Hyperthyroidism in children

Detail about etiologies and management of hyperthyroidism in child age group

1. Hyperthyroidism in Children Dr.C.S.N.Vittal

2. Concept map What are hyperthyroidism & thyrotoxicosis Epidemiology Causes Clinical features Diagnosis Management

3. Definitions Thyrotoxicosis - clinical state that results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels Hyperthyroidism – a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid Bahn et al. Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid, 2011 Jun;21(6):593-646 & Endocr Pract , 2011 May-Jun;17(3):456-520

4. Epidemiology Estimated prevalence of hyperthyroidism in children is around 1 in 10,000 in the United States’ pediatric population. Prevalence : 1.2 % (0.5% - overt, 0.75% subclinical) Hyperthyroidism is much more common in women and in older people. 5 % of all cases of Graves’ disease occurs in children. Age Graves disease 20 to 40 Toxic MNG > 50 yrs Toxic Single Adenoma 35 to 50 Sub Acute Thyroiditis Any age Sex M : F ratio Graves Disease 1: 5 to 1:1 Toxic MNG 1: 2 to 1: 4

5. Possible Etiology of Hyperthyroidism Primary Graves’ Disease (Diffuse Toxic Goiter) Secondary Toxic Nodular Goiter (Multinodular Goiter) Thyroiditis Functioning adenoma of thyroid Rare Causes Excessive intake of thyroid hormones Abnormal secretion of TSH Excessive intake of iodine Pituitary tumors leading to excess TSH Thyrotoxicosis factitial: INF, amiodarone, SSRI Struma ovarii (dermoid and ovarian tumors)

6. Graves’ Disease Most common cause of thyrotoxicosis (50-60%) Organ specific autoimmune disease Most imp autoantibody: Thyroid stimulating immunoglobulin (TSI or TSA) which acts as a proxy for TSH and stimulates T4 and T3 via the adenyl cyclase cAMP system I 123 or TC 99m Normal v/s Graves Onset may be insidious Poor school performance may be marked, but usually from poor concentration, tiredness and behavior disturbances with temper tantrums and emotional lability

7. Toxic Multinodular Goiter (TMG) 2 nd most common cause of hyperthyroidism (20%) More in elderly individuals Lumpy bumpy thyroid Milder manifestations (apathetic hyperthyroidism) Mild elevation of FT4 and FT3 Slow progression Multiple firm nodules on palpation (Plummer’s disease) Scintigraphy: hot and normal areas

8. Sub Acute Thyroiditis (SAT) Second common hyperthyroidism – 15% T 4 and T 3 are extremely elevated in this condition Immune destruction of thyroid due to viral infection Destructive release of preformed thyroid hormone Thyroid gland is painful and tender on palpation Nuclear Scintigraphy scan - no RIU in the gland Treatment is NSAIDs and Corticosteroids

9. Toxic Single Adenoma (TSA) Single hyper functioning follicular thyroid adenoma. Benign monoclonal tumor that usually is larger than 2.5 cm It is the cause in 5% of patients who are thyrotoxic Nuclear Scintigraphy scan shows only a single hot nodule TSH is suppressed by excess of thyroxines. So the rest of the thyroid gland is suppressed

10. Medullary Thyroid Carcinoma (MTC) <10% of thyroid carcinomas arises from parafollicular (C) cells and nearly always secretes calcitonin and sometimes other hormones Associated with syndromes involving tumors of neuroectodermal origin (multiple endocrine neoplasia – MEN) inherited autosomal dominantly MEN type 2 (MEN 2)

11. Common Symptoms Excessive Sweating  Heat Intolerance  Increased Bowel Movements  Tremor (Usually Fine Shaking)  Nervousness / Agitation  Rapid Heart Rate / Palpitations  Insomnia  Breathlessness  Irregular or Scant Menstrual Periods  Fatigue  Weight Loss (despite increased appetite) Muscle Weakness  Hair Loss  irregular heart rhythms and heart failure / palpitations Psychiatric Symptoms in Graves' disease: Anxiety, nervousness, fluctuating moods and irritability 

