Primary hypothyroidism

Primary hypothyroidism is hypothyroidism that develops as a result of congenital or acquired dysfunction of the thyroid gland.

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

Epidemiology of primary hypothyroidism

The most common type of hypothyroidism (occurs in about 95% of all cases of hypothyroidism. The prevalence of clinically significant primary hypothyroidism in the population is 0.2-2%, the frequency of primary subclinical hypothyroidism reaches 10% in women and 3% in men. Congenital primary hypothyroidism occurs with a frequency 1: 4,000-5,000 newborns.

[7], [8], [9], [10]

Causes of Primary Hypothyroidism

Most often, primary hypothyroidism is the outcome of autoimmune thyroiditis, less commonly the result of treatment of thyrotoxicosis syndrome, although a spontaneous outcome of diffuse toxic goiter in hypothyroidism is also possible. The most common causes of congenital hypothyroidism are aplasia and dysplasia of the thyroid gland, as well as congenital enzymopathies, accompanied by impaired biosynthesis of thyroid hormones.

With extremely severe iodine deficiency, iodine intake of less than 25 mcg / day for a long time can develop iodine-deficient hypothyroidism. Many drugs and chemicals (propylthiouracil, thiocyanates, potassium perchlorate, lithium carbonate) can disrupt the function of the thyroid gland. In this case, hypothyroidism due to amiodarone most often has a transient nature. In rare cases, primary hypothyroidism is a consequence of substitutional pathological process thyroid tissue Sarcoidosis, cystinosis, amyloidosis, thyroiditis Riedel). Congenital hypothyroidism can be transient. It develops under the action of various causes including prematurity, intrauterine infections, transplacental transfer of antibodies to thyroglobulin and thyroperoxidase, and thyrostatic intake by the mother.

[11], [12], [13], [14]

Pathogenesis of primary hypothyroidism

Hypothyroidism is characterized by a decrease in the rate of metabolic processes, which is manifested by a significant decrease in oxygen demand, a slowdown in redox reactions, and a decrease in basal metabolism. Inhibition of synthesis and catabolism occurs. A universal symptom of severe hypothyroidism is mucinous edema (myxedema), most pronounced in connective tissue structures. The accumulation of glycosaminoglycans - products of protein breakdown, with increased hydrophilicity, causes fluid and sodium retention in the extravascular space. In the pathogenesis of sodium retention, an excess of vasopressin and a deficiency of natriuretic hormone play a certain role.

The deficiency of thyroid hormones in childhood inhibits physical and mental development and in severe cases can lead to hypothyroid nanism and cretinism.

[15], [16], [17], [18], [19], [20],

Symptoms of primary hypothyroidism

Clinical manifestations of hypothyroidism include:

•  hypothermic exchange syndrome: obesity, reduced body temperature, increased triglycerides and LDL. Despite a moderate excess of body weight, appetite for hypothyroidism is reduced, which, in combination with depression, prevents significant weight gain. Disruption of lipid metabolism is accompanied by slowing down and synthesis and degradation of lipids with a predominance of slower degradation, which ultimately leads to accelerated progression of atherosclerosis;
• hypothyroid dermopathy and ectodermal disorder syndrome: myxedematous edema of the face and extremities, periorbital edema, jaundice of the skin (due to hypercarotenemia), fragility and loss of hair on the lateral parts of the eyebrows, head, nest baldness and alopecia are possible. Due to the coarsening of the facial features, such patients sometimes become similar to patients with acromegaly;
• syndrome of damage to the sense organs, difficulty in nasal breathing (due to swelling of the nasal mucosa), hearing loss (due to edema of the auditory tube and middle ear), hoarseness of the voice (due to swelling and thickening of the vocal cords), disturbed night vision;
• syndrome of central and peripheral nervous system lesions: drowsiness, lethargy, memory loss, bradyfrenia, muscle pain, paresthesia, decrease in tendon reflexes, polyneuropathy. Perhaps the development of depression, delirium (myxedema delirium), rarely - typical paroxysms of panic attacks (with attacks of tachycardia);
• cardiovascular lesion syndrome ("myxedema heart") signs of heart failure, characteristic ECG changes (bradycardia, low QRS complex voltage, negative T wave), increased levels of CPK, ACT and lactate dehydrogenase (LDH). In addition, arterial hypertension, effusion in the pleural, pericardial, abdominal cavity are typical. There are atypical variants of damage to the cardiovascular system (with arterial hypertension, without bradycardia, with tachycardia in case of circulatory failure);
• syndrome lesions of the digestive system: hepatomegaly, diskinezinya biliary tract, colon dysmotility, tendency to constipation, reduced appetite, atrophy of the gastric mucosa;
• anemic syndrome: normochromic normocytic, or iron hypochromic, or macrocytic vitamin B12-deficient anemia. In addition, a platelet germ characteristic of hypothyroidism leads to a decrease in platelet aggregation, which, combined with a decrease in plasma levels of factors VIII and IX, as well as increased capillary fragility aggravates bleeding;
• hyperprolactinemic hypogonadism syndrome: oligopsomenorrhea or amenorrhea, galactorrhea, secondary polycystic ovary. The basis of this syndrome is hyperproduction of TRH by the hypothalamus with hypothyroxinemia, which contributes to an increase in the release of adenohypophysis, not only TSH, but also prolactin;
• obstructive hypoxemic syndrome: sleep apnea syndrome (due to myxedema infiltration of mucous membranes and reduced sensitivity of the respiratory center), myxedematous lesion of the respiratory muscles with a decrease in respiratory volume by alveolar hypoventilation (leads to hypercapnia until the development of hypothyroid coma).

