List of Abbreviations
AIT – autoimmune thyroiditis
Ab - antibodies
ATP - adenosine triphosphate
SH – secondary hypothyroidism
fT4 – free thyroxine
fT3 – free triiodothyronine
TSH – thyroid-stimulating hormone
TRH – thyrotropin-releasing hormone
T4 – thyroxine
T3 – triiodothyronine
SCH – subclinical hypothyroidism
TPOAb – thyroid peroxidase antibodies
US – ultrasound examination
levothyroxine sodium** – levothyroxine sodium** preparation
mcg – microgram
TG – thyroid gland
Terms and Definitions
Hypothyroidism is a deficiency of thyroid hormones in the body.
Primary hypothyroidism is hypothyroidism resulting from damage (destruction) to the thyroid gland itself.
Manifest hypothyroidism is an elevated TSH level combined with a free T4 level below the reference interval.
Subclinical hypothyroidism is an elevated TSH level with a free T4 level within the reference interval.
Secondary hypothyroidism is a clinical syndrome resulting from inadequate production of thyroid-stimulating hormone (TSH) in the absence of primary pathology of the thyroid gland itself that could lead to decreased function.
Autoimmune thyroiditis; synonyms: lymphocytic thyroiditis, chronic thyroiditis – an organ-specific autoimmune disease leading to hypothyroidism due to the destruction of thyroid tissue via the activation of T- and B-cell immunity with the formation of autoantibodies against thyroid tissue.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Hypothyroidism is a deficiency of thyroid hormones in the body.
Primary hypothyroidism is hypothyroidism resulting from damage (destruction) to the thyroid gland itself.
Manifest hypothyroidism is an elevated TSH level combined with a free T4 level below the reference interval.
Subclinical hypothyroidism is an elevated TSH level with a free T4 level within the reference interval.
Secondary hypothyroidism is a clinical syndrome resulting from inadequate TSH production in the absence of primary pathology of the thyroid gland itself that could lead to decreased function.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Based on pathogenesis, hypothyroidism can be primary (due to thyroid pathology) or secondary (due to TSH deficiency). More than 99% of all adult hypothyroidism cases are primary acquired hypothyroidism. Most commonly, hypothyroidism develops due to chronic autoimmune thyroiditis, as well as following medical interventions (iatrogenic) – postoperative or as an outcome of 131I therapy. Post-thyroidectomy hypothyroidism is permanent and irreversible. In destructive thyroiditis (postpartum, subacute, silent), transient hypothyroidism may develop, which is self-limiting during the natural course of the disease [1,2].
Chronic autoimmune thyroiditis (Hashimoto's thyroiditis, lymphocytic thyroiditis, AIT) is a chronic inflammatory disease of the thyroid gland of autoimmune origin, in which progressive lymphoid infiltration leads to gradual destruction of the thyroid parenchyma, potentially resulting in primary hypothyroidism. For a long time, sometimes throughout life, patients remain euthyroid. With the progressive course of the process, increased lymphocytic infiltration of the thyroid, and destruction of its follicular epithelium, thyroid hormone synthesis gradually decreases. As a result, TSH levels rise, leading to thyroid hyperstimulation. Due to this hyperstimulation, T4 production can remain normal for an indefinite period – the subclinical hypothyroidism phase. With further destruction of the thyroid gland, the number of functioning thyrocytes falls below a critical level, and the blood T4 concentration also decreases (overt hypothyroidism phase) [3].
Secondary hypothyroidism is extremely rare in adults, with main causes being hypothalamic-pituitary region tumors, as well as post-surgical and post-radiation states involving the hypothalamic-pituitary region.
Table 1. Etiology of hypothyroidism
Hypothyroidism | Main disorders |
|---|---|
Primary (thyroid disorders) | Autoimmune thyroiditis Surgical thyroidectomy Sodium iodide [131I] therapy Hypothyroidism in subacute, postpartum, or painless thyroiditis Severe iodine deficiency Thyroid developmental anomalies (dysgenesis and ectopy) |
Secondary (hypothalamo-pituitary pathology) | Large hypothalamo-pituitary region tumors Traumatic or radiation injury to the pituitary gland Vascular disorders Infectious, infiltrative processes Impaired TSH and/or thyrotropin-releasing hormone synthesis |
Thyroid hormone deficiency leads to alterations in absolutely all organs and systems, which determines the multisystem nature and variety of its clinical manifestations. The primary change at the cellular level is a decrease in cellular oxygen consumption, a reduction in the rate of oxidative phosphorylation, and ATP synthesis. The cell experiences an energy deficit, enzyme synthesis decreases, and cellular metabolic processes are suppressed.
