Download hypercalcemia - Technion moodle

ECF
Diet 0.5-1.5 gr
10%
complexed
citrate, sulphate
Resorption
0.3-0.5 g
Formation
0.3-0.5 g
calcium
8.5–10.5
mg/dl
Bone
1000 g
Filtration
5-7gr
40-45 % Absorption
ionized 0.25-0.5gr
40-45 %
albumin
bound
Secretion
0.1-0.2gr
Feces
0.35-0.6gr
• Total body Ca
Reabsorption
1 to 1.5 kg
4.9-6.7gr
• 99%- skeleton
98%
• 0.1% ECF
0.15-0.3 g/24h • rest intracellular
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
Calcium (Ionized) - Roles
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In bone: calcium salts provide structural
integrity of the skeleton ( mineralization)
Regulation of neuromuscular contractility
Regulation of activity of many enzymes
Cofactor in coagulation process ( factors VII, IX, X
and prothrombin)
Cellular activities: second messenger, mediating
the effects of membrane signals on release or
secretory products (neurotransmitters, amylase,
insulin, aldosteron)
Calcium and Albumin
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40-45% of circulating calcium is bound to albumin
Change in serum albumin
change in measured
total serum calcium concentration
Calcium is bound to carboxyl groups in albumin, this
binding is highly pH dependent
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Acute acidosis
binding
ionized calcium
Acute alkalosis
binding
ionized calcium
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These changes are not reflected at the total calcium
A shift of 0.1 pH unit produces a change in ionized
calcium of 0.04 to 0.05 mmol/L ( 0.16-0.2 mg/dl)
Calcium and Albumin
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At pH 7.4 each g/dl of serum albumin binds 0.8 mg/dl of
calcium
Serum calcium should be “corrected” according to
serum albumin level
Normal level of serum albumin is 4 g/dl
Change of 1 g/dl in serum albumin
serum calcium
0.8 mg/dl in total
Example: A patient with total serum calcium 7.5 mg/dl
albumin 2 mg/dl, has corrected serum calcium of 9.1
mg/dl
Disorders of Calcium Metabolism
• Hypercalcemia
• Hypocalcemia
Serum Calcium >10.4 mg/dl
Serum Calcium < 8.5 mg/dl
Causes of Hypercalcemia
Parathyroid related
I. Primary
hyperparathyroidism
 Solitary
adenoma
 Hyperplasia
 MEN
II. Lithium therapy
Malignancy related
I. Solid tumor with
metastasis (breast)
II. Solid tumor with humoral
mediation of
hypercalcemia (lung,
kidney)
III. Hematologic
malignancies (multiple
III. Familial Hypocalciuric
myeloma, lymphoma,
Hypercalcemia (FHH)
leukemia)
Causes of Hypercalcemia
Vitamin D related
I. Vitamin D intoxication
II.  1,25(OH)2D;
sarcoidosis and other
granulomatous
diseases
III. Idiopathic
hypercalcemia of
infancy
Associated with high
bone turnover
I. Hyperthyroidism
II. Immobilization
III. Thiazides
IV. Vitamin A intoxication
Associated with renal failure
I. Severe secondary
hyperparathyroidism
II. Aluminum intoxication
III. Milk- alkali syndrome
Diagnosis of Hypercalcemia
Serum Ca 
Measure serum albumin
or ionized calcium
Albumin corrected
calcium normal
Medical history
and medication use history
Measure PTH
PTH  or N
Check calciuria
PTH 
Check 1,25(OH)2D3
Malignancy
Diagnosis of Hypercalcemia
Check calciuria
Urine Ca
Urine Ca / N
FHH
Primary HPT
Check 1,25(OH)2D3
1,25(OH)2D3 
Granulomatous diseases
(Sarcoidosis), Lymphoma
Primary Hyperparathyroidism
 Incidence 42/100 000
 Age > 40
1/200; 1/1000
  X 3.5 after introduction of routine serum
calcium testing
 80% single gland involvement – adenoma
 20% multiple gland involvement – hyperplasia
 <2% carcinoma
 MEN
Hyperparathyroidism
Serum
Calcium
Primary
Secondary
Tertiary
Serum
Plasma PTH
Phosphorus

 / Normal
 / Normal
/ Normal
 / Normal / 
/

Normal / 

Clinical Manifestations
• CNS - Cognitive difficulties, apathy, drowsiness,
obtundation or even coma
• GI - Anorexia, nausea, vomiting, constipation and
rarely acute pancreatitis
• CVS - Hypertension, A-V nodal delay, shortened
QT interval, enhanced sensitivity to digitalis,
compete heart block, ventricular arrhythmias
• RENAL- Loss of concentrating ability, polyuria,
polydipsia, nephrolithiasis and occasionally
nephrocalcinosis, nocturia
Bone and Joint Manifestations in Primary
Hyperparathyroidism
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Osteoporosis
Diffuse bone pain without
osteitis fibrosa cystica
Osteitis fibrosa cystica
 Diffuse
demineralization
 Subperiostal bone
resorption
 Phalanges
 Lamina dura
 Distal clavicles
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Cystic lesions
Brown tumors
Cysts
Deformities, Fractures,
Pain
Arthritic symptoms
Resorption of articular
bone
Periarticular
metastatic calcification
Pseudogout
Gout
Treatment
When is surgery indicated in PHPT patients
?
