Calcium physiology and

associated disorder in
children
By: Wong Ann Cheng
MD (UKM) MRCPCH (UK)
Calcium physiology
Biological functions of calcium
Structural as component of bone
Functional for normal neuromuscular
activity
Multiple biological functions of
calcium
•Cell signalling
•Neural transmission
•Cardiac and skeletal muscle contraction
•Blood coagulation
•Enzymatic co-factor
•Secretion
•Biomineralization

30% increase in free Ca,

 nerves and muscles become unresponsive
35% decrease,
 nerves overexcitable and convulsions occur; 50% fatal
 Sources of calcium
bones and teeth provide huge reservoir of
Ca
98-99% Ca filtered from blood in kidneys is
reabsorbed
10-20% Ca consumed as food is absorbed
by brush border of intestinal cells
 Distribution in the body
99% deposited in bones and teeth
0.5% bound to plasma proteins in blood
0.5% free ionized calcium in extracellular
fluid
 Calcium in the blood
Free or ionized state 45%
Bound to plasma protein (albumin) 45%
Bound to anion (phosphate, citrate) 10%
 Calcium concentration
Ionized Calcium is metabolically active
Most lab only report total calcium
Total calcium concentration fluctuate with
serum albumin
Corrected Ca2 = Ca2 + 0.02 (40 - Alb)
Normal value 2.1-2.6 mmol/L
Degree of protein binding of plasma Ca2
proportional to plasma pH
 Beware correction acidosis in
renal failure
Total and ionized Ca2 already low
Acute rise in pH with NaHCO3
  increase protein bound Ca2
  reduce ionized Ca2
  tetany
 Pseudo-hypercalcemia
Dehydration or haemoconcentration
during blood taking may elevate serum
albumin and hence falsely elevated total
serum calcium
Calcium Homeostasis
 Principle organs involved
 Intestine
 Kidneys
 Bone
Principal hormones involved
1,25-dihydroxyvitamin D (1,25-OH2D)
Parathyroid hormone (PTH)
Calcitonin (CT)
Effects of 1,25-OH2D (1,25-dihydroxyvitamin D)
on Mineral Metabolism

Bone
Promotes mineralization of osteoid
Increases resorption at high doses

Kidney
Decreases calcium excretion
Decreases phosphorus excretion

Gastrointestinal Tract
Increases calcium absorption
Increases phosphorus absorption

Blood
Increases calcium
Increases phosphorus
Effects of Parathyroid Hormone on
Calcium and Skeletal Metabolism

Bone
Increases resorption
Increases formation, especially at low and intermittent concentrations

Kidney
Decreases calcium excretion (clearance)
Increases phosphorus excretion

Gastrointestinal Tract
Increases calcium and phosphorus absorption
Indirect effect via 1,25-OH2D production

Blood
Increases calcium
Decreases phosphorus
Effects of Calcitonin on Mineral Metabolism
Bone
Inhibits resorption
? Promotes formation

Kidney
Increases calcium excretion
Increases phosphorus excretion

Gastrointestinal Tract
? Inhibitory effect on calcium/phosphorus absorption

Blood
Decreases calcium
Decreases phosphorus
VITAMIN D SYNTHESIS

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL VITAMIN D3 25(OH)VITAMIN D

25-HYDROXYLASE 1α-HYDROXYLASE
uν

VITAMIN D3 25(OH)VITAMIN D 1,25(OH)2 VITAMIN D

(ACTIVE METABOLITE)

TISSUE-SPECIFIC VITAMIN D RESPONSES

CALCIUM HOMEOSTASIS

DIETARY CALCIUM
THE ONLY “IN”
BONE
DIETARY HABITS, ORGAN,
ENDOCRINE
SUPPLEMENTS
BLOOD CALCIUM

INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY KIDNEYS
ORGAN PHYS.
ENDOCRINE PHYSIOLOGY
ENDOCRINE PHYS.

