Levothyroxine: do we know everything about it? uMEDp

Levothyroxine: do we know everything about it?

Levothyroxine is the gold standard for replacement therapy for hypothyroidism. However, in some cases, taking levothyroxine does not lead to compensation for the disease due to impaired absorption of the drug. Various factors can interfere with adequate absorption of levothyroxine, including primary or secondary lactase deficiency. The use of a lactose-free form of levothyroxine reduces the need for the drug, neutralizes the lability of hormonal parameters and, as a result, significantly improves the quality of life of patients.

Diseases of the thyroid gland occupy second place in the structure of endocrine pathology. And this primarily applies to hypothyroidism. Hypothyroidism is a condition caused by a long-term, persistent lack of thyroid hormones. According to the literature, the current prevalence of manifest hypothyroidism in the general population is 0.2–2%, and subclinical hypothyroidism is 10–12% [1]. In women, this disease occurs 6 times more often than in men [2].

Since about 10 million people today require levothyroxine replacement therapy, a doctor of any profile must know the basics of treating hypothyroidism, and also take into account the individual characteristics of the patient when choosing a drug for replacement therapy.

Levothyroxine replacement therapy

The “gold standard” of replacement therapy for hypothyroidism is levothyroxine. The thyroid gland practically does not perform other functions except secretory. The synthesis of hormones by the thyroid gland is not related to the circadian rhythm. Therefore, a daily single dose of levothyroxine in a dose that replenishes the hormone deficiency helps maintain normal thyroid function.

Synthetic levothyroxine preparations appeared back in the 50s. last century. There is a sufficient number of studies confirming that levothyroxine is the best available drug for the treatment of hypothyroidism [3]. However, new studies on the effectiveness of levothyroxine replacement therapy are emerging, expanding the possibilities of its use.

One recent cross-sectional study conducted in Pakistan examined the detection of hypothyroidism in newborns. The criterion is the level of thyroid-stimulating hormone (TSH). If hypothyroidism was detected, treatment with levothyroxine was prescribed. Of 550 newborns, 4 (0.8%) had elevated TSH levels. Congenital hypothyroidism had a statistically significant relationship with maternal hypothyroidism (p = 0.0001) and her taking levothyroxine during pregnancy (p = 0.013) [4].

A population-based study conducted in the Netherlands proved the connection between patient age and decreased thyroid function. From 2002 to 2003, 5816 people of different ages without previously identified thyroid diseases took part in it. The mortality rate among older adults with TSH levels of 3.0–4.0 mIU/L was significantly higher than among patients with TSH levels in the intermediate range of 1.0–2.0 mIU/L (HR 1.8 (95 % CI 1.0–3.1)). The authors suggested that there was the potential for levothyroxine replacement therapy in such patients [5].

A meta-analysis conducted in Kuwait showed that suppressive therapy with levothyroxine for solitary thyroid nodules helps to reduce the size of the nodes by 2 times and reduces the risk of cancer by 50%. Thus, it has been proposed to consider this type of treatment as an alternative in patients receiving levothyroxine, but on the condition that the risk of side effects in such patients is minimal [6]. However, the clinical effectiveness and safety of such therapy are still controversial.

At present, we can confidently say that the indication for the use of levothyroxine is not only hypothyroidism of various origins (including during pregnancy, lactation, and also when planning pregnancy [7]), but also mixed goiter. The drug is prescribed as part of complex therapy for diffuse toxic goiter (after achieving a euthyroid state), euthyroid hyperplasia of the thyroid gland, for the prevention of relapses after surgical treatment of nodular and malignant neoplasms of the thyroid gland, and for cretinism. Levothyroxine is also recommended for use when testing for thyroid suppression.

The half-life of levothyroxine is quite long - 6-7 days. About 15% is excreted by the kidneys and bile (unchanged and in the form of conjugates). The bioavailability of the drug when taken orally is quite high. After taking levothyroxine, 48 to 79% of the drug is absorbed from the gastrointestinal tract (GIT). Taking on an empty stomach increases the absorption of the active substance. The maximum concentration in blood plasma is reached after approximately 6 hours. Binding to plasma proteins (thyroxine-binding globulin, prealbumin and albumin) is 99%. Volume of distribution – 0.5 l/kg. Distribution occurs mainly in the liver, brain and muscles. Monodeiodination (approximately 80% of levothyroxine sodium) occurs in various tissues to form triiodothyronine and inactive products. A small amount of the active substance undergoes deamination and decarboxylation to form tetraiodothyroacetic acid, as well as conjugation with sulfuric and glucuronic acids (in the liver).

