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Lecture 4 - Thyroid Disorders in Children: 1. 2. 3. 4. 5. 6. Objectives Define the clinical picture of hyperthyroidism and the typical onset in children. Recognize autoimmune disorders associated with both Graves Disease and Hashimoto’s Thyroiditis. Infer the treatment options for Grave’s Disease. Recognize the symptoms and physical exam seen with congenital hypothyroidism. Infer the importance of the neonatal state screen. Recognize the importance of treatment and implications of inadequate treatment of hypothyroidism in the neonate and young child. 7. Identify the causes and treatments for the most common causes of congenital and acquired hypothyroidism. 8. Differentiate lab findings between primary and central hypothyroidism. What Thyroid Hormone Does Increases O2 consumption Stimulates protein synthesis Influences growth and cell differentation Affects carbohydrate, lipid and vitamin metabolism T4 is critical to the myelinization of the central nervous system during the first 3 year of life The thyroid: How it works. How the Thyroid Works: (simple version) T4 binds tightly to Thyroxine Binding Globulin (TBG) Only 0.03% of T4 in serum is not bound 70% is bound to TBG (also binds to prealbumin, albumin, transthyretin) Unbound T4 is “free T4” T3 also bind to TBG (but less strongly) 0.3% of T3 in serum is not bound 50% is bound to TBG, 50% is bound to albumin Unbound T3 is “free T3” ONLY THE “FREE” T3 AND T4 IS ACTIVE T4 is also converted peripherally to T3 by thyroxine 5’ deiodinase Notes: Only 20% of circulating T3 is secreted by the thyroid; the remainder is produced by deiodination of T4 in the liver, kidney, and other peripheral tissues by type I 5′-deiodinase Thyroid Regulation: (Hypothalamic-Pituitary- Thyroid Axis) TRH: secreted by hypothalamus TSH: glycoprotein secreted by anterior pituitary Β subchain provides specificity TSH stimulates the thyroid gland to produce T3/T4 Notes: The thyroid is regulated by TSH, a glycoprotein produced and secreted by the anterior pituitary. This hormone activates adenylate cyclase in the thyroid gland and is important in all steps of thyroid hormone biosynthesis, from trapping of iodine to release of thyroid hormones. TSH is composed of 2 noncovalently bound subunits (chains): α and β TSH synthesis and release are stimulated by TSH-releasing hormone (TRH), which is synthesized in the hypothalamus and secreted into the pituitary. Case 1 CC: Heart beating fast HPI: 14 yo female presents to the ER with intermittent stabbing chest pain and rapid heart rate for 2 weeks. Pain is not associated with activity and does not radiate. Pain does not wake her at night. Patient reports shortness of breath with activity. Denies any recent illnesses or injuries. She has a history of anxiety, and her parents recently announced their intentions to divorce about 1 month ago. Review of Symptoms General: decreased appetite x 1 month, no change in activity. No fever. Apprx 5 pound weight loss over the last 2 months HEENT: No changes in vision, hearing or smell, Denies neck pain, sore throat or LAD. + nasal congestion (reports had a cold last week). Respiratory: Mild cough for 1 week. No difficulties breathing. +SOB as mentioned in HPI. No wheezing. Cardiovascular: +palpitations. No hx of heart murmur. Gastrointestinal: No abdominal pain. Denies vomiting, diarrhea. Soft, nonbloody stools daily. Genitourinary: Denies dysuria, polyuria or nocturia. Regular monthly menses since age 12. Denies pregnancy. Musculoskeletal: Denies joint pain or swelling. No reported muscle weakness. Neurological: Daily headaches since onset of intermittent chest pain. +dizziness with chest pain. No syncopal episodes. PMH: frequent ear infections, speech delay PSH: myringotomy tubes at 1 year old FH: Mother is hypothyroid. Congenital hearing loss in father. SH: Lives at home with mother, 18yo and 7yo brothers. Denies use of TOB, ETOH or other illicit drugs. Denies sexual activity. Is in the 8th grade, making B’s and C’s (decreased from A’ s and B’s at the beginning of the year) Medications: none Allergies: none Physical exam General: no acute distress, but does appear anxious, well hydrated, alert and oriented Height: 63” Weight: 52kg VSS: HR 112, BP 131/70, RR 27 HEENT: mild R side proptosis, + lid lag. oropharanyx normal, neck supple with palpable thyroid gland, no nodules Chest: No reproducible pain to fingerpoint palpation of the costochondral or costosternal junctions, no reproducible pain with trunk or shoulder movements. Breast tissue is nontender- Normal breast symmetry with secondary nipple mound Lungs: clear to ausciltation bilaterally Cardiovascular: tachycardic, heart is regular rhythm, no murmur. Normal S1 and S2. No ejection click. Brachial and femoral pulses