URINE
THE PRINCIPLE “OUT”
CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS

BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION

RISING BLOOD Ca

NORMAL BLOOD Ca
FALLING BLOOD Ca

BONE RESORPTION
STIMULATE PTH
URINARY LOSS
1,25(OH)2 D PRODUCTION
Calcium disorder in children
Hypercalcemia
 Differential Diagnosis of Hypercalcemia

Medications
Primary hyperparathyroidism Thiazide diuretics
Vitamin D intoxication
Malignant tumors
With skeletal metastases Vitamin A intoxication
Without skeletal metastases Total parenteral nutrition
Arising from the marrow Aminophylline intoxication
• Myeloma
• Leukemia with blastic crisis
Miscellaneous
Granulomatous diseases Immobilization
Sarcoidosis Pheochromocytoma
Active tuberculosis William syndrome
Histoplasmosis
Vasoactive intestinal peptide-producing
Coccidiomycosis tumor
Leprosy
Familial hypocalciuric hypercalcemia
Milk-alkali syndrome
Differential diagnosis of hypercalcemia

PTH-mediated
Hyperparathyroidism

Non-PTH-mediated
Malignancy
Granulomatous diseases
Endocrine conditions
Immobilization
Familial hypocalciuric hypercalcemia
Drugs or supplements
 Hypercalcemic disorders
A. Endocrine Disorders Associated with Hypercalcemia
Endocrine Disorders with Excess PTH Production
 Primary Sporadic hyperparathyroidism
 Primary Familial Hyperparathyroidism
MEN I
MEN IIA
FHH and NSHPT
Hyperparathyroidism - Jaw Tumor Syndrome
Familial Isolated Hyperparathyroidism
Endocrine Disorders without Excess PTH Production

Hyperthyroidism

Hypoadrenalism

Jansen's Syndrome

B. Malignancy-Associated Hypercalcemia (MAH)

MAH with Elevated PTHrP

Humoral Hypercalcemia of Malignancy

Solid Tumors with Skeletal Metastases

Hematologic Malignancies
MAH with Elevation of Other Systemic Factors

MAH with Elevated 1,25(OH)2D3

MAH with Elevated Cytokines

Ectopic Hyperparathyroidism

Multiple Myeloma
 Hypercalcemic disorders
C. Inflammatory Disorders Causing Hypercalcemia
Granulomatous Disorders
AIDS

D. Disorders of Unknown Etiology

Williams Syndrome
Idiopathic Infantile Hypercalcemia

E. Medication-Induced
Thiazides
Lithium
Vitamin D
Vitamin A
Estrogens and Antiestrogens
Aluminium Intoxication
Milk-Alkali Syndrome
 Disorder of vitamin D metabolism
Subcutaneous fat necrosis
Term infant with mild birth asphyxia
Developed hardened lumps in skin
Invaded by macrophages with inappropriately high 1α-
OHase activity

Sarcoidosis
Also cause by inappropriate formation 1α-OH2D by
macrophages in sarcoid tissue, usu in lung

Vitamin D toxicity
25-OHD formed from vitamin D, weak activity but sufficient
to cause hypercalcemia if vitamin D is given in excess
1α-OH2D much more potent
William’s syndrome
Abnormality elastin gene on
chromosome 7
‘elfin-like’ facies
‘cocktail party’ conversation
Developmental problems,
learning difficulties
Supravalvular aortic stenosis,
peripheral pulmonary stenosis
Hypercalcemia, hypercalciuria,
assoc with FTT
(hypercalcemia usu does not
extend beyond 1 year of life)
Hyperparathyroidism
 Hyperparathyroidism

Primary Secondary Tertiary

hyperparathyroidism hyperparathyroidism hyperparathyroidism

Autonomous Response to PTH hypertrophy

hypersecretion of PTH hypocalcemia persistent
- PTH hyperplasia - PTH hypertrophy after removal of
- PTH adenoma hypocalcemic stimulus
(renal transplantation)
High PTH High PTH High PTH
High Ca Low Ca High Ca
Parathyroid gland tumour associated with MEN

