Pathophysiol ogy of Calcium, Phosphate Homeostasis

Bone Structure Functions

Maintain, Support, Site of Muscle Attachment (Locomotion)

Protective for Vital Organs, Marrow

Metabolic (Reserve of Ions)(Especially Calcium, Phosphate)

(Maintain Serum Homeostasis)

Bone Structure

Bone Cells Matrix

Organic Inorganic

Osteoblast Collagen (95%) Calcium, Phosphate

Hydroxyapatite

(Ca10(PO4)6(OH)2)

Osteocytes Ground Substances (5%)

• Keratine Sulfate

• Chondroitin Sulfate

Osteoclasts

Anatomy

Bone Structure

Osteoblast (Bone Formation) Osteoclast (Bone Resorption)

3 Steps in Bone Formation Process

• Production of

Extracellular Organic Matrix

• Mineralization of Matrix

to form Bone

• Remodelling by

Resorption, Refor mation

Release Calcium into Systemic

Circulation

Actively unfixes the calcium

↑ Circulating Calcium Levels

Bone formation actively fixes

circulating calcium in its mineral form

(removing it from bloodstream)

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

Balance between

• Osteoclastic Resorption (of existing bone)

• Osteoblastic Formation (of new bone)

3 Major Influences on Equilibrium

• Mechanical Stress (Stimulating Osteoblastic Activity)

• Calcium, Phosphate level in ECF

• Hormones, Local Factors (Influencing Resorption, Formation)

Abnormalities

Serum Concentration of 2 Minerals (especially Calcium)

Serum Ca2+

Abnormally ↓ Abnormally ↑

Renal Failure Malignancy

Hypoparathyroidism 1° Hyperparathyroidism

Bone

Density

↓ ↑

Osteoporosis Paget’s Disease

Osteomalacia Osteopetrosis

Major Regulating Organ System

(Especially Parathyroid Gland, Kidney, GIT)

GIT

↓ Ca2+ Absorption ↑ Ca2+ Absorption

Malabsorptive Vitamin D Intoxication

Milk-Alkali Syndrome

Kidney

Fail to Excrete

Ca2+

Overexcrete

Ca2+

Underexcrete

Phosphorus

Overexcrete

Phosphorus

Hypercalcemic

disorders

Nephrolithiasis Renal Failure Renal Tubular

Disorders

Body Distribution of Calci um, Phosphate

Calcium Phosphate

Total Body Calcium (1kg)

• Bone, Teeth (99%)

• Blood, Body Fluids Intracellular

Calcium (1%)

Normal Plasma Calcium

• 2.2 – 2.6 mmol/L

Daily Recommended Intake (Adult)

• 1000 – 1500 mg

Ionized Ca2+ (Biologically Active)

Total Body Phosphate (700g)

• Bones, Teeth (85%)

• Soft Tissues (15%)

• ECF (0.1%)

Plasma Phosphate exists

• Inorganic Phosphate Ions

(HPO42-

, H2PO4-) (Largely)

• Bound to Proteins (10%)

• Freely Diffusible, Equilibrium with

Intracellular, Bone Phosphate

(Remainder)

Recommended Phosphate Intake

(Adult) – 700 mg

Distribution of Calcium in Body

Infants, Young Childre n

↑ Phosphate (influe nce of GH,

↑ Skeletal Growth Rate)

Neonates 1.2 – 2.8 mmol/L

< 7 y/o 1.3 – 1.8 mmol/L

< 15 y/o 0.8 – 1.3 mmol/L

Adult s 0.6 – 1.25 mmol/L

Importance

• Constituent of Cell Membranes

(affe ct permeability, electrical)

• ↓ Ca2+ in ECF

o ↑ Permeability

o ↑ Excitability of Cell Membrane (↓ Ca2+ in ECF - ↑ Excitabil ity of Nerve T issue,

Stimulate Muscle Contraction)

(Ca2+ - Coup ling Factor betwee n Excitation,

Contraction of Actomyosin)

• Influence Cardiac

Contractility, Automaticity

(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)

Importance

• Bones, Teeth

• Phospholipids (cell membranes)