The replacement dose of levothyroxine for primary hypothyroidism in adults is determined at the rate of 1.6 mcg/kg of the patient’s body weight. With age, the need for the drug sometimes decreases, and the dose of levothyroxine can be reduced to 1 mcg/kg. In overweight patients, the dose is calculated per 1 kg of ideal body weight. Previously, most researchers recommended increasing the dose to a full replacement gradually - over 2-4 weeks, while starting treatment with 50 mcg of the drug, increasing the dose by 25 mcg. However, recent evidence suggests that it is safe to initiate treatment at the full replacement dose in patients without cardiovascular disease and under age 50 years. In the presence of cardiovascular diseases, the initial dose should be 12.5–25 mcg, and then gradually increase.

If hypothyroidism is first detected during pregnancy, levothyroxine is prescribed at a full replacement dose. It should be taken into account that during pregnancy the need for levothyroxine increases significantly and the total replacement dose will be about 2.3 mcg/kg [8].

Endocrinologists at the US Children's National Medical Center (Washington) analyzed the results of treatment of 55 patients with congenital hypothyroidism over 3 years. The patients were divided into three groups depending on the dose of levothyroxine received: the first group – 6–9.9 mcg/kg, the second – 10–11.9 mcg/kg and the third – 12–15 mcg/kg. The overdose criterion is thyroxine levels > 16 mcg/dl, free thyroxine > 2.3 ng/dl and TSH 6 mIU/l after a month. The level of thyroid hormones that meets the criteria for conditions such as euthyroidism, hyperthyroidism and thyrotoxicosis, after a month, was noted in the first group in 46, 37 and 17% of patients, respectively, in the second - in 30, 55 and 15% of patients, in the third - in 0 , 75 and 25% of patients. The authors concluded that at the time of diagnosis, initial doses of levothyroxine are 10–11.9 mcg/kg (TSH level > 100 mIU/L) and 8–10 mcg/kg (TSH level

Causes of decompensation of hypothyroidism

Oral levothyroxine in doses that provide hormonal balance is the most convenient form for treating hypothyroidism. However, one third of patients receiving levothyroxine replacement therapy experience decompensated hypothyroidism [10].

OE Okosieme et al., having studied 58,567 medical records, identified a group of patients with hypothyroidism (n = 1037) treated with levothyroxine in UK hospitals from 2004 to 2009. The researchers noted that 385 (37.2%) patients did not achieve target TSH levels. An analysis of controlled and cohort studies, as well as systematic reviews published since 1960 and devoted to the problem of uncompensated hypothyroidism, showed that in 50% of cases, levothyroxine replacement therapy does not allow achieving the target TSH level [11].

Malabsorption

The fact is that various factors can influence decreased absorption of levothyroxine. The most common cause of failure or resistance to levothyroxine treatment is pseudomalabsorption syndrome.

Already in 2006, M. Muñoz-Torres et al. stated that the cause of resistance to levothyroxine therapy in a 55-year-old patient was previously undiagnosed lactose intolerance. Researchers have suggested that 7–20% of the adult population is lactose intolerant

is the cause of impaired bioavailability of levothyroxine, which is apparently associated with the presence of gastrointestinal diseases. According to the authors, this pathology can be corrected with the help of diet [12]. This is confirmed by recent work.

Turkish scientists conducted a study of 83 patients with autoimmune thyroiditis (Hashimoto's thyroiditis) complicated by hypothyroidism. All patients took levothyroxine. A test for lactose intolerance showed its presence in 75.9% of patients. The final analysis included 38 subjects with lactose intolerance (30 patients in euthyroid status and 8 with subclinical hypothyroidism) and 12 subjects without this pathology. Patients with lactose intolerance were on a lactose-free diet. Observation lasted 8 weeks. The results showed a significant decrease in TSH levels in patients with lactose intolerance: in euthyroid patients - from 2.06 ± 1.02 to 1.51 ± 1.1 mU/ml, in patients with subclinical hypothyroidism - from 5.45 ± 0.74 to 2.25 ± 1.88 mU/ml, respectively (p 0.05). The authors concluded that lactose intolerance is common in patients with autoimmune thyroiditis, and reducing lactose intake reduces TSH levels. Therefore, patients with hypothyroidism who require increasing doses of levothyroxine and who have unstable TSH levels and are resistant to thyroxine treatment should be evaluated for lactose intolerance [13].

The effectiveness of levothyroxine therapy in patients with lactose intolerance was assessed in a study conducted in Rome. It involved 34 patients with autoimmune thyroiditis and hypothyroidism. The work was carried out from 2009 to 2012. A prerequisite for the study was adherence to a lactose-free diet.

