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Pathophysiol ogy of Calcium, Phosphate Homeostasis

Bone Structure Functions Abnormalities

Maintain, Support, Site of Muscle Attachment (Locomotion ) Serum Concentration of 2 Minerals (especially Calcium)
Protective for Vital Organs, Marrow Serum Ca2+
Metabolic (Reserve of Ions)(Especially Calcium, Phosp hate) Abnormally ↓ Abnormally ↑
(Maintain Serum Homeostasis) Renal Failure Malignancy
Hypoparathyroidism 1° Hyperparathyroidism
Bone Structure Bone
Matrix Density
Bone Cells
Organic Inorganic ↓ ↑
Osteoblast Collagen (95%) Calcium, Phosp hate Osteoporosis Paget’s Disease
Osteocytes Ground Substances (5%) Hydroxyapatite Osteomalacia Osteopetrosis
Osteoclasts • Keratine Sulfate (Ca10 (PO4 )6 (OH)2 ) Major Regulating Organ System
• Chondroitin Sulfate (Especially Parathyroid Gland, Kidney, GIT)
GIT
Anatomy ↓ Ca2+ Absorption ↑ Ca2+ Absorption
Malabsorptive Vitamin D Intoxication
Milk-Alkali Syndrome
Kidney
Fail to Excrete Overexcrete Underexcrete Overexcrete
Ca2+ Ca2+ Phosphorus Phosphorus
Hypercalcemic Nephrolithiasis Renal Failure Renal Tubular
disorders Disorders

Body Distribution of Calci um, Phosphate

Calcium Phosphate
Total Body Calcium (1kg) Total Body Phosphate (700g)
• Bone, Teeth (99%) • Bones, Teeth (85%)
• Blood, Body Fluids Intracellular • Soft Tissues (15%)
Calcium (1%) • ECF (0.1%)
Normal Plasma Calcium Plasma Phosphate exists
• 2.2 – 2.6 mmol/L • Inorganic Phosphate Ions
Bone Structure Daily Recommended Intake (Adult) (HPO4 2- , H2 PO4- ) (Largely)
Osteoblast (Bone Formation) Osteoclast (Bone Resorption) • 1000 – 1500 mg • Bound to Proteins (10%)
Ionized Ca2+ (Biologically Active) • Freely Diffusible, Equilibrium with
3 Steps in Bone Formation Process Release Calcium into Systemic
Circulation Distribution of Calcium in Body Intracellular, Bone Phosphate
• Production of
Extracellular Organic Matrix Actively unfixes the calcium (Remainder)
Recommended Ph osphate Intake
• Mineralization of Matrix ↑ Circulating Calcium Levels
(Adult) – 700 mg
to form Bone
Infants, Young Childre n
• Remodelling by
↑ Phosphate (influe nce of GH,
Resorption, Refor mation
↑ Skeletal Growth Rate)
Bone formation actively fixes
Neonates 1.2 – 2.8 mmol/L
circulating calcium in its mineral form < 7 y/o 1.3 – 1.8 mmol/L
(removing it from bloodstream) < 15 y/o 0.8 – 1.3 mmol/L
Adult s 0.6 – 1.25 mmol/L

Peak Bone Mass Schematic Representation

Crossover of Formation/ Resorption occurs during 4th Decade
In Osteoporosis, Accelerated Loss of Bone (↑ Resorption, ↓ Formation)
Equilibrium of Bone Tissue Importance Importance
Balance between
• Constituent of Cell Membranes • Bones, Teeth
• Osteoclastic Resorption (of existing bone) (affe ct permeability, electrical) • Phospholipids (cell membranes )
• Osteoblastic Formation (of new bone) • ↓ Ca2+ in ECF • 1° Anions in ICF (Metabolism of
3 Major Influences on Equilibrium o ↑ Permeability Proteins, Fats, Carbohydrates)
• Mechanical Stress (Stimulating Osteoblastic Activity) o ↑ Excitability of Cell Membrane • Metabolic Processes (ATP)
• Calcium, Phosp hate level in ECF (↓ Ca2+ i n ECF - ↑ Excitabil ity of Nerve T issue, • Muscle, Neurologic Function,
• Hormones, Local Factors (Influencing Res orption, Formation) Stimulate Muscle Contraction)
(Ca2+ - Coup ling Factor betwee n Excitation, 2,3-DPG in RBC
Contraction of Actomyosin) • Maintain Acid-Base balance
• Influence Cardiac through action as Urinary Buffer
Contractility, Automaticity (Excrete ↑ Daily Acid Load)
(via Slow Ca2+ channels in Heart)
• Release of Preformed Hormones in
Endocrine Cells, Release of ACh at
Neuromuscular Junctions
• MOA of Hormones within Cells
(cyclic AMP, cAMP)
2° intracellular messenger
• Adhesive
(Enzyme, Blood Coagulation)
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Homeostasis (Balance between Input, Output from ECF )

