Unformatted text preview: HYPERCALCEMIA
CHATLERT PONGCHAIYAKUL MD
ENDOCRINE UNIT , MEDICINE . KKU CALCIUM
q q q
q 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
Syed Nasrat Imam, MD CALCIUM
• 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
• Chelators such as citrate may transiently decrease ionized
• Total body Ca -1 to 1.5 kg, 99%- skeleton, 0.1% ECF , rest
• One gram per deciliter of albumin binds approximately 0.8
mg/dl of calcium
Syed Nasrat Imam, MD FORMULA
q 0.8 for each gm of Albumin
0.16mg/dl for each gm of globulin.
(Uca/Pca) = Uca/Pca x Pcr/Ucr
(Ucr/Pcr) FEca <1% Familial hypocalciuric hypercalcemia, FEca >2% primary hyperparathyroidism
↑↓ in pH will ↑↓ protein bound Ca by 0.12mg/dl
8090% of protein bound Ca is bound to Albumin.
Increase in serum pH of 0.1 may cause decrease in ionized Ca of 0.16mg/dl
Calcium : Protein bound 40%; Complexed 13%; Ionized fraction 47% Syed Nasrat Imam, MD CLINICAL MANIFESTATIONS
q GI Anorexia, Nausea, Vomiting, Constipation and rarely acute Pancreatitis. q CVS Hypertension, shortened QT interval, and enhanced sensitivity to digitalis. q RENAL Polyuria, Polydipsia, and occasionally Nephrocalcinosis. q CNS Cognitive difficulties, Apathy, Drowsiness, Obtundation, or even Coma. Most common symptom is probably nocturia
Syed Nasrat Imam, MD SYMPTONS
More than 50% of all patients with primary hyperparathyroidism are asymptomatic when hypercalcemia is first discovered.
Diagnostic Finding Frequency (%) Likelihood Ratio In Primary HPT In Malignancy Finding +nt Finding nt Renal Calculi Peptic Ulcer
Mental status change
31 4 10 25 29 33 34 36 58 58 64 64 73 7.3 0.74 1.3 0.97 2 0.68
0.7 1.1 0.74 1.1
Syed Nasrat Imam, MD SIGNS
* 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 Syed Nasrat Imam, MD SIGNS
* 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) Syed Nasrat Imam, MD COMPLICATIONS
* Sinus bradycardia
* Increase in the degree of a heart block
* Cardiac arrhythmia
* Accelerated vascular calcification
Syed Nasrat Imam, MD CALCIUM HOMEOSTASIS
THREE HORMONE AND THREE ORGAN
ACTIVATED VITAMIN D
SMALL INTESTINE Syed Nasrat Imam, MD THREE HORMONES
PTH (84 amino acid) *Actions on Bone *Actions on Kidney *Actions on GI * Parathyroid cells are unusual in the respect that hormone degradation rather than synthesis is adjusted according to physiological demand. As much as 90% can be destroyed within the chief cells.
* If blood levels of ionized calcium drop by as little as 0.1 mg/dl, secretion of PTH is stimulated
* Halflife of PTH is minutes
• Kidney reacts quickly to changes in PTH and is responsible for minute to minute adjustments of blood calcium. PTH acts directly on distal portion of the nephron to decrease urinary excretion of calcium mediated by cAMP. PTH powerfully inhibits tubular reabsorption of phosphate and thus increases the amount excreted in the urine, mainly in proximal tubules
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.
Action of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemia
Syed 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
*Bone responds in 2-3 hours 1st phase to small increases of PTH. PTH→Receptors on
surface osteocytes→ intervention of GTP binding protein→activates adenylate
cyclase→Increases permeability to of osteocytes to calcium in surrounding bone fluid
compartment→Calcium enters cytosol and then extruded to ECF compartment on other
side of bone membrane and shifts equilibrium to solubilization
2nd 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
Syed Nasrat Imam, MD VITAMIN D
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
•Mineralization of osteoid occurs spontaneously when adequate amounts of
calcium and phosphorous are available
•1,25(OH)2D3 increases the number and activity of osteoclasts but osteoblasts
have the receptors
•Effect 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.
Syed Nasrat Imam, MD CALCITONIN ( 32 amino acid )
Parafollicular cells of the Thyroid gland inresponse of hypercalcemia * Decrease osteoclast activity. * 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 Syed Nasrat Imam, MD TARGET ORGAN
q 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. q Kidney : Glumerulus filters out the Ca that is not bound to protein. – Proximal tubule - approx. 50% to 70% is reabsorbed, Ca reabsorption mirrors Na
– 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.
