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CLINICAL PATHOPHYSIOLOGY OF THE ENDOCRINE SYSTEM

June 18, 2024

CLINICAL PATHOPHYSIOLOGY OF THE ENDOCRINE SYSTEM

Etiology of endocrine disorders

Reasons and kinds of endocrine disorders. Among numerous ethiological factors of endocrine disorderss it is possible to select the following main ones: a mental trauma, necrosis, tumour, inflamatory process, bacterial and viral infections, intoxications, local disorders of blood circulation (hemorrhage, thrombosis), alimentary disorders (deficiency of iodine and cobalt in food and drinking water, redundant consumption of carbohydrates), ionising radiation, inherent chromosome and gene defects.

There are three variants of endocrine functions disorders :

1. Hyperfunction of endocrine glands

2. Hypofunction of endocrine glands

3. Disfunction of endocrine glands.

Disfunction is characterized by different changes of hormonal production and production physiologic active precursors of their biosynthesis in the same endocrine gland or synthesis and entering in blood of atypical hormonal products.

Pathogenesis of endocrine disorders

The mechanisms of function disorders of an endocrine gland can be various depending on localization and character of process.

In pathogenesis of endocrine disorders it is possible to select three main mechanisms:

1) Disorders of regulation of endocrine glands – disregulatory disorders;

2) Disorders of biosynthesis of hormones and their secretion – glandular disorders;

3) Disorders of the transport, reception and metabolism of hormones – peripheral disorders.

Disorders of endocrine gland regulation

Regulation of endocrine gland activity can be carried out with the help of four mechanisms:

1. Nervous (impulse-mediators) or parahypophysis regulation. With the help of direct nervous influences the activity of following structures is regulated: а) adrenal medulla; b) neuroendocrine structures of hypothalamus; c) epiphysis.

2. Neuroendocrine or transhypophysar regulation. It is carried out by neuroendocrine cells of hypothalamus, which transform nervous impulses in specific endocrine process. Along releasing-hormones, which regulate activity of adenohypophysis are synthesized and get secreted in the system of portal vessels of hypophysis .

3. Endocrine regulation. It is that some hormones influence on synthesis and other influence secretion of the others. An example of this mechanism is the influence of adenohypophysis tropic hormons on activity of adrenal cortex, thyroid gland, sexual glands.

4. Non-endocrine humoral regulation is carried out by unspecific humoral factors, in particular by metabolites, ions.

Pathological processes which are primarity developed in hypothalamus lead to disorders of transhypophysar and parahypophysar regulation of endocrine glands function. The activity of hypothalamic centres can be disturbed also secondarily in connection with disorders in limbic system (hypocampus, tonsil, olfactory brain) and upper parts of central nervous system which are closely connected with hypothalamus. At that the large role belongs to mental trauma and other stress influences.

Transhypophysar regulation includes synthesis of peptides which are moving by axons and reach adenohypophysis in neurosecretory cells of mediobasal part of hypothalamus. Here they either stimulate or inhibit formation of tropic hormones. Stimulating peptides have received the name of liberins or releasing-factors, they are: thyroliberin, gonadoliberin, somatoliberin etc. inhibiting peptides are named statins – thyrostatin, somatostatin etc. Their ratio among themselves is determined formation of appropriate tropic hormone. Then formation of tropic hormones begins in adenohypophysis – somatotropic (STH), gonadotropic (GTH) etc. Tropic hormones act on appropriate targets and stimulate derivation of hormones in appropriate glands, and STH stimulates formation of somatomedines in tissues – polipeptide hormones, through which they act.

By means of parahypophysar mechanism secretory, vessel and trophic influence of CNS on the function of endocrine glands is carried out. For adrenal medulla, Langerhans’ islets and parathyroid glands it is a major pathway of their regulation. In realization of the function of other glands both pathways of regulation take place. So, the function of thyroid gland is determined not only by TTH, but also by sympathetic impulsation. The direct irritation of sympathetic nerves increases absorption of iodine by the gland, synthesis of thyroid hormones and their secretion. Denervation of ovaries causes their atrophy and weakens response on gonadotropic hormones.

