Hypercalcemia: Parathyroid Disease or Not? Dwight M. Deter PA-C, CDE, DFAAPA Clinical Assistant Professor Texas Tech University Health Science Center Southwest Endocrine Consultants El Paso, Texas 2011

WHEN WAS THE LAST TIME SOMEONE CAME INTO YOUR OFFICE AND ASKED……..

“……I THINK I HAVE SOMETHING WRONG WITH MY PARATHYROID GLAND OR MY CALCIUM IS ABNORMAL.”

Parathyroid Glands (PTH) Increase osteoclastic activity in bone Increase renal tubular reabsorbtion of calcium Inhibit net absorption of phosphate and bicarbonate by the renal tubule stimulate synthesis of 1,25 dihydroxycholecalciferol by the kidney

Differential Diagnosis of Hypercalcemia Primary hyperparathyroidism: Benign or CA Hypercalcemia of malignancy i.e. breast, lung, or pancreas Multiple Myeloma Multiple Endocrine Neoplasia Type 1 & 2 (MEN 1 and MEN 2)

Differentials Diagnosis of Hypercalcemia cont. Excess 1,25 (OH) 2 D production: Sarcoid or other granulomatous disorders, Lymphomas, Vitamin D intoxication Familial hypocalciuric hypercalcemia Miscellaneous i.e. Immobilization, Milk-alkali syndrome, Parenteral nutrition

Differentials Diagnosis of Hypercalcemia cont. Drug related hypercalcemia: Vitamin D difficiency or intoxication, Thiazide diuretics, or Lithium Nonparathyroid endocrine causes i.e. Hyperthyroidism, Pheochromocytoma, Addisons Disease, Islet cell tumors

Clinical Manifestations of Hypercalcemia Mild hypercalcemia ( mg/dl) is usually asymptomatic Polyuria and polydypsia Renal stones and nephrocalcinosis Constipation, nausea, and weight loss

Clinical Manifestations of Hypercalcemia cont. Decreased mental alertness and depression especially if calcium >12 mg/dl Bone pain, arthralgias, and decreased bone density (with longstanding hypercalcemia) EKG changes including bradycardia, AV block and short QT interval

Primary Hyperparathyroidism Usually caused by parathyroid adenoma. Parathyroid carcinoma is rare Renal stones, polyuria, hypertension, constipation, fatigue, mental changes Serum and urine calcium elevated Serum phosphate low or normal Urine phosphate high Elevated parathyroid hormone

Familial Hypocalciuric Hypercalcemia (FHH) Mildly elevated PTH Hypercalcemia A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine /serum creatinine) of <0.01 is suggestive of FHH particularly if family history of mild hypercalcemia Parathyroid surgery is ineffective in this condition

Laboratory Findings Elevated PTH levels The hallmark is hypercalcemia especially the ionized calcium When serum albumin is reduced, a corrected calcium is calculated by adding 0.8 mg.dL to the total calcium for every decrement in serum albumin of 1.0 g/dL below the reference value of 4.1 g/dL for albumin

Laboratory Findings cont. Serum phosphate is often low except in secondary hyperparathyroidism due to renal failure when phosphate is high Urine calcium excretion may be high or normal

Laboratory Findings cont. A suppressed PTH level in the face of hypercalcemia suggests non-parathyroid- mediated hypercalcemia often due to malignancy Hypercalcemia of malignancy is usually symptomatic and severe (≥15 mg/dl)

Imaging Studies for Localization Tc-99 sestamibi scan Thallium/technetium subtraction scan MRI scan CT scan Ultrasound Bone x-rays are usually not required

Complications Renal stones and UTI’s Peptic Ulcer Pancreatitis During pregnancy produces neonatal hypocalcemia Altered mental status

TREATMENT OF HYPERPARATHYROIDISM.

Surgical Intervention Recommended for patients with kidney stones, bone disease or symptomatic patients Urine calcium excretion >400 mg/24 hours Osteoporosis on DEXA scan Patients <50 years old Surgical removal of parathyroid adenoma usually results in a cure Endocrine Practice Vol 11 No

Surgical Intervention cont. Operative management should also be considered for all other asymptomatic patients with a suitable risk and a reasonable life expectancy Endocrine Practice Vol 11 No

Surgery cont. Post-op paresthesias or even tetany (usually transient) as a result of rapid fall in calcium Frequent post-op monitoring of calcium and albumin Calcium, Rocaltrol, and magnesium salts may be necessary post-op Endocrine Practice Vol 11 No

Medical Treatment Patients with mild asymptomatic hypercalcemia may be followed, advised to keep active, drink adequate fluids, and avoid immobilization Large fluid intake unless contraindicated

