By

Amr S. Moustafa, M.D., Ph.D.

Ass. Prof. & ConsultantClinical Biochemistry & Molecular Biology

College of Medicine and Obesity Research CenterKing Saud University

Calcium Homeostasis -II

Objectives:Physiological importance of calcium

Distribution and forms of calcium

Regulation of blood level of calcium

Measurement of calcium level

Clinical problems: Hypo- and hyper-calcemia

Calcium: Physiological importance

Neuromuscular excitability

Blood coagulation

Mineralization of bones

Release of hormones & neurotransmitters

Intracellular actions of some hormones

Distribution and Forms of Calcium

One Kg of calcium in human body

99% in bone (mainly, hydroxyapatite crystals)

1% in blood and ECF

45% Free, ionized form

40% Bound to protein (mostly albumin)

15% Bound to HCO3-, PO4

-, citrate, lactate

Regulation of Blood Level of Calcium

Parathyroid hormone (PTH)

Calcitriol: Active form of vitamin D

? Calcitonin

Calcium Homeostasis: PTH & Calcitriol

Response to low blood calcium

Reference Ranges:

Serum ionized calcium: Child (< 12 years): 1.20 – 1.38 mmol/LAdult: 1.16 – 1.32

Serum total calcium:Child (< 12 years): 2.20 – 2.7 mmol/LAdult: 2.15 – 2.5

Hypocalcemia: Primary hypoparathyroidism Pseudohypoparathyroidism Hypo- / hyper-magnesemia Hypoalbuminemia Acute pancreatitis Secondary hyperparathyroidism

Vitamin D deficiency

Renal disease Rhabdomyolysis

Hypocalcemia: 1. Primary hypoparathyroidism

Parathyroid gland:Aplasia, destruction or removal

PTH: Undetectable

Increased calcium excretion

Decreased activation of vitamin D:More hypocalcemia

Hypocalcemia: 2. Pseudohypoparathyroidism

Rare hereditary disorder PTH target tissue response: Decreased

Decreased Ca Normal PTH secretion No increase of cAMP

Common physical features:Short stature

Obesity

Short metacarpals and metatarsals

Abnormal calcification

Hypocalcemia: 3. Hypomagnesemia

More frequent in hospitalized patients

Mechanisms: Decreases PTH secretion

Impairs PTH actions on bone receptors

Vitamin D resistance

Hypocalcemia: 4. Hypermagnesemia

More frequent in nursing homes patientsRenal problems

Mg-containing medications:

Antacids, laxatives, enemas Mechanisms:

Decreases PTH secretion

Impairs PTH actions on bone receptors

Hypocalcemia: 5. Hypoalbuminemia

Low total calcium (but not ionized Ca2+)

1.0 g/dL S. albumin 0.2 mmol/L total calcium

Causes:

Chronic liver disease

Nephrotic syndrome

Malnutrition

Hypocalcemia: 6. Acute Pancreatitis

Intestinal lipase activity

Intestinal FFAs and bound calcium

Hypocalcemia: 7. Secondary Hyperparathyroidism

Vitamin D deficiency and malabsorption:

Ca absorption and PTH secretion

Chronic renal disease:

Altered albumin, Mg2+, PO4 and pH

PO4 binds and lowers ionized Ca2+

Mg2+ impairs PTH secretion and action

Altered vitamin D metabolism

Renal osteodystrophy

Hypocalcemia: 8. Rhabdomyolysis

Major crush injury and muscle damage

PO4 release from cells

binds and lowers ionized Ca2+

Neonatal Hypocalcemia

Abnormal PTH and vitamin D metabolism Hyperphosphatemia Hypomagnesemia Hypercholestrolemia

Hypocalcemia: Symptoms

Neuromuscular irritability

Parasethesia, muscle cramps, tetany

Seizures Cardiac irregularities

Arrhythmias

Heart block

Hypocalcemia: Total calcium < 1.88 mmol/L

Hypocalcemia: Laboratory Diagnosis

Total and ionized blood calcium level Serum phosphorus and magnesium Serum alkaline phosphatase Serum PTH level Serum 25 hydroxycholicaciferol Renal function tests Serum albumin Labs for etiological diagnosis

Hypocalcemia: Treatment

Oral or parenteral calcium

Slow I.V. calcium injection

Vitamin D

Magnesium (with associated hypomagnesemia)

Hypercalcemia:

Primary hyperparathyroidism

Hyperplasia or adenoma

Malignancy

Benign familial hypocalciuria

Thiazide diuretics

Prolonged immobilization

Hypercalcemia: 1. Primary hyperparathyroidism

Increased PTH blood level Adenoma (80%), Hyperplasia (19%) Older women Clinical signs or asymptomatic Increase total and/or ionized calcium Decreased serum phosphorus

(Compare Lab results with secondary hyperparathyroidism)

Hypercalcemia: 2. Malignancy

PTH-related peptide secreting tumors

Binds to PTH receptors hypercalcemia

Specific assays for PTH-rP

Not detected by PTH assays

e.g., Squamous cell carcinoma of lung Osteolytic metastases Severe hypercalcemia and low PTH:

Exclude malignancy

Hypercalcemia: 3. Other Causes

Thiazide diuretics: Calcium reabsorption

Prolonged immobilization: Bone resorption

Rare, benign, familial hypocalciuria

Hyperthyroidism

Hypercalcemia: Symptoms Mild (2.6 – 3.0 mmol/L): Asymptomatic

Neurologic: Drowsiness, lethargy & coma

G.I.: Constipation, nausia, vomiting & peptic ulcer

Renal: Nephrolithiasis (nephrocalcinosis)

Nephrogenic diabetes insipidus:

Polyuria & hypovolemia: Hypercalcemia

Hypercalcemia: Laboratory Diagnosis

Total and ionized blood calcium level Serum phosphorus Serum alkaline phosphatase Serum PTH level and PTH-rP Serum 25 hydroxycholicaciferol Renal function tests Labs for etiological diagnosis

Hypercalcemia: Treatment

Estrogen-replacement: Postmenopausal woman

Surgical: Parathyroidectomy

Measure to reduce blood calcium level:Salt and water intake: Calcium excretion

Bisphosphanates: Bone resorption

Discontinue thiazide diuretics