The association of neuropsychiatric disorders and endocrine parameters in hashimoto thyroiditis

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INTRODUCTION

Thyroid gland (TG) pathology currently ranks first in terms of vulnerability and morbidity among all endocrinopathies. Chronic Hashimoto autoimmune thyroiditis (AIT) is the most common disease among thyropathies, which is sometimes considered to occur with Graves–Basedow disease as a single autoimmune TG disease [10]. Untreated AIT results in hypothyroidism. Clinically overt hypothyroidism occurs in 0.2%–2% and subclinical hypothyroidism occurs in 10%–12% of the general population [1]. Due to the ubiquitous nature of thyroid hormone receptors in all body cells, hypothyroidism can disguise as various somatic forms of pathology, including neuropsychiatric disorders [9]. In 1949, Richard Asher gave the classic description of “myxoedematous madness,” revealing its direct relationship with hypothyroidism [18].

The neuropsychiatric symptomatology of hypothyroidism is often diagnosed as a psychiatric disorder; and in such cases, patients with an unrecognized endocrine disease can be monitored by psychiatrists for years [19].

With hypothyroidism, thyroid hormone levels, namely, free triiodothyronine (FT3) and free thyroxine (FT4), are decreased in the blood, and the levels of thyroid-stimulating hormone (TSH) and prolactin (hyperprolactinemia, due to the prolactin-releasing hormone effect of compensatory thyroliberin production) are increased. Therefore, the prolactin level in the blood must be controlled in such patients [28]. Prolactin promotes the development of autoimmunity and autoimmune pathology as a systemic and paracrine immunostimulant; therefore, hyperprolactinemia can be an immunopathogenic factor contributing to the emergence and progression of AIT according to the vicious cycle principle [13].

Thyroid hormones control both differentiation and functions of neuronal networks and neuroglia; therefore, hypothyroidism is characterized by neuropsychiatric abnormalities such as drowsiness, asthenia, loss of interest in the environment, decreased memory and cognitive decline, delirium and delirium–hallucinatory conditions, anxiety and depressive disorders, and panic attacks [2, 5, 8, 11, 14, 15, 29].

Psychiatric disorder also occurs in euthyroid AIT, when no deficiency of thyroid hormones are noted, hence the occurrence of neuropsychiatric disorders in such patients can not be explained by hypothyroidism.

Perhaps not all of these disorders are due solely to a lack of thyroid hormones. Other immunoendocrine mechanisms associated with various serum bioregulators (autoantibodies, other hormones, and autacoids) may be involved in the pathogenesis of these disorders.

In 1966, Hashimoto’s encephalopathy (HE), a new nosological unit, was described, although its etiology and pathogenesis have not been studied yet [19]. HE is believed to be an autoimmune inflammatory disease of the brain, also known as steroid responsive encephalopathy associated with autoimmune thyroiditis [20, 23, 25]. HE can occur with various clinical manifestations, such as tremors, transient aphasia, epileptic seizures, paranoid, visual hallucinations, and behavioral disorders. Historically, the first descriptions were associated with cerebellar symptoms [3, 6, 21, 22–24]. Generally, in case of HE, an increase in the level of autoantibodies to thyroperoxidase (aTPO) is noted, but the etiology and pathogenesis remain a subject of debate, since HE is also associated with autoantibodies against other autoantigens, including extrathyroid ones, and with the vasculitis of cerebral vessels and the effects of TSH excess on the brain.

HE is most often considered an autoimmune cerebral vasculitis or a result of an autoimmune cross-reaction of antithyroid antibodies against antigens present on brain cells. However, the role of autoantibodies towards neuronal α-enolase and/or other autoantigens of the brain is not excluded [4, 21, 26]. According to the literature, HE can be registered in patients with various thyroid states, for example, 35% of the patients have subclinical hypothyroidism, 20% have clinically pronounced hypothyroidism, 30%–40% have euthyroidism, and 10% have hyperthyroidism. Therefore, the relationship of HE and thyroid hormone level is considered ambiguous, and it should not be reduced to myxedematous brain damage only [22].

In 2019, we first proposed a synthetic concept of HE pathogenesis (Fig. 1) [23].