12. Common Signs Hyperactivity / Hyperkinesis Sinus tachycardia or atrial arrhythmia, AF, CHF Systolic hypertension, wide pulse pressure Warm, moist, soft and smooth skin, warm hands Excessive perspiration, palmar erythema, onycholysis Lid lag and stare (sympathetic overactivity Fine tremor Large muscle weakness Gynaecomastia

13. Specific to Graves’ Diseases Diffuse painless and firm enlargement of thyroid gland Thyroid bruit is audible with bell of stethoscpe Ophthalmopathy in 50% cases Sand in eyes, periodic edema, conjunctival edema ( chemsis ), Von Graefe's sign (lid lag sign) Möbius sign (poor convergence) Joffroy sign (absent creases in the forehead on superior gaze) Stellwag sign (incomplete and infrequent blinking) Extra ocular muscle dysfunction, diplopia, pain on eye movements and proptosis Dermo-acropathy in 20% cases Deposition of glycosaminoglycans in dermis of lower leg – non pitting edema, thickening of skin without pain or pruritus (pre tibial myxedema)

14. MNG and Graves Huge Toxic MNG Diffuse Graves Thyroid

15. Proptosis Lid lag (Von Graefe's sign) Thyroid Ophthalmopathy

16. Ophthalmopathy in Graves Thyroid associated orbitopathy is thought to be due to antibody reaction against thyroid stimulating hormone receptor (TSHR) with orbital fibroblast modulation of T-Cell lymphocytes Periorbital edema and chemosis

17. (incomplete and infrequent blinking) (absent creases in the forehead on superior gaze)

18. Ophthalmopathy in Graves Ocular muscle palsy Laka Laka Laka

19. Thyroid Dermopathy Pink and skin coloured papules, plaques on the shin Pretibial myxoedema Stimulation of fibroblasts by anti-TSHR antibodies and production of glucosamnoglycans

20. Clubbing and Osteoarthropathy Thyroid Acropathy

21. Onycholysis

22. Non specific changes Hyperglycemia, Glycosuria Osteoporosis and hypercalcemia ↓ LDL and Total Cholesterols Atrial fibrillation, LVH, ↑ LV EF Hyperdynamic circulatory state High output heart failure

23. Diagnosis – Clinical Clues Hyperthyroidism can be suspected in patients with:  tremors,  excessive sweating,  smooth velvety skin,  fine hair,  a rapid heart rate, and  an enlarged thyroid gland. 

24. Diagnosis Typical clinical presentation Markedly suppressed TSH (<0.05 µIU/mL) Elevated FT 4 and FT 3 (Markedly in Graves) Thyroid antibodies – by Elisa – anti-TPO, TSI ECG to demonstrate cardiac manifestations Nuclear Scintigraphy to differentiate the causes

25. Diagnosis - Labs Blood levels of thyroid hormones can be measured directly and usually are elevated with hyperthyroidism.  Measurement of the blood TSH levels – which is low (In secondary hyperthyroidism – TSH levels elevated) Antibody screening (for Graves' disease) and Thyroid scan using radioactively-labelled iodine 

26. Diagnosis - Labs Low TSH, High RAIU Graves; disease Toxic MNG Toxic Adenoma Chronic gonadotrophin induced Inherited non-immune hyperthyroidism (TSH receptor of G protein mutation) Normal or elevated TSH TSH-secreting pituitary tumors Thyroid hormone resistance higher ratio of FT3 to FT4 suggests that the patient may have Graves' disease,

27. Diagnosis - Labs Low TSH, Low RAIU Iodine induced hyperthyroidism Amiodarone associated hyperthyroidism (due to excess iodine release) Thyroiditis Autoimmune ( Hashimato’s , Lymphocytic thyroiditis) Viral or post viral (subacute granulomastous thyroiditis) Drug induced Amiodarone, lithium, interferon, IL -2, GM-CSF Infectious – acute Post partum Iatrogenic: Over replacement Thyrotoxic factitia Ingestion of natural products containing thyroid hormone Hamburger thyroiditis Thyromimetic compounds ( Tiracol ) Stroma ovarii Metastatic functioning thyroid carcinoma

