Calcium and phosphate metabolism disorders

 

Calcium and phosphate metabolism disordersIntroduction:

The last few years have witnessed considerable advances in the field of calcium and phosphate metabolism. These advances have made very significant progress in understanding the physiopathology of the disorders of these metabolisms. Mention may be made of the identification of the parathyroid-related peptide (or PTH-rP), the cloning of the PTH receptor gene, the identification of the calcium-sensitive receptor, the molecular identification of the sodium / phosphate membrane cotransport mechanism and the cellular mechanisms of its determinants. At the same time, some clinical pictures have changed and diagnostic methods have improved and structured.

Physiology of calcium:

BALANCE OF CALCIUM:

The body of a healthy adult of 70 kg contains approximately 25,000 mmol (1000 g) of calcium, mostly distributed in bone (99%), while less than 1% is present in the extracellular fluid (22 mmol or 880 mg). In healthy adults, calcium is constant over time, whereas it is increasing in children and adolescents and decreasing in women after menopause and in the elderly. A young adult usually ingests about 800 to 1000 mg / d of calcium, 30-35% of which is absorbed by the mucosa of the small intestine, partly under the influence of 1.25 (OH) 2 vitamin D; due to calcium secretion from the extracellular fluid to the intestinal lumen, evaluated at 150 mg / d, the net intestinal absorption was close to 150 mg / d. An identical amount of calcium (150 mg / d) is eliminated in the final urine and the (external) calcium balance is zero. Bone remodeling activity is daily responsible for the release of 200 mg of bone calcium (bone resorption activity) and the incorporation in bone of 200 mg of calcium (activity of mineralization of the newly formed bone protein matrix synthesized): thus, there is normally no net calcium flux in the young adult between the extracellular fluid and the bone and the internal calcium balance is also zero.

Despite the extreme predominance of bone calcium, it appears that the regulated variable is the extracellular concentration of calcium and, more precisely, the concentration of ionized calcium. Indeed, total serum calcium is a heterogeneous variable and comprises several fractions: approximately 50-55% of the total serum calcium exists in ionized (free) form and constitutes both the biologically active fraction and the regulated fraction; the remainder is biologically inert, composed of a fraction bound to the blood proteins (mainly albumin) and a fraction bound to the anions of the serum (bicarbonate, phosphate, citrate, etc.). The sum of the ionized calcium and the calcium complexed to the anions of low molecular weight represents the calcium diffusible or ultrafiltrable.

Measured by atomic absorption spectrophotometry, normal adult serum calcium concentrations range from 2.10 to 2.53 mmol / L on an empty stomach (95% confidence interval of mean calcemia in normal subjects); they are moderately superior, about 0.1 mmol / L, in children and adolescents. It is important to perform the measurement on an empty stomach because, in the postprandial period, the total calcium concentration increases: the observed variation can reach 0.15 mmol / L in the normal subjects, or even more in the subjects who have an intestinal hyperabsorption of the calcium.

Although the regulated variable is the serum concentration of ionized calcium, the diagnosis of hypo- or hypercalcemia can be established regularly on the finding of an abnormally low or high total calcium concentration, respectively, because changes in concentration of free calcium are accompanied by parallel variations in total calcium concentration.

However, abnormalities in the concentration of serum proteins and / or anomalies in the acid-base state are responsible for dissociations. Thus, a decrease in the serum albumin concentration produces a decrease in the total calcium fraction bound to this protein, and therefore a decrease in serum calcium, apart from any variation in the concentration of ionized calcium; in contrast, an increase in the serum albumin concentration, or immunoglobulins (as in myeloma), results in an increase in total calcium without modification of the ionized calcium. Similarly, changes in the blood concentration of H + ions (ie extracellular pH) are able to induce variations in the calcium fraction bound to albumin because H + and the Ca ++ ions compete for binding to albumin. Thus, acute acidosis, characterized by an increase in the extracellular concentration of H + ions, causes a redistribution of serum calcium between its different fractions; calcium bound to albumin decreases, free calcium increases and the total calcium concentration does not change. If the acidosis is prolonged (chronic acidosis), the concentration of ionized calcium, regulated variable, normalizes, thanks to the intervention of the “calciotropic” hormones and the total calcium concentration decreases.Opposite modifications are observed in cases of extracellular alkalosis. In particular, acute ventilatory alkalosis, which may occur during a painful specimen or in an emotional subject, causes a sudden decrease in serum ionized calcium and an increase in calcium bound to proteins. Such a variation of the acid-base state is recognized by the ionized calcium measuring instruments, which have, besides the specific electrode for the measurement of free calcium, a pH electrode. This allows these devices to provide a “corrected” ionized calcium concentration value, calculated for a blood pH of 7.40. The taking into account of this “corrected” value is permissible in the event of a sudden disturbance of the acid-base state.

It is obviously illegitimate in case of prolonged disorder of the acid-base state.

In summary, in the absence of blood protein abnormalities and extracellular pH, an abnormality of the ionized calcium concentration can be reliably detected by measuring total calcium. On the other hand, in the case of one or both of these anomalies, the direct measurement of the concentration of the ionized calcium by means of a specific electrode must be carried out. This measure requires some precautions as to the technique of sampling, which must be performed on a limb at rest and, at best without a tourniquet, to avoid variations in blood pH. When access to this measurement is not possible, one can calculate a corrected serum calcium, knowing that each gram of albumin complex normally 0.02 to 0.025 mmol of calcium. Thus, in a subject whose albumin is measured at 20 g / L, the measured calcium concentration can be increased from 0.4 to 0.5 mmol / L in order to obtain a “corrected” calcemia.This procedure provides a fairly approximate result.

REGULATION OF THE CALCULATION:

The calcemia of a normal subject is maintained at a remarkably stable value by regulating calcium fluxes between the bone and the extracellular fluid, on the one hand, and between the extracellular fluid and the kidney, on the other hand. Usually, intestinal absorption of dietary calcium only affects calcium levels temporarily and is not involved in the short-term regulation of serum calcium. However, intestinal absorption of normal calcium (150 to 200 mg / d) is necessary to maintain normal calcium and, in particular, stability of bone calcium content. Indeed, serum calcium is maintained stable on an empty stomach because the renal calcium loss necessarily present in this situation is exactly compensated by mobilization of the bone calcium responsible for a net flux of calcium from the bone to the extracellular fluid . Thus, in the absence of adequate dietary intake (800 to 1000 mg / d) and / or intestinal absorption of normal calcium, serum calcium remains at the expense of a progressive decrease in bone calcium content. Under normal conditions, the bone calcium content is maintained because bone calcium mobilized during fasting is replaced by an identical amount in the postprandial period. Accordingly, in a normal individual with intestinal intake and absorption of normal calcium, 24-hour calciuria is equal to the net intestinal absorption of calcium.