 

Fig. 1. Scheme of pathogenesis of Hashimoto’s encephalopathy. Abbreviations: aTG –autoantibodies against thyroglobulin; aTPO – autoantibodies against thyroid peroxidase; aNAE – autoantibodies against N-terminal peptide of alfa-enolase; a1DMA – autoantibodies against 1-dimethylarginase; a1AR – autoantibodies against 1-aldoreductase; aGS – anti-ganglioside autoantibodies; aMOG – autoantibodies against myelin-oligodendrocyte glycoprotein; TSH –thyroid stimulating hormone

Рис. 1. Схема патогенеза энцефалопатии Хасимото. АИТ — Аутоиммунный тироидит; АТ к ТГ — антитела к тироглобулину; АТ к ТПО — антитела к тиропероксидазе; aNAE — антитела к N-терминальному пептиду альфа-енолазы; a1DMA — антитела к 1-диметиларгиназе; a1AR — антитела к 1-альдоредуктазе; aGS — антиганглиозидные антитела; aMOG — антитела к миелин-олигодендроцитарному гликопротеину; ТТГ — тиротропный гормон

 

Nowadays, AIT and HE are considered two non-identical nosological entities; in both cases, there is an increase in the level of antithyroid antibodies, but they have different clinical manifestations. However, a fair practical question arises, i.e., should patients with AIT criteria (including diagnostic titers of the corresponding autoantibodies) and various psychiatric diagnoses be treated as having AIT alone, AIT with psychiatric disorder, or as patients with HE? This question is not speculative and is not related only with the perfectionism of the diagnosticians. Modern antipsychotics, having a dopaminolytic effect, aggravate hyperprolactinemia in most cases [16].

At the same time, for AIT, hyperprolactinemia is one of the key pathogenetic links. Therefore, clarification of the origin of psychiatric manifestations for such patients may imply the need for pathogenetic variations in antipsychotic therapy.

MATERIALS AND METHODS

We examined three groups of patients:

• AIT group with psychiatric disorder (n = 17), which included 16 women (94.1%) and one man (5.9%), with the average patient age of 50.4 ± 15.5 years.
• AIT group without psychiatric disorder (n = 21), which included 19 women (90.5%) and two men (9.5%), with an average age of 51.3 ± 13.7 years.
• Control group of healthy individuals (n = 20; in this group, the average age was 42.0 ± 14.9 years, which included 18 women (90%) and two men (10%).

The AIT group with psychiatric disorder included patients with a diagnosis of AIT confirmed by the criteria of the Japanese Thyroidological Association in combination with various psychiatric diagnoses verified in a psychiatric hospital [18]. Schizophrenia was diagnosed in 14 patients (82.4%), Alzheimer’s disease was registered in one patient (5.9%), and dementia (5.9%) and obsessive–compulsive disorder (5.9%) were identified with one case each (Fig. 2).

 

Fig. 2. The structure of psychiatric diagnoses in the autoimmune thyroiditis group in comorbidity with a psychiatric disorder

Рис. 2. Структура психиатрических диагнозов в группе с аутоиммунным тироидитом в коморбидности с психиатрическим расстройством

 

Research methods step by step included the following: history taking; physical examination and blood sampling; ultrasonography (US) of the TG with an assessment of the location, anatomical shape, echogenicity of the parenchyma, echo structure of the parenchyma, TG volume, mass lesions, type of formations (node, cyst), and characteristics of peripheral lymph nodes; and immune enzyme assay for blood serum levels of TSH, FT3, FT4, aTPO, aTG, and prolactin. Studies were performed on an Epoch 2 plate spectrophotometer (BioTek Instruments Inc., USA).

Collected laboratory data (TSH, FT3, FT4, prolactin, aTPO, and aTG levels) were analyzed statistically. Given that the study presented a heterogeneous sample of patients (sex, age, cycle phases, etc.), the use of standard statistical methods for comparing parameters within a group as well as between groups was impossible. Therefore, we applied the method of standardization of parameters, followed by the calculation of the decimal logarithm and the use of a logistic regression model.

RESEARCH RESULTS

In the AIT group, symptoms of neuropsychiatric disorders were assessed regardless of the presence and type of psychiatric diagnosis. In the AIT group without psychiatric disorder, phobias were detected in four (19%) patients and sleep disturbances in the form of hypersomnia were registered in four (19%) patients (Fig. 3).

