Calcium functions and significance

Calcium- Functions and Clinical Calcium- Functions and Clinical SignificanceSignificance

By – Professor (Dr.) Namrata ChhabraBiochemistry For Medics- Lecture Notes

04/07/23By- Professor Namrata Chhabra (MD Biochemistry)

1

http://www.namrata.co/category/about-the-author/

http://www.namrata.co/category/about-the-author/

IntroductionIntroduction

Calcium(Ca) is required for the :•Muscle contraction,•Nerve conduction, •Hormone release, and •Blood coagulation•In addition, specific Calcium concentration is required for various other metabolic processes.

04/07/23 By- Professor Namrata Chhabra (MD Biochemistry) 2

Sources of calciumSources of calcium• It is an important nutrient. The daily

intake is approximately 1000mg/day, about the amount of one litre of milk.

• Widely distributed in food substances such as

o Milko Cheeseo Egg- yolko Fisho Beanso Lentilso Nuts and o Cabbage


Intestinal Absorption of calciumIntestinal Absorption of calcium

Two mechanisms have been proposed-• Simple passive diffusion• Active transport- involving energy and calcium

pump.o Vitamin D is important for the active process.o Active calcium transport depends on the

presence in the intestinal cell of calbindin protein , the biosynthesis of which is totally dependent on vitamin D.


Intestinal absorptionIntestinal absorption

• 30-80% of ingested calcium is absorbed, primarily in the upper small intestine.

• Absorption is related to calcium intake. • If intake is low, active transcellular calcium

transport in the duodenum is increased and a larger proportion of calcium is absorbed by the active process compared with the passive paracellular process that occurs in the jejunum and ileum.



• Passive absorption in the jejunum and ileum predominates when dietary calcium intake is adequate or high.

• Calcium reaching the large intestine is absorbed by active and passive processes.

• Usually, not more than 10% of total absorption takes place in the large intestine, but this site becomes nutritionally important in conditions of significant small bowel resection.



• In a balanced diet, roughly 1000 mg of Ca is ingested each day and about another 200 mg/day is secreted into the GI tract in the bile and other GI secretions.

• Depending on the concentration of circulating vitamin D, particularly 1,25(OH)2D (1,25 Dihydroxycholecalciferol, Calcitriol, or active vitamin D, roughly 200 to 400 mg of Ca is absorbed from the intestine each day.

• The remaining 800 to 1000 mg appears in the stool. • Ca balance is maintained through renal Ca excretion

averaging 200 mg/day.


Factors affecting calcium absorptionFactors affecting calcium absorptionA) Factors favoring calcium absorption• An acidic pH • Presence of sugar acids, organic acids and citric acid• High protein diet- Lysine and Arginine cause maximal absorption• Presence of vitamin D• Ca : P ratio- A ratio of dietary Ca: P not more than 2:1 is adequate

for optimal absorption, ratio of less than 1:2 reduces absorption• State of health and intact mucosa- A healthy adult absorbs about

40% of dietary calcium.• PTH (Parathormone) stimulates the activation of vitamin D, thus

indirectly increases absorption of vitamin D


Factors affecting calcium absorptionFactors affecting calcium absorptionB) Factors inhibiting absorption of calcium• Alkaline pH• High fat diet- Fatty acids form calcium soaps that can not be

absorbed• Presence of Phytates and oxalates- Insoluble calcium salts are

formed• Dietary fiber in excess inhibits absorption• Excess phosphates, magnesium and iron decrease absorption• Glucocorticoids reduce intestinal absorption of calcium• Calcitonin reduces calcium absorption indirectly by inhibiting the

activation of vitamin D• Advancing age and intestinal inflammatory disorders inhibit

absorption of calcium


Distribution of Body calciumDistribution of Body calcium• The adult human body contains approximately 1100g

(27.5mol) of calcium. • 99% of the calcium is in bone. • Blood calcium levels are normally 9-10.2mg/dL (2.25-

2.55mmol/L). • Of the total amount, 50% is free ionized calcium, 9% is

combined with various anions (including bicarbonate, citrate, phosphate, lactate and sulphate) and the remaining 41% is bound to serum proteins mainly albumin.

