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Calcium Metabolism

andHypocalcemia

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Calcium metabolism

99% of total body calcium in the bone .

1% in ICF ,ECF ,& cell membranes .

Calcium weight is 400mg/kg in infant &

950mg/kg in adult .

The 1% can be divided in 3 components :

1) 50% ionized . 2) 40% bound to protein .3)10% complex w/anions{citrate,phosphate,..

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Calcium metabolism

physiologic functions :

1.blood coagulation .

2.muscle contraction .3.neuromuscular transmission .

4.Skeletal growth & mineralization

Ionized Ca is physiologically important .

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Three Forms of Circulating Ca2+

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Physiological Importance of Calcium

Ca salts in bone provide structural integrity of the skeleton.

Ca is the most abundant mineral in the body.

The amount of Ca is balance among intake, storage, and

excretion.

This balance is controlled by transfer of Ca among 3

organs: intestine, bone, kidneys.

Ca ions in extracellular and cellular fluids is essential to

normal function of a host of biochemical processes

Neuoromuscular excitability and signal transduction

Blood coagulation Hormonal secretion

Enzymatic regulation

Neuron excitation

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Intake of Calcium

About 1000 mg of Ca is ingested per day.

About 200 mg of this is absorbed into the

body. Absorption occurs in the small intestine,

and requires vitamin D (stay tuned....)

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Calcium metabolism

Serum CA level is determined by net

absorption (GI) & excretion (RENAL).

Each components is tightly regulated-hormonally- to keep normal serum level .

Total CA is usually measured & provides

satisfactory assessment of ionized form .

However we have exceptions:

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Storage of Calcium

The primary site of storage is our bones (about 1000 grams). Some calcium is stored within cells (endoplasmic reticulum and

mitochondria). Bone is produced by osteoblast cells which produce collagen,

which is then mineralized by calcium and phosphate(hydroxyapatite). Bone is remineralized (broken down) by osteoclasts, which secrete

acid, causing the release of calcium and phosphate into thebloodstream.

There is constant exchange of calcium between bone and blood.

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Excretion of Calcium

The major site of Ca excretion in the body is the

kidneys.

The rate of Ca loss and reabsorption at the kidney

can be regulated. Regulation of absorption, storage, and excretion of

Ca results in maintenance of calcium homeostasis.

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Calcium metaolism

However we have exceptions: Decreased serum albumin .

Each 1 g/dl of serum albumin binds about 0.8

mg/dl of calcium .Cac=Cam+{0.8* decrease in serum albumin .} Acid base disturbance .

( Affect binding to protein .)Increase when PH increased .

Decrease when PH decreased .

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Regulation of [Calcium]

The important role that calcium plays in so

many processes dictates that its

concentration, both extracellularly and

intracellularly, be maintained within a verynarrow range.

This is achieved by an elaborate system of

controls

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Control of cellular Ca homeostasis is as carefullymaintained as in extracellular fluids

[Ca2+]cyt is approximately 1/1000th of

extracellular concentration

Stored in mitochondria and ER

pump-leak transport systems control [Ca2+]cyt Calcium leaks into cytosolic compartment and is

actively pumped into storage sites in organelles to shiftit away from cytosolic pools.

Regulation of Intracellular [Calcium]

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Three definable fractions of calcium in

serum: Ionized calcium 50%

Protein-bound calcium 40% 90% bound to albumin

Remainder bound to globulins

Calcium complexed to serum constituents 10% Citrate and phosphate

Extracellular Calcium

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Binding of calcium to albumin is pH dependent

Acute alkalosis increases calcium binding to

protein and decreases ionized calcium

Patients who develop acute respiratory alkalosishave increased neural excitability and are prone to

seizures due to low ionized calcium in the

extracellular fluid which results in increased

permeability to sodium ions

Extracellular Calcium

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Calcium and the Cell

Translocation across the plasma membrane Translocation across the ER and mitochondrion;

Ca2+ ATPase in ER and plasma membrane

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Calcium Turnover

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Calcium homeostasis

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PTH,

Calcium &

Phosphate

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Calcium in Blood and Bone

Ca2+ normally ranges from 8.5-10 mg/dLin the plasma.

The active free ionized Ca2+ is only about

48% 46% is bound to protein in a non-diffusible state while 6% is complexed tosalt.

Only free, ionized Ca2+ is biologicallyactive.

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Phosphate Turnover

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Phosphorous in Blood and Bone

PO4 normal plasma concentration is 3.0-

4.5 mg/dL. 87% is diffusible, with 35%

complexed to different ions and 52%

ionized.

13% is in a non-diffusible protein bound

state. 85-90% is found in bone.

The rest is in ATP, cAMP, and proteins

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Osteoclasts and Ca2+

Resorption

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Hormonal

Control ofBones

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Hormonal Control of Ca2+

Three principal hormones regulate Ca2+ and three

organs that function in Ca2+ homeostasis.

