hypercalcemia chatlert pongchaiyakul md endocrine unit, medicine. kku

HYPERCALCEMIAHYPERCALCEMIA

CHATLERT PONGCHAIYAKUL MDCHATLERT PONGCHAIYAKUL MD

ENDOCRINE UNIT , MEDICINE . KKUENDOCRINE UNIT , MEDICINE . KKU

CALCIUMCALCIUM 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

Syed Nasrat Imam, MD

• Respiratory alkalosis and elevated pH cause increase in the binding of calcium and 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

• Total body Ca -1 to 1.5 kg, 99%- skeleton, 0.1% ECF , rest intracellular.

• One gram per deciliter of albumin binds approximately 0.8 mg/dl of calcium

CALCIUMCALCIUM


FORMULAFORMULA

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. (Uca/Pca)(Uca/Pca)

(Ucr/Pcr)(Ucr/Pcr)

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 ionized Ca of Increase in serum pH of 0.1 may cause decrease in ionized Ca of

0.16mg/dl0.16mg/dl Calcium : Protein bound - 40%; Complexed - 13%; Ionized fraction - Calcium : Protein bound - 40%; Complexed - 13%; Ionized fraction -

47%47%

FEca = = Uca/Pca x Pcr/Ucr


CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS

GI- Anorexia, Nausea, Vomiting, Constipation and rarely acute Pancreatitis.

CVS- Hypertension, shortened QT interval, and enhanced sensitivity to digitalis.

RENAL- Polyuria, Polydipsia, and occasionally Nephrocalcinosis.

CNS- Cognitive difficulties, Apathy, Drowsiness, Obtundation, or even Coma.


Most common symptom is probably nocturia

SYMPTONSSYMPTONSMore than 50% of all patients with primary hyperparathyroidism are More than 50% of all patients with primary hyperparathyroidism are asymptomatic when asymptomatic when hypercalcemia is first discovered. is first discovered.

Diagnostic Finding Frequency (%) Diagnostic Finding Frequency (%) Likelihood RatioLikelihood Ratio In Primary HPT In Malignancy Finding +nt Finding -nt In Primary HPT In Malignancy Finding +nt Finding -nt Renal CalculiRenal Calculi 2929 4 4 7.3 7.3 0.74 0.74 Peptic Ulcer Peptic Ulcer 1313 10 10 1.3 1.3 0.97 0.97HypertensionHypertension 4949 25 25 2 0.68 2 0.68PolyuriaPolyuria 2222 29 29 0.760.76 1.1 1.1 Mental status Mental status changechange 2323 33 33 0.70.7 1.1 1.1 GI DistressGI Distress 2525 34 34 0.740.74 1.1 1.1 Muscular Muscular weaknessweakness 3232 36 36 0.890.89 1.1 1.1 Bone PainBone Pain

2828 58 58 0.480.48 1.7 1.7 ConstipationConstipation1919 58 58 0.330.33 1.9 1.9 Weight LossWeight Loss1919 64 64 0.300.30 2.3 2.3 AnorexiaAnorexia1919

64 64 0.300.30 2.3 2.3 FatigueFatigue 3131 73 73

0.420.42 2.6 2.6


* Band keratopathy

The deposition of Ca as corneal opacities is usually sign of long standing hypercalcemia -most commonly associated with primary hyperparathyroidism.

Calcium deposition begins near the limbus at the 3 & 9 o’clock position, presumbly because there is less friction from the lids near the limbus & because the tear film is most alkaline in the most exposed area, band running across the cornea from the 3 to 9 o’clock position

SIGNSSIGNS


* Bony tenderness

* Hyperactive tendon reflexes

* Tongue fasciculations

Hypercalcemia in pregnant female may cause hypocalcemia in her neonates by suppressing the fetal parathyroid.

