Hypercalcemia Hypercalcemia secondary to Primary secondary to Primary HyperparathyroidismHyperparathyroidism

Emily Kingsley, MDEmily Kingsley, MD

Med-Peds IIMed-Peds II

90% of cases of hypercalcemia are due to 90% of cases of hypercalcemia are due to hyperparathyroidism and malignancyhyperparathyroidism and malignancy– HyperPTH: HyperPTH: asymptomatic with chronic hypercalcemia,

postmenopausal woman, normal physical examination, family history of hyperparathyroidism, and evidence of multiple endocrine neoplasia

– Malignancy: HMalignancy: 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 Primary HyperparathyroidismHyperparathyroidism

Usually due to parathyroid adenomaUsually due to parathyroid adenoma Typically have only small elevations Typically have only small elevations

in serum calcium concentrations in serum calcium concentrations (less than 11 mg/dL) and sometimes (less than 11 mg/dL) and sometimes values are high-normalvalues are high-normal– May require multiple measurementsMay require multiple measurements

– Parathyroid crisisParathyroid crisis: uncommon but : uncommon but acute onset of severe, symptomatic acute onset of severe, symptomatic hypercalcemiahypercalcemia

Secondary HyperPTHSecondary HyperPTH

Seen in severe chronic kidney diseaseSeen in severe chronic kidney disease Usually low or normal serum calcium Usually low or normal serum calcium

valuesvalues Few with hypercalcemia have Few with hypercalcemia have

decreased bone turnoverdecreased bone turnover Tertiary HyperPTH: Parathyroid Tertiary HyperPTH: Parathyroid

hyperplasia to autonomous hyperplasia to autonomous overproduction of PTHoverproduction of PTH

MalignancyMalignancy

Mechanism of increased bone resorption Mechanism of increased bone resorption depends on the cancerdepends on the cancer– Bony mets: direct induction of osteolysis by Bony mets: direct induction of osteolysis by

tumor cells through the use of cytokines (TNF, tumor cells through the use of cytokines (TNF, IL-1)IL-1)

– Nonmetastatic solid tumors: PTHrPNonmetastatic solid tumors: PTHrP– Lymphoma: PTH-independent extrarenal Lymphoma: PTH-independent extrarenal

production of calcitriol from mononuclear cellsproduction of calcitriol from mononuclear cells

Hypercalcemia with values above 13mg/dLHypercalcemia with values above 13mg/dL– Unusual in hyperparathyroidismUnusual in hyperparathyroidism

Other causes of Other causes of hypercalcemiahypercalcemia

Thyrotoxicosis: usu. mild hypercalcemiaThyrotoxicosis: usu. mild hypercalcemia ImmobilizationImmobilization Paget disease of bonePaget disease of bone Hypervitaminosis AHypervitaminosis A Hypervitaminosis DHypervitaminosis D

– Calcitriol used with renal failure has short Calcitriol used with renal failure has short half lifehalf life

– Calcidiol has longer half life so symptomatic Calcidiol has longer half life so symptomatic pts. may need steroids and bisphosphonatepts. may need steroids and bisphosphonate

Sarcoidosis, Wegener’s granulomatosisSarcoidosis, Wegener’s granulomatosis

Milk Alkali Syndrome: can occur in the setting of Milk Alkali Syndrome: can occur in the setting of excess calcium carbonate supplementation to excess calcium carbonate supplementation to treat osteoporosis or dyspepsiatreat osteoporosis or dyspepsia

Lithium: increased secretion of PTH due to an Lithium: increased secretion of PTH due to an increase in the set point at which calcium increase in the set point at which calcium suppresses PTH releasesuppresses PTH release

Thiazide diureticsThiazide diuretics PheochromocytomaPheochromocytoma Adrenal insufficiencyAdrenal insufficiency Theophylline toxicityTheophylline toxicity Familial hypocalciuric hypercalcemia: loss-of-Familial hypocalciuric hypercalcemia: loss-of-

function mutation in the calcium-sensing sensor function mutation in the calcium-sensing sensor on the parathyroid cells and in the kidneys on the parathyroid cells and in the kidneys

