Diffuse euthyroid goiter: diagnosis and treatment

The term "diffuse euthyroid goiter" (ECD) refers to the visible and / or palpable enlargement of the thyroid gland.

ECD is a common diffuse enlargement of the thyroid gland without impairing its function. The main cause of the ECD is the lack of iodine in the environment and, as a consequence, its reduced consumption by the population with the usual foods. Depending on the prevalence of ECD, sporadic and endemic goiter are distinguished in the population.

Goitre is considered endemic if in the surveyed region the incidence of goiter in children of primary and secondary school age is more than 5%. ECD - the pathology of young people. In more than 50% of cases, it develops before the age of 20. and in women, the goiter develops 2–3 times more often than in men, while, as a rule, during periods when the need for iodine is increased (puberty, pregnancy, breast-feeding).

In accordance with the criteria adopted by WHO, UNICEF (United Nations Children's Fund) and ICCIDD (International Council for the Control of Iodine Deficiency Disorders), a region can be considered free from iodine deficiency if the median of ioduria is within 100–300 µg / l, and the prevalence goiter does not exceed 5%. In Russia, there is practically no territory prosperous in terms of the risk of iodine deficiency goiter. According to epidemiological surveys of 1991–2006, the frequency of various forms of goiter in the Russian Federation ranges from 10 to 40%.

The most common cause of development of the ECD is iodine deficiency. At the same time, hypertrophy and hyperplasia of the thyroid gland are compensatory in nature and are aimed at providing the body with thyroid hormones. What are the mechanisms of such adaptation to iodine deficiency?

First, the absorption of iodine by the thyroid gland increases due to the enhancement of its active uptake.

Secondly, the predominant synthesis of triiodothyronine (T3), which is the most active tyrsoid hormone, occurs, and its synthesis requires not 4, but only 3 iodine atoms.

Thirdly, the secretion of iodine by the kidneys decreases, the utilization of endogenous iodine increases, which increases the efficiency of the biosynthesis of thyroid hormones.

Fourthly, the content of iodine in the colloid is reduced (due to the predominant synthesis of monoiodotyrosine, and not diiodotyrosine) and thyroglobulin in the colloid (due to increased proteolysis).

In the early stages of goiter development (t. P. In children, adolescents and young people), compensatory hypertrophy of thyrocytes occurs. The thyroid gland is represented by a mass of small follicles, practically free of colloid. This goiter is called parenchymal, it is the result of successful adaptation.

Another morphological variant of the ECD is a colloid goiter. It consists of large follicles containing a huge amount of colloid. When forming this type of goiter, a number of mechanisms prevent the optimal functioning of the thyroid gland. There is an imbalance between the synthesis and hydrolysis of thyroglobulin, the degree of iodination of thyroglobulin decreases. There is a leak of iodine from the thyroid gland and a decrease in the synthesis of iodothyronines. Changes of this type predominate in the thyroid tissue of the operated patients.

There is no doubt that all adaptation reactions are stimulated and controlled by thyroid-stimulating hormone (TSH). However, as has been shown in many papers, the level of TSH does not increase with the ECD. In a series of studies in vivo and in vitro, new data were obtained on autoregulation of the thyroid gland with iodine and autocrine growth factors (ARF). According to modern concepts, an increase in the production of TSH or an increase in the sensitivity of thyrocytes to it is only of secondary importance in the pathogenesis of iodine deficient goiter. The main role here is assigned to ARF, such as type 1 insulin-like growth factor (IGF-1), epidermal growth factor (ERF) and fibroblast growth factor (FGF), which, under conditions of reducing iodine in the thyroid gland, have a powerful stimulating effect on thyrocytes. It was experimentally shown that when thyrocyte KI was added to culture, a decrease in TSH-induced cAMP (cyclic adenosine monophosphate) -mediated expression of IRF-1 M-RNA was observed, with its complete cessation with a significant increase in iodide dose.

