Calcium Homeostasis

Calcium is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, calcium is required as a cofactor for various enzymes.

Calcium balance 

Calcium is an important nutrient. The daily intake is approximately 1000 mg/day. The adult human body contains approximately 1100 g (27.5 mol) of calcium. 99% of the calcium is in the bone. Blood calcium levels are normally 9-10.2 mg/dL (2.25-2.55mmol/L). Of the total amount, 50% is free ionized calcium, 10% is combined with various anions (including bicarbonate, citrate, phosphate, lactate, and sulfate), and the remaining 40% 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).

Intestinal 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.

Vitamin D is important for the active process. Active calcium transport depends on the presence in the intestinal cell of calbindin protein, the biosynthesis of which is totally dependent on vitamin D. 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, no 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. Calcium absorption is inhibited by phosphates and oxalates because these anions form insoluble salts with calcium in the intestine.

Physiological functions of calcium

Calcium plays a central role in a number of physiological processes that are essential for life. 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. It is also a co-factor for many steps during blood coagulation. Intracellular calcium is involved as a second messenger in many intracellular responses to chemical and electrical stimuli and is required by many enzymes for full activity. 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. 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.

Intracellular calcium levels are much lower than extracellular ones 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.

Despite its important intracellular role, 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 concentration

Total plasma calcium value varies with the plasma concentration. 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.  Ionized calcium level increases with acidosis, and decreases with alkalosis.

Regulation of calcium homeostasis

The metabolism of Ca and of PO4 is intimately related.

Three principal hormones are involved in calcium homeostasis, acting at three target organs, the intestine, bone, and kidneys:

1) Vitamin D

Vitamin D, a fat-soluble vitamin, is 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-cholecalciferol is converted in the proximal tubules of the kidneys to the more active metabolite 1,25-dihydroxy-cholecalciferol (Figure 1). 1,25-dihydroxycholecalceriferol synthesis is regulated in a feedback fashion by serum calcium and phosphate. Its formation is facilitated by the parathyroid hormone.

The actions of Vitamin D are as follows:

1. Enhances calcium absorption from the intestine
2. Facilitates calcium absorption in the kidney
3. Increases bone calcification and mineralization
4. In excess, it mobilizes bone calcium and phosphate

2) 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 hypocalcemia, parathyroid hormone secretion is stimulated. The actions of PTH are aimed at raising serum calcium.

1. Increases bone resorption by activating osteoclastic activity
2. Increases renal calcium reabsorption by the distal renal tubules
3. Increases renal phosphate excretion by decreasing tubule phosphate reabsorption
4. Increases the formation of 1,25-dihydrocholecalciferol by increasing the activity of alpha-1-hydroxylase in the kidney (Figure-3).

A 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 the parathyroid hormone.

Figure 1- showing  activation of vitamin D

3. 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 resorption
2. Increases renal calcium excretion

The 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.

The calcium-sensing receptor (C ASR)

It is a G protein-coupled receptor that plays an essential part in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to calcium control, i.e., parathyroid glands, thyroid C-cells, kidneys, intestines, and bones. By virtue of its ability to sense small changes in plasma calcium concentration and to couple this information to intracellular signaling pathways that modify PTH secretion or renal calcium handling, the CASR plays an essential role in maintaining calcium ion homeostasis (Figure 2)

Figure- 2- A decrease in extracellular (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via activation of the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from the bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.

Bone and calcium

The calcium in bone exists in two forms: a larger reservoir of stable calcium and a readily exchangeable pool 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 prevent 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. 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.

Effects of other hormones on calcium metabolism

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 through an anti-vitamin D action and increase renal excretion. The decrease in serum calcium concentration increases the secretion of parathyroid hormone, and bone resorption is facilitated. Growth hormone increases calcium excretion in the urine, but it also increases intestinal absorption of calcium, and this effect may be greater than the effect on excretion, with a resultant positive calcium balance. Thyroid hormones may cause hypercalcemia, hypercalciuria, and, in some instances, osteoporosis. Estrogens prevent osteoporosis, probably by a direct effect on osteoblasts. Insulin increases bone formation, and there is significant bone loss in untreated diabetes.

Key points in calcium homeostasis

1) Calcium homeostasis is regulated by three hormones, parathyroid hormone, vitamin D and calcitonin. The free, ionized calcium concentration is physiologically important for the functions of excitable tissues such as nerve and muscle.

2) Parathyroid hormone increases plasma calcium by mobilizing it from bone, increases reabsorption from the kidney and also increases the formation of 1, 25 dihydroxycholecalciferols.

3) 1,25-dihydroxycholecalciferol increases calcium absorption from the intestine, mobilizes calcium from the bone and increases calcium reabsorption in the kidneys

4) Calcitonin inhibits bone resorption and increases the amount of calcium in the urine, thus reducing plasma calcium

5) The calcium-sensing receptor (CASR) plays an important role in the regulation of extracellular calcium.

Figure 3- showing the role of PTH in maintaining calcium homeostasis

 Variation of serum Calcium levels

Hypocalcemia

The causes of hypocalcemia include Hypoalbuminemia, hypomagnesemia, hyperphosphatemia, multifactorial enhanced protein binding, medication effects, surgical effects, PTH deficiency or resistance, and vitamin D deficiency or resistance. Protein binding is enhanced by elevated pH and free fatty acid release in high catecholamine states. Hypocalcemia can occur following the rapid administration of citrated blood or lavage volume of albumin, and in alkalosis, it is caused by hyperventilation. Acute hypocalcemia can also occur in the immediate postoperative period, following the removal of the thyroid or parathyroid glands.

Hypocalcemia may present with acute symptoms or be asymptomatic. Clinical signs include tetany, carpopedal spasm, and laryngeal stridor. Hypocalcemia may lead to cardiac dysrhythmias, decreased cardiac contractility, hypotension, heart failure, or both. Electrocardiographic changes include prolongation of the QT interval. Hypocalcemia may be accompanied by changes in magnesium concentrations.

Hypercalcemia

Hypercalcemia is divided into PTH-mediated hypercalcemia (primary hyperparathyroidism) and non–PTH-mediated hypercalcemia.

PTH-mediated hypercalcemia is related to increased calcium absorption from the intestine. Primary hyperparathyroidism originally was the disease of “stones, bones, and abdominal groans.” In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced Calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected.

Non–PTH-mediated hypercalcemia includes the following:

Hypercalcemia associated with malignancy, granulomatous disorders, and metastasis to the bone from the breast, multiple myeloma, and hematologic malignancies (Breast cancer is one of the most common malignancies responsible for hypercalcemia.).Causes of hypercalcemia also include hyperthyroidism, adrenal insufficiency, pheochromocytoma, drug therapy such as thiazides and lithium, and immobilization.

Hypercalcemia may present with renal problems, polyuria and polydipsia, neuropsychiatric disorders, nausea, vomiting, and peptic ulceration. The cardiovascular effects include raised blood pressure, a shortened Q-T interval, and dysrhythmias.

Specific treatment is aimed at the cause, but it may also be necessary to decrease calcium levels by increasing excretion and decreasing bone resorption.