Clinical ManifestationsClinical Manifestations Ranges from asymptomatic to obtundation and Ranges from asymptomatic to obtundation and

comacoma Mild hypercalcemia (calcium <12 mg/dl):Mild hypercalcemia (calcium <12 mg/dl):

Asymptomatic or nonspecific symptoms Asymptomatic or nonspecific symptoms (constipation, fatigue, and depression)(constipation, fatigue, and depression)

Moderate hypercalcemia (calcium 12 to 14 Moderate hypercalcemia (calcium 12 to 14 mg/dL):mg/dL): – may be well-tolerated chronically may be well-tolerated chronically

– Acute rise to these concentrations may cause marked Acute rise to these concentrations may cause marked symptoms: polyuria, polydipsia, dehydration, anorexia, symptoms: polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and changes in sensorium. nausea, muscle weakness, and changes in sensorium.

Severe hypercalcemia (calcium >14 mg/dL):Severe hypercalcemia (calcium >14 mg/dL): progression of symptomsprogression of symptoms

NEURO/PSYCHNEURO/PSYCH– AnxietyAnxiety– DepressionDepression– Cognitive dysfunctionCognitive dysfunction– LethargyLethargy– Stupor Stupor – ComaComa

GIGI– ConstipationConstipation– AnorexiaAnorexia– NauseaNausea– PancreatitisPancreatitis– Peptic ulcer diseasePeptic ulcer disease

MSKMSK– Bone painBone pain– Profound muscle Profound muscle

weaknessweakness

CARDIACCARDIAC– Shortening of the QT interval Shortening of the QT interval – BradycardiaBradycardia– HypertensionHypertension

RENALRENAL– Polyuria: decr. concentration in Polyuria: decr. concentration in

distal tub.distal tub.– NephrolithiasisNephrolithiasis– Acute/Chronic renal insuffic.Acute/Chronic renal insuffic.

Serum calcium of 12 to 15 mg/dL can Serum calcium of 12 to 15 mg/dL can lead to a reversible fall in GFR from lead to a reversible fall in GFR from direct renal vasoconstrictiondirect renal vasoconstriction

Long-standing hypercalcemia and Long-standing hypercalcemia and hypercalciuria: Calcification, hypercalciuria: Calcification, degeneration, and necrosis of the degeneration, and necrosis of the tubular cells tubular cells →T→Tubular atrophy and ubular atrophy and interstitial fibrosis and calcification interstitial fibrosis and calcification (nephrocalcinosis). (nephrocalcinosis).

……Bones, stones, moans, and Bones, stones, moans, and groansgroans

AssessmentAssessment

Correction for the measured calcium concentration in hypoalbuminemia

Ca = Serum Ca + 0.8 * (Normal Albumin – Pt Albumin)

Calcium PTHPrimary HyperPTH

MalignancyVit D intoxicationGranulomatous dis.

PTHrPVitamin D levelsTSHSPEP/UPEPVitamin 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 ingestion25-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

PhosphateHyperPTHPTHrP malignancy

-Inhibition of renal proximal tubular Phosphate resorption

Normal orGranulomatous dis. Milk Alkali SyndromeVitamin D intoxication Metastatic bone dis.Thyrotoxicosis Immobilization

Treatment of HypercalcemiaTreatment of Hypercalcemia

Degree of hypercalcemia and rate of Degree of hypercalcemia and rate of rise determine symptoms and rise determine symptoms and urgency of treatmenturgency of treatment– Calcium >14mg/dL: Require treatment Calcium >14mg/dL: Require treatment

regardless of symptomsregardless of symptoms– Calcium 12-14mg/dL: Calcium 12-14mg/dL:

Chronically maybe be toleratedChronically maybe be tolerated Acutely may lead to AMSAcutely may lead to AMS

