hypercalcemia heidi chamberlain shea, md endocrine associates of dallas

HypercalcemiaHypercalcemia

Heidi Chamberlain Shea, MDHeidi Chamberlain Shea, MD

Endocrine Associates of DallasEndocrine Associates of Dallas

Goals of DiscussionGoals of Discussion

Review Calcium metabolismReview Calcium metabolism Differential Diagnosis of HypercalcemiaDifferential Diagnosis of Hypercalcemia Treatment options Treatment options Calcium case presentationsCalcium case presentations

Calcium PhysiologyCalcium Physiology An essential intracellular and extracellular cation Extracellular calcium is required to maintain normal

biological function of nervous system, the musculoskeletal system, and blood coagulation

Intracellular calcium is needed for normal activity of many enzymes

Preservation of the integrity of cellular membrane Regulation of endocrine and exocrine secretory activities Activation of compliment system Bone metabolism

Role of CalciumRole of Calcium

Bone mineralizationBone mineralization Muscle contractionMuscle contraction

SkeletalSkeletal CardiacCardiac Smooth muscleSmooth muscle

Blood clottingBlood clotting Nerve impulse transmissionNerve impulse transmission

Bone metabolismBone metabolism Parathyroid Parathyroid

hormone (PTH)hormone (PTH) CalciumCalcium PhosphorusPhosphorus Vitamin DVitamin D CalcitoninCalcitonin

CalciumCalcium 41% combined with plasma proteins41% combined with plasma proteins

Not diffusibleNot diffusible One gram per deciliter of albumin binds

approximately 0.8 mg/dl of calcium 9% combined with anionic substances9% combined with anionic substances

Citrate and phosphateCitrate and phosphate Not ionizedNot ionized DiffusibleDiffusible

50% is diffusible and ionized50% is diffusible and ionized Most important in bodily functionsMost important in bodily functions

Effects of CalciumEffects of CalciumHypocalcemiaHypocalcemia

Increased neuronal Increased neuronal membrane permeability membrane permeability to sodium ions facilitates to sodium ions facilitates action potentialsaction potentials

When calcium levels When calcium levels < 6mg/dl< 6mg/dl

TetanyTetany Chvostek’s signChvostek’s sign Trousseau’s signTrousseau’s sign

Calcium Calcium <<4mg/dl = 4mg/dl = DeathDeath

Effects of Effects of HypercalcemiaHypercalcemia

Calcium >12 mg/dlCalcium >12 mg/dl Nervous system Nervous system

depresseddepressed FatigueFatigue DepressionDepression ConstipationConstipation AnorexiaAnorexia PolyuriaPolyuria

Most common nocturiaMost common nocturia

Parathyroid Parathyroid poisoningpoisoning Calcium > 17mg/dlCalcium > 17mg/dl Calcium phosphate Calcium phosphate

crystals precipitatecrystals precipitate

Findings with HypercalcemiaFindings with Hypercalcemia

Bony tenderness Hyperactive tendon reflexes Tongue fasciculations Hypercalcemia in pregnancy

May cause hypocalcemia in the neonate Suppressing the fetal parathyroid

Hypercalcemia Small decrease in GFR

Hemodynamic effects & hyposthenuria (a loss of renal concentrating abilities)

Findings with HypercalcemiaFindings with Hypercalcemia Band KeratopathyBand Keratopathy

Deposition of Calcium Corneal opacities Long standing hypercalcemia Associated with primary

hyperparathyroidism Calcium deposition begins near

the limbus at the 3 & 9 o’clock position

Less friction from the lids near the limbus

Tear film is most alkaline in the most exposed area, band running across the cornea from the 3 to 9 o’clock position

Complications of HypercalcemiaComplications of Hypercalcemia

Sinus bradycardia Increase in the degree of a heart block Cardiac arrhythmia Hypertension Pancreatitis Peptic ulcer disease Nephrolithiasis Accelerated vascular calcification

Calcium HomeostasisCalcium Homeostasis

HormonesHormones PTHPTH Vitamin DVitamin D CalcitoninCalcitonin

OrgansOrgans BoneBone KidneyKidney Small intestineSmall intestine

1,25-OH Vitamin D

Calcium PhysiologyCalcium PhysiologyTarget OrgansTarget Organs

Small intestine : approx. 40% absorbed, 50% of that - excreted into bile and other intestinal secretions. So only 20% of the total amount of Ca ingested daily is available to circulate between bone and extracellular fluid.