Bone remodeling, ie the continuous activity of destruction and renewal of bone, does not participate in the control of serum calcium because these two activities (osteoclast destruction and osteoblast formation ) are very closely coordinated, each responsible for a calcium flux between the bone and the identical but opposite extracellular fluid, the resulting flux remaining zero. Even when there is a significant increase in bone remodeling, such as that observed in Paget’s disease, serum calcium levels do not change, as long as the coupling between osteoclastic and osteoblastic activities persists. Bone remodeling is a slow, low-amplitude but high-capacity phenomenon since it potentially has access to the entire skeleton.

Nevertheless, bone contributes to the control of serum calcium through a different cellular system, osteocytes, which allows a rapid release of calcium bone. Thus (see above), the maintenance of fasting serum calcium is ensured by a net entry into the extracellular fluid of bone calcium, quantitatively identical to the concomitant calcium kidney loss.Unlike remodeling, the mobilization of osseous calcium dependent on osteocytes is a rapid phenomenon, of great amplitude but of low capacity since it affects only the recently mineralized bone.

The regulation of serum calcium is under the control of two hormones, PTH and the active metabolite of vitamin D or 1.25 (OH) 2 vitamin D (calcitriol), as well as serum calcium itself via a recently discovered calcium-sensing receptor (CaSR) receptor: this receptor plays a central role in the control, by serum calcium, of PTH secretion and, presumably, in the regulation of renal reabsorption of calcium. PTH is a peptide hormone that acts on its target organs (bone and kidney) through a membrane receptor coupled to one or more G proteins. Calcitriol is a steroid hormone that binds to a specific cytosolic receptor present in many cell types including renal tubular cells, cells of the intestinal epithelium, as well as bone cells. The hormone-receptor complex acts in the nucleus by modulating transcription in specific chromatin sites, called vitamin D responsive elements. These two hormones stimulate osteoclastic bone resorption, but due to the normal coupling between osteoclastic osteoclast and osteoblastic osteo-formation, the resulting net bone resorption is minimal and bone calcium content varies little or no. In other words, even when stimulated by supraphysiological concentrations of PTH, a normally coupled bone remodeling does not result in appreciable changes in serum calcium levels.

However, PTH stimulates osteolar osteolysis and, as a result, increases serum calcium levels. In addition, PTH increases renal tubular reabsorption of calcium and stimulates renal alpha-hydroxylase activity and thus the production of calcitriol. This latter hormone is essential for the normal expression of the biological effects of PTH.

A decrease in serum calcium causes, in a few seconds, an increase in PTH secretion; Indeed, parathyroid cells possess in their plasma membrane a specific receptor (CaSR) of which extracellular free calcium is the physiological ligand; the role of this receptor is to adapt the parathyroid secretion of PTH to the extracellular free calcium concentration. Thus, a decrease in serum calcium inactivates the receptor and leads to an increase in PTH secretion.If hypocalcaemia persists, hypersecretion of PTH is amplified by a decrease in intracellular PTH degradation. Then, the expression of the PTH gene is increased, resulting in an increase in the prepro-PTH intracellular messenger ribonucleic acid (mRNA). Finally, chronic hypocalcaemia leads to an increase in parathyroid tissue mass by cell division (parathyroid hyperplasia). Thus, in response to hypocalcaemia, several mechanisms of adaptation appear successively which make it possible to increase the secretion of PTH. This excess PTH stimulates the mobilization of bone calcium dependent on osteocytes, renal tubular reabsorption of filtered calcium and renal synthesis of calcitriol and normalizes calcemia. Conversely, an increase in serum calcium inhibits parathyroid secretion of PTH, and therefore the mobilization of bone calcium and renal tubular reabsorption of calcium, in order to correct hypercalcemia.

Anomalies of calcemia:

MECHANISMS OF HYPERCALCEMIA:

Two types of disorders can cause hypercalcemia.

The first is a shift in the relationship between calcemia and PTH secretion to higher serum calcium levels, indicating a decrease in the sensitivity of PTH secretion to calcemia. In this situation, increased secretion (and concentration) of PTH observed for a normal serum calcium value causes increased mobilization of bone calcium and increased renal tubular reabsorption of filtered calcium, resulting in necessarily to an increase in calcemia; it stabilizes at a new value, higher than the normal value, for which the entries of bone origin and renal outputs become identical again. In this new situation, the calcium balance and, in large part, the bone mineral mass, remain unchanged compared to a normal situation. The stable hypercalcemia resulting from a primary alteration of the secretion of PTH is, for this reason, called hypercalcemia in “equilibrium”. In the new stable state, serum calcium is elevated and serum PTH concentration is high or normal, inappropriate for hypercalcemia. The 24-hour calciuria may be normal or increased; in the latter case, it reflects an increase in the intestinal absorption of calcium, mostly due to an increase in the synthesis of calcitriol induced by the excess of PTH. In its usual form, primitive hyperparathyroidism (HPTP) is a typical example of “balance” hypercalcemia.

The second situation is that of a primary alteration of bone remodeling, resulting in a significant increase in net bone resorption, a decrease in bone mineral mass and a negative calcium balance. This is observed when an increase in osteoclastic resorption is associated with decoupled (ie, not increased or even inhibited) osteoblastic bone formation.The large net flux of calcium in the extracellular fluid that results can exceed the ability of the kidney to eliminate calcium, causing progressive hypercalcemia called “imbalance” hypercalcemia. Indeed, a decrease in extracellular volume is frequently associated with vomiting and a decrease in sodium renal reabsorption directly due to hypercalcemia: this decrease in extracellular volume causes a decrease in the glomerular filtration rate and a increase in tubular proximal reabsorption of calcium, which aggravate hypercalcemia. More generally, all factors known to increase tubular renal tubular reabsorption of calcium may aggravate a hypercalcemia initially due to increased inputs.In the presence of hypercalcaemia, serum PTH concentration is low, adjusted, and calcium is elevated, reflecting excessive calcium entry into the extracellular fluid. Hypercalcemia which complicates the evolution of certain neoplasias is a typical example of hypercalcemia in “disequilibrium”.

GENERAL CHARACTERISTICS OF HYPERCALCEMIA:

Symptoms of Hypercalcemia:

Whatever its cause, hypercalcaemia is the more tolerated because it is more moderate or, more importantly, it settles more gradually. This explains why a large number of hypercalcaemia is accidentally discovered in patients with no signs of call. The symptoms attributable to hypercalcemia, when they exist, concern different devices: cardiovascular apparatus, central nervous system, digestive system, renal system.

