Tubulopathy manifested by rickets like syndrome
Vitamin D-resistant rickets( phosphate-diabetes) .The leading signs are ricket-like changes in the skeleton, mainly the lower extremities. Most often, the first signs of vitamin D-resistant rickets appear in the second year of life and are progressive.
However, the manifestation( the first manifestation) of vitamin D-resistant rickets may be in the first year of life( early manifestation) and at 6-8 years of age( late manifestation).Changes in the bone system are accompanied by a delay in physical development and a violation of the child's gait( "duck walk").Changes in the skeleton are progressive and contribute to the retardation of the development of the static-motor functions of the sick child. Intellect of children, as a rule, does not suffer. Typical biochemical signs of phosphate-diabetes are: low serum phosphorus levels, increased excretion of phosphate in the urine;the blood calcium level remains, as a rule, normal. The activity of alkaline phosphatase of blood is increased.
The body's resistance to vitamin D was first described in 1937. Initially, it was associated with a violation of calcium absorption in the intestine, secondary hyperparathyroidism( increased function of the parathyroid glands), and a decrease in the reabsorption( reverse absorption) of phosphates in the kidneys. However, in the following this mechanism was not confirmed, usually the content of calcium in the blood of patients does not change, the activity of parathyroid hormone( parathyroid hormone) is significantly increased.
A decrease in the concentration of phosphate in the blood plasma leads to an increase in their reabsorption in the proximal tubules. Parathyroid hormone( the parathyroid hormone hormone) plays the main regulating role, its increase in blood concentration suppresses the reabsorption of phosphates, which leads to the appearance of its excess in the urine. In the distal tubules, the reabsorption of phosphates is also inhibited by parathyroid hormone.
Vitamin D enhances the reabsorption of phosphate in the renal tubules, ie, the effect of this substance is the opposite of the effect of parathyroid hormone and is localized in the proximal tubules.
At present, there are 4 hypotheses according to which the following metabolic and functional disorders can lie at the basis of phosphate-diabetes:
1) primary defect in disturbance of absorption processes of calcium and phosphorus in the intestine;
2) tubulopathy with a primary disruption of the reabsorption of phosphates in the renal tubules;
3) genetically determined combined defect of renal tubules and intestines;
4) a violation of the synthesis of vitamin D and insufficient formation of its active forms in the liver.
As a result of genetic defects in the transport of phosphates in phosphate-diabetes, a significant deficit of phosphorus and calcium in the body develops, which leads to the formation of ricket-like changes in the skeleton. This is facilitated in some cases by the excessive secretion of parathyroid hormone( the hormone of the parathyroid glands).Phosphate-diabetes is characterized by a pronounced variety of clinical manifestations. Depending on the timing of the manifestation( the first manifestation), clinical and biochemical features, the nature of the response to the introduction of vitamin D, there are 4 variants of the disease.
The first variant of is characterized by early manifestation of the disease( at the 1 st year of life), a minor degree of bone deformities, a decrease in the calcium content in the blood, an increase in the release of phosphorus in the urine, an increase in the level of parathyroid hormone in the blood, a good tolerance of vitamin D.variant of the disease is associated with simultaneous involvement in the pathological process of the intestine and renal tubules and significant losses of phosphorus and calcium through the intestine and kidneys.
The second variant of is characterized by a later manifestation - at the 2nd year of life, expressed by bone changes, a decrease in the amount of phosphorus in the serum, urinary excretion of a significant amount of phosphate, resistance to high doses of vitamin D. Development of this variant of the diseaseis caused by the primary defect of the renal tubules( decrease in the intensity of the reverse absorption of phosphates) and phosphate losses, mainly in the urine.
The third variant of is characterized by a late manifestation of the disease - at 5-6 years of age, the severity of skeletal anomalies, a marked decrease in the amount of calcium in the blood serum, a significant decrease in absorption of phosphate in the intestine with a normal or insignificant excretion of these compounds in the urine. There is marked resistance( resistance) to vitamin D. The development of this variant of the disease is associated with the predominant involvement in the pathological process of the intestine and a violation of absorption and assimilation of phosphorus and calcium in the intestine.
The 4th variant of is characterized by increased sensitivity to vitamin D and the tendency to develop a clinical and biochemical picture of hypervitaminosis D( vomiting, nausea, thirst, increased calcium content in the blood, as well as increased excretion from the urine) in response to smalldose of vitamin D. Clinically characterized by manifestation at the 2nd year of life and a moderate degree of bone deformities.
