Dr. IFTHAQAR. H. F

CALCIUM METABOLISM

Dr. IFTHAQAR. H. F

INTRODUCTION

Calcium is the most abundant mineral in the body.

The body of a young adult human contains about

1100 g (27.5 mol) of calcium.

Normal levels ranges from 8.5 to 10.5 mg/dl

About 99% of body calcium is in the form of

hydroxyapatite crystal in the bone.

1% in ECF, ICF .

THE 1% CALCIUM

In blood, calcium is found in 3 forms:

Ionised (biologically active) 50%

Bound to proteins 40% &

as Complexes with substances(anions) such as

HCO3, citrate, etc.. 10%

DISTRIBUTION OF CALCIUM

WE ARE INTERESTED IN IONIZED CALCIUM

LEVELS: WHY??BECAUSE,

Calcium messenger system – regulates cell

function.

Activates cellular enzyme cascades.

Muscle contraction.

Nerve impulse conduction.

Blood coagulation.

CALCIUM ABSORPTION (DRAW)

Ca2+ is transported across the brush border of

intestinal epithelial cells via channels – TRPV6

Binds to intracellular protein known as calbindin-

D9k

Transported into the bloodstream by either a

sodium/calcium exchanger (NCX1) or a calcium-

dependent ATPase.

The overall transport process is regulated by 1,25-

dihydroxycholecalciferol

CALCIUM EXCRETION

Plasma Ca2+ is filtered in the kidneys.

98–99% of the filtered Ca2+ is reabsorbed.

(proximal(60%), loop of henle & distal-40%)

Distal tubular reabsorption depends on the TRPV5

channel. – controlled by PTH

CALCIUM HOMEOSTASIS

Three hormones

–PTH

–1,25 (OH)2 CC

–Calcitonin

Three target organs

–Bone

–Gut

–Kidney

Three bone cells

–Osteoblasts

–Osteocytes

–Osteoclasts

Hormone Effect on bones Effect on gut Effect on

kidneys

Parathyroid

hormone

increase Ca++,

decrease PO4

levels in blood

Supports

osteoclast

resorption

Indirect effects via

increase calcitriol

from 1-

hydroxylation

Supports Ca++

resorption and

PO4 excretion,

activates 1-

hydroxylation

Calcitriol

(vitamin D)

Ca++, PO4 levels

increases in

blood

No direct effects

Supports

osteoblasts

Increases Ca++

and PO4

absorption

No direct effects

Calcitonin

causes Ca++,

PO4 levels

decrease in blood

when

hypercalcemia is

present

Inhibits osteoclast

resorption

No direct effects Promotes Ca++

and PO4 excretion

CALCIUM, PTH, AND VITAMIN D

FEEDBACK LOOPS

CALCIUM LEVELS ARE AFFECTED BY:

Albumin

Blood pH

Serum phosphate

Serum magnesium

Serum bicarbonate

HYPOCALCEMIA

Dr. IFTHAQAR. H. F

Hypocalcemia is defined as a total serum calcium

concentration of

less than 2.1 mmol/L (8.5 mg/dL) in children,

less than 2 mmol/L (8 mg/dL) in term neonates,

less than 1.75 mmol/L (7 mg/dL) in preterm

neonates.

Hypocalcemia can present as an asymptomatic

laboratory finding

or

as a severe, life-threatening condition.

CAUSES OF HYPOCALCEMIA

Neonatal hypocalcemia:

Early neonatal hypocalcemia (48-72 hours)

Prematurity

Poor intake, hypoalbuminemia, reduced responsiveness to vitamin D

Birth asphyxia

Delay feeding, increased calcitonin, endogenous phosphate load high, alkali therapy

Infant to diabetic mother

Magnesium depletion → functional hypoparathyroidism → hypocalcemia

IUGR

Late neonatal hypocalcemia

Exogenous phosphate load

Phosphate-rich formulas / cow’s milk

Magnesium deficiency

Transient hypoparathyroidism of newborn

Congenital Hypoparathyroidism

CAUSES OF HYPOCALCEMIA

In childhood:

Vitamin D deficiency.

Hypoparathyroidism.

PTH resistance – Pseudohypoparathyroidism.