Kidney : Glomerulus filters out the Ca that is not bound to protein. Proximal tubule - approx. 50% to 70% is reabsorbed, Ca reabsorption Proximal tubule - approx. 50% to 70% is reabsorbed, Ca reabsorption

mirrors Na reabsorption.mirrors Na reabsorption. Ascending limb of the loop of henle - approx. 30% to 40% reabsorbedAscending limb of the loop of henle - approx. 30% to 40% reabsorbed Distal nephron - about 10% reabsorbed. PTH and activated Vit D increases Distal nephron - about 10% reabsorbed. PTH and activated Vit D increases

Ca absorption during Ca deficient states.Ca absorption during Ca deficient states.

Normally kidney excretes approx. 200 mg /day of Ca to maintain homeostasis. During states of severe Ca depletion, the Kidney can decrease urinary excretion to 50mg /day or less.

PTH

CALCITONIN

BONEECF Poolof

Calcium

1,25(OH)2 D3

GI Tract

URINE

_

+

+

+

+

_

_

+

CALCIUM REGULATION

Parathyroid Parathyroid

Four glands located Four glands located behind the thyroidbehind the thyroid

Length 6 millimetersLength 6 millimeters Width 3 millimetersWidth 3 millimeters Thickness 2 millimetersThickness 2 millimeters Often accidentally Often accidentally

removedremoved Normal function with at Normal function with at

least 2 glandsleast 2 glands

ParathyroidParathyroid

ComposedComposed Chief cellsChief cells

Synthesize, secrete Synthesize, secrete and store PTHand store PTH

Oxyphil cellsOxyphil cells ? function? function

Responsible for Responsible for calcium homeostasiscalcium homeostasis KidneyKidney BoneBone

Parathyroid ActionsParathyroid Actions

Increases calcium Increases calcium Regulates intestinal absorptionRegulates intestinal absorption

25-OH vitamin D 1,25-OH vitamin D25-OH vitamin D 1,25-OH vitamin D Renal absorption of calcium/excretion of Renal absorption of calcium/excretion of

phosphorusphosphorus Bone reabsorptionBone reabsorption

OsteolysisOsteolysis

Parathyroid and BoneParathyroid and Bone

Osteoblasts + Osteocytes = Osteocytic Osteoblasts + Osteocytes = Osteocytic membrane systemmembrane system

Osteocytic pumpsOsteocytic pumps Pump calcium from bone to ECFPump calcium from bone to ECF To maintain calcium concentration in bone To maintain calcium concentration in bone

fluid, osteolysis occurs and calcium fluid, osteolysis occurs and calcium phosphate is resorbed from bonephosphate is resorbed from bone

Fibrous and gel matrix remain intactFibrous and gel matrix remain intact

Parathyroid and BoneParathyroid and Bone

PTH stimulates osteocytic pumpPTH stimulates osteocytic pump Increases permeability of osteocytic membrane Increases permeability of osteocytic membrane

allowing calcium to diffuseallowing calcium to diffuse Osteoblasts,cytes and clasts Osteoblasts,cytes and clasts do notdo not have have

PTH receptorsPTH receptors PTH stimulates osteoblasts and cytes, which then PTH stimulates osteoblasts and cytes, which then

activate osteoclasts via “signaling” systemactivate osteoclasts via “signaling” system PTH indirectly stimulates formation of new PTH indirectly stimulates formation of new

osteoclastsosteoclasts Both cell lines are activated but clastic activity > Both cell lines are activated but clastic activity >

blasticblastic

CalcitoninCalcitonin Secreted by Secreted by

Parafollicular (C cells) in Parafollicular (C cells) in the thyroidthe thyroid

Temporarily lowers Temporarily lowers calcium levelscalcium levels

Decreases osteoclastic Decreases osteoclastic activityactivity

Stimulated by high Stimulated by high calcium levelscalcium levels

Stimulating a distal Stimulating a distal tubular - mediated tubular - mediated calciuresiscalciuresis

Calcium CaveatsCalcium Caveats

Respiratory alkalosis and elevated pH Increase in the binding of calcium Lowers ionized calcium.

