calcium metabolism and disorders (hanan)

8/8/2019 Calcium Metabolism and Disorders (Hanan)

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Hanan FathyHanan Fathy

Pediatric nephrology unitPediatric nephrology unit

University of AlexandriaUniversity of Alexandria


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Calcium is the most abundant mineral in the body

Plays important roles in the body

- As a cofactor for many enzymes (e.g. Lipase) and proteins

Mineralized tissue (Ca10(PO4)6(OH)2 in

bone, dentin, cementum & enamel)

Neuromuscular excitability

Clot formation Cell-cell adhesion

Intracellular second messenger


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Life Stage Age Males (mg/day) Females (mg/day)

Infants 0-6 months 210 210

Infants 7-12 months 270 270

Children 1-3 years 500 500

Children 4-8 years 800 800

Children 9-13 years 1,300 1,300

Adolescents 14-18 years 1,300 1,300

Adults 19-50 years 1,000 1,000

Adults 51 years and older 1,200 1,200

Pregnancy 18 years and younger - 1,300

Pregnancy 19 years and older - 1,000

Breastfeeding 18 years and younger - 1,300

Breastfeeding 19 years and older - 1,000


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www.drsarma.in

Diet1000 mg

GUT

800 mgexcreted

absorbs

350 mg

secretes

150 mg

Ca2+

PoolBone

500 mg

500 mg

Kidney 2% filteredload

200 mgexcreted

CALCIUM


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Active and passive transport mechanismsActive: is a saturable, transcellular process which

involves calbindin (calcium-binding protein) regulated by the active form of vitamin D

Passive: The paracellular mechanisms occur by thetight junctions, which are made up of a combination of

proteins including, amongst others, the claudins: the

most important, claudin 16 , also known as paracellin 1,

facilitates the passive transport of calcium andmagnesium across intestinal and renal tubular cells

which is not affected by calcium status or parathyroid

hormone

Both processes occur throughout the small intestine


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Absorption increased by:- Body need

- Vitamin D

- Protein

- Lactose - Acid medium

Absorption decreased by:- Vitamin D deficiency

- Calcium-phosphorus imbalance

- Oxalic acid

- Phosphorous- Dietary fiber

- Excessive fat

- High alkalinity

- Also stresses and lack of exercise

Excretion increased by:- Low parathyroid hormone (PTH)

- High extracellular fluid volume

- High blood pressure

- Low plasma phosphate- Metabolic alkalosis

Excretion decreased by:- High parathyroid hormone

- Low extracellular fluid volume

- Low blood pressure

- High plasma phosphate- Metabolic acidosis

- Vitamin D 3


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Daily filtered load

10 gm (diffusible)

99% reabsorbed

Two general mechanisms

Active - transcellular

Passive - paracellular

Proximal tubule and Loopof Henle reabsorption

Most of filtered load

Mostly passive

Inhibited by furosemide

Distal tubule reabsorption

10% of filtered load

Regulated (homeostatic)

stimulated by PTH inhibited by CT

vitamin D has small

stimulatory effect

stimulated by thiazides

Urinary excretion

50 - 250 mg/day

0.5 - 1% filtered load


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Perspiration

Lactation


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Normal serum calcium levels are 8.8 - 10.3mg/dL (2.0 to 2.5 mmol/L)

Normal ionized calcium levels are 2.24 - 2.46meq/L (1 to 1.4 mmol per L)


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0.8 for each gm of Albumin

0.16mg/dl for each gm of globulin.

(Uca/Pca)

(Ucr/Pcr)

FEca 2% - primary hyperparathyroidism

oq in pH will oqprotein 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

FEca = = Uca/Pca x Pcr/Ucr


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Minerals; serum concentration

Calcium (Ca2+); 2.2-2.6 mM (total)

Phosphate (HPO42-); 0.7-1.4 mM

Magnesium (Mg2+); 0.8-1.2 mM

Organ systems that play an import role in Ca2+ metabolism

Skeleton GI tract

Kidney

Calcitropic Hormones

Parathyroid hormone (PTH) Calcitonin (CT)

Vitamin D (1,25 dihydroxycholecalciferol)

Parathyroid hormone related protein (PTHrP)

Fibroblast growth factor 23


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20

K Bone Resorption

K Intestinal Absorption

L Renal Excretion


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Physiologic Anatomy of the Parathyroid Gland


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Derived embryologically from the third (lower glands)and fourth (upper glands) branchial arches.

Transcription factors are involved in their development :

Hoxa3 (thyroid and thymus)

GATA3 ( mutation : sensorineural deafness, renalanomalies, chromosome 10p13-14)

Several genes, including Tbx1 (thymus, cardiac outowtract and the face, chromosome 22q11) and UDF1L, arelocated on the long arm of chromosome 22.

Mutati ns within the genesresp nsi e forthese fa tors

result in congenital hypoparathyroidism

he SRY-related HMG-box gene 3 (SOX3) ,

located on the X chromosome, isalso thought to be involvedin PT glanddevelopment

andmutationsmay be responsible forX-linkedrecessive FIH .