Hypercalcemia - small dec. in GFR - due to hemodynamic effects & hyposthenuria (a loss of renal concentrating abilities)

SIGNSSIGNS


COMPLICATIONSCOMPLICATIONS* Sinus bradycardia

* Increase in the degree of a heart block

* Cardiac arrhythmia

* HTN

* Pancreatitis

* PUD

* Nephrolithiasis

* Accelerated vascular calcificationSyed Nasrat Imam, MD

CALCIUM HOMEOSTASISCALCIUM HOMEOSTASIS

PTHPTH ACTIVATED VITAMIN DACTIVATED VITAMIN D CALCITONINCALCITONIN

BONEBONE KIDNEYKIDNEY SMALL INTESTINESMALL INTESTINE

THREE HORMONE AND THREE ORGANTHREE HORMONE AND THREE ORGAN


THREE HORMONESTHREE HORMONESPTHPTH ((84 amino 84 amino acid)

**Actions on Bone Actions on Bone **Actions on Kidney Actions on Kidney **Actions on GI Actions on GI

** Parathyroid cells are unusual in the respect that hormone Parathyroid cells are unusual in the respect that hormone degradation rather than synthesis is adjusted according to degradation rather than synthesis is adjusted according to physiological demand. As much as 90% can be destroyed within the physiological demand. As much as 90% can be destroyed within the chief cells.chief cells.

** If blood levels of ionized calcium drop by as little as 0.1 mg/dl, If blood levels of ionized calcium drop by as little as 0.1 mg/dl, secretion of PTH is stimulatedsecretion of PTH is stimulated

** Half-life of PTH is minutesHalf-life of PTH is minutesKidney reacts quickly to changes in PTH and is responsible for minute to Kidney reacts quickly to changes in PTH and is responsible for minute to minute adjustments of blood calcium. minute adjustments of blood calcium.

PTH acts directly on distal portion of the nephron to decrease urinary PTH acts directly on distal portion of the nephron to decrease urinary excretion of calcium mediated by cAMP. excretion of calcium mediated by cAMP.

PTH powerfully inhibits tubular reabsorption of phosphate and thus increases PTH powerfully inhibits tubular reabsorption of phosphate and thus increases the amount excreted in the urine, mainly in proximal tubulesthe amount excreted in the urine, mainly in proximal tubules

PTH stimulates the renal enzyme that converts vit D to its active form but PTH stimulates the renal enzyme that converts vit D to its active form but has no direct effects on intestinal transport of calcium or phosphate.has no direct effects on intestinal transport of calcium or phosphate.

Action of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemiaAction of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemiaSyed Nasrat Imam, MD

ACTIONS OF PARATHYROID HORMONE

The principal regulator of calcium concentration in extracellular fluid

*Increases the calcium concentration and decreases the phosphate concentration in the blood.

*Bone responds in 2-3 hours 1st phase to small increases of PTH. PTHReceptors on surface osteocytes intervention of GTP binding proteinactivates adenylate cyclaseIncreases permeability to of osteocytes to calcium in surrounding bone fluid compartmentCalcium enters cytosol and then extruded to ECF compartment on other side of bone membrane and shifts equilibrium to solubilization2nd phase- becomes evident about 12 hours later characterized by widespread resorbtion of both mineral and organic components of matrix. Osteoclastic activity predominates

*Activity of all bone cell types is increased by PTH but only osteocytes and osteoblasts have receptors for PTH. Activation of and recruitment of osteoclasts must be accomplished indirectly by some paracrine or endocrine signal produced by osteocytes and osteoblasts


Activated Vit D GI - increase Ca absorption.Bone - increase Ca mobilization.Kidney - increase reabsorption within the distal tubule.Deficiency of vitamin D severely impairs intestinal transport of both calcium and

phosphorousMineralization of osteoid occurs spontaneously when adequate amounts of

calcium and phosphorous are available1,25(OH)2D3 increases the number and activity of osteoclasts but osteoblasts

have the receptorsEffect on calcium absorption in the distal nephron

Regulation- Hydroxylation of carbon 1 by cells in the proximal tubules of the kidney which converts a nearly inactive precursor to a highly active hormone is stimulated primarily by PTH and by low phosphate concentrations. 1,25(OH)2D3 inhibits hydroxylation of carbon in the kidney and carbon 25 in the liver and stimulates hydroxylation of carbon 24 which diverts precursor to a degradative pathway.

VITAMIN D


CALCITONINCALCITONIN ( ( 32 amino acid 32 amino acid ))

Parafollicular cells of the Thyroid gland in response of Parafollicular cells of the Thyroid gland in response of hypercalcemiahypercalcemia

* Decrease osteoclast activity.* Decrease osteoclast activity.