Decrease in pH has the opposite effect. As a general rule a shift of 0.1 pH unit produces a

change in ionized calcium of 0.04 to 0.05 mmol/L Chelators such as citrate may transiently

decrease ionized calcium Blood transfussions

Formulas for CorrectionFormulas for Correction 0.8 for each gm of Albumin0.8 for each gm of Albumin 0.16mg/dl for each gm of globulin.0.16mg/dl for each gm of globulin. FEca= (uCA x sCR)/(sCA x uCR) FEca= (uCA x sCR)/(sCA x uCR)

FEca <1% - Familial hypocalciuric hypercalcemia, FEca <1% - Familial hypocalciuric hypercalcemia, FEca >2% - primary hyperparathyroidismFEca >2% - primary hyperparathyroidism

in pH will in pH will protein bound Ca by 0.12mg/dl protein bound Ca by 0.12mg/dl 80-90% of protein bound Ca is bound to Albumin.80-90% of protein bound Ca is bound to Albumin. Increase in serum pH of 0.1 may cause decrease in Increase in serum pH of 0.1 may cause decrease in

ionized Ca of 0.16mg/dlionized Ca of 0.16mg/dl Calcium : Protein bound - 40%; Complexed - 13%; Calcium : Protein bound - 40%; Complexed - 13%;

Ionized fraction - 47%Ionized fraction - 47%

Etiology of HypercalcemiaEtiology of Hypercalcemia

TT Thiazide, Thiazide, other drugs - other drugs -

LithiumLithium R R RabdomyolysisRabdomyolysis AA AIDSAIDS PP Paget’s disease, Paget’s disease,

Parental nutrition, Parental nutrition,

Pheochromocytoma,Pheochromocytoma,Parathyroid diseaseParathyroid disease

Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism

VV VitaminsVitamins II ImmobilizationImmobilization TT ThyrotoxicosisThyrotoxicosis AA Addison’s diseaseAddison’s disease MM Milk-Milk-alkali

syndromesyndrome II Inflammatory Inflammatory

disorders NN Neoplastic Neoplastic related

diseasedisease SS SarcoidosisSarcoidosis

H YPER C ALC EMIA

PT H highHyperparathroidism

PT H - N or LowM alig- prim . or m ets

Vit highconsider Sarcoidosis

CXR

Consider other*Hyperthyroidism

*M ilk-alkali syndrom e*Fam ilia l hypocalciuric hypercalcem ia

If cause rem ain unclearm easure V it D

M easure PT H

Determ ine w heather hypercalcem ia is real, m easure ionized Caadjust for change in serum album in level, careful drug hx Li, V it D or A,

SE R UM C ALC IUM> 10.6

HyperparathyroidismHyperparathyroidism Stones

Bonesones

Groansans

MoansMoans

Normal bone Hyperparathyroid

HyperparathyroidismHyperparathyroidism

PTH Calcium

Primary normal /

Secondary / normal

Tertiary

Intact PTH PTHrP 1,25 -D Ca++

Prim. HPT

PTHrP malignency

Non-PTHrP malig

HyperparathyroidismHyperparathyroidismSurgical ManagementSurgical Management

Serum calcium > 12mg/dl Hypercalciuria > 400mg/day

Normal <200 mg/day Presence of signs and

symptoms Nephrolithiasis Osteitis fibrosa Cystica Neuromuscular

symptoms

Markedly reduced cortical bone density Most common Long bones

Decreased creatinine clearance

Patient age < 50 years Markedly reduced

cancellous bone density Spine

Silverberg et al., JCEM:1996

HyperparathyroidismHyperparathyroidismMedical ManagementMedical Management

Alendronate therapyAlendronate therapy 37 patients37 patients

>50% female>50% female 53 to 80 years53 to 80 years Primary HyperparathyroidismPrimary Hyperparathyroidism

Cross overCross over 24 months Alendronate24 months Alendronate 12 placebo and 12 treatment12 placebo and 12 treatment

Khan et. al., JCEM 2004

HyperparathyroidismHyperparathyroidismMedical ManagementMedical Management

Khan et. al., JCEM 2004

Treatment for HypercalemiaTreatment for Hypercalemia

Gallium nitrate Steroids IV Phosphate Dialysis Others

Hydration Furosemide Bisphosphonate Calcitonin Mithramycin

Treatment for Hypercalemia Treatment for Hypercalemia HydrationHydration

First step in the management of severe hypercalcemia. --isotonic saline

Usually reduces - 1.6-2.4mg/dl Hydration alone rarely leads to

normalization in severe hypercalcemia Rate of IV saline based on severity of

hypercalcemia and tolerance of volume expansion

Treatment for HypercalemiaTreatment for HypercalemiaLoop DiureticsLoop Diuretics

Facilitate urinary excretion of calcium Inhibits calcium reabsorption in the thick Inhibits calcium reabsorption in the thick

ascending limb of the loop of Henle ascending limb of the loop of Henle Guard against volume overload

