Calcium Regulation and Vitamin D

Calcium

• The body of an adult contains about 1200g of calcium

• 99% of calcium is found in bones as hydroxyapatite

• Normal plasma concentration of calcium ranges from 2.14 to 2.53 mmol/l.

• Plasma calcium exists in free or ionized form (1.13-1.30 mmol/l)

• Plasma calcium exists in unionized form, bound to inorganic anions like citrates, bicarbonates, and phosphates

• Plasma calcium exist bound to proteins

• Only the ionized form of calcium is biologically active

• Calcium is an ion with a +2 charge and is the most abundant metal in the body

• The amount of total calcium in plasma is affected protein, free fatty acids, anion concentration, and pH of blood

• Protein concentration effects:

  • Calcium intake reduces in hypoproteinemias
  • Calcium intake increases in hyperproteinemias
  • The concentration of biologically active ionized calcium remains unchanged

• Increased concentration of free fatty acids, such as in acute pancreatitis, diabetic ketoacidosis, and sepsis, results in hypocalcemia

• Increased concentration of free fatty acids causes increased binding of ionized calcium to serum proteins

• Infusion of citrate, phosphate, and bicarbonate does not alter the total amount or concentration of calcium, but it reduces the amount of ionized calcium

• Alkalosis reduces the concentration of ionized calcium

• Acydosis increases the concentration of ionized calcium

• Hydrogen and calcium ions compete for binding sites on proteins

Role of Calcium

• Calcium maintains bones and teeth
• Calcium maintains neuromuscular excitability
• Calcium maintains muscular contraction
• Calcium maintains hearty rhythm
• Calcium maintains blood coagulation
• Calcium maintains secretion of hormones
• Calcium maintains liberation of neurotransmitters
• Calcium is a cofactor in enzymes
• Calcium is an intracellular secondary messenger

Phosphates

• The total amount of phosphate in the body is from 15 to 20 mmol/l
• Phosphates are mostly found in bones as hydroxyapatite
• Also exists as intracellular phosphates, such as creatine phosphate, ATP, nucleic acids, and phosphoproteins
• Exists as extracellular phosphates, such as phospholipids, phosphate esters, and inorganic phosphate compounds
• Normal concentration of phosphorus in serum ranges from 0.9 to 1.6 mmol/l

Role of Phosphate

• Phosphate forms buildings and teeth
• Phosphate allows the production of high energy compounds
• Phosphate contributes to the synthesis of RNA and DNA and Synthesis of coenzyme
• Phosphate contributes to the synthesis of phosphoproteins and phospholipids
• Phosphate activates enzymes by the process of phosphorylation
• Phosphate maintains of acid-base balance
• Phosphate transports oxygen to tissues (2.3 DPG)

Control of Calcium and Phosphate Metabolism

• Metabolism of calcium and phosphate are closely related to the skeletal system, kidney function, and gastrointestinal tract
• Metabolism is regulated neurohumoral through parathyroid hormone (parathormone), an active agent derived vitamin D (calcitriol), and calcitonin.
• Calcium and phosphate concentrations in serum are maintained in a very small range, and the product of their concentration is constant.
• Calcium level is regulated by absorption of calcium from the gastrointestinal tract and redistribution of calcium between the bone system and extracellular fluid
• Phosphate levels in serum are mainly regulated by the control of phosphate excretion through the kidneys

Parathormone

• Parathormone is synthesized and secreted by the parathyroid glands in response to a reduced concentration of ionized calcium
• Parathormone effects in the bone system and kidneys,
• Parathormone indirect effects by stimulating the direct synthesis of the active form of vitamin D.
• Vitamin D increases absorption of calcium in the gastrointestinal tract