1.3 Epidemiology of the Disease or Condition
Primary hypothyroidism is one of the most common endocrine disorders. According to a large population-based NHANES-III study, the prevalence of primary hypothyroidism was 4.6% (0.3% overt, 4.3% subclinical). On average, the incidence of new cases of spontaneous hypothyroidism in women is 3.5 cases per 1,000 individuals per year, and hypothyroidism resulting from radical treatment of thyrotoxicosis is 0.6 cases per 1,000 individuals per year [1].
The prevalence of autoimmune thyroiditis (AIT) is quite difficult to estimate because it lacks precise diagnostic criteria in the euthyroid phase. The prevalence of antibodies to thyroid peroxidase (TPOAb) positivity is about 10% among women and depends on the ethnic composition of the population.
Secondary hypothyroidism (SH) is a rare disorder, accounting for no more than 1% of all cases of hypothyroidism. SH is diagnosed with equal frequency in both men and women; its population prevalence varies from 1:16,000 to 1:100,000 population depending on age and etiology [4].
1.4 Features of Coding the Disease or Condition
Congenital hypothyroidism without goiter (E03.1)
Hypothyroidism caused by drugs and other exogenous substances (E03.2)
Postinfectious hypothyroidism (E03.3)
Thyroid atrophy (acquired) (E03.4)
Myxedema coma (E03.5)
Other specified hypothyroidism (E03.8)
Hypothyroidism, unspecified (E03.9)
Postprocedural hypothyroidism (E89.0)
Autoimmune thyroiditis (E06.3)
1.5 Classification of the disease or condition
Primary hypothyroidism is classified by severity into subclinical and manifest (overt) [1].
Table 2. Classification of hypothyroidism
Severity grade | Laboratory findings |
|---|---|
Subclinical | TSH elevated, free T4 normal |
Manifest (overt) | TSH elevated, free T4 decreased |
1.6 Clinical presentation of the disease or condition
The clinical presentation of hypothyroidism varies significantly depending on the severity and duration of thyroid hormone deficiency, the patient's age, and comorbid conditions. The more rapidly hypothyroidism develops, the more pronounced its manifestations are.
The main challenges associated with the clinical diagnosis of hypothyroidism include:
Absence of specific symptoms;
High prevalence of symptoms similar to those of hypothyroidism but related to other chronic conditions;
Lack of a direct correlation between symptom severity and the degree of thyroid hormone deficiency.
The most common symptoms of hypothyroidism include: severe fatigue, drowsiness, dry skin, hair loss, slowed speech, puffiness of the face, fingers and toes, constipation, memory impairment, feeling cold, hoarseness, depressed mood.
Patients frequently present with symptoms predominantly from a single system, leading to diagnoses of 'masked' forms of the disease:
'Cardiological': diastolic hypertension, dyslipidemia, hydropericardium;
'Gastroenterological': chronic constipation, cholelithiasis, chronic hepatitis ('jaundice' combined with elevated transaminases);
'Rheumatological': polyarthritis, polysynovitis, progressive osteoarthritis;
'Dermatological': alopecia, onycholysis, hyperkeratosis;
'Psychiatric': depression, dementia;
'Gynecological': dysfunctional uterine bleeding, infertility [3].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Recommendation 1. It is recommended to use diagnostic signs whose combination allows establishing AIT as the cause of hypothyroidism: primary hypothyroidism (overt or persistent subclinical); presence of antibodies to thyroid tissue and ultrasound signs of autoimmune pathology [1];
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommendation 2. It is recommended to screen for SH in all patients with a personal or family history of hypothalamo-pituitary disorders and deficiencies, moderate or severe head injury, stroke, cranial irradiation, hemochromatosis, especially in the presence of symptoms of hypothyroidism [11, 12, 13, 14].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
2.1 Complaints and Anamnesis
The most common symptoms of hypothyroidism: severe fatigue, drowsiness, dry skin, hair loss, slowed speech, facial and extremity puffiness, constipation, memory impairment, cold intolerance, hoarseness, depressed mood
2.2 Physical Examination
On physical examination, patients with severe and prolonged thyroid hormone deficiency may exhibit characteristic external manifestations: generalized and periorbital edema, pale-yellowish puffy face, and sluggish facial expressions.
2.3 Laboratory Diagnostics
Recommendation 3. It is not recommended to measure blood levels of thyroid tissue antibodies dynamically to assess the development and progression of AIT [1];
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: In the absence of at least one of the listed criteria, the diagnosis of AIT is considered probable, since an isolated elevation of TPOAb levels or thyroid hypoechogenicity detected by ultrasound (US) does not yet indicate AIT and does not allow for a definitive diagnosis. 'Classic' antibodies—TgAb and TPOAb—are detected in 80–90% of patients with AIT. Carrying thyroid tissue antibodies in euthyroidism requires only dynamic monitoring of TSH levels [3].