 

Fig. 3. Structure of psychiatric symptoms in groups of patients with autoimmune thyroiditis (AIT)

Рис. 3. Структура психиатрических симптомов в группах пациентов с аутоиммунным тироидитом (АИТ)

 

In the AIT group with psychiatric disorder, the psychiatric symptoms were as follows: delirium (n = 16, (94.1%), hallucinations (n = 15, 88.2%), generalized anxiety (n = 15, 88.2), panic attacks (n = 9, 52.9%), phobias or irritability (n = 7, 41.2%), hypochondria (n = 2, 11.8%), depression (n = 4, 23.5%), mania (n = 4, 23.5%), sleep disturbances as insomnia (n = 7 patients, 41.2%) or hypersomnia (n = 4, 23.5%), and attention deficit (n = 6, 35.3%). Eating disorders were noted in two patients (11.8%) (Fig. 3).

In all patient groups, clinical signs and symptoms of hypothyroidism were assessed. In the AIT group, a positive Stroev’s symptom (i.e., habitual biting of the cheeks and tongue) was noted in 9 (42.9%), decreased knee reflexes in 7 (33.3%), brittle nails in 8 (38.1%), dry elbows in 14 (66.7%), positive Chvostek’s symptom (i.e., contraction of facial muscles upon tapping on the skin in the area of innervation of the facial nerve) in 4 (19%), and limb cramps in 8 (38.1%) patients (Fig. 4).

 

Fig. 4. Structure of psychiatric symptoms in groups of patients with autoimmune thyroiditis

Рис. 4. Структура клинических признаков гипотироза в группе пациентов с аутоиммунным тироидитом

 

In the AIT group with psychiatric disorder, a positive Stroev’s symptom was noted in 5 (29.4%), decreased knee reflexes in 8 (47.1%), brittle nails in 5 (29.4%), dry elbows in 9 (52.9%), positive Chvostek’s symptom in 3 (17.6%), and limb cramps in 11 (64.7%) patients (Fig. 5).

 

Fig. 5. Structure of psychiatric symptoms in groups of patients with autoimmune thyroiditis and psychiatric disorder

Рис. 5. Структура клинических признаков гипотироза в группе пациентов с аутоиммунным тироидитом в сочетании с психиатрическим расстройством

 

In the control group, no clinical signs of hypothyroidism were found. In the AIT group with psychiatric disorder, the average FT3 level was 3.84 ± 0.23 pmol/L, and the FT4 level was 9.8 ± 4.76 pmol/L, which was lower than the reference values of the norm; the average TSH level was 2.54 ± 2.29 mIU/L, the average aTPO level was above the norm (2040.1 ± 4982.5 IU/ml), and the average aTG level was also above the norm (354.3 ± 836.3 IU/mL). The average prolactin level was 1105 ± 734 mIU/L, which exceeded the reference value of the norm (Table 1).

 

Table 1 / Таблица 1 The average levels of laboratory parameters in patients of all clinical groups in comparison with reference values of the norm Средние уровни лабораторных показателей у пациентов всех клинических групп в сравнении с референсными значениями нормы
Laboratory parameter / Лабораторный показатель	Patients with AIT + psychiatric disorder / Группа пациентов с АИТ + психиатрическое расстройство	Patients with AIT / Группа пациентов с АИТ	Healthy control group / Контрольная группа здоровых лиц	Reference values / Референсные значения нормы
FT3	3.84 ± 0.23	3.5 ± 0.3	4.2 ± 0.8	2.5–5.8 pmol/l / пмоль/л
FT4	9.8 ± 4.76	12.4 ± 1.8	14.1 ± 2.1	10.0–21.0 pmol/l / пмоль/л
TSH / ТТГ	2.54 ± 2.29	1.3 ± 1.0	1.0 ± 0.7	0.3–4.0 mIU/l / мМЕ/л
antiTPO Ab / АТ к ТПО	2040.13 ± 4982.5	230 ± 299	9.4 ± 12.3	<30 IU/ml / ME/мл
antiTG Ab / АТ к ТГ	354.32 ± 836.3	95.9 ± 163.2	21.8 ± 14	<100 IU/ml / ME/мл
Prolactin / Пролактин	1105 ± 734	472 ± 511	461 ± 420	Men 60–560 mIU/l / Мужчины 60–560 мМЕ/л Women / Женщины Cycle phases / Фазы цикла: Follicular 60–600 mIU/l / Фолликулярная 60–600 мМЕ/л Luteal 120–900 mIU/l / Лютеиновая 120–900 мМЕ/л Menopause 40–550 mIU/l / Менопауза 40–550 мМЕ/л
Note. AIT – autoimmune thyroiditis; TSH – thyroid stimulating hormone; antiTPO Ab – autoantibodies against thyroid peroxidase; antiTG Ab – autoantibodies against thyroglobulin. Примечание. АИТ — аутоиммунный тироидит; ТТГ — тиротропный гормон; АТ к ТПО — антитела к тиропероксидазе; АТ к ТГ — антитела к тироглобулину.