* Stimulating a distal tubular - mediated calciuresis.* Stimulating a distal tubular - mediated calciuresis.

Other hormones affecting calcium balance - many including prostaglandins that mobilize calcium, various growth factors, growth hormone, somatomedins, thyroid hormones(decrease skeletal mass), gonadal hormones which help maintain bone mass, adrenal cortical hormones


TARGET ORGANTARGET ORGAN

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 : Glumerulus filters out the Ca that is not bound to protein.

– Proximal tubule - approx. 50% to 70% is reabsorbed, Ca reabsorption mirrors Na reabsorption.

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


ETIOLOGYETIOLOGY

TT Thiazide, Thiazide, other drugs - Lithiumother drugs - Lithium

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 syndrome syndrome II Inflammatory Inflammatory

disorders NN Neoplastic Neoplastic related

diseasedisease SS SarcoidosisSarcoidosis

HYPERPARATHYROIDISMHYPERPARATHYROIDISMPTH Calcium

Primary normal /

Secondary / normal

Tertiary

Intact PTH PTHrP 1,25 -D Ca++

Prim. HPT

PTHrP malignency

Non-PTHrP malig


HYPERPARATHYROIDISMHYPERPARATHYROIDISM

STONES,

BONES,

GROANS, AND

MOANS


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 PTH

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


Pseudohypercalcemia Sporadic---adenoma/hyperplasia>5.2 Prim HPT

MEN 1 / MEN 2 Heriditary fami hypocaU hypercalcem

Isolated adult HPT

Ectopic Li

HYPERCALCEMIA----- N or low Miscellaneous Recovery from ARF

malabsorption Secondary HPT renal failure

Tertiary HPT

>81pmol/l

vit D intoxication Hyperthyroidism>55pg/ml tumor production of vit D Adrenal insufficieny

sarcoidosis PheochromocytomaPancreatic cholera

N or low PTH EndocrineImmobilization

Increased bone release Malignency Check Vit D 10-55ng/ml-N Hypervitaminosis A

Thiazide diuretics Dialysis osteomalacia

Milk-alkali syndrome

Checks.albumin

Check PTH


PARATHYROIDECTOMYPARATHYROIDECTOMY

A serum calcium > 12mg/dl Hypercalciuria > 400mg/d Presence of sign and symptoms--S,B,G,M Markedly reduced cortical bone density Hypercalcemia causing decreased GFR Patient age under 50 years?

NIH consensus development conference recommendation


TREATMENT OPTIONTREATMENT OPTION

Gallium nitrate.

Steroids. IV Phosphate. Dialysis. Others.


Hydration. Furosemide. Bisphosphana

te. Calcitonin. Mithramycin.

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 CVS for volume expansion.


LOOP DIURETICSLOOP DIURETICS

Facilitate urinary excretion of calcium– By inhibiting calcium reabsorption in the thick

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

– Volume expansion must precede the administration of furosemide, because the drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of lytes and water


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

MITHRAMYCINMITHRAMYCIN Toxic effect limits it’s use, reserved for difficult cases of Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancyhypercalcemia that are related to malignancy

GALLIUM NITRATEGALLIUM NITRATENeed to infuse it over 5 days, nephrotoxity limits it’s use, not used frequentlyNeed to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently

CORTICOSTEROIDSCORTICOSTEROIDSFor myeloma, lymphoma, Sarcoidosis, or vit D For myeloma, lymphoma, Sarcoidosis, or vit D toxicity decrease GI absorption, decrease GI absorption, 200-300mg hydrocort for upto 5 days, slow response limits it’s use200-300mg hydrocort for upto 5 days, slow response limits it’s use

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


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 dessolution 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, S. ca begins to

decrease within 2 days after first dose. Response better if pt well hydrated before t/t. Oral to prevent recurrent hypercalcemia.. Adverse effect-increase s. cr, phosphate, long term use-impair bone formation, osteomalacia,


PAMIDRONATEPAMIDRONATE Inhibits osteoclast functionInhibits osteoclast function The most potent bisphosphonate.The most potent bisphosphonate. 60mg to 90 mg IV over 24hr.60mg to 90 mg IV over 24hr. 70% to 100% of patients had decreased s. calcium 70% to 100% of patients had decreased s. calcium

within 24 hr of t/t, 2/3rd of this group had normal s within 24 hr of t/t, 2/3rd of this group had normal s cal within 7 days.cal within 7 days.