Volume expansion must precede the Volume expansion must precede the administration of furosemideadministration of furosemide

Drug’s effect depends on delivery of calcium to the Drug’s effect depends on delivery of calcium to the ascending limb. ascending limb.

Needs frequent measurement of lytes and urine Needs frequent measurement of lytes and urine outputoutput

Treatment for HypercalemiaTreatment for Hypercalemia CalcitoninCalcitonin

Not as effective as Not as effective as bisphosphonate, bisphosphonate, tachyphylaxis quickly tachyphylaxis quickly occurs and limits occurs and limits therapeutic efficacytherapeutic efficacy

MithramycinMithramycin Toxic effect limits it’s use, Toxic effect limits it’s use,

reserved for difficult cases reserved for difficult cases of hypercalcemia that are of hypercalcemia that are related to malignancyrelated to malignancy

Gallium NitrateGallium Nitrate Need to infuse it over 5 Need to infuse it over 5

days, nephrotoxity limits it’s days, nephrotoxity limits it’s use, not used frequentlyuse, not used frequently

CorticosteroidsCorticosteroids For myeloma, lymphoma, For myeloma, lymphoma,

Sarcoidosis, or vit D Sarcoidosis, or vit D toxicity Decreases GI absorptionDecreases GI absorption 200-300mg hydrocortisone 200-300mg hydrocortisone

for up to 5 daysfor up to 5 days Slow response limits it’s Slow response limits it’s

useuse HemodialysisHemodialysis

Zero or low calcium bath, Zero or low calcium bath, In selected condition, In selected condition, eg-hypercalcemia eg-hypercalcemia complicated bycomplicated by renal failurerenal failure

Treatment for HypercalemiaTreatment for Hypercalemia BisphosphonateBisphosphonate

Structurally related to pyrophosphate P-C-P bound is a back bone that renders them resistant to

phosphates. They bind to hydroxyapatite in bone and inhibit the

dissolution of crystals. Their great affinity for bone and their resistance to

degradation account for their extremely long half life in bone.


Poor GI absorption- <10% ETIDRONATE, PAMIDRONATE,CLODRONATE Etidronate- 7.5mg/kg iv over 4 hr for 3-7 days

Serum calcium begins to decrease within 2 days after first dose

Response better if patient is well hydrated Oral bisphosphonate to prevent recurrent

hypercalcemia. Adverse effect-increase creatinine, phosphate Long term use-impair bone formation, osteomalacia


PamidronatePamidronate Inhibits osteoclast functionInhibits osteoclast function The most potent bisphosphonateThe most potent bisphosphonate 60mg to 90 mg IV over 24hr60mg to 90 mg IV over 24hr 70% to 100% of patients 70% to 100% of patients

Decreased calcium within 24 hr of treatmentDecreased calcium within 24 hr of treatment 2/3rd of this group had normal calcium within 7 days2/3rd of this group had normal calcium within 7 days

Adverse effect- Adverse effect- Mild transient increase in temp(<2Mild transient increase in temp(<2○○ C), transient C), transient

leukopenia, small reduction in phosphate levelleukopenia, small reduction in phosphate level

Excreted by kidney- dose adjustmentExcreted by kidney- dose adjustment

Treatment for HypercalemiaTreatment for Hypercalemia MithramycinMithramycin

An inhibitor of RNA synthesis in osteoclasts

IV 25 microgram/kg over 4-6 hr

Begins to decrease in 12hr, max in 48-72 hr

Duration of normocalcemia ranges from a few days to several weeks Depending on the extent of

ongoing bone resorption

Adverse effect- Nausea- Minimize with slow iv Avoid extravasation-cellulitis Hepatotoxic- in 20% patients Nephrotoxic- increase in

creatinine, proteinuria Thrombocytopenia

Contraindication-liver, kidney dysfunction, thrombocytopenia, or any coagulopathy

