Calcium Metabolism and Hypocalcemia

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,..

Calcium metabolism
physiologic functions : 1.blood coagulation . 2.muscle contraction . 3.neuromuscular transmission . 4.Skeletal growth & mineralization Ionized Ca is physiologically important .

Three Forms of Circulating Ca2+

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

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....)

Calcium metabolism
Serum CA level is determined by net absorption (GI) & excretion (RENAL). Each components is tightly regulatedhormonally- to keep normal serum level . Total CA is usually measured & provides satisfactory assessment of ionized form . However we have exceptions:

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 the bloodstream. There is constant exchange of calcium between bone and blood.

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.

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 .

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 very narrow range. This is achieved by an elaborate system of controls

Regulation of Intracellular [Calcium]

Control of cellular Ca homeostasis is as carefully maintained 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 shift it away from cytosolic pools.

Extracellular Calcium

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

Binding of calcium to albumin is pH dependent Acute alkalosis increases calcium binding to protein and decreases ionized calcium Patients who develop acute respiratory alkalosis have 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

Calcium and the Cell

Translocation across the plasma membrane Translocation across the ER and mitochondrion; Ca2+ ATPase in ER and plasma membrane

Calcium Turnover

Calcium homeostasis

PTH, Calcium & Phosphate

Calcium in Blood and Bone

Ca2+ normally ranges from 8.5-10 mg/dL in the plasma. The active free ionized Ca2+ is only about 48% 46% is bound to protein in a nondiffusible state while 6% is complexed to salt. Only free, ionized Ca2+ is biologically active.

Phosphate Turnover

Phosphorous in Blood and Bone

PO4 normal plasma concentration is 3.04.5 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

Osteoclasts and Ca2+ Resorption

Hormonal Control of Bones

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.

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

PTH and Osteoblastogenesis

Osteoclast Mediated Bone Resorption

PTH and Kidney

PTH acts on the distal tubule

Calcium metabolism

Calcium regulation :mainly by 3 common hormones : 1}Parathyroid hormone . 2}Vitamin D . 3}Calcitonin .

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-OHcholecalciferol(kidney) MOA: steroid so enter nucleus & bind receptor that leads to expose part of DNAmRNACalbindin-D protein in epithlium of intestine,kidney,..that do the action .

Calcium metabolism Vitamin D

Synthesis of Vitamin D

Vitamin D3 synthesis occurs in keratinocytes in the skin. 7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously converts to vitamin D3. Previtamin D3 will become degraded by over exposure to UV light and thus is not overproduced. Also 1,25-dihydroxy-D (the end product of vitamin D synthesis) feeds back to inhibit its production.

Synthesis of Vitamin D

PTH stimulates vitamin D synthesis. In the winter or if exposure to sunlight is limited (indoor jobs!), then dietary vitamin D is essential. Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxy-D. The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D. Then 25-hydroxy D is transported to the kidney where the second hydroxylation reaction takes place.

Synthesis of Vitamin D

The mitochondrial P450 enzyme 1-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D. The 1-hydroxylase enzyme is the point of regulation of D synthesis. Feedback regulation by 1,25-dihydroxy D inhibits this enzyme. PTH stimulates 1-hydroxylase and increases 1,25-dihydroxy D.

Synthesis of Vitamin D

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

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 .

Vitamin D Metabolism

Transport and Metabolic Sequence of Activation of Vitamin D

Proposed Mechanism of Action of 1,25-DihydroxyD3 in Intestine

Calcium metabolism Vitamin D

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

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 1hydroxylase activity (negative feedback). Low phosphate concentrations also increase 1-hydroxylase activity (vitamin D increases phosphate reabsorption from the urine).

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

Clinical correlate
Vitamin D-dependent rickets type II Mutation in 1,25-(OH)2-D receptor Disorder characterized by impaired intestinal calcium absorption Results in rickets or osteomalacia despite increased levels of 1,25-(OH)2-D in circulation

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

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 .

Parathyroid Glands

Synthesized in the 4 parathyroid glands PreProPTH 115 aa precursor giving a 90 aa prohormone Cleaved at -6/-7 84 residues in the mature peptide Regulator of Ca2+ homeostasis

Parathyroid Hormone Structure

Parathyroid Hormone Biosynthesis

Regulation of PTH
The dominant regulator of PTH is plasma Ca2+. 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 is maximally inhibited.

