Symptoms of metabolic syndrome in children

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

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

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

In pediatric practice, preclinical and clinical manifestations of metabolic syndrome can often be hidden under the guise of a diagnosis of hypothalamic syndrome of puberty (juvenile dyspituitarism, juvenile basophilism, etc.).

Hypothalamic syndrome of puberty is a neuroendocrine syndrome of age-related restructuring of the body with dysfunction of the hypothalamus, pituitary gland and other endocrine glands. This disease can develop both primarily (in people with initially normal body weight) and secondarily (in children and adolescents who already have primary, leptin obesity). The disease is most often observed at the age of 10 to 18 years.

Clinical manifestations of hypothalamic syndrome of puberty: obesity, pink striae on the skin, accelerated physical development, tall stature, disorders of puberty, abnormal growth of hair on the face and body, menstrual dysfunction, lability of blood pressure, various vegetative disorders. The uniformity of clinical manifestations of hypothalamic syndrome of puberty allowed to identify a clinical triad characteristic of this disease, which includes:

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

In children and adolescents with hypothalamic syndrome of puberty (usually secondary), abdominal obesity, high blood pressure, severe insulin resistance and hyperinsulinemia, diabetic carbohydrate metabolism disorders and atherogenic lipid metabolism disorders are often recorded, which indicates the formation of juvenile metabolic cardiovascular syndrome already in childhood and adolescence.

Obesity

Obesity is the leading clinical marker of metabolic syndrome.

The simplest and most reliable methods (criteria) for diagnosing obesity based on fat distribution include:

• waist circumference (WC) measurement, cm;
• Calculation of the waist to hip ratio (WHR).

In children, normative data (nomograms) have now been developed. In adolescents, adult criteria can be used. In the case of abdominal obesity:

• OT/OB for boys is more than 0.81; for girls - more than 1.0;
• The waist circumference for boys is more than 94 cm, for girls - more than 80 cm.

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

In children aged 2 years and older, the degree of obesity can be determined using the Quetelet index for a specific age and gender: BMI = weight (kg)/height (m) ². For example, height is 1.5 m, body weight is 48 kg; BMI = 48 kg/(1.5 m) ² = 21.3 kg/m ². Body weight within the 85th-95th percentile of BMI is assessed as overweight, and above the 95th percentile as obesity. Obesity assessment using BMI may be erroneous in athletically built adolescents.

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

Classification of obesity	BMI, kg/ m2
Normal body weight	18.5-24.9
Pre-obesity	25.0-29.9
Obesity stage I	30.0-34.9
Obesity stage II	35.0-39.9
Obesity stage III	>40,0

Central (abdominal-visceral) obesity is detected by an indirect parameter - WC measurement, it is independently associated with each of the other components of the metabolic syndrome, including insulin resistance, and should be the main criterion for the diagnosis of metabolic syndrome. When determining the standard WC parameters for children and adolescents, you can use the IDF recommendations (2007). For adolescents (10-16 years old), you can use the WC standards for adults (Europeans), for children (6-10 years old) - parameters exceeding the 90th percentile. Due to the fact that BMI correlates to a lesser extent than WC with visceral fat and insulin resistance, this parameter is advisable to use only to determine the degree of obesity (in children and adolescents, BMI standards are determined using nomograms depending on gender and age). Considering that WC is still an indirect parameter for assessing visceral obesity (a direct method is determining the area of visceral fat using CT), identifying WC and the HOMA-R index as mandatory criteria allows avoiding errors in diagnosing metabolic syndrome (both over- and underdiagnosis) in children and adolescents.

Insulin resistance

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

HOMA-R is calculated using the formula:

Fasting blood glucose level, mmol/l x fasting insulin level, μU/ml/22.5.

HOMA-R values of 3-4 are considered borderline (normal HOMA-R is up to 2). Insulin resistance is determined at HOMA-R equal to 4 or more. Direct methods for assessing insulin resistance include the insulin tolerance test and the euglycemic hyperinsulinemic clamp test.

