Pharmacotherapeutic approach to Thyroid and Parathyroid Disorders

1. Pharmacotherapeutic approach to Thyroid and Parathyroid Disorders Anantha Harijith, MD Assistant Professor of Pediatrics University of Illinois, Chicago

2. Case report Two month old male infant - recently migrated from Kabul. Parents worked as interpreters in the US embassy. Birth weight 3.1kg, Current weight 5.1kg-growing well Parents –happy, only complaint-baby passing stools once in 5-7days no newborn screen report

3. Case report Persistent jaundice, puffy coarse facies, large tongue, large anterior and posterior fontanelle, floppy, umbilical hernia, short arms, large pudgy hands Parents are extremely happy with the baby and want you to prescribe prune juice for constipation. They are confident that investigations are unnecessary. What will you do? Will you -Reassure the parents and see the patient again in two months OR will you investigate?

4. Knee & Skull XR- They agree for X rays but no blood tests Another 2 month old healthy infant Our patient What will you tell them? 1. X rays are normal and no further investigation needed now 2. Immediate blood tests are needed

5. Blood tests done! CBC Hematocrit 40%, WBC 9.8k, Platelet 202k Serum Na141, K 4.6, Cl 105, HCO3- 25, Ca 9.8mg/dl TSH-76 µIU/mL(Normal0.5 - 4.70 µIU/mL) T4 and T3 – not detected What is the diagnosis?

6. Parathyroid glands

8. Thyroxine (T4, tetraiodothyronine) • Liothyronine (T3, triiodothyronine) • Iodinated diphenyl ether structure • Built and stored on thyroglobulin • >99% protein bound in plasma • Only free form has physiologic effects • T3 more potent; T4 longer lasting • Peripheral deiodination

13. Hypothyroid Euthyroid Hyperthyroid

14. Physiological Effects • Increases transcription (nuclear) • Increases mitochondrial metabolism • Net effects are target dependent • Oxygen consumption • Heat production • Metabolism, growth, differentiation • Promotes effects of hormones • Steroids, catecholamines

15. Congenital Hypothyroidism 1 in 4000 newborns 90% Thyroid agenesis maternal T4 crosses the placenta, entering fetal blood well before the fetal thyroid is secreting its own T4 So early protection but in second trimester high demand for T4 not met by transfer- so signs of hypothyroidism sets in Treatment- T4 ie Thyroxine supplementation

16. Other causes -Primary Idiopathic Autoimmune Traumatic Iatrogenic -Secondary Pituitary dysfunction Increased protein binding estrogen; HIV; liver dysfunction; heroin

17. Case Report 38 y/o computer professional lady reports over phone seeking an immediate appointment palpitations, tremulousness for 6 months weight loss, heat intolerance of 12 weeks duration Menstrual periods have been scanty for 6months She used to be a regular in Chicago marathon until last year and wants to be tested for uterine problems because of lack of periods She is now walking into your office

18. PE reveals HR = 120 bpm BP = 170/90 fine tremor of outstretched hands and ... …..

19. Lab reports free T4 = 40 pmol/L, free T3 = 10.6 pmol/L TSH – undetectable elevated thyroid-stimulating globulins confirming a Dx of ?

20. Hyperthyroidism • Causes • Grave’s disease (TSHR autoantibodies) • 0.1% to 1% prevalence, higher in women • Thyroiditis • Toxic adenoma • Non-pharmacologic treatments • Subtotal thyroidectomy • Radioiodine • Arterial embolization (2005)

21. Grave’s Disease

22. Pharmacologic Treatments Thionamides (thiourelynes) Hyperthyroidism • Methimazole (Tapazole) • Typical dose 15 – 30 mg QD • Rapidly absorbed (Cmax < 2 hours) • Half-life 13 – 18 hours • Propylthiouracil (PTU) • Typical dose 50– 600 mg BID • Good bioavailability • Half-life 2 – 4 hours • Blocks peripheral T4 -> T3 conversion

23. Thionamide MOA Coupling is also highly sensitive to drug

25. Thionamide Side Effects • Rash/itch • Fever • Rarely: • Liver dysfunction • Leucocytopenia

26. Cooper DS. N Engl J Med 005;352:905-917.

27. Other Antithyroid Options • Iodide loading • High doses can inhibit iodide formation • Effect transient • May be useful prior to RAI or surgery • Debulk and devascularize gland • Side effects • Rash, hypersalivation, oral ulcers • CI in pregnancy (may cause fetal goiter)