The disorders of trans– and parahypophysar regulation leads to disfunction of endocrine glands. The disturbanc of one gland function is called monoglandular process, several glands – pluriglandular process. The disorders of the glandular function can be partial, when production of only one hormone is disturbed, or total, when secretion of all hormones is changed .

Role of mechanisms feedback bond in endocrine disturbances

The mechanism of feedback bond is obligated link in self regulation of glandular activity. The essence of negative adverse effects is that formed hormones oppress activity of structures which carry out the previous stages of regulation. Therefore the increase of secretion of effectory hormone through certain parts causes decrease of its formation and entering in blood, and on the contrary, the decreasing of the hormone contents in blood causes increase of intensity of its formation and secretion. In this way regulation of cortizol secretion, thyroid and sexual hromones is carried out.

By the principle of the mechanism of feedback bond inhibition of the function (even atrophy) of the gland during treatment by their or other hormones can occur.

Disorders of hormones biosynthesis and their secretion

Strictly glandular disorders of endocrine functions can be conditioned:

1. By changes of functionally active endocrine cells amount :

a) by decrease of their amount (removal of gland or its part, damage, necrosis), that results to endocrine hypofunction;

b) by increase of their amount (benignt and malignant tumors of glandular epithelium) that is accompanied by features of endocrine hyperfunction.

2. Qualitative changes in cells:

a) by disorders of biosynthesis of hormones;

b) by disorders of processes of their secretion.

The main possible reasons of protein-peptide hormones synthesis disorders are:

1) disorders of transcription;

2) disorders of translation;

3) deficiency of essential aminoacids;

4) deficiency of ATP;

5) disorders of posttranslatory modification and activation.

Disorders of transport, reception and hormones metabolism.

The peripheral mechanisms determine activity of hormones excreted into blood , development of peripheral disorders of endocrine functions occurs due to:

1. Disorders of the hormones transport in organism.

2. Disorder of metabolic inactivation of hormones.

3. Disorders of interaction of hormones with peripheral cells – targets.

All hormones is excreted from gands associate with proteins in blood and circulate in two forms – connected and free. From these two forms connected hormone is biologically inactive. The activity is peculiar only to free form of hormone.

The disorders of the hormone transport in an organism can appear in two types of endocrine function disorders:

а) hypofunction – increase of hormone binding and decrease of its contents in the free form;

b) hyperfunction – decrease of hormone binding and increase in blood of concentration of the free form.

Disorders of endocrine functions, connected with disturbances of interaction of hormones with peripheral cells

The influence of hormones on cells – targets is carried out through their action on specific proteins – receptors and is performed in three ways:

1) influences on permeability of biological membranes;

2) stimulation or oppression of enzymes activity;

3) influences on the genetic apparatus of a cell.

There are two types of cytoreception of hormones.

1. Membrane type of cytoreception. It is the main mechanism of action of protein- peptide hormones and catecholamines. Nowadays we known secondary intermediaties which are represented by the following substances: a) cyclic nucleotides – cAMP, cGМP; b) ions of Са⁺⁺; c) phospholipide messangers– diacilglycerol (DAG) and inozitoltriphosphate (ITP). The specificity of the answer of a cell on this or other hormone is determined by specificity of the receptor, which is connected only with a certain hormone, and also by nature of specific to a cell proteinkinase and protein substrats.

2. Intracellular type of cytoreception. It is in the base of mechanism of steroid and thyroid hormones action.

The blockade of hormonal receptor is the widespread mechanism, which results to hormonal insufficiency: active hormone does not find receptor on a cell or in it because of receptor loss or fixing on its surface of antagonist, conformation changes of the receptor, which interfere connection with the hormone. Usually concentration of hormone in such cases is normal or increased. The introduction of the hormones with the medical purpose is not accompanied by appropriate effect.

Disorder of endocrine functions, connected with disturbances of hormones metabolism

The destruction of protein-peptide hormones is realized in liver with the help of peptidase enzymes. The disturbances of metabolic hormones transformations can stimulate development of peripheral disorders of endocrine function. So, in case of slowing– down of hormones inactivation their contents in blood is increased, that appears in glands hyperfunction. And on the contrary, the accelerated transformation of hormones in their inactive forms is accompanied by development of endocrine hypofunction. In hepatitis and cyroses of a liver hormones metabolism is oppressed.

