Rickets

Rakhit (from the Greek rhachis - "ridge", "spine") was known to doctors in ancient times. In 1650 the English anatomist and orthopedist Glisson described the clinical picture of rickets, which was called "English disease", "slum disease". A significant contribution to the study of rickets was made by Russian pediatric scientists: N.F. Filatov, AA Kissel, G.N. Speransky, A.F. Tour, K.A. Svyatkina, E.M. Lukyanov.

The violation of bone formation is localized mainly in the area of bone epimetamizations (growth zones). Since bone growth and speed of their reorganization (remodeling) are highest in early childhood, bone manifestations of rickets are most pronounced in children of the first 2-3 years of life. Rickets are also characterized by changes in other organs and systems, a decrease in the immune reactivity of the child.

Infant rickets are widespread in children of the first years of life. The first mention of rickets occurs in the writings of Soran of Ephesus (98-138 AD), which revealed a deformation of the lower limbs and spine in children. Galen (131-201 AD) gave a description of the rickety changes in the bone system, including the deformation of the chest. In the Middle Ages, rickets were called English sickness, since it was in England that the prevalence of its severe forms was noted, which was due to insufficient insolation in the given climatic zone. A complete clinical and pathoanatomical description of rickets was made by the English orthopedist Francis Epispison in 1650. In his opinion, the main risk factors for the development of rickets in children are the weighed heredity and maternal nutrition. In 1847, in the book "Pediatrica" S.F. Khotovitsky described not only the defeat of the bone system in rickets, but also changes in the gastrointestinal tract, autonomic disorders, muscle hypotension. In 1891, N.F. Filatov noted that rickets is a common disease of the body, although it manifests, mainly, a peculiar change in bones.

According to modern ideas, rickets is a disease characterized by a temporary discrepancy between the needs of a growing organism in phosphorus and calcium and the inadequacy of their transport systems in the body. It is a disease of a growing organism caused by a metabolic disorder (primarily, phosphorus-calcium metabolism), the main clinical syndrome of which is the defeat of the bone system (disruption of formation, proper growth and mineralization of bones), in which the pathological process is localized mainly in the field of metaepiphysis bones. Since the growth and speed of bone restructuring are highest in early childhood, the lesions of the bone system are most pronounced in children 2-3 years old. Rickets is a multifactorial metabolic disease, in the diagnosis, prevention and treatment of which should take into account all the factors of pathogenesis: insufficiency and imbalance of calcium and phosphorus intake with food, immaturity of the endocrine system of the child, concomitant diseases, etc. In addition to the pathology of phosphorus-calcium metabolism, protein metabolism and microelements (magnesium, copper, iron, etc.), multivitamin deficiency, activation of lipid peroxidation.

ICD-10 code

E55.0. Rickets is active.

Epidemiology of rickets

Rickets are found in all countries, but especially among northern peoples who live in conditions of lack of sunlight. Children born in autumn and winter are more likely to get rickets more heavily. At the beginning of the XX century. Rickets were noted in 50-80% of young children in Western Europe. Up to 70% of children in Ukraine during these years also had rickets. According to A.I. Ryvkina (1985), rickets in children of the first year of life is found up to 56.5%, according to the CB. Maltsev (1987), his prevalence reaches 80%. The disease is most severe in premature infants.

To date, classical (vitamin D-deficient) rickets occupies a significant place in the structure of the incidence of young children. In Russia, its frequency in recent years ranges from 54 to 66%. According to pediatricians in Moscow, classical rickets are currently found in 30% of young children. This indicator can be considered underestimated, because only heavy and moderate forms of the disease are recorded. In developed countries, where specific prevention of rickets with vitamin D and vitaminization of baby foods has been introduced, severe forms of rickets have become rare, but subclinical and radiologic manifestations remain widespread. So. In France, a latent vitamin D deficiency was detected in 39%, and obvious clinical manifestations - in 3% of children admitted to hospitals for various diseases. In the northern provinces of Canada, hypovitaminosis D was detected in 43% of the children surveyed. In southern countries, despite the sufficient intensity of ultraviolet irradiation, rickets remains a very common disease. In Turkey, rickets were detected in 24% of children aged 3-6 months, although the introduction of prevention with vitamin D allowed to reduce its prevalence to 4%.