Treatment for HypercalemiaTreatment for Hypercalemia Gallium NitrateGallium Nitrate

Inhibit bone resorption by adsorbing to Inhibit bone resorption by adsorbing to and reducing the solubility of and reducing the solubility of hydroxyapatite crystalshydroxyapatite crystals

Adverse effect- Nephrotoxity, Adverse effect- Nephrotoxity, hypophosphatemia, small reduction in hypophosphatemia, small reduction in hemoglobin concentrationhemoglobin concentration

Clinical experience limitedClinical experience limited

Treatment for HypercalemiaTreatment for Hypercalemia

GLUCOCORTICOIDS- GLUCOCORTICOIDS- Inhibits the growth of neoplastic lymphoid tissue, Inhibits the growth of neoplastic lymphoid tissue,

counteracting the effects of vitamin Dcounteracting the effects of vitamin D PHOSPHATE- PHOSPHATE-

Can lower calcium rapidly and profoundly, Can lower calcium rapidly and profoundly, Very dangerousVery dangerous

Restricted to patient with extreme, life threatening Restricted to patient with extreme, life threatening hypercalcemiahypercalcemia

Last resortLast resort

Contraindications-Hyperphosphatemia and Contraindications-Hyperphosphatemia and azotemiaazotemia

Treatment for HypercalemiaTreatment for Hypercalemia Choice of AgentChoice of Agent

Mild (<12mg/dl)Mild (<12mg/dl) Hydration with salineHydration with saline LasixLasix

Moderate (12-14 mg/dl) Moderate (12-14 mg/dl) with symptomswith symptoms BisphosphonateBisphosphonate

Severe life threatening Severe life threatening (>14mg/dl)(>14mg/dl) Saline + Calcitonin + Saline + Calcitonin +

mithramycinmithramycin Alternatively Alternatively

bisphosphonate, bisphosphonate, Steroids if sensitiveSteroids if sensitive

Hypercalcemia secondary to Hypercalcemia secondary to malignancy-malignancy- Survival after the appearance of Survival after the appearance of

hypercalcemia is very poorhypercalcemia is very poor Median of 3 months.Median of 3 months.

What Is The Diagnosis?What Is The Diagnosis?

52 yr old African 52 yr old African American female American female presents with broken presents with broken hiphip

Poor light exposurePoor light exposure FatigueFatigue ConstipationConstipation Difficulty concentratingDifficulty concentrating History of kidney History of kidney

stonesstones


Calcium 13mg/dl (9-10.5)Calcium 13mg/dl (9-10.5) Phosphorus 2mg/dl (3-4.5)Phosphorus 2mg/dl (3-4.5) 25-OH vitamin D 33 ng/ml (20-40)25-OH vitamin D 33 ng/ml (20-40) PTH 90 pg/ml (10-80) PTH 90 pg/ml (10-80)

Diagnosis: Primary Hyperparathyroidism


10 day old infant presents to ER with 10 day old infant presents to ER with seizuresseizures

Calcium 5.5mg/dl (9-10.5) Calcium 5.5mg/dl (9-10.5) Ionized calcium 3 mg/dl (4-5.6) Ionized calcium 3 mg/dl (4-5.6) Phosphorus 10 mg/dl (3-4.5)Phosphorus 10 mg/dl (3-4.5)

• PTH 5 pg/ml (10-80)

Diagnosis: Hypoparathyroidism

What Is The Diagnosis?What Is The Diagnosis? 18 month old African American male18 month old African American male Presents with abnormal gaitPresents with abnormal gait Low sunlight exposureLow sunlight exposure Breast fed as infant with current poor dairy Breast fed as infant with current poor dairy

intakeintake Calcium 8 mg/dl (9-10.5)Calcium 8 mg/dl (9-10.5) Phosphorus 4mg/dl (3-4.5)Phosphorus 4mg/dl (3-4.5)

• PTH 85 pg/dl (10-80)• 25-OH Vitamin D 10 ng/ml (20-40)

DiagnosisDiagnosis

Vitamin D deficiency Vitamin D deficiency with secondary with secondary hyperparathyroidismhyperparathyroidism

Tibial and femur Tibial and femur bowingbowing

Treatment: Treatment: Ergocalciferol and Ergocalciferol and calciumcalcium

hypercalcemia heidi chamberlain shea, md endocrine associates of dallas

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