DIABETES MELLITUS

Diabetes mellitus is heterogenic diseases group which arise on base of absolute or relative insulin insufficiency and have hyperglicemia as general symptom. Classification of diabetes mellitus up to nows remains clinical. Main types – insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus. These two diabetes types affect the majority of patient.

There are counts six millions of patient with insulin-dependent diabetes mellitus in the world. This is mainly illness of white race. It occur more frequent in highly developed countries (Finland, Italy, Sweden, Denmark, Canada, Norway, USA, England). There are about 100 millions of patient with insulin-dependent diabetes mellitus. They consist 85 % of all diabetics. They belong to mainly native population of USA (american indians), Fiji, South Africa, India, Polynesia.

Causes of Diabetes Mellitus

Diabetes mellitus is caused by an absolute or relative lack of insulin that, among other consequences, leads to an increase in plasma glucose concentration The disease was given its name because of the glucose excretion in the urine. The disease can be classified into several types, depending on its cause and course. This classification is useful, even though it is greatly simplified.

In type I (insulin-dependent diabetes mellitus [IDDM], previously called juvenile diabetes) there is an absolute lack of insulin, so that the patient needs an external upply of insulin. The condition is caused by a lesion in the beta cells of the pancreas, as a rule produced by an autoimmune mechanism that may, in certain circumstances, have been triggered by a viral infection. The pancreatic islets are infiltrated by T lymphocytes and autoantibodies against islet tissue (islet cellantibodies [ICA]) and insulin (insulin autoantibodies [IAA]) can be detected. ICA may in some cases be detected years before the onset of the disease. After the death of the beta cells, the ICA again disappear. 80% of patients form antibodies against glutamatedcarboxylase expressedthe beta cells. Type I diabetes mellitus occurs more frequently in the carriers of certain HLA antigens (HLA-DR3 and HLA-DR4), i.e., there is a genetic disposition.

Type II (non-insulin-dependent diabetes mellitus [NIDDM], formerly called maturityonset diabetes) is by far the most common form of diabetes. Here, too, genetic disposition is important. However, there is a relative insulin deficiency: the patients are not necessarily dependent on an exogenous supply of insulin. Insulin release can be normal or even increased, but the target organs have a diminished sensitivity to insulin.

Most of the patients with type II diabetes are overweight. The obesity is the result of a genetic disposition, too large an intake of food, and too little physical activity. The imbalance between energy supply and expenditure increases the concentration of fatty acids in the blood. This in turn reduces glucose utilization in muscle and fatty tissues. The result is a resistance to insulin, forcing an increase of in sulin release. The resulting down-regulation of the receptors further raises insulin resistance. Obesity is an important trigger, but not the sole cause of type II diabetes. More important is the already existing genetic disposition to reduced insulin sensitivity. Frequently, insulin release has always been abnormal. Several genes have already been defined that promote the development to obesity and type II diabetes. Among other factors, the genetic defect of a mitochondrial decoupling protein limits substrate consumption. If there is a strong genetic disposition, type II diabetes can already occur at a young age (maturity-onset diabetes of the young [MODY]).

Reduced insulin sensitivity predominantly affects the insulin effect on glucose metabolism, while the effects on fat and protein metabolism are still well maintained.

Glucose rugulation

Thus, type II diabetics tend especially toward massive hyperglycemia without corresponding impairment of fat metabolism (ketoacidosis). Relative insulin deficiency can also be caused by autoantibodies against receptors or insulin as well as by very rare defects in the biosynthesis of insulin, of insulin receptors, or of intracellular transmission. Even without any genetic disposition, diabetes can occur in the course of other diseases, such as pancreatitis, with destruction of the beta cells (pancreas-deprived diabetes), or by toxic damage to these cells. The development of diabetes mellitus is promoted by an increased release of antagonistic hormones. Among these are somatotropin (in acromegaly), glucocorticoids (in Cushing’s disease or stress [so-called steroid diabetes]), epinephrine (in stress), progestogens and choriomammotropin (in pregnancy), ACTH, thyroid hormone, and glucagon. Severe infections increase the release of several of the above hormones and thus the manifestation of diabetes mellitus. A somatostatinoma can cause diabetes because the stomatostatin secreted by it inhibits the release of insulin.