Diagnosis of hypercalcaemia:

In addition to questioning (the age of hypercalcemia, the use of potentially hypercalcemic treatments, the existence of an underlying disease already known) and clinical examination, the diagnosis of hypercalcemia usually a reasoned approach in which the measurement of certain biological variables is essential.

Estimation of PTH secretion:

The cornerstone of the diagnosis of hypercalcemia is the estimation of PTH secretion. In the presence of hypercalcemia, a high or normal PTH secretion indicates its inappropriateness and allows the diagnosis of hypercalcemia of parathyroid origin (HPTP or, more rarely, benign familial hypercalcemia [HFB]) to be established. In contrast, a low PTH secretion, appropriate for hypercalcemia, leads to the diagnosis of extraparathyroid hypercalcemia, the causes of which are dominated by cancers. Since PTH secretion is not clinically measurable, it is estimated by measuring the serum concentration of PTH. The concentration of PTH varies in proportion to the parathyroid secretion only insofar as the metabolic clearance of the hormone is stable, a condition that was not verified by the oldest immunoassay systems. The first assay systems used antibodies recognizing epitopes present on both the intact PTH molecule and the carboxyterminal moiety. Thus, they did not reliably estimate biologically active PTH secretion by parathyroid cells. This low specificity was illustrated by the overlap between the values ​​measured in subjects with HPTP (where intact PTH secretion is high) and those with hypercalcemia of cancers (where intact PTH secretion is low). More recently, a method of immunoradiometric assay (IRMA) of circulating intact PTH has been introduced: this measurement uses two antibodies, one directed against the aminoterminal part and the other against the carboxyterminal part of the peptide. Unlike the previous ones, this measurement technique is very specific and very sensitive for the measurement of low concentrations of PTH. It allows an excellent separation between the values ​​of patients with hyperparathyroidism and those with hypercalcemia of cancers or sarcoidosis. In 10 years of use, this type of measure has largely demonstrated its diagnostic performance. A non-isotopic immunometric measure of intact PTH is now available; in this technique, one of the two members of the pair of antibodies used is associated, not with iodine 125, but with an acridinium ester producing a light signal in the presence of an alkaline peroxide. For this reason, this type of test is called immunochemiluminometric assay (ICMA) and its performances are superimposable to those of the IRMA tests.

Measurement of fasting calciuria:

As discussed above, fasting calcium is maintained stable because the mandatory renal calcium loss that exists then is exactly compensated by a clear intake of calcium of bone origin. Thus, fasting calcium measurement estimates net bone resorption, provided there is no intestinal calcium input at the time of measurement. This condition is generally satisfied by imposing on the subject, in addition to a total nocturnal fast, a diet depleted in calcium, obtained by the foreclosure of milk, dairy products and mineralized drinking measured. Urinary calcium flow should be related to creatinine flow, so as to avoid urinary collection errors. In normal subjects, the value of this ratio (expressed in mmol / mmol) is between 0.03 and 0.36 according to a non-normal but log-normal distribution (such as 24-hour calcium distribution , in normal subjects).

Measurements of Nephrogenic Cyclic 3 ‘, 5’ Monophosphate Adenosine Production and PTHrP Concentration

Situations of hypercalcemia during which the concentration of serum PTH is low, adapted, are dominated by cancers.

In this group, hypercalcemia humoral neoplasia (HHC) accounts for 80% of hypercalcemia. PTHrP secreted by the tumor plays a central role in this syndrome: by binding to the renal and bone receptor of PTH, it explains a large part of the biological signs characterizing this syndrome. Its measurement is therefore an essential element in establishing the diagnosis of HHC. Moreover, by binding to the renal PTH receptor, it stimulates the production of cAMP by the tubular cells, which are essentially proximal. The production rate of cAMP by the tubular cells constitutes nephrogenic cAMP and the dissociation between a low PTH concentration and a high nephrogenic cAMP production is pathognomonic of the HHC syndrome.

Measurement of vitamin D metabolites:

Outside of cancers, some hypercalcemia with low PTH secretion is due to vitamin D (or a metabolite) intoxication or excessive endogenous production of calcitriol by granulomatosis.

In daily practice, only the measurements of 25-OH vitamin D and 1,25 (OH) 2 vitamin D are of interest: the first because it represents the best estimate of vitamin D allows the diagnosis of deficiency or poisoning with vitamin D; the second because it is the biologically active hormone.

The circulating 25-OH vitamin D is formed by hepatic hydroxylation of cholecalciferol (vitamin D 3 ) of endogenous or animal origin, and ergocalciferol (vitamin D 2 ), of vegetable origin.

Since hepatic hydroxylation is a direct function of the amount of precursor, the measurement of the blood concentration of 25-OH vitamin D reflects the vitamin D 2 and D 3 vitamin D status. After extraction and separation chromatography, the assay (usually by radiocompetition) does not distinguish between cholecalciferol and ergocalciferol; it does not recognize dihydrotachysterol. Normal values ​​differ considerably depending on sunlight and dietary intakes. In France, the values ​​considered normal are of the order of 5 to 40 ng / mL (12.5-100 nmol / L). A very high value (greater than ten times the normal value) is usually considered necessary for the diagnosis of intoxication;however, tolerance to treatment with high doses of vitamin D varies greatly from one patient to another.

The synthesis of 1,25 (OH) 2 vitamin D is essentially renal and rigorously controlled by calcium and phosphate (which inhibit it) and PTH (which stimulates it). Due to this close regulation, measurement of the concentration of calcitriol does not constitute an estimate of the vitamin D level. The indications of the dosage are therefore situations in which the synthesis is abnormally low (inherited deficit of calcitriol synthesis, renal insufficiency) or abnormally high (granulomatosis, idiopathic hypercalcemia of the infant, lymphoma), as well as suspicion of intoxication by calcitriol (Rocaltrol t ) or alphacalcidiol (Un Alfa t ). Normal values ​​in adults are usually between 20 and 50 pg / mL (48 to 120 pmol / L) and are negatively correlated with dietary calcium intakes.

Physiologically higher values ​​are observed in children and during pregnancy (during which there is a placental production of calcitriol).

CAUSES OF HYPERCALCEMIA:

Hypercalcemia of parathyroid origin:

Primary Hyperparathyroidism:

HPTP is the leading cause of hypercalcemia. It is defined by an excessive secretion of PTH, inappropriate to the serum calcium value. Predominantly, HPTP affects the woman after the age of 40 years. For many years, HPTP has been considered a rare and serious disease, responsible for two specific complications: renal calcium lithiasis and fibrocystic osteitis. More recently, the introduction of automated serum calcium measurement methods has completely changed the apparent epidemiology of HPTP, allowing the discovery of hypercalcemia leading to diagnosis in asymptomatic patients. Currently, the estimated prevalence of HPTP is 100 cases per 100,000 population and the absolute incidence has been multiplied by 4. Specific complications have become rare: renal lithiasis is present in less than 20% of patients , fibrocystic osteitis in less than 1% and neuromuscular syndrome virtually disappeared. Thus, the vast majority of patients did not have a directly attributable sign to HPTP at the time of diagnosis.