In all patients with autoimmune thyroiditis with good lactose tolerance, stabilization of TSH (median TSH - 1.02 mU/l) was achieved with an average dose of levothyroxine 1.31 mcg/kg per day. With the same dose of the drug (1.29 mcg/kg per day) in patients with lactose intolerance, only 5 out of 34 patients achieved the target TSH level (median TSH - 0.83 mU/l). For the remaining 29 patients, the dose of levothyroxine was gradually increased: the target TSH level (median TSH - 1.21 mU/l) was achieved with an average levothyroxine dose of 1.81 mcg/kg per day (+38%, p

Lactose intolerance is a pathological condition caused by a decrease in lactase levels. Lactase deficiency is encoded by a single gene (LCT) located on chromosome 2q21. Lactase is an enzyme necessary to break down lactose. It has been observed that lactase activity decreases upon transition to an adult diet. In Northern Europeans, lactose intolerance usually develops after age 20 [15]. The frequency of constitutional lactase deficiency in the population also depends on ethnicity [16]. Some studies have shown that in northern regions lactose intolerance occurs in 35% of the population [17].

Lactase deficiency manifests itself in the form of osmotic diarrhea and increased gas formation in the intestines. The severity of symptoms depends on the level of enzyme production, the characteristics of the intestinal biocenosis, as well as the amount of lactose entering the body.

By eliminating foods containing lactose from your diet (which is not an easy task), you can reduce the severity of symptoms or even eliminate this disorder [18].

Lactase deficiency can be primary (hereditary) and secondary (damage to the mucous membrane of the small intestine by infectious agents, toxins, drugs, or as a result of surgical operations on the gastrointestinal tract) [19].

Possible damage to the mucous membrane of the small intestine, leading to irreversible lactose intolerance, has been described with the use of neomycin and kanamycin, colchicine, aminosalicylic acid and antineoplastic agents.

Cases of clinical symptoms of lactase deficiency in patients receiving drugs containing lactose as an excipient have been described with the use of flutamide, lithium carbonate, tranylcypromine, cromolyn sodium and acyclovir [20].

Therefore, if a patient with hypothyroidism has confirmed lactose intolerance, it is necessary to either prescribe a lactose-free diet or use lactose-free levothyroxine.

Another factor that prevents adequate absorption of levothyroxine is non-compliance with the drug dosage regimen.

, for example, changing the interval between taking the drug and eating. In patients with persistently high TSH levels who require more than 2 mcg/kg levothyroxine per day, inappropriate use of levothyroxine should first be excluded and only then examined for the presence of the pathology in question.

Gastrointestinal diseases

. A decrease in bioavailability can be affected by the presence of celiac disease in patients, inflammatory diseases of the gastrointestinal tract and parasitic infestation, intestinal resection, as well as atrophic gastritis and Helicobacter pylori infection.

It has been shown that in patients who have undergone surgical interventions on the gastrointestinal tract, the dose of levothyroxine is usually higher than that ensuring the achievement of euthyroidism in normal cases [21].

A gluten-free diet for celiac disease, as a rule, allows you to stabilize the dose of levothyroxine, a similar effect is achieved as a result of eliminating Helicobacter pylori infection or parasitic infestation. In cases of atrophic gastritis or the development of inflammatory processes in the intestines, treatment of the disease and restoration of the normal state of the gastrointestinal tract can increase the absorption of the drug.

The normal metabolism of levothyroxine is interfered with by certain foods, dietary fiber and coffee.

Many drugs

, such as cholic acid, ferrous sulfate, sucralfate, calcium carbonate, aluminum-containing antacids, phosphate binders, raloxifene, proton pump inhibitors, also negatively affect the absorption of levothyroxine [22].

Reduced activity of the active substance

Different excipients have different effects on the stability of levothyroxine sodium. The activity of levothyroxine, which contains lactose, decreases more rapidly during storage than the activity of levothyroxine made using dibasic calcium phosphate. Thus, tablet forms of the drug, which use lactose as an excipient, no longer meet the requirements of the United States Pharmacopeia (USP) after 3 months of storage at a temperature of 40 ° C and a relative humidity of 75%. Under the same storage conditions, the decrease in the activity of levothyroxine sodium in a preparation produced using dibasic calcium phosphate was only 15% [23].

Modern drugs of levothyroxine

In order to improve the tolerability and safety profile of its drugs, it decided to exclude lactose from the excipients used in the production of levothyroxine. Dibasic calcium phosphate was used as a filler. An example of such a drug is L-Thyroxine Berlin-Chemie. Taking it allows you to reduce the dose of the drug and achieve target TSH values in patients with hypothyroidism and concomitant lactose intolerance. This makes the treatment of hypothyroidism safer and more effective and opens up broad prospects for the use of the drug L-Thyroxine Berlin-Chemie.

Replacement and suppressive therapy with levothyroxine in the practice of an endocrinologist

E.A. Troshina, N.V. Mazurina, E.M. Skrynnik

Federal State Institution Endocrinological Research Center of the Ministry of Health of the Russian Federation, Moscow

Thyroid hormone preparations are among the most commonly used drugs in clinical practice. They are prescribed for the purpose of replacement or suppressive therapy for a number of thyroid diseases.

The purpose of replacement therapy

is to maintain normal metabolism in patients
with hypothyroidism
of any etiology.