Pathogenesis of DM

Acute Effects of Insulin Deficiency

Insulin acts to create energy reserves. It promotes the uptake of amino acids and glucose, especially in the muscle and fat cells. In hepatic, muscle, and fat cells (among others) insulin stimulates protein synthesis and inhibitis protein breakdown; in the liver and muscles it promotes glycogen synthesis, inhibits its breakdown, stimulates glycolysis, and inhibits gluconeogenesis from amino acids. Also in the liver, insulin promotes the formation of triglycerides and lipoproteins as well as the hepatic release ofVLDL. At the same time it stimulates lipoprotein lipase and thus accelerates the splitting of triglycerides into lipoproteins in blood (especially chylomicrons). The free fatty acids and glycerol are then taken up by the fat cells and stored again as triglycerides. Insulin stimulates lipogenesis and inhibits lipolysis in the fat cells. Lastly, it promotes cell growth, increases renal tubular absorption of Na+, and cardiac contractility. Part of insulin action is mediated by cell swelling (especially antiproteolysis) and intracellular alkalosis (stimulation of glycolysis, increased cardiac contractility). Insulin achieves this effect by activating the Na +/H+exchanger (cell swelling and alkalinization), the Na+-K+-2 Cl– cotransporter (cell swelling), and Na+-K+-ATPase. This results in K + uptake by the cell and hypokalemia. As glucose is coupled to phosphate in the cell, insulin also reduces plasma phosphate concentration. It further stimulates the cellular uptake of Mg2+. Insulin also paracrinally in hibits the release of glucagon and thus diminishes its stimulating action on glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis.

In acute insulin deficiency the absence of its effect on glucose metabolism results in hyperglycemia. The extracellular accumulation of glucose leads to hyperosmolarity. The transport maximum of glucose is exceeded in the kidney so that glucose is excreted in the urine. This results in anosmotic diuresis withrenal loss of water (polyuria), Na+, and K+, dehydration, and thirst. Despite the renal loss of K+, there is no hypokalemia because the cells give up K+ as a result of reduced activity of Na+-K+ -2 Cl^–cotransport and of Na+-K+-ATPase. The extracellular K+ concentration, which is therefore more likely to be high, disguises the negative K+balance. Administration of insulin then causes a life-threatening hypokalemia. Dehydration leads to hypovolemia with corresponding impairment of the circulation. The resulting release of aldosterone increases the K+ deficiency, while the release of epinephrine and glucocorticoids exacerbates the catabolism. The reduced renal blood flow diminishes the renal excretion of glucose and thus encourages the hyperglycemia.

The cells further lose phosphate (P) and magnesium that are also excreted by the kidney. If there is an insulin deficiency, proteins are broken down to amino acids in muscles and other tissues. This breakdown of muscles will, together with electrolyte abnormalities, lead to muscular weakness. Prevailing lipolysis leads to release of fatty acids into blood (hyperlipidacidemia). The liver produces acetoacetic acid and β-hydroxybutyric acid from the fatty acids. Accumulation of these acids leads to acidosis, which forces the patient to breathe deeply (Kussmaul breathing). Some of the acids are broken down to acetone (ketone bodies). In addition, triglycerides are formed in the liver from fatty acids and incorporated into VLDL. As the insulin deficiency delays the breakdown of lipoproteins, the hyperlipidemia is further aggravated. Some of the triglycerides remainin the liver anda fatty liver will develop. The breakdown of proteins and fat as well as polyuria will result in weight loss. The abnormal metabolism, electrolyte disorders and the changes in cell volume brought about by changed osmolarities can impair neuronal function and cause hyperosmolar or ketoacidotic coma. The main effects of relative insulin deficiency are hyperglycemia and hyperosmolarity, while in absolute insulin deficiency the consequences of increased proteolysis and lipolysis (ketoacidosis) are added to these effects.