Ways to Correct Ways to Correct HypercalcemiaHypercalcemia

Isotonic SalineIsotonic Saline– Treats volume depletion from calcium-induced urinary Treats volume depletion from calcium-induced urinary

salt wastingsalt wasting– Increases renal perfusion and urinary calcium clearance Increases renal perfusion and urinary calcium clearance

– AdministrationAdministration: Initial rate of 200-300ml/hr adjusted for : Initial rate of 200-300ml/hr adjusted for urinary output of 100ml/hurinary output of 100ml/h Limited in those with cardiac or renal diseaseLimited in those with cardiac or renal disease Should be discontinued with development of edemaShould be discontinued with development of edema

– GoalGoal: Euvolemia: Euvolemia Rarely normalizes calcium levelRarely normalizes calcium level

BisphosphonatesBisphosphonates– 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 CalcitoninMore potent than Saline and Calcitonin

– AdministrationAdministration: IV Zoledronic acid preferred due : IV Zoledronic acid preferred due to potency and short administration time (15 to potency and short administration time (15 min.)min.) Single dose due to risk of osteonecrosis of jaw with Single dose due to risk of osteonecrosis of jaw with

repeat doses repeat doses

– EffectEffect: Seen in 2-4 DAYS: Seen in 2-4 DAYS

CalcitoninCalcitonin– Decrease bone reabsorption by interfering with Decrease bone reabsorption by interfering with

osteoclast maturationosteoclast maturation– Increase renal calcium excretionIncrease renal calcium excretion

– AdministrationAdministration: IM or subcut, nasal not : IM or subcut, nasal not effectiveeffective

– EffectEffect: Rapid with lowering : 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 HOURSEfficacy limited to 48 HOURS

GlucocorticoidsGlucocorticoids– Useful with calcidiol ingestionUseful 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

– AdministrationAdministration: 20-40mg/day: 20-40mg/day– EffectEffect: Seen in 2-5 days: Seen in 2-5 days

DialysisDialysis– Indications:Indications:

Severe hypercalcemia (Severe hypercalcemia (18 to 20 mg/dL) with neurologic symptoms

Limited use of IV hydration:Limited use of IV hydration:– Renal insufficiencyRenal insufficiency– Heart failureHeart failure

In Sum…In Sum… Mild (<12mg/dl):Mild (<12mg/dl): No therapy No therapy

– Avoid thiazide diuretic, lithium, calcium ingestion Avoid thiazide diuretic, lithium, calcium ingestion (>1000mg/day), volume depletion, prolonged (>1000mg/day), volume depletion, prolonged bedrestbedrest

Moderate (12-14mg/dl):Moderate (12-14mg/dl): Treat if Treat if symptomatic or an acute risesymptomatic or an acute rise

Severe (>14mg/dl):Severe (>14mg/dl): IV saline (immediate IV saline (immediate effect), calcitonin (immediate effect), effect), calcitonin (immediate effect), bisphosphonate (delayed but most effective)bisphosphonate (delayed but most effective)

Primary hyperparathyroidism: Primary hyperparathyroidism: ParathyroidectomyParathyroidectomy

And the calcium lived And the calcium lived happily ever after…happily ever after…

(What would a Med-Peds presentation (What would a Med-Peds presentation

be without a Sponge Bob reference?!?!)be without a Sponge Bob reference?!?!)

HUNGRY BONE SYNDROMEHUNGRY 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

HypocalcemiaHypocalcemia– Tetany, seizures, heart failureTetany, seizures, heart failure– Treatment: 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

HypophosphatemiaHypophosphatemia: With significant bone disease: 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

HypomagnesemiaHypomagnesemia– Can contribute refractory hypocalcemia by diminishing PTH

secretion and inducing PTH resistance

HyperkalemiaHyperkalemia

THANK YOU!THANK YOU!

ReferencesReferences

Bilezikian, J. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab 1993; 77: 1445-1449.

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: 1863-1875.

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