APPROACH TO HYPERCALCEMIA Elizabeth George M.D. Department of Medicine University of Wisconsin-Madison * No Financial Disclosures

WHY IS IT IMPORTANT? Rising Incidence: 100,000 new cases / year in the United States Asymptomatic Hyperparathyroidism is not a benign condition Skeletal loss1 Impaired renal function May herald underlying occult malignancy2 / sarcoidosis

LEARNING OBJECTIVES To be able to interpret an abnormal calcium and diagnose its cause Review key elements of diagnostic evaluation Review indications for medical monitoring vs. surgical treatment 4,5 in patients with asymptomatic hyperparathyroidism

LEARNING OBJECTIVES (cont.) Review medical therapy Review surgical treatment Role of gland localization techniques Merits of minimally invasive parathyroid surgery

CASE REPORT - 1 Ms. K is a 51 year old patient who came in for a routine exam Past medical history Menorrhagia Carpal tunnel syndrome Medications – MVI Social / Family History - unremarkable Review of systems Mild depression – attributed to increased stress at work Fatigue Difficulty concentrating

CASE REPORT - 1 Physical exam – completely unremarkable Laboratory Data: CBC - normal TSH - 2.06 (0.5 – 4.00) BMP – normal except calcium 12.4 mg/dl (8.4 – 10.4 mg/dl) Further work up iPTH – 509 (12-72 pg/ml) 24 hr urine calcium – 649.3 (50 – 400 mg/24 hr) 1,25 dihydroxyvitamin D3 - 75 (22 – 67 ng/ml)

CASE REPORT - 1 Parathyroid scan (sestamibi) – negative

CASE REPORT - 1 Subtraction scan

CASE REPORT - 1 Subtraction scan

CASE REPORT - 1 Left upper lobe parathyroid adenoma

CASE REPORT - 1 Rx Minimally invasive parathyroidectomy Yielded an 880 mg parathyroid adenoma

CASE REPORT - 2 Ms. C is a 67 year old patient who came in for a routine exam Past medical history HTN TAH with BSO 20+ years ago Hyperlipidemia Medications Propanalol Triamterene / HCTZ Lipitor MVI Calcium

CASE REPORT - 2 Social / Family History – nonsmoker, completely unremarkable family history ROS – negative Physical exam - normal Screening Mammogram – recent normal Colonoscopy – current normal except hemorrhoids Bone density scan (DEXA) ordered

CASE REPORT - 2 Results of bone density scan t-score – 1.3 (spine) – 2. 8 (femur) Metabolic evaluation for low bone density pursued

CASE REPORT - 2 Calcium – 11. 5 (8.4 – 10.4 mg/dl) Ionized calcium – 6.2 (4.6 – 5.4) iPTH 41 (10 – 65.0 pg/ml) 24 hr urine calcium – 129.5 (100 – 300 mg/24 hr) 1,25 dihydroxy vitamin D – 38 (15 – 60 ng/ml)

CASE REPORT - 2 Chest X-ray multiple lung nodules

CASE REPORT - 2 Chest X-ray multiple lung nodules

CASE REPORT - 2 CT scan chest large 4.3 cm nodule R lung multiple nodules no adenopathy

CASE REPORT - 2 CT scan chest large 4.3 cm nodule R lung multiple nodules no adenopathy

CASE REPORT – 2 CT abdomen and pelvis – negative Biopsy of lung mass Well differentiated, low grade neuroendocrine carcinoma (carcinoid)

WORK-UP OF HYPERCALCEMIA IN AN ASYMPTOMATIC PATIENT Re-review History Classic presentation very rare Stones Bones Abdominal groans Psychic moans Subtle manifestations more common Fatigue Weakness Arthralgias

WORK-UP (cont.) History Associated conditions Non specific GI complaints Depression Impairment of intellectual performance Associated conditions Pseudogout Nephrolithiasis

WORK-UP (cont.) Review medications Thiazides Theophylline Lithium Antacids Food additives Health food store preparations Pursue symptoms of underlying malignancy Breast Lung Hematological Past History of Neck irradiation3