Late Complications of Prolonged Hyperglycemia

The metabolic abnormalities of inadequately treated relative or absolute insulin deficiency will in the course of years or decades lead to extensive irreversible changes in the organism. Hyperglycemia plays a central role in this.

Glucose is reduced to sorbitol in cells that contain the enzyme aldosereductase. This hexahydric alcohol cannot pass across the cell membrane, as a result of which its cellular concentration increases and the cell swells. Due to an accumulation of sorbitol in the lens of the eye, water is incorporated, impairing lenticular transparency (clouding of the lens [cataract]). Accumulation of sorbitol in the Schwann cells and neurons reduces nerve conduction (polyneuropathy), affecting mainly the autonomic nervous system, reflexes, and sensory functions. To avoid swelling, the cells compensate by giving off myoinositol which then, however, will not be available for other functions. Cells that do not take up glucose in sufficient amounts will shrink as a result of extracellular hyperosmolarity. The functions of lymphocytes that have shrunk are impaired (e.g., the formation of superoxides, which are important for immune defense). Diabetics are thus more prone to infection, for example, of the skin (boils) or kidney (pyelonephritis). These infections, in turn, increase the demand for insulin, because they lead to an increased release of insulin-antagonistic hormones. Hyperglycemia promotes the formation of sugar-containing plasma proteins such as fibrinogen, haptoglobin, α2-macroglobulin as well as clotting factors V–VIII. In this way clotting tendency and blood viscosity may be increased and thus the risk of thrombosis raised.

By binding of glucose to free amino-groups of proteins and a subsequent, not fully understood, irreversible Amadori reaction, advanced glycation end products AGEs) are formed. They also occur in increasing amounts in the elderly. A proteietwork can be formed through the formation of pentosin. AGEs bind to respective receptors of the cell membrane and can thus promote the deposition of col lagenin the basement membranes of the blood vessels. The formation of connective tissue is in part stimulated via transforming growth factor β (TGF-β). Additionally, however, the collagen fibers can be changed by glycosylation. Both changes produce thickening of the basement membranes with reduced permeability and luminal narrowing (microangiopathy). Changes occur in the retina, also as a result of microangiopathies, that ultimately may lead to blindness (retinopathy). In the kidney glomerulosclerosis (Kimmelstiel–Wilson) develops, which can result in proteinuria, reduced glomerular filtration rate due to a loss of glomeruli, hypertension, and renal failure. Because of the high amino acid concentration in plasma, hyperfiltration takes place in the remaining intact glomeruli, which as a result are also damaged. Together with a rise of VLDL in blood and the raised clotting tendency of the blood (see above), hypertension promotes the development of a macroangiopathy that can further damage the kidneys and cause myocardial infarction, cerebral infarction, and peripheral vascular disease. Lastly, glucose can react with hemoglobin (HbA) to form HbA 1c, whose increased concentration inblood points to a hyperglycemia that has been present for some time. HbA 1c has a higher oxygen affinity than HbA and thus releases oxygen in the periphery less readily. The persisting insulin deficiency further leads to a reduction in the erythrocytic concentration of 2,3-bisphosphoglycerate (BPG), which, as allosteric regulator of hemoglobin, reduces its oxygen affinity. The BPG deficiency also results in an increased oxygen affinity of HbA. Diabetic mothers have a statistically higher chance of giving birth to a heavier thaormal baby. This may be the result of an increased concentration of amino acids in blood, producing an increased release of somatotropin.

Pathogenesis of diabetes mellitus symptoms

Clinical manifestations of DM

Atherosclerosis due to DM

Diabetic retinopathy

Diabetic nephropathy

CLINICAL PATHOPHYSIOLOGY OF THYROID GLAND

Hyperfunction of thyroid gland is designated by the term “thyrotoxicosis” or “hyperthyrosis”.