Guidelines for Surgery
NIH Consensus 1990 NIH Consensus 2002
Serum
1 – 1.6 mg/dl > upper 1 mg/dl > upper limit of
Calcium limit of normal
normal
Urine
> 400 mg/24h
> 400 mg/24h
Calcium
 by 30 % compared  by 30 % compared
CCT
with age matched
with age matched
 2 SD of gender,
T score (– 2.5) at any
BMD
age, race matched
site
Age
< 50
< 50
Patients for whom medical surveillance is either not
desirable or not possible
Femoral Neck BMD Change in PHPT
Patients
Silverberg et al NEJM
Other Considerations
• Neuropsychological disturbances
• Weakness and easy fatigability
• Depression
• Intellectual weariness
• Increased sleep requirements
Improved by surgery
• Onset of Menopause
• Increased bone loss
99mTc-
sestamibi Parathyroid Scan
20 min
3 hours
90% sensitivity in parathyroid tissue detection
Patients’ Monitoring
Goal – early detection of:
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Worsening of hypercalcemia
Renal impairment
Loss of bone mass
Stones
Fractures
Guidelines for Monitoring
NIH Consensus 1990 NIH Consensus 2002
Serum
Calcium
Urine
Calcium
x2 year
x2 year
x1 year
Not recommended
CCT
x1 year
Not recommended, s-cr
Abdom.
X-Ray, US
x1 year
Not recommended
x1 year (forearm)
x1 year (3 sites: lumbar
spine, hip, forearm)
BMD
General Measures
• Hydration
• Adequate Mobility
• Diet neither restrictive nor excessive in
calcium
• Adequate vitamin D status
• Prompt medical attention for the possibility of
worsening of hypercalcemia (intercurrent
illness accompanied by risk of dehydration)
Calcium-sensing Receptor
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A member of the G protein-coupled receptor family
Contains seven hydrophobic helices that anchor it in the plasma
membrane. The large (~600 amino acids) extracellular domain critical to interactions with extracellular calcium
Large (~200 amino acids) cytosolic tail.
Inactivating Mutations in Calcium
Sensing Receptor
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Inactivating mutation
– Familial hypocalciuric hypercalcemia (FHH) heterozygous
Calcium set point
serum calcium
Urinary calcium reabsorption
urinary
calcium
– Neonatal severe hyperparathyroidism (NSHPT) –
homozygous
-‫מחלה קטלנית אם לא מבצעים כריתה של בלוטות ה‬
parathyroid
Hypercalcemia of Malignancy
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Lung, breast, and prostate cancer frequently invade
skeleton and destroy bone tissue
Breast and lung cancer also cause hypercalcemia of
malignancy (HCM), without invading skeleton
Multiple myeloma has skeletal complications in
virtually 100% of cases
Damage to skeleton usually late in course of disease
Bone damage associated with considerable worsening
in patient’s quality of life
‫‪PTHrP-PTH related peptide‬‬
‫• גן על כרומוזום ‪12‬‬
‫• הגן מצוי ברקמות עוברים‪ :‬סחוס‪ ,‬לב‪ ,‬זקיקי שיערות‪,‬‬
‫אפיתל‬
‫• הגן ל‪ PTHrP -‬מבוטא ברקמות של מבוגר‪ :‬חשוב‬
‫להתפתחות רקמת שד‪ ,‬ריכוז גבוה בחלב‬
‫מוטציה בעכבר‬
‫הומוזיגוטים מוטציה לטלית‬
‫פגמים בהתפתחות העצם והסחוס‬
‫הטרוזיגוטים תקינים‬
PthrP Induced Hypercalcemia
Squamous cell carcinoma
Islet cell tumor (pancreas)
Adult T cell leukemia
Renal cell carcinoma
Breast carcinoma
Paracrine Effect of Bone Resorbing
Substances
Malignant cells travel through
bloodstream & invade bone
Release substances into immediate area:
• PTHrP
• TGF- (transforming growth factoralpha)
• IL-1 (interleukin-1)
• TNF (tumor necrosis factor)
• IL-6 (interleukin-6)
Cause osteoclast activation andlocal
bone destruction & can lead to
hypercalcemia
Plasma Cell Myeloma
Skeletal Metastasis
Treatment
 Hydration
 Furosemide
 Bisphosphonates
 Calcitonin
 Glucocorticoids
 Dialysis
Hydration
• First step in the management of severe
hypercalcemia - Isotonic saline
• Usually  serum calcium by 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, if possible achieve
urine output of 300 ml/hr
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 electrolytes and water
Bisphosphonates
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Structurally related to pyrophosphate
Bind to hydroxyapatite in bone and inhibit the
dessolution of crystals
Great affinity for bone and their resistance to
degradation
Extremely long half life in bone
Poor GI absorption < 1%
Pamidronate
• Inhibits osteoclast function
• 60mg to 90 mg IV over 24hr
• 70% to 100% of patients had  serum
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calcium within 24 hrs, 2/3rd of this group
had normal serum calcium within 7 days
Adverse effects:
– mild transient  in temp (<2deg C)
– transient leukopenia
– small  in s phosphate level
Excreted by kidney  dose adjustment
Relative Potencies of Bisphosphonates
Potency relative to pamidronate disodium in vivo
(hypercalcemic rat), linear scale
Potencies of Bisphosphonates
900
847
800
700
600
500
400
300
200
100
0.05
1.00
2.77
7.44
35.90
olpadronate
alendronate
risedronate
43.60
0
clodronate
pamidronate
disodium
ibandronate ZOMERA®
(zoledronic acid)
1. Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res. 1994;9:745-751.
