physiology, pathology and Diagnosis

1. Dr. IFTHAQAR. H. F

2. CALCIUM METABOLISM
Dr. IFTHAQAR. H. F

3. 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 .

4. 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%

5. DISTRIBUTION OF CALCIUM

6. 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.

7. 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

8. 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

9. CALCIUM HOMEOSTASIS
Three hormones
 –PTH
 –1,25 (OH)2 CC
 –Calcitonin
Three target organs
 –Bone
 –Gut
 –Kidney
Three bone cells
 –Osteoblasts
 –Osteocytes
 –Osteoclasts

12. 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

13. CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS

15. CALCIUM LEVELS ARE AFFECTED BY:
 Albumin
 Blood pH
 Serum phosphate
 Serum magnesium
 Serum bicarbonate

16. HYPOCALCEMIA
Dr. IFTHAQAR. H. F

17.  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.

18. 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

19.  Late neonatal hypocalcemia
Exogenous phosphate load
Phosphate-rich formulas / cow’s milk
Magnesium deficiency
Transient hypoparathyroidism of newborn
Congenital Hypoparathyroidism

20. CAUSES OF HYPOCALCEMIA
In childhood:
 Vitamin D deficiency.
 Hypoparathyroidism.
 PTH resistance – Pseudohypoparathyroidism.
 Autoimmune parathyroiditis
 Mitochondrial DNA mutations.
 Hypomagnesaemia

21. OTHER CAUSES
 Malabsorption syndromes.
 Hyperphosphatemia.
 Alkalosis.
 Pancreatitis.
 Pseudohypocalcemia (ie, hypoalbuminemia)
 Hungry bones syndrome

22. SYMPTOMS AND SIGNS OF HYPOCALCEMIA
Neuromuscular irritability
Paresthesias
Laryngospasm / Bronchospasm
Tetany
Seizures (focal, petit mal, grand mal)

23. Muscle cramps
Muscle weakness
 Chvostek sign
Trousseau sign
 Prolonged QT interval(>0.4sec) on ECG

25.  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.

26. APROACH
HISTORY THAT SUGGESTS HYPOCALCEMIA
Newborns (can be unspecific)
 Asymptomatic
 Lethargy
 Poor feeding
 Vomiting
 Abdominal distention
 Children
 Seizures
 Twitching
 Tingling & numbness of fingers
 Cramping
 Laryngospasm

27. WORKUP - BLOOD
Total and ionized serum calcium levels
 Serum magnesium levels
Phosphorus levels.
 Parathormone levels. (PTH challenge)
 Serum electrolyte and glucose levels

28.  Vitamin D metabolite (25-hydroxyvitamin D and
1,25-dihydroxyvitamin D) levels
 Serum alkaline phosphatase levels
 Urine calcium, magnesium, phosphorus, and
creatinine levels
 RFT

29. WORKUP - IMAGING
Chest X Ray.
Ankle and wrist X Ray.
Other:
 ECG
 Malabsorption workup
 Karyotyping (22q11 & 10p13 deletion)
 Family screening

30. 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

31. TREATMENT OF HYPOCALCAEMIA
Symptomatic 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]

32.  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.

33. HYPERCALCEMIA
Dr. IFTHAQAR. H. F

34.  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)

36. 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.

37. 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.

38. 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.

40. CLINICAL MANIFESTATIONS:
HISTORY:
 muscular weakness,
 fatigue,
 headache, anorexia,
 abdominal pain,
 nausea, vomiting,
 constipation,
 polydipsia, polyuria,
 loss of weight, and fever

41. SAYING:
“painful bones, renal stones,
abdominal groans, psychic
moans, and
neuropsychiatric
overtones”

43. 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

44. 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

45.  Primary hyperparathyroidism : PTH↑
MALIGNANCY :
1.solid tumors(humoral hypercalcemia) :PTHrP↑ ,
PTH↓
2.Multiple myeloma and breast cancer(osteolytic
hypercalcemia ) : alkaline phosphatase ↑, PTH↓

47.  Granulomatous(sarcoidosis, tuberculosis,
Hodgkin's lymphoma) :
calcitriol (1,25-OH vitamin D3 ) ↑, PTH↓
 Familial hypocalciuric hypercalcemia :
24-hour urinary calcium ↓, PTH ↑

48. 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

50. 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

51. • 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

52.  Glucocorticoids :
Inhibits vitamin D conversionto calcitriol
Hydrocortisone, 200 mg IV daily for 3 days
 Hemodialysis :
used in patients with renal failure

53. 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

54. 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