The contingent for a special examination for phosphate-diabetes is children:
1) with the clinic vitamin D-deficient rickets and the lack of the effect of conventional antirherapeutic therapy with vitamin D;
2) having one of the parents with a rickets-like disease;
3) with bone deformities of the lower limbs;
4) from families with impaired phosphoric-calcium metabolism.
The main criteria for diagnosis of phosphate-diabetes are:
1) clinical manifestations:
a) progressive nature of bone deformities of the lower limbs;B) lag in physical development;
2) type of inheritance:
a) dominant;B) linked to the X chromosome;
3) biochemical abnormalities:
a) low serum phosphorus levels;B) an increase in the excretion of phosphorus in the urine;
c) normal values of total blood calcium;D) increase of activity of alkaline phosphatase of blood;E) increasing the level of parathyroid hormone in the blood;
e) reduced absorption of calcium and phosphorus in the intestine.
Features of treatment of phosphate-diabetes. Apply conservative and surgical methods of treatment. Drug treatment should be carried out taking into account individual drug tolerance, activity of the process in bone tissue and clinical and biochemical variants of the disease.
Indications for conservative therapy are: active process in bone tissue( by X-ray data), increased activity of alkaline phosphatase of blood, increased excretion of phosphate in urine, preparation of children for surgical correction.
Contraindications for conservative therapy with vitamin D are individual intolerance to vitamin D, excessive excretion of calcium in the urine, the lack of an active process in the bone tissue according to laboratory and radiological studies.
The main drugs in therapy are vitamin D and its metabolites. The initial dose of vitamin D is 10 000-15 000 units per day. Increase in initial doses of vitamin D should be carried out under the control of calcium and phosphorus levels of blood serum and urine, the activity of alkaline phosphatase of blood, the study of which should be carried out every 10-14 days. The increase in blood phosphorus levels, the decrease in the activity of alkaline phosphatase of blood, and the restoration of the structure of bone tissue on the basis of X-ray data give grounds not to increase the dose of vitamin D. The maximum daily doses of vitamin D depending on the variants of phosphate-diabetes are: for the 1st variant, 85-100 thousand units per day, with the second - 150-200 thousand units per day, with the third - 200-300 thousand units per day. At the 4th variant the appointment of vitamin D is contraindicated. Of the metabolites of vitamin D, a domestic preparation is used - oxydevit in a daily dose of 0.25-3 μg. When it is used, especially strict control of the level of blood calcium is required( it is determined once every 7-10 days);In the outpatient setting, a Sulkovich trial can be used for these purposes.
Calcium( calcium gluconate or calcium chloride) and phosphorus( inorganic phosphates, phytin or calcium glycerophosphate) are necessarily used in the complex treatment of phosphate-diabetes. To improve the absorption of calcium and phosphate in the intestine is recommended a long( 5-6 months) application inside citrate mixtures( citric acid, sodium citrate and distilled water) to 20-50 ml per day. In the active phase of the disease, when there may be pain in the bones and joints, a two-week bed rest is recommended. During the period of clinical-laboratory remission and observation in polyclinic conditions, it is recommended to limit physical exertion( prohibition of jumping, exercise by special gentle program), medical massage, salt-coniferous baths, sanatorium treatment. The indicators of the effectiveness of conservative therapy are: improving the general condition, increasing the growth rate of children, normalizing or significantly improving the parameters of phosphorus-calcium metabolism, lowering the activity of alkaline phosphatase and positive development of structural changes in bone tissue( according to the X-ray study).
Comprehensive treatment with massive doses of vitamin D should be carried out under constant medical supervision of the individual reactions of the child( daily monitoring) and calcium and phosphorus levels of blood and urine( their levels are determined every 10-14 days).The appearance of clinical signs of hypervitaminosis D( thirst, vomiting, abdominal pain, refusal to eat) or biochemical signs( increased blood calcium, increased excretion in the urine) is an indication for the abolition of vitamin D or its metabolites.
A prerequisite for conducting surgical treatment is the achievement of a stable clinical and biochemical remission for at least 2 years.