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Structure of PTH


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Single-chain 84-amino-acid polypeptide hormone encoded by a

gene on chromosome 11 from prepro PTH, which has an additional31 amino acids.

Synthesis occurs in the ribosomes, where the initial 25 amino acidpre sequence acts as a signal peptide to aid transport through therough endoplasmic reticulum.

The pre sequence is cleaved and pro-PTH then travels to the Golgiapparatus where the 6 amino acid pro sequence is cleaved to yield

the mature hormone, which is stored in secretory vesicles that fusewith the plasma membrane before secretion of the hormone .

Little PTH is stored within the glands and most of the secretedhormone is newly synthesized. Mutations in the PTH gene have

been described.

Normal concentra-

tionsare about 16 pmol/L (1060 pg/mL) but vary depending

on the assay


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You are called urgently to examine a term, 2-hour-oldnewborn who has had temperature instability, difficultywith feeding, and a suspected seizure. He has atypicalfacies (wide-set eyes, a prominent nose, and a smallmandible), a cleft palate, and a holosystolic murmur. Statlaboratory tests and chest radiograph reveal markedhypocalcemia, a boot-shaped heart, and no apparent

thymus. Which of the following is the most likelydiagnosis?

A. Ataxiatelangiectasia

B. DiGeorge syndrome

C. Hyper-IgE syndrome

D. SCID

E. Wiskott-Aldrich syndrome


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PTH is co-secreted

with chromogranin

A, a protein;

significanceunknown


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Stimulators

Decreased serum [Ca2+].

Mild decreases in serum [Mg2+].

An increase in serum phosphate (Since increasedphosphate will complex with serum calcium to

form calcium phosphate, which causes the Ca-sensitive receptors (CaSr) to think that serum Cahas decreased, as CaSR do not sense Calciumphosphate, thereby triggering an increase in PTH)


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Intracellular magnesium may serve this secretoryfunction in the parathyroids in that hypermagnesemia

can inhibit PTH secretion and hypomagnesemia can

stimulate PTH secretion.

However, prolonged depletion of magnesium will

inhibit PTH biosynthesis and secretion, as it will the

function of many cells.

Hypomagnesemia also attenuates the biological effect

of PTH by interfering with its signal transduction.


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Most studies fail to demonstrate a direct effect ofserum phosphate on PTH secretion, but some recent

studies show that high phosphate increases PTH

biosynthesis and vice versa .

However, serum phosphate has an inverse effect on

calcium concentration and ambient phosphate directly

increases 1,25-D production. Thus, serum phosphatemay directly and indirectly regulate PTH expression.


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Inhibitors

Increased serum [Ca2+].

Severe decreases in serum [Mg2+]


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The calcium-sensing receptor

Present in many tissues, particularly the parathyroid glands ,renal tubule, in bone, cartilage and other tissues .

Its gene is located on chromosome 3q13-21 and the CaSR is alarge molecule consisting of 1078 amino acid residues of which610 form the extracellular calcium-binding domain, 250comprise the seven-transmembrane domain and another 210 theintracellular cytosolic component.

Ca2+binds to the extracellular domain and inuences PTHsecretion by both phospholipase Cb and G-protein second

messengers.

As a consequence, PTH secretion changes in a sigmoidal fashionin response to acute changes in plasma calcium and there is acontinuous tonic secretion of PTH, which maintains plasma-

ionized calcium at whatever concentration is set by the CaSR .


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Calcium Sensing Receptor


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Result in either inactivation or activation of the receptor, whichresult in hypercalcemia and hypocalcemia, respectively.

Inactivating mutations cause insensitivity to calcium, which shiftsthe curve of PTH secretion in response to plasma calcium to theright . As a consequence, PTH secretion is switched off at a higher

concentration than normal and hypercalcemia results .

The receptors are also present in the renal tubule and renal calciumexcretion is thereby reduced. The resulting condition is known asfamilial benign hypercalcemia (FBH) or familial hypocalciuric

hypercalcemia (FHH) .

In contrast, activating mutations of the receptor shift the PTHsecretion curve to the left , causing chronic hypocalcemia andhypercalciuria, a condition known as autosomal dominant

hypocalcemia (ADH)


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Parathyroid Hormone Receptors

Type 1 PTH receptor:

PTH and amino-

terminal peptides of

PTHrP.

G protein-coupled

receptor

Type 2 PTH receptor: Binds PTH, but

has very low affinity for PTHrP.Only expressed in a few tissues- its

structure and physiologic

significance are poorly

characterized.


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Bone

Increases resorptionIncreases formation, especially at low and intermittent

concentrations

Kidney

Decreases calcium excretion (clearance)Increases phosphorus excretion

Gastrointestinal Tract

Increases calcium and phosphorus absorption

Indirect effect via 1,25-D production Blood

Increases calcium

Decreases phosphorus


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Bone fluid calcium in the canaliculi is rapidly mobilized andtransferred to blood by calcium pumps in the membrane.

Mineralized calcium is mobilized more slowly by osteoclast

activity (not shown here).

