pathophysiology of calcium

8/6/2019 Pathophysiology of Calcium

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a op ys o ogy o a c um, osp a e omeos as s

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 CellsMatrix

Organic Inorganic

Osteoblast Collagen (95%) Calcium, Phosphate

Hydroxyapatite

(Ca10(PO4)6(OH)2)

Osteocytes Ground Substances (5%)

y Keratine Sulfatey Chondroitin Sulfate

Osteoclasts

Anatomy

Bone Structure

Osteoblast (Bone Formation) Osteoclast (Bone Resorption)

3 Steps in Bone Formation Process

y Production ofExtracellular Organic Matrix

y Mineralization of Matrixto form Bone

y Remodelling byResorption, Reformation

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

y Osteoclastic Resorption (of existing bone)y Osteoblastic Formation (of new bone)3 Major Influences on Equilibrium

y Mechanical Stress (Stimulating Osteoblastic Activity)y Calcium, Phosphate level in ECFy 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 Pagets 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

Nephrolithias is Renal Failure Renal Tubular

Disorders

Body Distribution of Calcium, Phosphate

Calcium Phosphate

Total Body Calcium (1kg)

y Bone, Teeth (99%)y Blood, Body Fluids Intracellular

Calcium (1%)Normal Plasma Calcium

y 2.2 2.6 mmol/LDaily Recommended Intake (Adult)

y 1000 1500 mgIonized Ca2+ (Biologically Active)

Total Body Phosphate (700g)

y Bones, Teeth (85%)y Soft Tissues (15%)y ECF (0.1%)Plasma Phosphate exists

y Inorganic Phosphate Ions(HPO4

2-, H2PO4

-) (Largely)

y Bound to Proteins (10%)y Freely Diffusible, Equilibrium with

Intracellular, Bone Phosphate

(Remainder)

Recommended Phosphate Intake

(Adult) 700 mg

Distribution of Calcium in Body

Infants, Young Children

Phosphate (influence 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

Adults 0.6 1.25 mmol/L

Importance

y Constituent of Cell Membranes(affect permeability, electrical)

y Ca2+ in ECFo Permeabilityo Excitability of Cell Membrane

( Ca2+ in ECF - Excitability of Nerve Tissue,

Stimulate Muscle Contraction)

(Ca2+ - Coupling Factor between Excitation,

Contraction of Actomyosin)

y Influence CardiacContractility, Automaticity

(via Slow Ca2+ channels in Heart)

y Release of Preformed Hormones inEndocrine Cells, Release of ACh at

Neuromuscular Junctions

y MOA of Hormones within Cells(cyclic AMP, cAMP)

2 intracellular messenger

y Adhesive(Enzyme, Blood Coagulation)

Importance

y Bones, Teethy Phospholipids (cell membranes)y 1 Anions in ICF (Metabolism of

Proteins, Fats, Carbohydrates)

y Metabolic Processes (ATP)y Muscle, Neurologic Function,

2,3-DPG in RBC

y Maintain Acid-Base balancethrough 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

y 15 20% Absorptiony Duodenum > Jejunum > Ileumy Adaptive changes

o Dietary Ca2+oAgeoPregnancyoLactation

Daily Filtered Load 10gm

Filtered Calcium (98%) are

reabsorbed along renal tubule

2 General Mechanisms

y Active Transcellulary Passive ParacellularReabsorption

(Proximal Tubule, Loop of Henle)

y Filtered Load (70%)y Mostly Passivey Inhibited by Furosemide

Mechanism of GI Ca2+ Absorption

y Active Transport across Celly Transcellular Transporty Endocytosis, Exocytosis Ca

(CaBP Complex)Distal Tubule Reabsorption

y Filtered Load (10%)y 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-

HPO42-

Distal Tubule (10% Reabsorbed)

Absorption is a Linear Function of

Dietary Pi Intake

Intestinal Absorption in 2 Routes

y Cellular mediated ActiveTransport mechanism

y Diffusional Flux(Paracellular Shunt Pathway)