Rickets, especially of medium and severe severity, suffered in early childhood, can have an adverse effect on the subsequent development of children. Such children develop impaired posture, flat feet, flattening and deformation of pelvic bones, caries, myopia. The role of rickets in the development of osteopenia and osteoporosis, which are widespread in adolescents, is proved. The effects of vitamin D deficiency in childhood are shown in Table. 11-1.

The effects of vitamin D deficiency

Organs	Consequences of the deficit
Bones and bone marrow	Osteoporosis, osteomalacia, myelofibrosis, anemia, myelodic dysplasia
GIT	Decreased absorption of calcium, phosphorus, magnesium, hepatolienal syndrome, a violation of the motility of the gastrointestinal tract
Lymphoid system	Decreased immunity, synthesis of interleukins 1, 2, phagocytosis, production of interferon. Inadequate expression of la antigen, realizing predisposition to atopy
Muscular system	Muscular hypotension, convulsions (spasmophilia)

[1], [2], [3], [4], [5], [6], [7], [8],

Causes of rickets

The main etiologic factor of rickets is vitamin D deficiency. At the same time, rickets is considered as a multifactorial disease, in which there is a discrepancy between the high demand of a growing child in phosphorus-calcium salts and the inadequate development of regulatory systems ensuring the supply of these salts to the tissues.

There are two ways to provide the body with vitamin D: the intake of food and the formation of the skin under the influence of ultraviolet rays. The first way is associated with the intake of cholecalciferol (vitamin D3) with products of animal origin (cod liver, fish caviar, egg yolk, to a lesser extent - female and cow's milk, butter). In vegetable oils, ergocalciferol (vitamin D2) can occur. The second way is associated with the formation of vitamin D in the skin of 7-dehydrocholesterol under the influence of ultraviolet rays with a wavelength of 280-310 microns. It used to be believed that these two ways of providing vitamin D are equivalent. However, recently it became known that more than 90% of vitamin D is synthesized by ultraviolet irradiation, and 10% comes from food. Under favorable conditions, the necessary amount of vitamin D is formed in the baby's skin. In case of insufficient insolation due to climatic conditions (smoke, atmospheric air, clouds, fogs), the intensity of vitamin D synthesis decreases.

[9], [10], [11], [12], [13], [14], [15], [16],

Formation of active metabolites of vitamin D

Entering the body, vitamin D is converted into more active metabolites through complex transformations in the liver and kidneys.

The first stage of activation is due to the fact that the vitamin D that enters the digestive tract or formed in the skin is transported to the liver, where it is converted into 25-hydroxycholecalciferol, or calcidiol, under the influence of the enzyme 25-hydroxylase, the main form of vitamin D circulating in the blood. In healthy children, the content of 25-hydroxycholecalciferol in the serum is about 20-40 ng / ml.

The second stage of vitamin D metabolism is repeated hydroxylation in the kidneys, where 25-hydroxycholecalciferol is transferred with the help of vitamin D-binding protein (transcalciferin). At the level of mitochondria of the kidneys, the most active metabolite is formed - 1,25-dihydroxycholecalciferol, or calcitriol, as well as 24,25-dihydroxycholecalciferol. The formation of the main metabolite - calcitriol - occurs with the participation of the renal enzyme 1-a-hydroxylase. The concentration of calcitriol in blood plasma is about 20-40 pg / ml.

The content of metabolites of vitamin D in the blood serves as an objective criterion for the provision of the child with vitamin D.

[17], [18], [19], [20], [21], [22]

The basic physiological function of vitamin D

The main physiological function of vitamin D is the control of the transport of calcium ions in the body (hence the name "calciferol" - "carrier calcium") - by regulating the absorption of calcium ions in the intestine and enhancing reabsorption in the renal tubules, as well as stimulating the mineralization of bone tissue. When the level of calcium and inorganic phosphates in the blood decreases or when the secretion of parathyroid hormone increases, the activity of renal 1-a-hydroxylase and the synthesis of 1,25-dihydroxycholecalciferol are sharply increased.

At normal and elevated levels of calcium and phosphorus, another enzyme of the kidneys, 24-hydroxylase, is activated in the plasma, with the participation of which 24,25-dihydroxycholecalciferol is synthesized, which contributes to the deposition of calcium and phosphates in the bone tissue and suppresses the secretion of parathyroid hormone.