Fig. 19-21a , Sherwood

12


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PHT decreases OPG production,allowing the protein rank-L, alsomade by osteoblasts, to bind therank-L receptors. This stimulatesosteoclast production andmaturation.

Osteoblasts produce the protein OPG

(osteoprotegerin) which binds

osteoclast rank-L receptors and down

regulates osteoclast production.

2004 Science 305:1420

+PTH

14


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PTHrP is encoded by a single gene that is highly conservedamong species.

It should probably be described as a polyhormone, because afamily of peptide hormones are generated by alternativesplicing of the primary transcript and through use ofalternative post-translational cleavage sites.

To make matters even more complex, some cells appear to usealternative translational initiation codons to produce forms ofthe protein that are targeted either for secretion or nuclearlocalization.


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It is clear that amino-terminal peptides of PTHrP

share a receptor with PTH, but they also bind to atype of receptor in some tissues that does not bindPTH.

In addition to the secreted forms, there is considerable

evidence that a form of PTHrP is generated in somecells that is not secreted and, via nuclear targetingsequences, is translocated to the nucleus, where itaffects nuclear function.

The consequences of this "intracrine" mode of actionare not yet well characterized, but may modulate suchimportant activities as programmed cell death.


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.

PTHrP is secreted from a large and diverse set of cells,

and during both fetal and postnatal life.

Among tissues known to secrete this hormone are

several types of epithelium, mesenchyme, vascular

smooth muscle and central nervous system.

Although PTHrP is found in serum, a majority of its

activity appears to reflect paracrine signaling


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Cartilage and Bone Development ,stimulates theproliferation of chondrocytes These effects of PTHrPappear due to interaction of the PTH-like peptide withthe PTH receptor

Placental Transfer of Calcium

Smooth Muscle Functioning

It acts to relax smooth muscle, thereby serving, amongother things, as a vasodilating hormone.


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Other Effects: PTHrP is highly expressed in skin.Overexpretion of PTHrP in skin show alopecia .

Another interesting defect in PTHrP-null mice is that

teeth develop normally, they fail to erupt.

Finally, both PTHrP and its receptors are widelyexpressed in the CNS, and appear to influence neuronal

survival by several mechanisms. It should be clear fromthe above examples that PTHrP hormones haveprofound effects on a large number of physiologicprocesses.


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An 8-month-old infant presents with the primary complaint ofirritability. He has been exclusively breastfed since birth. Hismother was not interested in providing any supplemental foods

because her milk supply has been adequate. Physicalexamination reveals a fussy infant who has frontal bossing andwhose weight and height are both at the 25th percentile. Theinfant becomes irritable with movement of the left arm. Armradiography reveals a humeral fracture and bowing of both

radii. Chest radiography demonstrates enlargement of thecostochondral junctions.

Of the following, the MOST likely diagnosis is

A. congenital syphilis

B. osteogenesis imperfecta

C. vitamin D-deficient rickets

D. vitamin D-resistant rickets

E. vitamin E deficiency


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At least four different vitamin D 25 hydroxylases distinguishable

by their different affinities and capacities and intracellularlocalization

The first, a low-affinity high-capacity enzyme (CYP27A1) , is located in

mitochondria. There are no reports of rickets resulting from mutations in this gene

but they do cause cerebrotendinous xanthomatosis .

A second high-affinity low-capacity enzyme (CYP2R1),which

may be of greater physiological significance, is located within

hepatic microsomes. Although they have not yet been fully characterized, cases of

rickets are described associated with mutations

Two other enzymes, CYP3A4 and CYP2J2 , probably also have some effect on

25-hydroxylase but are mainly involved in drug metabolism.


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System Tissue

Gastrointestinal hepatocytes Esophagus, stomach, intestine, colonCardiovascular cells Cardiomyocytes, Vascular Smooth

Muscle, Endothelial

Renal Proximal and Distal Tubules, collecting

duct

Endocrine Parathyroid, pancreatic cells, Thyroid Cells

Reproductive Testis, ovary, placenta, uterus,

endometrium

Immune Thymus, bone marrow, B cells, T cells

Respiratory Lung alveolar cells Skeletal Osteoblasts, osteocytes, chondrocytes

Muscle/Connective Tissue Striated, Fibroblasts, stroma

Skin Epidermis, Breast, hair follicles

CNS Neurons, glia, astrocytes


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Inhibited by Vitamin D


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Mutations in the vitamin D receptor occur throughout themolecule but particularly in either the ligand-binding (ligandbinding negative) or the DNA-binding (ligand-bindingpositive) domains.

These mutations cause severe rickets and many individuals,especially those with defects in DNA binding, also havealopecia.

Originally referred to as vitamin D-dependent rickets type II(VDRR-II), it is now more properly called hereditary1,25(OH)2D-resistant rickets (HVDRR) .

In another form of HVDRR, no mutations of the receptor havebeen identified but is thought to be caused by over expressionof a nuclear ribonucleoprotein that binds with the hormone

receptor complex to attenuate its action


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Measure 25 OH Vitamin D

Normal- obtained by population measurement,

30-80 ng/mL

Deficient-


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Pediatrics 0 12 months

1000 IU / Day

All others

2000 IU / Day


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to minimize the health risks associated withUVB radiation exposure while maximizing thepotential benefits of optimum vitamin D status,

{dietary} supplementation and small amountsof sun exposure are the preferred methods ofobtaining vitamin D.

