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Calcium metabolism (PowerPoint)

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					Calcium Metabolism
       and
   Hypocalcemia




  Prepared by: Dr. Bassim A. Rahmeh
  Directed by: Dr. A. Hamam
         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)…cholecalciferol
25-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 .
        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 neonates
        I.  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 hypoparathyroidism
      4.     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)
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.
        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: 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:
        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, …)
                       Diagnosis
A.    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).
    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   I.Ca   PO4   PTH
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
 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, 1,25-
      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
   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.)
Thank You

				
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