha fluorocortisol (florinef) 0.05 – 0.1 mg/day Salt 1-3 g/day Follow up 17 OHP hydrocortisone Plasma renin activity fluorocortisol Growth height and weight Fever & surgery hydrocortisone 3-10 times Surgery for ambiguous genitalia

    74. Cortisol production rate (CPR) 12-15 mg/m2/day in infant and younger child 8-10 mg/m2/day in older child and adult

    75. Glucocorticoid preparations

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