It is now established that most, if not all, of parathyroid tumors are monoclonal. The precise cause of HPTP is not known, although this condition appears to be favored by prior irradiation of the cervical region and several gene abnormalities.

Hypercalcemia is usually moderate (2.7-3 mmol) and remains remarkably stable for years. The serum concentration of PTH, measured by IRMA or ICMA, is high in 90% of patients. In 10% of patients, the PTH concentration is not quite high, but in the upper half of the normal range, inappropriate for hypercalcemia. Renal tubular reabsorption of phosphate is frequently decreased due to hypersecretion of PTH, causing hypophosphatemia in 60-70% of patients.

Hypercalciuria is observed in 40 to 50% of patients, due to an increased synthesis of calcitriol which stimulates the intestinal absorption of calcium.

The acid-base condition is usually normal, with hyperchloremic metabolic acidosis being observed only in severe phosphate depletion or nephrocalcinosis.

Excellent general reviews have recently been devoted to the bone damage of HPTP and its specific treatment, which will not be detailed here.

Benign familial hypercalcemia and severe neonatal hyperparathyroidism:

HFB (hypercalcaemia-familial hypocalciuria) is significantly rarer than HPTP, but it is the main differential diagnosis that contraindicates parathyroidectomy. It is an autosomal dominant disease with a high degree of penetrance, characterized by hypercalcemia, mostly asymptomatic, which lasts all the life, associated with comparatively low renal calcium excretion since the fractional excretion of calcium is usually less than 1%.

Typically, circulating concentration of PTH is normal, inappropriate, and magnesemia is moderately high or in high values ​​of normal. The only symptoms are, sometimes, acute pancreatitis and chondrocalcinosis. Inbred marriages in siblings with HFB may occur in children with severe neonatal HPT. These children have life-threatening hypercalcemia and are suffering from growth retardation, dehydration, bone demineralization, chest wall deformities, multiple fractures and hypotonia in the first weeks of life, as these complications often require parathyroidectomy total. The mode of transmission of these two diseases had suggested that they could represent a different assay of the same mutation, with HFB being the heterozygous form and severe neonatal hyperparathyroidism being the homozygous form. These hypotheses have recently been confirmed: an allele of the gene encoding the calcium-sensitive receptor (which sits on the long arm of chromosome 3 in humans) is mutated in the HFB whereas the two alleles are the site of a mutation in severe neonatal hyperparathyroidism.

Numerous point mutations have been described to date which most often result in a non-conservative modification of an amino acid. The mutations described are distributed throughout the gene and may affect translation, routing or function of the receptor.

Prolonged lithium treatment decreases the clearance of calcium and magnesium and may increase PTH secretion, causing hypercalcemia which sometimes regresses when treatment can be interrupted.

Extraparathyroid hypercalcemia:

Hypercalcemia of cancers:

The occurrence of hypercalcaemia during the course of a cancer is a frequent occurrence since its annual incidence has been estimated at 150 new cases per million inhabitants. However, not all neoplasms have the same tendency to become hypercalcemic: this event is common in bronchial cancers, head and neck epitheliomas, breast cancer and certain malignant haemopathies such as multiple myeloma .

In all cases, the initial mechanism of hypercalcaemia is intense osteolysis resulting from decoupling between osteoconstruction and osteororesis. The calcium flux entering the extracellular fluid rapidly exceeds the renal elimination capacity, especially if there is renal insufficiency or an increase in tubular reabsorption of calcium.Hypercalcemia appears and then worsens rapidly.

Humoral hypercalcemia of cancers:

HHC is a syndrome occurring in patients with solid neoplasia, mostly due to the tumor production of a circulating humoral factor (endocrine) which causes hypercalcemia. It is important to note that these patients do not necessarily have secondary bone localization of their neoplasia. HHC is common in the development of epidermoid cancers of the bronchi, head and neck, but has also been described in all histological types of cancers, including malignant hematologic disorders. Rapid, poorly tolerated hypercalcemia is associated with a low, adequate, serum PTH concentration, in contrast to high nephrogenic cAMP production, increased tubular calcium reabsorption, and decreased tubular phosphate reabsorption ; the blood concentration of calcitriol is normal or low and the intestinal absorption of calcium decreased. The main factor involved in the occurrence of HHC is the secretion of PTHrP by the tumor. Due to the great similarity of the amino acid sequence of the aminoterminal ends of PTH and PTHrP, the latter binds to the renal and bone receptor of PTH and induces hypercalcemia, hypophosphatemia and an increase in the production of Nephrogenic cAMP. However, the decoupling of bone remodeling and the decrease in calcitriol synthesis are not explained by the binding of PTHrP to the PTH receptor and could be due to the interaction of PTHrP with another type of receptor and / or to the tumor’s duplication of substances such as transforming growth factor alpha (TGF alpha ).

· Malignant local osteolysis

Local malignant osteolysis (OLM) accounts for 20% of hypercalcemia complicating cancers. The mechanism is an increased osteoclastic resorption, activated by a paracrine mechanism by malignant cells infiltrating the bone marrow and secreting cytokines (interleukin 1alpha, interleukin 1 beta , interleukin 6, tumor necrosis factor [TNF] alpha and beta , TGF alpha ) acting on the osteoclasts. Typically, this mechanism is observed during myeloma and breast cancer. Calcium is elevated, usually normal phosphate, and very high calciuria, indicating the massive entry of bone calcium into the extracellular fluid. The concentrations of PTH, calcitriol and cAMP production are low, suited to hypercalcemia.

Finally, hypercalcemia associated with excessive and uncontrolled production of calcitriol has been observed in some malignant lymphomas. The mechanism of hypercalcemia is the same as in granulomatosis.