 

In the AIT group, the average FT3 level was 3.5 ± 0.3 pmol/L, the FT4 level was 12.4 ± 1.8 pmol/L, the average TSH level was 1.3 ± 1 mIU/L, the average aTPO level was above normal at 230 ± 299 IU/ml, the average aTG level was 95.9 ± 163.2 IU/ml, and the average prolactin level was 472 ± 511 mIU/L.

In the control group, the average FT3 level was 4.2 ± 0.8 pmol/L, the FT4 level was 14.1 ± 2.1 pmol/L, the average TSH level was 1.0 ± 0.7 mIU/L, the average aTPO level was 9.4 ± 12.3 IU/ml, and the average aTG level was 21.8 ± 14 IU/ml. The average prolactin level was 461 ± 420 mIU/L. All indicators in this group were within the normal reference values.

Using a logistic regression model, the FT3 level was not beyond the normal values in all three groups of patients, while it was statistically significantly different between the AIT group and the control group (p < 0.001) and between the AIT group and the AIT group with psychiatric disorder (p < 0.001). No statistically significant difference in this parameter was found between the AIT group with psychiatric disorder and the control group (p = 0.598).

Moreover, the FT4 level was not beyond the reference intervals of the norm in the AIT group and control group, but was below the norm in the AIT group with psychiatric disorder, while it differed statistically significantly in the AIT group and the control group (p = 0.048), as well as in the AIT group and AIT group with psychiatric disorder (p = 0.048). Differences in this parameter between the AIT group with psychiatric disorder and the control group (p < 0.001) were also verifiable and statistically significant (Fig. 6).

 

Fig. 6. Laboratory results (FT3 and FT4) using the logistic regression model. AIT – autoimmune thyroiditis

Рис. 6. Результаты лабораторных исследований (FT3 и FT4) с использованием модели логистической регрессии. АИТ — аутоиммунный тироидит

 

In this study, the TSH level was not beyond the reference intervals of the norm in all three groups, while it differed statistically significantly in the AIT group and the AIT group with psychiatric disorder (p = 0.030); its differences were also significant between the AIT group with psychiatric disorder and the control group (p < 0.001). No considerable statistically difference was noted between the AIT group and the control group (p = 0.193) (Fig. 7).

 

Fig. 7. Results of laboratory tests (prolactin and thyroid stimulating hormone (TSH)) using a logistic regression model

Рис. 7. Результаты лабораторных исследований (пролактин и тиротропный гормон (ТТГ)) с использованием модели логистической регрессии

 

The prolactin level in the AIT group with psychiatric disorder was higher than the normal level and differed credibly statistically significantly between the AIT group and the AIT group with psychiatric disorder (p = 0.001) and between the control group and the AIT group with psychiatric disorder (p = 0.002). No statistically significant difference was found in prolactin levels between the AIT group and the control group (p = 0.997) (Fig. 7).

In the analysis of aTG and aTPO indicators, the aTG level exceeded the norm in the AIT group with psychiatric disorder; however, no statistically significant difference was found among the clinical groups of patients. In addition, the aTPO level was higher than normal in the AIT group with psychiatric disorder and in the AIT group. A significant statistically significant difference in the latter parameter was observed between the AIT group and control group (p < 0.001). No statistically significant difference was noted between the AIT group with psychiatric disorder and the AIT group for this parameter (p = 0.3), as well as between the AIT group with psychiatric disorder and the control group (p = 0.164) (Fig. 8).