Syed Nasrat Imam, MD CALCIUM REGULATION
_ + _ PTH 1,25(OH)2 D3 +
GI Tract CALCITONIN
of Calcium + BONE URINE
Syed Nasrat Imam, MD ETIOLOGY
ETIOLOGY Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism
Neoplastic related disease
Sarcoidosis q q
q T Thiazide,
other drugs - Lithium
P Paget’s disease,
Parathyroid Syed Nasrat Imam, MD HYPERPARATHYROIDISM
Primary Calcium normal / ↑ Secondary ↑ Tertiary ↑ ↓ormal
Intact PTH ↑
PTHrP 1,25 -D Ca++ Prim. HPT ↑ ↓ ↑↑ PTHrP malignency ↓ ↑ ↓↑ Non-PTHrP malig ↓ ↓ ↓↑
Syed Nasrat Imam, MD HYPERPARATHYROIDISM
q STONES, q BONES, q GROANS, AND q MOANS
Syed Nasrat Imam, MD H Y P E R C A L C E M IA
S E R U M C A L C IU M
> 1 0 .6
D e te r m in e w h e a th e r h y p e r c a lc e m ia is r e a l, m e a s u r e io n iz e d C a
a d ju s t fo r c h a n g e in s e r u m a lb u m in le v e l, c a r e fu l d r u g h x L i, V it D o r A , M e a s u re P T H
P T H h ig h
H y p e r p a r a th r o id is m PTH - N or Low
M a lig - p r im . o r m e ts If c a u s e r e m a in u n c le a r
m e a s u r e V it D V it h ig h
c o n s id e r S a r c o id o s is
CXR C o n s id e r o th e r
* H y p e r th y r o id is m
* M ilk -a lk a li s y n d r o m e
* F a m ilia l h y p o c a lc iu r ic h y p e r c a lc e m ia Syed Nasrat Imam, MD Pseudohypercalcemia
s.albumin MEN 1 / MEN 2
fami hypocaU hypercalcem
Isolated adult HPT Ectopic
Miscellaneous N or low Li
Recovery from ARF Secondary HPT HYPERCALCEMIA----- malabsorption
renal failure Check PTH Tertiary HPT
>55pg/ml N or low PTH vit D intoxication
tumor production of vit D
Increased bone release Check Vit D Hyperthyroidism
Pancreatic cholera 10-55ng/ml-N
Thiazide diuretics Immobilization
Dialysis osteomalacia Milk-alkali syndrome Syed Nasrat Imam, MD PARATHYROIDECTOMY
A serum calcium > 12mg/dl
q Hypercalciuria > 400mg/d
q Presence of sign and symptomsS,B,G,M
q Markedly reduced cortical bone density
q Hypercalcemia causing decreased GFR
q Patient age under 50 years?
q NIH consensus development conference recommendation Syed Nasrat Imam, MD TREATMENT OPTION
q Hydration. q Gallium nitrate. q Bisphosphanate. q IV Phosphate. q Furosemide.
q Calcitonin. q Mithramycin. q Steroids.
q Others. Syed Nasrat Imam, MD HYDRATION
First step in the management of severe hypercalcemia. isotonic saline.
q Usually reduces 1.62.4mg/dl.
q Hydration alone rarely leads to normalization in severe hypercalcemia.
q Rate of IV saline based on severity of hypercalcemia and tolerance of CVS for volume expansion.
q Syed Nasrat Imam, MD LOOP DIURETICS
q Facilitate urinary excretion of calcium
– By inhibiting calcium reabsorption in the thick
ascending limb of the loop of Henle. q 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 Syed Nasrat Imam, MD q CALCITONIN Not as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy
q MITHRAMYCIN q GALLIUM NITRATE Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancy
Need to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently q CORTICOSTEROIDS For myeloma, lymphoma, Sarcoidosis, or vit D toxicity decrease GI absorption, 200300mg hydrocort for upto 5 days, slow response limits it’s use
q HEMODIALYSIS Zero or low calcium bath, In selected condition, eghypercalcemia complicated by renal failure Syed Nasrat Imam, MD BISPHOSPHONATE
BISPHOSPHONATE q q
q Structurally related to pyrophosphate. PCP 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 7.5mg/kg iv over 4 hr for 37 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 effectincrease s. cr, phosphate, long term useimpair bone formation, osteomalacia, Syed Nasrat Imam, MD PAMIDRONATE
q q q Inhibits osteoclast function
The most potent bisphosphonate.
60mg to 90 mg IV over 24hr.
70% to 100% of patients had decreased s. calcium within 24 hr of t/t, 2/3rd of this group had normal s cal within 7 days.
Adverse effect mild transient increase in temp(<2deg C), transient leukopenia, small reduction in s phosphate level.
Excreted by kidney dose adjustment. Syed Nasrat Imam, MD MITHRAMYCIN
q q q An inhibitor of RNA synthesis in osteoclasts
IV 25 microgram/kg over 46 hr.
Begins to decrease in 12hr, maxm in 4872 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 extravasationcellulitis.Hepatotoxic in 20% pt. Nephrotoxic increase s. cr, proteinuria. Thrombocytopenia.
Contraindicationliver, kidney dysfunction, thrombocytopenia, or any coagulopathy. Syed Nasrat Imam, MD GALLIUM NITRATE
Inhibit bone resorption by adsorbing to and reducing the solubility of hydroxyapatite crystals.
q Adverse effect Nephrotoxity, hypophosphatemia, small reduction in Hb concentration.
q Clinical experience limited.
q Syed Nasrat Imam, MD OTHERS
q q q GLUCOCORTICOIDSinhibiting the growth of neoplastic lymphoid tissue, counteracting the effects of vitamin D.
PHOSPHATE Can lower rapidly and profoundly, but very dangerous. Restricted to pt with extreme, life threatening hypercalcemia in whom all other measure failed. Hyperphosphatemia and azotemia are contraindications.
Syed Nasrat Imam, MD CHOICE OF AGENT
CHOICE OF AGENT
Mild (<3 mmol/l)Hydration with saline.
q Moderate(>3.5mmol/l) with moderate symptoms Bisphosphonate.
q Severe life threatening( >4mmol/l) Saline + Calcitonin + mithramycin,alternatively bisphosphonate, if steroids sensitive + steroids.
q Hypercalcemia secondary to malignancy survival after the appearance of hypercalcemia is very poor median of 3 months.
Syed Nasrat Imam, MD REFERENCES
q q q
q Recognizing hypercalcemia: The ‘3hormone, 3organ 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:s9s13
Mallette LE. The Hypercalcemia. Semin Nephro. 1992;12:159190.
Edelson GW, Kleenehoper M. Hypercalcemic crisis. Med Clin North Am. 1995;79:7992 Syed Nasrat Imam, MD ...
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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.
- Fall '11