Parathyroid hormone (PTH), 1,25-dihydroxy

Vitamin D3 (Vitamin D3), and Calcitonin,regulate Ca2+ resorption, reabsorption, absorption

and excretion from the bone, kidney and intestine.

In addition, many other hormones effect bone

formation and resorption.

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Calcium and the Skeleton

A, absorption is stimulated by Vit D; S, secretion GF, glomerular filtration; TR, tubular reabsorption

of Ca2+ is stimulated by PTH

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PTH and Osteoblastogenesis

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Osteoclast Mediated Bone Resorption

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PTH and

Kidney

PTH acts on the

distal tubule

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Calcium metabolism

Calcium regulation :mainly by 3 commonhormones :

1}Parathyroid hormone .

2}Vitamin D .

3}Calcitonin .

Calcium metabolism

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Calcium metabolism

Vitamin D Vitamin D :provide Ca & PO4 to ECF for bone

mineralization . Deficiency in children..Rickets Deficiency in adult..Osteomalacia 7-dehydrocholestrol(skin)cholecalciferol

25-OH- cholecalciferol(liver)1- 25-OH-cholecalciferol(kidney) MOA: steroid so enter nucleus & bind receptor that leads

to expose part of DNAmRNACalbindin-D protein inepithlium of intestine,kidney,..that do the action .

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Vitamin D3 synthesis occurs in keratinocytes in theskin.

7-dehydrocholesterol is photoconverted toprevitamin D3, then spontaneously converts tovitamin D3.

Previtamin D3 will become degraded by overexposure to UV light and thus is not overproduced.

Also 1,25-dihydroxy-D (the end product of vitaminD synthesis) feeds back to inhibit its production.

Synthesis of Vitamin D

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PTH stimulates vitamin D synthesis. In the winteror if exposure to sunlight is limited (indoor jobs!),then dietary vitamin D is essential.

Vitamin D itself is inactive, it requires modificationto the active metabolite, 1,25-dihydroxy-D.

The first hydroxylation reaction takes place in theliver yielding 25-hydroxy D.

Then 25-hydroxy D is transported to the kidneywhere the second hydroxylation reaction takesplace.


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The mitochondrial P450 enzyme 1-hydroxylaseconverts it to 1,25-dihydroxy-D, the most potentmetabolite of Vitamin D.

The 1

-hydroxylase enzyme is the point ofregulation of D synthesis. Feedback regulation by 1,25-dihydroxy D inhibits

this enzyme.

PTH stimulates 1-hydroxylase and increases1,25-dihydroxy D.


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25-OH-D3 is also hydroxylated in the 24 position

which inactivates it.

If excess 1,25-(OH)2-D is produced, it can also by

24-hydroxylated to remove it. Phosphate inhibits 1-hydroxylase and decreased

levels of PO4 stimulate 1-hydroxylase activity


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Calcium metabolism

Vitamin D Actions:

1)increase Ca absorption from intestine.

2) increase PO4 absorption from intestine.3) increase renal reabsorption of Ca &PO4.

4) increase bone resorption from old bone

&mineralize new bone{net resorption} .Overall effect :increase serum Ca & PO4 .

Vit i D M t b li

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Vitamin D Metabolism

Transport and Metabolic Sequence of

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Transport and Metabolic Sequence ofActivation of Vitamin D

Proposed Mechanism of Action of

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Proposed Mechanism of Action of

1,25-DihydroxyD3 in Intestine

l i b li

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Calcium metabolism

Vitamin D Regulation :

Ca..-ve PTH . PO4.-ve VIT D . VIT D..-ve PTH . VIT D.-ve 25OHD . PTH +ve VIT .

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Regulation of Vitamin D Metabolism

PTH increases 1-hydroxylase activity, increasing

production of active form.

This increases calcium absorption from the intestines,

increases calcium release from bone, and decreases loss of

calcium through the kidney.

As a result, PTH secretion decreases, decreasing 1-

hydroxylase activity (negative feedback).

Low phosphate concentrations also increase 1-hydroxylase

activity (vitamin D increases phosphate reabsorption from

the urine).

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Vitamin D promotes intestinal

calcium absorption

Vitamin D acts via steroid hormone like

receptor to increase transcriptional and

translational activity

One gene product is calcium-binding

protein (CaBP)

CaBP facilitates calcium uptake by

intestinal cells

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Clinical correlate

Vitamin D-dependent rickets type II

Mutation in 1,25-(OH)2-D receptor

Disorder characterized by impairedintestinal calcium absorption

Results in rickets or osteomalacia despite

increased levels of 1,25-(OH)2-D in

circulation

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Vitamin D Deficiency: Rickets Inadequate intake and absence of sunlight

The most prominent clinical effect of Vitamin D

deficiency is osteomalacia, or the defective

mineralization of the bone matrix

Osteoblasts contain the vitamin D receptor Vitamin D deficiency in children produces rickets

A deficiency of renal 1-hydroxylase produces

vitamin D-resistant rickets Sex linked gene on the X chromosome

Renal tubular defect of phosphate resorption

Teeth may be hypoplastic and eruption may be retarded

C l i b li

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Calcium metabolism

PTH hormone Major hormone in regulation serum Ca .]