• 1° Anions in ICF (Metabolism of

Proteins, Fats, Carbohydrates)

• Metabolic Processes (ATP)

• Muscle, Neurologic Function,

2,3-DPG in RBC

• Maintain Acid-Base balance

through action as Urinary Buffer

(Excrete ↑ Daily Acid Load)

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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, Phosphate Absorption, Excretion

3 Organs (Calcium, Phosphate) (Supply to Blood, Remove it from Blood)

Small Intestine

Bone

Kidney

Calcium

Absorption Excretion

1° in Duodenum

• 15 – 20% Absorption

• Duodenum > Jejunum > Ileum

• Adaptive changes

o ↓ Dietary Ca2+

o Age

o Pregnancy

o Lactation

Daily Filtered Load – 10gm

Filtered Calcium (98%) are

reabsorbed along renal tubule

2 General Mechanisms

• Active – Transcellular

• Passive – Paracellular

Reabsorption

(Proximal Tubule, Loop of Henle )

• Filtered Load (70%)

• Mostly Passive

• Inhibited by Furosemide

Mechanism of GI Ca2+ Absorption

• Active Transport across Cell

• Transcellular Transport

• Endocytosis, Exocytosis Ca

(CaBP Complex)

Distal Tubule Reabsorption

• Filtered Load (10%)

• Regulated

Stimulated Inhibited

PTH CT

Vitamin D

Thiazides

Absorption of Ca2+ from GIT

Phosphate (Pi)

Absorption Excretion

Greatest in Jejunum, Ileum

Less in Duodenum

Filtered (90%)

Proximal Tubule (90% Reabsorbed)

Active Passive

H2PO4- HPO4

2-

Distal Tubule (10% Reabsorbed)

Absorption is a Linear Function of

Dietary Pi Intake

Intestinal Absorption in 2 Routes

• Cellular mediated Active

Transport mechanism

• Diffusional Flux

(Paracellular Shunt Pathway)

Regulation

• Diet

• Calcitropic Hormones

↑ Excretion ↓ Excretion

PTH Vitamin D

CT

Regulation – Calcitropic Hormones

Increased Absorption

• Vitamin D

• PTH

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Major Mediators of Calcium, Phosphate Balance

Parathyroid Hormone

(PTH)

Calcitriol

(active form of Vit D3) Calcitonin

Role

• Stimulate Renal

Reabsorption of Ca2+

• Inhibit Renal

Reabsorption of

Phosphate

• Stimulate Bone

Resorption

• Inhibit Bone

Formation,

Mineralization

• Stimulate Calcitriol

Synthesis

Stimulates GI

Absorption of both

Calcium, Phosphate

Exact role Unknown

Does not seem to be

involved in homeostasis

of Calcium, Phosphate Stimulates Renal

Reabsorption of

Calcium, Phosphate

Hypercalcemia of

Hypermagnesemia

stimulates secretion Stimulates Bone

Resorption ↓ Plasma Calcium

(by ↓ Bone Resorption) Net Effect

• ↑ Serum Calcium

• ↑ Serum Phosphate

↑ Reabsorption of

Calcium, Phosphorus,

Magnesium

1° Function

Prevent Hypercalcemia

after ingestion of meal

Net Effect

• ↑ Serum Calcium

• ↓ 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 Phosphate Homeostasis

Hypocalcaemia Hypophosphatemia

Hypercalcaemia Hyperphosphatemia

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Hypercalcaemia

Etiologies of Hypercalcaemia

↑ GI Absorption ↑ Loss from Bone ↓ Bone

Mineralization

↓ Urinary

Excretion

Milk-Alkali

Syndrome

↑ Net Bone

Resorption

↑ PTH Thiazide

Diuretics Aluminium

Toxicity ↑ Calcitriol ↑ PTH

(Hyperparathyroidism)

↑ Calcitriol

Vitamin D Excess

(Excess Dietary

Intake,

Granulomatous

Diseases)

↑ PTH

Malignancy

(Osteolytic

Metastases, PTHrP

Secreting Tumour)

