Vol 93, No 10 (2021)

Cover Page

Full Issue


Modern problems of hyper- and hypoparathyroidism

Mokrysheva N.G., Eremkina A.K., Kovaleva E.V., Krupinova J.A., Vikulova O.K.


The parathyroid glands are the most important regulators of mineral metabolism. The parathyroid glands were first discovered only in 1880 and their function went the long way unrecognized. Even the term "parathyroid gland" itself speaks of the initial misconception of it as an underdeveloped part of the thyroid. To date, there is a large amount of data regarding the role of this endocrine gland in the human body and the significant changes associated with their dysfunction, including such widespread diseases such primary, secondary and tertiary hyperparathyroidism, hypoparathyroidism. This review covers the problem of the main disturbances in calcium-phosphorus metabolism, presents the results of databases of patients with primary hyperparathyroidism and hypoparathyroidism, as well as current epidemiological trends in Russia and in the world.

Terapevticheskii arkhiv. 2021;93(10):1149-1154
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Original articles

Advanced glycation end products and oxidative stress as a basis for metabolic abnormalities in patients with type 1 diabetes after successful simultaneous pancreas-kidney transplantation

Larina I.I., Severina A.S., Maganeva I.S., Ainetdinova A.R., Eremkina A.K., Gavrilova A.O., Shamhalova M.S., Dmitriev I.V., Pinchuk A.V., Shestakova M.V.


Aim. To compare advanced glycation end-products (AGE, RAGE) and 3-nitrotyrosine (3-HT) in patients with DM 1 after successful simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). To assess relationship between levels of AGE, RAGE, 3-HT and renal transplant (RT) function, carbohydrate and mineral metabolism.

Materials and methods. The study included 58 patients who received kidney transplantation in end-stage renal disease (ESRD). 36 patients received SPK. There were performed routine laboratory, examination of AGE, RAGE, 3-NT, parathyroid hormone (PTH), 25(OH)vitamin D, calcium, phosphorus, FGF23, osteoprotegerin (OPG), and fetuin-A levels.

Results. All patients after SPK reached normoglycemia (HbA1c 5.7 [5.3; 6.1] %; C-peptide 3.24 [2.29; 4.40] ng/ml) with the achievement of significant difference vs patients after KTA. Arterial hypertension (AH) was more frequent in recipients of SPK before transplantation than after (p=0.008). AH also persisted in greater number of cases in patients after KTA than after SPK. Patients after SPK had higher AGE (р=0.0003) and lower RAGE (р=0.000003) levels. OPG in patients after SPK was significantly higher (р=0.04). The correlation analysis revealed significant positive correlation between 3-HT and OPG (p<0.05; r=0.30), RAGE and eGFR (r=-0.52), HbA1c (r=0.48), duration of AH (r=0.34), AGE with HbA1c (r=0.51).

Conclusion. The results of the "metabolic memory" markers analysis may indicate their contribution to the persistence of the metabolic consequences of CKD and DM 1 after achievement of normoglycemia and renal function restoration and their possible participation in development of recurrent nephropathy, vascular calcification, and bone disorders.

Terapevticheskii arkhiv. 2021;93(10):1155-1163
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Polymorphic variants of glutathione reductase – new genetic markers of predisposition to type 2 diabetes mellitus

Azarova I.E., Klyosova E.Y., Polonikov A.V.


Aim. To study the associations of three common single nucleotide variants of the gene encoding antioxidant system enzyme, glutathione reductase GSR with a predisposition to type 2 diabetes (T2D).

Materials and methods. The observational mono-center transverse controlled study involved 1032 type 2 diabetics (640 women, 392 men; mean age 61.1±4.8 years) and 1056 healthy volunteers (676 women, 380 men; mean age 60.9±6.2 years). Eating habits were evaluated retrospectively according to questionnaire data. A 10 ml blood sample was drawn from all participants in the study for genetic and biochemical tests. Genotyping was done with the use of the iPLEX technology on MassArray System.

Results. We first identified the relationship of the polymorphisms rs2551715, rs2911678, rs3757918 of the GSR gene with a reduced risk of developing T2D in the Russian population. At the same time, the protective effects of the variants of the glutathione reductase gene manifested only in individuals with normal body weight provided they consumed fresh vegetables and fruits, whereas in those with insufficient consumption of plant foods, as well as in all overweight and obese patients, the protective effect of GSR was not observed. In patients with T2D, the plasma levels of hydrogen peroxide and the glutathione dimer were sharply increased compared with the controls. We also found that the rs2551715 polymorphism was associated with a lower concentration of hydrogen peroxide in the blood plasma of patients with T2D, while SNP rs2911678 was associated with a decrease in the concentration of the oxidized form of glutathione. Bioinformatical analysis confirmed the positive effect of alternative alleles on GSR expression and revealed the closest protein partners of the enzyme and their joint participation in the metabolism of acetyl-CoA, the catabolism of hydrogen peroxide and the control of cellular redox homeostasis.

