Acute and chronic thyroiditis (excluding autoimmune and amiodarone-induced thyroiditis): clinical guidelines

List of Abbreviations

AIT – autoimmune thyroiditis

Abs – antibodies

TRAb – TSH receptor antibodies

TgAb – thyroglobulin antibodies

TPOAb – thyroid peroxidase antibodies

HIV – human immunodeficiency virus

GC – glucocorticoids

DRP – diagnostic radiopharmaceuticals

CT – computed tomography

NSAIDs/ antirheumatic drugs – nonsteroidal anti-inflammatory and antirheumatic drugs

CBC – complete blood count

AT – acute thyroiditis

ST – subacute thyroiditis

RIT – radioiodine therapy

FT3 – free triiodothyronine

FT4 – free thyroxine

ESR – erythrocyte sedimentation rate

T3 – triiodothyronine

T4 – thyroxine

FNA – fine-needle aspiration biopsy

RT – Riedel's thyroiditis

TSH – thyroid-stimulating hormone

US – ultrasound examination

HR – heart rate

TG – thyroid gland

HLA – human leukocyte antigen

IgG4 – immunoglobulin G4

Terms and Definitions

Compression syndrome – a set of symptoms caused by the compression of surrounding organs and tissues. Compression syndrome due to a significant enlargement of the thyroid gland proceeds with impaired swallowing and breathing, leading to mechanical asphyxia and respiratory failure.

Multifocal fibrosing disorder – the progressive development of dense fibrous connective tissue of unknown etiology, involving multiple organs and tissues.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Thyroiditis is a group of thyroid diseases varying in etiology, pathogenesis, and clinical manifestations [1].

Due to the extreme heterogeneity of this group of diseases, for the reader's convenience, the authors were forced to make minor changes to the structure of the clinical guidelines, presenting the classification first and then describing each nosological entity separately.

AIT and amiodarone-induced thyroiditis are not discussed in these clinical guidelines. Painless (silent) thyroiditis as well as postpartum thyroiditis as variants of AIT are not described in these clinical guidelines [2].

Acute thyroiditis (AT, acute suppurative thyroiditis, bacterial thyroiditis, acute strumitis) is an acute inflammation of the thyroid gland caused by a bacterial infection.

Acute non-suppurative thyroiditis is an inflammatory disease of the thyroid gland resulting from radiation exposure (radioactive iodine therapy), trauma, or hemorrhage into the thyroid gland.

Subacute thyroiditis (ST, granulomatous thyroiditis, de Quervain's thyroiditis, viral thyroiditis, giant cell thyroiditis) is an inflammatory disease of the thyroid gland, presumably of viral etiology, lasting from one week to several months, at the peak of the disease most often manifesting with severe pain in the thyroid area and fever, sometimes accompanied by symptoms of thyrotoxicosis; having a tendency to recur [3, 4, 5].

Cytokine-induced thyroiditis consists of destructive thyroid diseases (most commonly) arising as a result of the use of immunostimulants.

Thyroiditis resulting from lithium preparations is a group of diseases accompanied by thyroid dysfunction arising from the use of lithium preparations [6, 7].

Riedel's thyroiditis (RT) is a rare disease characterized by extensive fibrosis often involving surrounding structures in addition to the thyroid gland [8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Vary depending on the disease.

Acute thyroiditis. In adults, the disease is predominantly caused by Staphylococcus aureus, Streptococcus hemolytica, Streptococcus pneumoniae, or anaerobic streptococci, which are found in more than 80% of cases [9].

In children, alpha- and beta-hemolytic streptococci and various anaerobes are detected in approximately 70% of cases, while mixed pathogens are identified in 50% or more of patients [10].

Among other pathogens of acute thyroiditis, the following are described: Salmonella brandenberg, Salmonella enteritidis, Actinomyces naeslundii, Actinobacillus actinimycetemcomitans, Brucella melitensis, Clostridium septicum, Eikenella corrodens, Enterobacter spp., Escherichia coli, Haemophilus influenzae, Klebsiella spp., Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter baumanii i Staphylococcus non-aureus, and cases of fungal, tuberculous, parasitic, and syphilitic thyroid lesions are also described in the literature.

There is a clear link between the onset of acute thyroiditis and a prior acute infectious disease of the ENT organs (e.g., tonsillitis, sinusitis, otitis media) and pneumonia, predominantly in immunocompromised patients (patients with HIV, Hodgkin lymphoma, after organ autotransplantation, after chemotherapy, alcohol abusers, etc.) [11, 12, 13]. Infection occurs hematogenously or lymphogenously, or as a result of direct inoculation of the infection into the thyroid gland during trauma or a wound, as well as a result of invasive medical procedures (e.g., puncture biopsy, sclerotherapy, laser photocoagulation, radiofrequency thermoablation). Primarily one lobe of the thyroid gland is affected. The inflammatory process in the thyroid gland goes through all stages: alteration, exudation, proliferation.

A frequent cause of recurrent thyroiditis (predominantly occurring in childhood) is the presence of a communication (fistula) between the thyroid lobe and the pyriform sinus. A distinguishing feature of this pediatric pathology is the involvement of only the left lobe of the thyroid gland [9, 13].

Infection routes predisposing to the development of acute thyroiditis:

Subacute thyroiditis. Usually, subacute thyroiditis develops after a viral infection (most commonly an upper respiratory tract viral infection) [4]. The viral etiology is supported by a prolonged prodromal period, epidemic pattern of incidence, and seasonal (autumn-winter) increase in case numbers. Putative causative agents include mumps virus, Coxsackie virus, adenoviruses, ECHO viruses, influenza viruses (including H1N1), Epstein-Barr virus, and more recently, coronavirus-2 – SARS-CoV-2. The mumps virus has been cultured directly from the thyroid tissue of patients with subacute thyroiditis, apparently acting as a specific etiological factor. In addition, subacute thyroiditis has been associated with other viral diseases, such as infectious mononucleosis, HIV, etc. [14, 15, 16, 17, 18].

Over the past few years, there has been an increase in the prevalence of subacute thyroiditis, which is undoubtedly associated with the coronavirus disease 2019 (COVID-19) pandemic. Interestingly, prior to this pandemic, coronaviruses were not reported as potential causes of subacute thyroiditis [19]. The causes of subacute thyroiditis are considered to be the direct effect of SARS-CoV-2 on thyroid cells via angiotensin-converting enzyme 2 (ACE2) receptors, followed by an inflammatory reaction and subsequent destruction of thyrocytes [20].