 

Fig. 8. Results of laboratory tests using the logistic regression model. AIT – autoimmune thyroiditis; antiTG – autoantibodies to thyroglobulin; antiTPO – autoantibodies to thyroid peroxidase

Рис. 8. Результаты лабораторных исследований с использованием модели логистической регрессии. АИТ — аутоиммунный тироидит; АТ к ТГ — антитела к тироглобулину; АТ к ТПО — антитела к тиропероксидазе

 

TG US data were analyzed. Using a logistic regression model, we revealed that the TG volume exceeded the norm in the AIT group and in the AIT group with psychiatric disorder. The TG volume was statistically significantly greater in the AIT group with psychiatric disorder than in the control group (p = 0.016). No statistically significant difference was observed between the AIT group with psychiatric disorder and the AIT group (p = 0.371), as well as between the AIT group and the control group (p = 0.343) (Fig. 9).

 

Fig. 9. Comparative analysis of thyroid volume according to the results of ultrasound using a model of logistic regression

Рис. 9. Сравнительный анализ объема щитовидной железы по результатам ультразвукового исследования с использованием модели логистической регрессии

 

A statistically significant correlation was also found between psychiatric symptoms and the examined immunoendocrine parameters, as well as the symptoms of hypothyroidism and data from laboratory and instrumental studies.

Thus, the FT4 level was statistically significantly lower in patients with phobias, irritability, and attention deficit than in patients without these symptoms (p < 0.05) (Fig. 10). The TSH level was statistically significantly higher in patients with delirium and generalized anxiety than in patients without these symptoms (p < 0.05) (Fig. 10). The prolactin level was statistically significantly higher in patients experiencing panic attacks, delirium, and generalized anxiety than in patients without these symptoms (p < 0.05) (Fig. 10). The TG volume was statistically significantly higher in patients with delirium, generalized anxiety, and attention deficit (Figs. 9 and 10).

The FT3 level was statistically significantly lower in patients with dry elbows than in those without this symptom (p < 0.05). The level of antibodies to TG was statistically significantly higher in patients with reduced knee reflexes (p < 0.05). The aTPO level was statistically significantly higher in patients with dry elbows, reduced knee reflexes, and increased TG volume than in patients without these signs (p < 0.05) (Fig. 11).

 

Fig. 10. Statistically significant associations between psychiatric symptoms and laboratory instrumental data. TSH – thyroid stimulating hormone

Рис. 10. Статистически значимые связи между психиатрическими симптомами и данными лабораторно-инструментальных исследований. ТТГ — тиротропный гормон

 

Fig. 11. Statistically significant relationships between symptoms of hypothyroidism and laboratory instrumental findings. antiTG – autoantibodies to thyroglobulin; antiTPO – autoantibodies to thyroid peroxidase

Рис. 11. Статистически значимые связи между симптомами гипотироза и данными лабораторно-инструментальных исследований. АТ к ТГ — антитела к тироглобулину; АТ к ТПО — антитела к тиропероксидазе

 

Moreover, a statistically significant verifiable relationship was found between the aTPO level and the TG volume (p < 0.05) (Fig. 12).

 

Fig. 12. The correlation between antiTPO level and thyroid gland volume

Рис. 12. Связь между уровнем антител к тиропероксидазе (АТ к ТПО) и объемом щитовидной железы

 

DISCUSSION

AIT can occur with various neuropsychiatric disorders; however, in our study, in patients with AIT and comorbid mental disorders, a schizophrenic-like clinical manifestation prevailed. At the same time, HE initially manifests as neuropsychiatric disorders. Thus, the following question arises: should patients with increased levels of antithyroid antibodies and other AIT criteria, and different verified psychiatric disorders, be considered patients with AIT and comorbid psychiatric disorder or as patients with HE? As regards to the diagnostic difficulties, HE does not have specific clinical signs or generally recognized laboratory markers [23]. AIT with hypothyroidism does not have clinical manifestations that would be incompatible with the diagnosis of HE. The obtained data so far do not enable drawing an unambiguous conclusion of any of the interpretations, but it is necessary to establish the mechanistic role of the same factors in the pathogenesis of both AIT and HE.

According to the well-known principle of Hans Selye, diseases are interesting for the clinician, that is, in the way they differ from each other, but for the pathologist, they are interesting in a way that they are similar to each other [4].