Conclusion. Polymorphic variants of the GSR gene rs2551715, rs2911678, rs3757918 are associated with a predisposition to T2D, but their relationship with the disease is modulated by the consumption of fresh vegetables and fruits and depends on body mass index.

Terapevticheskii arkhiv. 2021;93(10):1164-1170
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Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization

Golounina O.O., Belaya Z.E., Rozhinskaya L.Y., Marova E.I., Pikunov M.Y., Khandaeva P.M., Arapova S.D., Dzeranova L.K., Kuznetsov N.S., Fadeev V.V., Melnichenko G.A., Dedov I.I.


Aim. To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome – EAS (ACTH – adrenocorticotropic hormone ).

Materials and methods. A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed.

Results. The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 – thymic carcinoid, 7 – pancreatic NET, 5 – pheochromocytoma, 1– cecum NET, 1– appendix carcinoid tumor, 1 – medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients – in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) – had relapse of the disease and 26 (20%) – died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1).

Conclusion. In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

Terapevticheskii arkhiv. 2021;93(10):1171-1178
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Type 2 diabetes and cognitive functions in patients with chronic cerebrovascular diseases

Tanashyan M.M., Surkova E.V., Antonova K.V., Lagoda O.V., Naminov A.V., Berdnikovich E.S., Fedin P.A., Titkova I.I.


Background. Type 2 diabetes (Т2DM) both directly and indirectly impacts the development of morphological and functional changes of the central nervous system.

Aim. The study was to determine clinical and neurophysiological patterns of cognitive impairment (CI) in patients with chronic cerebrovascular diseases (CCD) and Т2DM.

Materials and methods. We examined 132 patients with CCD. First group included 58 patients without Т2DM aged 64.5 [58; 72], second group – 74 patients with CCD and Т2DM 63 [57; 70]. Clinical, neurological, neuropsychological, neurophysiological (cognitive evoked potentials (EP) and neurovisualisation (brain MRI) examination was carried out to all patients.

Results. Somatic and neurological characteristics of the patients were similar in both groups with the exception of more distinct metabolic changes in Т2DM patients. Neurovisualisation study of the brain MRI in Т2DM patients revealed more distinct changes in the form of white matter hyperintensity and subarachnoidal spaces enlargement. Neuropsychological examination in patients revealed the reduction of intellectual flexibility, constructive praxis disruption, optical spatial dysfunction and deteoration of delayed word recall. Significant disorders in the way of overall cognitive impairment, lobar dysfunction and impaired verbal associative productivity, proved by statistically lower amplitude and higher latency of P300 EP peak were noted in Т2DM patients. Correlation links were detected: for P300 amplitude and direct and inverse number listing test (r=0.366 and r=0.520; p=0.006 and p<0.001 respectively); P300 latency and HbA1c (r=0.32; р<0.05) in group 2 and glucose levels in both groups (r=0.30; p<0.05); inverse relationship of latency with control functions evaluation (r=-0.34; p=0.008).

Conclusion. CCD especially with Т2DM manifests with neurocognitive imbalance, including control functions disruption and are accompanied by neurophysiological and neurovisualistion changes.

Terapevticheskii arkhiv. 2021;93(10):1179-1185
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Leptin and leptin receptor evaluation in atherosclerotic plaques in patients with type 2 diabetes mellitus

Dimitrova D.A., Mikhailov I.A., Tokarev K.Y., Michurova M.S., Gorbacheva A.M., Danilova N.V., Malkov P.G., Kalashnikov V.Y.


Background. Diabetes mellitus (DM) is a significant predictor of atherosclerosis, cardiovascular disease, and cardiovascular mortality. It is known that atherosclerosis occurs earlier in patients with diabetes, reducing the duration of their life. Leptin as well as other inflammatory markers can contribute to the progression of atherosclerosis in patients with DM, participate in the development of a local inflammatory reaction.

Aim. Determine the cells immunophenotype of atherosclerotic plaques in patients with diabetes.

Materials and methods. We analyzed 24 patients (20 men and 4 women), who underwent aortofemoral bypass, femoral-tibial bypass or carotid endarterectomy. During the operation, a fragment of the arterial wall with an atherosclerotic plaque was obtained for further immunohistochemical studies. Five histologic plaque characteristics (CD68+, α-SMA, CD34, leptin and leptin receptor) were compared.