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

Intact, active PTH of 84 aa Inactive carboxyterminal fragments lack the 1-34 active domain PTH t1/2 (half life) is 2-3 min Liver (2/3rds) and kidney (1/3rd) are major sites of fragmentation

Regulation of PTH

PTH secretion responds to small alterations in plasma Ca2+ within seconds. A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca2+. This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclaseresult is increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

Calcium regulates PTH secretion

Parathyroid Hormone Receptor

7 TM GPCR

PTH Biosynthesis

PTH is co-secreted with chromogranin A, a protein; significance unknown

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 indirectly by increase VITD . 4)decrease PO4 reabsorption from proximal tubules increase ionized Ca . Overall effect :increase serum Ca & decrease serumPO4 .

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(by decreasing Ca level ) . Mg decrease leads to deacrease PTH level .

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

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).

PTH-Related Peptide

Has high degree of homology to PTH, but is not from the 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?

PTHrP; Parathyroid Related Protein

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
Product of parafollicular C cells of the thyroid 32 aa Inhibits osteoclast mediated bone resorption

This decreases serum Ca2+

Promotes renal excretion of Ca2+

Calcitonin

Calcitonin acts to decrease plasma Ca2+ levels. While PTH and vitamin D act to increase plasma Ca2+-- only calcitonin causes a decrease in plasma Ca2+. Calcitonin is synthesized and secreted by the parafollicular cells of the thyroid gland. They are distinct from thyroid follicular cells by their large size, pale cytoplasm, and small secretory granules.

Calcitonin
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
The target cell for calcitonin is the osteoclast. Calcitonin acts via increased cAMP concentrations to inhibit osteoclast motility and cell shape and inactivates them. The major effect of calcitonin administration is a rapid fall in Ca2+ caused by inhibition of bone resorption.

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

Decreased resorption

Calcitonin

Role of calcitonin in normal Ca2+ control is not understoodmay be more important in control of bone remodeling. Used clinically in treatment of hypercalcelmia and in certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous. Chronic excess of calcitonin does not produce hypocalcemia and removal of parafollicular cells does not cause hypercalcemia. PTH and Vitamin D3 regulation dominate. May be more important in regulating bone remodeling than in Ca2+ homeostasis.

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 (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.

Other Factors Influencing Bone and Calcium Metabolism

Estrogens and Androgens: both stimulate bone formation 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 bone fractures.

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 has predominant role

Causes of Hypocalcemia
Hypoparathyroid Postoperative Idiopathic Post radiation Nonparathyroid Vitamin D deficiency Malabsorption Liver disease Kidney disease Vitamin D resistance PTH Resistance Pseudohypoparathyroidism

Sequence of Adjustments to Hypocalcemia

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.)

II.
1.

Late neonatal hypocalcemia: happen from 5 days of birth, may appear till 6 weeks of age.
Causes: Exogenous PO4 load, most common due to high PO4 content in formula, or cows milk and decreased in GFR contribute also. Mg deficiency. Transient hypoparathyroidism Hypoparathyroidism due to other causes: (idiopathic, congenital, maternal hyperparathyroidism, hypomagnesemia)

2. 3. 4.

Hypoparathyroidism:
1. DiGeorge syndrome: aplasia or hypoplasia of parathyroid gland. associated with different anomalies including cardiac and facial anomaly mainly and also VATER and CHARGE associations. X-linked hypoparathyroidism (absent of the gland that affect boys and appeared with the first 6 months of age. AR hypoparathyroidism with dymorphic features: mutation of parathyroid hormone gene. HDR syndrome: AD consist from (nerve deafness, renal dysplasia, and hypoparathyroidism)

3.

4. 4.

5. Autoimmune polyglandular syndrome type I: AR, due to mutation in autoimmune regulator gene Consist from (hypoparathyroidism, addisson disease, mucocutaneous candidiasis). 6. Calcium sensor receptor gene mutation.