Manifest hypothyroidism

Levothyroxine is prescribed at the rate of 1.6–1.8 mcg per 1 kg of body weight (approximate initial dose for women 75–100 mcg/day; men – 100–150 mcg/day).

The target value of thyroid-stimulating hormone (TSH) during levothyroxine replacement therapy for primary hypothyroidism is 0.5–1.5 mIU/l.

When carrying out replacement therapy for central (secondary) hypothyroidism, it is necessary to maintain blood thyroxine at a level corresponding to the upper third of the normal values for this indicator.

Subclinical hypothyroidism

Thyroxine is prescribed at the rate of 1 mcg per 1 kg of body weight (approximate initial dose 50–75 mcg/day).

The goal of suppressive therapy

It is also important to achieve a TSH concentration below the lower limit of normal to prevent its possible stimulating effect on the growth of thyroid tissue (including the growth of residual tumor tissue).

The target TSH value is less than 0.1 mIU/L. For this purpose, doses of levothyroxine from 2.2 to 2.5 mcg per 1 kg of body weight per day are used.

Principles of levothyroxine replacement therapy

Changes in the secretion of thyroid hormones and a decrease in thyroid function (hypothyroidism) can occur as a result of a breakdown in the biosynthesis of thyroid hormones at its different stages: the entry of iodide from the blood, its oxidation into elemental iodine, the inclusion of iodine in the composition of tyrosines with the formation of monoiodotyrosine and diiodotyrosine, the condensation of iodotyrosine molecules with formation of T4 and T3. Regardless of which stage the thyroid hormone metabolism is disrupted, the physiological effects for which thyroid hormones are responsible will change.

The main physiological effects of thyroid hormones:

regulation of energy metabolism
regulation of growth and development
regulation of protein, carbohydrate and fat metabolism
effect on the cardiovascular system
effect on the musculoskeletal system
influence on the psyche

Treatment of all forms of hypothyroidism is replacement and lifelong. The only exception is hypothyroidism caused by the administration of any medications or substances that block the production of thyroid hormones.

Levothyroxine preparations

are the drugs of choice for replacement therapy of hypothyroidism, and are synthetic thyroxine (sodium salt of thyroxine), which is completely identical to thyroxine produced by the thyroid gland. It is well absorbed from the gastrointestinal tract (GIT), and in hypothyroidism its absorption is not impaired.

One of the levothyroxine drugs is Eutirox (). Its difference from other drugs in this group is the ability to easily select the desired dosage - 25, 50, 75, 100, 125 or 150 mcg, which greatly facilitates both replacement and suppressive therapy.

During replacement therapy with Eutirox, the T3 concentration remains constant.

The dosage regimen of the drug is set individually, taking into account those possible situations when the need for thyroxine may change.

Since the main goal of treating hypothyroidism is to restore the normal physiological functions of all organs and systems that are impaired due to hypothyroidism, then for both primary and secondary (tertiary) hypothyroidism, the basis of treatment is adequate replacement therapy with thyroid hormone preparations. The criterion for the adequacy of treatment is the disappearance of clinical and laboratory manifestations of hypothyroidism.

Compensation for manifest hypothyroidism is 1.6–1.8 mcg of levothyroxine per day. Average daily dose 75–150 mcg

Compensation for subclinical hypothyroidism – 1 mcg of levothyroxine per 1 kg of body weight. Average daily dose 50–75 mcg

Therapy begins with a small dose of Eutirox, and in the elderly it can be 12.5 mcg/day. The drug is taken in the morning, on an empty stomach. The dose is gradually increased to maintenance (in young patients over 4 weeks, in older patients over 2 months, and sometimes, in the presence of concomitant cardiac pathology, over 3–4 months).

TSH levels should be assessed during treatment no earlier than 2 months after the start of therapy. Further, this indicator should be studied at intervals of 1 time every 6 months and the dose of Eutirox should be adjusted depending on the results obtained.

In the treatment of secondary hypothyroidism, the drug prescription regimen is similar, however , for obvious reasons, it is not TSH that should be monitored, but free T4

Patients with cardiac pathology and/or over 65 years of age

The initial dose is 12.5 mcg of levothyroxine per day (increase by 12.5 mcg at intervals of 2 months until TSH levels normalize; if cardiac symptoms appear or worsen, adjust therapy).

The severity and duration of hypothyroidism are the main criteria that determine the doctor’s tactics at the time of initiation of treatment.

The more severe the hypothyroidism and the longer it has been uncompensated, the higher the overall susceptibility of the body to thyroid hormones will be, especially for cardiomyocytes. Therefore, the process of adaptation to the drug should be gradual and smooth, regardless of the patient’s age.

When prescribing thyroxine to a patient with hypothyroidism, you need to find out what other medications he is receiving, since many drugs can increase the need for thyroxine. If this effect is not taken into account, compensation for hypothyroidism may be difficult.

