Hypercalcemia secondary to Primary Hyperparathyroidism Emily Kingsley, MD Med-Peds II

90% of cases of hypercalcemia are due to hyperparathyroidism and malignancy 90% of cases of hypercalcemia are due to hyperparathyroidism and malignancy –HyperPTH: –HyperPTH: asymptomatic with chronic hypercalcemia, postmenopausal woman, normal physical examination, family history of hyperparathyroidism, and evidence of multiple endocrine neoplasia –Malignancy: H –Malignancy: Higher concentrations of and more rapid increases in serum calcium and subsequently are more symptomatic Ambulatory: Healthy patients, usually due to primary hyperparathyroidism Hospital: Usually due to malignancy

Primary Hyperparathyroidism Usually due to parathyroid adenoma Usually due to parathyroid adenoma Typically have only small elevations in serum calcium concentrations (less than 11 mg/dL) and sometimes values are high-normal Typically have only small elevations in serum calcium concentrations (less than 11 mg/dL) and sometimes values are high-normal –May require multiple measurements –Parathyroid crisis: uncommon but acute onset of severe, symptomatic hypercalcemia

Secondary HyperPTH Seen in severe chronic kidney disease Seen in severe chronic kidney disease Usually low or normal serum calcium values Usually low or normal serum calcium values Few with hypercalcemia have decreased bone turnover Few with hypercalcemia have decreased bone turnover Tertiary HyperPTH: Parathyroid hyperplasia to autonomous overproduction of PTH Tertiary HyperPTH: Parathyroid hyperplasia to autonomous overproduction of PTH

Malignancy Mechanism of increased bone resorption depends on the cancer Mechanism of increased bone resorption depends on the cancer –Bony mets: direct induction of osteolysis by tumor cells through the use of cytokines (TNF, IL-1) –Nonmetastatic solid tumors: PTHrP –Lymphoma: PTH-independent extrarenal production of calcitriol from mononuclear cells Hypercalcemia with values above 13mg/dL Hypercalcemia with values above 13mg/dL –Unusual in hyperparathyroidism

Other causes of hypercalcemia Thyrotoxicosis: usu. mild hypercalcemia Thyrotoxicosis: usu. mild hypercalcemia Immobilization Immobilization Paget disease of bone Paget disease of bone Hypervitaminosis A Hypervitaminosis A Hypervitaminosis D Hypervitaminosis D –Calcitriol used with renal failure has short half life –Calcidiol has longer half life so symptomatic pts. may need steroids and bisphosphonate Sarcoidosis, Wegener’s granulomatosis Sarcoidosis, Wegener’s granulomatosis

Milk Alkali Syndrome: can occur in the setting of excess calcium carbonate supplementation to treat osteoporosis or dyspepsia Milk Alkali Syndrome: can occur in the setting of excess calcium carbonate supplementation to treat osteoporosis or dyspepsia Lithium: increased secretion of PTH due to an increase in the set point at which calcium suppresses PTH release Lithium: increased secretion of PTH due to an increase in the set point at which calcium suppresses PTH release Thiazide diuretics Thiazide diuretics Pheochromocytoma Pheochromocytoma Adrenal insufficiency Adrenal insufficiency Theophylline toxicity Theophylline toxicity Familial hypocalciuric hypercalcemia: loss-of-function mutation in the calcium-sensing sensor on the parathyroid cells and in the kidneys Familial hypocalciuric hypercalcemia: loss-of-function mutation in the calcium-sensing sensor on the parathyroid cells and in the kidneys

Clinical Manifestations Ranges from asymptomatic to obtundation and coma Ranges from asymptomatic to obtundation and coma Mild hypercalcemia (calcium <12 mg/dl): Asymptomatic or nonspecific symptoms (constipation, fatigue, and depression) Mild hypercalcemia (calcium <12 mg/dl): Asymptomatic or nonspecific symptoms (constipation, fatigue, and depression) Moderate hypercalcemia (calcium 12 to 14 mg/dL): Moderate hypercalcemia (calcium 12 to 14 mg/dL): –may be well-tolerated chronically –Acute rise to these concentrations may cause marked symptoms: polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and changes in sensorium. Severe hypercalcemia (calcium >14 mg/dL): progression of symptoms Severe hypercalcemia (calcium >14 mg/dL): progression of symptoms

NEURO/PSYCH NEURO/PSYCH –Anxiety –Depression –Cognitive dysfunction –Lethargy –Stupor –Coma GI GI –Constipation –Anorexia –Nausea –Pancreatitis –Peptic ulcer disease MSK MSK –Bone pain –Profound muscle weakness CARDIAC CARDIAC –Shortening of the QT interval –Bradycardia –Hypertension RENAL RENAL –Polyuria: decr. concentration in distal tub. –Nephrolithiasis –Acute/Chronic renal insuffic.  Serum calcium of 12 to 15 mg/dL can lead to a reversible fall in GFR from direct renal vasoconstriction  Long-standing hypercalcemia and hypercalciuria: Calcification, degeneration, and necrosis of the tubular cells → Tubular atrophy and interstitial fibrosis and calcification (nephrocalcinosis). …Bones, stones, moans, and groans

Assessment Correction for the measured calcium concentration in hypoalbuminemia Ca = Serum Ca * (Normal Albumin – Pt Albumin) CalciumPTH Primary HyperPTH Malignancy Vit D intoxication Granulomatous dis. PTHrP Vitamin D levels TSH SPEP/UPEP Vitamin A levels Normal or

Haden, ST, Brown, EM, Hurwitz, S, et al. The effects of age and gender on parathyroid hormone dynamics. Clin Endocrinol 2000; 52:329.