Ca, P Input Ca, P Output
Amount Ingested Amount Secreted into GIT
Amount Mobilized from Skeletal Pool Urinary Excretion
Deposition in Bone
Balance of Bone Formation, Bone Resorption
Calcium, Phosp hate Absorption, Excretion

3 Organs (Calcium, Ph osphate) (Sup ply to Blood, Remove it from Blood )

Small Intestine
Bone
Kidney

Calcium Phosphate (Pi)

Absorption Excretion Absorption Excretion
1° in Duodenum Daily Filtered Load – 10gm Greatest in Jejunum, Ileum Filtered (90%)
• 15 – 20% Absorption Filtered Calcium (98%) are Less in Duodenu m Proximal Tubule (90% Reabsorbed )
• Duodenum > Jejunum > Ileum reabsorbed along renal tubule Absorption is a Linear Function of Active Passive
• Adaptive changes 2 General Mechanisms Dietary Pi Intake H2 PO4 - HPO4 2-
o ↓ Dietary Ca2+ • Active – Transcellular Intestinal Absorption in 2 Routes Distal Tubule (10% Reabsorbed)
o Age • Passive – Paracellular • Cellular mediated Active Regulation
o Pregnancy Reabsorption Transport mechanism • Diet
o Lactation (Proximal Tubule, Loop of Henle ) • Diffusional Flux • Calcitropic Hormones
Mechanism of GI Ca2+ Absorption • Filtered Load (70%) (Paracellular Shunt Pathway) ↑ Excretion ↓ Excretion
• Active Transport across Cell • Mostly Passive Regulation – Calcitropic Hormones PTH Vitamin D
• Transcellular Transport • Inhibited by Furosemide Increased Absorption CT
• Endocytosis, Exocytosis Ca Distal Tubule Reabsorption • Vitamin D
(CaBP Complex) • Filtered Load (10%) • PTH
Absorption of Ca2+ from GIT • Regulated
Stimulated Inhibited
PTH CT
Vitamin D
Thiazides
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Major Mediators of Calcium, Phosphate Balance

Parathyroid Hormone Calcitriol
Calcitonin
(PTH) (active form of Vit D3)
Role Stimulates GI Exact role Unknown
• Stimulate Renal Absorption of both Does not seem to be
Reabsorption of Ca2+ Calcium, Phosp hate involved in homeostasis
• Inhibit Renal Stimulates Renal of Calcium, Ph osphate
Reabsorption of Reabsorption of Hypercalcemia of
Phosphate Calcium, Phosp hate Hypermagnesemia
• Stimulate Bone Stimulates Bone stimulates secretion
Resorption Resorption ↓ Plasma Calcium
• Inhibit Bone Net Effect (by ↓ Bone Resorption )
Formation, • ↑ Serum Calcium ↑ Reabsorption of
Mineralization • ↑ Serum Phosphate Calcium, Phosp horus,
• Stimulate Calcitriol Magnesium
Synthesis 1° Function
Net Effect Prevent Hypercalcemia
• ↑ Serum Calcium after ingestion of meal
• ↓ Serum Phosphate
Regulation
• ↓ Serum [Ca2+]
(↑ PTH Secretion)
• ↑ Serum [Ca2+]
(↓ PTH Secretion)

Overview of Calcium-Phosphate Regulation

Disruption of Homeostasis
Failure to achieve, restore homeostasis (result in death)
• Injury
• Illness
• Disease
Disruption of Ca2+ Homeostasis Disruption of Phos phate Homeostasis
Hypocalcaemia Hypophosphatemia
Hypercalcaemia Hyperphosphatemia
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Hypercalcaemia Hypocalcaemia