are equal and strong. Abdomen: Soft, nontender. +BS. No masses GU: normal external genitalia- Pubic hair distribution is across the pubis but not extending to the inner thighs Musculoskeletal: no joint swelling or redness Neurologic: No focality. Cerebellar function intact. CN 2-12 intact. Strength 5/5 in all extremities. Sensation and proprioreception normal. +2 DTRS in extremities Clicker Question What is the Tanner Stage of this patient? A. 1 B. 2 C. 3 D. 4 E. 5 Tanner Stages Know breast buds occur in tanner 4 staging Tanner 2 for boys enlargement of the scrotum Differential Dx of heart palpitations Cardiac Arrhythmia Wolff Parkinson White syndrome Prolonged QT syndrome Hypertrophic cardiomyopathy (HCM) Myocarditis Sick sinus syndrome Cardiac structural abnormalities (eg, congenital heart disease, intracardiac tumors Premature atrial contractions Premature ventricular contractions Mitral valve prolapse Italics = more life threatening etiologies Back to Case 1 Workup and Evaluation Chest x-ray EKG CBC (complete blood count) Thyroid studies BMP (basic metabolic panel) Noncardiac Fever Anemia Exercise Emotional arousal Anxiety Panic attack Hyperventilation syndrome Drug-induced (caffeine, herbal medications, dietary supplements, albuterol, isotretinoin) Hypoglycemia Toxic exposure Pheochromocytoma Hyperthyroidism Hyperthyroidism Symptoms Hyperactivity, irritability, altered mood, insomnia, anxiety Heat intolerance, increased sweating Palpitations Fatigue, weakness Dyspnea Weight loss with increased appetite Pruritus Thirst and polyuria Oligomenorrhea or amenorrhea, loss of libido Signs Sinus tachycardia, atrial fibrillation (rare in children), supraventricular tachycardia Fine tremor, hyperkinesis, hyperreflexia Warm, moist skin Palmar erythema, onycholysis Hair loss Muscle weakness and wasting High-output heart failure Chorea Diffuse Goiter Ophthalmopathy, with proptosis and a gritty sensation **** more commonly seen with Graves Disease**** Hyperthyroidism results from excessive secretion of thyroid hormone and, during childhood, with few exceptions, is due to Graves disease The clinical manifestations of hyperthyroidism in children and adolescents are similar to those seen in adults. In addition, the disorder has unique effects on growth and development. Delay in puberty causes a secondary ammnorrhea loosening of the nails from the nail bed Graves Disease Most common form of hyperthyroidism in children (90% of cases) Etiology: Excessive thyroid hormone production, caused by thyrotropin receptor-stimulating antibodies (TRSAb) Ages 11-15yo most common Girls > boys Incidence 1:5000 children Family history of autoimmune disorder May be at increased risk for other autoimmune disorders Notes: thyrotropin receptor-stimulating antibody (TRSAb). TRSAb binds to the receptor for TSH and stimulates cyclic adenosine monophosphate, analogous to TSH itself. Graves disease is also associated with other HLA-D3-related disorders such as Addison disease, insulindependent diabetes mellitus, myasthenia gravis, and celiac disease. Systemic lupus erythematosus, rheumatoid arthritis, vitiligo, idiopathic thrombocytopenic purpura, and pernicious anemia have been described in children with Graves disease Ophthalmopathy is a hallmark of Graves disease The ophthalmopathy occurring in Graves disease appears to be caused by antibodies against antigens shared by the thyroid and eye muscle. TSH receptors have been identified in retro-orbital adipocytes and may represent a target for antibodies Ophthalmopathy is characterized by inflammation of the extraocular muscles and orbital fat and connective tissue, which results in proptosis (exophthalmos), impairment of eye muscle function, and periorbital edema. symptoms tend to be milder than those seen in adults Lid lag is evaluated by having the patient follow the examiner's finger as it is moved up and down. The patient has lid lag if sclera can be seen above the iris as the patient looks downward. in forward displacement and entrapment of the eye from behind by the eyelids Diagnosis and Treatment Diagnosis Elevated T3/T4 Decreased TSH + TRS-Ab (Thyrotropin-receptor stimulating antibodies) +/- TPO-Ab (Thyroid peroxidase antibodies); + TBII (Thyrotropin binding inhibitor immunoglobulin) High, diffuse RAI (radioactive iodine) Treatment: Antithyroid drugs Thionamides: methimazole (MMI), propylthiouracil (PTU) B-blockers Radioactive iodine Thyroidectomy Notes: MMI- Inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine in the thyroid gland, blocking iodine's ability to combine with tyrosine to form thyroxine (T4) and triiodothyronine (T3) PTU - Inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine in the thyroid gland; blocks synthesis of thyroxine and triiodothyronine Clicker Question What is