WORK-UP (cont.) Physical exam Generally unrevealing Band keratopathy with slit lamp Breast mass Adenopathy Bone tenderness

WORK-UP (cont.) Step 1 Step 2 Confirm hypercalcemia Ionized calcium Serum albumin levels Artifactual – tourniquet Step 2 Once obvious causes ruled out, obtain serum intact PTH

WORK-UP (cont.) Serum Parathyroid Hormone levels - ELEVATED Primary hyperparathyroidism – 75-80% (sporadic) Familial (MENI and MENII) Familial hypocalciuric hypercalcemia Ectopic PTH secretion by tumors (rare)

WORK-UP (cont.) Normal / Low Malignancy associated Vitamin D mediated Osteolytic Humoral Vitamin D mediated Intoxication Granulomatous disorders Thyrotoxicosis Prolonged immobilization Pagets Acute renal failure Milk alkali syndrome

MEDICAL vs. SURGICAL Rx FOR ASYMPTOMATIC HYPERPARATHYROIDISM Indications for medical monitoring Mildly elevated calcium No previous episodes of life threatening hypercalcemia Normal renal function Normal bone status

INDICATIONS FOR SURGICAL TREATMENT (J. Clin Endocrinology Metab, Dec. 2002, 87(12): 5353-5361) Overt clinical manifestations Serum calcium > 1mg/dl above upper limits of normal 24 hr urine calcium > 400mg Bone density < 2.5 SD below peak bone mass (t score < -2.5) Age < 50 years Medical surveillance not desirable / not possible

MEDICAL THERAPY Monitoring Blood pressure Biannual serum calcium Annual serum creatinine Annual bone density Baseline abdominal radiographs for silent stones

MEDICAL MANAGEMENT Avoid prolonged immobilization Maintain adequate hydration Avoid a diet with restricted or excess calcium Caution with loop/thiazide diuretics Estrogen therapy – limited data Bisphosphonates, calcitonin only in symptomatic patients who are non surgical candidates

SURGICAL THERAPY Role of gland localization Pre-op localization mandatory when Minimally Invasive Parathyroidectomy (MIP) procedure planned Procedure used – 99Tc labeled sestamibi scan

SURGICAL THERAPY (cont.) Minimally Invasive Parathyroidectomy (MIP) Pre-op localization Intra-op PTH level obtained before and after adenoma removed If PTH levels fall by greater than 50% operation terminated IF PTH Levels fall by less than 50%, full neck exploration performed

SURGICAL THERAPY (cont.) Conventional Full exploration of neck Rationale -15-20% patients have > 1 gland removed Requires highly skilled surgeon Complications- rate 1-4% Vocal cord paralysis Permanent hypoparathyroidism Bleeding Laryngospasm

POST OPERATIVE MONITORING Watch for symptomatic hypocalcemia Provide oral calcium and 1,25 (OH)2 D3, once oral intake established Check serum calcium at intervals of several days

MANAGEMENT OF HYPERCALCEMIA OF MALIGNANCY Vigorous rehydration / saline diuresis Bisphosphonates Pamidronate Etidronate Calcitonin Definitive measure Rx underlying tumor

SUMMARY OF WORKUP FOR HYPERCALCEMIA

SUMMARY OF WORKUP FOR HYPERCALCEMIA

References Khosla S. et al., Primary hyperparathyroidism and the risk of fracture” A population based study, J. Bone Miner Res, 1999; 14: 1700-1707. Ralston SH, et al., Cancer associated hypercalcemia: Morbidity and mortality. Ann Intern Med, 1990; 112: 499-504. Schneider AB, Gierlowski TC, Shore-Freedman et al., Dose response relationships for radiation induced hyperparathyroidism, J Clin Endo Metab, 1995; 80: 254-257. Potts JT Jr (editor), Proceedings of the NIH consensus development conference on diagnosis and management of asymptomatic primary hyperparathyroidism, J. Bone Miner Res, 1991; 6 (suppl) s9-s13. J Clin Endo Metab, 2002; 87 (12); 5353-5361.