Etiologies of Hypercalcaemia Etiologies of Hypocalcaemia

↓ Bone ↓ Urinary ↓ GI AbsorpƟon ↓ Bone Resorption ↑ Urinary Excretion
↑ GI Absorption ↑ Loss from Bone
Mineralization Excretion (↑ Mineralization)
Milk-Alkali ↑ Net Bone ↑ PTH Thiazide Poor dietary intake of ↓ PTH ↓ PTH
Syndrome Resorption Aluminium Diuretics Calcium (Hypoparathyroidism) (Thyroidectomy,
↑ Calcitriol ↑ PTH Toxicity ↑ Calcitriol Impaired absorption PTH Resistance I131 Treatment,
Vitamin D Excess (Hyperparathyroidism) ↑ PTH of Calcium (Pseudohyp oparathyroidism) Autoimmune
(Excess Dietary Malignancy Vitamin D Deficiency Vitamin D Deficiency Hypoparathyroidism)
Intake, (Osteolytic (Poor dietary Intake, (↓ Calcitriol) PTH Resistance
Granulomatous Metastases, PTHrP Malabsorption Hungry Bones Syndrome Vitamin D Deficiency
Diseases) Secreting Tumour) Syndromes) Osteoblastic Metastases (↓ Calcitriol)
↑ PTH ↑ Bone Turnover ↓ Conversion of
Hypophosphatemia Paget’s Disease Vitamin D → Calcitriol
Hyperthyroidism (Liver Failure, Renal
Failure, ↓ PTH,
Hypercalcaemia Hyperphosphatemia)
Serum Calcium Levels > 2.55 mmol/L
1% Prevalence in General Population Hypocalcaemia
1 – 4% Prevalence in Hospital Population Serum Calcium Levels < 2.2 mmol/L (< 1.1 mmol/L Ionized Calcium)
Malignancy (common cause in Hospital Patient) Common finding (5 – 8% of Hospitalized Patients)
1° Hyperparathyroidism (commonest in General Population) Majority due to ↓ Plasma Albumin (True Hypocalcemia is ↓ common)

Causes Causes of Hypocalcaemia

Hyperparathyroidism ↓ PTH
1° Hyperparathyroidism Hypoparathyroidism (Idiopathic, Surgical)
2° Hyperparathyroidism (Chronic Renal Failure, Vitamin D Malabsorption) Hypomagnesemia
Malignancies Abnormal Metabolism of Vitamin D
Solid Tumours without Bone Metastasis Deficiency (↓ Intake, ↓ Sunlight Exposure, Malabsorption Disease)
(Squamous Cell Carcinoma of Lu ng, Head, Neck) Impaired 25-Hydroxylation in Liver (Alcoholic Liver Disease)
Solid Tumour with Bone Metastasis (Carcinoma of Breast) Impaired Renal Hydroxylation (Chronic Liver Failure, Hypoparathyroidism,
Hematologic Malignancies (Multiple Myeloma, Acute Leukemia) Hypophosphatemic Ri ckets)
Abnormal Vitamin D Metabolism Impaired Response to 1,25 (OH ) 2 D3 (Anticonvulstant Drugs)
Sarcoidosis Alkalosis, Hypoalbuminemia, Hyperphosphatemia, Acute Pancreatitis
Tuberculosis Drugs (Chemotherapy, Phosphates, Loop Diuretics, Citrate-Buffered Blood,
Endocrine Radiographic Contrast Media)
Hyperthyroidism
Adrenal Insufficiency Signs, Symptoms (Consequences of Hypocalcaemia)
Prolonged Immobilization Cardiovascular
Drugs ECG Changes
Thiazide Diuretics Dysrhythmias
Lithium Neuromuscular
Vitamin A Intoxication Paresthesias (Circumoral, Hands, Feet)
Vitamin D Intoxication Hyperactive Reflexes
1,25 (OH)2 D3 Intoxication Tetany (Trousseu’s Sign, Chvostek’s Sign)
Milk-Alkali Syndrome CNS
Altered Mood
Signs, Symptoms (Consequences of Hypocalcaemia) Impaired Memory
Cardiovascular Confusi on
Hypertension Convulsive Seizures
ECG Changes GIT
Dysrhytmias Diarrhoea
Neuromuscular Loose Stool
Generalized Muscle Weakness Malabsorption
Depressed Deep Tendon Refle xes Steatorrhea
Metastatic Calcification in Soft Tissue Skin
CNS Dry Skin
Impaired Concentration Scaly Skin
Confusi on Dry Hair
Altered State of Consciousness
GIT
Polydipsia
Anorexia
Nausea, Vomiting Overview of Calcium Balance
Weight Loss
Constipation
Renal
Polyuria
Nephrolithiasis
Nephrocalcinosis
Renal Failure
Skeletal
Bone Resorption
Formation of Bone Cysts
Subperiosteal Erosion of Lone Bone
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Hyperphosphatemia Hypophosphatemia

