Pathophysiology-of-Calcium

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					                                                                                                                                                    jslum.com | Medicine
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)
                                                                                                                                   jslum.com | Medicine

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
                                                                               jslum.com | Medicine

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
                                                                                                                                       jslum.com | Medicine
Hypercalcaemia                                                                  Hypocalcaemia

Etiologies of Hypercalcaemia                                                    Etiologies of Hypocalcaemia
                                                   ↓ Bone         ↓ Urinary         ↓ GI Absorp on           ↓ 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
                                                                                                                                   jslum.com | Medicine
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 Excre on
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

				
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