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
1. Menorrhagia 2. 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
1. HTN 2. TAH with BSO 20+ years ago 3. 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
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
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
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
1. 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.

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