Autoimmune parathyroiditis

Mitochondrial DNA mutations.

Hypomagnesaemia

OTHER CAUSES

Malabsorption syndromes.

Hyperphosphatemia.

Alkalosis.

Pancreatitis.

Pseudohypocalcemia (ie, hypoalbuminemia)

Hungry bones syndrome

SYMPTOMS AND SIGNS OF HYPOCALCEMIA

Neuromuscular irritability

Paresthesias

Laryngospasm / Bronchospasm

Tetany

Seizures (focal, petit mal, grand mal)

Muscle cramps

Muscle weakness

Chvostek sign

Trousseau sign

Prolonged QT interval(>0.4sec) on ECG

Tetany is not caused by increased excitability of the

muscles.

Muscle excitability is depressed

hypocalcemia delays ACh release at NM junctions

However, the increase in neuronal excitability

overrides the inhibition of muscle contraction.

HISTORY THAT SUGGESTS HYPOCALCEMIA

Newborns (can be unspecific) Asymptomatic

Lethargy

Poor feeding

Vomiting

Abdominal distention

Children Seizures

Twitching

Tingling & numbness of fingers

Cramping

Laryngospasm

APROACH

WORKUP - BLOOD

Total and ionized serum calcium levels

Serum magnesium levels

Phosphorus levels.

Parathormone levels. (PTH challenge)

Serum electrolyte and glucose levels

Vitamin D metabolite (25-hydroxyvitamin D and

1,25-dihydroxyvitamin D) levels

Serum alkaline phosphatase levels

Urine calcium, magnesium, phosphorus, and

creatinine levels

RFT

WORKUP - IMAGING

Chest X Ray.

Ankle and wrist X Ray.

Other:

ECG

Malabsorption workup

Karyotyping (22q11 & 10p13 deletion)

Family screening

MANAGEMENT

1. Dependent on the underlying cause and

severity

2. Administration of calcium alone is only

transiently effective

3. Mild asymptomatic cases: Often adequate to

increase dietary calcium by 1000 mg/day

4. Symptomatic: Treat immediately

TREATMENT OF HYPOCALCAEMIASymptomatic hypocalcaemia

IV Calcium should only be given with close monitoring

Should be on cardiac monitor.

Dose: Cal gluconate (10mg/kg -1ml/kg of 10% solt)

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

solutions)

Risks

Tissue necrosis/calcification if extravasates

Calcium can inhibit sinus node bradycardia + arrest

Stop infusion if bradycardia develops

Avoid complete correction of hypocalcaemia

With acidosis and S-Ca – give Ca before correcting

acidosis [Acidemia increases the ionized calcium levels by

displacing calcium from albumin. If acidemia is corrected

first, ionized calcium levels decrease]

If Mg is cause of S-Ca – treat and correct

hypomagnesaemia

Oral supplementation 50 mg/kg/day of

elemental Ca

Cal carbonate is best as it contains 40% of

elemental cal.

Most cases require Vit D supplementation.

HYPERCALCEMIA

Dr. IFTHAQAR. H. F

Hypercalcemia is defined as total serum calcium >

10.5 mg/dl(>2.6 m mol/L ) or ionized serum

calcium > 5.6 mg/dl ( >1.4 m mol/L )

Severe hypercalemia is defined as total serum

calcium > 14 mg/dl (> 3.5 mmol/L)

PATHOPHYSIOLOGY:

Hypercalcemia is caused by

Increased bone resorption,

increased gastrointestinal absorption of calcium,

and

decreased renal excretion of calcium

Hypercalcemia leads to hyperpolarization of cell

membranes.

CAUSES OF HYPERCALCEMIA:

1. Parathyroid hormone (PTH) excess. - HPTH

2. Parathyroid Hormone–related Peptide (Pthrp)

Excess

Seen in malignancies.