7. Kearns-Sayre syndrome: mitochondrial inherited

disorder. (ie, external ophthalmoplegia, ataxia, sensorineural deafness, heart block, and elevated cerebral spinal fluid [CSF] protein), are associated with hypoparathyroidism. Hypothyroidism affect after age of 5 years 8. Hemochromatosis: iron overload

9. Wilson disease: copper overload 10. Postsurgical and irradiational hypoparathyroidism.

Hypoparathyroidism
Hypocalcemia occurs when there is inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuli Hypocalcemia is often multifactorial Hypocalcemia is invariably associated with hypoparathyroidism Bihormonalconcomitant decrease in 1,25-(OH)2-D

Hypoparathyroidism

PTH-deficient hypoparathyroidism
Reduced or absent synthesis of PTH Often due to inadvertent removal of excessive parathyroid tissue during thyroid or parathyroid surgery

PTH-ineffective hypoparathyroidism
Synthesis of biologically inactive PTH

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

Symptoms and signs Hypocalcemia Hyperphosphatemia Characteristic physical appearance: short stature, round face, short thick 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 eruption occurs in 50% of people with the disorder Rx: vitamin D and calcium

Pseudohypoparathyroidism

Pseudohypoparathyroidism

Elfin facies, short stature, enamel hypoplasia

Hypormagnesemia by: decrease parathyroid hormone secretion and by blunting tissue response to PTH. Pseudohypoparathyroidism lack of response of inadequate available PTH.
1. 2. 3. 4. Decerease Ca, increase phosphorus, decrease Vit D. Defect in alpha subunit of G proteins (2nd messenger) Administration of synthetic PTH fail to increase Ca level or increasing excretion of phosphorus in urine. 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

CONTINUE.. 12.Pseudohypoparathyroidism

Albright hereditary osteodystrophy characterized by Short stature, obesity, round face, short distal phalanges of the thumbs, brachymetacarpals and brachymetatarsals, subcutaneous calcifications, dental hypoplasia, and developmental delay characterize this phenotype. Pseudopseudohypoparathyroidism (PPHP) is characterized by normal calcium homeostasis in the setting of the AHO phenotype.

Vit D defficiency: causes

1. Poor intake 2. Inadequate exposure to UV light 3. Malabsorption (liver disease, GI disease, pancreatic insufficiency). 4. Increase metabolism (as in anticonvulsant that activate P450 system enzyme in liver that increase degradation of vit D. 5. Renal disease: CRF mainly. 6. Vitamin D dependent ricket type 1(AR absence of one alpha hydroxylase enzyme). 7. Vitamin D dependent ricket type 2(AR defect in vit D receptor, 50% have alopecia

Redistribution of plasma Ca:

1. Hyperphosphatemia due to:
2. 3. 4. 5. 6. Excessive phosphate intake because of inproper formula and decreased GFR. Loading in TPN. Ecessive intake by inappropriate PO4 enema or laxative. Renal failure. 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 causes binding to ionized Ca but normal total Ca. Drugs like thiazide. Septic shock and ICU cases: unkown mechanism

Clinical picture
Symptoms:

Related to degree and rate of hypocalcemia. Mild hypocalcemia is asymptomatic. Most clinical picture due to neuromuscular irritability. Symptoms can be provoked by hyperventilation.

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 hand area. Others like basal ganglia calcification in PHP, rikets in vit D deficiency, others depend on syndrome. Arrhythmia

 Physical

findings:

Hyper-reflexia (carpopedal spasm, chvostec sign- 10-20% nonspecific, trousseau sign, stridor and cyanosis). Abdominal distention. Seizure. Lethargy. Apnea. Depend on syndrome (PHP, DiGeorge, )

Diagnosis
A. B.

History 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). Poor intake, malabsorption, decrease light exposure, excessive metabolism cause decrease in 25 OH and normal 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 1-25 OH. Decrease PTH causes decrease 1-25 OH PHP causes increase 1-25 OH

Alkaline phosphatase: increase in vit D defeciency and normal to decrease in Hypoparathyroidism. Total protein, albumin, PH KFT Urine Ca, Mg, PO4 and Cr in renal tubular defect and RF

T.CA
HYPOALUMEIA ALKALOSIS VIT D DEF CRF HYPOPTH

I.Ca N DEC DEC DEC DEC DEC DEC

PO4 N N DEC INC INC INC

PTH N N/INC INC INC DEC INC

DEC N DEC DEC DEC DEC DEC

PHP

PACREATITIS

N/DEC INC

Radiology
CXR: loss of thymic shadow in DiGeorge syndrome and osteopenia in rickets. Wrist X-ray: rickets changes. Hand X-Ray: in PHP Echocardiogram in DiGeorge syndrome there is cardiac anomaly. Brain MRI: basal ganglion calcification in PHP. Renal ultrasonography: Treatment of hypoparathyroidism can lead to nephrocalcinosis as a result of calciuria. Baseline renal ultrasonography with initial treatment should be performed.