For decades, it was believed that the most frequent complaints of patients with subacute thyroiditis were pain in the anterior neck radiating to the jaw and upper mediastinum, as well as odynophagia [21]. However, the clinical presentation of the disease has changed significantly since 2019. An increase in the number of painless subacute thyroiditis cases has been reported, with its frequency reaching 6.25% in 2019 (prior to the emergence of SARS-CoV-2) but rising to nearly 90% since the beginning of the pandemic [19, 22]. These changes in the clinical course of subacute thyroiditis can be explained by the widespread use of NSAIDs and glucocorticoids [22].

There is a genetic predisposition to subacute thyroiditis, as the incidence is higher in individuals with HLA-BW35 [4]. In one study, the risk of subacute thyroiditis recurrence was HLA-dependent, with the co-presence of HLA-B*18:01 and -B*35 being the determining factor. The authors suggest that such patients require a treatment regimen using high doses of glucocorticoids and a slow taper [23]. In another study involving 60 patients with subacute thyroiditis and 1,023 healthy controls, in addition to the previously described association of subacute thyroiditis with HLA-B*35, genetic susceptibility to subacute thyroiditis was associated with the presence of HLA-B*18:01, DRB1*01, and C*04:01, with HLA-B*18:01 and DRB1*01 alleles being independent risk factors for subacute thyroiditis [24].

Upon entering the cell, the virus induces the formation of atypical proteins, to which the body reacts with an inflammatory response. The inflammatory process in the thyroid gland leads to the destruction of follicular cells and follicles, and the loss of colloid by the follicles. Thyroid invasion by polynuclear leukocytes and lymphocytes is observed, and granulomas containing multinucleated giant cells are formed. Along with destructive changes, proliferation of thyroid cells and the formation of new follicles are observed. All contents of the damaged thyroid follicle enter the bloodstream (thyrotoxicosis without thyroid hyperfunction) [25, 26].

Cytokine-induced thyroiditis. Frequently, for the treatment of malignant neoplasms (such as multiple myeloma, Kaposi sarcoma, melanoma, hairy cell leukemia, chronic myeloid leukemia, renal cell carcinoma, follicular (non-Hodgkin) lymphoma, etc.), viral diseases (hepatitis B and C, condyloma acuminata, etc.), and demyelinating diseases (multiple sclerosis), immunostimulatory drugs that modulate the immune response are used [27, 28, 29].

Cytokines are small soluble proteins secreted by cells of the immune system and other cells, forming part of the intercellular communication system responsible for the immune response. These proteins, by binding to specific cellular receptors, either induce or inhibit the genes they regulate. During a viral infection, various cytokines play a role in both viral clearance and tissue damage [30].

In the presence of hepatitis C virus in the body, the virion can infect follicular cells in immunocompetent patients, which is likely a potential mechanism for the development of thyroid dysfunction [31].

However, the mechanism of cytokine-induced thyroid dysfunction is not yet fully understood [27].

Lithium-induced thyroiditis. Patients taking lithium preparations used in psychiatric practice have an increased risk of developing thyroid dysfunction: diffuse and nodular goiter, hypothyroidism, and more rarely, thyrotoxicosis [6, 7].

The development of hypothyroidism is explained by several mechanisms: direct inhibition of the enzyme responsible for regulating thyrocyte proliferation, impaired iodine uptake and release of thyroid hormones, and decreased sensitivity of receptors to TSH. Due to the established ability of lithium preparations to suppress the functional activity of thyrocytes, its use was previously considered as a potential therapeutic measure in thyrotoxicosis. The development of goiter is explained not so much by the feedback effect of elevated TSH levels as by a direct effect on intracellular proliferation mechanisms. This conclusion follows from the results of a study confirming a higher frequency of goiter development during lithium therapy, as well as the absence of a correlation between structural changes in the thyroid gland and thyroid hormone levels [32, 33].

In addition, it has been noted that lithium intake can intensify the development of pre-existing thyroiditis by increasing the titer of circulating TPO autoantibodies. However, no evidence has been obtained regarding the ability of lithium preparations to induce the synthesis of TPO autoantibodies de novo. Furthermore, no correlation was found between lithium intake and TRAb levels [34, 35].

One form of lithium-associated thyroiditis is characterized by a transient triphasic course with a potential outcome of hypothyroidism, similar to that seen in painless thyroiditis. However, histological findings in patients with lithium-induced silent thyroiditis show a picture distinct from painless thyroiditis, revealing cell destruction in the absence of lymphocytic infiltration [36].

The lack of confirmation of a link between lithium intake and TRAb levels, together with histological findings, points more toward a direct cytotoxic effect of lithium preparations rather than an autoimmune mechanism of damage. Cell destruction with the release of thyroid hormones is considered the most likely cause of transient thyrotoxicosis during lithium therapy. Nevertheless, clinically they are indistinguishable [37].

Riedel thyroiditis. The etiology of RT is unknown. This condition may be a very rare variant of chronic autoimmune Hashimoto's thyroiditis or a manifestation of systemic fibrosis associated with IgG4 production. The presence of thyroid autoantibodies, eosinophil infiltration, and a positive response to treatment suggest an autoimmune nature of the lesion. TPOAb are detected in approximately 90% of patients with AIT.

RT can be combined with orbital fibrosis, primary sclerosing cholangitis, mediastinal and retroperitoneal fibrosis, and can be part of a multifocal idiopathic fibrosing disorder [8, 38, 39].

A characteristic feature of RT is the replacement of thyroid tissue with dense fibrous connective tissue. Fibrosis can spread to adjacent tissues: parathyroid glands, neck muscles, laryngeal nerves, and blood vessels. Fibrous tissue invades the skeletal muscles of the neck, fusing tightly with the esophagus and trachea, causing their stenosis. The disease has a malignant course. Aggressive growth of fibrous tissue continues even after removal of the goiter and progresses after repeated surgeries aimed at freeing the trachea from stenosing proliferations of coarse fibrous connective tissue [40].

1.3 Epidemiology of the Disease or Condition

Provided for each disease.

Acute thyroiditis is a rare disease. Its prevalence accounts for 0.1–0.7% of all thyroid pathologies [10, 41, 125]. At the same time, the disease occurs in 92% of cases in children, and the remaining 8% occur in adults, most commonly aged 20–40 years [42, 43]. The disease occurs with equal probability in men and women.