It is well known that iodine itself is not only a substrate for the synthesis of thyroid hormones, but also regulates the growth and function of the thyroid gland. The proliferation of thyrocytes is inversely related to the intrathyroid iodine content. High doses of iodine inhibit the absorption of iodine, its organization, synthesis and secretion of thyroid hormones, absorption of glucose and amino acids. Iodine, entering the thyrocyte, interacts not only with tyrosyl residues in thyroglobulin, but also with lipids. The compounds resulting from this (iodolactones and iodaldehydes) are the main physiological blockers of ARF production. In the human thyroid gland many different iodolactones have been identified, which are formed due to the interaction of membrane polyunsaturated fatty acids (arachidonic, doxhexenic, etc.) with iodine in the presence of lactoperoxidase and hydrogen peroxide.

Under conditions of chronic iodine deficiency, a reduction in the formation of iodiplides occurs - substances that inhibit the proliferative effects of ARF (IGF-1, FGF, EGF). In addition, if the iodine content is insufficient, the sensitivity of these ARPs to the growth effects of TSH increases, the production of transforming growth factor-β (TGF-β) decreases, which normally is an inhibitor of proliferation, and angiogenesis is activated.

All this leads to an increase in the thyroid gland, the formation of iodine-deficient goiter.

In general, the development of the ECD depends on many factors that are not fully understood. In addition to iodine deficiency, other factors related to the development of goiter include smoking, taking certain medications, emotional stress, and foci of chronic infection. Sex, age, hereditary predisposition also matter.

With endemic goiter, genetic predisposition can be realized only if there is an appropriate external factor - iodine deficiency in the environment. In the absence of genetic predisposition, a light or even moderate iodine deficiency may not lead to the formation of goiter, since this deficiency will be compensated by a more efficient operation of the systems providing the synthesis of thyroid hormones. In severe iodine deficiency, even the maximum activation of compensatory processes cannot always prevent the formation of goiter in individuals who do not have a genetic predisposition.

To assess the degree of enlargement of the thyroid gland by palpation method, WHO (2001) recommends the following classification.

Zero degree - no goiter (the volume of each lobe does not exceed the volume of the distal phalanx of the thumb of the subject).

1st degree - goiter is palpable, but not visible in the normal position of the neck. This includes nodules that do not lead to an increase in the gland itself.

Grade 2 - goiter is clearly visible in the normal position of the neck.

The sensitivity and specificity of the method of palpation to assess the degree of goiter is rather low. Therefore, for accurate determination of the size and volume of the thyroid gland in the context of an epidemiological study, an ultrasound examination is recommended.

The volume of the thyroid gland is calculated taking into account the width (W), length (D) and thickness (T) of each lobe and the coefficient of correction for ellipsoidness using the following formula Vshchzh = [(Shpr x Dpr x Tpr) + (Sh x x Dl x Tl)] x 0.479.

In adults, goiter is diagnosed if the volume of the gland, according to an ultrasound scan, exceeds 18 ml in women and 25 ml in men. In a child, the volume of the thyroid gland depends on the degree of physical development, therefore, before the study, the height and weight of the child are measured and the surface area of ​​the body is calculated using a special scale or formula. In children, the volume of the thyroid gland is compared with standard indicators (depending on the surface area of ​​the body).

The clinical picture of the ECD depends on the degree of enlargement of the thyroid gland, since its function remains normal. By itself, the fact of a small enlargement of the thyroid gland with its normal function does not practically affect the work of other organs and systems. In the overwhelming majority of cases, in conditions of mild and moderate iodine deficiency, a slight enlargement of the thyroid gland is detected only with targeted examination. In conditions of severe iodine deficiency goiter can reach gigantic proportions. Against the background of the ECD, a nodular goiter may develop in the future, including with autonomously functioning nodes.