Arterial hypertension

The pathogenesis of arterial hypertension in metabolic syndrome is based on insulin resistance and the 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 arterial hypertension is so obvious that it is always possible to predict the rapid development of arterial hypertension in individuals with untreated hyperinsulinemia. The latter leads to the development of arterial hypertension through the mechanisms listed below.

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

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

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

Blood pressure levels in children and adolescents are assessed using centile tables depending on gender, age, and height. Blood pressure (systolic or diastolic) > 95th percentile for a child of a given age, gender, and height is considered elevated.

Dyslipidemia

In conditions of insulin resistance in abdominal-visceral obesity, due to changes in the activity of lipoprotein lipase and hepatic triglyceride lipase, the breakdown of lipoproteins rich in triglycerides slows down. Hypertriglyceridemia develops, which leads to enrichment of high-density lipoproteins (HDL) and LDL with triglycerides. This leads to an increase in the concentration of small dense LDL particles and a decrease in the level of plasma HDL. Excessive intake of free fatty acids in the liver promotes increased synthesis of triglycerides and secretion of very low-density lipoproteins and apolipoprotein B.

Dyslipidemia in abdominal-visceral obesity is characterized by:

• increased levels of free fatty acids;
• hypertriglyceridemia;
• decreased HDL;
• increased LDL;
• increase in the content of small dense LDL particles;
• increased levels of apolipoprotein B;
• increase in LDL/HDL ratio;
• marked postprandial rise in triglyceride-rich lipoproteins.

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

Patients with visceral obesity are also characterized by a combination of hyperinsulinemia, increased apolipoprotein B and the fraction of small dense LDL particles, which is known as the atherogenic metabolic triad.

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 glycemia in children and adolescents with metabolic syndrome and identify early disorders of carbohydrate metabolism. The following fasting plasma glucose levels are of diagnostic value:

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

When conducting an oral glucose tolerance test, the following values of plasma glucose concentration 2 hours after a glucose load serve as starting points:

• <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) - impaired glucose tolerance;
• >11.1 mmol/L (>200 mg/dL) - preliminary diagnosis of diabetes mellitus, which should be confirmed by subsequent studies.

Type 2 diabetes mellitus

Type 2 diabetes mellitus is now often found in young people. If earlier the registration of this disease in children and adolescents was reported extremely rarely, then at present the manifestation of type 2 diabetes mellitus at 10-14 years of age no longer surprises anyone. However, due to the erased clinical picture of the disease at this age, its diagnosis is often carried out late.

In establishing the determining contribution of genes to the development of type 2 diabetes, it is necessary to distinguish between diabetogenic genes and non-specific, or facilitating genes (genes regulating appetite, energy expenditure, accumulation of intra-abdominal fat, etc.), which can be included in the risk factors for the development of type 2 diabetes. There is a close relationship between genetic and environmental factors (irrational diet, low physical activity, diseases, etc.) in the pathogenesis of type 2 diabetes. About 90% of patients with type 2 diabetes are overweight or obese. Obesity is the most important modifiable risk factor for this disease, which is why a special term “DiObesity” has even appeared.

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

Diagnostic criteria for type 2 diabetes mellitus, like type 1 diabetes mellitus, were proposed by WHO (1999). In children with type 2 diabetes mellitus, the disease usually develops slowly, over several weeks or months. It is often first diagnosed during preventive examinations at school or when visiting a doctor about skin itching, furunculosis and other diseases. Sometimes diabetes mellitus is diagnosed only when a sick child first visits a doctor about its complications. Retrospectively, many patients can be found to have had latent clinical manifestations of diabetes mellitus for a long time: moderate polydipsia and polyuria with a predominance at night, increased fatigue, decreased performance and academic performance at school, an increase or unexplained decrease (in children with excess weight) in body weight with a preserved appetite, susceptibility to various colds and skin diseases, etc.

At the same time, 6-9% of children and adolescents with type 2 diabetes mellitus have cases with vivid 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 at manifestation does not exclude type 2 diabetes mellitus. However, most often, the debut of type 2 diabetes mellitus 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 mellitus are heredity, obesity, and belonging to the female gender.