Vitamin D-dependent rickets( pseudovitamin D-deficiency rickets). The first signs of vitamin D-dependent rickets are characterized by functional changes in the central nervous system, which is manifested by increased sweating, sleep disturbance, and startle. Later, bone changes( deformations of the lower limbs, thorax, skulls, rachitic "rosary", "bracelets") are added. Sometimes, against the background of these changes, children experience short-term convulsions, often caused by an increase in body temperature. Most often, vitamin D-dependent rickets develops during the first 3-5 months of a child's life and has a progressive nature, despite previous prevention of rickets or usually conducted anti-cancer treatment. Less often the disease can begin at the age of 3-5 years.
The disease is characterized by the following biochemical disorders: low serum calcium, normal or slightly reduced blood phosphate levels, increased activity of alkaline phosphatase of blood, a significant decrease in the release of calcium in the urine, an increase in the number of amino acids excreted per day in urine. Deficiency of vitamin D and its active metabolites is accompanied by an increase in the production of parathyroid hormone, which leads to the appearance in the urine of phosphates and amino acids( phosphaturia and aminoaciduria, respectively).
Vitamin D-dependent rickets are caused by an autosomal recessive type of inheritance, but sporadic cases of the disease, which are apparently characterized by fresh primary mutations, are often observed. Depending on the depth of metabolic disorders, two clinical and biochemical variants of D-dependent rickets are distinguished with a severe and moderate degree of expression of metabolic disorders and bone deformities.
The primary variant is characterized by severe bone changes( deformities of the lower limbs, deformations of the chest, forearm), marked decrease in calcium concentration in the blood( hypocalcemia), high rates of alkaline phosphatase activity, deep bone structure abnormalities based on X-ray data.
The second variant is characterized by mild or moderate deformities of bones, especially of the lower extremities, a moderate decrease in serum calcium, and non-structured changes in the structure of bone tissue from x-ray data.
The development of the first variant is associated with a pronounced vitamin D deficiency, and the second variant - with a decrease in the sensitivity of the organs to this compound.
Symptoms for a special examination:
1) marked and progressive ricketic changes in the skeleton;
2) lack of curative effect from preventive therapeutic doses of vitamin D;
3) convulsive syndrome of unclear origin combined with rickety changes in young children. Specific features of metabolic disorders in this pathology include:
1) decreased serum calcium( hypocalcemia);
2) increased activity of alkaline phosphatase of blood;
3) increased excretion of phosphates and amino acids in urine;
4) normal levels of vitamin D blood.
Efficacy of anti-cancer treatment: no effect, despite anti-cancer treatment with vitamin D.
The greatest difficulties arise when distinguishing between vitamin D-dependent and normal rickets in young children. The main arguments in favor of vitamin D-dependent rickets are: the progressive nature of bone deformities, in spite of the traditional anti-cancer treatment, low serum calcium and normal vitamin D. As a diagnostic test, a control injection of vitamin D at a dose of 4000 units per day for6-8 weeks. With vitamin D-deficiency rickets, clinical and biochemical parameters normalize, and when D-dependent this dose is ineffective. Due to the fact that vitamin D deficiency is the leading factor in the development of the disease, oxide replacement is the most suitable alternative to biologically active vitamin D. Daily doses of oxydevitum are prescribed depending on the individual tolerability and severity of the course of the disease. In the absence of oxydevit, vitamin D can be used. Initial doses are 10-15 thousand units, maximum - 40-60 thousand units per day.
It is recommended to include calcium preparations( calcium gluconate) and phosphorus( phytin), vitamins A, C, E, citrate mixtures for 3-5 months in a complex of therapeutic agents.
When using preparations of vitamin D, especially its active metabolites, a systematic( once in 10-14 days) control of the level of calcium and phosphorus of blood and their excretion in the urine is necessary. An increase in the calcium content of the blood or its excretion in the urine testifies to the development of hypervitaminosis D and requires the withdrawal of the drug. The repeated administration of vitamin D or oxydevitum is possible only after 7-10 days at half( from the original) dose with careful clinical and laboratory monitoring.
In children with vitamin D-dependent rickets, the positive dynamics of the parameters of phosphorus-calcium metabolism on the background of treatment usually comes in 4-6 weeks after the beginning of the complex therapy. It should be borne in mind that after the withdrawal of vitamin D preparations in children( usually in 3-6 months), there may be an exacerbation, the re-emergence of clinical symptoms of the disease, so treatment of patients should be carried out continuously for several years. With early prescribed and adequate therapy, especially when using oxydevit, clinical and biochemical signs of the disease in young children are reversed. In cases of late diagnosis, when severe and gross bone deformities of the lower limbs that impede movement have already developed, surgical treatment is indicated.