Treatment of ECD

Measures to eliminate iodine deficiency in the USSR were taken as a result of epidemiological studies, started before the Second World War by an outstanding endocrinologist and preventive specialist O.V. Nikolayev. They included the mass production of iodized edible table salt, the use of tableted iodine preparations among at-risk groups, and the creation of anti-pest dispensaries. Against the background of this program, iodine deficiency in Russia was largely overcome in the period from 1955 to 1970. After this was accomplished, as a sign of “victory over the ECD”, it was decided to phase out measures to eliminate it, and the diagnosis of endemic goiter replace with "thyroid hyperplasia".

In Western Europe, up to the 60s of the last century, preparations of extracts of the thyroid gland were used, whose effectiveness was determined not only by the content of thyroid hormones, but also by a large amount of iodine.

To date, there are three options for the conservative treatment of ECD:

• levothyroxine monotherapy,
• iodine monotherapy,
• combination therapy with iodine and levothyroxine.

Levothyroxine monotherapy was scientifically grounded in the treatment of ECD when describing the regulation of the thyroid gland of the hypothalamic-pituitary system. In an experiment on rats, it was shown that artificially modeled heavy iodine deficiency leads to an increase in the level of TSH, which, in turn (as well as exogenously administered TSH), can lead to the formation of goiter. It was assumed that under conditions of iodine deficiency, the synthesis and secretion of thyroxin T4 and T3 are reduced, for which iodine is the main structural component, which, by the principle of negative feedback, leads to increased TSH secretion. Therefore, the main goal of treatment with levothyroxine was suppression of TSH, contributing to an increase in thyroid volume (suppressive therapy). However, it has been repeatedly shown that a decrease in the glandular volume does not depend on the degree of suppression of TSH. There are also studies that prove that the average level of TSH in iodine-deficient areas is significantly lower than in those areas where iodine consumption is normal. Moreover, there are experimental data showing that it is not possible to stimulate the growth of follicles containing a sufficient amount of iodine by administering TSH.

As mentioned above, the prescription of levothyroxine has been widely used for the treatment of ECD in the past. At the same time, excellent results were achieved at the initial stage. Many clinical studies have shown that after 3-4 months from the start of therapy, there was a significant (at least 20%) decrease in the volume of the gland. The literature provides data on the effectiveness of the use of various doses and combinations of thyroid hormones. So T3 at a dose of 50 micrograms per day is most effective for reducing the volume of the thyroid gland. Further, as efficiencies decrease, options follow:

• (T4 50 µg + Тз 12.5 µg) twice a day;
• T4 150 mcg per day + iodine 150 mcg per day;
• T4 75 µg per day + T3 18.75 µg per day;
• T4 200 mcg per day;
• T3 37.5 mcg per day.

The most commonly used in clinical practice doses were 150 μg in adults and 100 μg in adolescents. However, numerous works have unequivocally demonstrated the "phenomenon of cancellation" - an increase in the size of the thyroid gland almost to the initial level a short time after the cessation of treatment. This phenomenon is primarily explained by the fact that suppression of TSH decreases the activity of the Na + / I-symporter, and, consequently, the active uptake of iodine by the thyroid gland decreases. Against the background of a sharp drop in the intrathyroid iodine content, with the abolition of the drug, a new growth of the gland occurs. Also, side effects of thyroid hormone therapy include the possible occurrence of drug thyrotoxicosis, tachyarrhythmias, osteoporosis, which limits the use of this group of drugs during long-term treatment of ECD. However, sometimes in order to quickly achieve a therapeutic effect, they resort to the appointment of a short course of treatment with levothyroxine with a further transition to maintenance therapy with iodine preparations.

Mototherapy with iodine preparations is etiotropic therapy. The work of the last 10-15 years has shown that an increase in TSH production or an increase in the sensitivity of thyrocytes to it is only of secondary importance in the pathogenesis of iodine deficient goiter. With insufficient intake of iodine in the gland, the amount of iodized lipids (the main inhibitors of growth factors) decreases, which has a powerful stimulating effect on the growth of thyrocytes.