Recommendation 4. To rule out hypothyroidism, it is recommended to evaluate thyroid function (blood thyroid-stimulating hormone (TSH) and serum free thyroxine (fT4) levels) at the preconception stage in women who have previously tested positive for thyroid antibodies and/or ultrasound signs of AIT. In these women, TSH levels should be monitored in each trimester of pregnancy [5, 6, 58, 59].
Level of Evidence AGrade of Evidence 3Level of Recommendations A (Grade of Evidence – 3)
Recommendation 5. In cases of newly detected elevated TSH and normal fT4, it is recommended to repeat the blood thyroid-stimulating hormone (TSH) test and serum free thyroxine (fT4) test in 2–3 months, and determine blood anti-thyroperoxidase antibody levels to establish further patient management [1, 3, 7, 8, 9, 10].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
Comments: The diagnosis of overt (manifest) hypothyroidism is established when TSH is elevated and free T4 is below the reference range; subclinical hypothyroidism is diagnosed when TSH is elevated and free T4 is within the reference range. Confirmation of persistent subclinical hypothyroidism requires a repeat blood thyroid-stimulating hormone (TSH) and serum free thyroxine (fT4) test in 2–3 months, because in some cases TSH elevation may be transient and caused by various factors: recent severe non-thyroidal illness, subacute, postpartum, or painless thyroiditis, medication use (including amiodarone**, lithium carbonate), or macro-TSH phenomenon. In most patients, subclinical hypothyroidism is characterized by a mild TSH elevation of less than 10 mIU/L. The proportion of patients with subclinical hypothyroidism and a TSH level >10 mIU/L is about 10%. With a TSH level <10 mIU/L, euthyroidism spontaneously recovers in 20–50% of cases.
Recommendation 6. The diagnosis of SH is recommended to be established based on a serum free T4 level below the reference range combined with an inappropriately low/low-normal TSH level on repeat testing [15, 16].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Recommendation 7. In adults being monitored for hypothalamo-pituitary disorders, blood thyroid-stimulating hormone (TSH) and serum free thyroxine (fT4) levels are recommended to be checked annually for the diagnosis of SH [14].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: In adults, with extremely rare exceptions, acquired central hypothyroidism is encountered. Its main causes include tumors of the hypothalamo-pituitary region, as well as conditions following surgical and radiation treatment of the hypothalamo-pituitary region. Thus, in more than 50% of cases, acquired central hypothyroidism is caused by hormonally active and inactive pituitary macroadenomas [17]. Following radiation therapy for brain tumors, central hypothyroidism develops in 65% of cases, and this can occur years after the treatment [18, 19]. Tropin hormone deficiency typically develops after radiation exposure to the adenohypophysis at a cumulative dose of 20 Gy or more. Another cause of central hypothyroidism in adults can be severe traumatic brain injury: according to various authors, the prevalence of hypothyroidism in such patients ranges from 5 to 29%, which is determined by the severity of the injury and the time elapsed since its occurrence [20, 21].
Today, the diagnosis of central hypothyroidism is based on the simultaneous measurement of blood thyroid-stimulating hormone (TSH) and serum free thyroxine (fT4) levels. The classic laboratory criterion for diagnosing central hypothyroidism is a combination of low TSH and low serum fT4 concentrations [15, 16]. However, in central hypothyroidism, the TSH concentration can be low, normal, or even slightly elevated; in this case, the detected TSH lacks biological activity. Measuring serum free thyroxine (fT4) is preferred for diagnosing central hypothyroidism, whereas measuring total thyroxine (T4) is impractical because it depends on thyroid hormone-binding globulin (TBG) concentration. When TBG levels decrease (with age, androgen therapy) or increase (during pregnancy, use of estrogens, systemic hormonal contraceptives), the total T4 concentration will change accordingly [4].
Currently, the TRH stimulation test (thyrotropin-releasing hormone test) is practically not used for diagnosing central hypothyroidism, since routine laboratory methods allow for a sufficiently accurate determination of TSH and fT4 levels. The need for a TRH stimulation test (thyrotropin-releasing hormone test) is limited only to specific clinical situations that require an additional method to confirm the diagnosis of central hypothyroidism.