[21]

Hypothyroid or myxedema coma

This is a dangerous complication of hypothyroidism. Its causes are the absence or insufficient replacement therapy. They provoke the development of hippothyroid coma, cooling, infections, intoxication, blood loss, severe intercurrent diseases and taking tranquilizers.

Manifestations of hypothyroid coma include hypothermia, bradycardia, hypotension, hypercapnia, mucinous edema of the face and extremities, symptoms of CNS damage (confusion, lethargy, stupor and possible urinary retention or intestinal obstruction. The cardiac cause of death may be heart tamponade due to hydropericardium.

[22]

Classification of primary hypothyroidism

Primary hypothyroidism is classified by etiology. Allot

Primary hypothyroidism due to destruction or lack of functional activity of the thyroid tissue:

• chronic autoimmune thyroiditis;
• surgical removal of the thyroid gland;
• hypothyroidism due to iodine radioactive therapy;
• transient hypothyroidism in subacute, postpartum, and painless thyroiditis;
• hypothyroidism in infiltrative and infectious diseases;
• agenesis and thyroid dysgenesis;

Primary hypothyroidism due to impaired synthesis of thyroid hormones:

• birth defects in thyroid hormone biosynthesis;
• severe iodine deficiency or excess;
• drug and toxic effects (thyreostatics, lithium perchlorate, etc.).

[23], [24], [25], [26], [27]

Diagnostics 

Diagnosis of primary hypothyroidism includes establishing the diagnosis of hypothyroidism, determining the level of the lesion and clarifying the causes of primary hypothyroidism.

Diagnosis of hypothyroidism and the determination of the level of the lesion: assessment of the level of TSH and free T ₄ using highly sensitive methods.

For primary hypothyroidism characterized by increased levels of TSH and lower levels of free T ₄. Determining the level of total T ₄ (i.e., both protein bound and free biologically active hormone) has less diagnostic value, since the level of total T depends largely on the concentration of transporter proteins binding it.

Determining the level of T _{3 is} also impractical, since in hypothyroidism, along with elevated TSH levels and a decrease in T ₄, normal or even slightly elevated T ₃ levels can be determined due to compensatory acceleration of the peripheral conversion of T ₄ to the more active hormone T ₃

Clarification of the causes of primary hypothyroidism:

• Ultrasound of the thyroid gland;
• thyroid scintigraphy;
• puncture biopsy of the thyroid gland (if indicated);
• determination of antibodies to thyroperoxidase (in case of suspected autoimmune thyroiditis).

Differential diagnostics

Primary hypothyroidism is primarily differentiated from secondary and tertiary. The leading role in differential diagnostics is played by the determination of the level of TSHT T ₄. In patients with normal or slightly elevated TSH levels, it is possible to conduct a test with TRH, which allows differentiation of primary hypothyroidism (an increase in the level of TSH in response to administration of TRH) with a secondary and tertiary (reduced or delayed response to TRH).

CT and MRI can detect changes in the pituitary and hypothalamus (usually a tumor) in patients with secondary or tertiary hypothyroidism.