Zoledronic Acid (ZOMERA)
• Zoledronic acid belongs to a new class of highly
•
potent bisphosphonates
Heterocyclic, nitrogen-containing bisphosphonate
composed of:
• A core bisphosphonate moiety
• An imidazole-ring side chain containing 2 critically positioned
nitrogen atoms
OH
O
N
P
N
OH
O
OH
P
HO
OH
Glucocorticoids
• Inhibit the growth of neoplastic lymphoid
tissue
• Counteract the effects of vitamin D
Functionally Based Classification of
Hypocalcemia
I. PTH absent
A. Hereditary hypoparathyroidism
B. Acquired hypoparathyroidism
Autoimmune
Post surgical
C. Hypomagnesemia
Functionally Based Classification of
Hypocalcemia
III. PTH overwhelmed
A. Severe acute hyperphosphatemia
1. Tumor lysis
2. Acute renal failure
3. Rhabdomyolysis
B. “Hungry bone syndrome” after
parathyroidectomy
Functionally Based Classification of Hypocalcemia
II. PTH ineffective
A. Chronic renal failure
B. Active vitamin D lacking
1.Dietary intake or sunlight
2.Defective metabolism
Anticonvulsant therapy
Vitamin D dependent rickets type I
C. Active vitamin D ineffective
1.Intestinal malabsorption
2.Vitamin D dependent rickets type II
D. Pseudohypoparathyroidism
Differential Diagnosis of Hypocalcemia
Correct calcium for albumin: Ca = measured Ca + 0.8 for
each mg/dl albumin below 4.0
Hypovitaminosis D
Manifestations of Acute Hypocalcemia
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CNS
– Psychiatric disturbances
– Seizures
Neuromuscular
– Tremor, twitching, movement disorders
– Positive Chvostek and Trousseau signs
– Carpopedal spasm
– Tetany
Cardiac
– Q-T prolongation on ECG
– Ventricular Arrhitmia
– Heart block
ECG in Hypocalcemia
• Sinus rhythm with diffuse T wave inversion
• T waves -inverted, but of relatively normal width
• QT prolongation (The corrected qtc is 560 ms )
• Prolongation is in the ST segment rather than the T waves
Carpopedal Spasm
Treatment of Acute Hypocalcemia
Calcium Repletion
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Promptly correct symptomatic or severe
hypocalcemia with cardiac arrhythmias or tetany
with parenteral administration of calcium salts
Administer 1-2 ampules 10% calcium gluconate (93
mg/10 mL) in 50-100 mL of D5W over 5-10 minutes
then NS with 15 mg/kg of calcium
Each 10 cc ampule of 10% calcium gluconate
contains 1 gm of calcium gluconate but less than
100 mg of calcium then therefore, if want to give 15
mg/kg calcium to 70 kg pt, have to give 10 amps
Measure serum calcium every 4-6 hours to maintain
serum calcium levels at 8-9 mg/dL
Treatment of Acute Hypocalcemia
• Patients with cardiac arrhythmias or patients
on digoxin therapy need continuous ECG
monitoring during calcium replacement
because calcium potentiates digitalis toxicity.
• In case of extreme emergency: Calcium
chloride 10% solution (273 mg/10-mL ampule)
delivers higher amounts of calcium and has
advantages when rapid correction is needed,
but it is very irritating when administered
intravenously and probably only should be
administered centrally.
Treatment of Acute Hypocalcemia
• Identify and treat the cause of hypocalcemia
and taper the infusion.
• Start oral calcium and vitamin D treatment
early. Patients with postparathyroidectomy
hungry bone disease, especially those with
osteitis fibrosa cystica, can present with a
dramatic picture of hypocalcemia.
Activating Mutation
• Familial hypercalciuric hypocalcemia the opposite of what is seen with
inactivating mutations
Calcium set point
serum calcium
Urinary calcium reabsorption
Urinary calcium