3. Ca2+-sensing Receptor Inactivating Mutation.

1. Familial Hypocalciuric Hypercalcemia(FHH)

2. Neonatal Severe Hyperparathyroidism.

4. Activating Mutation of PTH/PTHrP Receptor.

5. Inactivating Mutation of PTH/PTHrP Receptor.

6. VITAMIN D EXCESS

1. Iatrogenic

2. Ectopic production

3. Sarcoidosis, tuberculosis, granulomatous lesions,

subcutaneous fat necrosis

4. Excessively fortified milk

7. OTHER:

1. Prolonged Immobilization

2. Thyrotoxicosis

3. Hypervitaminosis A

4. Leukemia

5. Hypophosphatasia.

6. Williams Syndrome.

7. Drugs – esp, thiazide, TPN, theophyllin, lithium.

CLINICAL MANIFESTATIONS:

HISTORY:

muscular weakness,

fatigue,

headache, anorexia,

abdominal pain,

nausea, vomiting,

constipation,

polydipsia, polyuria,

loss of weight, and fever

SAYING:

“painful bones, renal stones, abdominal groans, psychic

moans, and neuropsychiatric

overtones”

APPROACH TO A CHILD WITH

HYPERCALCEMIA:

Evaluation of a patient with hypercalcemia

should include a careful history and

physical examination focusing on

clinical manifestations of hypercalcemia,

risk factors for malignancy,

causative medications, and

family history of hypercalcemia

LABORATORY TEST

Serum calcium & Ionized calcium

PTH (intact)

Serum phosphate

1,25-dihydroxyvitamin D

Alkaline phosphatase

Urine calcium

Urine Ca/Cr ratio

ECG

Shortened QT interval

Bradycardia

Widened T wave

Primary hyperparathyroidism : PTH↑

MALIGNANCY :

1.solid tumors(humoral hypercalcemia) :PTHrP↑ ,

PTH↓

2.Multiple myeloma and breast cancer(osteolytic

hypercalcemia ) : alkaline phosphatase ↑, PTH↓

Granulomatous(sarcoidosis, tuberculosis,

Hodgkin's lymphoma) :

calcitriol (1,25-OH vitamin D3 ) ↑, PTH↓

Familial hypocalciuric hypercalcemia :

24-hour urinary calcium ↓, PTH ↑

IMAGING STUDIES

Plain X-ray

demineralization, pathologic fractures, bone cysts, and

bony metastases.

Renal imaging:

calcifications or stones

USG of the parathyroid glands:

hyperplasia or adenoma

MANAGEMENT:

Medical:

Initial treatment involves hydration to improve

urinary calcium output. (Normal saline)

Loop diuretic is also added. (Furosemide)

Bisphosphonates serve to block bone resorption

over the next 24-48 hours.

Etidronate

Clodronate

Pamidronate

Alendronate

Inhibits osteoclast action and bone resporption

Indication: hypercalcemia of malignancy

• Calcitonin :

inhibition bone resorption and increases renal calcium excretion

4 to 8 IU per kg IM or SQ every 6 hours for 24 hours

Plicamycin (Mitharmycin) :

decreases bone resorption

25 mcg per kg per day IV over 6 hours for 3 to 8 doses

Gallium nitrate :

inhibition bone resorption

100 to 200 mg per m2 IV over 24 hours for 5 days

Glucocorticoids :

Inhibits vitamin D conversionto calcitriol

Hydrocortisone, 200 mg IV daily for 3 days

Hemodialysis :

used in patients with renal failure

Surgery:Patients with primary HPTH

Criteria for Surgery in Primary Hyperparathyroidism

Serum total calcium level > 12 mg per dL (3 mmol per L) at any time

Hyperparathyroid crisis (discrete episode of life-threatening hypercalcemia)

Marked hypercalciuria (urinary calcium excretion more than 400 mg per day)

Nephrolithiasis

Impaired renal function

Osteitis fibrosa cystica.

Reduced cortical bone density

REFERENCE:

1. Ganong’s Review of Medical Physiology – 24th Ed.

2. Nelson text book of pediatrics 19th edition.

3. Hypocalcemia: Diagnosis and Treatment, Uptodate: Updated 1 October 2011

4. Pediatric Hypocalcemia, Author: Sunil Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD - emedicine

5. A Practical Approach to Hypercalcemia, American Family Physician. 2003 May 1;67(9):1959-1966

6. Pediatric Hypercalcemia, Author: Ilene A Claudius, MD; Chief Editor: Stephen Kemp, MD, PhD – emedicine

7. Google search - images