This study is pathophysiologically significant due to the demonstration of immunoendocrine aspects that correlate with psychiatric disorders in AIT. The study demonstrated that a number of hormonal parameters (such as prolactin, TSH, and FT4 levels) correlate with the presence of psychiatric disorders in AIT. The literature presents data on hyperprolactinemia in untreated schizophrenia in both sexes [17, 27]. Polish scientists have established a link between TSH levels and psychotic disorders [31]. Findings of the influence of FT4 on bioelectric processes, neurogenesis, and neuronal plasticity of the brain have been published [12].

All this is consistent with our data and raises the question of the intrinsic effects of the dysfunction of these endocrine parameters in psychotic disorders. Moreover, we did not establish a correlation between mental disorders and titers of autoantibodies to thyroid antigens, although this was previously reported by Japanese scientists [30, 32]. The results indicate that further research is required to explore the immunoendocrine basis of cerebral dysfunctions in AIT.

CONCLUSIONS

1. A significant relationship (p < 0.05) was found between a number of immunoendocrine parameters and some psychiatric symptoms, namely, between a decreased FT4 level and presence of psychiatric symptoms such as phobias, irritability, attention deficit; between elevated TSH levels and symptoms such as delirium and generalized anxiety; and between increased prolactin levels and psychiatric symptoms such as panic attacks, delirium, and generalized anxiety.
2. A significant relationship (p < 0.05) was established between psychiatric symptoms (such as delirium, generalized anxiety, and attention deficit) and an enlarged TG.
3. A significant relationship (p < 0.05) was noted between the symptoms of hypothyroidism and laboratory parameters, that is, between a decreased FT3 level and dry elbows, between an increased aTG level and a decrease in knee reflexes, and between an increased aTPO level and symptoms of hypothyroidism such as decreased knee reflexes and dry elbows.
4. A significant relationship (p < 0.05) was established between an enlarged TG and an increased aTPO level.

The study was performed in accordance with the Decree of the Government of the Russian Federation No. 220 and agreement 14.W03.31.0009 on the allocation of a grant from the Government of the Russian Federation for state support of scientific research conducted under the guidance of leading scientists. This study also presents results of scientific research of the Laboratory of the Mosaic of Autoimmunity of St. Petersburg State University, obtained using the resource center for the development of molecular and cellular technologies in the St. Petersburg State University Science Park.

About the authors

Polina A. Sobolevskaia

Saint Petersburg State University

Author for correspondence.
Email: dr.polinasobolevskaia@bk.ru

Researcher, Laboratory of the Mosaic of Autoimmunity

Russian Federation, Saint Petersburg

Boris V. Andreev

St. Petersburg State Budgetary Healthcare Institution “Psychiatric Hospital No. 1 named after P.P. Kashchenko”

Email: bandreev1947@list.ru

MD, PhD, Dr Med Sci, Professor

Russian Federation, Nikolskoe, Leningrad Region

Anton N. Gvozdetckii

Saint Petersburg State University

Email: comisora@yandex.ru

Graduate Student

Russian Federation, Saint Petersburg

Anastasia A. Dolina

Saint Petersburg State University

Email: dolinanast.357@mail.ru

Student, Research Assistant

Russian Federation, Saint Petersburg

Anna M. Stepochkina

Saint Petersburg State University; Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: annastepochkina23.11@mail.ru

Student, Research Assistant, Senior research assistant

Russian Federation, Saint Petersburg

Yurii I. Stroev

Saint Petersburg State University

Email: svetlanastroeva@mail.ru

MD, PhD, Professor

Russian Federation, Saint Petersburg

Vladimir J. Utekhin

Saint Petersburg State University; St. Petersburg State Pediatric Medical University of the Ministry of Healthcare of the Russian Federation

Email: utekhin44@mail.ru

MD, PhD, Associate Professor

Russian Federation, Saint Petersburg

Tamara V. Fedotkina

Saint Petersburg State University; St. Petersburg State Pediatric Medical University of the Ministry of Healthcare of the Russian Federation

Email: t.v.fedotkina@gmail.com

PhD, Leading Researcher, Associate Professor

Russian Federation, Saint Petersburg

Leonid P. Churilov

Saint Petersburg State University; St. Petersburg Scientific Research Institute of Phthisiopulmonology of the Ministry of Healthcare of the Russian Federation

Email: elpach@mail.ru

MD, PhD, Associate Professor, Head of the Department of Pathology, Leading Researcher

Russian Federation, Saint Petersburg

References

Supplementary files