Symptoms of metabolic syndrome in children

Violations, united by the metabolic syndrome, for a long time are asymptomatic, often begin to form in adolescence and adolescence, long before the clinical manifestation of type 2 diabetes, arterial hypertension and atherosclerotic vascular lesions. The earliest manifestations of the metabolic syndrome are dyslipidemia and hypertension. Often not all components of this syndrome occur simultaneously. What phenotype it will manifest depends on the interaction of genetic factors and environmental factors in ontogenesis.

Metabolic syndrome combines a group of metabolic and clinical signs (markers), which can be considered in its framework only in the presence of insulin resistance. Virtually all components of this syndrome are established risk factors for the development of cardiovascular diseases:

• abdominal obesity (the deposition of fat in the abdominal cavity, the anterior abdominal wall, trunk, neck and face - android type of obesity);
• insulin resistance (low sensitivity of cells to insulin);
• hyperinsulinemia;
• a violation of glucose tolerance or type 2 diabetes mellitus;
• arterial hypertension;
• dyslipidemia;
• hyperandrogenia in girls;
• violation of hemostasis (decreased fibrinolytic activity of the blood);
• hyperuricemia;
• microalbuminuria.

In pediatric practice, the preclinical and clinical manifestations of the metabolic syndrome may be masked by the diagnosis of the hypothalamic syndrome of the pubertal period (juvenile dyspititarism, youthful basophilism, etc.).

Hypothalamic syndrome of the pubertal period is the neuroendocrine syndrome of the age-related alteration of the organism with dysfunction of the hypothalamus, pituitary gland and other endocrine glands. This disease can develop as a primary (in individuals with initially normal body weight), and again (in children and adolescents who already have primary, leptin obesity). The disease is more often observed at the age of 10 to 18 years.

Clinical manifestations of the hypothalamic syndrome of the pubertal period: obesity, pink striae on the skin, accelerated physical development, high stature, impaired puberty, abnormal growth of facial and body hair, menstrual irregularities, lability of blood pressure, various vegetative disorders. The uniformity of clinical manifestations of the hypothalamic syndrome of the pubertal period made it possible to distinguish a clinical triad typical for this disease, which includes:

• obesity with pink striae;
• tallness;
• arterial hypertension.

Children and adolescents with a hypothalamic syndrome of the pubertal period (often secondary) are often registered with abdominal obesity, high blood pressure, expressed insulin resistance and hyperinsulinemia, diabetic disorders of carbohydrate and atherogenic disorders of lipid metabolism, which indicates the formation of adolescent metabolic cardiovascular syndrome already in childhood and adolescence .

Obesity

Obesity is the leading clinical marker of metabolic syndrome.

The most simple and reliable methods (criteria) for diagnosing obesity on the basis of fat distribution are:

• measurement of waist circumference (OT), cm;
• Calculation of the ratio of the circumference of the waist to the circumference of the hips (OT / OB).

Regulatory data (nomograms) have now been developed in children. Adolescents can use adult criteria. With abdominal obesity:

• FROM / OB in young men - more than 0.81; girls have more than 1.0;
• From the young men - more than 94 cm, girls - more than 80 cm.

In pediatric practice, obesity is most often subdivided in terms of excess body weight. Its diagnosis is based on measuring the body weight, comparing it with the maximum tabulated index for a child of a given age, sex and height and calculating (in%) its excess. In this case, the degree of obesity is distinguished: I degree - excess weight of body 10-25%, II degree - 26-49%, III degree - 50-99%, IV degree - 100% and more.

In children 2 years and older, to determine the degree of obesity, one can calculate the Quetelet index for a certain age and each sex: BMI = mass (kg) / height (m) ². For example, growth is -1.5 m, body weight is 48 kg; BMI = 48 kg / (1.5 m) ² = 21.3 kg / m ². The body mass within the 85-95th percentile of the BMI is estimated as excessive, over the 95th percentile - as obesity. Assessment of obesity using BMI may be mistaken for athletic-built adolescents.