Synthesis & secreted from chief cells of

parathyroid gland .

MOA :

polypeptide that binds to specific receptors

{G proteins} that lead to increase 2nd

messenger cAMP that leads to physiologic

actions of the hormone .

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Parathyroid Glands

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Parathyroid Hormone Structure Synthesized in

the 4 para-thyroid glands

PreProPTH 115 aa precursor

giving a 90 aaprohormone Cleaved at -6/-7

84 residues in

the maturepeptide Regulator of

Ca2+

homeostasis

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Parathyroid Hormone Biosynthesis

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Regulation of PTH

The dominant regulator of PTH is plasmaCa2+.

Secretion of PTH is inversely related to

[Ca2+]. Maximum secretion of PTH occurs at

plasma Ca2+ below 3.5 mg/dL.

At Ca2+ above 5.5 mg/dL, PTH secretion ismaximally inhibited.

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Calcium Sensing

Receptor (CaSR)

Parathyroid chief cells contain a Ca2+ sensing receptor (CaSR)

7 transmembrane segments (We will see a lot of 7 TM receptors)

mM affinity for Ca2+

GPCR of the GPLC and GI varieties Generates inositol 1,4, 5-trisphosphate which increases

intracellular Ca2+

There are two paradoxes

The receptor responds to decreasing concentrations of agonist

Low extracellular Ca2+ increases intracellular Ca2+

Also found in thyroid C cells (calcitonin), kidney, and brain

Circulating Forms of PTH

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Circulating Forms of PTH

Intact, active PTH of 84 aa

Inactive carboxyterminal fragments lack the 1-34 activedomain

PTH t1/2 (half life) is 2-3 min Liver (2/3rds) and kidney (1/3rd) are major sites of

fragmentation

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PTH secretion responds to small alterations inplasma Ca2+ within seconds.

A unique calcium receptor within the parathyroidcell plasma membrane senses changes in theextracellular fluid concentration of Ca2+.

This is a typical G-protein coupled receptor thatactivates phospholipase C and inhibits adenylatecyclaseresult is increase in intracellular Ca2+via generation of inositol phosphates and decreasein cAMP which prevents exocytosis of PTH fromsecretory granules.

Regulation of PTH

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Calcium

regulates

PTHsecretion

P h id H R

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Parathyroid Hormone Receptor 7 TM

GPCR

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PTH

Biosynthesis PTH is co-secreted

with chromogranin

A, a protein;significance

unknown

Calcium metabolism

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Calcium metabolism

PTH hormone Actions : 1)increase bone resorption..increase Ca & PO4 in

serum .

2)increase renal Ca reabsorption . 3)increase Ca absorption from intestine indirectlyby increase VITD .

4)decrease PO4 reabsorption from proximal

tubules increase ionized Ca . Overall effect :increase serum Ca & decrease

serumPO4 .

Calcium metabolism

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Calcium metabolism

PTH hormone Regulation: Ca senor proteins that increase PTH when

Ca level decreased & decrease PTH when

Ca level increased . PTH increase VIT D level by activation

1-Ohlase .

Increase PO4 leads to increase PTH(bydecreasing Ca level ) . Mg decrease leads to deacrease PTH level .

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Mechanism of Action of PTH

PTH binds to a G protein-coupled receptor. Binding of PTH to its receptor activates 2 signaling

pathways:

- increased cyclic AMP

- increased phospholipase C Activation of PKA appears to be sufficient to decrease

bone mineralization Both PKA and PKC activity appear to be required for

increased resorption of calcium by the kidneys

Regulation of PTH Secretion

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Regulation of PTH Secretion

PTH is released in response to changes in plasma calcium levels.

- Low calcium results in high PTH release.

- High calcium results in low PTH release. PTH cells contain a receptor for calcium, coupled to a G protein. Result of calcium binding: increased phospholipase C, decreased

cyclic AMP. Low calcium results in higher cAMP, PTH release.

Also, vitamin D inhibits PTH release (negative feedback).

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PTH-Related Peptide

Has high degree of homology to PTH, but is not fromthe same gene.

Can activate the PTH receptor. In certain cancer patients with high PTH-related

peptide levels, this peptide causes hypercalcemia. But, its normal physiological role is not clear.

- mammary gland development/lactation?

- kidney glomerular function?

- growth and development?

PTH P P th id R l t d P t i

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PTHrP; Parathyroid Related Protein

Calcium metabolism

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Calcium metabolism

Calcitonin Is synthesized & secreted by Para follicular cells of

thyroid . MOA :1) Peptide that inhibit bone osteoclast

& so inhibit bone resorption .

2)increase renal excetion . Increase secretion when Ca level increase . Action:decrease CA level .

Overall effect : decrease serum Ca .