Carbohydrate metabolism disorders in type 2 diabetes mellitus are characterized by varying degrees of compensation. Conventionally, three degrees of severity of type 2 diabetes mellitus can be distinguished. Mild degree (degree I) includes cases of diabetes mellitus in which compensation of the disease (normoglycemia and aglucosuria) is achieved only by diet. Moderate diabetes mellitus (degree II) is characterized by the possibility of achieving compensation of carbohydrate metabolism by using either only oral hypoglycemic agents or the latter in combination with insulin. Severe diabetes mellitus (degree III) is considered in the presence of pronounced vascular complications: microangiopathy (proliferative retinopathy, nephropathy stages II and III), neuropathy. It is important to note that many doctors perceive type 2 diabetes mellitus as a mild disease or a mild form of diabetes mellitus. This is often due to the assumption of less strict criteria for compensation of this disease, which is not true.

Hyperandrogenism syndrome

Relatively recently - at the end of the 20th century - the concept was proposed and thoroughly argued that two interrelated components are involved in the pathogenesis of polycystic ovary syndrome:

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

There is much convincing evidence that there is a single universal abnormality in polycystic ovary syndrome that determines excessive phosphorylation of serine (instead of tyrosine) in both steroidogenic enzymes (17beta-hydroxylase and C17,20-lyase) and in the substrates of the beta subunit of the insulin receptor (IRS-1 and IRS-2). However, the final effects of such a pathological phenomenon differ: the activity of steroidogenesis enzymes doubles on average, which entails hyperandrogenism, while insulin sensitivity at the post-receptor level in peripheral tissues decreases almost twofold, which adversely affects the state of metabolism as a whole. Moreover, reactive hyperinsulinism, which arises compensatorily in response to pathological resistance of target cells to insulin, further contributes to excessive activation of androgen-synthesizing cells of the ovarian-adrenal complex, which further potentiates hydrogenation of the body of a girl and a woman, starting from childhood.

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

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

Polycystic ovary syndrome includes a variety of metabolic disorders caused by hyperinsulinism.

Hirsutism is not only a symptom of polycystic ovary syndrome, the most striking and eye-catching when it comes to medical diagnosis, but also a factor that is most traumatic for the psyche of girls.

Androgenetic alopecia is a reliable diagnostic marker of virile variants of AGA. Like other types of endocrine alopecia, it is diffuse rather than focal (nesting). However, unlike alopecia in other diseases of the endocrine glands (primary hypothyroidism, polyglandular insufficiency, panhypopituitarism, etc.), androgenetic alopecia is characterized by a certain dynamics. As a rule, it manifests itself with hair loss in the temporal region (bitemporal alopecia with the formation of symptoms of temporal bald spots or "privy councilor's bald spot" and "widow's peak"), and then spreads to the parietal region (parietal alopecia, baldness).

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

• on the 7th-10th day of the menstrual cycle - gonadotropic index (LH/FSH) >2, prolactin is normal or slightly elevated (in approximately 20% of cases);
• on the 7th-10th day of the menstrual cycle, characteristic signs are revealed by ultrasound;
  • bilateral increase in ovarian volume (more than 6 ml/m2 ^of body surface area, i.e. taking into account individual parameters of physical development according to height and body weight at the time of the pelvic ultrasound);
  • ovarian tissue is of the polycystic type, i.e. 10 small immature follicles or more with a diameter of up to 8 mm are visualized on both sides, as well as an increase in the area of the hyperechoic stroma of the medulla of both ovaries;
  • ovarian-uterine index (average ovarian volume/uterine thickness) >3.5;
  • thickening (sclerosis) of the capsule of both ovaries.

