APPROACH TO HYPERCALCEMIAElizabeth George M.D.

Department of MedicineUniversity 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. Menorrhagia2. 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 - 1Subtraction scan

CASE REPORT - 1Subtraction scan

CASE REPORT - 1Left 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. HTN2. TAH with BSO 20+ years ago3. 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

Metabolic evaluation for low bone density pursued

Results of bone density scan t-score – 1.3 (spine)

– 2. 8 (femur)

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 - 2Chest X-ray

multiple lung nodules

CASE REPORT - 2Chest X-ray

multiple lung nodules

CASE REPORT - 2CT scan chest

large 4.3 cm nodule R lung multiple nodules no adenopathy

CASE REPORT - 2CT 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.

2. Ralston SH, et al., Cancer associated hypercalcemia: Morbidity and mortality. Ann Intern Med, 1990; 112: 499-504.

3. Schneider AB, Gierlowski TC, Shore-Freedman et al., Dose response relationships for radiation induced hyperparathyroidism, J Clin Endo Metab, 1995; 80: 254-257.

4. 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.

5. J Clin Endo Metab, 2002; 87 (12); 5353-5361.