• Free ionized calcium is the physiologically important component of the total calcium.

• In plasma, the ionized calcium concentration is normally maintained within a tight range (1.0-1.25mmol/l).


Distribution of Body calciumDistribution of Body calcium


Distribution of Body calciumDistribution of Body calcium• Both extracellular and intracellular Ca concentrations are

tightly regulated by bidirectional Ca transport across the plasma membrane of cells and intracellular organelles, such as the endoplasmic reticulum, the sarcoplasmic reticulum of muscle cells, and the mitochondria.

• Cytosolic ionized Ca is maintained within the micromolar range (<1/1000 of the serum concentration).

• Despite its important intracellular roles, roughly 99% of body Ca is in bone, mainly as hydroxyapatite crystals.

• Roughly 1% of bone Ca is freely exchangeable with the ECF and, therefore, is available for buffering changes in Ca balance.


Influences on calcium concentrationsInfluences on calcium concentrations• The plasma pH and the total plasma protein concentration

influence the total calcium levels• Since a significant proportion of calcium in the blood is

bound to albumin, it is important to know the plasma albumin concentration when evaluating the total plasma calcium.

• In general, 0.2mmol/L must be added to the total calcium concentration for each 1g/dL decrease in albumin concentration

• Ionized calcium increases with acidosis, and decreases with alkalosis.

• Therefore, for each 0.1 decrease in pH, ionized calcium rises by about 0.05mmol/L.


Physiological functions of calcium

1) Calcium is necessary for several physiological processes including neuromuscular transmission, smooth and skeletal muscle contraction, cardiac automaticity, nerve function, cell division and movement, and certain oxidative processes.

2) It is also a co-factor for many steps during blood coagulation.


Physiological functions of calciumPhysiological functions of calcium

3) Ca is also involved in the action of other intracellular messengers, such as cyclic adenosine monophosphate (cAMP) and Inositol 1,4,5-triphosphate, and thus mediates the cellular response to numerous hormones, including epinephrine, glucagon, ADH (vasopressin), secretin, and cholecystokinin.



4) Calcium binding proteins• Many different calcium binding proteins have

been described, but the two with well established functions are troponin and calmodulin.

• Troponin is involved in muscle contraction, whereas calmodulin causes configurational changes to proteins and enzyme activation.



6) Release of neurotransmitters and hormones-Intracellular calcium levels are much lower than the extracellular, due to relative membrane impermeability and membrane pumps employing active transport.

• Calcium entry via specific channels leads to direct effects, e.g. neurotransmitter release in neurons, or further calcium release from intracellular organelles, e.g. in cardiac and skeletal muscle.


Regulation of calcium homeostasisRegulation of calcium homeostasis

Three principal hormones are involved in calcium homeostasis

• Vitamin D, • Parathormone and • Calcitonin Acting at three target organs, • Intestine, • Bone and • Kidneys


Role of vitamin D in calcium Role of vitamin D in calcium homeostasishomeostasis

•Vitamin D is a group of closely related sterols produced by the action of ultraviolet light. •Vitamin D3 (Cholecalciferol) is produced by the action of sunlight and is converted to 25-hydroxycholecalciferol in the liver. •The 25-hydroxy-cholaecalciferol is converted in the proximal tubules of the kidneys to the more active metabolite 1,25-hydroxy-cholaecalciferol. •1,25-hydroxychlecalceriferol synthesis is regulated in a feedback fashion by serum calcium and phosphate. •Its formation is facilitated by parathyroid hormone.


Role of vitamin D in calcium Role of vitamin D in calcium homeostasishomeostasis

The actions of Vitamin D are as follows:1. Enhances calcium absorption from the

intestine2. Facilitates calcium absorption in the kidney3. Increases bone calcification and

mineralization4. In excess, mobilizes bone calcium and

phosphate


Role of Parathyroid hormone (PTH)Role of Parathyroid hormone (PTH)

• Parathyroid hormone is a linear polypeptide containing 84 amino acid residues.

• It is secreted by the chief cells in the four parathyroid glands.

• Plasma ionized calcium acts directly on the parathyroid glands in a feedback manner to regulate the secretion of PTH.