Subacute thyroiditis is a relatively rare disease with an incidence rate of 4.9 cases per 100,000 population per year, with a female predominance [4]. Although the disease has been described at all ages, it is rare in children [44, 45]. Middle-aged individuals are most commonly affected, although cases also occur in the elderly [46, 47].

The share of SAT in the structure of thyroid diseases is 1–5%. An increase in incidence is noted in the autumn-winter period during viral disease epidemics [4, 48].

Cytokine-induced thyroiditis. Interferon alfa** therapy in patients with chronic hepatitis C increases the risk of thyroid dysfunction: 5–20% of patients manifest thyropathies (primary hypothyroidism resulting from AIT, Graves' disease, and destructive thyroiditis). Endocrine ophthalmopathy is rare [27, 49, 50, 51]. During the treatment of malignant neoplasms (for solid tumors) with Interferon alfa**, thyroid diseases occur in 2.4–31% of patients [27].

Thyroid dysfunction occurs more frequently in women than in men—13% and 3%, respectively [50, 52, 53]. According to meta-analysis data, 50% of patients with TPOAb prior to Interferon alfa** therapy developed thyroid dysfunction compared to 5.4% of patients without baseline antibodies [51, 54].

Lithium-induced thyroiditis. The prevalence of lithium-associated hypothyroidism ranges from 6% to 52% according to various studies. A recent meta-analysis confirmed that patients receiving lithium preparations had a significantly higher incidence of lithium-associated goiter compared to those receiving other mood stabilizers (40% vs. 18%) [55, 56, 57].

The development of thyrotoxicosis during lithium therapy is a rarer phenomenon. A recent study showed that among patients referred to the clinic for thyroid pathology over a 12-year period, only 1.4% (23 individuals) had lithium-associated thyrotoxicosis, predominantly represented by Graves' disease (47.8%). Other conditions included multinodular goiter, silent thyroiditis, and SAT [57].

Riedel thyroiditis is a rare disease. The prevalence is 1.06 cases per 100,000 population, which accounts for about 0.06% of thyroidectomies. RT is more common in women [40].

1.4 Features of Coding the Disease or Condition

E06 Thyroiditis (excluding E06.3 Autoimmune thyroiditis)

E06.0 Acute thyroiditis;

E06.1 Subacute thyroiditis;

E06.2 Chronic thyroiditis with transient thyrotoxicosis;

E06.4 Drug-induced thyroiditis;

E06.5 Other chronic thyroiditis;

E06.9 Thyroiditis, unspecified.

1.5 Classification of the disease or condition

There are several classification options for thyroiditis.

I. By histological pattern:

1. Acute:

- bacterial (suppurative) [38, 55];

- fungal (Candida, Aspergillus, Pneumocystis, Histoplasma);

- parasitic (Echinococcosis, Cysticercosis) [3];

- radiation-induced (following sodium iodide [131I] administration) [21];

- post-traumatic (following rough palpation, trauma, neck injury) [55].

2. Subacute:

- de Quervain's thyroiditis (granulomatous thyroiditis, giant cell thyroiditis) [4, 56, 57];

- subacute lymphocytic thyroiditis (sporadic, painless, silent thyroiditis, postpartum thyroiditis) [55, 58].

3. Chronic:

a) autoimmune:

- Hashimoto's thyroiditis [59];

- Graves' disease [60];

- euthyroidism in the presence of autoantibodies [61];

- atrophic thyroiditis (primary myxedema) [62];

- focal lymphocytic thyroiditis in papillary carcinoma [63, 64];

- juvenile [65].

b) drug-induced:

o resulting from the use of class III antiarrhythmic drugs – amiodarone**:

· amiodarone-induced thyroiditis:

- amiodarone-induced hypothyroidism: subclinical / overt, transient / permanent;

- amiodarone-induced thyrotoxicosis:

- type I (iodine-induced);

- type II (destructive);

- mixed type [66, 67].

· resulting from the use of iodine-containing radiocontrast agents [68]:

o resulting from the cytotoxic action of drugs:

- resulting from lithium preparations [34];

- thyroiditis caused by certain systemic antibacterial drugs (Minocycline, Rifampicin**) [68].

o cytokine-induced thyroiditis:

- resulting from the use of interferons, interleukin-2;

- resulting from the use of tumor necrosis factor alpha (TNF-alpha) inhibitors (Infliximab**) [68];

- resulting from the use of monoclonal antibodies inhibiting immune checkpoints, also known as checkpoint inhibitors: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockers – Ipilimumab**; programmed cell death protein 1 (PD-1) blockers – Pembrolizumab**, Nivolumab**, Prolgolimab**; programmed cell death ligand 1 (PD-L1) blockers – Atezolizumab**, Durvalumab**, Avelumab** [69, 70];

- resulting from the use of monoclonal antibodies specifically binding to the CD52 glycoprotein (Alemtuzumab**) [71].

o resulting from the ischemic action of drugs:

- protein kinase inhibitors (Sorafenib**, Lenvatinib**, Regorafenib**) [71].

c) fibrous thyroiditis (Riedel's goiter):

- without compression syndrome;

- with compression syndrome [72].

II. By thyroid functional state:

1. Destructive thyroiditis:

- subacute granulomatous thyroiditis (de Quervain's thyroiditis);

- subacute sporadic lymphocytic thyroiditis (painless, "silent");

- postpartum thyroiditis;

- amiodarone-induced thyroiditis type 2;

- cytokine-induced thyroiditis;

- lithium salt-associated thyroiditis;

- iodine-containing radiocontrast media-induced thyroiditis;

- thyrotoxic phase of chronic autoimmune thyroiditis [73];

- radiation-induced thyroiditis;

- post-traumatic thyroiditis;

- thyroiditis caused by Pneumocystis jiroveci infection.

2. Non-destructive thyroiditis – other types of thyroiditis lacking a thyrotoxic phase in their clinical course.

3. Specific and non-specific thyroiditis:

- associated with tuberculosis, amyloidosis, sarcoidosis; however, from our perspective, these conditions are best covered in clinical guidelines dedicated to the respective diseases;

- Riedel's thyroiditis.

