The total amount of calcium in the body is about 1–2 kg. Over 98% of this is found in the mineral phase, i.e., in the crystalline hydroxyapatite in the extracellular matrix of bone tissue. One percent of skeletal calcium is exchangeable with the organism in a cyclic alternation between the production and degradation of the newly formed matrix that constitutes bone turnover. In the formation phase, calcium is sequestered in the skeleton through incorporation into the matrix by osteoblasts; in the degradation phase, which immediately follows the previous one, calcium is released into the circulation by the degradation process of the same newly formed matrix by osteoclasts (bone resorption). Bone metabolism is based on the continuous alternation of the phases of formation and degradation described above; for this reason, it is considered an extremely dynamic metabolism.

Reference values for calcemia are generally between 8.5 and 10.2 mg/dL; however, depending on the determination method, they may vary up to ±0.5 mg/dL.

This circulating share is divided as follows: about 50% is free or ionized calcium and is biologically active; about 40% is bound to plasma proteins (mainly albumin) and is biologically inactive; finally, about 10% is complexed in salts and is also inactive. This distribution assumes importance in diagnosing calcemia alterations since variations in plasma proteins determine fictitious calcemia alterations.

Plasma calcium levels must be kept rigidly within the upper and lower limits of the reference range since even slight variations correspond to severe clinical effects.

The hormonal systems controlling calcemia are finely tuned to keep calcemia consistently within baseline limits.

Homeostasis is regulated, under physiological conditions, by PTH and vitamin D3, both of which have a hypercalcemic effect. Calcitonin has a role only in paraphysiological and/or frankly pathological conditions and is hypocalcemic.

As mentioned above, PTH plays a crucial role in correcting changes in calcemia promptly.

Vitamin D is a steroid hormone involved in numerous processes, including maintaining calcium homeostasis (Table 1).

Table1. Actions of vitamin D

Vitamin D3 can be synthesized in the skin, starting from 7-dehydrocholesterol, by the action of ultraviolet rays, or taken with the diet (Fig.1). Once in circulation, vitamin D of endogenous and exogenous origin undergoes a first hepatic hydroxylation that converts it into 25(OH) cholecalciferol, or calcidiol, a biologically inactive form, which undergoes a second renal hydroxylation, giving rise to the biologically active form of vitamin D, 1,25(OH)2- cholecalciferol, or calcitriol. The latter increases serum calcium and phosphate concentrations by three mechanisms:

• At intestinal level, it determines the synthesis of calbindins, proteins involved in the absorption of calcium and phosphate

• At the level of osteoblasts, it stimulates the expression of the ligand RANK-L, which interacts with the RANK receptor, expressed on resting osteoclasts, thus accelerating the process of bone resorption

 • At the level of the distal renal tubules, it increases the reabsorption of calcium and phosphate

Fig1. Biosynthesis and calcemic actions of vitamin D. Vitamin D can be synthesized in the skin following exposure to ultraviolet rays (UVB) from the sun, which mediate the conversion of 7- dehydrocholesterol (pro-vitamin D) into pre-vitamin D3 (pre-D3), which is converted into vitamin D3 by heat. Vitamin D can also come from food as vitamin D2 and D3. After ingestion, they are incorporated in the chylomicrons and absorbed in the lymphatic system, through which they reach the circulation, where they are bound to the vitamin D binding protein (DBP) and lipoproteins. In the liver, vitamin D undergoes the first hydroxylation to 25-hydroxyvitamin D (25(OH)D), which, mainly in the kidney, undergoes a second hydroxylation which converts it into the active form, 1,25 dihydroxy vitamin D (1,25 (OH)2D), by the enzyme 1α-hydroxylase. 1,25 (OH)2-D performs numerous functions, including maintaining calcium homeostasis and acting on osteoblasts, enterocytes, and the renal tubule. At the renal level, there is another hydroxylase (24-hydroxylase) which converts 25(OH)D into the inactive form, 24.25-dihydroxyvitaminD [24.25(OH)D]. (Copyright EDISES 2021. Reproduced with permission)

PTH-Related Peptide

PTH-related protein (PTHrP) is a 141 amino acid peptide that exhibits a high degree of homology with PTH. It is involved in bone growth during skeletal development through regulating chondrocyte proliferation and differentiation. The same receptor and transduction system mediate the biological activity of PTHrP as PTH. Hypercalcemia during neoplasia is associated with abnormal hypersecretion of PTHrP.

Phosphorus

 The total inorganic phosphorus in a healthy adult is about 1 kg, 85% in the skeleton. The circulating portion amounts to 2.8–4 mg/dL and is represented by free ions HPO42 and NaHPO4. Only 12% of circulating phosphorus is bound to plasma proteins, unlike calcium.