MEN type 1 MEN type 2a MEN type 2b

PTH adenoma PTH hyperplasia PTH hyperplasia

Pituitary tumour Medullary thyroid cancer Medullary thyroid cancer
Pancreatic tumour Phaeochromocytoma Phaeochromocytoma
(gastrinoma, insulinoma)

Mucocutaneous
neurofibroma
Dysmorphic features
(marfanoid habitus,
skeletal abN, abN dental
enamel)
Hypercalcemia of malignancy
The most frequent cause of hypercalcemia with
nonmetastatic solid tumors is the release of
PTHrP.
This protein is immunologically distinct from PTH,
yet is similar enough in structure to permit binding
to identical receptors and simulation of second
messengers.
Ability of PTHrP to induce most of the actions of
PTH including increases in bone resorption and
inhibition of proximal tubule phosphate transport.
In general, patients with PTHrP-induced
hypercalcemia have advanced cancer and a poor
prognosis.
 Groans, moans, bones, stones

Manifestations of Hypercalcemia
Acute Chronic
Gastrointestinal Anorexia, nausea, Dyspepsia,
vomiting constipation,
pancreatitis

Renal Polyuria, polydipsia Nephrolithiasis,

nephrocalcinosis

Neuro-muscular Depression, Weakness

confusion, stupor,
coma

Cardiac Bradycardia, first Hypertension

degree atrio- block, digitalis
ventricular sensitivity
Management of Acute Hypercalcemia

Hydration
•Saline (0.9%) infusion, 2 - 4 L over 24 hours
Inhibition of Bone Resorption
•Bisphosphonate
Pamidronate (60 to 90 mg over 4 hours IV) or
Zoledronate (4 mg over 15 min IV)
•Calcitonin
•4 IU/kg to 8 IU/kg q12h sc or IM x 1 to 2 days
4.Calciuresis
•Loop diuretics
•Furosemide 10 to 20 mg IV every 6 to 12 hours
Glucocorticoids (when indicated)
•Hydrocortisone 200 - 300 mg IV daily for 3 to 5 days
Dialysis (in renal failure)
Hypocalcemia
Causes of hypocalcemia in children
Neonatal hypocalcemia
Vitamin D deficiency
 Vitamin D deficient rickets
 Vitamin D dependent rickets
 Vitamin D resistant rickets
Magnesium deficiency
Renal failure
Parathyroid disorder

Genetic: Di George syndrome, APECED syndrome

Acquired: Surgical, irradiation, infiltration
 Pseudohypoparathyroidism (PTH resistance)
 Neonatal hypocalcemia
Fetal bone has high demand for calcium due to
high rate of bone turnover
Physiological hypocalcemia occur as plasma Ca
falls to 2.0 mmol/L during first 24 - 48H before
recovering by end of 1st week
Symptomatic hypocalcemia more likely in
premature or unwell neonates
Profound and prolonged hypocalcemia if failure
of PTH gland (Di George synd) or maternal
vitamin D deficient or hypercalcemic
 Vitamin D deficiency
Most common symptomatic hypocalcemia
outside neonatal period
Nutritional vitamin D deficiency, esp in black
children with increase skin pigmentation
which inhibits synthesis of vitamin D
May present with

symptoms of hypocalcemia
 or rickets
Vitamin D Deficiency Vitamin D Dependent Vitamin D Resistant
Rickets Rickets Rickets

Cause Cause Cause

Lack exposure to sunlight Deficiency enzyme that Phosphate leak at level of
Lack of intake convert 25-D3 to 1,25-D3 proximal tubules
Anticonvulsant therapy (not a disease of vitamin
D metabolism)
Intestinal malabsorption