The main role is assigned to the local ARF, such as IGF-1, ERF and FGF.

The stage of the “revival” of the treatment of DES by iodine began in the 80s of the last century. Many studies were limited by the fact that at that time ultrasound measurement of the size of the thyroid gland could not be performed. So, G. Hintze and D. Emrich in 1983 in their work on the treatment of iodine deficient goiter, as the main marker of changes in the volume of the thyroid gland used the value of the circumference of the neck. The authors have shown that the administration of 400 µg iodine also effectively reduces the volume of the thyroid gland, as well as 150 µg of levothyroxine (estimated 12 months after the start of treatment), and, unlike levothyroxine, the result of iodine therapy persists for a long time after its cancellation .

As UZI is being introduced into practical medicine, randomized controlled studies on the effect of various treatment regimens on iodine deficiency goiter are being conducted. In this case, the dose of iodine ranged from 100 μg and above, including pharmacological, in the case of using iodized oil. The appointment of 100-150 mcg of iodine has proven itself in the treatment of goiter in children.

In adults, iodine in a dose of 100-150 mcg per day was not as effective as in children, but the tendency to a decrease in the volume of the thyroid gland is also observed. In the scientific literature of the 80s of XX century. You can find jobs where iodine was used in the treatment of goiter in doses of 500 µg, and 400 µg, and 300 µg per day. And they all demonstrate the comparable efficacy of iodine monotherapy with levothyroxine monotherapy and combination therapy with iodine and levothyroxine, as well as the most lasting effect after drug withdrawal. However, there is evidence that the use of high doses of iodine sometimes causes thyroid dysfunction (hypo- or hyperthyroidism). And although for the recognition of this fact we need more weighty evidence, at present, the following is generally accepted: the medical vines of iodine in the DEZ are almost the same as prophylactic and are 150–200 mcg per day. Thus, when conducting a double-blind, placebo-controlled study in Germany, the effectiveness of 200 μg iodine for the treatment of iodine deficient goiter was confirmed. The volume of the thyroid gland decreased by 38% over 6 months and remained so at least the same time. In another study, the effect on gland size was estimated to be 200 μg iodine and 100 μg levothyroxine. A comparable efficacy of these two dosages was shown, and again attention was focused on the fact that the degree of reduction of the thyroid gland does not depend on the level of TSH.

Numerous modern works have demonstrated success in reducing the prevalence of goiter due to the introduction of universal salt iodization programs. As for group prophylaxis, 150 mcg of iodine per day is now sufficient for adolescents, 200 mcg for pregnant and lactating women.

In the scientific literature of recent years, the development of autoimmune processes in the thyroid gland in the presence of iodine-containing preparations is widely discussed. At the same time, there are works both confirming this influence and denying it. G. Kahaly in his works studied the efficacy and safety of low doses of iodine in the ECD. He noted that when using 200 µg of iodine per day, an increase in the level of antibodies to thyroid peroxidase, antibodies to thyroglobulin, a significant increase in lymphocytic infiltration in gland tissue occurs only in 97% of cases. In contrast to these facts, a group of researchers from Austria did not find the above changes at all when prescribing 200 mg of iodine to patients with iodine deficient goiter. In general, the development of autoimmune processes in the thyroid gland most likely depends on the population characteristics of the region, which requires more detailed, carefully planned studies.

Combined therapy with iodine and levothyroxine can be carried out by the simultaneous administration of levothyroxine and potassium iodide, as well as the use of their fixed combinations. Among them, the most frequently used drugs containing 100 μg of levothyroxine and 100 μg of iodide (iodotyrox). Therapy with iodotyrox, as has been repeatedly shown, has several advantages.