Calcitonin

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Calcitonin

Product of

parafollicular C cellsof the thyroid

32 aa

Inhibits osteoclastmediated bone

resorption

This decreases serumCa2+

Promotes renal

excretion of Ca2+

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Calcitonin

Calcitonin acts to decrease plasma Ca2+ levels. While PTH and vitamin D act to increase plasma

Ca2+-- only calcitonin causes a decrease inplasma Ca2+.

Calcitonin is synthesized and secreted by theparafollicular cells of the thyroid gland.

They are distinct from thyroid follicular cells by

their large size, pale cytoplasm, and smallsecretory granules.

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The major stimulus of calcitonin secretion

is a rise in plasma Ca2+ levels

Calcitonin is a physiological antagonist to

PTH with regard to Ca2+ homeostasis

Calcitonin

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The target cell for calcitonin is theosteoclast.

Calcitonin acts via increased cAMP

concentrations to inhibit osteoclast motilityand cell shape and inactivates them.

The major effect of calcitoninadministration is a rapid fall in Ca2+ causedby inhibition of bone resorption.

Calcitonin

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Actions of Calcitonin

The major action of calcitonin is on bone metabolism. Calcitonin inhibits activity of osteoclasts, resulting in

decreased bone resorption (and decreased plasma Ca

levels).

calcitonin(-)

osteoclasts: destroy bone to

release Ca

Decreasedresorption

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Role of calcitonin in normal Ca2+ control is notunderstoodmay be more important in control of boneremodeling.

Used clinically in treatment of hypercalcelmia and in

certain bone diseases in which sustained reduction ofosteoclastic resorption is therapeutically advantageous. Chronic excess of calcitonin does not produce

hypocalcemia and removal of parafollicular cells does notcause hypercalcemia. PTH and Vitamin D3 regulation

dominate. May be more important in regulating bone remodeling

than in Ca2+ homeostasis.

Calcitonin

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What is the Role of Calcitonin in Humans?

Removal of the thyroid gland has no effect on plasma

Ca levels!

Excessive calcitonin release does not affect bone

metabolism! Other mechanisms are more important in regulating

calcium metabolism (i.e., PTH and vitamin D).

Calcitonin Gene-Related Peptide

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Calcitonin Gene-Related Peptide

(CGRP)

The calcitonin gene produces several products due to

alternative splicing of the RNA.

CGRP is an alternative product of the calcitonin gene.

CGRP does NOT bind to the calcitonin receptor. CGRP is expressed in thyroid, heart, lungs, GI tract,

and nervous tissue.

It is believed to function as a neurotransmitter, not as

a regulator of Ca.

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Oth F t I fl i B d C l i

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Other Factors Influencing Bone and Calcium

Metabolism

Estrogens and Androgens: both stimulate boneformation during childhood and puberty.

Estrogen inhibits PTH-stimulated bone resorption.

Estrogen increases calcitonin levels Osteoblasts have estrogen receptors, respond to

estrogen with bone growth. Postmenopausal women (low estrogen) have an

increased incidence of osteoporosis and bonefractures.

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Hypocalcemia

Causes of hypocalcemia Specific causes in neonates Early neonatal hypocalcemia:(within 48-72 hour of birth)

Causes: 1- prematurity: poor intake, decrease response to

Vit. D, increase calcitoni, decrease albumin. 2- birth asphyxia: delayed introduction to feed,

increase calcitonin, increased endogenous PO4 load,

alkali therapy.

3- infant of diabetic mother: functional

parahypothyroidism induced by Mg defficiency haspredominant role

Causes of Hypocalcemia

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Causes of HypocalcemiaHypoparathyroid Nonparathyroid PTH Resistance

Postoperative Vitamin Ddeficiency

Pseudo-hypoparathyroidism

Idiopathic MalabsorptionPost radiation Liver disease

Kidney disease

Vitamin Dresistance

Sequence of Adjustments to

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q jHypocalcemia

Specific causes in neonates (cont )

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Specific causes in neonates (cont.)

4- IUGR: interruption Ca delivery across

placenta, prematurity, asphyxia.

Serum Ca correlate directly to gestational age.

Specific causes in neonates (cont )

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Specific causes in neonates (cont.)

II. Late neonatal hypocalcemia: happen from 5

days of birth, may appear till 6 weeks of age. Causes:

1. Exogenous PO4 load, most common due to highPO4 content in formula, or cows milk and decreased

in GFR contribute also.

2. Mg deficiency.

3. Transient hypoparathyroidism4. Hypoparathyroidism due to other causes: (idiopathic,

congenital, maternal hyperparathyroidism,

hypomagnesemia)

Hypoparathyroidism:

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Hypoparathyroidism:

1. DiGeorge syndrome: aplasia or hypoplasia of

parathyroid gland.

associated with different anomalies includingcardiac and facial anomaly mainly and also VATER

and CHARGE associations.

3. X-linked hypoparathyroidism (absent of the gland

that affect boys and appeared with the first 6 months

of age.

4. AR hypoparathyroidism with dymorphic features:

mutation of parathyroid hormone gene.