Subclinical hypothyroidism

characterized by the absence of clear clinical manifestations of the disease. The patient's complaints are usually nonspecific and often boil down to increased weakness and fatigue. Laboratory parameters include a slight increase in TSH with normal T3 and T4 levels. Often, subclinical hypothyroidism is an incidental finding during a general examination of the patient. This syndrome is more often found in elderly patients.

To verify the diagnosis, the patient needs to re-determine the TSH level after 6 months. If a patient experiences a persistent increase in TSH levels, the issue of treatment should be decided on an individual basis. There is currently no clear opinion on the advisability of specific therapy for subclinical hypothyroidism. But if such therapy is carried out, it must be accompanied by adequate and timely monitoring of the patient, including determination of TSH levels. As a rule, replacement therapy for subclinical hypothyroidism begins when the TSH level is 10 mU/l or higher, and Eutirox is prescribed at a dose of 1 mcg per 1 kg of body weight (daily dose is 50–75 mcg).

Hypothyroidism and pregnancy

With uncompensated hypothyroidism, pregnancy is extremely unlikely. If pregnancy does occur, then treatment for hypothyroidism should be started immediately. During pregnancy, the need for levothyroxine increases on average by 45% of the calculated initial dose. If pregnancy occurs in a woman with compensated hypothyroidism, the dose of the drug should be increased in accordance with the increased need for it.

Principles of suppressive therapy with levothyroxine
Well-differentiated thyroid cancer (HDTC)
For many years, the main method of therapy for patients who have received radical treatment for HDTC remains the administration of thyroid hormones in doses exceeding physiological ones (2.5 mcg per 1 kg of body weight per day), in order to reduce the concentration of serum TSH. Thyroid cancer cells originating from the follicular epithelium have TSH receptors, and in response to their stimulation, adenylate cyclase activity increases. It is assumed that these thyroid tumors can grow under the influence of TSH. Many researchers have noted a decrease in the frequency of relapses of tumor growth due to the suppression of TSH secretion under the influence of suppressive therapy in both papillary and follicular thyroid carcinoma.

Today it is recommended to use third-generation TSH analysis methods, which make it possible to detect its presence in serum in concentrations of the order of 0.01 mU/l.

The question of what is more dangerous for the patient is still being actively debated: preventing cancer relapse while maintaining subclinical thyrotoxicosis or the adverse effects of drug-induced thyrotoxicosis on the heart and bones. Side effects of suppressive doses of levothyroxine include myocardial contractility disorders, increased heart rate and atrial arrhythmias, and can also cause accelerated bone turnover and osteoporosis. For this reason, many experts believe that complete suppression of pituitary TSH secretion over a long period (to 0.01–0.1 mU/L or lower) is advisable only in patients at high risk - primarily with an increased likelihood of relapses or death in patients with VDTC. At the same time, most clinicians believe that the vast majority of patients with papillary thyroid carcinoma, classified as low risk based on the results of the prognostic scoring, benefit from relatively weak suppression of TSH secretion. In such patients, serum TSH concentrations should be maintained at 0.1–0.4 mU/L. In general, in the treatment of VDTC, according to the data from controlled studies available to date, the administration of high doses of levothyroxine to suppress TSH levels has advantages compared to conventional replacement therapy, which maintains euthyroidism, i.e. normal TSH level. Exceptions may include elderly patients or patients with severe heart disease and severe osteoporosis.

In low-risk patients without signs of disease, after a year of therapy, the dose of Eutirox can be reduced to maintain serum TSH levels at the lower limit of the normal range (0.5–1.0 mU/l).

Nodular colloid goiter

Currently, in accordance with the RAE Consensus, the decision on the advisability of suppressive therapy with levothyroxine for nodular colloid goiter is determined on an individual basis. Treatment with thyroxine preparations is most effective for solitary colloid nodes of parenchymal type of structure

, combined with an enlarged thyroid gland and/or the presence of goiter changes in the gland tissue, determined by ultrasound examination (ultrasound).

Levothyroxine in the treatment of diffuse nontoxic goiter

Diffuse nontoxic goiter

Diffuse nontoxic goiter is a general diffuse enlargement of the thyroid gland without disrupting its function. The main cause of diffuse goiter is insufficient iodine content in the environment and, as a consequence, reduced iodine consumption by the population through usual food products. Depending on the prevalence of diffuse goiter (DG) in the population, sporadic and endemic goiter are distinguished. Goiter is considered endemic if in the surveyed region the incidence of goiter in children of primary and secondary school age is more than 5%. Although in the vast majority of cases the cause of ID is insufficient intake of iodine into the human body, a number of patterns suggest the influence of genetic factors on its formation. Noteworthy is the fact that in the same region, with the same iodine supply, goiter is not detected in the entire population, but only in a part. The importance of genetic factors has been confirmed by many population, family and twin studies. In addition, in ID, some mutations have been identified in genes such as TPO, NIS, TG, TSHR.