28. Issues in Biochemical Evaluation TSH has highest sensitivity and specificity Diagnostic accuracy improves with measurement of free T4 Free T4 gives baseline measurement of degree of thyrotoxicosis Important for monitoring success of initial treatment Though not always related to severity of symptoms T3 toxicosis Can be sign of early disease

29. 9 Square Interpretation of Thyroid Hormones High Normal Low Low Normal High fT4 TSH PRIMARY HYPERTHYROIDISM EUTHYROID SECONDARY HYPERTHYROIDISM PRIMARY HYPOTHYROIDISM SECONDARY HYPOTHYROIDISM SUBCLINICAL HYPERTHYROIDISM SUBCLINICAL HYPOTHYROIDISM NON THYROID ILLNESS Or Pt is on Thyroid Hormones NON THYROID ILLNESS

30. Role of Imaging in Hyperthyroidism Thyroid Ultrasound Color Doppler Flow helpful in AIT 1 vs. AIT 2. May reveal nodular disease or increased vascularity (seen in Grave’s) Thyroid Uptake & Scan High uptake: Graves’, toxic MNG, toxic adenoma Low uptake: Thyroiditis, iodine-induced hyperthyroidism

31. Toxic adenoma Nucleotide Scintigraphy

32. Destructive Thyroiditis Ultrasonography Doppler US Graves Disease Toxic Adenoma Thyrotoxicosis Suspected Thyrotoxicosis Confirmed Detailed history, PE, TSH, FT4, TSH receptor Abs, if needed Diffuse hypoechogenicity or normoechogenicity (no nodules) h vascularity Absent or minimal vascularity Nodular RAIU and Scan Toxic MNG Cold Nodule RAI therapy OR Surgery FNAB Algorithm

33. Treatment Goals: Normalize serum TSH levels Reverse\correct clinical signs & symptoms and metabolic derangements. Steps: Rest Sedation Beta-blockers Antithyroid medication NSAIDs and Corticosteroids – for SAT I - 131 Surgery Thyroidectomy – Subtotal or Total

34. Symptom Relief Rehydration is the first step β – blockers to decrease the sympathetic excess Propranalol , Atenelol , Metoprolol valuable during the first 2–3 weeks of treatment in providing symptomatic relief of tachycardia, nervousness and tremor and can then be discontinued as the specific antithyroid drug becomes clinically effective Rate limiting CCBs if β – blockers contraindicated

35. Symptom Relief Iodinated contrast ( Idopate 0.001 μ g/kg/day) and Lugol iodine (5% iodine and 10% potassium iodide; 126 mg/mL iodine, 1 drop 8 hourly) are effective in reversing of features of hyperthyroidism. Prednisolone (1- 2 mg/kg/day) inhibits peripheral conversion of T4 to T3 and is useful in treatment of hyperthyroid storm. Treatment of CHF, Arrhythmias

36. Treatment - Medical Methimazole (MMI) – 5-30 mg daily Inhibit thyroid hormone synthesis by interfering with the thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin Effects seen 1-2 weeks after initiation of therapy. Propylthiouracil (PTU) – 100-300 mg per day divided BID/TID PTU can also block the conversion of thyroxine (T4) to triiodothyronine (T3) Side effects: Rash, arthralgias, nausea Vasculitis Liver function tests abnormalities (liver failure with PTU) Agranulocytosis Embryopathy Check baseline CBC/diff and LFT’s

37. Anti Thyroid Drugs (ATD) Imp. considerations Methimazole Propylthiouracil Efficacy Very potent Potent Duration of action Long acting BID/OD Short acting QID/TID In pregnancy Contraindicated Safely can be given Mechanism of action Iodination, Coupling Iodination, Coupling Conversion of T4 to T3 No action Inhibits conversion Adverse reactions Rashes, Neutropenia Rashes, ↑Neutropenia Dosage 20 to 40 mg/ OD PO 100 to 150mg qid PO