Results. No difference in the expression of CD68 (p=0.922), α-SMA (p=0.192), CD34 (p=0.858), leptin receptor (p=0.741) and leptin (p=0.610) in atherosclerotic plaques were observed between patients with and without DM. The lack of significant differences between the two groups was possibly due to the small number of observations with DM. In particular, when assessing the expression of selected markers in atherosclerotic plaques, patients with DM showed significantly more leptin receptors than patients without DM (2160.716 and 1205.88 respectively); and also significantly less CD68+ (0.39 and 0.98 respectively) and α-SMA+ (6.5 and 13.5 respectively).

Conclusion. Based on the expression of CD68, α-SMA, CD34, leptin receptor and leptin, no significant differences were observed in atherosclerotic plaque between patients with and without DM. At the same time, despite the limitations of the study (a small number of patients, moderate severity of DM, elderly patients in the DM group), we found a tendency in the increased number of leptin receptors and a decreased number of α-SMA+, CD68+ in DM atherosclerotic plaques. Further study needed, taking into account the limitations of this work.

Terapevticheskii arkhiv. 2021;93(10):1186-1192
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Retrospective analysis of clinical outcomes of patients with COVID-19 depending on receiving antihypertensive, lipid-lowering and antihypertensive therapy

Demidova T.Y., Lobanova K.G., Perekhodov S.N., Antsiferov M.B., Oynotkinova O.S.


Background. The main factors that increase the risk of cardiovascular accidents and mortality among patients with COVID-19 include hyperglycemia, arterial hypertension and dyslipidemia. Therefore, all patients with COVID-19 and metabolic syndrome should receive antihypertensive (AHT), hypolipidemic (GLT) and hypoglycemic therapy (GGT). Currently, there is a limited number of studies regarding the effectiveness and safety of this therapy in patients with COVID-19.

Aim. Evaluate the clinical outcomes of patients with COVID-19, depending on the recipient of AHT, GLT and GGT.

Materials and methods. A retrospective analysis of the clinical outcomes "discharged/died" of 1753 patients with COVID-19 was carried out depending on the received AHT, GLT and GGT.

Results. A significant reduction in the risk of mortality among patients with COVID-19 was observed during therapy with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers – ACE inhibitors/ARBs (OR 0.39, 95% CI 0.21–0.72; p<0.05) and b-adrenergic blockers – b-AB (OR 0.53, 95% CI 0.28–1; p<0.05). At the same time, against the background of therapy with ACE inhibitors/ARBs and b-ABs, the chance of mortality decreased more significantly among patients with type 2 diabetes mellitus (T2DM) compared with patients without T2DM. Diuretic therapy was associated with a 3-fold increase in the chances of death: OR 3.33, 95% CI 1.88–4.79; p<0.05. Statin therapy did not affect clinical outcomes in COVID-19 patients. On the background of therapy with oral hypoglycemic drugs, the risk of mortality decreased 5-fold (OR 0.19, 95% CI 0.07–0.54; p<0.05). Against the background of insulin therapy, there was an increase in mortality risk by 2.8 times (OR 2.81, 95% CI 1.5–5.29; p<0.05).

Conclusion. A significant reduction in mortality among patients with COVID-19 was observed during therapy with ACEI/ARB, b-AB, and oral hypoglycemic therapy. Increased risk of death was associated with insulin therapy and diuretic therapy.

Terapevticheskii arkhiv. 2021;93(10):1193-1202
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Prognostic factors for the carbohydrate metabolism normalization in patients with type 2 diabetes mellitus and obesity using liraglutide 3.0 mg per day

Sklyanik I.A., Shestakova M.V.


Background. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are innovative drugs that effectively reduce glycemic levels and overweight in patients with type 2 diabetes mellitus (T2DM). However, the criteria for predicting the hypoglycemic effect of this group of drugs have not been practically defined.

Aim. To assess the factors contributing to the achievement the glycemia normalization in patients with diabetes mellitus and obesity by adding to antihyperglycemic therapy (AT) a drug from the GLP-1 RA group – liraglutide 3.0 mg per day.

Materials and methods. A single-center, prospective, non-randomized study was provided. The objects of the study were patients with T2DM and obesity (n=22). Liraglutide 3.0 mg per day was added to the current AT of patients. Initially, the parameters of carbohydrate metabolism, hormones of the incretin system on an empty stomach and during the mixed-meal test, insulin resistance using the euglycemic hyperinsulinemic clamp test, and body composition were studied. After 9 months of therapy, all studies were repeated and a search for possible predictors of the carbohydrate metabolism normalization was made.