It is known that the prevalence of any form of goiter in the population varies significantly depending on age. It is believed that ID, as the first stage of iodine deficiency disease, is more common in young people. This fact was confirmed in the territory of Moscow, a zone of mild iodine deficiency, when comparing the frequency of occurrence of ID in different age groups of the adult population.

ID was significantly more common in people under 45 years of age.

Although patients with ID, as a rule, do not complain, their thyroid function is not impaired, they still need treatment for this disease, since it is the first phase (reversible with proper treatment) of the formation of nodular and multinodular iodine deficiency goiter, including with the development of thyrotoxicosis syndrome in the later stages of the process.

Today, there are three options for conservative treatment of ID:

Monotherapy with levothyroxine (Euthirox).
Monotherapy with iodine preparations (Iodine balance).
Combination therapy with iodine and levothyroxine.

Monotherapy with levothyroxine was scientifically substantiated in the treatment of ID when describing the regulation of the thyroid gland by the hypothalamic-pituitary system. It was assumed that under conditions of iodine deficiency, the synthesis and secretion of thyroxine and triiodothyronine, for which iodine is the main structural component, is reduced, which, according to the principle of negative feedback, leads to increased secretion of TSH. Therefore, the main goal of levothyroxine therapy was to suppress TSH, which contributes to an increase in thyroid volume (suppressive therapy). However, it has been repeatedly shown that the decrease in thyroid volume does not depend on the degree of thyrotropin suppression. There are studies showing that the average TSH level in iodine-deficient areas is significantly lower than in those areas where iodine intake is normal. Moreover, there is experimental data demonstrating that the administration of TSH cannot stimulate the growth of follicles containing a sufficient amount of iodine.

As noted, the administration of levothyroxine has been widely used for the treatment of euthyroid ID in the past. At the same time, excellent results were achieved at the initial stage. Many clinical studies have shown that within 3–4 months from the start of therapy there was a significant (at least 20%) decrease in the volume of the gland. Most often in clinical practice, doses of 150 mcg in adults and 100 mcg in adolescents were used. However, numerous studies have clearly demonstrated the “withdrawal phenomenon” - an increase in the size of the thyroid gland almost to the initial level a short time after stopping treatment. This phenomenon is explained primarily by the fact that when TSH is suppressed, the activity of the Na-I symporter decreases, and consequently, the active uptake of iodine by the thyroid gland decreases. Against the background of a sharp drop in intrathyroidal iodine content when the drug is discontinued, new growth of the gland occurs. Also, undesirable side effects of thyroid hormone therapy include the possible occurrence of drug-induced thyrotoxicosis, tachyarrhythmia, and osteoporosis, which limits the use of this group of drugs in long-term treatment of ID. However, sometimes, in order to quickly achieve a therapeutic effect, they resort to a short-term course of treatment with Eutirox with a further transition to maintenance therapy with Iodine Balance.

Monotherapy with iodine and combination therapy

The most preferable method of treating ID is etiological. Iodine preparations are prescribed in physiological dosages (200 mcg per day) for 6 months, followed by assessment of the dynamics of thyroid volume.

If there is no significant effect from taking iodides after 6 months, switching to combination therapy may be recommended. In this case, preference should be given to either a fixed combination of 75 mcg of levothyroxine + 150 mcg of iodide, or an individually selected dose of Eutirox at the rate of 1 mcg per 1 kg of body weight in combination with 150 mcg of iodide per day.

Currently, clinicians have the opportunity to use combination drugs for these purposes, which include both levothyroxine and iodine. Thus, the drug Yodtirox (Nycomed) optimally combines levothyroxine sodium - 100 mcg and potassium iodide - 100 mcg. The daily dose of Yodtirox is taken once a day in the morning, on an empty stomach, 30 minutes before breakfast, with a small amount of liquid and without chewing the tablet.

Combination therapy with iodine and thyroxine preparations has been repeatedly shown to have a number of advantages. Firstly, by influencing several pathogenetic mechanisms of goiter formation, both hypertrophy and hyperplasia of thyrocytes are suppressed. This makes it possible to achieve results comparable in effectiveness to thyroxine monotherapy (with a much lower content), which in turn reduces the number of side effects associated with taking thyroid drugs. Secondly, the tendency to the “withdrawal effect” during a short break in treatment is also reduced. Thirdly, the suppression of TSH levels is less pronounced, for example, compared to the effect of thyroxine at a dose of 150 mcg.

The results of a study of the dynamics of thyroid volume in people with ID against the background of different treatment regimens, carried out at the Federal State Institution ERC, are presented in Fig. 2, 3. In the group as a whole, the thyroid volume decreased by 20% by the time of completion of treatment, which was statistically significant ( p

1–2<0.001), and continued to remain at approximately the same level at least another 4 months after its cessation (
p
2–3=0.31). There were no cases of changes in thyroid function (development of hyper- and hypothyroidism), and fluctuations in TSH levels did not go beyond normal values.