1.6 Clinical presentation of the disease or condition

It should be noted that several types of thyroiditis—acute (suppurative), subacute, and certain forms of drug-induced thyroiditis (along with painless [silent] thyroiditis, traumatic thyroiditis, and postpartum thyroiditis)—can lead to thyroid tissue destruction, classically manifesting as thyrotoxicosis. This is most often temporary and presents as part of a classic triphasic course (thyrotoxicosis, hypothyroidism, euthyroidism). Overall, thyroid dysfunction caused by destructive thyroiditis is less pronounced than other forms of endogenous thyrotoxicosis [77].

The symptoms of acute suppurative thyroiditis present as a clinical triad:

- hyperthermia (39–40°C) with a hectic fever curve;

- neck pain radiating to the jaw, ear, and shoulder on the affected side;

- local inflammatory signs in the neck (hyperemia, edema, tenderness upon palpation, head turning, and swallowing).

In acute non-suppurative thyroiditis, the main clinical complaints include pain of varying intensity, neck discomfort, and symptoms of thyrotoxicosis [10, 41, 58, 78, 79].

Subacute thyroiditis clinically presents as a typical inflammatory disease. At the onset of SAT, patients may experience prodromal signs: general weakness, low-grade fever, pharyngitis symptoms, fatigue, and myalgia. At the peak of the disease, SAT manifests with moderate to severe pain in the thyroid gland, often radiating to the parotid region, neck, occiput, jaw, or throat, and sometimes pain upon swallowing and turning the head. Pain may begin focally and spread from one side of the gland to the other over several weeks. In rare cases, disease can reach its peak within 3–4 days and resolve within a week, but typically SAT is characterized by a gradual onset [3]. SAT is a common cause of thyroid pain.

The development of SAT itself comprises 4 stages (phases):

1 – thyrotoxic (3–10 weeks according to various sources) [4, 60, 80]. The thyrotoxic phase ends when the stores of preformed thyroid hormone are depleted;

2 – euthyroid (1–3 weeks);

3 – hypothyroid (2 to 6 months);

4 – recovery. Permanent primary hypothyroidism may develop instead of full recovery. This phenomenon is observed in approximately 5–25% of patients [4, 46, 47]. Disease recurrence is observed in 1–4% of cases [4, 46, 60].

The clinical presentation of cytokine-induced thyroiditis is highly variable and depends on the functional status of the thyroid gland. Destructive thyroiditis occurs in 50–70% of cases. Typically, it is characterized by a triphasic course: a short phase of transient thyrotoxicosis is followed by a more prolonged hypothyroid phase, after which a euthyroid state may be restored. Of particular clinical importance is the fact that cytokine-induced thyroiditis can manifest at any stage of treatment (most commonly within the first 3 months, and less frequently in the late period). In the vast majority of patients with preexisting autoimmune thyroiditis, its manifestations worsen during treatment of the underlying disease [49].

The clinical presentation of thyroidopathies resulting from lithium therapy is variable and depends on the specific syndrome.

Riedel's thyroiditis presents with obstructive symptoms such as dyspnea, dysphagia, and hoarseness due to involvement of organs and tissues adjacent to the thyroid. Dyspnea is caused by tracheal compression, dysphagia is associated with esophageal involvement, stridor develops due to recurrent laryngeal nerve involvement, and venous sinus thrombosis occurs due to vascular network involvement. Secondary exophthalmos occurs when the extraocular muscles and retrobulbar tissues are affected.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is based on:

1) patient complaints;

2) anamnesis data;

3) laboratory tests confirming thyroid dysfunction;

4) instrumental examination.

Differential diagnosis is performed among all described types of thyroiditis, most frequently between acute thyroiditis (AT) and subacute thyroiditis (SAT), especially prior to abscess formation. In SAT, hyperthermia with a hectic fever curve is typically absent; pain is present, but its intensity is significantly lower than in AT. The severity of local inflammatory symptoms ranges from mild to moderate.

Differential diagnosis for suspected AT must rule out:

It may be necessary to differentiate SAT from IgG4-associated thyroiditis, as neck tenderness can occasionally be detected in the latter. Unfortunately, clinical diagnostic criteria for IgG4-related thyroiditis have not been fully established; a conditional guideline is the persistence of pain despite prolonged glucocorticoid therapy, while the "gold standard" for diagnosing IgG4-related thyroiditis is IgG4 immunostaining of postoperative material [81, 82].

2.1 Complaints and Anamnesis

The description is presented in Section "1.6. Clinical Presentation".

During history taking, it is advisable to clarify information regarding a recent viral infection and current or past therapy with specific drugs (e.g., lithium preparations, etc.).

• In suspected Riedel's thyroiditis, it is recommended to look for the following complaints: dysphagia, cough, voice coarsening, and breathing difficulties [39, 40].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: these symptoms occur due to compression of adjacent organs and tissues by fibrous tissue. Involvement of the parathyroid glands in the pathological process may lead to tetany.

2.2 Physical Examination

Comments: in Riedel's thyroiditis, palpation reveals a hard thyroid gland that may be fixed during swallowing due to adhesion to surrounding tissues. Positive Chvostek's and Trousseau's signs indicate the development of secondary hypoparathyroidism [83].

Comments: patients receiving therapy with immunostimulant drugs or lithium preparations, as well as those scheduled to receive them, require an assessment of thyroid functional state and structure to identify baseline thyroid pathology for targeted subsequent monitoring due to the potential development of induced thyroidopathies. Classic signs of thyroid pathology may be detected already at the examination stage. Attention should be paid to typical signs of hypothyroidism (e.g., dry, pale, and cold skin, chills, impaired concentration, edema, slowed speech, weakness, intellectual sluggishness) and thyrotoxicosis (e.g., tremor, unexplained weight loss, myopathy, exacerbation of arrhythmia or angina pectoris, heat intolerance).

2.3 Laboratory Diagnostics

2.3.1 Acute thyroiditis

Comments: Complete blood count (CBC) reveals a significant increase in leukocyte count due to the neutrophilic lineage of leukopoiesis with a left shift of the leukocyte formula. In addition, an increase in ESR is noted, the results of which depend on the severity of the disease.

Comments: in patients with acute thyroiditis, thyroid function is rarely impaired. Symptoms of destructive thyrotoxicosis may appear only in massive lesions involving the entire thyroid lobe.

2.3.2 Subacute thyroiditis

Comments: in subacute thyroiditis, an accelerated ESR > 40–60 mm/h (and in some cases > 100 mm/h) is observed [4]. At the same time, the leukocyte count and leukocyte formula are usually within the reference interval, though leukocytosis may occur in rare cases.