4. HDR syndrome: AD consist from (nervedeafness, renal dysplasia, and hypoparathyroidism)

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5. Autoimmune polyglandular syndrome type I: AR, dueto mutation in autoimmune regulator gene

Consist from (hypoparathyroidism, addisson disease,

mucocutaneous candidiasis).

6. Calcium sensor receptor gene mutation.

7. Kearns-Sayre syndrome: mitochondrial inherited

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7. Kearns Sayre syndrome: mitochondrial inheriteddisorder. (ie, external ophthalmoplegia, ataxia,

sensorineural deafness, heart block, and elevated

cerebral spinal fluid [CSF] protein), are associated withhypoparathyroidism. Hypothyroidism affect after age of

5 years

8. Hemochromatosis: iron overload

9. Wilson disease: copper overload

10. Postsurgical and irradiational hypoparathyroidism.

H th idi

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Hypoparathyroidism

Hypocalcemia occurs when there isinadequate response of the Vitamin D-PTHaxis to hypocalcemic stimuli

Hypocalcemia is often multifactorial Hypocalcemia is invariably associated with

hypoparathyroidism

Bihormonalconcomitant decrease in1,25-(OH)2-D

H th idi

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PTH-deficient hypoparathyroidism Reduced or absent synthesis of PTH

Often due to inadvertent removal of excessive

parathyroid tissue during thyroid or parathyroidsurgery

PTH-ineffective hypoparathyroidism

Synthesis of biologically inactive PTH

Hypoparathyroidism

P d h th idi

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Pseudohypoparathyroidism

PTH-resistant hypoparathyroidism Due to defect in PTH receptor-adenylate

cyclase complex

Mutation in Gs subunit Patients are also resistant to TSH, glucagon

and gonadotropins


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yp p y Symptoms and signs

Hypocalcemia

Hyperphosphatemia

Characteristic physical appearance: short stature, round face, shortthick neck, obesity, shortening of the metacarpals

Autosomal dominant Resistance to parathyroid hormone The patients have normal parathyroid glands, but they fail to respond

to parathyroid hormone or PTH injections The rise in urinary cAMP after parathyroid hormone fails to occur The cause of the disease is a 50% deficiency of Gs in all cells

Symptoms begin in children of about 8 years Tetany and seizures

Hypoplasia of dentin or enamel and delay or absence of eruptionoccurs in 50% of people with the disorder

Rx: vitamin D and calcium


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yp p y

Elfin facies, short stature,enamel hypoplasia

Hypormagnesemia by: decrease parathyroid hormone

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yp g y p ysecretion and by blunting tissue response to PTH.

Pseudohypoparathyroidism lack of response of

inadequate available PTH.1. Decerease Ca, increase phosphorus, decrease Vit D.

2. Defect in alpha subunit of G proteins (2nd messenger)

3. Administration of synthetic PTH fail to increase Ca level orincreasing excretion of phosphorus in urine.

4. There are three types- Type IA: (Alpright hereditory oasteodystrophy)

- Type IB.

- Type II.

5. Diagnostic test is by failure to increase CAMP in urine

in response to PTH infusion

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CONTINUE.. 12.Pseudohypoparathyroidism

Albright hereditary osteodystrophycharacterized by Short stature, obesity, roundface, short distal phalanges of the thumbs,brachymetacarpals and brachymetatarsals,subcutaneous calcifications, dental hypoplasia,

and developmental delay characterize thisphenotype.

Pseudopseudohypoparathyroidism (PPHP) ischaracterized by normal calcium homeostasisin the setting of the AHO phenotype.

Vit D defficiency: causes

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1. Poor intake

2. Inadequate exposure to UV light

3. Malabsorption (liver disease, GI disease,pancreatic insufficiency).

4. Increase metabolism (as in anticonvulsant thatactivate P450 system enzyme in liver that

increase degradation of vit D.5. Renal disease: CRF mainly.

6. Vitamin D dependent ricket type 1(ARabsence of one alpha hydroxylase enzyme).

7. Vitamin D dependent ricket type 2(AR defectin vit D receptor, 50% have alopecia

Redistribution of plasma Ca:

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p

1. Hyperphosphatemia due to:2. Excessive phosphate intake because of inproper formula and

decreased GFR.

3. Loading in TPN.

4. Ecessive intake by inappropriate PO4 enema or laxative.

5. Renal failure.

6. Increase endogenous phosphorus by anoxia, TLS,Rhabdomyolysis.

7. Hungry bone syndrome classicaly happen after

parathyroidectomy of hyperparathyroid tumor(decrease Ca, phosphorus and Mg).

8. Pancreatitis: break down omentum by lipase.

Citrate in transfused blood products that

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Citrate in transfused blood products that

causes binding to ionized Ca but normal

total Ca. Drugs like thiazide.

Septic shock and ICU cases: unkown

mechanism

Cli i l i t

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Clinical picture

Symptoms: Related to degree and rate of hypocalcemia.

Mild hypocalcemia is asymptomatic.

Most clinical picture due to neuromuscularirritability.

Symptoms can be provoked by

hyperventilation.