In recent years, the concept of the role of vitamin D has been significantly supplemented by data on the conversion of this vitamin in the body, which led to a change in views on vitamin D as a typical vitamin. According to modern ideas, vitamin D should be considered a potent hormone-active compound, as, like hormones, it affects specific receptors. It is known that the metabolite of vitamin D (1,25-dihydroxycholecalciferol) transmits a signal to the gene device (DNA) of cells and activates genes that control the synthesis of functional transport proteins for calcium ions. Target organs for this metabolite are the intestines, kidneys, bones. In the intestine, vitamin D stimulates absorption of calcium and equivalent amounts of inorganic phosphates. In kidneys with his participation, active reabsorption of calcium and inorganic phosphates takes place. Vitamin D regulates the mineralization of cartilage tissue, bone apatites. It is believed that the metabolite plays an important role in the embryogenesis of bone tissue.

Vitamin D is involved in the regulation of the activity of the enzymes of the main bioenergetic cycle of Krebs, enhances the synthesis of citric acid. It is known that citrates are part of the bone tissue.

Vitamin D and its active metabolites affect the cells of the immune system, therefore, with vitamin D deficiency, infants develop secondary immune deficiency (phagocytosis activity, interleukin 1 and 2 production, interferon production).

Neuroendocrine regulation of phosphorus-calcium metabolism is carried out by the secretion of parathyroid hormone. The decrease in the level of ionized calcium, associated with vitamin D deficiency, serves as a signal for increasing the level of parathyroid hormone. Under the influence of parathyroid hormone, calcium of bone apatites passes into a soluble form, due to which the level of ionized calcium can be restored. The antagonist of parathyroid hormone is calcitonin. Under its influence, the content of ionized calcium in the blood serum decreases, the processes of bone mineralization increase.

What causes rickets?

Pathogenesis of rickets

The process of formation of rickets is complex and depends on many factors, but primarily on the factors that regulate the phosphorus-calcium balance. In the complex picture of the pathogenesis of rickets, cause and effect are constantly changing places, so it is difficult to determine what is primary in rickets and what is secondary. Conditionally, there are several stages in the development of the disease.

First step

Due to vitamin D deficiency, the permeability of cell membranes in the intestine changes, which leads to a violation of calcium absorption. In response to hypocalcemia, parathyroid gland activity is activated. Parathyroid hormone slows the reabsorption of phosphate in the kidneys. In addition, with vitamin D deficiency, inorganic phosphorus is not cleaved from organic compounds contained in food. All this leads to a decrease in the level of phosphorus. Hypophosphatemia is one of the first biochemical manifestations of rickets. The level of calcium during this period is normal, as the parathyroid hormone enhances the formation of 1, 25-dihydroxycholecalciferol and temporarily increases the resorption of bone tissue, and also simultaneously increases the intake of calcium from the intestine.

[23], [24], [25], [26], [27], [28], [29], [30]

Second phase

As the calcium deficiency increases, not only calcium absorption in the intestine is disrupted in the body, but its mobilization from the skeleton becomes clearly inadequate, which leads to a decrease in the level of calcium and phosphorus in the blood serum. As a result, the synthesis of the organic matrix of bone tissue, the growth of bones, their mineralization are violated, the phenomena of osteoporosis (uniform decrease of bone volume and other signs) and osteomalacia develop (bones soften and easily curl). There can be a proliferation of defective osteoid tissue due to the accumulation of osteoclasts in different areas, since parathyroid hormone stimulates their formation. The activity of alkaline phosphatase, produced by osteoclasts, increases.

In rickets, muscle tone is disturbed, which contributes to the development of diffuse ricketsic muscular hypotension. In addition, electrolyte imbalance leads to a disruption in the relationship between the sympathetic and parasympathetic parts of the autonomic nervous system and the development of autonomic dysfunction.

The third stage

Hypophosphatemia causes a decrease in the alkaline reserve of blood and the development of acidosis, which is accompanied by a violation of the exchange of proteins, fats and carbohydrates. There is a decrease in the level of citrates in the blood because of insufficient formation of them from pyruvic acid in the tricarboxylic acid cycle. In the case of rickets, the metabolism of calcium and phosphorus, as well as other trace elements (magnesium, potassium, iron, zinc, etc.) is disturbed, so rickets is a disease accompanied by a violation not only of phosphorus-calcium, but all other types of metabolism.