Sarcoidosis and other granulomatoses:

A majority of patients with sarcoidosis have hypercalciuria and 10 to 20% develop hypercalcaemia during the course of their disease. The accepted physiopathological mechanism associates an increase in digestive and bone inputs with a decrease in the ability of the kidney to excrete calcium due to renal failure associated with specific interstitial nephropathy. The increase in calcium intakes is attributed to excessive and unregulated synthesis of calcitriol by granuloma macrophages. The 1α-hydroxylase activity of macrophages differs from that normally expressed in proximal tubule cells, in that it is not regulated by the concentrations of calcitriol and PTH: for this reason macrophage synthesis of calcitriol is extremely dependent on the availability of the 25-OH vitamin D substrate, which explains why the occurrence of hypercalcemia (and hypercalciuria) is favored by sun exposure and / or by ingestion of vitamin D administered at physiological dose. In addition, the alpha-hydroxylase activity of macrophages is stimulated by interferon gamma produced by activated lymphocytes and nitric oxide (NO); in contrast, it is inhibited by glucocorticoids, chloroquine and ketoconazole, which explains the efficacy of these treatments. Glucocorticoids, in the daily dose of 40 to 60 mg of prednisone, produce a decrease in the concentration of calcitriol in a few hours and a normalization of serum calcium and calcium in a few days: they constitute the treatment of choice of hypercalcemia of granulomatosis.

TREATMENT OF HYPERCALCEMIA:

The indication for symptomatic treatment of hypercalcemia depends on several factors. Any symptomatic patient whose calcemia exceeds 3.25 mmol / L requires urgent treatment. An asymptomatic patient with a serum calcium level of less than 3.25 mmol / L does not require immediate treatment, except in cases where the hypercalcemia is due to cancer because it is likely to become rapidly worsening. Treatment of hypercalcemia should be individualized with careful consideration of several factors: the cause of hypercalcemia, its pathogenic mechanism, and the existence of contraindications specific to a particular type of treatment.

The basic principles of treating hypercalcemia are correcting contraction of extracellular volume, increasing the kidney’s ability to eliminate calcium, and decreasing calcium inputs into the extracellular fluid.

Restoration of normal extracellular volume by intravenous infusion of isotonic saline is the first step in the treatment of severe hypercalcemia. Daily administration of 3 to 6 L of isotonic saline increases the rate of glomerular filtration and decreases calcium renal tubular reabsorption so that a decrease in serum calcium in the range of 0.4 to 0.6 mmol / L can be obtained by this single treatment. The amount of solute administered is, of course, guided by the cardiovascular tolerance of the patient.

The use of high doses of a loop diuretic has often been advocated in the past. Such treatment, which requires that the extracellular volume be previously standardized, is no longer useful in the majority of patients because of the efficacy of current treatments. However, use of moderate doses (20 to 40 mg / day furosemide) may be useful in patients with poor cardiovascular expansion of extracellular volume.

Drugs that inhibit bone resorption are an extremely effective way of treating severe hypercalcemia, especially when it is due to cancer. Calcitonin inhibits bone resorption and increases the renal elimination of calcium. When administered at a dose of 4 MRC units / kg every 12 hours by subcutaneous or intravenous route, it produces a decrease in serum calcium in a few hours, with a maximum effect obtained in 12 to 24 hours. However, the effect of calcitonin is generally moderate, with calcemia rarely decreasing by more than 0.5 mmol / L, and especially transient. This is why it is necessary to associate it with a treatment whose effect is more prolonged such as the administration of diphosphonates. Diphosphonates are stable synthetic analogues of pyrophosphate and are potent inhibitors of osteoclastic activity. Administered intravenously, etidronate, clodronate or pamidronate (in increasing order of efficacy) all result in a decrease in serum calcium, which occurs only 24 to 48 hours after initiation of therapy, during the first week. A single dose of pamidronate as a 4-hour intravenous infusion (30-60 mg if serum calcium is less than 3.40 mmol / L, 90 mg if greater than this value) is usually sufficient to cause prolonged normalization (sometimes up to 1 month) of serum calcium.

Other previously used treatments (mithramycin, gallium nitrate, phosphate perfusion) are also effective, but their toxicity is high, which explains their disaffection.

MECHANISMS OF HYPOCALCEMIA:

Since PTH plays a central role in maintaining serum calcium levels (see Regulation of serum calcium), prolonged hypocalcaemia can occur only if there is no or insufficient PTH secretion, or if there is resistance to the action of PTH in its target organs, or, finally, if there is a net flux of calcium to bone (or soft tissue) provided it is of sufficient intensity to exceed antihypocalcaemic “effects of PTH.

In the first situation, stable and prolonged hypocalcemia exists due to a primary decrease in parathyroid secretion of PTH. As a result, for normal calcium excretion, calcium excretion is higher than normal and bone calcium is released lower than normal. This results in a gradual decline in serum calcium to a new stable state characterized by a calcium urinary excretion equal to the net bone release of calcium. The serum concentration of PTH is then low or normal, unsuitable for hypocalcemia and low or normal 24 hour calcium. Hypoparathyroidism is a typical example.

In the second situation, hypocalcaemia occurs because the bone and kidney are resistant to the biological action of PTH. As a result, for normal calcium excretion, calcium excretion is higher than normal and bone calcium is lower than normal. This results in a gradual decrease in serum calcium, which stimulates the parathyroid secretion of PTH; it may eventually restore peripheral effects of normal PTH but at the cost of hypocalcemia.

In this situation, serum PTH concentration is high, appropriate for hypocalcemia.

Finally, in the third situation, bone formation causes a net flux of calcium from the extracellular fluid to the bone, sufficiently intense to overcome the maintenance mechanisms of calcemia, even in the presence of a high PTH secretion; this type of anomaly is mainly observed in the healing phases of metabolic osteopathies and is called hungry bone syndrome.

GENERAL CHARACTERISTICS OF HYPOCALCEMIA:

Symptoms of hypocalcaemia:

Whatever its cause, a hypocalcaemia is better tolerated as it is more moderate or, more importantly, it settles more gradually. Symptoms attributable to hypocalcemia, where they exist, concern, above all, the neuromuscular system and the cardiovascular system.

Diagnosis of hypocalcaemia:

In addition to questioning (including the age of hypocalcaemia, the concept of cervical surgery, the use of potentially hypocalcemic treatments, the existence of an underlying disease) and clinical examination, the diagnosis of hypocalcemia requires usually a reasoned approach in which the measurement of certain biological variables is essential.

As stated in the diagnosis of hypercalcemia, the cornerstone for the diagnosis of hypocalcaemia is the estimation of PTH secretion by measuring the intact PTH blood concentration. In the presence of a hypocalcaemia, a low or normal PTH secretion indicates its inappropriateness and makes it possible to establish the diagnosis of parathyroid hypocalcemia (hypoparathyroidism or, more rarely, autosomal dominant hypocalcemia). In contrast, a high PTH secretion, appropriate to hypocalcemia, leads to the diagnosis of hypocalcemia of extraparathyroid origin. These situations are dominated by deficiencies in vitamin D or its metabolites; PTH or vitamin D resistance syndromes are more rare.