S d d h

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Symptoms depend on the age: In neonate: lethargy, vomitting, poor feeding

(sepsis picture), abdominal distention, seizure,jitterness.

In children: seizure, muscle cramp, tetany,

larygospasm, parasthesia of perioral and handarea.

Others like basal ganglia calcification in PHP,

rikets in vit D deficiency, others depend on

syndrome. Arrhythmia

Physical findings:

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y g

Hyper-reflexia (carpopedal spasm, chvostecsign- 10-20% nonspecific, trousseau sign,

stridor and cyanosis).

Abdominal distention. Seizure.

Lethargy.

Apnea. Depend on syndrome (PHP, DiGeorge, )

Diagnosis

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DiagnosisA. History

B. Lab: Serum Ca: total and ionized. Serum Mg. Phosphorus: increase in hypoparathyroidism, renal failure, others,

decrease in vit D deficiency.

Serum Lytes and glucose mainly in neonate with seizure . PTH level in serum: indicated if hypocalcemia persist in presence

of normal Mg and normal or increased phosphorus Decrease or normal in hypoparathyroidism: PTH challenge, increase Ca level.

decrease PTH due to vit D deficiency and PHP, no increase in Ca when doing

PTH challenge

Vit D (1-25 OH vit D and 25 OH vit D levels). Poorintake, malabsorption, decrease light exposure,

i b li d i d

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excessive metabolism cause decrease in 25 OH andnormal or increase or decrease 1-25 OH.

Vit D1 rickets cause normal 25 OH and decrease 1-25 OH.Vit D2 rickets causes increase in both of 25 OH and 1-25OH.

Decrease PTH causes decrease 1-25 OH

PHP causes increase 1-25 OH

Alkaline phosphatase: increase in vit D defeciency andnormal to decrease in Hypoparathyroidism.

Total protein, albumin, PH KFT

Urine Ca, Mg, PO4 and Cr in renal tubular defect andRF

T.CA I.Ca PO4 PTH

HYPOALUMEIA C

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HYPOALUMEIA DEC N N N

ALKALOSIS N DEC N N/INC

VIT D DEF DEC DEC DEC INC

CRF

DEC DEC INC INC

HYPOPTH DEC DEC INC DEC

PHP DEC DEC INC INC

PACREATITIS DEC DEC N/DEC INC

Radiology

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Radiology

CXR: loss of thymic shadow in DiGeorge syndromeand osteopenia in rickets. Wrist X-ray: rickets changes. Hand X-Ray: in PHP

Echocardiogram in DiGeorge syndrome there iscardiac anomaly.

Brain MRI: basal ganglion calcification in PHP. Renal ultrasonography: Treatment of

hypoparathyroidism can lead to nephrocalcinosis as aresult of calciuria. Baseline renal ultrasonographywith initial treatment should be performed.

D Others

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D. Others

A. ECG show prolonged QT interval

B. Malabsorption work up

C. Total lymphocytes

Treatment

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Treatment

Symptomatic hypocalcemia needs IV calcium andcontinuous monitoring for arrhythmias.

Once serum Ca is in safe range ( >7 mg/dl) IV Ca canbe stopped, and oral Ca started.

Oral Ca and vit D are initiated as soon as possible whenpatient is tolerating oral feed.

Active form of vit D is preferred in treatment of HPHor PHP and hyperphosphatemia because both impair

activation of 25 OH vit D by one alpha hydroxylase. Diet, no specific diet is required but adequate Ca and

vit D intake is recommended. (in late neonatalhypocalcemia low phosphorus formula needed likeSemilac PM 60/40.)

Calcium, intravenous

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Calcium gluconate 10% (ie, 100 mg/mL) IV solution

contains 9.8 mg/mL (0.45 mEq/mL) elemental calcium.

Calcium chloride 10% (ie, 100 mg/mL) contains 27mg/mL (1.4 mEq/mL) elemental calcium.

Calcium chloride is more irritating to the veins and

may affect pH; therefore, it is typically avoided in

pediatric patients.Dose:

10-20 mg/kg elemental calcium (1-2 mL calcium

gluconate/kg) IV slowly over 5-10 min to control

seizures; may be continued by 50-75 mg/kg/d IVinfusion over 24 h

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Use extreme care in peripheral infusion becauseextravasation can cause severe tissue necrosis.

rapid IV infusion may cause bradycardia and

hypotension.

may cause liver necrosis if administered in anumbilical venous catheter lodged in a branch of portal

vein.

prolonged use of calcium chloride may lead to

hyperchloremic acidosis

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Calcium glubionate (Neo-Calglucon) -- Calciumsupplement for PO use. The glubionate salt (1800

mg/5 mL) contains 115 mg elemental calcium/5

mL.

Dose: 50-75 mg/kg/d (as elemental calcium) PO

divided q6-8h

Use with caution in small neonates because of highosmolar load; may cause diarrhea in older children

Calcium carbonate (Oystercal, Caltrate, Tums, Os-Cal)

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Calcium carbonate (Oystercal, Caltrate, Tums, Os Cal) Supplement for PO use.