D.

Others
A. ECG show prolonged QT interval B. Malabsorption work up C. Total lymphocytes

Treatment

Symptomatic hypocalcemia needs IV calcium and continuous monitoring for arrhythmias. Once serum Ca is in safe range ( >7 mg/dl) IV Ca can be stopped, and oral Ca started. Oral Ca and vit D are initiated as soon as possible when patient is tolerating oral feed. Active form of vit D is preferred in treatment of HPH or 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 neonatal hypocalcemia low phosphorus formula needed like Semilac PM 60/40.)

Calcium, intravenous
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 27 mg/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 IV infusion over 24 h

Use extreme care in peripheral infusion because extravasation can cause severe tissue necrosis. rapid IV infusion may cause bradycardia and hypotension. may cause liver necrosis if administered in an umbilical venous catheter lodged in a branch of portal vein. prolonged use of calcium chloride may lead to hyperchloremic acidosis

Calcium glubionate (Neo-Calglucon) -- Calcium supplement 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 high osmolar load; may cause diarrhea in older children

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 added to formula (eg, Similac PM 60/40 to make a calcium-phosphorous ratio of 4:1) -Children: 20-65 mg/kg/d PO divided bid/qid Hypercalcemia or hypercalcuria may occur when therapeutic amounts are given

Calcitriol (Rocaltrol)
Active metabolic form of vitamin D (ie, 1,25dihydroxycholecalciferol). Especially useful in impaired liver or renal function causing inability to hydroxylate vitamin D to its active forms. 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 attained May cause hypercalciuria; give with calcium salts to attain optimum results; may add hydrochlorothiazide to regimen to control hypercalciuria

Dihydrotachysterol (DHT, Hytakerol)

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 :

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 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:

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

In pacreatitis and rhabdomyolysis complete correction of hypocalcemia should be avoided because with resolution of the primary problem there is release of the complexed Ca and hypercalcemia may happen. If acidemia is present hypocalcemia should if possible be corrected first, acidemia increases the ionized Ca concentration by displacing Ca from albumin, 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:

Intravenous infusion with calcium-containing solutions can cause severe tissue necrosis. Failure to distinguish calcium receptor defects from hypoparathyroidism Failure to consider an associated cardiac lesion in an infant with hypocalcemia Failure to monitor serum calcium concentrations for at least 24 hours after intravenous calcium withdrawal (Rebound hypocalcaemia can occur when intravenous calcium is withdrawn, even on adequate amounts of oral calcium.)

Causes of Hypercalcemia
Common Malignant disease, e.g. some lung cancers Hyperparathyroidism Vitamin D toxicity (excessive intake) Uncommon Renal failure Sarcoidosis Multiple myeloma

Signs and Symptoms of 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

Calcium homeostatic loss due to excessive PTH secretion Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.

Hypercalcemia of Malignancy
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)

Hypercalcemia of Malignancy
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

Rare disease known as Jansens metaphyseal 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

Osteoporosis is characterized by a significant reduction in bone mineral 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 the US per year Women lose 50% of their trabecular bone and 30 % of their cortical bone 30% of all postmenapausal women will sustain an osteoporotic fracture 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

Sequelae of Osteoporosis

Bone Density as a Function of Age

FDA Approved Rxs for Osteoporosis

Bisphosphonates (alendronate and risedronate), calcitonin, estrogens, parathyroid hormone and raloxifene are approved by the US Food and Drug Administration (FDA) for the prevention and/or treatment of osteoporosis The bisphosphonates (alendronate and risedronate), calcitonin, estrogens and raloxifene affect the bone remodeling cycle and are classified as anti-resorptive medications Teriparatide, a form of parathyroid hormone, is a newly approved osteoporosis medication. It is the first osteoporosis medication to increase the rate of bone formation in the bone remodeling cycle

Treatments (Continued)

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)

Raloxifene (Brand name Evista) is a selective estrogen receptor modulator Decreases in estrogen levels after menopause lead to increases in bone resorption and bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. This imbalance between resorption and formation is related 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 bone mineral density (BMD) Raloxifenes biological actions, like those of estrogen, are mediated through binding to estrogen receptors. This binding results in the modulation of expression of multiple estrogen-regulated genes in different tissues

Treatments (Continued)

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 D toxicity

Treatments (Continued)

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 a fracture 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

http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/w

Thank You