2.4 Instrumental Diagnostics
Recommendation 8. Ultrasound examination of the thyroid gland and parathyroid glands is advisable in the presence of palpable nodular lesions and/or a palpable thyroid enlargement to confirm or refute the presence of thyroid enlargement and/or nodular goiter in the patient [55].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
Comments: Ultrasound changes characteristic of autoimmune thyroiditis (AIT) may appear earlier than an increase in blood antibodies (Abs) to thyroid tissue is detected. Ultrasound examination of the thyroid gland and parathyroid glands is advisable in the presence of palpable nodular lesions and/or a palpable thyroid enlargement. Fine-needle aspiration biopsy of the thyroid or parathyroid gland (A11.22.002) is not indicated to confirm the diagnosis of AIT. It is predominantly performed as part of the diagnostic workup for nodular goiter.
2.5 Other Procedures
Not required
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
3.1.1 Replacement therapy for primary hypothyroidism in adults
Recommendation 9. All patients with a confirmed diagnosis of overt hypothyroidism are recommended to receive replacement therapy. The drug of choice for replacement therapy is levothyroxine sodium** [22, 23, 24].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Recommendation 10. The goal of replacement therapy for primary hypothyroidism is recommended to be considered the achievement and maintenance of normal blood levels of TSH and thyroid hormones [1, 3]. Following a change in the dose of levothyroxine sodium**, monitoring of TSH levels (measurement of blood thyroid-stimulating hormone (TSH)) is recommended after 6–8 weeks [27], and at least once a year after achieving a normal TSH level.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Recommendation 11. Levothyroxine sodium** in tablet form is recommended to be taken in the morning, on an empty stomach, at least 30–40 minutes, optimally 60 minutes, before a meal [25, 26, 29]. The liquid form of levothyroxine sodium** can be taken immediately before a meal in the morning [56].
Evidence Level 2, Recommendation Grade B – tablets: Grade of Recommendation B (Level of Evidence – 2)
Evidence Level 4, Recommendation Grade C – solution: Grade of Recommendation C (Level of Evidence – 4)
Comments: Levothyroxine sodium** is the drug of choice for the replacement therapy of hypothyroidism due to its efficacy, long-standing clinical experience, high bioavailability, favorable adverse event profile, and ease of administration.
T4 is the primary hormone secreted by the thyroid gland. In peripheral tissues, T4 is deiodinated to form T3, through which the effects of thyroid hormones are realized. Gastrointestinal absorption of levothyroxine sodium** tablets ranges from 70–80% in healthy adults when taken on an empty stomach [25]. The long half-life (approximately 7 days) allows for once-daily administration and ensures the maintenance of stable blood levels of both T4 and T3 [26]. When levothyroxine sodium** is taken on an empty stomach, peak blood levels of T4 and fT4 are reached after 4 hours. T4 and TSH levels stabilize 6 weeks after initiating therapy or changing the dose [27]. During monotherapy with levothyroxine sodium**, with normal serum TSH and T3 levels, an increase in T4 levels is observed [27, 28]. Accordingly, normal serum T4 and TSH levels are accompanied by lower T3 values than in healthy individuals, sometimes even below the reference range [30]. The goal of levothyroxine sodium** replacement therapy in primary hypothyroidism is to achieve and maintain a state of euthyroidism, as determined by normal serum TSH and T4 values [1, 3]. Euthyroidism is defined as the normalization of thyroid hormone action indicators and the absence or regression of symptoms and clinical signs associated with hypothyroidism. One of the factors reducing patient adherence to treatment is the requirement to take tablet formulations of levothyroxine sodium** on an empty stomach, at least 30 minutes before a meal. Currently, a liquid form of levothyroxine sodium** is available, ensuring adequate drug absorption when taken immediately before breakfast [56].
Recommendation 12. If it is necessary to take medications in the morning that may affect the absorption of levothyroxine sodium** (preparations containing calcium carbonate, ferrous sulfate), it is recommended to maintain an interval of about 4 hours [27, 34, 53].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Physicians most frequently encounter the prescription of medications containing calcium carbonate, ferrous sulfate, and aluminum hydroxide, which can significantly impact TSH dynamics. In one study, with the simultaneous intake of a preparation containing 300 mg of ferrous sulfate and levothyroxine sodium**, an increase in TSH levels from 1.6 to 5.5 mIU/L was observed after 12 weeks. When observing the minimum recommended interval of 4 hours, no marked dynamics are observed. Similar results were obtained when studying the effect of simultaneous intake of calcium carbonate-containing preparations and levothyroxine sodium**: this study included patients with compensated hypothyroidism who were prescribed a preparation containing 1200 mg of calcium carbonate in the morning, simultaneously with levothyroxine sodium**. With the addition of the calcium carbonate preparation, a significant increase in TSH levels was noted. After its discontinuation, TSH levels returned to baseline. Moreover, in 20% of patients, TSH levels rose above the upper limit of the reference range. In adults, the intake of preparations containing calcium carbonate or calcium acetate reduces the absorption of levothyroxine sodium** by 20% [34].