Regulation

y Diety Calcitropic Hormones

Excretion Excretion

PTH Vitamin D

CT

Regulation Calcitropic Hormones

Increased Absorption

y Vitamin Dy PTH


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Major Mediators of Calcium, Phosphate Balance

Parathyroid Hormone

(PTH)

Calcitriol

(active form of Vit D3)Calcitonin

Role

y Stimulate RenalReabsorption of Ca2+

y Inhibit RenalReabsorption of

Phosphate

y Stimulate BoneResorption

y Inhibit BoneFormation,

Mineralizationy Stimulate Calcitriol

Synthesis

Stimulates GI

Absorption of both

Calcium, Phosphate

Exact role Unknown

Does not seem to be

involved in homeostasis

of Calcium, PhosphateStimulates Renal

Reabsorption of

Calcium, Phosphate

Hypercalcemia of

Hypermagnesemia

stimulates secretionStimulates Bone

Resorption Plasma Calcium

(by Bone Resorption)Net Effect

y Serum Calciumy Serum Phosphate

Reabsorption of

Calcium, Phosphorus,Magnesium

1 Function

Prevent Hypercalcemia

after ingestion of meal

Net Effect

y Serum Calciumy Serum PhosphateRegulation

y Serum [Ca2+]( PTH Secretion)

y Serum [Ca2+]( PTH Secretion)

Overview of Calcium-Phosphate Regulation

Disruption of Homeostasis

Failure to achieve, restore homeostasis (result in death)

y Injuryy

Illnessy Disease

Disruption of Ca2+ Homeostasis Disruption of Phosphate Homeostasis

Hypocalcaemia Hypophosphatemia

Hypercalcaemia Hyperphosphatemia


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Etiologies of Hypercalcaemia

GIAbsorption Loss from Bone Bone

Mineralization

Urinary

Excretion

Milk-Alkali

Syndrome

Net Bone

Resorption

PTH Thiazide

DiureticsAluminium

Toxicity Calcitriol PTH

(Hyperparathyroidism)

Calcitriol

Vitamin D Excess

(Excess Dietary

Intake,

Granulomatous

Diseases)

PTH

Malignancy

(Osteolytic

Metastases, PTHrP

Secreting Tumour)

PTH Bone Turnover

Hypophosphatemia Pagets DiseaseHyperthyroidism

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 Reflexes

Metastatic Calcification in Soft Tissue

CNS

Impaired Concentration

Confusion

Altered State of Consciousness

GIT

Polydipsia

AnorexiaNausea, Vomiting

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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Etiologies of Hypocalcaemia

GIAbsorption 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)


( 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 Rickets)

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 (Trousseus Sign, Chvosteks Sign)

CNS

Altered MoodImpaired Memory

Confusion

Convulsive Seizures

GIT

Diarrhoea

Loose Stool

Malabsorption

Steatorrhea

Skin

Dry Skin

Scaly Skin

Dry Hair

Overview of Calcium Balance


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Etiologies of Hyperphosphatemia

GI Intake

Fleets 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

HyperphosphatemiaSerum Concentration of Inorganic Phosphorus > 1.5 mmol/L

May be a consequences of

y Intake of Piy Excretion of Piy 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 Consequences

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

Soft Tissue Calcification, 2 Hyperparathyroidism

Long Term Consequences

Due to Renal Insufficiency, Renal Pi Excretion

Overview of Phosphate Balance

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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 Excretion

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

y Oral Intakey Shift of Phosphate from ECF into Cells/ Boney Excessive Renal Loss of PhosphateCauses of Hypophosphatemia

Intake, Intestinal Absorption

Deficiency of Dietary Phosphate

Antacid Abuse

Malabsorption States


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 DysfunctionMuscle

Weakness

Rhabdomyolysis

Skeletal

Osteomalacia, Rickets

CNS

Irritability

Paresthesias

Dysarthria

Confusion

Seizures

Coma

Renal

Ca2+, HCO3, Mg2+ Excretion

1,25 (OH)2D3 Synthesis

Metabolic Acidosis

Respiratory Insufficiency

Respiratory Acidosis

Hypoxia

Cardiomyopathy

Cardiac Output

Hypotension

pathophysiology of calcium

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