Classification of obesity depending on the body mass index (WHO, 1997)

Classification of obesity	BMI, kg / m 2
Normal body weight	18.5-24.9
Fatigue	25.0-29.9
Obesity of the 1st degree	30.0-34.9
Obesity of the 2nd degree	35.0-39.9
Obesity of the third degree	> 40.0

Central (abdominal-visceral) obesity is detected by an indirect parameter - measurement of RT, it is independently associated with each of the other components of the metabolic syndrome, including insulin resistance, and should be the main criterion for diagnosis of the metabolic syndrome. In determining the normative parameters for children and adolescents, MDF recommendations (2007) can be used. For adolescents (10-16 years), you can use the OT for adults (Europeans), for children (6-10 years) - parameters that exceed the 90th percentile. Due to the fact that BMI correlates to a lesser degree than OT with visceral fat and insulin resistance, this parameter should be used only to determine the degree of obesity (in children and adolescents, BMI standards are determined using nomograms depending on sex and age). Given that RT is still an indirect parameter for assessing visceral obesity (a direct method is to determine the visceral fat area in CT), identifying as mandatory RT criteria and the HOMA-R index helps to avoid errors in the diagnosis of the metabolic syndrome (both hyper- and hypodiagnosis) in children and adolescents.

Insulin resistance

There are indirect and direct methods for assessing insulin resistance. Indirect indicators characterizing insulin resistance include: PGTT, the level of basal insulinemia and a small model of homeostasis with the definition of the parameter HOMA-R.

HOMA-R is calculated by the formula:

Fasting glycemia, mmol / L x insulin level on an empty stomach, mcD / ml / 22.5.

Indicators HOMA-R, equal to 3-4, regarded as borderline (HOMA-R in the norm - up to 2). Insulin resistance is determined with HOMA-R, equal to 4 or more. Direct methods for evaluating insulin resistance include an insulin tolerance test, an euglycemic hyperinsulinemic test.

Arterial hypertension

At the heart of the pathogenesis of arterial hypertension in the metabolic syndrome is insulin resistance and compensatory hyperinsulinemia caused by it, which serves as the main mechanism that triggers a number of pathological links - renal, cardiovascular, endocrine. The relationship between hyperinsulinemia and hypertension is so obvious that one can always predict the rapid development of hypertension in people with untreated hyperinsulinemia. The latter leads to the development of arterial hypertension through the mechanisms listed below.

• Insulin increases the reabsorption of sodium in the proximal tubules of the kidneys, which leads to hypervolemia and an increase in the sodium and calcium content in the walls of the vessels, causing them to narrow and increase the OPSS.
• Insulin increases the activity of the sympathetic nervous system, thereby increasing cardiac output, causes vasoconstriction and increased OPSS.
• Insulin as a mitogenic factor enhances the proliferation of vascular smooth muscle cells, narrowing their lumen and increasing the OPSS.

Increased OPSS leads to a decrease in renal blood flow, which causes the activation of the renin-angiotensin-aldosterone system. Excessive secretion of renin by the kidneys maintains a persistent increase in systemic arterial pressure and forms arterial hypertension.

In addition, recently discussed mechanisms of the pathogenesis of hypertension in obesity associated with giperleptinemia. With long-term dyslipidemia, atherosclerotic changes in renal vessels develop, which can also lead to the development of renovascular arterial hypertension.

Assessment of blood pressure in children and adolescents is carried out using centile tables depending on gender, age and height. Elevated blood pressure (systolic or diastolic)> 95th percentile for a child of a given age, sex, and height is considered to be elevated.

Dyslipidemia

In conditions of insulin resistance in abdominal-visceral obesity, the disintegration of lipoproteins rich in triglycerides slows down due to a change in lipoprotein lipase activity and liver triglyceridylase. Developing hypertriglyceridemia, which leads to the enrichment of triglycerides of high-density lipoprotein (HDL) and LDL. This increases the concentration of small dense LDL particles and reduces the level of HDL plasma. Excess intake of free fatty acids in the liver contributes to the enhancement of the synthesis of triglycerides and the secretion of very low density lipoproteins and apolipoprotein B.