Recommendation 13. Levothyroxine sodium** preparations differ in bioavailability, and when switching products, all patients are recommended to undergo additional TSH monitoring after 6–8 weeks [36, 37, 57, 60, 61].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Levothyroxine sodium preparations from various manufacturers are available on the pharmaceutical market. Levothyroxine sodium preparations have a narrow therapeutic index and, at the same time, are not sufficiently bioequivalent, which is largely due to differences in their manufacturing technology and, accordingly, varying bioavailability. Furthermore, when a drug's manufacturing technology is altered, the new and old products may not be bioequivalent. The narrow therapeutic index of levothyroxine sodium requires careful titration of its dose, as it may vary depending on the etiology of hypothyroidism, the patient's body weight, the presence of comorbidities, and the use of other medications. Overdose of levothyroxine sodium leading to drug-induced thyrotoxicosis is a risk factor for atrial fibrillation [38] and osteoporosis in postmenopausal women [39]. Inadequate dosing of levothyroxine sodium is accompanied by symptoms and manifestations of hypothyroidism.
Recommendation 14. Levothyroxine sodium therapy is recommended to be initiated at a full or partial replacement dose with its gradual increase until the target TSH level is achieved [40].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: The principles of initiating replacement therapy are based primarily on the experience of many generations of physicians. Studies investigating this issue have been predominantly retrospective, with practically no prospective studies conducted. It is generally accepted to prescribe a full replacement dose immediately (calculated based on body weight) for young and middle-aged patients, whereas for elderly patients and those with concomitant cardiac pathology, initiation with low doses is recommended, followed by subsequent titration under TSH monitoring.
When discussing hypothyroidism that naturally develops after surgical removal of the thyroid gland—i.e., in a situation where the patient was euthyroid just yesterday (let alone thyrotoxic)—a full replacement dose of levothyroxine sodium should be prescribed immediately after surgery. A similar situation arises when withdrawing suppressive therapy for scintigraphy in patients treated for well-differentiated thyroid cancer, where hypothyroidism persists for a relatively short time and a full dose of levothyroxine sodium can be prescribed immediately after the examination.
Recommendation 15. In elderly patients, levothyroxine sodium therapy is recommended to be initiated at low doses with gradual escalation under TSH level monitoring. The normal TSH level in elderly patients is somewhat higher than in individuals under 65 years of age; therefore, a higher TSH level may be chosen as the target [1, 3, 41].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: In principle, older patients (over 65–70 years of age) without established cardiovascular disease or significant cardiovascular risk factors can have levothyroxine sodium therapy initiated at a full replacement dose [40]. However, most experts adhere to the concept of starting with a low dose and gradually increasing it. As a rule, the full replacement dose of levothyroxine sodium required to achieve normalization of TSH levels is lower in older patients than in younger ones due to a decrease in lean body mass [41]. Dose titration in this age group is particularly important because the development of thyrotoxicosis in them is associated with a high risk of cardiac arrhythmias and fractures. In the elderly population without thyroid pathology, the 97.5th percentile of TSH is 7.5 mIU/L. Accordingly, a target TSH level of 4–6 mIU/L can be considered for patients over 70–80 years of age, although no randomized clinical trials dedicated to this issue have been conducted.
Recommendation 16. When prescribing drugs that affect the metabolism or synthesis of transport proteins, an additional assessment of blood thyroid-stimulating hormone (TSH) level is recommended. Such drugs include: androgens, estrogens, phenobarbital, phenytoin, carbamazepine, rifampicin, sertraline [1, 3].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Drugs that increase thyroxine-binding globulin (TBG) levels include: estrogens, tamoxifen. Drugs that decrease TBG levels include: androgens, high doses of glucocorticoids. Taking these drugs may lead to an increased or decreased requirement for levothyroxine sodium, respectively. It should be noted that the use of transdermal forms of estrogens and androgens has no significant effect on TSH levels, as their administration avoids the first-pass hepatic metabolism.