Medical Treatment cont. Cinecalcet (Sensipar®) approved for treatment of Primary Hyperparathyroidism, Secondary Hyperparathyroidism due to CRF and parathyroid carcinoma Mode of action by binding to the parathyroid glands’ extracellular CaSRs (calcium sensing receptor) to increase their affinity for extracellular calcium and decreasing PTH secretion

Medical Treatment cont. Bisphosphonates such as IV Zoledronic acid are potent inhibitors of bone resorption and can temporarily treat hypercalcemia especially in malignancy or severe hyperparathyroidism. Oral bisphosphonates are not effective

Medical Treatment cont. Avoid thiazide diuretics, Vitamin A, Vitamin D, and calcium supplements Caveat is in the face of Vitamin D deficiency, correct the Vitamin D level to ng/dL Patients with 1,25 (OH) 2 D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone) as they decrease 1,25 (OH) 2 D production.

Medical Treatment cont. Monitor Calcium and albumin at least every 3 months Monitor Renal function at least every 6 mo 24 hour urine calcium annually Bone density annually

Prognosis The disease is usually chronic and progressive unless surgically cured Prognosis is directly related to the degree of renal impairment Presence of pancreatitis increases the mortality rate.

Multiple Endocrine Neoplasia Disorder with neoplasms in two or more different hormonal tissues in several members of a family DNA based genetic testing is now available MEN 1 is the most common with prevalence of 2-20 per 100,000 population Each child born to an affected parent has a 50% probability of inheriting the gene

Multiple Endocrine Neoplasia Type 1 (MEN 1) Neoplasia of the parathyroid glands Primary hyperparathyroidism is the most common manifestation (95-100%) Enteropancreatic tumors (80%) Anterior Pituitary Adenomas (20-30%) –Prolactinoma –Acromegaly –Cushings

MEN 1 cont. Other neuroendocrine tumors –Carcinoid Tumors –Thymus, lung stomach or duodenum

Medullary Thyroid Carcinoma is most common manifestation Pheochromocytoma occurs in approx 50% Hyperparathyroidism occurs in 15-20% MEN Type 2

Secondary Hyperparathyroidism Chronic renal failure is usually the cause Hyperphosphatemia and decreased 1,25(OH) 2 Vitamin D produce a decrease in ionized calcium The parathyroid glands are stimulated and enlarge

Conclusions Calcium and parathyroid disorders can be complex and challenging Understanding and recognizing the symptoms and workup for these conditions will improve outcomes New medical and surgical treatments for Primary and Secondary HPT have added greater success

Case # 1 CR 70 yo female presents for routine checkup. 5 years prior had vitamin D deficiency treated with 50,000 units vitamin D weekly for 1 year then 2,000 units per day thereafter. Do not have copies of prior labs.

Case #1 Current Labs Calcium 11.1 ( mg/dl) Ionized calcium 6.2 ( mg/dl) Phosphorus 2.2 ( mg/dl) PTH 88 (10-65 pg/ml) 24 hr urine calcium 180 ( mg/24 hr)

Case # 1 CR cont. Thyroid Ultrasound 0.9 cm RLL hypoechoeic mass probably parathyroid adenoma. 1.4 RLL thyroid cyst. FNA both nodules benign Patient referred for endocrine consult

Case # 1 CR cont. No vitamin D level had been drawn recently 25 OH Vitamin D level 17.3 (30-60 ng/ml) PTH 122 ( pg/ml) Treatment with Vitamin D 50,000 units M-W-F and repeat lab in 2 months

21 yo female referred by urologist with recurrent calcium renal stones x 3 years. 24 hr urine calcium 448 ( mg/24 hr) Serum calcium 11.5 ( mg/dl) Serum phosphorus 2.4 ( mg/dl) PTH 198 (7-53 pg/ml) Parathyroid scan normal with no evidence of adenoma Case #2 KK

Case #2 KK cont. 25 OH Vitamin D level 12.6 Patient treated with Vitamin D 50,000 units M-W-F After 6 wks of therapy, 25 OH Vitamin D 28 and PTH 164 After 4 months therapy, 25 OH Vitamin D 33, PTH 175, Calcium 12.4, Phosphorus 2.0 Discussed possible surgical referral

Case #2 KK cont. The patient was lost to follow up for 18 months during which time she had 10 more renal stones. Calcium 11.3, Phosphorus 2.0, PTH 204 Parathyroid scan and thyroid ultrasound positive for parathyroid adenoma RLL Surgical referral

References 1.The American Association of Clinical Endocrinologist and The American Association of Endocrine Surgeons Position Statement on Diagnosis and Management of Primary Hyperparathyroidism, Endocrine Practice, Volume 11 No.1, January/February Current Medical Diagnosis and Treatment, McGraw Hill, ; Harrison’s Endocrinology, 2010 second edition, , Netter’s Internal Medicine, 2009 second edition, The Journal of Clinical Endocrinology & Metabolism, February 1, 2009, vol 94 no

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