Dyslipidemia in abdominal-visceral obesity is characterized by:

• increase in the level of free fatty acids;
• hypertriglyceridemia;
• decreased HDL;
• increased LDL;
• increase in the content of fine dense LDL particles;
• increase in the level of apolipoprotein B;
• increased LDL / HDL ratio;
• pronounced postprandial rise in the level of lipoproteins, rich in triglycerides.

The most frequent variant of dyslipidemia in the metabolic syndrome is the lipid triad: a combination of hypertriglyceridemia, low HDL-P and an increase in the fraction of small dense LDL particles.

For patients with visceral obesity, a combination of hyperinsulinemia, an increase in apolipoprotein B, and a fraction of small dense LDL particles, which is called an atherogenic metabolic triad, is also characteristic.

In recent years, many researchers have attached great importance to hypertriglyceridemia, especially in the postprandial period, as a factor accelerating the development of cardiovascular diseases.

Disorders of carbohydrate metabolism

It is necessary to regularly monitor the glycemia in children and adolescents with a metabolic syndrome and identify early violations of carbohydrate metabolism. The following fasting plasma glucose levels are diagnostic value:

• up to 6.1 mmol / l (<110 mg / dl) is the norm;
• > 6.1 (> 110 mg / dl), but <7.0 mmol / l (<126 mg / dl) - impaired fasting glycemia;
• > 7.0 (> 126 mg / dL) is a preliminary diagnosis of diabetes mellitus, which must be confirmed by a re-determination of blood glucose levels on other days.

When carrying out an oral glucose tolerance test, the following values of glucose concentration in blood plasma are used as starting values after 2 hours after loading with glucose:

• <7.8 mmol / l (<140 mg / dl) - normal glucose tolerance;
• > 7.8 mmol / L (> 140 mg / dl), but <11.1 mmol / l (<200 mg / dl) is a violation of glucose tolerance;
• > 11.1 mmol / l (> 200 mg / dL) is a preliminary diagnosis of diabetes mellitus, which must be confirmed by subsequent studies.

Diabetes mellitus type 2

Diabetes mellitus type 2 is now often found at a young age. If earlier the registration of this disease in children and adolescents was reported extremely rarely, at present, the manifestation of type 2 diabetes mellitus at 10-14 years already does not surprise anyone. However, in connection with the erosion of the clinical picture of the disease at this age, its diagnosis is often carried out late.

Stating the determining contribution of genes to the development of type 2 diabetes, it is necessary to isolate diabetogenic genes and nonspecific or accessory genes (genes regulating appetite, energy consumption, accumulation of intra-abdominal fat, etc.) that can be included in risk factors for the development of diabetes mellitus 2-nd type. There is a close relationship between genetic and external factors (irrational diet, low physical activity, diseases, etc.) in the pathogenesis of type 2 diabetes mellitus. About 90% of patients with type 2 diabetes have excessive body weight or obesity. Obesity is the most important modifiable risk factor for this disease, so there has even appeared a special term "DiObesity", i.e. "Di-fat".

At present, numerous studies have established that in most patients with type 2 diabetes mellitus, insulin resistance plays a leading role in the pathogenesis of the disease. In connection with this, since the 90s of the 20th century, type 2 diabetes is classified as a group of clinical markers of the metabolic syndrome.

Diagnostic criteria for type 2 diabetes mellitus, as well as type 1 diabetes, were proposed by WHO (1999). In patients with diabetes mellitus type 2, the disease usually develops slowly, within a few weeks or months. Often, it is diagnosed for the first time during preventive examinations at school or when contacting a doctor for skin itching, furunculosis and other diseases. Sometimes diabetes is diagnosed only when the sick child first consults a doctor about his complications. In retrospect, in many patients it is possible to establish the presence of erased clinical manifestations of diabetes mellitus for a long time: moderate polydipsia and polyuria with predominance at night, increased fatigue, decreased efficiency and progress in school, an increase or inexplicable decrease (in children with excess) of body weight at the saved appetite, susceptibility to various catarrhal and skin diseases and others.