Regulation of Parathormone Secretion

• Calcium receptors on the membrane of parathyroid cells detect changes in calcium concentration in the extracellular fluid
• Receptors are G-protein coupled receptors such as adenylate cyclase (cAMP) and phospholipase C ( inositol phosphate)
• Reduced concentration of Calcium
• CAMP increases, IP3 decreases and PTH is secreted
• In hypocalcemia ↑ cAMP ↓ IP3; increased release of PTH
• In hypercalcemia ↓ cAMP ↑ IP3, reduced release PTH

Mechanism of Action of Parathormone on Bones

• PTH increases decomposition of bones (Liberation calcium and phosphates ):
• Release of cytokines from osteoblasts which stimulates activity of osteoclasts
• Stimulates stem cells in bones to mature into osteoclasts
• The effect of PTH on bone depends on the presence of the vitamin D

Mechanism of Action of Parathormone on Kidneys

• PTH increases calcium reabsorption in the kidneys, reducing excretion. Increases the excretion of phosphate, while decreasing the excretion of hydrogen
• PTH increases the production of the active form of vitamin D 3 in the kidneys, which helps with the absorption of calcium and phosphate in the intestines

Mechanism of Action of Parathormone in Intestines

• Parathormone stimulates the synthesis of the active form of vitamin D
• Vitamin D stimulates the absorption of calcium and phosphate in intestines
• In response to parathyroid activity, calcium concentration blood will increase and phosphate concentration in blood is reduced

Vitamin D

• A liposoluble vitamin with a steroid structure.

• Binds to nuclear receptors similarly to hormones.

• Can be produced de novo.

• Vitamin D has hormone properties because it acts on distant target cells and leads to a response after binding to high- affinity cell receptors

• Not a classic hormone because it is not produced and secreted from the endocrine gland

• Ergocalciferol (vitamin D2) is created from ergosterol in plants

• Cholecalciferol (vitamin D3) is found in meat, fish oil and is created in the skin under UV radiation

• Ergocalciferol and cholecalciferol are provitamins D

• Vitamin D is inactive, requiring modification to an active metabolite 1,25-(OH) 2 -D

• Vitamin D first hydroxylation occurs in the liver, forming 25-(OH) -D

• Vitamine D is then transported to kidneys subject to the second hydroxylation to form 1.25- (OH) 2 - D (calcitriol ) active form of vitamin D

• Mechanism of action of vitamins D in bowels- The main is an increase of calcium and phosphate absorbtion

• In the intestinal epithelium, Vitamin D synthesizes calcium transport proteins , which increases calcium absorption

• Mechanism of action of vitamins D on bones-

• Osteoblasts contain Vitamine D receptros

• 1,25- (OH) 2 - D stimulates the active calcium transport from osteoblasts into fluid from bones.

• Vitamin D prevents demineralization.

• Mechanism of action of vitamins D on kidneys - reabsorption of calcium and phosphate (reduced excretion)

• Action Result:

  • absorption of calcium and phosphate from intestines
  • resorption of calcium and phosphate from bones
  • reabsorption of calcium and phosphate from the kidneys, resulting in reduced excretion

• Action result : calcium and phosphates ↑

Calcitonin

• Secreted from the parafollicular cells of the thyroid gland
• Response is pronounced In hypercalcemia
• Decreased secretion In hypocalcemia
• Reduces the level of calcium in the serum
• Main place of action are bones
• Inhibits bone tissue reabsorption from osteoclasts
• Reduces the level of calcium in the serum
• Inhibits absorption of calcium in the intestines Summary of Regulation :
• PTh increases resorption of bones
• Increases reabsorption of calcium in kidney
• Increases absorption of calcium in intestine
• Calcitonin , bone Ca postpone, gut and kidney low Ca

Disorders of Calcium Metabolism

• Disorders of serum calcium levels : calcium is low/calcium is high-calcium
• Urinary urinary calcium excretion : calcium is low/calcium is high-calcium

Hypocalcemia

• A condition in which the concentration of total calcium in the serum is less than 2.14 mmol/l
• Ionized calcium concentration is less than 1.13 mmol/l.
• It results in a reciprocal increase of phosphate concentration in the blood