• In hypercalcemia, secretion is inhibited, and the calcium is deposited in the bones.

• In hypocalcaemia, parathyroid hormone secretion is stimulated.


Parathyroid glandsParathyroid glands


Role of Parathyroid hormone (PTH)Role of Parathyroid hormone (PTH)

The actions of PTH are aimed at raising serum calcium. It -1. Increases bone resorption by activating osteoclastic activity2. Increases renal calcium reabsorption by the distal renal

tubules3. Increases renal phosphate excretion by decreasing tubule

phosphate reabsorption4. Increases the formation of 1,25-dihydrocholecalciferol by

increasing the activity of alpha-hydroxyls in the kidneyA large amount of calcium is filtered in the kidneys, but 99% of

the filtered calcium is reabsorbed. About 60% is reabsorbed in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule. Distal tubule absorption is regulated by parathyroid hormone.


Regulation of calcium homeostasisRegulation of calcium homeostasis


Role of CalcitoninRole of Calcitonin

Calcitonin is a 32 amino acid polypeptide secreted by the parafollicular cells in the thyroid gland. It tends to decrease serum calcium concentration and, in general, has effects opposite to those of PTH. The actions of calcitonin are as follows:1. Inhibits bone resorption2. Increases renal calcium excretionThe exact physiological role of calcitonin in calcium homeostasis is uncertain.The effects of calcitonin on bone metabolism are much weaker than those of either PTH or vitamin D.


Role of Calcitonin, Calcitriol and PTHRole of Calcitonin, Calcitriol and PTH


Glucocorticoids and calcium Glucocorticoids and calcium homeostasishomeostasis

• Glucocorticoids lower serum calcium levels by inhibiting osteoclast formation and activity, but over long periods they cause osteoporosis by decreasing bone formation and increasing bone resorption.

• They also decrease the absorption of calcium from the intestine by an anti-vitamin D action and increased its renal excretion.

• The decrease in serum calcium concentration increases the secretion of parathyroid hormone, and bone resorption is facilitated.


Growth hormone and calcium levelsGrowth hormone and calcium levels

• Growth hormone increases calcium excretion in the urine

• it also increases intestinal absorption of calcium, and

• this effect may be greater than the effect on excretion, with

• a resultant positive calcium balance.


Effect of other hormones on calcium Effect of other hormones on calcium levelslevels

• Thyroid hormones may cause hypercalcemia, hypercalciuria, and, in some instances, osteoporosis.

• Oestrogens prevent osteoporosis, probably by a direct effect on osteoblasts.

• Insulin increases bone formation, and there is significant bone loss in untreated diabetes.


Bone and calciumBone and calcium

The calcium in bone exists in two forms: 1.A readily exchangeable pool and which is about 0.5 to 1% of the total calcium salts and is the first line of defense against changes in plasma calcium. It provides a rapid buffering mechanism to keep the serum calcium ion concentration in the extracellular fluids from rising to excessive levels or falling to very low levels under transient conditions of excess or hypo availability of calcium. 2.Stable Pool- The other system is mainly concerned with bone remodeling by the constant interplay of bone resorption and deposition, which accounts for 95% of bone formation.


Extracellular calcium homeostasisExtracellular calcium homeostasisCalcium-sensing receptor (C ASR)The CASR plays an essential role in maintaining

calcium ion homeostasis-• This receptor is expressed in all tissues related to

calcium control, i.e. parathyroid glands, thyroid C-cells, kidneys, intestines and bones.

• It has the ability to sense small changes in plasma calcium concentration

• This information is conveyed to intracellular signaling pathways that modify PTH secretion or renal calcium handling.


Calcium-sensing receptor (C ASR)Calcium-sensing receptor (C ASR)

It is a G protein-coupled receptor that plays an essential part in regulation of extracellular calcium homeostasis.


Key points in calcium homeostasis•Calcium homeostasis is regulated by three hormones, parathyroid hormone, vitamin D and calcitonin. •Parathyroid hormone increases plasma calcium by mobilizing it from bone, increases reabsorption from the kidney and also increases the formation of 1, 25 dihydrocholecalciferol.•1,25-dihydrocholecalciferol increases calcium absorption from the intestine, mobilizes calcium from the bone and increases calcium reabsorption in the kidneys•Calcitonin inhibits bone resorption and increases the amount of calcium in the urine, thus reducing plasma calcium•The calcium-sensing receptor (CASR) plays an important role in regulation of extracellular calcium.