At the same time, 6-9% of children and adolescents with type 2 diabetes have cases with bright manifestations of hyperglycemia (weakness, thirst, itching) and ketoacidosis. In these cases, the clinical symptoms of the disease do not allow verifying the type of diabetes mellitus, and the presence of diabetic ketoacidosis during manifestation does not exclude type 2 diabetes mellitus. However, most often the debut of type 2 diabetes in childhood is characterized by moderately expressed disorders of carbohydrate metabolism against the background of normal basal and increased stimulated secretion of insulin. The most significant risk factors for the development of type 2 diabetes are heredity, obesity, belonging to the female sex.

Violation of carbohydrate metabolism in type 2 diabetes mellitus is characterized by a different degree of compensation. Conditionally, we can distinguish three degrees of severity of type 2 diabetes mellitus. To an easy degree (I degree) include cases of diabetes mellitus, in which compensation for the disease (normoglycemia and aglucosuria) is achieved only by diet. Diabetes mellitus of medium severity (grade II) is characterized by the possibility of achieving compensation for carbohydrate metabolism using either only oral hypoglycemic agents or the latter in combination with insulin. Severe diabetes mellitus (grade III) is considered in the presence of severe vascular complications: microangiopathy (proliferative retinopathy, stage II and III nephropathy), neuropathy. It is important to note that many doctors perceive type 2 diabetes mellitus as a disease of a mild course or a mild form of diabetes mellitus. Often this is due to the assumption of less strict criteria for compensating this disease, which is not true.

Syndrome of hyperandrogenism

More recently - at the end of XX century. - the concept that in the pathogenesis of the polycystic ovary syndrome is involved two interrelated components were proposed and thoroughly argued:

• increased activity of cytochrome P450 C17-a, which determines excessive production of androgens in the ovaries / adrenal glands;
• hyperinsulinemic insulin resistance, leading to multiple defects in the regulation of carbohydrate, fat, purine and other metabolic species.

A lot of convincing information on the existence of a single universal anomaly in the syndrome of polycystic ovaries, which determines the excessive phosphorylation of serine (instead of tyrosine) in both steroidogenic enzymes (17beta-hydroxylase and C17.20-lyase) and substrates of the beta-subunit of the insulin receptor (IRS -1 and IRS-2). However, the final effects of this pathological phenomenon are different: the activity of steroidogenesis enzymes on average doubles, which leads to hyperandrogenism, whereas insulin sensitivity at the post-receptor level in peripheral tissues almost halves, which adversely affects the metabolic state as a whole. Moreover, reactive hyperinsulinism, compensatory in response to the pathological resistance of target cells to insulin, further promotes excessive activation of androgen-synthesizing cells of the ovarian-adrenal complex, which further potentiates the hydrogenation of the organism of the girl and woman, starting from childhood.

From the point of view of classical terminology, the polycystic ovary syndrome is characterized by two obligate signs:

• chronic anovulatory dysfunction of the ovaries, determining the formation of primary infertility;
• a symptom complex of hyperandrogenia, which has distinct clinical (most often) and / or hormonal manifestations.

Polycystic ovary syndrome includes a variety of metabolic disorders due to hyperinsulinism.

Hirsutism is not only a sign of the syndrome of polycystic ovaries, the most vivid and catchy when it comes to medical diagnosis, but also the factor most traumatizing the psyche of girls.

Androgenic alopecia is a reliable diagnostic marker of viral variants of MHA. Like other types of endocrine baldness, it has a diffuse, not focal (nesting) character. However, unlike baldness in other diseases of the glands of internal secretion (primary hypothyroidism, polyglandular insufficiency, panhypopituitarism, etc.) and androgenic alopecia, there is a certain dynamics. As a rule, it manifests as hair loss in the temporal region (bitemporal alopecia with the formation of symptoms of temporal lobes or "secretory advisors" and "widow peak"), and then spreads to the parietal area (parietal alopecia, baldness).