The reasons of hyperthyrosis can be the following:

1. Central disturbances – increase of thyroliberin and thyrotropic hormone (ТТH) secretion.

2. Strictly glandular disturbances (primary hyperthyrosis). The most widespread clinical forms of primary hyperthyrosis are:

а) Diffuse toxic goiter (Bazed’s disease, Graves’ disease, Parri’s disease);

b) Toxic adenoma of thyroid gland;

c) Nodular goiter.

The most often reason of development hyperthyrosis is diffuse toxic goiter.

Consider that diffuse toxic goiter is autoimmune disease, in which occurrence matter are thyroid-stimulating antibodies which like ТТH are capable to contact with receptors on basal membrane of thyrocyte, that results in cell activation.

3. Peripheral disorders :

а) Increase of cell sensitivity to action of Т₃ and Т₄;

b) Decrease of binding of thyroid hormonees by transport proteins;

c) Decrease of thyroid hormonees’ metabolism in liver in its insufficiency.

The starting mechanism of diffuse toxic goiter occurrence in patients with hereditary defect of immune system can be psychoemotional stress or virus which is forming in thyrocyte membrane complex, on which the antibodies will be derivated.

Main manifestations of diffuse toxic goiter:

а) goiter (increase of thyroid gland)

Goiter

b) tachycardia, arrhythmia, cardiac insufficiency;

c) increase of basic metabolism more than 10 %;

d) increase of temperature;

e) weigth loss;

f) muscular weakness;

g) exophtalmus

Exophtalmus

h) disorders of nervous system –– irritability, instability of mood, inconsistency of acts, tremor.

In pathogenesis of hyperthyrosis manifestations the following mechanisms are important:

1. Anabolic effects. They are high-dose effects of thyroid hormones. They are:

а) delay of growth;

b) atrophy of muscles and weakness;

c) weight loss;

d) negative nitrogen balance;

e) increase of nitrogen leading out, phosphorum, potassium, ammonia;

f) increase in blood of residual nitrogen and nitrogen-containing aminoacids.

2. Strengthening heat-forming action of thyroid hormones. It appears:

a) by increase of basic metabolism;

b) by increase heat formation and increase of body temperature;

c) by good adaptation to cold and bad – to high temperature;

d) hyperphagia – increased consumption of energy.

Triiodthyronine separates oxidation and phosphorilation in cell mitochondria, therefore the energy of oxidation of NADPH₂ is not accumulated in ATP. The decrease of ATP synthesis increases concentration of its precursors – organic phosphate. The carry of ADP in mitochondria is changed also, as Т₃ contacts to a carrier of ADP tarnslocase that in turn strengthens oxidizing processes and by that dispersion of energy, causing increase of basic metabolism.

3. Increase of functional activity of excitable tissues. It is connected with increase of activity of Na-K–pumps in cell membranes and increase of cell sensitivity to catecholamines.

It stipulates the following manifestations of hyperthyrosis:

a) disorders of activity of central nervous system – acceleration of mental processes, anxiety, excitation, insomnia;

b) constant spontaneous contractive activity of skeletal muscles – fibrillar twitching, tremor. It is connected with muscular weakness, tiredness;

c) changes of activity the increase of heart minute volume, arterial pressure in cardiovascular system – tachycardia;

d) increase contractive activity of smooth intestinal muscles – diarrhea;

e) increase of absorbtive and excretive processes intensity. It is connected with hyperglycemia and hypocholesterinemia.

4.Catecholamine effects are stipulated by increase of cells sensitivity to action of catecholamins.

In clinic of hyperthyreosis the greatest significance have the functional effects of catecholamins, in particular, their influence on heart – vassel system and metabolic changes.

In tissue the utilization of glucose is increased. There is activated phosphorylase of liver and muscles, therefore glucogenolis amplifies and there is no glycogen in these tissue. Increase activity of hexokinase and glucose absorbtion in intestines, is accompanied with alimentary hyperglicaemia.

5. Disturbance with unstablished mechanisms of development – orbitopathy and two-sided exophtalm. It is supposed, that in conditions of hyperthyreosis is allocated special exophtalmic factor, however it is not revealed till now .

Thyreotoxic adenoma of thyroid gland functions autonomously and produces surplus of thyroid hormones irrespective of ТТH. Nodal toxic goiter is characterized by absence of changes on the part of orbits an eye and mixedema.