First, by acting on several pathogenetic mechanisms of goiter formation, hypertrophy and hyperplasia of thyrocytes are also suppressed. This allows you to achieve results that are comparable in effectiveness with ion therapy with levothyroxine (with a much lower content), which, in turn, reduces the number of side effects associated with the administration of thyroid drugs.

Secondly, the tendency to the development of the "phenomenon of withdrawal" is also reduced with a short break in treatment.

Thirdly, suppression of the level of TSH is less pronounced, for example, compared with the effect of levothyroxine at a dose of 150 μg.

1. The decrease in goiter is more pronounced in the case of combination therapy (40%) than in monotherapy with levothyroxine (24%) (Schumm et al.).
2. There are fewer side effects of levothyroxine and potassium iodide (as lower dosages are used than with monotherapy).
3. The effect (reduction of goiter) develops faster than with monotherapy with potassium iodide.
4. Titration of the dose of levothyroxine is not required, as the ratio of active ingredients is optimally selected.

There are many papers confirming these benefits. In one of them, the treatment of DES in 74 randomly selected patients was compared. Patients received either 150 µg of levothyroxine or 100 µg of levothyroxine + 100 µg of iodine for 6 months. In combination therapy, the decrease in the gland volume was slightly more pronounced (by 30% compared with 25%, the difference is not significant). Reducing the size of the gland is not dependent on the degree of suppression of TSH. In addition, in the group of patients who received the combined treatment, it was further possible to maintain the reduced volume of the gland during replacement therapy with 100 μg of iodine daily. In the group of patients treated only with levothyroxine, such prophylactic treatment was less effective. In the second study, 82 patients were included, who were randomly assigned for treatment for either 100 μg of levothyroxine or 100 μg of levothyroxine + 100 μg of iodine for the same 6 months. The decrease in the volume of the gland on the background of levothyroxine was 24% compared with 40% on the background of the combination of drugs, the differences were of statistical significance. Thus, in adult patients, the combination of "levothyroxine plus iodine" is the preferred treatment compared with iodine monotherapy (at least in the same doses) and is comparable to the similar dose of levothyroxine. Many researchers note that 150 µg iodine in combination with an individually selected dose of levothyroxine at the rate of 1 µg / kg of weight is more preferable for the treatment of endemic goiter in adults.

Summarizing the above, we can conclude that the main goal in the treatment of iodine deficiency goiter is not only reducing the volume of the thyroid gland, but also maintaining the achieved result. For this purpose, iodine preparations are suitable both in the form of monotraphy and as part of combination therapy with levothyroxine.

The question remains what to assign first. It is obvious that the intrathyroid concentration of iodine is significantly higher at the initial intake of iodine preparations than the drugs combined with levothyroxine. This fact once again confirms the etiotropic nature of iodine therapy, as well as the feasibility of starting treatment precisely with the administration of iodine preparations.

In our opinion, the algorithm of therapy of the ECD can be represented as follows.

• For the treatment of children with ECD, potassium iodide is recommended at a dose of 100–150 mcg per day, adolescents at a dose of 150–200 mcg per day.
• Treatment of adults should be carried out at a young age (up to 45-50 years), since it is often possible to achieve the desired result, and there is also a small risk of functional autonomy of the thyroid gland, in which iodine intake can provoke thyrotoxicosis. In the first 6 months, 200 µg of potassium iodide per day is justified.

Persons with ECDs older than 45-50 years are shown active dynamic observation with annual determination of the level of TSH and an ultrasound of the thyroid gland.

• In the absence of a pronounced effect from taking iodine preparations after 6 months, a transition to a combination therapy can be recommended. In this case, preference should be given to either a fixed combination of 100 µg iodine and 100 µg levothyroxine (iodotyrox), or an individually selected dose of levothyroxine at the rate of I µg / kg of weight in combination with 150 µg iodine per day.

But, on the basis of modern ideas, whatever initial treatment of goiter could be, a sharp cessation of it cannot be recommended without further preventive measures - the use of iodized salt.