most one the earliest symptoms of hyperthyroid disease presenting in children/adolescents? A. Decline in school performance B. Thyroid enlargement C. Exophthalmos D. Extreme weight loss E. Hair loss Notes: Symptoms develop gradually; the usual interval between onset and diagnosis is 6–12 mo and may be longer in prepubertal children compared with adolescents. The earliest signs in children may be emotional disturbances accompanied by motor hyperactivity. The children become irritable, excitable, and cry easily because of emotional lability. They are restless sleepers and tend to kick their covers off. Their schoolwork suffers as a result of a short attention span and poor sleep Case 2: CC: poor feeding HPI: A 25 day old male infant is in your office with his mother because of poor feeding and sleeping too much. She attempts to breastfeed every 2 hours but reports the infant does not seem interested and will not stay awake after latching on. Mother feels like he has not gained enough weight since his birth. He voids normally. Has 1-2 hard stools every 3-4 days. He has been a good baby at home and cries very little. Birth history: Born at 41 weeks to G1 mother. Natural water birth at home by a doula with no complications. Mother denies any prenatal infections, medications or health issues during her pregnancy. GBS unknown. Birthweight: 7#10 ounces Length: 19 inches Head circumference: 13 inches Family history: Non contributory Social history: Lives at home with mother and father. No pets. No smokers. Physical exam General: quite newborn but arousable. Vitals: HR 130 RR 33 BP 89/65 Temp 99.1 Weight: 7lbs 11ounces Length: 20 inches HC: 13.5 inches Head: Normocephalic with large soft anterior fontanels, posterior fontanel is open and soft, measures about 1.5 cm EENT: PEERL. Palate intact. + macroglossia. Neck is soft without palpable masses Chest: symmetric, normal breath sounds Heart: RRR. No murmurs. Abdomen: soft, no masses. +BS GU: normal male. Testis descended bilaterally. Uncircumcised. Extremities: no deformities Neuro: + suck/moro/grasp reflexes. Decreased tone. Congenital Hypothyroidism Worldwide incidence 1/4000 worldwide Most common preventable cause of mental retardation Most cases are not hereditary 85 % secondary to thyroid dysgenesis (aplasia, hypoplasia or ectopic gland) Girls > Boys Notes: 1/3 cannot be found radionuclide scans 2/3 are in another location (ligual thyroid) or normal position (hypoplasia) 10% or inborn irro of thyroxine synthesis 5% are result of transplacental maternal thyrotropin receptor blocking antibody (TRBAb) Signs and Symptoms Asymptomatic at birth First month of life = nondescript symptoms Poor feeding/poor weight gain Sluggishness/somnolence Choking spells Noisy respirations, nasal obstructions, respiratory difficulties Constipation Anemia (macrocytic) Prolonged neonatal jaundice Notes: Asymptomatic at birth secondary to transplacental passage of maternal T4 which provides levels of 33% of normal Prolonged jaundice secondary to delayed maturation of glucoronide conjugation Physical Exam Enlarged anterior and posterior fontanels Only 3% of normal infants have posterior fontanels > 0.5cm Large thick tongue (macroglossia) Hypotonia Large abdomen with umbilical hernia Cold mottled skin Edema of genitals and extremities Heart murmurs Slow heart rate Below normal temperature (<95 degrees F) Labs/Diagnosis Blood work Serum levels of T4 or free T4 are low Serum levels of T3 are not helpful and may be normal TSH is elevated Radiographs Retardation of osseous development on x-ray Cardiac enlargement on ultrasound Thyroid ultrasonography Radioiodine (123I) or sodium technetium 99m pertechnetate (99mTc) thyroid uptake and/or scan to identify functional thyroid tissue Notes: One must keep in mind that serum T4 concentrations are higher in the first few weeks of life in normal infants than in adults because of the surge in TSH secretion that occurs soon after birth Clinical course Symptoms are progressive Clinical picture fully developed by 3-6 months Child’s growth stunted Shortened extremities Dentition delayed Myxedema of the eyelids, back of hands and genitals Carotemia (yellow discoloration of skin) Hair coarse, brittle and scanty Newborn Screen Programs common in North America and developed countries Pilot programs started in Pittsburg in 1974 Screening methods Primary T4 With Backup TSH Measurements*** Primary TSH With Backup T4 Measurements Combined Primary TSH Plus T4 Measurements Helpful in detecting affected infants before clinical symptoms and findings occur Ideal blood collection done between 2-4 days of life Routinely done prior to discharge IMPORTANT: Treatment is most effective if started before 2 weeks of age, so early screening is essential Notes: May result in increase false