The diagnosis of polycystic ovary syndrome is the diagnosis of an exception. For its verification, in addition to the presence of two clinical inclusion criteria referred to above (anovulation + hyperandrogenism), a third one is necessary - the absence of other endocrine diseases (congenital dysfunction of the adrenal cortex, virilizing tumors, Itenko-Cushing's disease, primary hyperprolactinemia, pathology thyroid gland). In connection with this, the diagnosis of the polycystic ovary syndrome should be completed by three additional examinations (this is extremely important not only and not so much to confirm the diagnosis, but for further use as criteria in the selection of differentiated therapy on an individual basis):

• on the 7th-10th day of the menstrual cycle - gonadotropic index (LH / FSH)> 2, prolactin is normal or insignificantly elevated (in about 20% of cases);
• on the 7-10th day of the menstrual cycle, ultrasound reveals characteristic features;
  • bilateral increase in ovarian volume (more than 6 ml / m ² body surface area, ie taking into account individual parameters of physical development by height and body weight at the time of pelvic ultrasonography);
  • ovarian tissue of polycystic type, i.e. On both sides visualize 10 small immature follicles and more than 8 mm in diameter, as well as an increase in the area of the hyperechoic stroma of the medulla of both ovaries;
  • ovarian-uterine index (mean ovarian volume / uterine thickness)> 3.5;
  • thickening (sclerosis) capsule of both ovaries.

Violations from the coagulation system of blood

In the metabolic syndrome, the increase in the level of fibrinogen and the content of inhibitors of fibrinolysis - factor 7 and an inhibitor of the plasminogen I activator are recorded. This against the background of damage to the vascular wall sharply increases the likelihood of blood clots. In this regard, the use of antiplatelet agents and other drugs that improve microcirculation in the complex treatment of this syndrome is pathogenetically justified.

Hyperuricemia

It has now been shown that the concentration of uric acid in the blood significantly correlates with the degree of severity of abdominal obesity and triglyceridemia, and hypertensive hypertrophy of left ventricular myocardium is more often observed in patients with arterial hypertension and hyperuricemia. For the initial stages of the development of the metabolic syndrome, the development of hyperuricemia is less common. Violation of purine metabolism occurs in parallel with an increase in body weight and the Quetelet index, as well as an increase in the level of triglycerides of blood, i.e. As the formation of a violation of fat metabolism. At the same time, a significant increase in glycemia and the activity of the renin-angiotensin-aldosterone system occurs at later stages of the disease than the appearance of uricemia. Further elevated levels of uric acid in the blood can lead to the development of urate tubolointerstitial nephritis, in which the fibroblast degeneration of the interstitial cells occurs as a result of the immunological mechanism. Hyperuricemia also serves as a factor leading to the progression of cardiovascular damage in the metabolic syndrome, a factor in the progression of hypertension. In addition, the presence of an elevated uric acid level makes additional requirements for the therapy of hypertension. It is known, in particular, that long-term thiazide diuretics contribute to the development and progression of hyperuricemia, hence their use in arterial hypertension associated with the metabolic syndrome should be limited.

Psychological and cardiovascular disorders in children and adolescents with metabolic syndrome

High frequency of registration of anxiety-depressive conditions, violations of cognitive functions, introversion and neuroticism, violations in the emotional-volitional sphere and communicative-interpersonal interactions. The accentuation of certain traits of character (unbalanced, distimate, excitable and anxious types) in children and adolescents with obesity and metabolic syndrome are accompanied by a decrease in their quality of life.