Results. The body mass index of patients decreased from 42.4 [37.7; 45.0] to 35.9 [33.0; 40.9] kg/m2. Fasting blood glucose and glycated hemoglobin levels decreased from 9.02 [7.40; 11.37] mmol/L and 7.85 [7.43; 8.65]% up to 5.90 [5.12; 6.18] mmol/L and 6.40 [5.90; 6.60]%, respectively. 14 (63.6%) patients reached normoglycemia. Insulin resistance according to the clamp test did not change over the study. Basal concentrations of oxyntomodulin, glycentin and the area under the GLP-1, oxyntomodulin, glycentin curve significantly decreased 9 months after liraglutide administration. The prognostic marker of the achievement of normoglycemia during therapy with liraglutide 3.0 mg/day is the level of endogenous GLP-1>5.5 pmol/L before the appointment of arGPP-1 therapy.

Conclusion. The concentration of endogenous GLP-1 before the appointment of liraglutide therapy at a dose of 3.0 mg per day can be used for prediction the drug hypoglycemic effect and achieving normoglycemia possibility.

Terapevticheskii arkhiv. 2021;93(10):1203-1208
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The first Russian multicenter non-interventional registry study to study the incidence of vitamin D deficiency and insufficiency in Russian Federation

Suplotova L.A., Avdeeva V.A., Pigarova E.A., Rozhinskaya L.Y., Karonova T.L., Troshina E.A.


Aim. To assess the incidence of vitamin D deficiency and insufficiency among the adult population living in the regions of the Russian Federation located at latitudes from 45 to 70º.

Materials and methods. Russian multicenter non-interventional registry study using the "cross-sectional" method.

Results. In this study, 72.1% of the examined have the status of vitamin D deficiency and insufficiency, while an adequate level was diagnosed in 27.8% of cases. When assessing the degree of vitamin D deficiency depending on the season, statistically significant differences (p<0.00001) were found between the periods: vitamin D deficiency or insufficiency was observed in 84.2% of autumn and in 62.4% of spring. The highest incidence of vitamin D deficiency and insufficiency was recorded in males compared with females (p=0.013, 79 and 70.3% respectively). Vitamin D deficiency is observed in young people in the age subgroup of 18–25 years (p<0.001, 54% in the study as a whole) much more often than in older people

Conclusion. The widespread high prevalence of vitamin D deficiency in the Russian Federation is not related to geographic region of residence, but to some extent depends on the season. The high-risk group for vitamin D deficiency and insufficiency is young men. The significant role of vitamin D in the human body justifies the need to supplement and clarify a single concept for the prevention, diagnosis and treatment of conditions associated with deficiency, so higher implementation of National Clinical Guidelines is needed.

Terapevticheskii arkhiv. 2021;93(10):1209-1216
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Clinical notes

Myxedema coma. Case report

Maksimova O.V., Chobitko V.G.


A rare case of hypothyroid coma developed in a patient with diagnosed primary hypothyroidism, complicated by the development of rhabdomyolysis and prolonged oppression of the respiratory center is presented. The predominance of previous cardiovascular pathology, marked oedema syndrome, and hypercholesterolemia in the clinical picture of the disease initially directed the diagnostics of cardiac pathology, which delayed the diagnosis of hypothyroidism. This publication aims to draw clinicians' attention to hypothyroid coma as a rare complication of hypothyroidism, which in this case was “disguised” as ischemic heart disease with the development of chronic heart failure.

Terapevticheskii arkhiv. 2021;93(10):1217-1220
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Primary hyperparathyroidism and vitamin D deficiency

Runova G.E., Golounina O.O., Glinkina I.V., Fadeev V.V.


Primary hyperparathyroidism (PHPT) is the third most common endocrine disease after diabetes mellitus and thyroid pathology. Recent epidemiological and experimental data have shown that long-term maintenance of low vitamin D levels in the blood can lead to the development of hyperplastic processes in the cells of the parathyroid glands, followed by autonomous production of parathyroid hormone. In PHPT vitamin D insufficiency or deficiency according to various sources occurs with a frequency of 53–77% of cases. The literature review indicates more severe disease in patients with concomitant vitamin D deficiency. The expediency of preoperative assessment of vitamin D levels in all patients with PHPT in order to minimize the risk of hypocalcemia after parathyroidectomy is discussed. This article presents the relationship between vitamin D deficiency and PHPT, as well as possible methods for correcting vitamin D deficiency in PHPT. Molecular and cellular mechanisms of the occurrence of pathological processes in the parathyroid glands under conditions of low vitamin D levels are presented.