Pathogenesis of syndromes of hyperthyroidism

Hypothyrosis

In a basis of hypofunction of thyroid gland the following reasons can be.

1. Central disorders: decrease of formation both secretion of thyreoliberine and thyreotropic hormone (ТТH).

2. Gland disorders , which result in development primary hypothyrosis:

a) destruction of a gland tissue, for example, radioactive iod;

b) deficiency of iod drinking water and food – endemic goiter;

c) autoimmune damage of gland cells – autoimmune thyroiditis of Chaschimoto;

d) inherent disorders – hypo- and aplasia of thyroid gland, enzymopathy.

3. Peripheral disorders:

а) nonsensitivity of peripheral cells for action of thyroid hormones;

b) increased binding of thyroid hormones with plasma proteins of blood;

c) strengthened metabolism in liver.

In development of manifestations of hypothyrosis the following mechanisms.

1. Disturbances of growth and defferenciation of tissue.

Thyroid hormonees a necessary for normal process of enchondrial ossification on boundary between diaphysis and epiphysis, in conditions of hypothyreosis the growth of bones in length is decreased. For want of it periostal growth of bones is saved, in this connection they become thick. The complex of changes of a skeleton – hyperthyroid dwarfism develops. Along side with it the mental development – gradually is developed also arises cretinism.

2. The decrease heat formation of action thyroid hormones, which appears:

а) decrease of base metabolism (falling on 20-40 of %);

b) by decrease of heat production, in this connection temperature falls;

c) bad adaptation to a cold for want of preservation of adaptation to high temperature.

3. Decrease of functional activity of exitated tissues.

This is connected with falling of activity Nа–К–АТPаs and changes of processes of ions active transport. Besides that decrease sensitivity of tissues to catecholamins, has significance that is stipulated by decrease of an amount β-adrenoreceptors on cells. The functional changes of exitated organs and tissues are:

а) disorders of the central nervous system activity – decrease of mental activity, slackness, lethargy,sleepiness etc.;

b) decrease of functional activity of skeletal muscles – weakness, decrease tone, fast tiredness;

c) by disorders of heart activity – vessel system – bradycardia, decrease of heart minute volume, decrease of arterial pressure;

d) decrease of contraction of the of smooth muscles function of intestines – constipation;

e) disturbance of processes absorbtion and excretion. The decrease glucose absorbtion in intestin couse hypoglycemia and disorders of excretion of cholesterine in structure of bile to hypocholesterinemia and hereinafter to atherosclerosis.

4. Disturbances with the unknown mechanisms of development. They are mucous edema – mixedema. This is characterized by increasing tissues the quantity glycosaminglycans, connecting water; by a thickening of a skin, puffy face. It is admited mixedema is consiquence of action thyrotropic hormone on connective tissue, amount it is increased on glandular and peripheral forms of hypothyrosis vitally increase.

The forms of manifestation of thyroid gland hypofunction depend on age.

1. Cretinism – arises because of insufficiency of thyroid gland, which arises in embrional or early postnatal period. The main reasons are:

а) inherent athyrosis;

b) introduction of antithyroid preparations of the pregnant woman;

c) hereditary defects of thyroid hormones synthesis .

Characteristic signs of cretinism are:

a) dwarfism;

b) mental undedevelopment (imbecility);

c) infantilism;

d) a combination of different defects – surdomutism, short neck, low front , thick lips, plane nose, languid muscles, large stomach, rare hair, caries of teeth, clumsy gait, enuresis.

2. Child mixedema. Arises for want of to loss of thyroid gland function in children’s age. The main reasons –thyroiditis, tuberculosis, hypopituitarism.

Characteristic signs of a child mixedema are:

а) delay of growth, natural and mental development;

b) lethargy;

c) bad appetite;

d) pale and yellow skin;

e) hypercholesteremia;

f) delay occification of bones and cartilages.

Child mixedema you may treat by thyroid hormones.

3. Mixedema of the adults. Characteristic signs:

а) pale, dry and thick skin;

b) mucous edema;

c) thick nose, thick lips, drooped cheek;