CAUSES OF HYPOCALCEMIA:

Parathyroid hypocalcaemia:

Hypoparathyroidism:

Hypoparathyroidism is the consequence of insufficient synthesis and / or secretion of PTH. In this situation, the serum calcium decreases and can reach as low as 1.2 mmol / L.

Simultaneously, the concentration of PTH is undetectable or low, unsuitable for hypocalcemia. Hyperphosphatemia is common, associated with increased renal phosphate reabsorption. The 24-hour calciuria is low since the synthesis of calcitriol and, consequently, the intestinal absorption of calcium are decreased.

The most common cause of hypoparathyroidism is cervical surgery. The parathyroid glands may be removed or injured during extensive cervical surgery (thyroid or laryngeal cancer, repeated parathyroid surgery); transient or permanent hypoparathyroidism may also be the result of edema or hemorrhage altering the vascularization of the parathyroid glands. Rarely, destruction of the parathyroid glands is secondary to cervical irradiation, exceptional neoplastic or granulomatous infiltration, overload (Wilson disease, hemochromatosis, thalassemia), sporadic autoimmune disease or disease the most common of which is associated with hypoparathyroidism, Addison’s disease and moniliasis (HAM syndrome or polyglandular autoimmune disease type I).

Agenesis or congenital hypoplasia of the parathyroid glands, isolated or associated with other embryological abnormalities, also causes hypoparathyroidism.

Finally, PTH secretion can be functionally altered in severe hypomagnesaemia.

Autosomal dominant hypocalcaemia:

This condition, also known as familial hypercalciuric hypocalcemia, is the result of a heterozygous activating mutation of the calcium-sensitive receptor. The concentration of PTH is normal but inappropriate for hypocalcemia. The important point is that any attempt to treat calcium and derived from vitamin D is complicated by significant hypercalciuria, calcium renal lithiasis and / or nephrocalcinosis, and renal insufficiency.

Extraparathyroid hypocalcaemia:

This set of conditions is characterized by a high PTH secretion appropriate to hypocalcemia: hypocalcaemia occurs due to resistance to peripheral PTH actions, or because the underlying pathophysiological phenomenon exceeds the capacity of PTH to maintain normal serum calcium levels.

Abnormalities of vitamin D and its metabolites:

These disorders are divided into three groups: absolute vitamin D deficiency, vitamin D metabolism abnormalities, and vitamin D action-resistance syndromes. Overall, hypocalcaemia is not clinically isolated but fits into a picture of rickets or osteomalacia.

Vitamin D deficiency results from insufficient solar exposure (for geographical, social or customary reasons), insufficient dietary intake or intestinal lipid malabsorption syndrome (celiac disease, primary biliary cirrhosis, chronic pancreatitis, intestinal resections …).

The lack of hepatic hydroxylation of vitamin D, leading to a deficiency of 25-OH vitamin D, can be observed in cholestatic chronic liver disease or prolonged treatment with enzyme inducers such as barbiturates or phenytoin. The lack of renal hydroxylation of 25-OH vitamin D in 1.25 (OH) 2 vitamin D is observed either in vitamin-dependent rickets type 1, autosomal recessive rare disorder   characterized by a functional deficiency of the renal 1alpha-hydroxylase enzyme, either during renal insufficiency, by reduction of the functional nephronic mass and the expression of the enzyme.

Finally, autosomal recessive type II vitamin-dependent rickets is characterized by resistance to the action of calcitriol on its target organs by mutation of the binding sites of the vitamin D receptor.

TREATMENT OF HYPOCALCEMIA:

The decision to treat hypocalcaemia depends on its severity, speed of installation, and clinical tolerance.

Whatever the context, hypomagnesemia must be sought and, if necessary, treated; in the case of associated metabolic acidosis, the treatment of hypocalcaemia must precede, not follow, that of acidosis under pain of a worsening of hypocalcemia.

Acute hypocalcaemia:

A moderate hypocalcaemia of between 1.9 and 2.1 mmol / L in an asymptomatic patient usually requires oral calcium supplementation (500 to 1000 mg calcium-element every 6 hours) with clinical and biological monitoring .

In contrast, symptomatic or severe hypocalcaemia (less than 1.9 mmol / L) justifies parenteral therapy.

10% calcium gluconate exists in 10 mL ampoules containing 94 mg of elemental calcium. After intravenous injection of an ampule in 5 minutes, an infusion of 10 ampoules diluted in 1 L of isotonic glucose solute is administered at the rate of 50 mL / h (47 mg / h of calcium), the flow being secondarily adapted to desired result. 10% calcium chloride exists in 10 mL ampoules, each containing 272 mg of calcium-element, a high concentration, making this preparation significantly more aggressive to the veins.

Chronic hypocalcaemia:

Treatment of chronic hypocalcaemia requires the use of oral calcium intakes as well as, most often, vitamin D or its derivatives to increase the intestinal absorption of calcium.

Calcium may be supplied as a carbonate, gluconolactate, citrate, lactobionate or glubionate, calcium phosphate being avoided due to the risk of aggravation of pre-existing hyperphosphatemia. The daily dose is usually between 1 and 2 g of calcium element, distributed throughout the day and ingested away from meals. The choice of the vitamin D derivative depends on the situation. Deficiencies in the intake or synthesis of vitamin D justify supplementation with vitamin D at physiological dose (400 to 800 IU / d). Higher doses (50,000 to 100,000 IU) are warranted in patients with intestinal calcium malabsorption syndrome. 25-OH vitamin D in doses of 1 to 5 μg / d is justified in patients with deficiencies in the hepatic hydroxylation of vitamin D. Finally, 1.25 (OH) 2 vitamin D ( 0.5 to 1 μg / d) or 1alpha-OH vitamin D (1-1.5 μg / day) are required in patients whose renal hydrolysis of 25-OH vitamin D is deficient.

In all cases, treatment should be adapted to maintain moderately decreased serum calcium or low normal values, and calciuria less than 6.5 mmol / d in order to avoid the risk of renal stones, nephrocalcinosis and renal insufficiency.

Physiology of phosphate, Phosphate balance and regulation of phosphatemia:

An adult of 70 kg contains about 23 mol of phosphate, distributed in 85% of the bone in the form of hydroxyapatite crystals, and 14% in the intracellular fluid, where it plays an essential role in many cellular functions adenosine triphosphate [ATP], nucleic acids, phospholipids, phosphoproteins, and regulation of enzymatic activities) and 1% in the extracellular fluid. Extracellular phosphate exists for two thirds in organic form and one third in inorganic form; the latter fraction is the one usually measured.