38. How long to give ATD ? Reduction of thyroid hormones takes 2-8 weeks Check TSH and FT 4 every 4 to 6 weeks In Graves, many go into remission after 12-18 months In such pts ATD may be discontinued and followed up 40% experience recurrence in 1 yr. Re treat for 3 yrs. Treatment is not life long. Graves seldom needs surgery MNG and Toxic Adenoma will not get cured by ATD. For them ATD is not the best. Treat with RAI.

39. Radio Active Iodine (RAI Rx.) In women who are not pregnant In cases of Toxic MNG and TSA Graves disease not remitting with ATD RAI Rx is the best treatment of hyperthyroidism in adults The effect is less rapid than ATD or Thyroidectomy It is effective, safe, and does not require hospitalization. Given orally as a single dose in a capsule or liquid form. Very few adverse effects as no other tissue absorbs RAI

40. Radio Active Iodine (RAI Rx.) I 123 is used for Nuclear Scintigraphy (Dx.) I 131 is given for RAI Rx. (6 to 8 milliCuries ) Goal is to make the patient hypothyroid No effects such as Thyroid Ca or other malignancies Never given for children and pregnant / lactating women Not recommended with patients of severe Ophthalmopathy Not advisable in chronic smokers

41. Surgical Treatment Subtotal Thyroidectomy, Total Thyroidectomy Hemi Thyroidectomy with contra-lateral subtotal ATD and RAI Rx are very efficacious and easy – so Surgical treatment is reserved for MNG with Severe hyperthyroidism in children Pregnant women who can’t tolerate ATD Large goiters with severe Ophthalmopathy Large MNGs with pressure symptoms Who require quick normalization of thyroid function

42. Treatment – Medical – Beta-blockers Pregnancy- absolute contraindication Graves’ disease – goal is hypothyroidism after treatment Fixed dose or calculation (weight [g] x 150 µCi/g x 1/24 hour uptake %) Toxic MNG and Toxic Adenoma – can be euthyroid following treatment May repeat in 6 months if initial dose not effective

43. Graves’ Ophthalmopathy Up to 50% may have eye involvement Can be euthyroid or hypothyroid in small minority (< 10 %) High dose steroids Radiation Surgery – orbital decompression Selenium Supportive therapies (lubricants, prisms, etc.) Alternative therapies (e.g. rituximab, botox )

44. Thyroid Storm Life threatening condition associated with untreated hyperthyroidism Dangerously high blood pressure, fever, and heart failure, mental changes, such as confusion and delirium Precipitating factors may be any major stress such as trauma, infection, etc. Treatment: 5 Bs Block hormone synthesis: Anti-thyroid drugs Block release: Iodine Block T4 into T3 conversion: High dose PTU, steroids Beta-blockers: propranolol Block enterohepatic circulation: Cholestyramine

45. Neonatal Hyperthyroidism Caused by the passage across the placenta of maternal stimulating antibodies directed against the TRAbs Generally transient, occurring in only about 2% of the offspring of mothers with GD.  Tachycardia, hyperexcitability, poor weight gain contrasting with a normal or large appetite, small anterior fontanel, advanced bone age, hepatosplenomegaly Craniostenosis , microcephaly, and psychomotor disabilities may occur in severely affected infants  MMI is preferred (1 mg/kg/day, in three doses). Propranolol (2 mg/kg/day, in two divided doses) can also be needed to control tachycardia during the first one to two weeks of treatment.

46. Summary Thyrotoxicosis is a common condition encountered in practice Subclinical disease is more common than overt thyrotoxicosis TSH best for screening and free T4 for confirmation and monitoring treatment Radioiodine uptake and scan preferred imaging modality Treatment with methimazole or I- 131 usually preferred

47. Dr.C.S.N.Vittal Thank You