hypercalcemia heidi chamberlain shea, md endocrine associates of dallas
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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
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
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
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.
Treatment for HypercalemiaTreatment for Hypercalemia BisphosphonateBisphosphonate
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
Treatment for HypercalemiaTreatment for Hypercalemia BisphosphonateBisphosphonate
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
What Is The Diagnosis?What Is The Diagnosis?
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
What Is The Diagnosis?What Is The Diagnosis?
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)