Consensus statement, 2006


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Depends on:

Age

Amount of vitamin D obtained from diet

Skin darkness

Sunshine intensity


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Significant skin exposure

Face, neck, arms, hands

Arms, legs

Adequate sun strength

Time

25% of the time it would take to cause

pinkness of the skin (Caucasians) People with dark skin require significantly

more sun exposure

Holick, 2004


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Cod liver oil 1 TBS

Salmon 3.5 oz.

Mackerel 3.5 oz.

Tuna, canned, in oil, 3 oz.

Sardines 3.5 oz.

Milk (fortified) 8 oz.

Ready to eat cereal (fortified) -1 cup

Egg 1 whole Liver, 3.5 oz.

Cheese, swiss 1 oz.

1,360 IU

360

345

200

250

98

40

20 15

12


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FGF23 is mainly secreted by osteoblasts and osteocytes.

It circulates in plasma and is one of a number of fibroblastgrowth factors that function by fibroblast growth factorreceptors (FGFRs) in a variety of tissues as a classic hormone.

FGF23 is the principal phosphotonin that acts by FGFR1c

to stimulate phosphate excretion by the Type 2c Na/Pi co-transporter.

It also inhibits 1-hydroxylase so that hyperphosphaturic

conditions caused by raised FGF23 are not accompanied bythe expected increase in 1,25(OH)2D.


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Normal Tissue

R1 9 S180

PHEX ??

Mesenchymal Tumor

ADHR

Active FGF23

Normal Pi level

Cartilage/bone mineralization

Renal Pi wasting ++

Inactive

S180R1 9

Active FGF23

Rickets/Osteomalacia

TIO

XLH

By H. I. cheong

NPT2a / NPT2c


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Normal Tissue

R1 9 S180

Inactive

Normal Pi level

Cartilage/bone mineralization

S180R1 9

Active FGF23

Dentin matrix proteinDentin matrix protein 11 (DMP(DMP11))

AR-hypophosphatemicrickets

Chr. 4q21

Non-collagenous

bone matrix formation

FGF 23

A new member regulating renal Pihandling ?

PHEX ?

DMP1 ?

?

NatGenet. 2006Nov;38(11)


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Hypophosphatemic rickets (HR) with decreased renal


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SLC34A3sequencing

= At discretion ofreferrer. Othertestsautomatic.

Hypophosphatemic rickets (HR) with decreasedrenalphosphate reabsorption

HR with noFH

HR with FH ofMale-Male

transmission

HR withhypercalciuria

HR with FH

consistent with

AR inheritance

PHEXsequencing

HR with FHconsistent with X-

linkeddominantinheritance

DMP1 sequencing PHEXsequencing

PHEX MLPA

FGF23sequencing

FGF23 sequencing

if consistent withAD inheritance

HR withhepatomegaly and/or

fastinghypoglycaemiawith

a FH consistent withAR inheritance

SLC2A2sequencing

PHEXMLPA

FGF23 sequencing

DMP1 sequencing

ENPP1 sequencing

HR with (orFH of)Generalised Arterial

Calcification ofinfancy

ENPP1sequencing


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Vitamin D Deficiency

Rickets

Vitamin D Dependent

Rickets

Vitamin D Resistant

Rickets


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Rickets Rickets Rickets

Cause

Lack exposure to sunlightLack of intake

Anticonvulsant therapy

Intestinal malabsorption

Cause

Deficiency enzyme thatconvert 25-D3 to 1,25-D3

Cause

Phosphate leak at level ofproximal tubules

(not a disease of vitamin D

metabolism)

Lab findings

Low Ca2

Low PO4

High ALP

High PTH

Low 1,25-D3

Lab findings

Low Ca2

Low PO4

High ALP

High PTH

Low 1,25-D3

Lab findings

Normal Ca2

Low PO4

Normal PTH

Treatment

Vitamin D

Treatment

Daily 1,25-D3

Treatment

Phosphate supplements


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Three-year-old boy with

vitamin D receptordefect

causing severe ricketswithalopecia

A 1 year old boy presents with generalized seizures His


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A 1-year-old boy presents with generalized seizures. Hisgeneral physical examination findings are normal exceptfor a prominently positive Chvostek response. Results of

laboratory studies include total serum calcium of 4.5mg/dL (1.1 mmol/L) and phosphorus of 8.2 mg/dL (2.73mmol/L). Blood urea nitrogen and creatinine values arenormal for age. Of the following, the MOST likely

diagnosis is

A. dietary calcium deficiency

B. hypoparathyroidism

C. hyperphosphatasia

D. vitamin D deficiency rickets

E. vitamin D-resistant rickets


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CALCITONIN


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Peptide hormone secreted by the thyroid gland that

tends to decrease plasma calcium concentration.