In this group, thyroid volume decreased on average by 20.6% after 8 months of treatment, which was significant relative to the start of treatment ( p

1–2<0.001), and remained at the same level 4 months after its discontinuation (
p
2–3<0.77). Subclinical thyrotoxicosis was detected in 1 patient at the 8th month of observation (TSH – 0.01 mU/l, free T4 – 19 pmol/l). In the group as a whole, TSH levels did not go beyond normal values throughout the entire observation period.

Using analysis of repeated changes, it was shown that both in the Monotherapy group and in the Combination Therapy group, thyroid volume decreased to normal during 8 months of treatment and remained approximately at the same level 4 months after treatment. To assess the advantage of one treatment method over another, the studied parameters of both groups were compared with each other (see Table 2).

When comparing indicators between groups at 8 and 12 months of observation, no statistically significant difference was found between the decrease in thyroid volume, TSH level, and anti-TPO antibodies. Thus, both monotherapy with potassium iodide preparations and combination therapy with potassium iodide and levothyroxine preparations are equally effective and safe for the treatment of euthyroid ID. It was also shown that the result of treatment of ID using monotherapy with iodine preparations may depend on genetic factors: carriers of the AA and AC genotypes of the polymorphic marker rs 3783949 of the TSHR gene more often had a satisfactory treatment result, carriers of the CC genotype had an unsatisfactory result. The result of treatment of ID with combination therapy did not depend on the distribution of polymorphic markers of the genes TSHR (rs 3783949, substitution - A/C), NIS (rs 7250346, substitution - C/G), DUOX1 (rs2467825, substitution - A/G) DUOX2 ( rs7171366, replacement – G/T), TPO (rs 17091737, replacement – G/T).

Conclusion

The decision to initiate replacement or suppressive therapy with levothyroxine (Eutirox) or combination therapy (Iodotirox) should be justified by clinical and laboratory examination of the patient. Despite the existence of well-defined algorithms for prescribing the drug and its dosage regimen, the individual characteristics of the patient should always be taken into account in each specific case in order to avoid possible side effects from the prescribed treatment.

Medicines index:

Levothyroxine sodium: EUTHYROX (Nycomed)

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Description of the drug LEVOTHYROXINE SODIUM

Levothyroxine sodium potentiates the effect of indirect anticoagulants (coumarin derivatives) and reduces the effectiveness of oral hypoglycemic agents.

In patients with hypothyroidism and concomitant diabetes mellitus, at the beginning of replacement therapy with thyroid hormone preparations, the need for insulin or oral hypoglycemic agents may increase.

Salicylates, dicoumarin, furosemide (250 mg), clofibrate can displace levothyroxine from binding to plasma proteins.

Sucralfate, aluminum hydroxide, calcium carbonate reduce the absorption of levothyroxine from the gastrointestinal tract.

Cholestyramine reduces the absorption of levothyroxine sodium from the gastrointestinal tract.

When using ritonavir, the need for levothyroxine may increase.

When using sertraline in patients with hypothyroidism, the effects of levothyroxine sodium may be reduced.

With rapid intravenous administration of phenytoin while taking levothyroxine sodium, the level of free levothyroxine in the blood plasma may increase, and arrhythmias may be observed.

With simultaneous use of chloroquine, an increase in the metabolism of levothyroxine is possible, apparently due to the induction of microsomal liver enzymes by chloroquine. In patients receiving levothyroxine sodium, an increase in TSH concentrations may occur when using proguanil or chloroquine.

The use of tricyclic antidepressants with levothyroxine sodium may lead to increased effects of the antidepressants.

Levothyroxine sodium reduces the effect of cardiac glycosides. With simultaneous use of cholestyramine, colestipol and aluminum hydroxide, they reduce the plasma concentration of levothyroxine sodium by inhibiting its absorption in the intestine.

When used simultaneously with anabolic steroids, asparaginase, tamoxifen, pharmacokinetic interaction is possible at the level of protein binding.

Somatotropin, when used simultaneously with levothyroxine sodium, can accelerate the closure of epiphyseal growth zones.

Taking phenobarbital, carbamazepine and rifampicin may increase the clearance of levothyroxine sodium and require an increase in dose.

Estrogens increase the concentration of the thyroglobulin-bound fraction, which may lead to a decrease in the effectiveness of the drug.

Amiodarone, aminoglutethimide, para-aminosalicylic acid (PAS), ethionamide, antithyroid drugs, beta-blockers, chloral hydrate, diazepam, levodopa, dopamine, metoclopramide, lovastatin, somatostatin affect the synthesis, secretion, distribution and metabolism of leothyroxine sodium. Products containing soy may reduce the absorption of levothyroxine sodium (dose adjustment may be required).