Adverse effect- mild transient increase in Adverse effect- mild transient increase in temp(<2deg C), transient leukopenia, small temp(<2deg C), transient leukopenia, small reduction in s phosphate level.reduction in s phosphate level.

Excreted by kidney- dose adjustment.Excreted by kidney- dose adjustment.


MITHRAMYCINMITHRAMYCIN An inhibitor of RNA synthesis in osteoclasts IV 25 microgram/kg over 4-6 hr. Begins to decrease in 12hr, maxm in 48-72 hr. Duration of normocalcemia ranges from a few days to

several wks. Depending on the extent of ongoing bone resorption.

Adverse effect- Nausea- can be mini- by slow iv. Avoid extravasation-cellulitis.Hepatotoxic- in 20% pt. Nephrotoxic- increase s. cr, proteinuria. Thrombocytopenia.

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


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 crystals.hydroxyapatite crystals.

Adverse effect- Nephrotoxity, Adverse effect- Nephrotoxity, hypophosphatemia, small reduction in hypophosphatemia, small reduction in Hb concentration.Hb concentration.

Clinical experience limited.Clinical experience limited.


OTHERSOTHERS

GLUCOCORTICOIDS- inhibiting the growth of GLUCOCORTICOIDS- inhibiting the growth of neoplastic lymphoid tissue, counteracting the neoplastic lymphoid tissue, counteracting the effects of vitamin D.effects of vitamin D.

PHOSPHATE- Can lower rapidly and profoundly, PHOSPHATE- Can lower rapidly and profoundly, but very dangerous. Restricted to pt with but very dangerous. Restricted to pt with extreme, life threatening hypercalcemia in extreme, life threatening hypercalcemia in whom all other measure failed. whom all other measure failed. Hyperphosphatemia and azotemia are Hyperphosphatemia and azotemia are contraindications.contraindications.

AMIFOSTINE(WR-2721)AMIFOSTINE(WR-2721) PGPG


CHOICE OF AGENTCHOICE OF AGENT

Mild (<3 mmol/l)-Hydration with saline.Mild (<3 mmol/l)-Hydration with saline. Moderate(>3.5mmol/l) with moderate Moderate(>3.5mmol/l) with moderate

symptoms- Bisphosphonate.symptoms- Bisphosphonate. Severe life threatening( >4mmol/l) - Saline Severe life threatening( >4mmol/l) - Saline

+ Calcitonin + mithramycin,alternatively + Calcitonin + mithramycin,alternatively bisphosphonate, if steroids sensitive + bisphosphonate, if steroids sensitive + steroids.steroids.Hypercalcemia secondary to malignancy- survival after the Hypercalcemia secondary to malignancy- survival after the appearance of hypercalcemia is very poor - median of 3 appearance of hypercalcemia is very poor - median of 3 months.months.


REFERENCESREFERENCES

Recognizing hypercalcemia: The ‘3-hormone, 3-organ rule’-Gregory W. Rutecki, MD and Frederick C. Whittier, MD, The journal Of Critical Illness. Vol 13, no. 1.Jan 1998

Management Of Acute Hypercalcemia, John P. Bilezikian, MD, The New England Journal Of Medicine,vol 326, No 18, April 30, 1992.

Cecil’s Text Book Of Internal Medicine Harrison’s Principle Of Internal Medicine. Renal and Electrolyte Disorders, Vth edition, Robert W. Schrier. Potts Jt, ed. 1991 NIH Consensus Development Conference Statement

on Primary Hyperparathyroidism. J Bone Miner Res. 1991;6:s9-s13 Mallette LE. The Hypercalcemia. Semin Nephro. 1992;12:159-190. Edelson GW, Kleenehoper M. Hypercalcemic crisis. Med Clin North Am.

1995;79:79-92


hypercalcemia chatlert pongchaiyakul md endocrine unit, medicine. kku

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