Etiology of Hypocalcemia

• Reduced intake or calcium absorption causes malabsorption and inadequate diet
• Vitamin D deficiency
• Kidney desease
• Decreased calcium mobilization from bones may be caused by parathyroid gland dysfunction
• Renal insufficiency
• Increased binding to proteins d/t ↑ pH: alkalosis reduces the concentration of ionized calcium
• increased free fatty acids
• increased deposition of calcium in soft tissues

Pathophysiological Consequences of Hypocalcemia

• Lowers and increases neuromuscular excitability
• Enhanced effect on blood-alkalosis
• Reduced effect on blood-acidosis

Clinical Manifestations

• Include paresthesias in the hands and legs, skeletal muscle spasms, hyperreflexia, tetany spasm, carpopedal spasm, laryngeal spasm, spasms in abdomen, hypotension, and hearty insufficiency
• Hypocalcemia may cause ventricular arrhythmias, osteomalacia, bone pains, deformities, and fractures

Hypercalcemia

• is a condition in which the concentration of total calcium in the serum is greater than 2.53 mmol/l or Concentration of ionized calcium is greater than 1.3 mmol/l
• It results in a decreased the concentration of phosphate in the blood Etiology /Increased absorption ↑ PTH ,milk syndrome, Increased bone resorption ↑PTH, malignancies Endocrine, hyperthyroidism

Pathophysiological Consequences of Hypercalcemia

• Neuromuscular excitability gets reduced
• Contractility of the smooth muscle cells of blood vessels strengthens

Soft Tissue Effects

• hypertensive encephalopathy and ischemia occurs in the nervous system
• Muscle get fatigue
• Heart arrhythmias
• gastrointestinal tract disorder Anorexia Nausea vomiting
• Kidney: polyuria
• soft tissue deposition

Disorders of Urinary Calcium Excretion

• Hypercalciuria (increased calcium excretion) occurs with increased absorption of calcium in the gastrointestinal tract
• Can occur in primary hyperparathyroidism with
  Increased filtrate or kidney reabsorption from bone ( use vasodilat and heavy met )
• Reduction is caused by Thiazide diuretics

Disorders of Phosphate Metabolism

• hypophosphatemia - too little phosphate
• hyperphosphatemia - too much phosphate

Hhpophoophatemia

• is a condition in which the serum concentration of inorganic phosphate is less than 0.9 mmol/l.
• At the same time, the level of calcium in the blood increases reciproc

Etiology of Hypophosphatemia

• Decreased absorbtion. GI malabsorbtion and alcoholism , infiltrative intestine
• Decreased absorto
• Renal excretion PTH,Vit d Kid,med

Pathophysiological Consequences

• Transport low Bone mineral low Oxydation low

Hyperphosphatemia

• Increased concentration , great than 6 milimol
• Calcium goes low 1- Increased intake and absorption 2- Cells destruction 3-Kidney: glomerular hypoparathyd

Pathophysiological Consequences of Hyperphosphatemia

• Manifestations from cal, deposition

Magnesium

• Mostly inside. Muscle CNS liver
• Conc 0.65 to 1.05 Metabolic activity and neuro excitability ( calcium act)

Control

• gi, kidney D and bone deposeses

Hypo

• magnesium is less than 0.65
• Caused, abalrition diairhree suxtion. Aldo diures

patho

• Neuromisc excit. K outside. Enerty deficit

Hyper

• Mg is highy 1.05
• Caused Increased ingrd
• Kidney insuf

CONSEQUENCE

• Nerves. Paralysis card reat

Explore the mechanisms of calcium regulation, the influence of Vitamin D, and the causes of conditions like hypocalcemia. This includes the role of 1,25-(OH)2-D, kidney function, and acid-base imbalances in maintaining calcium homeostasis.