Two ways:

1. decrease absorptive activities of the osteoclasts and the

osteocytic effect of the osteocytic membrane immediate effect

2. decrease formation of new osteoclasts more prolonged

effect

Promotesrenal excretion of Ca2+

Increased Plasma Calcium Concentration Stimulates CalcitoninSecretion

Calcitonin Has a Weak Effect on Plasma Calcium Concentration in

Adult Human


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Product of

parafollicular C cells

of the thyroid

32 aa


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Probably not essential for human survival

Potential treatment for hypercalcemia

7 transmembrane segment receptor Stimulates cAMP production in bone and

kidney

A 1 d ld i f t d l t t d l i H


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A 1-day-old infant develops tetany and convulsions. He

was born at 34 weeks gestation with Apgar scores of

2 and 4 (at 1 and 5 min, respectively) to a womanwhose pregnancy was complicated by diabetes

mellitus and pregnancy-induced hypertension. Which

of the following serum chemistry values is likely to

be the explanation for his condition?

a. Serum bicarbonate level of 22 meq/dL

b. Serum calcium of 6.2 mg/dL

c. Serum glucose of 45 mg/dL

d. Serum magnesium level of 5.0 mg/dL

e. Intracranial hemorrhage


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Denitions

A fall of total calcium below 7.5 mg/dL (1.75 mmol/L), or 2.5mg/dL (0.63 mmol/L) in the ionized calcium concentrationusually denes neonatal hypocalcemia.

In infants up to 3 months of age, hypocalcemia is dened as atotal serum calcium less than 8.8 mg/dL or ionized calciumless than 4.9 mg/dL (1.22-1.4 mM).

The relationship of the total calcium concentration to theionized calcium concentration is atypical in preterm infants,and measurement of the ionized calcium concentration isrequired for accurate assessment of these infants.


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Tetany

Seizure Laryngospasm/stridor

Arrhythmias (Prolonged Q-T interval, conductionabnormalities with bradycardia)

Circumoral numbness

Extremity parasthesiae

Trousseaus sign (carpal spasm by 3 minutes afterinterrupted vascular flow to arm)

Chvosteks sign (facial twitch caused by tapping belowzygoma)

Infants may show lethargy, vomiting, poor feeding

Neurological signs Mental status


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and symptoms

Extrapyramidal signs due to

calcification of basal ganglia Calcification of cerebral

cortex or cerebellum

Personality disturbances

Irritability Impaired intellectual ability

Nonspecific EEG changes

Increased intracranial

pressure Parkinsonism

Choreoathetosis

Dystonic spasms

Confusion

Disorientation Psychosis

Psychoneurosis

Adapted from Fitzpatrick, L.A.: The hypocalcemic states

. Disorders of Bone and Mineral Metabolism. M. Favus (ed),Lippincott Williams & Wilkins, Philadelphia, PA, pp. 568-588, 2002.

Ectodermal changes Smooth musclei l t


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Ectodermal changes

Dry skin

Coarse hair

Brittle nails

Alopecia

Enamel hypoplasia

Shortened premolar roots

Thickened lamina dura

Delayed tooth eruption

Increased dental caries

Atopic eczema

Exfoliative dermatitis

Psoriasis

Impetigo herpetiformis

involvement Dysphagia

Abdominal pain Biliary colic

Dyspnea

Wheezing

Ophthalmologic

manifestations Subcapsular cataracts

Papilledema

Cardiac

Prolonged QT intervalin EKG

Congestive heartfailure

Cardiomyopathy


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Infants and children Hypoparathyroidism

Impaired synthesis / secretion

Loss/ lack of PTH tissue or defective synthesis

Primary or acquired conditions

Defective calcium sensing receptor

End organ resistance to PTH(pseudohypoparathyroidism)

Hypovitaminosis D (MUCHMORECOMMON)

Hypomagnesemia

Other


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Genetic

Autosomal dominant

Autosomal recessive

X-Linked HDR (hypoparathyroidism associated with

sensorineural deafness and renal dysplasia)

DiGeorge's syndrome Mitochondrial disorders:

MELAS (mitochondrial encephalopathy, lactic

acidosis and stroke-like episode),


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Autoimmune APECED (autoimmune polyendocrinopathy-

candidiasis-ectodermal dystrophy syndrome)

Hypoparathyroidism Primary adrenal insufficiency

Chronic mucocutaneous candidiasis


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AcquiredThyroid surgery

Parathyroidectomy

Iron deposition with chronic transfusions

Wilsons disease

Gram negative sepsis, toxic shock, AIDS

? Macrophage-generated cytokines


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Target organ insensitivity to PTH

(bone / kidney)

Hypocalcemia

Hyperphosphatemia

Elevated PTH


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GNAS1 gene mutations intracellularsignals

Expression in tissues either paternally /

maternally determined Example: renal expression is maternal

Type 1a PHP AD (maternal transmission)

Albrights hereditary osteodystrophy

Albrights


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Short stature & limbs

Obesity Round, flat face

Short 4e/5emetacarpals

Archibald sign

Brachydactyly

Potter's thumb

Eye problems

IQ problems

Basal ganglia

calcifications


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Phenotype ofAlbrights

NORMAL serum

calcium

NO PTH resistance

Paternal GNAS1

gene mutation


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Type 1b Hypocalcemia, no phenotypic abnormality