Disorders of the blood coagulation system

In metabolic syndrome, an increase in fibrinogen levels and the content of fibrinolysis inhibitors - factor 7 and plasminogen activator inhibitor I - are recorded. This, against the background of damage to the vascular wall, sharply increases the likelihood of thrombus formation. 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 reliably correlates with the severity of abdominal obesity and triglyceridemia, and in patients with arterial hypertension and hyperuricemia, left ventricular myocardial hypertrophy is more often observed. For the initial stages of metabolic syndrome, the development of hyperuricemia is less typical. Impaired purine metabolism occurs in parallel with an increase in body weight and the Quetelet index, as well as an increase in the level of blood triglycerides, i.e. as the disorder of lipid metabolism develops. At the same time, a reliable increase in glycemia and the activity of the renin-angiotensin-aldosterone system occurs at later stages of the disease than the appearance of uricemia. In the future, an increased level of uric acid in the blood can lead to the development of urate tubolointerstitial nephritis, in which, as a result of an immunological mechanism, fibroblastic degeneration of interstitial cells occurs. Hyperuricemia also serves as a factor leading to the progression of cardiovascular damage in metabolic syndrome, a factor in the progression of arterial hypertension. In addition, the presence of elevated uric acid levels imposes additional requirements on the therapy of arterial hypertension. In particular, it is known that thiazide diuretics, when taken for a long time, contribute to the development and progression of hyperuricemia, therefore, their use in arterial hypertension associated with metabolic syndrome should be limited.

Psychological and cardiovascular disorders in children and adolescents with metabolic syndrome

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

The changes detected in the cardiovascular system in children and adolescents with metabolic syndrome should be combined into a single cardiovascular syndrome. It is advisable not to single out arterial hypertension separately in the structure of metabolic syndrome markers, 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 between metabolic syndrome and heart and vascular pathology, and on the other hand, such a relationship is not limited to arterial hypertension. It should be especially emphasized that not only the heart but also vessels of all levels are involved in the pathological process in metabolic syndrome, i.e. we are talking about cardiovascular pathology. Thus, cardiovascular syndrome, along with arterial hypertension, is represented by the syndrome of autonomic dysfunction (manifested, among other things, by disturbances in heart rate variability), endothelial dysfunction, and systolic-diastolic dysfunction of the myocardium. At the same time, the degree of expression of the above-described disorders of the cardiovascular system in children and adolescents with metabolic syndrome may vary individually and depends on the degree of expression of insulin resistance.

It should be noted that already at the stage of obesity and preserved sensitivity to insulin in children and adolescents, initial shifts in metabolic, psychological and cardiovascular parameters are recorded. In the future, with prolonged preservation 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 concepts, the unifying basis of all manifestations of metabolic syndrome is primary insulin resistance and concomitant, most likely genetically determined hyperinsulinemia.

The development of insulin resistance is associated with "breakdowns" at the receptor and post-receptor levels. Studies show that its nature is polygenic and may be associated with mutations in the following genes: insulin receptor substrate, glycogen synthase, hormone-sensitive lipase, beta3-adrenergic receptors (Trp64Arg (W/R) polymorphism of the beta3-AR gene), TNF-a, uncoupling protein, as well as with molecular defects in proteins that transmit insulin signals (Rad protein, intracellular glucose transporters GLUT-1, GLUT-2, GLUT-4).

According to the currently 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 neurohormonal and regulatory disorders accompanying obesity. Hyperinsulinemia acts, on the one hand, as a compensatory factor, i.e., necessary to overcome insulin resistance and maintain normal glucose transport into cells; on the other hand, as a pathological factor contributing to the emergence and development of metabolic, hemodynamic and organ disorders, ultimately leading to the development of type 2 diabetes mellitus and dyslipidemia.

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

Abdominal adipose tissue is divided into visceral (intra-abdominal) and subcutaneous. Adipose tissue has auto-, para- and endocrine functions and secretes a large number of substances with various biological effects that can, in particular, cause the development of complications associated with obesity, including insulin resistance. Among them are TNF-a and leptin. Many consider TNF-a to be a mediator of insulin resistance in obesity. Leptin, secreted primarily by adipocytes, acts at the hypothalamus level, regulating eating behavior and the activity of the sympathetic nervous system, as well as a number of neuroendocrine functions. A significant increase in the mass of visceral adipose tissue is usually 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 excess abdominal fat tissue, neurohormonal disorders associated with obesity, and increased activity of the sympathetic nervous system.

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

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