Recommendation 17. Levothyroxine sodium replacement therapy is recommended when blood TSH levels rise above 10 mIU/L, as well as in cases where a TSH level between 4–10 mIU/L is detected on at least two occasions; in individuals over 55 years of age and in the presence of cardiovascular diseases, levothyroxine sodium replacement therapy is recommended provided the drug is well tolerated and there is no evidence of decompensation of these diseases during treatment [1].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3.1.2 Replacement therapy for primary hypothyroidism during pregnancy
Recommendation 19. In overt hypothyroidism during pregnancy, levothyroxine sodium replacement therapy is recommended [42].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: According to numerous retrospective and case-control studies, overt hypothyroidism during pregnancy is associated with adverse outcomes for both the mother and the fetus [42]. One recently published retrospective study involving more than 1,000 pregnant women receiving levothyroxine sodium replacement therapy demonstrated that the risk of miscarriage increases in proportion to the rise in TSH levels, with the risk being no higher once TSH is normalized [42]. Although randomized clinical trials involving pregnant women with overt hypothyroidism have not been conducted—as they are ethically unfeasible—available data unequivocally indicate the necessity of prescribing replacement therapy to women with overt hypothyroidism during pregnancy. In hypothyroidism diagnosed during pregnancy, a full replacement dose of levothyroxine sodium must be prescribed immediately.
Recommendation 20. In pregnant women with overt and subclinical hypothyroidism (whether receiving replacement therapy or not), as well as in women at risk for hypothyroidism (carriers of thyroid antibodies, after hemithyroidectomy, or previously treated with sodium iodide [123I]), blood TSH (thyroid-stimulating hormone) levels are recommended to be measured approximately every 4 weeks until mid-pregnancy and at least once more around the 30th week [43, 44].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Recommendation 21. In women with hypothyroidism receiving levothyroxine sodium who become pregnant, it is necessary to increase the drug dose by 20–30% [43, 44].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Recommendation 22. Postpartum, the dose of levothyroxine sodium is recommended to be reduced to the pre-pregnancy dose. A follow-up TSH concentration measurement is recommended approximately 6 weeks postpartum [3].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: In hypothyroidism detected during pregnancy, a replacement dose of levothyroxine sodium is prescribed immediately, without gradual escalation. In a woman with hypothyroidism diagnosed during pregnancy, relying on TSH levels can be challenging because an initially high TSH will decrease gradually. The goal of replacement therapy during pregnancy is to maintain a low-normal TSH and a high-normal free T4 level. To adequately assess free T4 levels, the levothyroxine sodium dose is withheld prior to blood sampling.
If a woman with hypothyroidism was taking levothyroxine sodium before pregnancy, the requirement increases by approximately 4–6 weeks of gestation. Therefore, it is advisable to increase the levothyroxine sodium dose by 20–30% immediately upon the onset of pregnancy [43, 44]. The magnitude of the dose increase for levothyroxine sodium depends on the etiology of hypothyroidism. In hypothyroidism resulting from thyroidectomy or sodium iodide [131I] therapy, a greater increase in the levothyroxine sodium dose will be required than in hypothyroidism resulting from autoimmune thyroiditis (AIT).
Postpartum, the requirement for levothyroxine sodium decreases immediately; therefore, it is recommended to reduce the dose to the baseline (pre-pregnancy) level with subsequent TSH monitoring after 6 weeks. However, patients with AIT may subsequently experience an increased requirement for levothyroxine sodium compared to the baseline pre-pregnancy level due to the progression of the autoimmune process after childbirth [45].
Recommendation 23. In subclinical hypothyroidism during pregnancy, levothyroxine sodium** therapy is recommended for women with TPOAb(+) and TSH > 4 mIU/L and < 10 mIU/L [46];
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Recommendation 24. In subclinical hypothyroidism during pregnancy, levothyroxine sodium** therapy may be recommended for women with TPOAb(+) and TSH > 2.5 and < 4 mIU/L, and for women without TPOAb but with a TSH level > 4.0 and < 10 mIU/L [46, 47].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
3.1.3 Replacement therapy for secondary hypothyroidism in adults
Recommendation 25. In central hypothyroidism, replacement therapy with levothyroxine sodium** is recommended [15, 16].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Recommendation 26. In adults with central hypothyroidism, the dose of levothyroxine sodium** depends on age: a dose of 1.21–1.6 mcg/kg/day is recommended for patients under 60 years of age; 1.0–1.2 mcg/kg/day for patients over 60 years of age, or for younger patients with concomitant cardiovascular diseases [15, 16, 54].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Recommendation 27. In patients with central hypothyroidism, the adequacy of replacement therapy is recommended to be evaluated 6–8 weeks after treatment initiation based on free T4 levels, provided that blood is drawn before taking the daily dose of levothyroxine sodium** or at least 4 hours after taking the medication. The target free T4 level is recommended to be above the median of the reference range [15, 16, 48, 49].