calcium metabolism and hypocalcimia / dental implant courses by indian dental academy

CALCIUM METABOLISM AND HYPOCALCEMIA

INDIAN DENTAL ACADEMYLEADER IN CONTINUING DENTAL EDUCATION

www.indiandentalacademy.com

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 .


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:


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 .


Calcium metabolism Calcium regulation :mainly by 3 common

hormones :

1}Parathyroid hormone .

2}Vitamin D .

3}Calcitonin .


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)…cholecalciferol25-OH- cholecalciferol(liver)…1- 25-OH-

cholecalciferol(kidney) MOA: steroid so enter nucleus & bind receptor

that leads to expose part of DNA…mRNA…Calbindin-D protein in epithlium of intestine,kidney,..that do the action .


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 .


Calcium metabolism Vitamin D Regulation :

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


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 .


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 .www.indiandentalacademy.com

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 .


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 .


Hypocalcemia Causes of hypocalcemia

Specific causes in neonatesI. 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


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. 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

high PO4 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: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.

2. X-linked hypoparathyroidism (absent of the gland that affect boys and appeared with the first 6 months of age.

3. AR hypoparathyroidism with dymorphic features: mutation of parathyroid hormone gene.

4. HDR syndrome: AD consist from (nerve deafness, renal dysplasia, and hypoparathyroidism)www.indiandentalacademy.com

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 overload9. Wilson disease: copper overload10. Postsurgical and irradiational

hypoparathyroidism.


Hypormagnesemia by: decrease parathyroid hormone secretion 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 or increasing 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


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: causes1. Poor intake2. Inadequate exposure to UV light3. 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:

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.

2. Hungry bone syndrome classicaly happen after parathyroidectomy of hyperparathyroid tumor (decrease Ca, phosphorus and Mg).

3. 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,

…)www.indiandentalacademy.com

Diagnosis A. HistoryB. 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 RFwww.indiandentalacademy.com

T.CAT.CA I.CaI.Ca PO4PO4 PTHPTHHYPOALUMEIAHYPOALUMEIA DECDEC NN NN NN

ALKALOSISALKALOSIS NN DECDEC NN N/INCN/INC

VIT D DEFVIT D DEF DECDEC DECDEC DECDEC INCINCCRFCRF DECDEC DECDEC INCINC INCINC

HYPOPTHHYPOPTH DECDEC DECDEC INCINC DECDEC

PHPPHP DECDEC DECDEC INCINC INCINC

PACREATITISPACREATITIS DECDEC DECDEC N/DECN/DEC INCINCwww.indiandentalacademy.com

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. OthersA. ECG show prolonged QT intervalB. Malabsorption work upC. 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.)www.indiandentalacademy.com

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, 1,25-

dihydroxycholecalciferol). 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 www.indiandentalacademy.com

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.)


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