Comments: approximately 50% of patients with subacute thyroiditis have an initial thyrotoxic phase due to the unregulated release of thyroid hormones from damaged thyrocytes (destructive nature of thyrotoxicosis) [4]. Thyrotoxicosis may present with a decreased TSH level combined with elevated fT4 and fT3 levels. In the early stage of the disease, TSH levels may be normal. When determining serum antithyroglobulin antibody levels, they may be elevated in most patients for several weeks after symptom onset. After a few months, the antibodies disappear. However, this finding lacks additional diagnostic significance. In addition, antibody levels may be normal in approximately 25% of patients [4, 60, 84].

Comments: hypothyroidism, which is most often transient, reveals an elevated TSH level combined with a normal fT4 level in subclinical hypothyroidism or a decreased fT4 level in overt hypothyroidism. In the early stage of the disease, TSH levels may be normal [4].

2.3.3 Cytokine-induced thyroiditis

Comments: in patients indicated for therapy with immunostimulant drugs (interferons), blood TSH and antibody levels (anti-TPO and anti-thyroglobulin) should be assessed to rule out thyroid pathology before starting treatment, and thyroid function (blood TSH) should be monitored during treatment. If abnormalities are detected, additional testing is recommended to clarify the etiology of the condition.

Comments: if baseline TSH is within the laboratory reference interval and no elevated antibody titer for anti-TPO and anti-thyroglobulin is detected, measuring blood TSH every 3 months until the end of the course of therapy is recommended.

If baseline TSH is within the laboratory reference interval, but an elevated antibody titer for anti-TPO and anti-thyroglobulin is detected, measuring blood TSH every 2 months until the end of the course of therapy is recommended.

2.3.4 Thyroiditis resulting from lithium preparations

Comments: the risk of developing thyroid pathology increases with long-term lithium use. The studies required for differential diagnosis between possible forms of disorders (autoimmune, painless, subacute thyroiditis, diffuse/nodular, thyrotoxicosis) are described in the relevant sections.

2.3.5 Riedel's thyroiditis

2.4 Instrumental Diagnostics

2.4.1 Acute thyroiditis

Comments: thyroid and parathyroid ultrasound is performed using a linear transducer with a frequency of 7.5–10 MHz. In the early stage of the disease, decreased tissue echogenicity and blurred borders of the thyroid lobe are detected due to local edema. In later stages, signs of an abscess appear—a hypoechoic formation with liquid content. Thyroid and parathyroid ultrasound also makes it possible to evaluate the response of cervical lymph nodes.

Comments: in acute thyroiditis, there is a marked decrease in radiopharmaceutical uptake in the thyroid gland due to impaired thyroid function resulting from inflammation.

Comments: CT of the soft tissues of the neck organs is less informative than thyroid and parathyroid ultrasound, especially in the early stages of the disease. However, in the case of abscess formation, CT allows for diagnosing the extent of the process and the presence of developing or existing fistulas. When mediastinitis and phlegmon are suspected, CT of the neck organs is a mandatory study.

2.4.2 Subacute thyroiditis

Comments: during ultrasound in subacute thyroiditis, an increase in thyroid volume, diffuse heterogeneity, or focal "cloud-like" zones of decreased echogenicity in one or both lobes without clear margins may be detected. During dynamic follow-up, migration of these zones is possible: their appearance in other parts of the thyroid gland. Thyroid duplex scanning reveals a reduced or normal blood flow intensity, in contrast to increased vascularization in Graves' disease [4, 80, 90]. The use of new technologies, such as thyroid elastography, in subacute thyroiditis can demonstrate markedly decreased elasticity (increased stiffness) [91].

Comments: a decrease and sometimes complete absence of radiopharmaceutical uptake is noted during the thyrotoxic phase of subacute thyroiditis [4].

2.4.3 Cytokine-induced thyroiditis

Comments: in destructive thyroiditis, a decrease or complete absence of sodium pertechnetate [99mTc] uptake will be detected, whereas in Graves' disease, a significant increase in radiopharmaceutical uptake is observed.

2.4.4 Thyroiditis resulting from lithium preparations

Comments: patients taking lithium preparations are more likely to exhibit diffuse thyroid enlargement, as well as focal changes exceeding 1.0 cm in size [32, 33].

2.4.5 Riedel's thyroiditis

Comments: hypoechoic, hypovascular tissue is detected, involving adjacent tissues and sometimes the carotid arteries; on thyroid scintigraphy, these formations are most often identified as "cold" nodules.

Comments: the tissue has a grey color and stony consistency; the characteristic lobular structure is absent; dense hyalinized intercellular substance with sparse colloid and characteristic eosinophilic cellular infiltration is detected; malignant and giant cells are absent; obliterative phlebitis is frequently encountered (the definitive diagnosis of Riedel's thyroiditis can be established only on the basis of histological examination of postoperative material).

2.5 Other Procedures

2.5.1 Acute thyroiditis

Comments: acute suppurative thyroiditis does not require confirmation by puncture biopsy. However, in complex diagnostic cases for differential diagnosis with subacute thyroiditis and anaplastic carcinoma, the results of puncture biopsy allow for a refined diagnosis. In subacute thyroiditis, giant cells (multinuclear macrophages) are detected, while in anaplastic carcinoma, malignant tumor cells are found. The primary role of puncture biopsy in acute thyroiditis is therapeutic. It should be emphasized that puncture drainage is used only for small foci of local melting of the thyroid gland resulting from an infectious process, concurrently with antibacterial and symptomatic therapy.

2.5.2 Subacute thyroiditis

Comments: if subacute thyroiditis is confirmed, pain syndrome reduction and a gradual decrease in ESR should occur after the specified time [46, 47].

Comments: unlike other forms of endogenous thyrotoxicosis, in destructive thyrotoxicosis, the total T3 level may be within the normal range.

Comments: however, the literature describes a series of clinical cases combining neck pain with elevated ESR (of varying severity) in the complete (clinical) blood count, with no effect or a short-lived effect on conservative treatment, which subsequently turned out to be anaplastic carcinoma or metastases of other primary cancers. These forms of malignancies are overly aggressive: a delay of 1–2 weeks can significantly impact the patient's prognosis. Indications for fine-needle aspiration biopsy must be formulated based on ultrasound findings [99]. In true subacute thyroiditis, multinuclear giant cells are present in the cytological material against a background of macrophages, leukocytes, lymphoid elements, and destroyed follicles [4, 97].