Buy L-Thyroxine-Berlin-Chemie tablets 50mcg No. 50 in pharmacies

Instructions for use

L-Thyroxine-Berlin-Chemie tab. 50mcg No.50

Dosage forms

tablets 50mcg

Synonyms Bagotirox Eutirox Group Drugs that stimulate thyroid function International nonproprietary name Levothyroxine sodium Composition Active ingredient - sodium levothyroxine. Manufacturers Berlin-Chemie (Menarini) (Germany) Pharmacological action Synthetic levorotatory isomer of thyroxine. After partial conversion into triiodothyronine (in the liver and kidneys) and passage into the cells of the body, it affects the development and growth of tissues and metabolism. In small doses it has an anabolic effect on protein and fat metabolism. In medium doses, it stimulates growth and development, increases tissue oxygen demand, stimulates the metabolism of proteins, fats and carbohydrates, and increases the functional activity of the cardiovascular system and central nervous system. In large doses, it inhibits the production of TTRH from the hypothalamus and TSH from the pituitary gland. The therapeutic effect is observed after 7-12 days, during the same time the effect persists after discontinuation of the drug. The clinical effect for hypothyroidism appears after 3-5 days. Diffuse goiter decreases or disappears within 3-6 months. Side effects: Tachycardia, rhythm disturbances, chest pain, tremor, insomnia, anxiety, hyperhidrosis, alopecia, weight loss, diarrhea, adrenal dysfunction (with pituitary or hypothalamic hypothyroidism), renal dysfunction in children. Indications for use Hypothyroidism; euthyroid goiter; as a replacement therapy and for the prevention of goiter recurrence after resection of the thyroid gland; thyroid cancer (after surgical treatment); diffuse toxic goiter: after achieving a euthyroid state with thyreostatics (in the form of combination or monotherapy); as a diagnostic tool when performing a thyroid suppression test. Contraindications Increased individual sensitivity to the drug; untreated thyrotoxicosis; acute myocardial infarction, acute myocarditis; untreated adrenal insufficiency; hereditary lactose intolerance, lactase deficiency or impaired absorption of glucose or lactose. Method of administration and dosage The daily dose is determined individually depending on the indications. The drug in a daily dose is taken orally in the morning on an empty stomach, at least 30 minutes before a meal, washing down the tablet with a small amount of liquid (half a glass of water) and without chewing. When carrying out replacement therapy for hypothyroidism in patients under 55 years of age in the absence of cardiovascular diseases, the drug is prescribed in a daily dose of 1.6-1.8 mcg/kg body weight; patients over 55 years of age or with cardiovascular diseases - 0.9 mcg/kg body weight. In case of significant obesity, the calculation should be made on the “ideal body weight”. For hypothyroidism, it is usually taken throughout life. For thyrotoxicosis, it is used in complex therapy with antithyroid drugs after achieving a euthyroid state. In all cases, the duration of treatment with the drug is determined by the doctor. For infants and children under 3 years of age, the daily dose of the drug is given in one dose 30 minutes before the first feeding. The tablet is dissolved in water to a thin suspension, which is prepared immediately before taking the drug. Overdose Symptoms: thyrotoxic crisis, sometimes delayed for several days after administration. Treatment: prescription of beta-blockers, intravenous corticosteroids, plasmapheresis. Interaction Reduces the effect of insulin and oral antidiabetic drugs, cardiac glycosides, enhances the effect of indirect anticoagulants, tricyclic antidepressants. Phenobarbital and phenytoin accelerate metabolic Cl without increasing the proportion of free T3 and T4 in the blood. Cholestyramine, colestipol, aluminum hydroxide reduce plasma concentrations by inhibiting absorption in the intestine. Protein binding is altered by anabolic steroids, asparaginase, clofibrate, furosemide, salicylates, tamoxifen. Estrogens increase the concentration of the thyroglobulin-bound fraction (efficacy decreases). Synthesis, secretion, distribution and metabolism are influenced by amiodarone, aminoglutethimide, para-aminosalicylic acid, ethionamide, antithyroid drugs, beta-blockers, carbamazepine, chloral hydrate, diazepam, levodopa, dopamine, metoclopramide, lovastatin, somatostatin and others. Special instructions It is recommended to periodically determine the content of thyroid-stimulating hormone in the blood, an elevated level of which indicates an insufficient dose. In case of long-standing multinodular goiter, a stimulation test with thyrotropin-releasing hormone should be performed before starting treatment. For elderly patients, the initial dose should not exceed 50 mcg. Prescribe with caution for severe, long-term hypofunction of the thyroid gland. When used in the second and third trimesters of pregnancy, the dose is usually increased by 25%. Before starting treatment, the possibility of pituitary or hypothalamic hypothyroidism should be excluded. Storage conditions List B. At room temperature, protected from light.