1. Calcium Metabolism and Parathyroid Disease James McKinley MD University of Texas Health Center at Tyler

2. Calcium Metabolism Hypercalcemia – will be our primary focus Causes Diagnosis Treatment Hypocalcemia – briefly Eucalcemia – won’t be discussed at all! Hyperparathyroidism Causes Diagnosis treatment

3. Calcium Metabolism 99% of total body calcium resides in bone Remainder 40% bound to serum proteins 13% complexed with anions 47% free ionized calcium – physiologically active form, regulated by vitamin D and PTH

4. Calcium Metabolism Decreased serum calcium stimulates PTH secretion within seconds PTH ½ life in serum is 4 minutes

5. Parathyroid Hormone Renal effects Increase calcium reabsorption and increased phosphorus excretion from renal tubule Stimulates renal 1-alpha-hydroxylase to activate vitamin D Bone effects – stimulates osteoclastic bone reabsorption Net effect – increase serum calcium, decrease serum phosphorus

6. Vitamin D Active form (1,25–OH vitamin D) increases calcium and phosphorus absorption from GI tract

7. Calcium Metabolism What can go wrong?

8. Hypercalcemia - Symptoms Depend on Calcium level, rapidity of onset, state of hydration Most develop symptoms at a level > 12mg/dL, virtually all symptomatic > 14 Vague symptoms – fatigue, weakness, anorexia, nausea, polyuria, dehydration, lethargy, stupor, coma

9. Hypercalcemia - Etiology Primary Hyperparathyroidism Cancer (metastatic, lymphoma) – most common in hospitalized patients Multiple Myeloma Hyperthyroidism Hypervitaminosis D (or A) Immobilization Sarcoidosis Addisonian crisis

10. Hypercalcemia Idiopathic/spurious – venous stasis, postmenopausal women Thiazide diuretics – hold for 2 weeks Hypocalciuria – Familial Hypocalciuric Hypercalcemia Paget’s dz – hypercalcemia in conjunction with immobilization Milk-Alkali syndrome – excessive intake of NaHCO3 and milk (calcium salt) Aluminum toxicity - rare

11. Hypercalcemia - Treatment Treat if symptomatic (mental status changes, confusion, delusions) Treat if serum calcium > 15 NS bolus until volume restored, then 100 – 200 ml/hr and Lasix 40 – 80 mg (1 mg/kg) q 4-6 hours Bisphosphonates (onset 24-48 hrs) Calcitonin 4 – 8 IU q6-8 hrs (onset immediate, resistance develops in 24-48 hrs) Empiric Mg and K

14. Hyperparathyroidism Most common disorder of hypercalcemia (ambulatory patients) Males > 60 years : 100/100,000 Females > 60 years : 300-400/100,000 All ages : 250/100,000 Patients usually > 50 years of age Females > males 4 : 1

15. Hyperparathyroidism 1 person in 1000 will need parathyroid surgery

16. hyperparathyroidism

17. Hyperparathyroidism - Symptoms Painful bones, renal stones, abdominal groans, and psychic moans Bone and joint pain, renal stones – late findings

18. Hyperparathyroidism – Signs/symptoms Skeletal Bone pain and tenderness Cystic bone lesions (brown tumors) Skeletal demineralization Spontaneous fracture (compression fx’s) Osteoporosis Osteitis fibrosa cystica

19. Hyperparathyroidism – signs/symptoms Renal Nephrolithiasis Nephrocalcinosis Decreased GFR Polydipsia/polyuria

20. Hyperparathyroidism – signs/symptoms GI Abdominal distress Gastroduodenal ulcer Pancreatitis Constipation Pancreatic calcification Vomiting, anorexia, weight loss

21. Hyperparathyroidism – signs/symptoms Mental/psychiatric Fatigue Apathy Anxiety Depression Psychosis Coma/ diffuse EEG changes

22. Hyperparathyroidism – signs/symptoms Neuromuscular Muscle weakness, hypotonia Cardiovascular HTN Short QT interval Articular/periarticular Arthralgias/gout/pseudogout/calcifications

23. Hyperparathyroidism – signs/symptoms Ocular Band keratopathy Conjunctivitis Conjunctival calcifications

24. Hyperparathyroidism - Diagnosis Elevated serum calcium Repeated measurements (can vary, minimal venous occlusion, fasting) Ionized calcium may be more accurate, but not widely available, must be sent on ice, etc. Corrected for serum albumin Elevated serum parathyroid hormone (intact) Usually found during workup for osteoporosis or elevated calcium in lab work

25. Hyperparathyroidism Primary hyperparathyroidism Inappropriate secretion of PTH 85% single parathyroid adenoma 14 –15% diffuse hypertrophy of PT gland < 0.5-1% parathyroid carcinoma (palpable)

26. Parathyroid Adenoma

27. Hyperparathyroidism Secondary Results from physiologic or pathophysiologic response to hypocalcemia Can result from vitamin D deficiency or decreased calcium intake(dietary or malabsorption) Most cases due to chronic renal failure – decreased production of activated vitamin D