In patients with severe somatic diseases, primary hypothyroidism should be differentiated from euthyroid pathology syndromes characterized by a decrease in the level of T ₃, and sometimes T ₄ and TSH. These changes are usually interpreted as adaptive, aimed at conserving energy and preventing protein catabolism in the body in a severe general condition of the patient. Despite the reduced levels of TSH and thyroid hormones, thyroid hormone replacement therapy in euthyroid syndrome is not indicated.

[28], [29], [30], [31], [32]

Differential diagnostics

Primary hypothyroidism is primarily differentiated from secondary and tertiary ones. Determination of T4 and TSH level plays leading role in differential diagnostics. Tests with TRH may be conducted in patients with normal or slightly elevated levels of TSH, which allow to differentiate between primary hypothyroidism (TSH levels increase in response to TRH) and secondary and tertiary (reduced or delayed response to TRH).

CT and MRI can detect changes in pituitary and hypothalamus (usually tumors) in patients with secondary or tertiary hypothyroidism.

Primary hypothyroidism should be differentiated in patients with severe somatic diseases from euthyroid disease syndrome, which is characterized by decrease in T3 level and sometimes in T4 and TSH levels. These changes are usually interpreted as adaptive, aimed at preserving energy and preventing catabolism protein in body in severe general condition of patient. Replacement therapy by thyroid hormones is not shown in euthyroid pathology syndrome despite reduced level of TSH and thyroid hormones.

Treatment of primary hypothyroidism

The goal of the treatment of hypothyroidism is the complete normalization of the condition: the disappearance of the symptoms of the disease and the maintenance of the TSH level within the normal range (0.4–4 MED / l) In most patients with primary hypothyroidism, this is achieved by prescribing T ₄ at a dose of 1.6-1.8 µg / kg body weight. The need for thyroxin in newborns and children due to increased metabolism of thyroid hormones is noticeably greater.

Replacement therapy in primary hypothyroidism is usually carried out for life.

In patients younger than 55 years old who do not have cardiovascular diseases, T _{4 is} prescribed at a dose of 1.6-1.8 µg / kg body weight. In obesity, the dose of T ₄, calculated on the "ideal" for the patient's weight. Treatment begins with a full dose of the drug.

Patients over 55 years of age and those with cardiovascular diseases have an increased risk of T ₄ side effects. Therefore, they are prescribed T ₄ at a dose of 12.5-25 μg / day and slowly increase the dose of the drug until the level of TSH is normalized (on average, the required dose is 0.9 μg / kg body weight). If it is impossible to perfectly compensate for hypothyroidism in an elderly patient, the level of TSH may remain within 10 IU / l.

Special attention should be paid to compensating hypothyroidism during pregnancy. During this period, the need for T ₄ on average increases by 45-50%, which requires an adequate correction of the dose of the drug. Immediately after birth, the dose is reduced to the standard.

Taking into account the high sensitivity of the brain of the newborn to thyroid hormone deficiency, which subsequently leads to an irreversible decrease in intelligence, it is necessary to make all possible efforts to begin treatment of congenital hypothyroidism T ₄ from the first days of life.

In the vast majority of cases, monotherapy with levothyroxine sodium is effective.

Synthetic levogyrate isomer of thyroxine Bagotiroks stimulates tissue growth and development, increases tissue oxygen demand, stimulates the metabolism of proteins, fats and carbohydrates, increases the functional activity of the cardiovascular and central nervous systems. The therapeutic effect is observed after 7-12 days, during the same time the effect remains after discontinuation of the drug. Diffuse goiter decreases or disappears within 3-6 months. Bagotirox tablets 50, 100 and 150 mcg are produced using proprietary technology “Flexidosis”, which allows to obtain “dosing steps” from 12.5 mcg.

Patients younger than 55 years old who do not have cardiovascular diseases are prescribed:

• Levothyroxine sodium inside 1.6-1.8 mg / kg 1 time a day in the morning on an empty stomach, for a long time (in most cases - for life).

In this case, the estimated initial dose for women is 75-100 mcg / day, for men - 100-150 mcg / day.

Patients older than 55 years and / or in the presence of cardiovascular disease is prescribed.

• Levothyroxane sodium inside12.5-25 µg 1 time per day in the morning on an empty stomach, for a long time (every 2 months the dose should be increased by 25 µg / day to normalize the level of TSH in the blood or to achieve the target dose of 0.9 µg / kg / day).