AD, maternal transmission

Type 1c

Looks like type 1a

Type 2

No features of Albrights


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Newborns (can be unspecific)

Asymptomatic

Lethargy

Poor feeding

Vomiting Abdominal distention

Children

Seizures

Twitching

Cramping

Laryngospasm


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Neonatal hypocalcemia:

Early neonatal hypocalcemia (48-72 hours) Prematurity

Poor intake, hypoalbuminemia, reduced responsiveness tovitamin D

Birth asphyxia Delay feeding, increased calcitonin, endogenous phosphate load

high, alkali therapy

Infant to diabetic mother Magnesium depletion functional hypoparathyroidism

hypocalcemia

IUGR


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Late neonatal hypocalcemia

Exogenous phosphate load

Phosphate-rich formulas / cows milk

Magnesium deficiency

Transient hypoparathyroidism of newborn

Hypoparathyroidism

Gentamycin (24 hourly dosing schedule)


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Decrease intake or production

Increased catabolism

Decrease 25-hydroxylation by liver

Decrease 1-hydroxylation by kidney


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BowingWidening ofwrist


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Rickety rossary Frontal bossing


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Cupping andsplaying ofmetaphysis

Delayed closure offontanels


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fontanels

Bossing

Craniotabes Delayed eruption of teeth

Rickety rosary

Pectus carinatum

Harrison sulcii Splaying of distal ends of

long bones bones

Hypotonia

Weakness Growth retarded

Recurrent chest infections


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A mother brings in her 1-year-old boy for the firsttime because she is concerned about his bowedlegs . The mother is 4 ft 10 in tall and says sheneeded to have surgery to straighten out her bowedlegs when she was an adolescent, as did one of herbrothers. Radiographs of the boys long bones areobtained . Of the following, the MOST likelyserum laboratory findings are

A. low calcium and high phosphorus

B. low calcium and normal phosphorus

C. low calcium and low phosphorusD. normal calcium and high phosphorus

E. normal calcium and low phosphorus


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Magnesium is required for PTH release May also be required for effects on target

organs

Mechanisms:

End-organ unresponsiveness to PTH

Impaired release of PTH

Impaired formation of 1,25-vitamin D3


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Pancreatitis

Citrated products

Hungry bone syndrome

Hyperphosphatemia

Fluoride poisoning


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Hungry bone syndrome

After prolonged period of calcium

absorption

Rebound phase Avid uptake of calcium by bone

Parallel uptake of magnesium by bone

Following parathyroidectomy

Renal Osteodystrophy


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Renal Osteodystrophy

Associated with chronic renal failure

Ch. RF Hyperphosphataemiaand Hypocalcaemia

Secondary Hyperparathyroidism

Osteoclastic activity

a) Less excretionand

metabolism of PTH

b) Low orno alpha-1-

hydroxylation

c) Metabolic acidosis Release of calcium hydroxyapetitefrom bone

Osteomalacia Osteitis fibrosa


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Total and ionized calcium Magnesium

Phosphate

UKE and s-glucose

PTH

Vitamin D metabolite Urine-CMP and creatinine

S-ALP


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CXR

Ankle and wrist XR


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ECG

Malabsorption workup

Karyotyping and family screening


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You are measuring serum electrolytes at 12 hours of age in a 4,500-g infant deliveredby cesarean section at 36 weeks gestation. The Apgar scores were 6 and 8 at 1 and5 minutes, respectively. The infant is in no acute distress, breathing room air, andgenerally well appearing although he exhibits mild hypotonia The laboratory


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generally well-appearing, although he exhibits mild hypotonia. The laboratoryresults are:

Sodium, 135 mEq/L (135 mmol/L)

Potassium, 4 mEq/L (4 mmol/L) Chloride, 105 mEq/L (105 mmol/L)

Carbon dioxide, 18 mEq/L (18 mmol/L)

Calcium (total), 6.5 mg/dL (1.63 mmol/L)

Phosphorus, 5.5 mg/dL (1.8 mmol/L)

Magnesium 2 mg/dL (0.8 mmol/L) The serum glucose value is 30 mg/dL (1.7mmol/L).

Of the following, the MOST likely cause of neonatal hypocalcemia for this infant is

A.acute perinatal asphyxiaB. hypoglycemia

C. maternal diabetes mellitus

D. 22q11 deletion syndrome

E. vitamin D deficiency


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1. Dependent on the underlying cause and

severity

2. Administration of calcium alone is only

transiently effective

3. Mild asymptomatic cases: Often adequate

to increase dietary calcium by 1000

mg/day

4. Symptomatic: Treat immediately


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Symptomatic hypocalcaemia

IV Calcium should only be given with close monitoring Should be on cardiac monitor

Mix with NaCl or 5 % D/W (not bicarbonate/lactate containing

solutions)