↑ PTH ↑ Bone Turnover

Hypophosphatemia Paget’s Disease

Hyperthyroidism

Hypercalcaemia

Serum Calcium Levels > 2.55 mmol/L

1% Prevalence in General Population

1 – 4% Prevalence in Hospital Population

Malignancy (common cause in Hospital Patient)

1° Hyperparathyroidism (commonest in General Population)

Causes

Hyperparathyroidism

1° Hyperparathyroidism

2° Hyperparathyroidism (Chronic Renal Failure, Vitamin D Malabsorption)

Malignancies

Solid Tumours without Bone Metastasis

(Squamous Cell Carcinoma of Lung, Head, Neck)

Solid Tumour with Bone Metastasis (Carcinoma of Breast)

Hematologic Malignancies (Multiple Myeloma, Acute Leukemia)

Abnormal Vitamin D Metabolism

Sarcoidosis

Tuberculosis

Endocrine

Hyperthyroidism

Adrenal Insufficiency

Prolonged Immobilization

Drugs

Thiazide Diuretics

Lithium

Vitamin A Intoxication

Vitamin D Intoxication

1,25 (OH)2D3 Intoxication

Milk-Alkali Syndrome

Signs, Symptoms (Consequences of Hypocalcaemia)

Cardiovascular

Hypertension

ECG Changes

Dysrhytmias

Neuromuscular

Generalized Muscle Weakness

Depressed Deep Tendon Refle xes

Metastatic Calcification in Soft Tissue

CNS

Impaired Concentration

Confusi on

Altered State of Consciousness

GIT

Polydipsia

Anorexia

Nausea, Vomiting

Weight Loss

Constipation

Renal

Polyuria

Nephrolithiasis

Nephrocalcinosis

Renal Failure

Skeletal

Bone Resorption

Formation of Bone Cysts

Subperiosteal Erosion of Lone Bone

Hypocalcaemia

Etiologies of Hypocalcaemia

↓ GI Absorp9on ↓ Bone Resorption

(↑ Mineralization)

↑ Urinary Excretion

Poor dietary intake of

Calcium

↓ PTH

(Hypoparathyroidism)

↓ PTH

(Thyroidectomy,

I131 Treatment,

Autoimmune

Hypoparathyroidism)

Impaired absorption

of Calcium

PTH Resistance

(Pseudohypoparathyroidism)

Vitamin D Deficiency

(Poor dietary Intake,

Malabsorption

Syndromes)

Vitamin D Deficiency

(↓ Calcitriol) PTH Resistance

Hungry Bones Syndrome Vitamin D Deficiency

(↓ Calcitriol) Osteoblastic Metastases

↓ Conversion of

Vitamin D → Calcitriol

(Liver Failure, Renal

Failure, ↓ PTH,

Hyperphosphatemia)

Hypocalcaemia

Serum Calcium Levels < 2.2 mmol/L (< 1.1 mmol/L Ionized Calcium)

Common finding (5 – 8% of Hospitalized Patients)

Majority due to ↓ Plasma Albumin (True Hypocalcemia is ↓ common)

Causes of Hypocalcaemia

↓ PTH

Hypoparathyroidism (Idiopathic, Surgical)

Hypomagnesemia

Abnormal Metabolism of Vitamin D

Deficiency (↓ Intake, ↓ Sunlight Exposure, Malabsorption Disease)

Impaired 25-Hydroxylation in Liver (Alcoholic Liver Disease)

Impaired Renal Hydroxylation (Chronic Liver Failure, Hypoparathyroidism,

Hypophosphatemic Ri ckets)

Impaired Response to 1,25 (OH ) 2D3 (Anticonvulstant Drugs)

Alkalosis, Hypoalbuminemia, Hyperphosphatemia, Acute Pancreatitis

Drugs (Chemotherapy, Phosphates, Loop Diuretics, Citrate-Buffered Blood,

Radiographic Contrast Media)

Signs, Symptoms (Consequences of Hypocalcaemia)

Cardiovascular

ECG Changes

Dysrhythmias

Neuromuscular

Paresthesias (Circumoral, Hands, Feet)

Hyperactive Reflexes

Tetany (Trousseu’s Sign, Chvostek’s Sign)