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Recommendation 28. In patients with central hypothyroidism, replacement therapy with levothyroxine sodium** is recommended to be initiated only after adrenal insufficiency has been ruled out. If concomitant secondary adrenal insufficiency cannot be ruled out, hypothyroidism replacement therapy should be initiated only after glucocorticoids are prescribed to avoid the development of an adrenal crisis [52].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Recommendation 29. The criterion for levothyroxine sodium** overdose is recommended to be considered an elevation of free T4 levels above or to the upper limit of the reference range (provided blood is drawn before medication intake), combined with clinical manifestations of thyrotoxicosis or a high free T3 level. A sign of an insufficient dose of levothyroxine sodium** is recommended to be considered a borderline low or decreased free T4 level, especially when combined with an elevated TSH level > 1 mIU/L and the presence of hypothyroidism symptoms [50, 51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: monotherapy with levothyroxine sodium** is used to treat central hypothyroidism. Dose adjustment is carried out under the control of serum free T4 levels. Young patients with central hypothyroidism require higher doses of the drug than elderly patients. In most adult patients with central hypothyroidism, the daily dose is 1.2–1.6 mcg/kg/day [15, 16]. In elderly patients, patients with long-standing hypothyroidism, and those at risk for cardiovascular events, treatment with levothyroxine sodium** should be started at lower doses with a gradual increase over subsequent weeks or months until reaching 1.0–1.2 mcg/kg/day [48]. If concomitant secondary adrenal insufficiency cannot be ruled out, hypothyroidism replacement therapy should be initiated only after glucocorticoids are prescribed to avoid the development of an adrenal crisis [50].
In central hypothyroidism, the goal of treatment is to maintain free T4 concentrations in the upper half of the reference range. Blood sampling should be performed before taking levothyroxine sodium** or at least 4 hours after taking the drug [51]. The target free T4 concentration may be lower for elderly patients and patients with severe comorbidities. These recommendations are not supported by any prospective study data; they are based mainly on small retrospective studies.
In a number of cases, patients require dose adjustment of levothyroxine sodium**. When prescribing estrogen replacement therapy, an increase in the dose of levothyroxine sodium** is generally required due to an increase in thyroxine-binding globulin (TBG) levels. When prescribing growth hormone replacement therapy, central hypothyroidism may be detected for the first time, or an increase in the dose of levothyroxine sodium** may be required [52]. It is hypothesized that growth hormone may inhibit the peripheral conversion of T4 to T3 and also exert an inhibitory effect on TSH release.
3.2 Surgical Treatment
No surgical treatment methods have been developed for this disease.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
No rehabilitation measures have been developed for this disease.
5. Prevention and Dispensary Observation
No preventive measures have been developed for this disease.
6. Organization of Medical Care
Elective hospitalization. Inpatient / day hospital care.
Indications for elective hospitalization in a medical organization (inpatient facility):
- thyroid dysfunction that cannot be corrected on an outpatient basis;
Indications for discharge from the medical organization (hospital):
- persistent improvement in condition, when the patient can, without detriment to health,
continue treatment in an outpatient clinic or at home
conditions.
7. Additional Information
The prognosis is determined by the presence of severe comorbid somatic pathology in the patient.
Criteria for Evaluating the Quality of Medical Care
1. | A blood test was performed including thyroid-stimulating hormone (TSH) level and serum free thyroxine (fT4) level. | Yes/No |
|---|---|---|
2 | For newly detected elevated TSH levels with normal free T4, a follow-up blood test for thyroid-stimulating hormone (TSH) and serum free thyroxine (fT4) was performed after 2–3 months, along with determination of thyroid peroxidase antibody levels in the blood (A12.06.045). | Yes/No |
3 | Patients with overt hypothyroidism underwent replacement therapy with levothyroxine sodium**. | Yes/No |
4 | Replacement therapy with levothyroxine sodium** was performed in pregnant women with subclinical hypothyroidism. | Yes/No |
2. | Ultrasound examination of the thyroid gland and parathyroid glands (in primary hypothyroidism) was performed as clinically indicated. | Yes/No |
3. | The adequacy of the levothyroxine sodium** dose in primary hypothyroidism was assessed by achieving the target TSH level (within the reference range). | Yes/No |
References
Show references
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Appendix A1. Working Group Composition
LEADERS:
Dedov I.I., Professor, Academician of the RAS, Moscow
Melnichenko G.A., Professor, Academician of the RAS, Moscow
TEXT AUTHORS:
1. Fadeev V.V., Professor, Corresponding Member of the RAS, Moscow
2. Morgunova T.B., Candidate of Medical Sciences, Moscow
Conflict of interest:
The authors of the clinical guidelines declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience of these clinical guidelines:
1. endocrinologist;
2. general practitioner (family physician);
3. general practitioner (internist);
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)
LoE | Definitions |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Order of medical care delivery for the profile "endocrinology" (Order of the Ministry of Health of the Russian Federation dated November 12, 2012, No. 899n).