Risks Tissue necrosis/calcification if extravasates

Calcium can inhibit sinus nodepbradycardia + arrest

Stop infusion if bradycardia develops

Avoid complete correction of hypocalcaemia

With acidosis and q S-Ca give Ca before correcting acidosis

If q Mg is cause ofq S-Ca treat and correct

hypomagnesaemia


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Early neonatal hypocalcaemia

Neonates: Ca gluconate:10 mg/kg (1 ml/kg of 10%

solution) Slowly IV + monitoring ECG

Occasionally associated transient hypomagnesaemia

Treat prior to Ca administration

Start oral Calcium as soon as possible Early neonatal hypocalcaemia normalizes in 2-3 days

Oral Ca usually necessary for 1 week


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Late neonatal hypocalcaemia Associated with o S-phosphate

Decrease phosphate intake

Give calcium containing phosphate binder

Oral calcium (gluconate) supplementation

100 mg/kg/dose 4 hourly per os


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Same dose IV as for neonates

More often require continuous infusion

Oral supplementation 50 mg/kg/24 hr elemental Ca

Ca binds with phosphate in gutp q Ca absorption

Advantage in conditions with o s-phosphate

Renal failure

Hypoparathyroidism

Tumor lysis

Most need Vit D supplementation

A 9-month-old exclusively breastfed baby presents

with a seizure. A chest radiograph obtained to rule


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g p

out aspiration pneumonia reveals rachitic changes

of the ribs. Of the following, the MOST likelyserum laboratory findings are

A. low calcium and elevated phosphorus

B. low calcium and low phosphorus

C. low calcium and normal phosphorus

D. normal calcium and elevated phosphorus

E. normal calcium and low phosphorus


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A 15-year-old boy has been immobilized in a doublehip spica for 6 weeks after having fractured his femur


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hip spica for 6 weeks after having fractured his femurin a skiing accident. He has become depressed and

listless during the past few days and has complainedof nausea and constipation. He is found to havemicroscopic hematuria and a blood pressure of150/100 mmHg. You should

a. Request a psychiatric evaluation

b. Check blood pressure every 2 h for 2 days

c. Collect urine for measurement of the calcium-creatinine ratio

d. Order a renal sonogram and intravenous pyelogram(IVP)

e. Measure 24-h urinary protein


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Normal serum calcium levels are 8 to 10

mg/dL (2.0 to 2.5 mmol/L)

Normal ionized calcium levels are 4 to 5.6 mg

/dL (1 to 1.4 mmol per L)

Hypercalcemia is defined as total serum

calcium > 10.5 mg/dl(>2.5 m mol/L ) or

ionized serum calcium > 5.6 mg/dl ( >1.4 m

mol/L )


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Critical - > 14 mg %

Moderate - 12 to 14 mg %

Mild 10.4 to 11.9 mg %

Normal 8.5 to 10.3 mg %


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Severe hypercalemia is defined as totalserum calcium > 14 mg/dl (> 3.5 mmol/L)

Hypercalcemic crises is present whensevere neurological symptoms orcardiacarrhythmias are present in a patient with

a serum calcium > 14 mg/dl (> 3.5mmol/L) or when the serum calcium is >16 mg/dl (> 4 mmol/L)


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Ca++

PTH

VitaminD

Malignancy

Medicines

Endocrine

Genetic


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Most symptoms are not seen until serum [Ca+2] > 12mg/dL

Rare problem in children than hypocalcemia

When it occurs, it is a serious condition which requires correct

diagnosis before correct treatment can be instituted

Hypercalcemia in adulthood : malignancy

primary hyperparathyroidism

In children : causes are more diverse (particularly in neonate,infant)

Manifestations of Hypercalcemia

Groans, moans, bones, stones


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yp

Acute Chronic

Gastrointestinal Anorexia, nausea,vomiting

Dyspepsia,constipation,pancreatitis

Renal Polyuria, polydipsia Nephrolithiasis,

nephrocalcinosis

Neuro-muscular Depression,confusion, stupor,coma

Weakness

Cardiac Bradycardia, firstdegree atrio-ventricular

Hypertensionblock, digitalissensitivity


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Cardiovascular

Hypertension, Increased risk ofCHD

ECG changes of shortened QT interval, PR

prolonged, QRS widened, ST, Bradycardia

Cardiac arrhythmias; Vascular calcification

Others

Itching (Generalized Pruritus)

Keratitis, conjunctivitis

141


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Parathyroid gland tumour associated with MEN


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MEN type 1 MEN type 2a MEN type 2b

PTH adenoma

Pituitary tumour

Pancreatic tumour

(gastrinoma,

insulinoma)

PTH hyperplasia

Medullary thyroid cancer

Phaeochromocytoma

PTH hyperplasia

Medullary thyroidcancer

Phaeochromocytoma

Mucocutaneousneurofibroma

Dysmorphic features

(marfanoid habitus,

skeletal abN, abN

dental enamel)


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A rare genetic condition that causes medical

and developmental problems

1 in 7,500 births

Infantile hypercalcemia has been reported for

15% of infants and children with WS


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Deletion of multiple (20 to30) genes, including theelastin gene on chromosome#7