Plasma inorganic phosphate (PI) is weakly bound to proteins (10%) and circulates predominantly in free form (ionized), a small fraction being complexed with calcium and magnesium. The normal concentration of Pi is, on an empty stomach, between 0.82 and 1.40 mmol / L in adults; it is physiologically higher in children and adolescents until the end of growth. The extracellular concentration of Pi is not constant during the nycthémère: it is minimal in the morning on an empty stomach and then rises during the day, which underlines the importance of measuring in the morning on an empty stomach.

The phosphate balance, the difference between the inputs and outputs of the organism, is zero in normal adults, positive in growing children and adolescents, and negative in elderly subjects.

The entry of phosphate into the body is made only by intestinal route, from the phosphate contained in the diet.

Usual dietary intakes range from 800 to 2000 mg / day of phosphorus. About 70% of the ingested phosphate is absorbed into the intestine, mainly in the duodenum and jejunum. In these segments, the transport of phosphate is carried out by a double mechanism: a paracellular, diffusive, non-saturable, unregulated transport directly dependent on the phosphate concentration gradient between the intestinal lumen and the interstitial fluid and a transcellular transport, saturated, regulated, using an Na / Pi cotransport system located in the apical membrane of the enterocytes.Thus, it appears that paracellular transport dominates in a situation of normal or high food intake and that the transcellular transport dominates in situation of weak contribution.

Several factors modulate the intestinal (transcellular) transport of phosphate:

– calcitriol increases the apical Na / Pi cotransport activity;

– a phosphate-poor diet stimulates transcellular transport via direct action on Na / Pi cotransport and an increase in calcitriol synthesis;

– high intakes of calcium and magnesium, as well as alumina gels, decrease the intestinal transport of phosphate by causing the formation of complexes that are not easily absorbed.

In a normal adult, there is no net flux of phosphate between the bone and the extracellular fluid, nor between the cells and the extracellular fluid during the nycthemeral period. This situation is obviously not the case of the growing child or adolescent in whom a positive phosphate balance is required for bone mineralization and cell mass augmentation.

In normal adults, the phosphate balance is maintained at a nil value because renal excretion of phosphate is equal to net intestinal intake. To the extent that the intestinal absorption of phosphate is poorly regulated, the kidney plays a central role in maintaining a balanced phosphate balance and in controlling the value of phosphatemia.

The renal behavior of phosphate responds to a process of filtration-reabsorption. Eighty to 85% of the filtered phosphate is reabsorbed into the proximal tubule, which is the major and best known site of renal phosphate transport.Since proximal reabsorption of phosphate is a saturable phenomenon, it is possible to measure maximum renal transport (TmPi). The ratio of TmPi to glomerular filtration rate (TmPi / DFG) defines the renal phosphate threshold, which is the plasma phosphate concentration beyond which phosphate renal excretion increases linearly with phosphate. The renal phosphate threshold is the essential factor in regulating phosphate levels. In fact, when phosphate intakes rise (after a meal, for example), phosphatemia rises above the renal threshold, phosphaturia increases, allowing the excess phosphate to be eliminated, and phosphate levels normalized.

Conversely, when the phosphate inputs are zero, the downward trend of phosphate is interrupted as soon as the phosphate level reaches the value of the renal threshold, since for this value, the entirety of the filtered phosphate is reabsorbed and the phosphaturia also becomes nothing.

In addition, the determination of the renal phosphate threshold is a major factor in judging the renal or extrarenal character of hypophosphatemia: it is indeed increased (renal excretion of phosphate is very low or zero) in hypophosphatema and decreased (phosphaturia is maintained) in hypophosphatemia of renal origin.

The limiting step of tubular renal tubular reabsorption is transport through the apical membrane of the proximal tubule cells using a sodium / phosphate cotransport system.

Three groups of Na / Pi cotransporters are currently known in mammals and designated as Type I, Type II and Type III Na / Pi. If Type III Na / Pi cotransporters are distributed in many cell types, Type I and Type II Na / Pi cotransporters are preferentially localized in the kidney and particularly in the “brush” border of the tubule cells proximal. In addition, only the Na / Pi cotransporter

It appears to be physiologically involved in tubular phosphate reabsorption.

Renal tubular reabsorption of phosphate is regulated by several factors, the two most important being probably PTH and phosphate intake.

PTH inhibits renal reabsorption of phosphate. The action of the hormone is explained by an increase in the endocytosis of the apical Na / Pi type II transporter through activation of the adenylate cyclase pathways and protein kinase C.

Changes in dietary intake of phosphate cause a rapid change in tubular reabsorption. This regulation seems straightforward since it occurs independently of changes in PTH, calcitriol, serum calcium and growth hormone. The restriction of the phosphate intake is accompanied, within a few hours, by an increase in the proximal transport of phosphate and by the expression at the apical membrane of the Na / Pi cotransporter of type II and then by an increase in its mRNA. The increase in phosphate intake produces opposite variations.

Another humoral factor, still unknown today, could contribute to the regulation of proximal phosphate transport. Indeed, in the hereditary hypophosphatemic models in mice, the apical expression of the Na / Pi cotransporter type II is decreased, explaining the decrease in phosphate transport and hypophosphatemia observed. However, there is no abnormality of the gene encoding this cotransporter; on the other hand, a gene encoding a proteolytic molecule (PHEX) is mutated in this condition (see X-linked hypophosphatemic rickets). The hypothesis is that PHEX controls an endocrine factor involved in renal expression of the Type II Na / Pi cotransporter.

Phosphatemia abnormalities:

HYPOPHOSPHATEMIC MECHANISMS:

Schematically, an abnormal decrease in phosphate may occur in three types of circumstances: when dietary intakes are reduced or intestinal losses increase prolonged, when the capacity of the renal tubule to reabsorb the phosphate decreases, or, a portion of the extracellular phosphate is transferred to the intracellular area or bone; the latter event occurs mainly with carbohydrate or ventilatory alkalosis, two situations stimulating intracellular glycolysis and cellular phosphate consumption.

GENERAL CHARACTERISTICS OF HYPOPHOSPHATEMS:

Symptoms of hypophosphatemia:

Moderate hypophosphatemia, defined by a phosphate level between 0.3 and 0.8 mmol / L, is usually not accompanied by any particular symptoms; on the other hand, severe hypophosphatemia (less than 0.3 mmol / L) is usually symptomatic. It is important to note that hypophosphatemia is not necessarily synonymous with phosphate depletion and that, conversely, a phosphate depletion, possibly severe, may exist in the presence of a conserved or lessened phosphatemia.

The clinical consequences of severe hypophosphatemia with phosphate depletion are based on decreased cellular ATP content and red cell contents in 2,3-diphosphoglycerate, the latter being responsible for an increase in hemoglobin affinity for oxygen and cellular hypoxia.