HypocalcaemiaHypocalcaemia

Hypocalcemia is total serum Ca concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized Ca concentration < 4.7 mg/dL (< 1.17 mmol/L). Causes include hypoparathyroidism, vitamin D deficiency, and renal disease. •Acute hypocalcaemia can also occur in the immediate post-operative period, following removal of the thyroid or parathyroid glands. •Hypocalcaemia can occur following rapid administration of citrated blood or large volumes of albumin and in alkalosis caused by hyperventilation.


HypocalcaemiaHypocalcaemiaOther causes of hypocalcemia include-• Mg depletion (can cause relative PTH

deficiency and end-organ resistance to PTH action),

• Acute pancreatitis (when lipolytic products released from the inflamed pancreas chelate Ca)

• Hypoproteinemia (reduces the protein-bound fraction of serum Ca)


HypocalcaemiaHypocalcaemia

• Hungry bone syndrome-(persistent hypocalcemia and hypophosphatemia occurring after surgical or medical correction of moderate to severe hyperparathyroidism in patients in whom serum Ca levels had been supported by high bone turnover induced by greatly elevated parathyroid hormone)

• Septic shock (due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH)2D)

• Drugs including anticonvulsants (e.g., phenytoin , phenobarbital and rifampin which alter vitamin D metabolism)


Clinical manifestations of Clinical manifestations of HypocalcaemiaHypocalcaemia

• Hypocalcemia is frequently asymptomatic. • Major clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability.• Clinical signs include: tetany, carpopedal spasm and laryngeal stridor. • Sensory symptoms consisting of paresthesias of the lips, tongue, fingers, and feet• Generalized muscle aching and spasm of facial musculature are also there


Clinical manifestations of Clinical manifestations of HypocalcaemiaHypocalcaemia

• Hypocalcaemia may lead to cardiac Dysrhythmias, decreased cardiac contractility, causing hypotension, heart failure or both.

• Many other abnormalities may occur with chronic hypocalcemia, such as dry and scaly skin, brittle nails, and coarse hair.


Clinical manifestations of Acute Clinical manifestations of Acute HypocalcaemiaHypocalcaemia


Diagnosis of HypocalcaemiaDiagnosis of Hypocalcaemia

• Estimation of ionized Ca• Further testing with Mg, PTH, PO4, alkaline

phosphatase, and vitamin D concentrations in blood and cAMP and PO4 concentrations in urine

• Electrocardiographic changes include prolongation of the QT interval.


Treatment of HypocalcaemiaTreatment of Hypocalcaemia

• IV Ca Gluconate for tetany• Oral Ca for postoperative hypoparathyroidism• Oral Ca and vitamin D for chronic hypocalcemia• In patients without renal failure, vitamin D is

given as a standard oral supplement (e.g., Cholecalciferol 800 IU once/day).

• Vitamin D therapy is not effective unless adequate dietary or supplemental Ca and PO4


HypercalcaemiaHypercalcaemia

Hypercalcemia is total serum Ca concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum Ca > 5.2 mg/dL (> 1.30 mmol/L).Principal Causes of Hypercalcemia- Hypercalcemia usually results from excessive bone resorption. There are many causes of hypercalcemia


Principal Causes of HypercalcemiaPrincipal Causes of Hypercalcemia

A) Cancer with bone metastases• Carcinoma• Leukemia• Lymphoma• Multiple myeloma



B) Immobilization• Orthopedic casting or traction• Paget's disease of bone• Osteoporosis in the elderly• Paraplegia or quadriplegia• Young, growing patients



C) Parathyroid hormone excess• Parathyroid carcinoma• Primary hyperparathyroidism• Secondary hyperparathyroidismD) Vitamin Toxicity• Vitamin A toxicity• Vitamin D toxicity



E) Other disorders/causes• Hyperthyroidism• Milk-alkali syndrome• Addison's disease• Granulomatous disorders• Drug therapy such as thiazides and lithium


Hypercalcemia related to Hypercalcemia related to hyperparathyroidismhyperparathyroidism


Clinical manifestations of Clinical manifestations of HypercalcaemiaHypercalcaemia

• In mild hypercalcemia, many patients are asymptomatic.