If symptoms of cardiovascular disease appear or worsen, correction of therapy together with a cardiologist is necessary.

If it is impossible to perfectly compensate for hypothyroidism in an elderly patient, the TTT level can remain within 10 IU / l.

A newborn immediately after the identification of primary hypothyroidism is prescribed:

• Levothyroxine sodium inside 10-15 mkg / kg once a day in the morning on an empty stomach for a long time.

Children are prescribed:

• Levothyroxine sodium inside 2 mkg / kg (and more if necessary) once a day in the morning on an empty stomach, for life.

With age, the dose of levothyroxine should be reduced by 1 kg of body weight.

Age	Daily dose, T4, mcg	Dose of thyroxine per weight, µg / kg
1-6 months	25-50	10-15
6-12 months	50-75	6-8
1-5 years	75-100	5-6
6-12 years old	100-150	4-5
More than 12 years	100-200	2-3

Hypothyroid coma

The success of treating hypothyroid coma depends primarily on its timeliness. The patient should be hospitalized immediately.

Comprehensive treatment includes:

• administration of an adequate dose of thyroid hormones,
• use of glucocorticosteroids
• combating hypoventilation to hypercapnia;
• treatment of diseases that led to the development of coma

Treatment of coma begins with the introduction of glucocorticosteroids, it is difficult for a patient in a coma to reject the presence of Schmidt syndrome, and also to make a differential diagnosis between primary and secondary hypothyroidism. When hypothyroidism is combined with adrenal insufficiency, the use of thyroid hormones alone can provoke the development of a crisis of adrenal insufficiency.

Hydrocortisone intravenously 50-100 mg 1-3 times per day (up to a maximum dose of 200 mg / day), until stabilization.

Levothyroxine sodium 100-500 µg (for 1 hour), then 100 µg / day, to improve the condition and the possibility of transferring the patient to long-term / lifelong oral administration of the drug in the usual dosage (in the absence of injectable drugs, levothyroxine sodium tablets can be administered in powdered form gastric tube).

+

• Dextrose, 5% solution, intravenously 1000 ml / day, until the state stabilizes or
• Sodium chloride. 0.9% solution intravenously to 1000 ml / day, until the state stabilizes.

[33], [34], [35], [36]

Evaluation of the effectiveness of treatment of primary hypothyroidism

Evaluation of the effectiveness of treatment is performed by monitoring the level of TSH, which should be in the normal range (0.4-4). Recently, there have been reports that the level of TGG of 0.5-1.5 IU / l is optimal, which is noted in most healthy people. After the appointment of a full replacement dose of levothyroxine sodium, the adequacy of therapy is assessed after 2-3 months. At a normal level of TSH, it is recommended to re-check 4-6 months in connection with the possibility of increasing the clearance of levothyroxine sodium after reaching the euthyroid state, which will require an increase in the dose of the drug. In the future, the level of TIT is determined annually.

[37], [38], [39], [40]

Complications and side effects of treating primary hypothyroidism

An overdose of levothyroxine sodium, leading to the development of subclinical thyrotoxicosis, is dangerous mainly by two complications - this is myocardial dystrophy with the development of atrial fibrillation and osteopenia syndrome.

[41], [42], [43], [44],

Errors and unreasonable assignments

Late diagnosis of hypothyroidism and inadequate therapy are fraught with serious complications; lack of dose of levothyroxine sodium leads to an increased risk of developing and progression of coronary artery disease due dyslipidemia dyslipidemia, as well as impaired reproductive function in young women, depression.

Unreasonable prescription of levothyroxine sodium in Wilson syndrome (the presence of clinical signs of hypothyroidism in normal laboratory indicators of thyroid function). Symptoms of hypothyroidism are not specific and can often be the result of other causes, in particular a decrease in the activity of the sex glands in women of menopause. In the overwhelming majority of patients, in this case, therapy with levothyroxine sodium does not produce an effect, and sometimes the observed improvement in the condition is short-term and is explained by the “placebo effect”.

[45], [46], [47],

Forecast 

In most cases of hypothyroidism, the prognosis is favorable. It depends on the age of hypothyroidism (with long-term hypothyroidism, cardiovascular diseases become important for the prognosis of patients due to accelerated development of atherosclerosis), the adequacy of therapy and the development of complications (primarily hypothyroid coma). Even with early treatment, mortality in hypothyroid coma is 50%.