2.5.3 Riedel's thyroiditis

Comments: a hypodense mass that does not accumulate contrast media is detected.

Comments: intense uptake in the inflammation zone is detected; this is particularly informative for diagnosing fibrosis foci in other organs.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Acute thyroiditis

3.1.1 Conservative treatment

Comments: the recommendation is due to the severity of the clinical presentation and the rapid progression of the disease.

Comments: the initial stage of the disease is successfully treated without surgical intervention. However, it should be noted that patients rarely seek medical attention at the initial stage of acute thyroiditis development. The mainstay of conservative treatment is broad-spectrum antibiotic therapy: beta-lactam antibacterial drugs (penicillins, other beta-lactams such as cephalosporins), and macrolides. Non-steroidal anti-inflammatory drugs are used as symptomatic treatment, and beta-blockers are used if destructive thyrotoxicosis develops. In case of hemorrhages, ultrasound-guided puncture drainage under aseptic conditions is sometimes used for decompression.

3.1.2 Surgical treatment

Comments: when lysis of thyroid tissue areas begins, it is effective to use puncture drainage in parallel with antibacterial therapy. The method is used only for small lesions no larger than 1.0–1.5 cm in diameter. Under ultrasound guidance using the "free-hand" technique, puncture and drainage of the purulent focus are performed with a 21G needle. Any doubts regarding the efficacy of puncture drainage (persistence of the abscess after 2 puncture drainages) should be resolved in favor of surgical intervention (hemithyroidectomy). Concurrently with puncture drainage, the aforementioned antibacterial therapy and symptomatic treatment are utilized.

Comments: in the overwhelming majority of cases, the extent of surgical intervention is hemithyroidectomy (A16.22.001, A16.22.001.002). Surgical treatment is performed on an emergency basis under general anesthesia, allowing adequate debridement of the lesion. Hemithyroidectomy (A16.22.001, A16.22.001.002) is performed in a standard manner, if possible without opening the abscess cavity, with minimal trauma to surrounding tissues and fascial spaces. The wound must be washed with antiseptic and disinfectant solutions (hydroxymethylquinoxalinedioxide, chlorhexidine**), a sentinel drain is installed and brought out through a counter-incision, and the neck wound is sutured. In case of complications such as mediastinitis, surgical treatment is supplemented by debridement and drainage of the mediastinum. In thyroid-tracheal fistulae, the defect is sutured following conservative excision of affected tissues. In the presence of a fistula between the left thyroid lobe and the pyriform sinus in childhood, excision of the fistula and closure of the pyriform sinus are mandatory [105, 106].

Comments: During neck exploration for acute thyroiditis (AT), the tissues surrounding the abscessed thyroid lobe are extremely infiltrated. In such situations, searching for and identifying the recurrent laryngeal nerve on the affected side can be complicated by inflammatory infiltration. The use of continuous neural monitoring reduces the likelihood of recurrent laryngeal nerve palsy.

As a rule, antibacterial therapy is continued postoperatively, particularly in complicated cases. Symptomatic and infusion-detoxification therapy are also used.

3.2 Subacute thyroiditis

Treatment for subacute thyroiditis (SAT) is conservative in the vast majority of cases.

3.2.1 Conservative Treatment

The classic drugs for treating SAT are NSAIDs and GCs [109].

Comments: Beta-blockers are recommended as needed for patients with symptomatic thyrotoxicosis, especially the elderly and patients with a resting heart rate > 90 beats/minute, as well as individuals with cardiovascular diseases (except where contraindicated; use with caution in bronchial asthma). The dosage is individual; most commonly, propranolol** is used at 40-120 mg/day [9, 110, 112, 113]. NSAIDs provide pain relief in patients with mild symptoms and should be considered first-line therapy. When using NSAIDs, the median time to pain resolution is 5 weeks (possible range 1-20 weeks). Historically, acetylsalicylic acid** was used as an NSAID, but there is evidence of its ability to displace T4 from protein binding, making it preferable to use other drugs. Ibuprofen** may be used, but the long-acting drug naproxen is most preferred. Regimen and doses of naproxen: 500-1000 mg/day in 2 divided doses (morning and evening) with meals, with a possible transition to a maintenance dose regimen of 500 mg/day in 1 or 2 doses [4, 113].

Comments: Patients who do not respond to full doses of NSAIDs within a few days should be prescribed GCs. Standard recommendations involve the use of prednisolone** at doses of 20-30 mg/day, with the criterion for reducing the GC dose being the reduction or disappearance of thyroid pain (in 1-3 days) and normalization of ESR (control should be performed 2 weeks after treatment initiation). The lack of a clinical effect from GC use within 2 weeks may be a diagnostic sign of a different pathological process in the thyroid gland. However, in cases of pronounced symptom severity, prescribing prednisolone** at 40 mg/day for 1-2 weeks, followed by a gradual dose reduction over 2-4 weeks or longer depending on the clinical response, is also possible [4, 114, 115]. The results of one study demonstrated that a lower starting daily dose of 15 mg of prednisolone** with a 5 mg reduction every 2 weeks was effective. However, 20% of patients required more than 8 weeks to discontinue GCs [111]. This type of therapy can be recommended as an alternative regimen in special cases. During GC treatment, a decrease in thyroid volume and favorable echographic dynamics are noted. The normalization of the thyroid echographic picture in patients lags behind the normalization of clinical and laboratory data.

Comments: This recommendation is due to the fact that the nature of thyrotoxicosis in SAT is destructive, making the prescription of antithyroid drugs unjustified.

Comments: Prescribing antibiotic therapy is ineffective since the etiology of the disease is presumed to be viral.

Comments: Levothyroxine sodium** can be used during the hypothyroid phase, but should be discontinued after 3-6 months when normal thyroid function typically recovers, as confirmed by laboratory tests. The dose is selected individually depending on the severity of hypothyroidism.

3.2.2 Surgical treatment

Isolated cases of SAT resistant to prolonged treatment with high doses of prednisolone** (50 mg/day and above) have been described in the literature, with authors considering the possibility of thyroidectomy [118]. However, this approach is controversial, and thorough differential preoperative diagnosis is of particular importance in such cases.

3.3 Cytokine-induced thyroiditides

3.3.1 Conservative treatment

Comments: Cytokine-induced thyrotoxicosis is most often transient and resolves spontaneously. Beta-blockers can be used as symptomatic therapy. Antithyroid drugs can cause a hepatotoxic effect, which may exacerbate the underlying condition being treated with immunostimulants, and are not pathogenetically justified.