Terapevticheskii arkhiv. 2021;93(10):1221-1226
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Mineral metabolism and COVID-19: is there a connection?

Maganeva I.S., Gorbacheva A.M., Bibik E.E., Aboisheva E.A., Eremkina A.K., Mokrysheva N.G.


Due to global spread of COVID-19, the search for new factors that could influence its clinical course becomes highly important. This review summarize the relevant publications on the association between immune system and the main regulators of mineral homeostasis including. In addition, we have highlighted the various aspects of phosphorus-calcium metabolism related to the acute respiratory diseases and in particular to COVID-19. The data about the calcium-phosphorus metabolism in SARS-CoV-2 infection is required to understand the possible clinical implications and to develop new therapeutic and preventive interventions.

Terapevticheskii arkhiv. 2021;93(10):1227-1233
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Hyperprolactinemia in the postmenopause: versions and contraversions

Leshchenko O.Y.


The prevalence of hyperprolactinemia in postmenopausal women is unknown and has been estimated as infrequent by many studies. Prolactinomas found after menopause are usually macroadenomas and remain unrecognized for a long time due to atypical clinical signs or their absence. The growth potential of prolactinomas persists after menopause, most of them are invasive and accompanied by high prolactin levels. Treatment with dopamine agonists is usually long-term, the goals of which are to reduce tumor size, normalize prolactin levels and the negative effects of hyperprolactinemia. Treatment with cabergoline makes it possible to achieve remission of the disease in the first years after discontinuation, however, the proportion of relapses in postmenopausal women increases 5 years after discontinuation of the drug. Remission of prolactinomas is not evident in postmenopausal women. The modern management of patients with prolactinoma and/or hyperprolactinemia does not have clear positions in the postmenopausal period. Controversial issues remain: an ambiguous relationship between prolactin levels and breast cancer, there are no convincing conclusions on the improvement of bone mineral density and/or a decrease in the risk of fractures with normalization of prolactin levels, there are no data on metabolic parameters after the end of treatment with dopamine agonists, conflicting information about the relationship of prolactin levels and the severity of the manifold manifestations of the climacteric syndrome. The use of estrogen-progestin drugs in women with hyperprolactinemia/prolactinomas is also not well understood. Thus, the problem of hyperprolactinemia in the perimenopausal and postmenopausal period is underestimated and requires additional research, as well as the development of diagnostic and therapeutic strategies for potential benefits in terms of weight loss, improving insulin sensitivity, reducing the risk of fractures, maintaining sexuality and psycho-emotional well-being.

Terapevticheskii arkhiv. 2021;93(10):1234-1239
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Prevention of ischemic stroke in atrial fibrillation from the point of view of a neurologist. Standards and real clinical practice

Maksimova M.Y., Fonyakin A.V., Geraskina L.A.


The article outlines aspects of the current state of the problem of the priority choice of an oral anticoagulant for indefinite prevention of stroke and systemic thromboembolism in patients with atrial fibrillation. The advantages of direct oral angicoagulants over warfarin are presented, as well as a comparative analysis of the individual characteristics of the main direct oral angicoagulants from the point of view of personification of preventive therapy in accordance with modern treatment standards. The efficacy and safety of oral anticoagulant therapy has been reviewed in terms of the net clinical benefit. Particular attention is paid to the age-related aspects of choosing an anticoagulant for indefinite prophylaxis; an assessment of anticoagulants is presented in accordance with the FORTA concept, which regulates the use of drugs in elderly patients. In conclusion, recommendations are formulated for the choice of an anticoagulant in patients with atrial fibrillation in the most common clinical situations. As a general rule, the choice of a particular drug should be individualized based on risk factors, tolerability, net clinical benefit, patient preference, potential adverse interactions, and other clinical characteristics.

Terapevticheskii arkhiv. 2021;93(10):1240-1245
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History of medicine

The Rehberg–Tareev test in assessing the glomerular filtration rate

Bobkova I.N., Kamyshova E.S., Chebotareva N.V.


The history of glomerular filtration rate assessment is presented, an important step of which was the glomerular filtration rate evaluation by the endogenous creatinine clearance (known as the Rehberg–Tareev test). The article highlights the diagnostic value of the Rehberg–Tareev test and its place among modern methods for assessing glomerular filtration rate.

Terapevticheskii arkhiv. 2021;93(10):1246-1248
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Happy birthday to Academician of the Russian Academy of Sciences Irina Evgenievna CHAZOVA



Terapevticheskii arkhiv. 2021;93(10):1249-1249
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