Appendix B. Physician Action Algorithms
Figure 1: Laboratory diagnostics of hypothyroidism
Figure 2: Diagnosis and treatment of hypothyroidism during pregnancy
Appendix C. Patient Information
What is hypothyroidism?
Hypothyroidism is a condition in which the thyroid gland does not produce enough hormones. Thyroid hormones are essential for all organs, tissues, and cells without exception, which is why hypothyroidism can manifest with diverse disorders that are often similar to other diseases.
How common is hypothyroidism?
Hypothyroidism is a common disease. It occurs in 1–10% of adults. It is detected 8–10 times more frequently in women, and its prevalence progressively increases with age in individuals of both sexes.
What are the causes of hypothyroidism?
Hypothyroidism develops as a result of the destruction of thyroid cells that produce the hormone thyroxine (T4), and the destruction of the majority of these cells is required for hypothyroidism to develop. Most frequently, hypothyroidism develops due to autoimmune thyroiditis. Autoimmune thyroiditis is an autoimmune condition of the thyroid gland in which the immune system acts against thyroid cells. As a result, inflammation develops in the thyroid gland, leading to its destruction and cessation of adequate T4 production. In most cases, this destruction occurs slowly—over many years and even decades. In the blood of most patients with autoimmune thyroiditis, thyroid antibodies—proteins involved in the development of this disease—are detected. Hypothyroidism may also develop due to other causes; thyroid surgery and sodium iodide [131I] therapy are frequently the causes of hypothyroidism.
What are the manifestations and dangers of hypothyroidism?
In hypothyroidism, all metabolic processes in the body are impaired. Cardiac activity, the nervous system, stomach, intestines, kidneys, liver, and reproductive system are disrupted. Hypothyroidism can manifest as a dysfunction of any organ and system.
The most typical manifestations of hypothyroidism, requiring evaluation of thyroid function, are:
General symptoms: weakness, fatigue, weight gain, feeling cold, decreased appetite, edema and fluid retention, hoarseness, muscle cramps, dry skin and a slight yellowish tint, increased hair brittleness, anemia.
Nervous system: drowsiness, memory impairment and slowed thinking processes, inability to concentrate, hearing loss, depression.
Cardiovascular system: bradycardia, elevated diastolic blood pressure, pericardial effusion, elevated blood cholesterol levels.
Gastrointestinal tract: cholelithiasis and biliary dyskinesia, elevated liver enzymes, chronic constipation and a tendency toward it.
Reproductive system: any menstrual irregularities, infertility, erectile dysfunction in men, spontaneous miscarriage.
How is hypothyroidism diagnosed?
The diagnosis of hypothyroidism is established based on the thyroid-stimulating hormone (TSH) level. This is the most important test for diagnosing any thyroid disorders. A normal TSH level practically rules out thyroid dysfunction. In hypothyroidism, the TSH level will be elevated. If necessary, serum free thyroxine (fT4) is additionally determined: in overt hypothyroidism, fT4 levels are decreased; in subclinical hypothyroidism, fT4 is within normal limits.
Who should have their TSH level measured to rule out/confirm hypothyroidism?
women over 40 years old;
postpartum women (at 6 months);
presence of symptoms characteristic of hypothyroidism;
elevated blood cholesterol levels;
history of any thyroid disease;
history of radiation therapy to the head and/or neck region;
taking medications such as lithium carbonate and amiodarone**;
patients with conditions such as chronic adrenal insufficiency, type 1 diabetes mellitus, pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus (essentially, any autoimmune diseases);
first-degree relatives with a history of thyroid disease;
enlarged thyroid gland.
How is hypothyroidism treated?
Patients with overt hypothyroidism are prescribed replacement therapy. The dosage of the replacement drug is selected individually. The main parameter indicating the correct intake of the medication is the blood TSH level—it must be maintained within normal limits. After a patient with hypothyroidism is first prescribed a replacement medication, the first follow-up blood test for thyroid-stimulating hormone (TSH) is performed no sooner than 2–3 months later, since normalization of this indicator takes a relatively long time.
The question of whether treatment for subclinical hypothyroidism is necessary is also decided individually.
How long do replacement therapy medications need to be taken?
In most cases, the destruction of the thyroid gland leading to hypothyroidism is irreversible. An important exception to this rule is hypothyroidism that first develops in women during the first postpartum year. Such hypothyroidism is transient in approximately 50–80% of cases.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not required.