Etiologies of Hyperphosphatemia Etiologies of Hypophosphatemia

↑ GI Intake ↓ GI Absorption
Fleet’s Phospho-Soda ↓ Dietary Intake (Rare in Isolation)
↓ Urinary Excretion Diarrhoea, Malabsorption
Renal Failure Phosphate Binders (Calciu m Acetate, Al, Mg containing Antacids)
↓ PTH (Hypoparathyroidism) ↓ Bone Resorption (↑ Bone Mineralization)
(Thyroidectomy, I131 Treatment for Graves Disease of Thyroid Cancer, Vitamin D Deficiency,↓ Calcitriol
Autoimmune Hypoparathyroidism) Hungry Bones Syndrome
Cell Lysis Osteoblastic Metastases
Rhabdomyolysis ↑ Urinary ExcreƟon
Tumour Lysis Syndrome ↑ PTH (as in 1° Hyperparathyroidism)
Vitamin D Deficiency, ↓ Calcitriol
Hyperphosphatemia Fanconi Syndrome
Serum Concentration of Inorganic Phos phorus > 1.5 mmol/L Internal Redistribution (Due to Acute Stimulation of Glycolysis)
May be a consequences of Refeeding Syndrome (Starvation, Anorexia, Alcoholism)
• ↑ Intake of Pi During Treatment for DKA
• ↓ Excretion of Pi
• Translocation of Pi (Tissue Breakdown → ECF) Hypophosphatemia
Serum Phosphate Level < 0.6 mmol/L
Causes of Hyperphos phatemia Unusual unless there is
↓ Renal Phosphate Excretion • ↓ Oral Intake
Renal Failure • Shift of Phosphate from ECF into Cells/ Bone
Hypoparathyroidism • Excessive Renal Loss of Phosphate
Endocrine Disorders (Acromegaly, Adrenal Insufficiency, Hyperthyroidism)
Biphosph onate Therapy Causes of Hypophosphatemia
Redistribution ICF → ECF ↓ Intake, Intestinal Absorption
Chemotherapy for Neoplasm Deficiency of Dietary Phosphate
Respiratory, Metabolic Acidosis Antacid Abuse
Rhabdomyolysis Malabsorption States
Hemolysis Vitamin D Deficiency
↑ Intake, Intestinal Absorption Shift from ECF into Cells, Bones
Excess use of Phosphate (containing Laxatives, Enemas) Respiratory Alkalosis
IV Phosphate Total Parenteral Nutrition (TPN)
Vitamin D Intoxication (Vitamin D Medication, Sarcoidosis, Tuberculosis) Diabetic Ketoacidosis
Glucose, Insulin Infusion
Signs, Symptoms Severe Burns
Hypocalcemia, Tetany ↑ Urinary Loss
Important Short-Term Consequence s Hyperparathyroidism
Due to ↑ Pi load from any source (Exogenous, En dogenous ) Renal Tubular Disorders
Soft Tissue Calcification, 2° Hyperparathyroidism
Long Term Conseque nces Signs, Symptoms
Due to Renal Insufficien cy, ↓ Renal Pi Excretion Hematologic
Red Blood Cell Dysfun ction
Hemolysis
Leucocyte Dysfunction
Platelet Dysfunction
Overview of Phosphate Balance Muscle
Weakness
Rhabdomyolysis
Skeletal
Osteomalacia, Rickets
CNS
Irritability
Paresthesias
Dysarthria
Confusi on
Seizures
Coma
Renal
↑ Ca2+, HCO3, Mg2+ Excretion
↑ 1,25 (OH)2 D3 Synthesis
Metabolic Acidosis
Respiratory Insufficiency
Respiratory Acidosis
Hypoxia
Cardiomyopathy
↓ Cardiac Output
Hypotension