28. Other Antithyroid Options • Beta Blockers • Adjunctive treatment • May reduce T4 -> T3 conversion • Control HR and palpitations, sweats • Rapid action • Corticosteriods • Reduce T4 -> T3 conversion • May reduce TSHR antibody effect in Grave’s

30. Algorithm for the Use of Antithyroid Drugs among Patients with Graves' Disease.

31. Thyroid Storm • Potentially life threatening • Combined treatment strategy • High dose PTU • Give 1st; iodide will reduce drug uptake in gland • Iodide loading (IV Lugol’s solution) • Beta blockers • Corticosteriods

32. Parathyroid Basics Chief cells -Small dark numerous -produce Parathyroid hormone (PTH) Oxyphil cells -No known physiological function -May produce PTH related protein

33. Parathyroid Basics • Parathyroid Hormone • Small molecule (34 amino acids) • Activity based on amino terminal • No disulfide linkages • Encoded on chromosome 11 • Half-life only 2 – 4 minutes • Secreted by chief cells

34. Case report A 17 year old male was admitted with history of generalized seizures for 8 years & involuntary movements for 2 months short statured (138 cm),had hypoplastic dentition, thick dystrophic nails. The patient demonstrated tetany, a positive Chvostek's sign and generalized hyper-reflexia. Systemic examination was normal.

35. Labs: hypocalcaemia, hyperphosphataemia Eyes- Posterior subcapsular cataract CT Brain- basal ganglial calcification Dx: ?

36. Hypoparathyroidism • Causes • Surgical (most common) • Idiopathic • Genetic familial forms • Circulating receptor antibodies • Functional • Due to hypomagnesemia • Mg2+ necessary for PTH release

37. Hypoparathyroidism • Decreased bone resorption & osteocytic activity • Hypocalcemia • Increased neuromuscular excitability • Tetanic muscle contractions/spasms • Seizure • Prolonged QT interval • Cataract • Trousseau Sign • Chvostek Sign • Low or absent iPTH

38. Psuedohypoparathyroidism • Target organs resistant to PTH • Congential defect of PTHR1 • Plasma Ca2+ low • Plasma phosphate high • Renal phosphatase activity high

39. Hypoparathyroidism • Maintenance Treatment • Combined oral calcium + Vitamin D • Phosphate restriction may be used • Acute Treatment • Tetany or Hungry Bone Syndrome • Parenteral calcium followed by vitamin D supp + oral calcium

40. Hyperparathyroidism • Primary • Excess PTH high calcium, low phosphate • Tumor, adenoma, hyperplasia • More common in women • Marrow fibrosis • Osteitis fibrosa cystica • Metabolic acidosis • Increased Alk Phos • Kidney stones

41. Hyperparathyroidism • Primary – Diagnosis • Multiple elevated Ca2+ serum tests • Elevated iPTH • Alk Phos typically low • Corticosteroid suppression test • Prednisolone reduces serum Ca2+ • Indicates non-parathyroid origin • Sarcoid, vitamin D intoxication, etc.

42. Hyperparathyroidism • Treatment • Acute Severe forms • Adequate hydration, forced diuresis • Other Agents • Corticosteroids – Blood malignancies • Mythramycin • Toxic antibiotic used to inhibit bone resorption – hematologic and solid neoplasms

43. Hyperparathyroidism • Treatment • Other Agents • Calcitonin • Inhibits osteoclast activity and bone resorption • Biphosphonates • Given IV or orally to reduce bone resorption • Estrogen • Can be given to postmenopausal women with 1° hyperparathyroidism as medical therapy

44. Hyperparathyroidism • Treatment • Surgery • Definitive treatment

45. 2° Hyperparathyroidism Adaptive & unrelated to intrinsic disease of glands Due to chronic stimulation of glands by low serum Ca2+ levels

46. 2° Hyperparathyroidism • Causes • Dietary deficiency of vitamin D or Ca2+ • Decreased intestinal absorption of vitamin D or Ca2+ • Drugs such as phenytoin, phenobarbital • Renal Failure • Decreased activation of vitamin D3 • Hypomagnesemia