Comments: Since hypothyroidism is transient in the majority of patients, it is advisable to attempt to discontinue levothyroxine sodium** after one year.

If a patient develops Graves' disease, treatment is carried out according to the general principles of treating this condition and is described in the relevant clinical guidelines.

The management protocol for patients with cytokine-induced thyroiditis is presented in Appendix B.

3.4 Thyroiditis resulting from lithium therapy

3.4.1 Conservative treatment

Comments: Most patients with lithium-associated hypothyroidism recover euthyroid status after discontinuing therapy. Nevertheless, lithium preparations are a core component in the complex treatment of various psychiatric pathologies. Discontinuing lithium preparations due to developed thyroid pathology, which is satisfactorily compensated medically and is often transient in nature, is not justified [119, 120].

Levothyroxine sodium** replacement therapy is indicated for hypothyroidism. In cases of painless thyroiditis, treatment with beta-blockers is recommended to relieve symptoms. In some cases, the use of GCs should be considered, but only in pronounced thyrotoxicosis. GCs should be used with caution, taking into account their potential negative impact on mental status (development of manic episodes in patients with bipolar disorder). Management tactics for Graves' disease and toxic multinodular goiter are described in the relevant clinical guidelines [119, 120, 121].

3.5 Riedel's thyroiditis

In Riedel's thyroiditis (RT), there is no consensus regarding the choice of either conservative therapy or the optimal scope of surgical intervention due to the lack of research results, which is associated with the rarity of the disease.

Treatment of RT includes [39, 40]:

- antiestrogens;

- surgical treatment.

In addition, when hypoparathyroidism develops, calcium preparations and cholecalciferol are used (recommended for use in accordance with the indications, contraindications, methods of administration, and doses contained in the drug's package insert) [113], as described in the relevant clinical guidelines.

3.5.1 Conservative treatment

Comments: GCs are considered the backbone of conservative therapy, and their anti-inflammatory effect is most effective when used in the early stages of the disease. There is currently no single recommended dose.

Comments: #tamoxifen** is a selective estrogen receptor modulator (SERM) used to treat Riedel thyroiditis and other manifestations of systemic fibrosis. It induces transforming growth factor beta (TGF-β), which is a potent inhibitor of fibrous tissue growth.

3.5.2 Surgical treatment

Comments: there is a hypothesis regarding the potential so-called "staging" of Riedel thyroiditis; therefore, the likelihood of remission, including with minimal surgical intervention, likely depends on the stage at which the surgery is performed. There is no conclusive, clear data.

The management algorithm for patients with Riedel thyroiditis is presented in Appendix B.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not developed.

5. Prevention and Dispensary Observation

No specific prophylaxis has been developed for the described thyroiditis types. At the same time, timely treatment of primary infections can be considered prophylaxis for acute thyroiditis.

Follow-up monitoring depends on the severity of the patient's condition, the duration of a specific phase of the disease, and the involvement of surrounding organs and tissues in the pathological process. The frequency, scope of follow-up examinations, and specialist consultations are determined individually.

In the presence of Riedel thyroiditis, attention should be paid to provoking factors and conditions that exacerbate obstruction symptoms, such as: smoking, upper respiratory tract infections, environmental pollution with industrial and other waste, specific occupational hazards, and climatic conditions.

6. Organization of Medical Care

6.1 Acute thyroiditis

Indications for emergency hospitalization in a medical organization (inpatient facility) for acute thyroiditis: in all cases.

Discharge from a medical organization is possible:

- in case of conservative treatment, following completed antibacterial therapy with a positive treatment outcome and elimination of the threat of recurrence and persistence of the disease;

- following surgical intervention with radical removal of the lesion focus.

6.2 Subacute thyroiditis

Indications for emergency hospitalization in a medical organization (inpatient facility) for subacute thyroiditis are present if the patient has:

1) severe pain syndrome;

2) pronounced symptoms of thyrotoxicosis.

Discharge from a medical organization is possible:

- upon relief of pain syndrome;

- upon resolution of pronounced symptoms of thyrotoxicosis.

6.3 Cytokine-induced thyroiditis

Indications for emergency hospitalization in a medical organization (inpatient facility):

1) severity of thyrotoxicosis symptoms (severe course).

Indications for elective hospitalization in a medical organization (inpatient facility):

1) thyroid function impairment unresponsive to correction in an outpatient setting.

Discharge from a medical organization is possible:

- upon improvement of the condition, when the patient can continue treatment in an outpatient clinic or at home without detriment to health.

6.4 Thyroid disorders resulting from lithium therapy

Indications for emergency hospitalization in a medical organization (inpatient facility):

1) severity of thyrotoxicosis symptoms and development of its complications;

2) severe decompensation of hypothyroidism and its complications.

6.5 Riedel's thyroiditis

Indications for emergency hospitalization in a medical organization (inpatient facility):

1) development of tracheal and esophageal compression syndrome.

Indications for elective hospitalization in a medical organization (inpatient facility):

1) thyroid function impairment unresponsive to correction in an outpatient setting.

Discharge from a medical organization is possible:

- upon improvement of the condition, when the patient can continue treatment in an outpatient clinic or at home without detriment to health.

General indications for discharge from a medical organization for all diseases:

- if it is necessary to transfer the patient to another healthcare organization;

- gross violation of hospital rules;

- upon the written request of the patient or their legal representative, provided that discharge does not threaten the patient's life and is not dangerous to others. In this case, discharge may be performed only with the permission of the chief physician of the hospital or their deputy for medical work.

7. Additional Information

7.1 Acute thyroiditis

Complications of acute suppurative thyroiditis are pathologies arising from the spread of infection due to untimely treatment. These conditions include:

- mediastinitis;

- neck phlegmon;

- jugular vein thrombosis;

- compression of neck organs;

- sepsis.

The prognosis for acute thyroiditis with timely initiation of treatment is favorable. A recurrent course is most commonly detected in childhood and rarely in adults. The prognosis in a complicated course depends on how advanced the disease is. Mortality reaches 12% [13].

7.2 Subacute thyroiditis

The presence or absence of autoimmune thyroiditis has no additional significance in subacute thyroiditis [4].

In case of disease recurrence, repeated diagnosis and resumption of treatment are recommended.