Pathogenesis of rickets

Symptoms of rickets

The first symptoms of rickets appear already at the age of 1-2 months, and the unfolded clinical picture is usually observed at the age of 3-6 months. Initial clinical signs of the disease (sweating, decreased appetite, persistent red dermographism, increased excitability) arise from a violation of the functional state of the autonomic nervous system. Soon the dream may get worse, the child begins to turn his head, there is a "baldness" of the nape. It is important to emphasize that identifying only the symptoms of a violation of the autonomic nervous system is not a basis for establishing the diagnosis of "rickets." For the diagnosis is necessary to have changes in the bone system: softening along the cranial sutures (craniotabes), pain when pressing on the skull bones, yielding the edges of the large fontanelle, flattening the occiput. Due to hyperplasia of the osteoid tissue in rickets, hypertrophied parietal and frontal tubercles, "rachitic beads", thickening of the epiphyses of the forearm bones ("rachitic bracelets") can form. With severe rickets, one can observe an impending "Olympic forehead", which has sunk in the bridge of the nose. The front part of the chest with the breastbone protrudes forward, resembling a chicken breast. There is an arcuate curvature of the lumbar spine - pathological kyphosis (rachis hump). The ribs become soft, supple, the thorax deforms, flattenes laterally, its lower aperture widens. At the point of attachment of the diaphragm, ribs are drawn in, the so-called Harrison furrow. Hypotension of the muscles of the anterior abdominal wall leads to the formation of a characteristic "frog's stomach". In addition to muscle hypotension, weakness of the ligamentous apparatus is observed (joint looseness, phenomenon of "gutta-percha boy").

When the child starts to get up, O-or X-shaped curvature of the legs develops (depending on the predominance of flexor muscles or extensor flexion).

In patients with rickets, the closure of fontanelles and sutures, the later eruption of teeth, defects of tooth enamel are observed, and the development of early caries is characteristic.

In addition to bone and muscle disorders, this disease can have functional changes on the part of the respiratory system (due to the weakness of the respiratory musculature and chest deformation). In a number of cases, due to pronounced muscular hypotension, a slight enlargement of the heart borders is possible. On the ECG, the intervals QT, PQ, and, more rarely, the repolarization violation are noted.

Symptoms of rickets

Classification of rickets

In Russia it is customary to use the classification of rickets proposed by S.O. Dulicki (1947). According to this classification, the severity of rickets (light, medium, heavy), the periods of the disease (initial, high, convalescence, residual phenomena), as well as the nature of the current (acute, subacute, recurrent) are distinguished. In 1990, E.M. Lukyanova et al. Proposed to add to the classification three clinical variants of rickets, taking into account the leading mineral deficiency (calcipenic, phosphoropenic, without deviations in the calcium content and inorganic phosphorus in the blood serum).

The severity of rickets is assessed taking into account the severity of disorders in the bone system, as well as vegetative changes, muscle hypotension, changes in other organs. For rickets of an easy degree, changes in the bone system are characteristic against the background of pathological changes in the functional state of the autonomic nervous system. With moderate rickets, changes in the bone system are more pronounced, muscle hypotension develops. In severe rickets, along with pronounced bone changes and diffuse muscular hypotension, a delay in the development of motor, static functions, as well as impairment of the functions of many internal organs and systems (lung, cardiovascular system, etc.) is observed.

The acute course of rickets is most often noted in children of the first half of life, born with a mass of more than 4 kg, or in children with a large monthly increase. The subacute course of rickets is typical for children with intrauterine or postnatal hypotrophy, as well as for prematurity. In subacute rickets, the signs of osteoid hyperplasia predominate over the signs of osteomalacia, in addition, all the symptoms develop more slowly than with acute rickets. For recurrent rickets, periods of clinical improvement and deterioration are characteristic.

In the calcitic version of rickets, the level of total and ionized calcium in the blood is reduced in children. With the leading role of calcium deficiency, bone deformities are expressed with predominance of osteomalacia processes, increased neuromuscular excitability. In the phosphoropenic variant of rickets, a decrease in the level of inorganic phosphorus in the blood serum is observed. Bone changes are more pronounced due to osteoid hyperplasia, weakness of the ligamentous apparatus. For rickets with minor deviations in the content of calcium and inorganic phosphorus in the blood are characterized by subacute flow, moderate hyperplasia of the osteoid tissue, the absence of distinct changes from the nervous and muscular systems.