28. Hyperparathyroidism Tertiary Due to prolonged hypocalcemia (usually due to chronic renal failure) This results in parathyroid gland hyperplasia May need parathyroidectomy

29. Hyperparathyroidism Elevated calcium and PTH – Now what?

30. Hyperparathyroidism – localize the lesion Diagnostic studies – 80-85% of PT glands in normal location 15-20% ectopic – anywhere from hyoid bone superiorly to the aortopulmonary window inferiorly (anterior superior mediastinum most common)

31. Hyperparathyroidism - Imaging Ultrasound CT scan FNA MRI Angiography (with/without selective vein sampling) Sestamibi scan – with SPECT scanning, give 3-D image, 91% sensitivity, 98.8% specificity

32. Sestamibi scan

33. Surgery With localization, minimally invasive endoscopic procedure, small incision, as fast as 15 minutes PTH should drop to normal/near normal after surgery, confirm proper treatment If not, explore both sides of neck 90 – 95% success rate 1% morbidity

34. Surgery 20 – 30 % experience temporary hypoparathyroidism (hypocalcemia) Post op hypocalcemia nadir at 20 hrs (to 36), normalizes by the following day (post op day 2-3) Undetectable PTH at 8 hours, normal by 30 hours Post op calcium replacement only if symptomatic or positive Trousseau’s or Chvostek’s sign

35. Hypocalcemia - Symptoms Paresthesias, muscle stiffness and cramps, fasciculations, tetany Lower seizure threshold CHF, dysrhythmia, hypotension

36. Hypocalcemia - Treatment Check ionized calcium if able 10 – 30 ml of 10% calcium gluconate solution IV over 10 minutes (150 ml D5W) Calcium infusion start at 0.5 mg/kg/hr Telemetry Check serum calcium q 2 – 4 hours

37. Hyperparathyroidism – medical treatment Criteria Only mild serum calcium elevation No previous life threatening hypercalcemia Normal renal status (c.c. > 70%, no stones, nephrocalcinosis) Normal bone status (dexa > -2.5) asymptomatic

38. Hyperparathyroidism – medical management Monitoring (evidence level C, consensus opinion) Biannual serum calcium (PTH?) Annual serum creatinine Annual bone density testing

39. Hyperparathyroidism – Medical Management Recommendations Modest intake of calcium (1000 – 1200 mg per day) Vitamin D (400 – 600 IU per day) Up to 25% will develop surgical indications

40. Hyperparathyroidism Surgical indications Symptoms (stones, nephrocalcinosis, osteitis fibrosa cystica) Serum calcium > 1 mg per dL above normal Renal function reduced > 30% ( compared to age matched controls) Osteoporosis (T score < -2.5) Patient age < 50 years Medical surveillance not desirable or possible Surgery requested by the patient

41. Secondary and Tertiary Hyperparathyroidism Goal is to normalize calcium values Supplement calcium and vitamin D ESRD patients need phosphate binders Tertiary hyperparathyroidism and severe metabolic bone disease, may need parathyroidectomy

42. Calcium metabolism Kidney – PTH Bone – PTH GI – Vitamin D Hyper and hypocalcemia Hypercalcemia – hyperparathyroidism most common cause in ambulatory patients

43. Hyperparathyroidism Dx : Calcium and PTH levels Parathyroid adenoma most common cause of hyperparathyroidism Imaging/localizing techniques Tx : surgery vs medical management

44. References Taniegra ED, Hyperparathyroidism. Am Fam Physician 2004;69:333-9,340 Pou AM, Rosen FS, Parathyroid Disease: Diagnosis and Treatment. Grand Rounds, UTMB, Dept of Otolaryngology 3/27/2002 Bailey BJ, Calhoun KH, et al.Atlas of Head and Neck Surgery-Otolaryngology. Second Edition. Lippincott Williams and Wilkins. Philadelphia, PA. c. 2001:236- 245. Dackiw AP, Sussman JJ, et al. Relative Contributions of Technetium Tc 99m Sestamibi Scintigraphy, Intraoperative Gamma Probe Detection, and the Rapid Parathyroid Hormone Assay to the Surgical Management of Hyperparathyroidism. Archives of Surgery. 2000;135:550-557. Marx SJ. Medical Progress: Hyperparathyroid and Hypoparathyroid Disorders. The New England Journal of Medicine. 2000;343:1863-1875. Mitchell BK, Merrell RC, Kinder BK. Localization Studies in Patients with Hyperparathroidism. Surgical Clinics of North America. 1995;75:483-498. Reber PM, Hunter, H. Hypocalcemic Emergencies. Medical Clinics of North America. 1995; 79:93-106. Handbook of Emergency Cardiovascular Care for Healthcare Providers. American Heart Association. 2004.

45. Picture References Slide 12: www.aafp.org/afp/20040115/333.html www.aafp.org/afp/20040115/333.html Slide 16: www.endotext.org Slide 13: www.pathguy.comwww.pathguy.com Slides 26: www.edcenter.med.cornell.edu www.edcenter.med.cornell.edu Slide 33: www.parathyroid.com