• Clinical manifestations of hypercalcemia include constipation, anorexia, nausea and vomiting, abdominal pain, and ileus.

• Impairment of the renal concentrating mechanism leads to polyuria, nocturia, and polydipsia.



• Elevation of serum Ca > 12 mg/dL (> 3.00 mmol/L) can cause emotional lability, confusion, delirium, psychosis, stupor, and coma.

• Hypercalcemia may cause neuromuscular symptoms, including skeletal muscle weakness.



• Hypercalciuria with nephrolithiasis is common.

• Less often, prolonged or severe hypercalcemia produces reversible acute renal failure or irreversible renal damage due to nephrocalcinosis (precipitation of Ca salts within the kidney parenchyma).


Clinical manifestations of Hypercalcaemia

• Severe hypercalcemia causes a shortened QTc interval on ECG, and arrhythmias may occur

• Hypercalcemia > 18 mg/dL (> 4.50 mmol/L) may cause shock, renal failure, and death.


Diagnosis of HypercalcaemiaDiagnosis of Hypercalcaemia

• Total serum Ca concentration• Chest x-ray, measurement of electrolytes,

BUN, creatinine, ionized Ca, PO4, alkaline phosphatase, and serum protein immunoelectrophoresis to determine the cause

• Measurement of PTH and urinary excretion of Ca with or without PO4


Treatment of HypercalcaemiaTreatment of Hypercalcaemia

There are 4 main strategies for lowering serum Ca:

• Decrease intestinal Ca absorption• Increase urinary Ca excretion• Decrease bone resorption• Remove excess Ca through dialysis



• Oral PO4 for serum Ca < 11.5 mg/dL with mild symptoms and no kidney disease

• IV saline and diuretic (furosemide) for more rapid correction for serum Ca < 18 mg/dL

• Bisphosphonates or other Ca-lowering drugs for serum Ca < 18 mg/dL and > 11.5 mg/dL or moderate symptoms



• Hemodialysis for serum Ca > 18 mg/dL• Surgical removal for moderate, progressive

primary hyperparathyroidism and sometimes for mild disease

• PO4 restriction and binders and sometimes Calcitriol for secondary hyperparathyroidism


Summary of calcium metabolismSummary of calcium metabolism• Ca is required for the proper functioning of muscle

contraction, nerve conduction, hormone release, blood coagulation and for various other metabolic processes.

• Maintenance of body Ca stores depends on• Dietary Ca intake• Absorption of Ca from the GI tract• Renal Ca excretion• The regulation of both Ca and PO4 balance is greatly

influenced by concentrations of circulating PTH, vitamin D, and, to a lesser extent, calcitonin.


Summary of calcium metabolismSummary of calcium metabolism• Hypocalcemia is total serum Ca concentration < 8.8

mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized Ca concentration < 4.7 mg/dL (< 1.17 mmol/L).

• Causes include hypoparathyroidism, vitamin D deficiency, and renal disease.

• Manifestations include paresthesias, tetany, and, when severe, seizures, encephalopathy, and heart failure.

• Diagnosis involves measurement of serum Ca with adjustment for serum albumin concentration.

• Treatment is administration of Ca, sometimes with vitamin D.


Summary of calcium metabolismSummary of calcium metabolism• Hypercalcemia is total serum Ca concentration > 10.4

mg/dL (> 2.60 mmol/L) or ionized serum Ca > 5.2 mg/dL (> 1.30 mmol/L).

• Principal causes include hyperparathyroidism, vitamin D toxicity, and cancer.

• Clinical features include polyuria, constipation, muscle weakness, confusion, and coma.

• Diagnosis is by serum ionized Ca and parathyroid hormone concentrations.

• Treatment to increase Ca excretion and reduce bone resorption of Ca involves saline, Na diuresis, and drugs such as pamidronate.


Education

Calcium functions and significance