25-OH Vitamin D: Usually due to ingestion 25-OH Vitamin D: Usually due to ingestion 1,25-OH Vitamin D: Ingestion, 1,25-OH Vitamin D: Ingestion, granulomatous diseases, lymphoma, primary hyperparathyroidism – –Increased: Recommend CXR → Sarcoidosis, Lymphoma Phosphate HyperPTH PTHrP malignancy -Inhibition of renal proximal tubular Phosphate resorption Normal or Granulomatous dis. Milk Alkali Syndrome Vitamin D intoxication Metastatic bone dis. Thyrotoxicosis Immobilization

Treatment of Hypercalcemia Degree of hypercalcemia and rate of rise determine symptoms and urgency of treatment Degree of hypercalcemia and rate of rise determine symptoms and urgency of treatment –Calcium >14mg/dL: Require treatment regardless of symptoms –Calcium 12-14mg/dL:  Chronically maybe be tolerated  Acutely may lead to AMS

Ways to Correct Hypercalcemia Isotonic Saline Isotonic Saline –Treats volume depletion from calcium-induced urinary salt wasting –Increases renal perfusion and urinary calcium clearance –Administration: Initial rate of ml/hr adjusted for urinary output of 100ml/h  Limited in those with cardiac or renal disease  Should be discontinued with development of edema –Goal: Euvolemia  Rarely normalizes calcium level

Bisphosphonates Bisphosphonates – –Analogs of inorganic pyrophosphate that absorb to the surface of bone hydroxyapatite inhibiting calcium release by interfering with osteoclast-mediated bone resorption –More potent than Saline and Calcitonin –Administration: IV Zoledronic acid preferred due to potency and short administration time (15 min.)  Single dose due to risk of osteonecrosis of jaw with repeat doses –Effect: Seen in 2-4 DAYS

Calcitonin Calcitonin –Decrease bone reabsorption by interfering with osteoclast maturation –Increase renal calcium excretion –Administration: IM or subcut, nasal not effective –Effect: Rapid with lowering –Effect: Rapid with lowering within 4-6 HOURS   Decreases the serum calcium up to a maximum of 1 to 2 mg/dL  Efficacy limited to 48 HOURS

Glucocorticoids Glucocorticoids –Useful with calcidiol ingestion – –Useful with hypercalcemia from increased calcitriol production seen in granulomatous disease and lymphoma   Decreases calcitriol production by activated mononuclear cells in the lung and lymph nodes –Administration: 20-40mg/day –Effect: Seen in 2-5 days

Dialysis Dialysis –Indications:  Severe hypercalcemia (  Severe hypercalcemia (18 to 20 mg/dL) with neurologic symptoms  Limited use of IV hydration: –Renal insufficiency –Heart failure

In Sum… Mild (<12mg/dl): No therapy Mild (<12mg/dl): No therapy –Avoid thiazide diuretic, lithium, calcium ingestion (>1000mg/day), volume depletion, prolonged bedrest Moderate (12-14mg/dl): Treat if symptomatic or an acute rise Moderate (12-14mg/dl): Treat if symptomatic or an acute rise Severe (>14mg/dl): IV saline (immediate effect), calcitonin (immediate effect), bisphosphonate (delayed but most effective) Severe (>14mg/dl): IV saline (immediate effect), calcitonin (immediate effect), bisphosphonate (delayed but most effective) Primary hyperparathyroidism: Parathyroidectomy Primary hyperparathyroidism: Parathyroidectomy

And the calcium lived happily ever after… (What would a Med-Peds presentation be without a Sponge Bob reference?!?!)

HUNGRY BONE SYNDROME Develops in those with Develops in those with bone disease preoperatively due to a chronic increase in bone resorption from high levels of PTH Sudden withdrawal of PTH causes increased osteoblast-mediated bone formation and marked net increase in bone uptake of calcium, phosphate, and magnesium Syndrome most likely to be present if if the serum calcium concentration <8.5 mg/dL and the serum phosphate concentration <3.0 mg/dL on the 3rd postoperative day

Hypocalcemia Hypocalcemia –Tetany, seizures, heart failure –Treatment:   Oral calcium (2 to 4 g per day): Between meals to avoid phosphate binding   IV calcium: With rapid reduction in serum calcium OR symptoms related to hypocalcemia OR plasma calcium concentration below 7.5 mg/dL Hypophosphatemia: With significant bone disease Hypophosphatemia: With significant bone disease –Replacement only in severe hypoPO4 ( –Replacement only in severe hypoPO4 (below 1 mg/dL): Combines with calcium to further reduce calcium concentration – –BUT with lack of severe bone disease: See increase in phosphate due to reversal of PTH-induced phosphate loss in the urine Hypomagnesemia Hypomagnesemia – –Can contribute refractory hypocalcemia by diminishing PTH secretion and inducing PTH resistance Hyperkalemia Hyperkalemia

THANK YOU!

References Bilezikian, J. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab 1993; 77: Haden, ST, Brown, EM, Hurwitz, S, et al. The effects of age and gender on parathyroid hormone dynamics. Clin Endocrinol 2000; 52:329. Marx, S. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343: Up-To-Date.