Although it is a constituent element of the skeleton, phosphorus is widely represented in all tissues, being involved in all metabolic processes.

Although intestinal phosphorus absorption is very efficient, the organ most involved in its metabolism is the kidney. 85–90% phosphorus filtered at the glomerulus is reabsorbed in the proximal and distal tubules. Proximal reabsorption of phosphorus is sodium-dependent and increases under decreased dietary intake; as mentioned above, PTH induces inhibition of this reabsorption with a final effect of urinary excretion of the element. Decreased dietary phosphorus intake results in increased phosphorus clearance.

Hypercalcemia

 The clinical laboratory finding of increased serum calcium values, sometimes accompanied by hypophosphoremia, may be detected in asymptomatic individuals as an expression of chronic (hyperparathyroidism) or subtle (neoplasm) disease. Alternatively, it may be occasional. Clinically manifest hypercalcemias account for approximately 50% of cases of hypercalcemia and may present with a wide variety of signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, and hypertension.

The etiologic classification of hypercalcemias distinguishes them macroscopically into parathyroid and extra- parathyroid. Table 2 describes the main causes of hypercalcemia. Although these are numerous, most hyper calcemic syndromes depend on hyperparathyroidism and neoplasms. Forms caused by primary hyperparathyroidism (solitary adenomas of a gland) are often asymptomatic and have a benign course. In the forms resulting from neoplasia, this is rarely occult and the laboratory finding is included in the investigations.

Table2. Causes of hypercalcemia

In the presence of hypercalcemia (and altered calcemic values in general), it is crucial to ascertain that this is true and does not depend on an alteration of the plasma proteins (albumin). This is followed by the PTH measurement to assess the functionality of the parathyroids and the presence of hyperparathyroidism; the determination of 25-(OH) vitamin D3, and possibly of calcitriol, is recommended in the presence of PTH values within the reference values. Figure 2 describes the diagnostic algorithm for hypercalcemia.

Fig2. Diagnostic algorithm of hypercalcemia. (Copyright EDISES 2021. Reproduced with permission)

Treatment of hypercalcemia is etiologic.

Hypocalcemia

 Hypocalcemia is a less frequent clinical syndrome than hypercalcemia, characterized by decreased serum calcium levels, and often accompanied by hyperphosphatemia. The main causes of hypocalcemia are shown in Table 3.

Table3. Causes of hypocalcemia

A distinction is made between an acute and a chronic form of hypocalcemia. In the first one, the clinical relevance of the symptomatology varies according to the entity of hypocalcemia; indeed, mild hypocalcemia manifests with asthenia, paresthesias, cramps, and irritability, whereas severe hypocalcemia determines tetany and muscle spasms. Acute drug-induced forms are often transient and asymptomatic. On the contrary, chronic forms are characterized by striking symptoms, including neuromuscular signs, behavioral alterations, parkinsonian symptoms, and basal ganglia calcifications.

Again, albumin should be determined to ascertain hypo calcemia’s nature (true or false). In true hypocalcemia, renal function assessment is recommended to exclude losses secondary to chronic renal failure. Magnesium also enters the diagnostic algorithm for hypocalcemia, hypomagnesemia being invariably associated with hypocalcemia. If magne sium levels are in the normal range, evaluation of PTH, phosphate, and vitamin D3 levels, both the depot form and the biologically active form [25-(OH)-D3 and 1,25-(OH)2-D3, respectively], is performed. In particular, the 1,25-(OH)-D3 assay allows differential diagnosis between vitamin D3- resistant and -dependent forms of rickets. The diagnostic algorithm for hypocalcemias is illustrated in Fig. 3.

Fig3. Diagnostic algorithm of hypocalcemia. (Copyright EDISES 2021. Reproduced with permission)

In the presence of albuminemia <4 g/dL, it is necessary to correct calcemia, increasing its value of 0.8 mg/dL for each gram of albumin below the reference value, according to the formula:

Treatment of hypocalcemia is based on the administration of calcium and vitamin D3 per os.

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مواضيع ذات صلة

Biological Actions of Parathormone (PTH)

Synthesis, Secretion, Metabolism, and Mechanism of Action of Parathormone (PTH)

Regulation of Thyroid Hormone Secretion and TSH

Biosynthesis and Secretion of Thyroid Hormones

العمل الجزيئي لهرمون الغدة الدرقية

الغدة الدرقية Thyroid gland

الغدة جار الدرقية The Parathyroid gland

الغدة الدرقية Thyroid gland

فيتامين د3 (Cholecalciferol Vit.D3)

الكالسيتونين (الثايروكالسيتونين) (Calctionine CT, Thyrocalcitonin TCT)

الإفراط في إفراز هرمون جار الدرقية Hyperparathyroidism

هرمون جار الدرقية أو الباراثورمون (Parathyroid H -PTH)