positives secondary to elevated TSH that is transient at delivery Treatment and Prognosis Levothyroxine daily with monthly monitoring of TSH and T4 for the first 6 months Levothyroxine = T4 Only tablets should be used- no FDA approved suspension approved Thyroid hormone is critical for normal cerebral development Without treatment, affected infants are profoundly mentally deficient and growth retarded IF treated by 2 weeks of age, linear growth and intelligence comparable to unaffected siblings When replacement therapy is begun later but within the first 2 months of life, infants with severe hypothyroidism at birth may still have a low-to-normal IQ, but stature and linear growth is usually normal Figure 566-1 Congenital hypothyroidism in an infant 6 mo of age. The infant ate poorly in the neonatal period and was constipated. She had a persistent nasal discharge and a large tongue; she was very lethargic and had no social smile and no head control. A, Notice the puffy face, dull expression, and hirsute forehead. Tests revealed a negligible uptake of radioiodine. Osseous development was that of a newborn. B, Four months after treatment, note the decreased puffiness of the face, the decreased hirsutism of the forehead, and the alert appearance. Goiters Clicker Question Which of the following could be true of a person with a goiter? A. They may have normal function of the thyroid gland. B. They may have thyroid hormone deficiency. C. They may have an overproduction of thyroid hormones. D. The goiter may be congenital. E. The goiter may be acquired. Goiter is an enlargement of the thyroid gland. Notes: Initial step in evaulating a child with a goiter is to determing if they are euthyroid, hypothyroid or hyperthyroid. TSH, T4, antithyroid antibodies Autoimmune thyroiditis Most common cause of acquired goiter in the US in children > 6yo Peak incidence = adolescents Girls >> boys Genetic predisposition Characterized histologically by lymphocytic infiltration of the thyroid Thyroid feels enlarged, firm, irregular and nontender Can present as a euthyroid, hypothyroid or transient hyperthyroidism Most affected children are clinically asymptomatic Notes thyroiditis encompasses a diverse group of disorders characterized by some form of thyroid inflammation Clicker Question When describing hypothyroidism, which organ’s failure is responsible for “tertiary” hypothyroidism? A. Thyroid gland B. Pituitary gland C. Hypothalamus D. Parathyroid gland E. Thymus Notes: Results when the hypothalamus fails to produce sufficient thyrotropin-releasing hormone (TRH) Secondary : Occurs if the pituitary gland does not create enough thyroid-stimulating hormone (TSH Acquired Hypothyroidism Female predominance 90% secondary to Autoimmune Thyroiditis (Hashimoto’s Thyroiditis) Other causes: Mild inborn errors of thyroxine metabolism Side effects of medical therapy s/p treatment/surgery fro hyperthyroidism or thyroid cancer Iodine Defiency Strong familial pattern GROWTH FAILURE is most common presenting manifestation Acquired Hypothyroidism Presentation: Coarse, dry and thick skin Fatigue, lethargy Cold intolerance Pallor Somnolence Constipation Delayed linear growth Overweight for height Delayed reflexes Bradycardia Irregular menstrual cycles Delayed puberty (occasionally precocious puberty) Notes: Well behaved, do well in school. Obesity is rarely caused by hypothyroidism. Autoimmune Thyroiditis - Hashimoto Thyroiditis Most common cause of acquired hypothyroidism in children Hashimoto Thyroiditis = autoimmune destruction of the thyroid secondary to chronic lymphocytic thyroiditis Activation of the CD4 helper T lymphocytes specific for thyroid antigens Thyroid atrophy or goiter More common in girls Associated with other autoimmune disorders: Trisomy 21 Klinefelter’s syndrome Diabetes Type I Addison’s Disease Turner’s Syndrome Celiac Disease Diagnosis Primary hypothyroidism Elevated TSH, Decreased T4 Test for anti-thyroglobulin antibodies (Tg Ab) and anti-thyroid peroxidase antibodies (TPO Ab) 85 to 90 percent of children with chronic autoimmune thyroiditis have high serum anti-TPO antibody concentrations Treatment T4 replacement (Levothyroxine) Treat thru pubertal development and bone maturation before doing trial off medication Some patients will eventually become euthyroid and can be taken off medication Once patient becomes euthyroid, many of the symptoms disappear Autoimmune Thyroiditis Hashimoto Thyroiditis Clicker Question Which of the following results is most consistent with central hypothyroidism? A. Elevated TSH, normal T4 B. Elevated TSH, low T4 C. Decreased TSH, low T4 D. Decreased TSH, normal T4 E. Decreased TSH, elevated T4 Central Hypothyroidism Idiopathic Hypothalamic lesions Pituitary tumors, the most common of which is craniopharyngioma