[31], [32], [33]

Diagnosis of rickets

Laboratory criteria for active rickets

• decrease in the content of inorganic phosphates in the serum to 0.6-0.8 mmol / l;
• decrease in the concentration of total calcium in the blood to 2.0 mmol / l;
• decrease in ionized calcium content less than 1.0 mmol / l;
• increase of activity of alkaline phosphatase in blood serum in 1,5-2,0 times;
• reduction of 25-hydroxycholecalciferol in blood serum up to 20 ng / ml and below;
• a decrease in the level of 1, 25-dihydroxycholecalciferol in the blood serum to 10-15 pg / ml;
• compensated metabolic hyperchloremic acidosis with a deficiency of bases to 5.0-10.0 mmol / l.

X-ray criteria of rickets

On radiographs, the disturbance of the mineralization of bone tissue is manifested by the following signs:

• changes in the sharpness of the borders between the epiphysis and metaphysis (ie, in the zones of preliminary calcification the boundary becomes uneven, fuzzy, fimbriated);
• progressive osteoporosis in places of maximum bone growth, an increase in the distance between the epiphysis and diaphysis due to increasing metaphysis;
• violation of the contours and structure of the epiphyses ("saucer-like epiphyses"). X-ray signs in the course of the development of the disease are changing.

Differential diagnosis of rickets is carried out with other diseases that have similar clinical symptoms: renal tubular acidosis, vitamin D-dependent rickets, phosphate-diabetes, Debray de Toni-Fanconi's disease, hypophosphatase, cystinosis.

Diagnosis of rickets

[34], [35], [36], [37], [38], [39],

Treatment of rickets

Treatment of rickets should be comprehensive, it is necessary to prescribe therapeutic doses of vitamin D, as well as the use of medical and recreational activities. Depending on the degree of severity, therapeutic doses of vitamin D are 2000-5000 IU / day for 30-45 days. At the beginning of treatment, vitamin D is prescribed in a minimum dose of 2000 IU for 3-5 days, with good tolerability, the dose is increased to an individual therapeutic dose. After achieving the therapeutic effect, the therapeutic dose is replaced with a prophylactic dose (400-500 IU / day), which the child receives during the first 2 years of life and during the winter in the third year of life.

For the treatment and prevention of rickets for many years use preparations of vitamin D (solutions of ergocalciferol or cholecalciferol). The forms of release of many drugs cause certain problems due to the complexity of dosing. So, in recent years alcohol solution of vitamin D2 is practically not released because of the danger of overdose. For the treatment and prevention of rickets, you can use vigantol - an oil solution of vitamin D3 (in one drop - 600 IU) and domestic oil solutions of vitamin D2 (in one drop - 700 IU). However, the oil forms of vitamin D are not always well absorbed, therefore, in the syndrome of impaired intestinal absorption (celiac disease, exudative enteropathy, etc.), vitamin D oil solutions are used in a limited way. In recent years, for the prevention and treatment of rickets widely used aqueous form of vitamin D3 - aquadetrim, which has a convenient for taking and clear dosage form. One drop of cholecalciferol solution (aquadetrim) contains 500 IU of vitamin D3. The advantage of an aqueous solution is rapid absorption from the digestive tract. The solution is well absorbed and does not cause dyspeptic disorders.

In the presence of children with rickets in children with concomitant acute diseases (ARVI, pneumonia, etc.), vitamin D should be canceled for a period of high temperature (2-3 days), and then again appointed in a therapeutic dose.

In addition to vitamin D, in the treatment of rickets, calcium preparations are prescribed: calcium glycerophosphate (0.05-0.1 g / day), calcium gluconate (0.25-0.75 g / day), etc. To increase the absorption of calcium in the intestine, Citrate mixture, lemon juice or grapefruit juice. To normalize the function of the central and autonomic nervous system, magnesium and potassium aspartate (asparkam, panangin) are prescribed, as well as glycine. If rickets occur against a background of hypotrophy, you can prescribe a 20% aqueous solution of carnitine (carnitine chloride) from the calculation of 50 mg / (kghsut) for 20-30 days. Carnitine chloride contributes to the normalization of metabolic processes, under its influence, the indicators of physical development improve. In addition, orotic acid (potassium orotate) can be used at a rate of 20 mg / (kilogram). It is known that orotic acid enhances the synthesis of calcium-binding protein in intestinal enterocytes. Of particular importance is the use of antioxidants: tocopherol acetate (vitamin D) in combination with ascorbic acid (vitamin D), glutamic acid, beta-carotene. After 2 weeks from the beginning of drug therapy to the complex of therapeutic measures, all children are required to add exercise therapy and massage. After the end of medical treatment, children over six months are prescribed therapeutic baths (salt, coniferous).

