Causes and pathogenesis of hypothyroidism

In the overwhelming majority of cases (90-95%), hypothyroidism is caused by a pathological process in the thyroid itself, which reduces the level of production of hormones (primary hypothyroidism). Violation of the regulatory and stimulating effect of pituitary thyrotropin or hypothalamic releasing factor (thyreoliberin) leads to secondary hypothyroidism, which is significantly inferior to primary hypothyroidism. The issue of peripheral hypothyroidism, arising either in connection with the disturbance of the metabolism of thyroid hormones at the periphery, in particular, the formation of T ₄ not T ₃, but inactive, reversible T ₃, or as a result of a decrease in the sensitivity of nuclear receptors of organs and tissues to thyroid hormones. The issue of age-related degradation of the level of active thyroid hormones as a result of impaired peripheral metabolism and changes in the thyroid itself during the aging process remains controversial. In screening of populations over 60 years in some studies, apparent hypothyroidism was detected in 3.4%, preclinical in 5.2% of the subjects, and in others the detection rate was significantly lower.

Evaluation of thyroid function and its role in various clinical syndromes and diseases can be difficult due to a change in thyroid hormone peripheral metabolism leading to a decrease in the level of TK in a number of diseases and conditions, for example, in nephrotic syndrome, liver cirrhosis, sometimes in pregnancy .

Obviously, the significance of the syndrome of peripheral insensitivity to thyroid hormones in the genesis of hypothyroidism is underestimated in real clinical practice.

Currently, in adults, the most common primary hypothyroidism that occurs on the basis of chronic autoimmune thyroiditis. In this regard, the idea of the so-called idiopathic hypothyroidism as the main variant of spontaneous thyroid insufficiency has been significantly transformed. With chronic thyroid tissue of the thyroid gland, after the stage of lymphoid infiltration, gradually atrophies and is replaced by fibrotic. The gland may also decrease in size, and not significantly change, and hypertrophy due to compensatory hyperstimulation of TSH (goiter Hashimoto).

Primary hypothyroidism in various combinations with adrenal, gonadal, parathyroid and pancreatic lesions, and at a young age and in children with fungal skin diseases, alopecia and vitiligo is known as a syndrome of primary polyendocrine insufficiency, the autoimmune nature of which is indisputable. In addition to the endocrine system, patients may have other immune diseases (bronchial asthma, pernicious anemia, atrophic gastritis). Primary hypothyroidism occurs for a number of reasons.

1. Complications of treatment after:
   • operative treatment of various diseases of the thyroid gland;
   • treatment of toxic goiter with radioactive iodine;
   • radiation therapy for malignant diseases of organs located on the neck (lymphoma, laryngeal carcinoma);
   • poorly controlled treatment with thyrotoxic agents (mercazolil, lithium);
   • use of iodine-containing drugs, including X-ray contrast agents;
   • reception of glucocorticoids, estrogens, androgens, sulfanilamide preparations.
2. Destructive lesions of the thyroid gland: tumors, acute and chronic infections (thyroiditis, abscess, tuberculosis, actinomycosis and extremely rare amyloidosis, sarcoidosis, cystinosis).
3. Dysgenesis (aplasia or hypoplasia) of the thyroid gland due to intrauterine growth defects is usually in newborns and children 1-2 years, often combined with deafness and cretinism. Sometimes the remainder of thyroid tissue is in the sublingual-thyroid region and at the root of the tongue. The developmental defect of the thyroid gland can be caused by iodine deficiency in the environment, untreated maternal hypothyroidism, hereditary predisposition.

Secondary hypothyroidism develops with inflammatory, destructive or traumatic lesions of the pituitary and / or hypothalamus (tumor, hemorrhage, necrosis, surgical and radiation hypophysectomy) with insufficient isolation of TRH and TSH and subsequent decrease in thyroid functional activity. Isolated disturbance of synthesis of TSH is observed very rarely. More often secondary hypothyroidism occurs within the general pituitary pathology (mainly the anterior lobe) and is combined with hypogonadism, hypocorticism, an excess of growth hormone.

[1], [2], [3]

Pathogenesis of hypothyroidism

Pathogenesis (especially primary) of hypothyroidism is determined by a decrease in the level of thyroid hormones that have a spectrum of influence on physiological functions and metabolic processes in the body. As a result, all kinds of exchanges are depressed, tissue oxygen utilization is inhibited, oxidative reactions are inhibited and the activity of various enzyme systems is reduced, gas exchange and basic metabolism. The slowing down of the synthesis and catabolism of protein and protein fractions, as well as the process of their excretion from the body, leads to a significant increase in protein decay products in the extravascular spaces of organs and tissues, in the skin, in skeletal and smooth musculature. In particular, in the myocardium and in other muscle groups, creatine phosphate accumulates. Simultaneously, the content of nucleic acids (DNA, RNA) decreases, the protein blood spectrum changes in the direction of increasing globulin fractions, and a significant amount of albumin is concentrated in the interstitium, the hemoglobin structure changes. The pathogenesis of increased membrane and transcapillary permeability for protein, characteristic of hypothyroidism, has not been studied in many respects. Possible involvement of vasoactive substances (eg, histamine) is expected, a link with a slowing down of the lymph drainage, which reduces the return of protein to the vascular bed, is more likely.

In the heart, lungs, kidneys, serous cavities and above all in all layers of the skin, acidic glycosoaminoglycans (GAG), mainly glucuronic acid and, to a lesser extent, chondroitinserne, are excessively deposited. The level of glycosoaminoglycans in fibroblasts of blood, under the direct influence of thyroid hormones, rarely increases. In studies conducted by the authors together with AN Nazarov, it was shown that the level of glycosaminoglycans increases with the duration of the disease.