CNS

Altered Mood

Impaired Memory

Confusi on

Convulsive Seizures

GIT

Diarrhoea

Loose Stool

Malabsorption

Steatorrhea

Skin

Dry Skin

Scaly Skin

Dry Hair

Overview of Calcium Balance

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Hyperphosphatemia

Etiologies of Hyperphosphatemia

↑ GI Intake

Fleet’s Phospho-Soda

↓ Urinary Excretion

Renal Failure

↓ PTH (Hypoparathyroidism)

(Thyroidectomy, I131

Treatment for Graves Disease of Thyroid Cancer,

Autoimmune Hypoparathyroidism)

Cell Lysis

Rhabdomyolysis

Tumour Lysis Syndrome

Hyperphosphatemia

Serum Concentration of Inorganic Phosphorus > 1.5 mmol/L

May be a consequences of

• ↑ Intake of Pi

• ↓ Excretion of Pi

• Translocation of Pi (Tissue Breakdown → ECF)

Causes of Hyperphosphatemia

↓ Renal Phosphate Excretion

Renal Failure

Hypoparathyroidism

Endocrine Disorders (Acromegaly, Adrenal Insufficiency, Hyperthyroidism)

Biphosphonate Therapy

Redistribution ICF → ECF

Chemotherapy for Neoplasm

Respiratory, Metabolic Acidosis

Rhabdomyolysis

Hemolysis

↑ Intake, Intestinal Absorption

Excess use of Phosphate (containing Laxatives, Enemas)

IV Phosphate

Vitamin D Intoxication (Vitamin D Medication, Sarcoidosis, Tuberculosis)

Signs, Symptoms

Hypocalcemia, Tetany

Important Short-Term Consequence s

Due to ↑ Pi load from any source (Exogenous, Endogenous)

Soft Tissue Calcification, 2° Hyperparathyroidism

Long Term Conseque nces

Due to Renal Insufficiency, ↓ Renal Pi Excretion

Overview of Phosphate Balance

Hypophosphatemia

Etiologies of Hypophosphatemia

↓ GI Absorption

↓ Dietary Intake (Rare in Isolation)

Diarrhoea, Malabsorption

Phosphate Binders (Calcium Acetate, Al, Mg containing Antacids)

↓ Bone Resorption (↑ Bone Mineralization)

Vitamin D Deficiency,↓ Calcitriol

Hungry Bones Syndrome

Osteoblastic Metastases

↑ Urinary Excre9on

↑ PTH (as in 1° Hyperparathyroidism)

Vitamin D Deficiency, ↓ Calcitriol

Fanconi Syndrome

Internal Redistribution (Due to Acute Stimulation of Glycolysis)

Refeeding Syndrome (Starvation, Anorexia, Alcoholism)

During Treatment for DKA

Hypophosphatemia

Serum Phosphate Level < 0.6 mmol/L

Unusual unless there is

• ↓ Oral Intake

• Shift of Phosphate from ECF into Cells/ Bone

• Excessive Renal Loss of Phosphate

Causes of Hypophosphatemia

↓ Intake, Intestinal Absorption

Deficiency of Dietary Phosphate

Antacid Abuse

Malabsorption States

Vitamin D Deficiency

Shift from ECF into Cells, Bones

Respiratory Alkalosis

Total Parenteral Nutrition (TPN)

Diabetic Ketoacidosis

Glucose, Insulin Infusion

Severe Burns

↑ Urinary Loss

Hyperparathyroidism

Renal Tubular Disorders

Signs, Symptoms

Hematologic

Red Blood Cell Dysfunction

Hemolysis

Leucocyte Dysfunction

Platelet Dysfunction

Muscle

Weakness

Rhabdomyolysis

Skeletal

Osteomalacia, Rickets

CNS

Irritability

Paresthesias

Dysarthria

Confusi on

Seizures

Coma

Renal

↑ Ca2+, HCO3, Mg2+ Excretion

↑ 1,25 (OH)2D3 Synthesis

Metabolic Acidosis

Respiratory Insufficiency

Respiratory Acidosis

Hypoxia

Cardiomyopathy

↓ Cardiac Output

Hypotension

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