In many ways, the calcium supplement of choice because it

provides 40% elemental calcium. Thus, 1 g of calcium carbonate provides 400 mg of elemental

calcium.

Well absorbed orally and unlikely to cause diarrhea.

Available in tab and liquid forms.

Dose: -Neonates: 30-150 mg/kg/d PO divided qid; may be addedto formula (eg, Similac PM 60/40 to make a calcium-phosphorousratio of 4:1)

-Children: 20-65 mg/kg/d PO divided bid/qid

Hypercalcemia or hypercalcuria may occur when therapeuticamounts are given

Calcitriol (Rocaltrol) Active metabolic form of vitamin D (ie 1 25

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Active metabolic form of vitamin D (ie, 1,25-dihydroxycholecalciferol).

Especially useful in impaired liver or renal functioncausing inability to hydroxylate vitamin D to its activeforms.

Generally is rapidly acting.

however, may act more slowly in neonates (36-48 h).

Preterm infants may be resistant to its actions. Also used to treat acute hypocalcemia.

Dose: 0.01-0.05 mcg/kg/d IV qd/bid; adjust dosage until

normocalcemia is attainedMay cause hypercalciuria; give with calcium salts to

attain optimum results; may add hydrochlorothiazide toregimen to control hypercalciuria

Dihydrotachysterol (DHT, Hytakerol)

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Synthetic analog of vitamin D, which does not require

activation by renal 1 hydroxylase for activity.

Also available in liquid form facilitating administration

of variable doses in infants and young children.

1 mg equivalent to 120,000 U (ie, 3 mg) vitamin D-2.

Dose:Neonates: 0.05-0.1 mg/d PO

Children: 0.5-2 mg/d PO

May cause hypercalciuria; give with calcium salts to

attain optimum results; may add hydrochlorothiazide to

regimen to control hypercalciuria

Symptomatic hypocalcaemia :

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Symptomatic hypocalcaemia : In neonate: Ca gluconate of 100-200 mg/kg or

1-2ml/kg of 10% conc. Over 5-10 min & can repeated every 6 to 8 hrs , or may

continued as continuous infusion of 50-75 mg/kg over 24 hrs . In children: Ca gluconate of 100-200 mg/kg or

1-2ml/kg of 10% conc. Over 5-10 min & can repeated every 6 to 8 hrs

*The above medication should administered under cardiac monitoring .

Once symptoms resolved oral Ca used to correct serum level ,&Ca level should kept below half normal range of Ca

Tapering of oral dose depends on serum Ca level .

Ca supplement with food binds PO4 insid

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intestine so can decrease PO4 level when

used in TLS,CRF,hypoPTH . Ca supplement between meals prevent

decrease PO4so used when we have low Ca

& PO4 . Vit D used in: Malsbsorption, poor intake, and increase

metabolism with Ca supplements.

Children with CRF, HPT, PHP, and vit D1

rickets as a primary treatment

Further Outpatient Care:

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Further Outpatient Care: Carefully monitor medication dose and serum

calcium concentrations. Therapeutic goal is to

maintain serum calcium in the low-normal range

to decrease risk for nephrocalcinosis. Perform periodic renal ultrasonographic studies to

assess for nephrocalcinosis development

Certain Situations

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Certain Situations

In pacreatitis and rhabdomyolysis completecorrection of hypocalcemia should be avoidedbecause with resolution of the primary problemthere is release of the complexed Ca andhypercalcemia may happen.

If acidemia is present hypocalcemia should ifpossible be corrected first, acidemia increases theionized Ca concentration by displacing Ca fromalbumin, so the correction of acidemia causes the

ionized Ca concentration to decrease. In hypomagnesemia Mg should be corrected first Hungry bone syndrome some patients may need

supplemental phosphorus and Mg along with Ca.

Medical/Legal Pitfalls:

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Intravenous infusion with calcium-containingsolutions can cause severe tissue necrosis.

Failure to distinguish calcium receptor defects fromhypoparathyroidism

Failure to consider an associated cardiac lesion inan infant with hypocalcemia

Failure to monitor serum calcium concentrations forat least 24 hours after intravenous calciumwithdrawal (Rebound hypocalcaemia can occurwhen intravenous calcium is withdrawn, even onadequate amounts of oral calcium.)

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Causes of Hypercalcemia

Common Uncommon

Malignant disease, e.g.

some lung cancers

Renal failure

Hyperparathyroidism Sarcoidosis

Vitamin D toxicity

(excessive intake)

Multiple myeloma

Signs and Symptoms ofH l i

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Hypercalcemia

Neurologic Lethargy, drowsiness, depression, confusion Can lead to coma and death

Neuromuscular

Muscle weakness, hyptonia, decreased reflexes

Cardiac Arrhythmias

Bone Ache, pain, fracture

Primary Hyperparathyroidism

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Primary Hyperparathyroidism

Calcium homeostatic loss due to excessive PTHsecretion

Due to excess PTH secreted from adenomatous or

hyperplastic parathyroid tissue Hypercalcemia results from combined effects of

PTH-induced bone resorption, intestinal calciumabsorption and renal tubular reabsorption

Pathophysiology related to both PTH excess andconcomitant excessive production of 1,25-(OH)2-D.

