Transcript HYPERCALCEMIA - WorldMedic Information & Technology

HYPERCALCEMIA
CHATLERT PONGCHAIYAKUL MD
ENDOCRINE UNIT , MEDICINE . KKU
CALCIUM
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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
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
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
Syed Nasrat Imam, MD
FORMULA
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0.8 for each gm of Albumin
0.16mg/dl for each gm of globulin.
(Uca/Pca)
FEca = (Ucr/Pcr) = Uca/Pca x Pcr/Ucr
FEca <1% - Familial hypocalciuric hypercalcemia,
FEca >2% - primary hyperparathyroidism
 in pH will  protein bound Ca by 0.12mg/dl
80-90% 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
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GI- Anorexia, Nausea, Vomiting, Constipation and rarely
acute Pancreatitis.
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CVS- Hypertension, shortened QT interval, and enhanced
sensitivity to digitalis.
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RENAL- Polyuria, Polydipsia, and occasionally
Nephrocalcinosis.
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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
Renal Calculi
Peptic Ulcer
0.68
GI Distress
58
Frequency (%)
Likelihood Ratio
In Primary HPT In Malignancy
Finding +nt
29
4
7.3
13
10
1.3
Hypertension 49
25
Polyuria
22
29
0.76
1.1 Mental status change
33
0.7
1.1
25
34
0.74
Muscular weakness
32
0.89
1.1 Bone Pain28
0.48
1.7 Constipation
19
0.33
1.9 Weight Loss
64
0.30
2.3 Anorexia
64
0.30
2.3 Fatigue
73
0.42
2.6
Finding -nt
0.74
0.97
2
23
1.1
36
58
19
19
31
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
* HTN
* Pancreatitis
* PUD
* Nephrolithiasis
* Accelerated vascular calcification
Syed Nasrat Imam, MD
CALCIUM HOMEOSTASIS
THREE HORMONE AND THREE ORGAN
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PTH
ACTIVATED VITAMIN D
CALCITONIN
BONE
KIDNEY
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
* Half-life of PTH is minutes
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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
blood.
*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
and osteoblasts
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
phosphorous
 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 in response 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
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Small intestine : approx.
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Kidney :
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.
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.
Syed Nasrat Imam, MD
CALCIUM
REGULATION
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PTH
+
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+
1,25(OH)2 D3
+
+
GI Tract
+
CALCITONIN
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ECF Pool
of Calcium
BONE
URINE
Syed Nasrat Imam, MD
ETIOLOGY
Approx. 80% of all cases are caused by
Malignancy or Primary Hyperpathyroidism
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V
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S
Vitamins
Immobilization
Thyrotoxicosis
Addison’s disease
Milk-alkali syndrome
Inflammatory disorders
Neoplastic related disease
Sarcoidosis
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T
Thiazide,
other drugs - Lithium
R Rabdomyolysis
A AIDS
P Paget’s disease,
Parental nutrition,
Pheochromocytoma,
Parathyroid disease
Syed Nasrat Imam, MD
HYPERPARATHYROIDISM
PTH
Calcium
normal / 
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Secondary
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Tertiary
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Primary
Intact PTH
PTHrP
1,25 -D
Ca++
Prim. HPT
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PTHrP malignency
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Non-PTHrP malig
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Syed Nasrat Imam, MD
HYPERPARATHYROIDISM
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STONES,
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BONES,
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GROANS, AND
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MOANS
Syed Nasrat Imam, MD
HYPERCALCEMIA
SERUM CALCIUM
> 10.6
Determine wheather hypercalcemia is real, measure ionized Ca
adjust for change in serum albumin level, careful drug hx Li, Vit D or A,
Measure PTH
PTH high
Hyperparathroidism
PTH - N or Low
Malig- prim. or mets
If cause remain unclear
measure Vit D
Vit high
consider Sarcoidosis
CXR
Consider other
*Hyperthyroidism
*Milk-alkali syndrome
*Familial hypocalciuric hypercalcemia
Syed Nasrat Imam, MD
Syed Nasrat Imam, MD
PARATHYROIDECTOMY
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?
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NIH consensus development conference recommendation
Syed Nasrat Imam, MD
TREATMENT OPTION
 Hydration.
 Gallium
 Furosemide.
 Steroids.
 Bisphosphanate.
 IV
 Calcitonin.
 Mithramycin.
nitrate.
Phosphate.
 Dialysis.
 Others.
Syed Nasrat Imam, MD
HYDRATION
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.
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Syed Nasrat Imam, MD
LOOP DIURETICS
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Facilitate urinary excretion of calcium
– By inhibiting calcium reabsorption in the thick
ascending limb of the loop of Henle.
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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
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CALCITONIN
Not as effective as bisphosphonate, tachyphylaxis quickly occurs and
limits therapeutic efficacy
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MITHRAMYCIN
Toxic effect limits it’s use, reserved for difficult cases of
hypercalcemia that are related to malignancy
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GALLIUM NITRATE
Need to infuse it over 5 days, nephrotoxity limits it’s use, not used
frequently
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CORTICOSTEROIDS
For myeloma, lymphoma, Sarcoidosis, or vit D toxicity decrease GI
absorption, 200-300mg hydrocort for upto 5 days, slow response limits
it’s use
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HEMODIALYSIS
Zero or low calcium bath, In selected condition, eg-hypercalcemia
complicated by renal failure
Syed Nasrat Imam, MD
BISPHOSPHONATE
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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,
Syed Nasrat Imam, MD
PAMIDRONATE
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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
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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. Nephrotoxicincrease s. cr, proteinuria. Thrombocytopenia.
Contraindication-liver, 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.
 Adverse effect- Nephrotoxity,
hypophosphatemia, small reduction in Hb
concentration.
 Clinical experience limited.
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Syed Nasrat Imam, MD
OTHERS
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GLUCOCORTICOIDS- inhibiting 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.
AMIFOSTINE(WR-2721) PG
Syed Nasrat Imam, MD
CHOICE OF AGENT
Mild (<3 mmol/l)-Hydration with saline.
 Moderate(>3.5mmol/l) with moderate
symptoms- Bisphosphonate.
 Severe life threatening( >4mmol/l) - Saline +
Calcitonin + mithramycin,alternatively
bisphosphonate, if steroids sensitive +
steroids.
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Hypercalcemia secondary to malignancy- survival after the
appearance of hypercalcemia is very poor - median of 3 months.
Syed Nasrat Imam, MD
REFERENCES
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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
Syed Nasrat Imam, MD