Treatment of rickets

Prevention of rickets

There are antenatal and postnatal prophylaxis. It can be nonspecific and specific (using vitamin D).

Antenatal prophylaxis of rickets

Antenatal prophylaxis of rickets begins before the birth of a child. When patronizing pregnant women pay attention to the future mother for observing the daily routine, sufficient stay in the fresh air, on a rational diet. Pregnant women should consume at least 200 grams of meat, 100 grams of fish, 150 g of cottage cheese, 30 g of cheese, 0.5 l of milk or kefir, fruits and vegetables. In the last 2 months of pregnancy a woman should receive vitamin D daily for 500 IU, in the autumn-winter period - for 1000 IU. Pregnant women from risk groups (nephropathy, chronic extragenital pathology, diabetes mellitus, hypertension) need to prescribe vitamin D at a dosage of 1000-1500 IU from the 28-32th week of pregnancy.

[40], [41], [42], [43], [44], [45], [46], [47], [48],

Postnatal prevention

The main components of postnatal prophylaxis of rickets in children: outdoor walks, massage, gymnastics, natural feeding, timely introduction of yolk and other kinds of complementary foods. In the absence of breast milk, it is recommended to use modern adapted mixtures.

Postnatal specific prevention of rickets is carried out with the help of vitamin D. According to WHO experts, for healthy term infants, the minimum dose is up to 500 M E / day. This dose in the conditions of the middle band of Russia is prescribed in the spring, autumn and winter periods beginning at the 3- or 4-week age. With sufficient insolation of the child from June to September, specific prevention with vitamin D is not carried out, but in the case of cloudy summer, especially in the northern regions, specific prevention of rickets is carried out in the summer months. Preventive prescription of vitamin D is carried out during the first and second years of life.

Specific prophylaxis of rickets in prematurity has its own characteristics. Rickets of prematurity is osteopenia associated with deficiency of calcium and phosphorus, immaturity of the child, hypoplasia of bone tissue, insufficiency of its mineralization and rapid growth rate of bones in the postnatal period. Children with prematurity I degree vitamin D prescribed from 10-14 days of life at a dose of 400-1000 IU / day daily for the first 2 years, excluding the summer months. With prematurity of II-III degree, vitamin D is prescribed in a dose of 1000-2000 IU / day daily during the first year of life, and in the second year at a dose of 500-1000 IU / day, excluding summer months. The higher doses and early prescription of vitamin D, used in premature infants, can be explained by the fact that breast milk does not meet the need for these children in calcium and phosphorus.

Contraindications for the preventive administration of vitamin D: idiopathic hypercalciuria, organic CNS lesions with craniostenosis and microcephaly, hypophosphatase. Relative contraindications: small size of the fontanelle or its early closure. Such children should be delayed prophylaxis of rickets from 3-4 months of age. In such cases, an alternative may also be the appointment of sub-erythemic doses of UFD (1/2 biodosys) 15-20 procedures every other day, at least 2 courses per year for the first 2 years of life.

How to prevent rickets?

Prognosis for rickets

With early diagnosis of rickets and appropriate treatment, the disease proceeds favorably and without consequences. Without treatment, medium to severe rickets may adversely affect the subsequent development of children. There is flattening and deformation of the pelvis, flat feet, myopia, there may be multiple lesions of the teeth (caries). Infants suffering from rickets are prone to frequent acute respiratory infections, pneumonia, etc.

Under the clinical supervision (quarterly inspection) for 3 years should be children who have suffered moderate and severe rickets. Specific prevention is carried out during the second year of life in the autumn, winter and spring periods, and in the third year of life - only in winter.

Rickets are not contraindicated. The planned preventive vaccination can be done 2 weeks after the appointment of vitamin D.

Bibliography

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[49], [50], [51], [52]