Excess glycosoaminoglycans changes the colloid structure of the connective tissue, enhances its hydrophilicity and binds sodium, which forms a myxedema in conditions of obstructed lymph flow.

The mechanism of delay in the tissues of sodium and water can also be affected by an excess of vasopressin, whose production is inhibited by thyroid hormones, as well as a decrease in the level of the atrial natriuretic factor. Along with the tendency to increase the level of intracellular and interstitial sodium, there is a tendency to hyponatremia and a decrease in the level of intracellular potassium concentration. The saturation of tissues with free calcium ions is also reduced. Slowed down utilization and removal of lipolysis products, increased levels of cholesterol, triglycerides, beta-lipoproteins.

Deficiency of thyroid hormones inhibits the development of brain tissue and depresses higher nervous activity, which is especially noticeable in childhood. But adults develop hypothyroid encephalopathy, which is characterized by a decrease in mental activity and intelligence, a weakening of conditioned and unconditioned reflex activity. The physiological activity of other endocrine glands is limited, and primarily the adrenal cortex, which rapidly decreases its function under hypothermia. Peripheral metabolism of corticosteroids and sex hormones is also disturbed (the latter leads to anovulation). However, the level of catecholamines is compensated, but in the absence of thyroid hormones, their physiological effects are not realized due to a decrease in the sensitivity of beta adrenoreceptors. Reducing the level of thyroid hormones in the blood by the mechanism of negative feedback increases the secretion of thyroid-stimulating hormone and often prolactin. TTG stimulates compensatory hyperplasia of thyroid tissue, the formation of cysts, adenomas, etc.

The hypothyroid coma is based on the depression of the respiratory center and the progressive decrease in cardiac output, increasing brain hypoxia and hypothermia as a result of general hypometabolism as a result of a fall in the rate of major metabolic reactions and oxygen utilization. Along with the depression of the respiratory center, pulmonary ventilation is hampered by the accumulation of bronchial secretion and a decrease in the cough reflex. The most important link in pathogenesis, determining the severity and prognosis, is hypocorticism. The loss of consciousness is usually preceded by the pre-coma period, when the main symptoms of hypothyroidism are concentrated and weighted. In conditions of severe hypothermia (30 ° C and even lower), the functions of all internal organs and, above all, the adrenal glands decrease. However, the body temperature in hypothyroid coma in rare cases can be normal. Diagnosis and differential diagnosis can be difficult if there is no history of hypothyroidism or treatment with radioactive iodine. It is this type of therapy that leads to distant hypothyroidism, the main symptoms of which stimulate age-related involution.

Pathanatomy

The reason for the decline in thyroid function is most often atrophic changes in it, expressed in varying degrees. In severe atrophy, iron has a mass of no more than 3-6 g and is represented by a thickened capsule with well-developed connective tissue layers and vessels, between which there are few islets of thyroid tissue from small follicles with thick colloid and flat follicular cells or Gurtle-Ashkenazi cells. In the stroma there are a few lymphoid infiltrates with an admixture of macrophages and other cells. Sometimes there is marked fatty infiltration. Such changes usually occur in hypothyroidism due to a disorder of the thyrotropic function of the hypothalamus and / or pituitary gland.

If congenital hypothyroidism is caused genetically and is accompanied by the inability of the thyroid gland to produce hormones, goiter is noted. Iron at the same time increases due to hyperplasia and hypertrophy of the thyroid epithelium, forming strands, solid clusters, tubular and rarely - follicular structures with virtually no contents. The thyroid epithelium is large, often with a light vacuolated cytoplasm. The nuclei are especially hypertrophied. They can be gigantic and ugly. This epithelium intensively proliferates, which leads to rapid growth of goiter. The subtotal resection of the thyroid gland produced by these patients is often non-radical. The goiter recurs rapidly. The solidification and dysplastic changes in the thyroid epithelium become even more pronounced. Often, these cases are treated as cancers of the thyroid gland. However, the absence of phenomena of angioinvasion and germination of the gland capsule does not allow treating this pathology as malignant neoplasms. Relapses and increased proliferation of thyroid epithelium in these cases is due to hyperstimulation of their TSH. In such glands often there are numerous adenomas of a diverse structure, especially embryonic type.

In skeletal musculature with hypothyroidism, hypertrophy of a part of the muscle fibers is noted with the disappearance of transverse striation in them, rupture of myofibrils, disruption of the integrity of the sarcolemma, edema of individual fibers, an increase in the number of nuclei with their redistribution along the fiber. Sometimes there is lymphoplasmocytic infiltration as in polymyositis. All these changes are characteristic of myxedema and are considered as myxedemaemia myopathy.

In the heart of patients with myxedema often shows pericardial edema, and in the coronary arteries - multiple atheromas. The basal membrane of the myocardial capillaries is usually sharply thickened.

The pituitary gland is often enlarged, various changes can be found in it: a sharp decrease in the granulation of acidophiles, an increase in the number of slightly granulated basophils.

The adrenal cortex is atrophied. Autoimmune hypothyroidism can be combined with an autoimmune lesion of the adrenal cortex (Schmidt's syndrome).

Hypothyroid polyneuropathy is primarily due to neuroaxial degeneration, which in turn aggravates myxedematous myopathy.

The phenomena of hypothyroidism can accompany various variants of nodular goiter, mainly colloidal, as well as generalized or isolated amyloidosis of the thyroid gland, which cause atrophy of its parenchyma due to the massive deposition of amyloid in the basal membrane of the follicles and in the stroma of the gland.