Identified changes in the cardiovascular system in children and adolescents with a metabolic syndrome should be combined into a single cardiovascular syndrome. It is advisable in the structure of markers of metabolic syndrome not to separately isolate arterial hypertension, but to include it as one of the criteria of a single cardiovascular syndrome. This definition is justified and more accurate in its essence, since, on the one hand, there is a reliably confirmed relationship of the metabolic syndrome with the pathology of the heart and blood vessels, and on the other - this relationship is not limited to arterial hypertension. Especially it is necessary to emphasize the fact that in the pathological process in the metabolic syndrome not only the heart but also the vessels of all levels are involved, i.e. We are talking about cardiovascular pathology. Thus, cardiovascular syndrome along with arterial hypertension is represented by a syndrome of vegetative dysfunction (manifested including a violation of heart rate variability), endothelial dysfunction and systolic-diastolic dysfunction of the myocardium. In this case, the severity of the cardiovascular disorders described above in children and adolescents with metabolic syndrome can vary individually and depends on the degree of insulin resistance.

It should be noted that at the stage of obesity and preserved sensitivity to insulin in children and adolescents register the initial shifts in metabolic, psychological and cardiovascular parameters. In the future, with prolonged maintenance of excess body weight in children and the absence of timely corrective measures, these disorders against the background of increasing insulin resistance and chronic compensatory hyperinsulinemia continue to progress and lead to the formation of a vicious circle.

Etiological factor

According to modern ideas, the unifying basis of all manifestations of the metabolic syndrome is primary insulin resistance and concomitant, most likely, genetically caused hyperinsulinemia.

The emergence of insulin resistance is associated with "breakdown" at the receptor and postreceptor levels. Studies show that its nature is polygenic and in particular can be associated with mutations of the following genes: the substrate of the insulin receptor, glycogen synthetase, hormone sensitive lipase, beta3-adrenoreceptors (Trp64Arg (W / R) polymorphism of the beta3-AR gene), TNF- uncoupling protein, and also with molecular defects of proteins transmitting signals of insulin (Rad-protein, glutose intracellular transporters GLUT-1, GLUT-2, GLUT-4).

According to the prevailing opinion, an important role in the development and progression of insulin resistance is played by the accumulation of excess adipose tissue in the abdominal region and the associated neurohormonal and regulatory disorders. Hyperinsulinemia acts, on the one hand, compensatory, that is necessary to overcome insulin resistance and maintain normal transport of glucose into cells; on the other - a pathological factor contributing to the emergence and development of metabolic, hemodynamic and organ disorders, leading ultimately to the development of type 2 diabetes mellitus, dyslipidemia.

Until now, all possible causes and mechanisms of insulin resistance development in abdominal obesity have not been fully studied, not all components of the metabolic syndrome can be related and explained only by this phenomenon. Insulin resistance is a reduction in the reaction of insulin-sensitive tissues to insulin at a sufficient concentration. Among the exogenous factors that stimulate the appearance and progression of insulin resistance, consider hypodynamia, excessive intake of food rich in fats (both animal and vegetable) and carbohydrates, stress, smoking.

Adipose tissue in the abdominal region is divided into visceral (intra-abdominal) and subcutaneous. Adipose tissue has auto-, para- and endocrine function and secrets a large number of substances with different biological effects, which can, in particular, cause the development of obesity-related complications, including insulin resistance. Among them, TNF-a and leptin are found. Many consider TNF-a as a mediator of insulin resistance in obesity. Leptin, secreted predominantly by adipocytes, performs its action at the hypothalamus level, regulating food behavior and activity of the sympathetic nervous system, as well as a number of neuroendocrine functions. A significant increase in the mass of visceral adipose tissue, as a rule, is combined with metabolic disorders, primarily with insulin resistance, which leads to the formation of a vicious circle. An important role in the development and progression of insulin resistance and associated metabolic disorders is played by excessive adipose tissue, accompanying obesity neurohormonal disorders, increased activity of the sympathetic nervous system.

Hormonal disorders in the metabolic syndrome (increased concentration of cortisol, insulin, norepinephrine, testosterone and androstenedione in girls, decreased progesterone, decreased testosterone concentrations in boys and boys) contribute to the deposition of fat mainly in the visceral region, as well as the development of insulin resistance and metabolic disorders at the cell level .

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