Lab findings Lab findings Lab findings

Low Ca2 Low Ca2 Normal Ca2
Low PO4 Low PO4 Low PO4
High ALP High ALP Normal PTH
High PTH High PTH
Low 1,25-D3 Low 1,25-D3

Treatment Treatment Treatment

Vitamin D Daily 1,25-D3 Phosphate supplements
Clinical features of hypocalcemia

•Muscle cramps
•Paraesthesias
•Laryngospasm
•Bronchospasm
•Tetany
•Seizures

•Chvostek sign
•Trousseau sign
•Prolonged Q-T interval on ECG
 Findings of rickets
Reaction of the periosteum (may occur)
Indistinct cortex
Coarse trabeculation
Knees, wrists, and ankles affected predominantly
Epiphyseal plates, widened and irregular
Tremendous metaphysis (cupping, fraying, splaying)
Spur (metaphyseal)
Rickety rossary Frontal bossing
Widening of wrist Bowing
Cupping and splaying of metaphysis
 Magnesium deficiency
Deficiency commonly cause by
malabsorption
Causes hypoparathyroid state by
interfering with PTH secretion
Biochem resembles hypoparathyroidism
but with low plasma Mg
Corrected by treatment with Mg
 Renal Failure
Decreased glomerular filtration rate (GFR)  decreased
filtration of phosphate, phosphate retention, and
increased serum phosphate
Increased serum phosphate complexes with serum
calcium  decreased ionized serum calcium
Decreased production of active Vitamin D (1,25-
dihydroxycholecalciferol) by diseased renal tissue also
contributes to decreased ionized calcium
Decreased serum calcium causes secondary
hyperparathyroidism
The combination of increased PTH levels and decreased
active Vitamin D produces renal osteodystrophy, in which
there is increased bone resorption and osteomalacia
 Genetic hypoparathyroidism
DiGeorge Syndrome
Catch 22 spectrum
Microdeletion long arm chromosome 22
AbN 3rd and 4th branchial arches
 Absent parathyroid,
 Absent thymus gland,
 Anomalies of aortic arch

APECED Syndrome (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal

Dystrophy Syndrome)
Autoimmune parathyroid gland failure
AbN AIRE (autoimmune regulator) gene on chrom 21
Triad of
 Adrenal insufficiency (Addison disease)
 Hypoparathyroidism
 Chronic mucocutaneous candidiasis
Associated with polyendocrinopathy: DM, hypogonadotrophic hypogonadism,
autoimmune thyroid disease
 Acquired hypoparathyroidism
Infiltration
Iron in Beta thalassaemia
Copper in Wilson’s disease

Surgery
Damage during thyroid surgery
Removal of gland for hyperparathyroidism

Irradiation
Hypoparathyroidism Pseudo- Pseudopseudo-
hypoparathyroidism hypoparathyroidism

Cause Cause
Deficiency PTH End organ resistance to
raised PTH
Autosomal dominant

Phenotype Phenotype Phenotype

Normal phenotype Abnormal phenotype- Abnormal phenotype
short stature, obesity,
intellectual delay, round
face, short neck,
shortened 4th and 5th
metacarpal
Lab findings Lab findings Lab findings
Low Ca2 Low Ca2 Normal
High PO4 High PO4
Low PTH High PTH
Pseudohypoparatyroidism type 1a –
Albright hereditary osteodystrophy
Management of Hypocalcemia

IV 10% Ca gluconate 0.2 ml/kg diluted 1:5 with

D5% over 10 minutes with ECG monitoring,
followed by IV infusion
Oral Ca supplements
Vitamin D for vitamin D deficiency
Analogue alfacalcidol for defect in vitamin D
metabolism, hypoparathyroidism, renal failure
 Investigations of disorder of
calcium metabolism
Ca2, PO4, Mg3
ALP, Alb
BUSE, Creatinine
Capillary pH
PTH
25-OHD
Urine Ca, PO4, creatinine, a.a, glucose
X-ray wrist and knee
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