Diagnosis of hypophosphatemia:

The diagnosis of hypophosphatemia is strongly influenced by the context in which it occurs. Thus, a moderate and transient decrease in phosphatemia usually results in a transfer that occurs on the occasion of carbohydrate intake or acute alveolar hyperventilation. Prolonged hypophosphatemia should, on the contrary, lead to consider either a digestive loss of phosphate (global malnutrition, including chronic alcoholism, malabsorption syndromes, use of phosphate chelators) or renal phosphate loss. It is possible to distinguish these two categories of mechanisms by calculating the phosphate renal threshold (TmPi / DFG) as well as by measuring phosphaturia. A renal phosphate excretion threshold unsuitable for hypophosphatemia (low or even normal) and a conserved phosphaturia greater than 5 mmol / 24 h indicate renal phosphate loss; on the contrary, a high renal threshold and a phosphatura CAUSES OF HYPOPHOSPHATEEMIES

Hypophosphatemia of extrarenal origin:

Renutrition:

The initiation of renutrition in malnourished patients, in burns, or in alcoholics, allows a cell regeneration which is likely to be complicated by a hypophosphatemia by transfer, the need for phosphate cell increases suddenly. Such hypophosphatemia is usually prevented by adequate phosphate supplementation with other nutrients: an intake of 0.5 mmol of phosphate per kilogram of ideal body weight per day is required in this situation.

Prolonged use of phosphate binders:

Salts of alumina or magnesium, used in the treatment of peptic ulcers, complex phosphate and may lead to phosphate depletion with hypophosphatemia during prolonged treatments. However, this situation has become rare since the onset of other treatments for ulcerative disease (H 2 -receptors, H / K-ATPase inhibitors).

Hypophosphatemia of renal origin:

Fanconi Syndrome:

Renal phosphate loss is one of the components of Fanconi syndrome, which also includes renal loss of glucose, amino acids and bicarbonate, all indicating a malfunction of the proximal tubule. This syndrome is rare in adults, in whom it occurs during dysglobulinaemia, or poisoning by drugs or heavy metals.

X-linked hypophosphatemic rickets (vitamin D-resistant rickets):

This syndrome, characterized by selective deficiency of phosphate reabsorption in the proximal tubule by decreased activity of Na / Pi cotransport type II, combines renal hypophosphatemia, osteomalacia, and normal or low, unsuitable for hypophosphatemia. The cause of this syndrome is not a mutation of the Type II Na / Pi cotransport gene but an inactivating mutation of the PHEX gene on the X chromosome. The product of this gene is presumably a neutral endopeptidase which normally degrades a circulating factor misidentified (phosphatonin?) inhibitor of cotransport.

A variant of this syndrome associates, in addition to hypophosphatemia and rickets, an increase in the synthesis of calcitriol and hypercalciuria. The mutations involved concern a gene located at 12p13, the identification of which is ongoing.

Oncogenic osteomalacia:

It is defined by the occurrence of a renal loss of phosphate, an osteomalacia and a deficiency of synthesis of calcitriol in a patient carrying a mesenchymal, vascular or other tumor and whose removal causes the disappearance of symptomatology. The hypothesis is that such tumors secrete a thermosensitive factor, inhibitor of cotransport Na / Pi, called “phosphatonin”.

HYPOPHOSPHATEMIC TREATMENT:

Mild hypophosphatemia (0.6-0.8 mmol / L) does not justify special treatment other than that of the underlying causative disease; in particular, an acute transfer hypophosphatemia does not require phosphate intake since the phosphate stock of the organism is unchanged. When hypophosphatemia is moderate (0.4-0.6 mmol / L) or there are signs of phosphate depletion, phosphate intake is often justified in addition to eradication of the cause treatment with antacids, cessation of alcohol poisoning, treatment with vitamin D in case of deficient osteomalacia, balance of diabetes mellitus, etc.). The correction of depletion can be ensured by a supply of milk (each liter containing about 1 g of phosphorus) or an intake by a pharmaceutical preparation. Symptomatic hypophosphatemia is compatible with a deficiency of about 10 g of phosphorus which must be corrected in 1 week to 10 days by a total intake of about 20 g of phosphorus.

Severe symptomatic hypophosphatemia (coma, convulsions, hemolysis, heart failure, etc.) generally justifies the use of parenteral administration.

Finally, in moderate hypophosphatemia of renal origin, prolonged treatment with dipyridamole at a high dose (300 mg / day) has been reported to result in a moderate increase in phosphatemia and in the renal phosphate excretion threshold.

HYPERPHOSPHATEMIC MECHANISMS:

Since renal phosphate behavior is the major determinant of phosphate, hyperphosphatemia can occur when the ability of the kidney to remove phosphate decreases (by decreasing the glomerular filtration rate and / or increasing tubular renal tubular reabsorption of calcium), or when the phosphate inputs increase to such an extent that they exceed the phosphate kidney removal capacity.

SYMPTOMS OF HYPERPHOSPHATEMY:

Hypocalcaemia, possibly symptomatic, is a common complication of hyperphosphatemia, especially when the latter is rapidly established. The mechanism is precipitation of calcium phosphate in soft tissues and inhibition of calcitriol synthesis which induces resistance to the effects of PTH.

Ectopic calcifications (vessels, skin, cornea, periarticular tissue) are common in patients with prolonged hyperphosphatemia, but may also occur during more severe hyperphosphatemia.

Finally, hyperphosphatemia, by inhibiting the synthesis of calcitriol, plays an important role in the pathophysiology of secondary hyperparathyroidism and renal osteodystrophy of chronic renal insufficiency.

CAUSES OF HYPERPHOSPHATEMIA:

The causes of hyperphosphatemia can be grouped according to the main mechanism, increased endogenous or exogenous inputs, or decreased renal elimination capacity.

HYPERPHOSPHATEMIC TREATMENT:

Apart from the treatment of the cause, the treatment of hyperphosphatemia is based on the decrease in phosphate inputs. Since phosphate is widely distributed in the diet, a significant restriction of phosphate inputs is, in practice, impossible without causing overall malnutrition. However, it is desirable to limit moderately the protein intake, which should not exceed 1 g / kg / d.

Essentially, the decrease in phosphate inputs is achieved through the use of phosphate-complexing substances in the lumen of the digestive tract and preventing its absorption by the intestinal mucosa. Although effective, aluminum salts have been abandoned, particularly in chronic renal failure because their prolonged use resulted in an accumulation of aluminum responsible for encephalopathy, osteomalacia, proximal myopathy and anemia. Calcium salts, especially acetate, are nowadays used with an efficiency comparable to aluminum salts.

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