Overall, the prognosis is quite favorable: approximately 90% of patients experience a complete and spontaneous recovery and restoration of euthyroid thyroid function. However, morphologically, such patients may develop scar tissue in the thyroid tissue between islands of residual parenchyma, although any symptoms are absent. Subacute thyroiditis may recur in 2.8-4% of cases [4]. Just under 10% of patients may develop permanent hypothyroidism, requiring permanent replacement therapy with levothyroxine sodium**, while the presence of bilateral hypoechoic areas on thyroid ultrasound at the time of diagnosis appears to be a valuable prognostic marker for the subsequent development of permanent hypothyroidism [123]. Literature analysis yields contradictory data, but most researchers agree that the method of conservative treatment (NSAIDs or GCs) generally does not affect the prognosis regarding the development of permanent hypothyroidism [60, 124].

ESR and C-reactive protein levels at the time of diagnosis do not affect the likelihood of recurrence or permanent hypothyroidism.

7.3 Cytokine-induced thyroiditis

Risk factors for cytokine-induced thyroiditis: female sex, presence of hepatitis C virus, anti-TPO and anti-Tg antibodies.

The prognosis is determined by the patient's concomitant severe somatic pathology or the progression of the underlying disease (for the treatment of which immunostimulant drugs are used).

7.4 Riedel's thyroiditis

In Riedel thyroiditis, the prognosis is largely determined by the patient's concomitant severe somatic pathology.

Criteria for Evaluating the Quality of Medical Care

Acute thyroiditis

Subacute thyroiditis

Cytokine-induced thyroiditis

Thyroiditis due to lithium therapy

Riedel's thyroiditis

References

Appendix A1. Working Group Composition

1. Dr. Sc. (Med.), Prof., Corresponding Member of the RAS Troshina E.A.

2. Dr. Sc. (Med.) Platonova N.M.

3. Glibka A.A.

4. Panfilova E.A.

5. Ph.D. (Med.) Kim I.V.

6. Shifman B.M.

7. Senyushkina E.S.

8. Ph.D. (Med.) Larina A.A.

9. Ph.D. (Med.) Sheremeta M.S.

10. Ph.D. (Med.) Degtyarev M.V.

11. Dr. Sc. (Med.) Rumyantsev P.O.

12. Dr. Sc. (Med.), Prof. Kuznetsov N.S.

Edited by Academician of the RAS, Prof. Dedov I.I., Academician of the RAS, Prof. Melnichenko G.A.

Conflict of interest: none. None of the working group members had a conflict of interest during the development of these clinical practice guidelines, specifically a personal interest in receiving, personally or through a representative, material gain or other advantage that would or could affect the proper performance of their professional duties.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Endocrinologists

2. Surgeons

3. Radiologists

4. Internists

5. General practitioners (family physicians)

6. Cardiologists

7. Ultrasound diagnostics physicians

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix C. Patient Information

Acute thyroiditis is an inflammatory disease of the thyroid gland caused by a bacterial infection, radiation exposure, trauma, or hemorrhage into the thyroid gland. Typical main manifestations include: hyperthermia (39–40 °C), pain in the neck, sometimes radiating to the jaw, ear, or shoulder on the affected side, as well as local manifestations of inflammation in the neck (redness, edema, tenderness upon palpation, head turning, or swallowing). Treatment is carried out strictly in an inpatient setting. Treatment may be conservative, minimally invasive (rare), or radical (surgical treatment). The prognosis of the disease is favorable if treatment is initiated in a timely manner.

Subacute thyroiditis is a thyroid disease of viral etiology. Manifestations of the disease include: thyrotoxicosis, neck pain, and symptoms of an acute infectious process. The diagnosis is confirmed by: a characteristic clinical picture; high ESR; blood thyroid-stimulating hormone (TSH) level testing, blood free thyroxine (fT4) level testing, and blood free triiodothyronine (fT3) level testing; absence of radioisotope uptake on scintigraphy (if necessary); Crile's test. Medical treatment. In most cases, subacute thyroiditis resolves in recovery.

Cytokine-induced thyroiditis. When taking immunostimulant drugs (interleukin inhibitors or interferons) for a viral, oncological, or demyelinating disease, it is advisable to evaluate the thyroid functional status and determine the anti-TPO level before starting treatment. Thyroid dysfunction can occur at any time during the primary disease therapy (even in the remote period), although it most commonly occurs in the first 3 months of treatment. When thyroiditis develops during treatment of the underlying disease, the attending physician (or endocrinologist) may prescribe necessary instrumental follow-up examinations (thyroid ultrasound and scintigraphy) to determine the specific form of the disease. The clinical picture is highly variable and depends on the stage or functional activity of the thyroid gland, which confirms the need for regular dynamic monitoring of laboratory parameters in patients at risk of developing thyroiditis (female sex, presence of anti-TPO, combination therapy, etc.). Depending on the obtained laboratory data, the physician prescribes appropriate therapy. It should be noted that cytokine-induced thyroidites are often transient in nature, meaning the physician may attempt to discontinue therapy after completing the course of treatment for the underlying disease.

Thyroiditis resulting from lithium preparations. According to studies, the intake of lithium preparations in some patients can lead to changes in the structure and function of the thyroid gland due to the effect of lithium preparations on the functioning of its cells. The most expected abnormality is the development of hypothyroidism, i.e., a decrease in the secretion level of thyroid hormones, manifested by increasing weakness, drowsiness, fatigue, etc. In addition, structural changes may be detected: an increase in thyroid volume or the appearance of nodules. Patients planning to take or taking lithium preparations should undergo an examination to rule out thyroid pathology: blood thyroid-stimulating hormone (TSH) testing and anti-thyroid antibodies (anti-TPO and anti-Tg), thyroid and parathyroid ultrasound. Examinations (blood thyroid-stimulating hormone (TSH) testing + thyroid and parathyroid ultrasound) should also be repeated during lithium therapy 1–2 times a year or earlier if health deteriorates. The development of thyroid pathology during lithium therapy is not an indication for its discontinuation, but will require consultation with an endocrinologist to determine further management tactics.

Riedel's thyroiditis. A rare disease characterized by connective tissue proliferation and scarring changes. The cause remains incompletely understood to this day. Fibrous thyroiditis may be combined with lesions of other organs. The thyroid gland becomes firm, most often enlarged, impairing the normal function of surrounding tissues, which can lead to symptoms such as shortness of breath, swallowing disorders, hoarseness, and others. Medical and surgical treatments are possible. Surgical treatment does not guarantee a cure (there is a probability of disease recurrence).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not required.