Elastin (ELN) providesstrength and elasticity tovessel walls

The deletion of the elastingene likely accounts for

many of the physicalfeatures of Williamssyndrome


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Small, upturned nose

Long philtrum

Wide mouth

Full lips Small chin

Puffiness around the

eyes

Starburst (white lacy

pattern) on iris


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History

Symptomes suggestive of hypercalcemia

Symptomes suggestive of malignancy

Drug history includig vitamin D therapy, complementary alternateve

medicine, supplements

Family history of renal stone, hypercalcemia, parathyroidectomy,

multiple endocrine neoplasia


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Examination

Assessdegree ofdehydration

Syndromic feature

Presence of ectopic /subcutaneous calcification/rash

Short stature/disproportionate short stature

Generalised lymphadenopathy, organomegaly

Bone pain, fracture


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Initial investigation Serum Ca, Phospate, ALP, electrolyte, Cr, PTH, 25-(OH)D3

1,25(OH)2D, PTHrP, DNA for genetic analysis, Urine Ca/Cr

Subsequent investigation

Renal US

Investigation of parents for abnormalities of Ca homeostasis

Skeletal survey

Parathyroid gl. US scan Parathyroid gl. SestaMIBI scan


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Normal levels of PTH

CaSR abnormality (Familial benign hypercalcemia type

I,II,III)

Suppressed levels of PTH

Secondary hypercalcemia

Vitamin D excess (Wiliams syndrome, Idiopathic

hypercalcemia of infancy)


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Hypercalcemia

Hypercalciuria

Renal insufficiency

Soft tissue calcification

Hypercalcemia may persist for months after vit

D is discontinued due to fat stores

Can also occur in vit A intoxication


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Commonest cause of hypercalcemia, morecommon in females

80% will be caused by a single parathyroidadenoma

15% hyperplasia

5% multiple adenomas

Rarely caused by parathyroid cancer

Familial hyperparathryoidism is associated withMEN1 and MEN 2A, and usually see hyperplasia


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Usually asymptomatic

Symptoms:

Polyuria, polydipsia

Nephrolithiasis, nephrocalcinosis

Fatigue, weakness, myopathy

Depression

Osteopenia, osteoporosis, bone pain,pathologic fractures


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Labs: Usually mild hypercalcemia

Normal phosphate

Increased or inappropriately normal PTH

Increased urinary calcium excretion

Imaging Loss of cortical bone, see subperiosteal bone resorption

(on radial borders of phalanges)

salt and pepper appearance of skull

Osteitis fibrosa cystica (fibrous replacement of resorbed

bone) Brown tumors (collections of osteoclasts in poorly

mineralized bone)

Renal stones


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Malignancy

30% of adult pt. with cancer / much less in childhood cancer

Poor prognosis in adults / not the case with pediatric pt.

ALL : local osteolytic hypercalcemia (d/t cytokine, secretionof PTHrP)

Ovarian dysgerminoma: secrete 1.25(OH)2D

Sx : water-concentrating defect (nephrogenic DI) , neurological

dysfunction d/t rapid elevation in serum Ca


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Endocrine cause

Thyrotoxicosis (stimulation osteoclastic bone resorption by T3)

Acute adrenal insufficiency : d/t vol. depletion, change in vit Dmetabolism secondary to glucocorticoid deficiency

Chronic renal failure

P, Ca -> secondary hyperparathyroidism -> tertiaryhyperparathyroidism

Immobilisation

m/c during adolescence in those with spastic quadriplegia or

spinal cord injury Results from increased osteoclastic bone resorption and

decreased bone formation

4) I hibit b ti (i hibit t l ti


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4) Inhibit bone resorption (inhibit osteoclastic

activity )

Bisphosphonates (Pamidronate)

0.5~1.0mg/kg ov 4-6h -> reduction of Ca after 12-24h,

last for 2-4wks -> sustained period of hypocalcemia

may follow

Intravenous therapy is the preferred route of

administration

Calcitonin (10U/kg, q4h) : rapid effect , wears off aftera while,


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Analogs of pyrophosphate that adsorb to bone surface andinterfere with calcium release

Max effect in 2-4 days

Zolendronic acid is more potent and can be given rapidlyi.e. over 15 min. Longer Ca control following use(43days vs 18 days with pamidronate). Can be associatedwith jaw necrosis and renal toxicity in repeated use

Pamidronate, better tolerated. Occasional fevers.

All can have flu like symptoms, uveitis, hypocacemia,AKI


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Effective in PTH and PTH-rP

Inhibits osteoclast ATP-ase pumps and inhibits

PTH secretion from parathyroid cells

More effective than the bisphosphonates in one

study

Potential nephrotoxicity and need for continuous

infusion over 5 days


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1) Hydration with normal saline (up to 20 mL/kg).

2) Augmentation of calciuresis with furosemide

(2 mg/kg, q4h). require monitoring of intravascular volume

3) Administration of bisphosphonates:

Starting dose of pamidronate in children is 0.5 to 1 mg/kg IVS, over 4 hours.

4) Calcitonin therapy:

A decrease in serum calcium is seen within a few hours of administration


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calcium metabolism and disorders (hanan)

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