Hypercalcemia of Malignancy

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Underlying cause is generally excessive bone

resorption by one of three mechanisms

1,25-(OH)2-D synthesis by lymphomas Local osteolytic hypercalcemia 20% of all hypercalcemia of malignancy

Humoral hypercalcemia of malignancy Over-expression of PTH-related protein (PTHrP)


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Treatment improves quality of life when

Ca2+ is elevated but not yet life threatening

Treat with bisphosphonates Inhibits osteoclastic activity

When serum Ca2+ > 3.00 mM treat with

NaCl IV

PTH receptor defect

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PTH receptor defect

Rare disease known as Jansensmetaphyseal chondrodysplasia

Characterized by hypercalcemia,

hypophosphotemia, short-limbed dwarfism Due to activating mutation of PTH receptor

Rescue of PTH receptor knock-out with

targeted expression of Jansens transgene

Osteoporosis

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p

Osteoporosis is characterized by a significant reduction in bonemineral density compared with age- and sex-matched norms

There is a decrease in both bone mineral and bone matrix

Osteoporosis is the most common metabolic bone disease

Affects 20 million Americans and leads to 1.3 million fractures in theUS per year

Women lose 50% of their trabecular bone and 30 % of their cortical

bone

30% of all postmenapausal women will sustain an osteoporoticfracture as will 1/6th of all men

The cost of health care and lost productivity is $14 billion in the US

annually

Normal and Osteoporotic Bone

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No a a d Osteopo ot c o e

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Sequelae of

Osteoporosis

Bone Density as a Function of Age

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FDA Approved Rxs for Osteoporosis

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Bisphosphonates (alendronate and risedronate),

calcitonin, estrogens, parathyroid hormone andraloxifene are approved by the US Food and DrugAdministration (FDA) for the prevention and/ortreatment of osteoporosis

The bisphosphonates (alendronate and risedronate),calcitonin, estrogens and raloxifene affect the boneremodeling cycle and are classified as anti-resorptivemedications

Teriparatide, a form of parathyroid hormone, is a

newly approved osteoporosis medication. It is the firstosteoporosis medication to increase the rate of boneformation in the bone remodeling cycle

Treatments (Continued) Exercise, activity

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Exercise, activity

Calcium intake should be 1000-1500 mg/day

Postmenapausal women take in less than 500 mg/day

Males and females should take in 1000-1500 mg/day

All adults greater than 65 years should take 1500 mg/day

Three glasses of milk or three cups of yogurt per day provide 1000-1500

mg/day

Estrogen treatment Estrogen inhibits osteoclastic activity

Bone density increases 3-5% per year for the first three years after menopause

This therapy needs to be individualized Estrogen may increase the incidence of breast cancer, heart attacks, stroke, blood clots

That it may exacerbate cardiovascular disease is controversial

All the data are not in yet, and estrogen treatment is under review; for more

information go to http://www.fda.gov/bbs/topics/NEWS/2003/NEW00863.html

Treatments (Continued) R l if (B d E i t ) i l ti t t

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Raloxifene (Brand name Evista) is a selective estrogen receptormodulator

Decreases in estrogen levels after menopause lead to increases in boneresorption and bone loss. Bone is initially lost rapidly because thecompensatory increase in bone formation is inadequate to offsetresorptive losses. This imbalance between resorption and formation isrelated to loss of estrogen, and may also involve age-related

impairment of osteoblasts or their precursors Raloxifene reduces resorption of bone and decreases overall bone

turnover. These effects on bone are manifested as increases in bonemineral density (BMD)

Raloxifenes biological actions, like those of estrogen, are mediatedthrough binding to estrogen receptors. This binding results in themodulation of expression of multiple estrogen-regulated genes indifferent tissues

Treatments (Continued)

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Bisphosphonates inhibit osteroclasts Alendronate (Brand name Fosamax)

Risedronate (Brand name Actonel)

Calcitonin (Brand name Miacalcin )

From salmon

Given intranasaly Probably least effective Rx

Vitamin D

Most Americans consume less than recommended amount

800 IU per day seems safe and not enough to cause vitamin Dtoxicity

Treatments (Continued)

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Parathyroid hormone (Brand name Forteo) Teriparatide, a form of parathyroid hormone, is approved for the treatment of

osteoporosis in postmenopausal women and men who are at high risk for afracture

Chronically elevated PTH leads to bone loss; however, intermittent PTH(once daily bolus injection) leads to new bone synthesis

Must be injected daily, a major disadvantage

Cost about $7000 per year Future Rxs Sodium fluoride

Considered a possibility for years

Adoption seems unlikely

Strontium ranelate

NEJM 350 (2004) 459-468.

Calcium Content of Foods

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http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/
http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.htmlhttp://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.html

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Thank You

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