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BACKGROUND: Recent clinical descriptions have shown that in adult patients, the cause of nondiabetic hypoglycemia (NDH) may be various genetically determined disorders of glucose metabolism or insulin synthesis/bioavailability. In this connection, in adult patients with NDH of unclear genesis, it is important to conduct a genetic study in order to search for mutations in genes associated with congenital disorders of glucose metabolism (CDGM).AIM: To evaluate the effectiveness of genetic testing to exclude CDGM in adult patients with idiopathic NDH.MATERIALS AND METHODS: Based on the analysis of the literature, a targeted panel has been developed, including 30 genes, mutations in which are associated with the following groups of diseases: 1) congenital hyperinsulinism (KCNJ11, ABCC8, GLUD1, HADH, UCP2, HNF4A, HNF1A, GCK, INSR, SLC16A1); 2) glycogen storage diseases (AGL); 3) other carbohydrate metabolism disorders (ALDOB, FBP1); 4) glycosylation defects (PMM2, ALG3, PGM1, MPI); 4) defects in fatty acid oxidation (ACADM, ETFA, ETFB, ETFDH, FLAD1, SLC25A32, SLC52A1, SLC52A2, SLC52A3); 5) disorders of ketone body metabolism (CPT1A, CPT2, HMGCL); 6) mitochondrial disorders (DLD). Twenty nine patients (n=29: with idiopathic NDH n=17 and with insulinoma n=12) aged 19 to 66 years underwent a genetic study using this custom panel.RESULTS: As a result of the examination 12 genetic variants (all heterozygous) were identified in 8 patients with idiopathic NDH (47%, 95% CI (23%; 72%)), at that two mutations were detected in three patients: in the genes AGL and HMGCL; ACADM and FLAD1, respectively; and one patient had three mutations: one mutation in the ETFA gene and two mutations in the ABCC8 gene. Frequencies of genetic variants: AGL — 18%, 95% CI (4%; 43%), ETFA — 12% (1%; 36%), HMGCL — 6% (0%; 29%), ALDOB — 6% (0%; 29%), CPT1A — 6% (0%; 29%), ABCC8 — 6% (0%; 29%), ACADM — 6% (0%; 29%), FLAD1 — 6% (0%; 29%). 5 genetic variants (all heterozygous) were identified in 5 patients with insulinoma (42%, 95% ДИ (15%; 72%)). Frequencies of genetic variants: ABCC8 — 17%, 95% CI (2%; 48%), HNF1A — 8% (0%; 38%), ETFDH — 8% (0%; 38%), MPI — 8% (0%; 38%). We did not include benign variants in this analysis. At the same time, clinically significant variants were identified only in one patient from the group with idiopathic NDH (6%, 95% CI (0%; 29%)) in the ABCC8 gene and in one patient from the group with insulinoma (8%, 95% CI (0%; 38%)) in the same gene congenital hyperinsulinism (CHI).CONCLUSION: A panel of 30 genes has been developed, variants of which are associated with a CDGM. The results of our study confirm the possibility of detecting CDGM in adulthood, in particular CHI, and indicate the need for genetic testing, primarily in patients with idiopathic NDH.

BACKGROUND: Artificial hypoglycemia (ArH) is a decrease of blood glucose levels less than 3 mmol/l due to the deliberate use of hypoglycemic drugs by a patient outside of medical appointments. Timely diagnosis of this kind of hypoglycemia avoids unnecessary numerous examinations and hospitalizations. However, the detection of ArH still remains an extremely difficult task for both the healthcare facility and the attending physician. The foreign literature describes cases of successful detection of deliberate intake of oral hypoglycemic drugs (OHD) using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). Thus, it is relevant to develop and validate a method for determining OHD using HPLC-MS/MS.AIM: To optimize the diagnosis of ArH due to the use of OHD.MATERIALS AND METHODS: A total of 92 patients were examined. The development of the HPLC-MS/MS method for the detection of the studied OHD (sOHD; n=1-glibenclamide, n=1-gliquidone, n=1-gliclazide, n=1-glimepiride, n=1-glipizide, n=1-nateglinide and n=1-repaglinide) in the blood was carried out in a group of patients with diabetes mellitus type 2 (n=7) who received sOHD, and a group of conditionally healthy people who did not receive any medications (n= 7). To validate the method, the determination of sOHD substances was carried out on groups of patients with hyperinsulinemic nondiabetic hypoglycemia (NDH) of unknown origin (n=11) and with insulinoma (n=67).RESULTS: In the study of blood samples by HPLC-MS/MS in the group of patients with diabetes mellitus type 2, was confirmed in 100% of the cases the use of the drug that the patient received, in the group of conditionally healthy — sOHD were not detected. A false positive result was not obtained in any conditionally healthy and in any patient with insulinoma. ArH was diagnosed in 5 out of 11 patients in the group with hyperinsulinemic NDH of unknown origin, the method identified sOHD glibenclamide and gliclazide in the patients’ blood samples. In the remaining 6 patients of this group, examinations were continued and other causes of NDH were diagnosed. The sensitivity of the method was 100% [74%; 100%], specificity — 100% [95%; 100%].CONCLUSION: The HPLC-MS/MS method has high diagnostic accuracy in the detection and identification of sOHD (glibenclamide, gliquidone, gliclazide, glimepiride, glipizide, nateglinide and repaglinide) in blood samples of patients receiving these drugs. Currently, due to the low availability of the method, this study is advisable to use in patients with hyperinsulinemic hypoglycemia with negative results of first-line insulinoma imaging methods (computed tomography with contrast enhancement, ultrasound and magnetic resonance imaging of the abdominal cavity).

BACKGROUND: It is known that insulinoma in approximately 5% of cases is associated with multiple endocrine neoplasia type 1 syndrome (MEN1), in which the prognosis and management tactics of patients have been developed in detail. The diagnosis of MEN1 often does not require genetic confirmation, since the syndrome has a typical clinical picture. At the same time, a combination of this tumor with other hereditary syndromes is found in the literature, which are characterized by the presence of malignant neoplasms of various localizations, primary multiple lesions, hormonal and other disorders. Thus, it is relevant to search for the genetic causes that cause the development of insulinoma, in addition to MEN1.AIM: to evaluate the frequency of detection of genetic causes of the development of insulin-producing tumors of the pancreas, in addition to MEN1; to analyze the phenotypic characteristics of patients with such tumors.MATERIALS AND METHODS: Based on the analysis of literature for the period up to 2020, a panel has been developed that includes coding regions of 10 genes (MEN1, VHL, TSC1, TSC2, KRAS, YY1, CDKN2A, MLH1, ADCY1, CACNA2D2) involved in the development of insulinoma. In 32 patients diagnosed with insulinoma, verified by pathomorphological examination, with the absence of clinical and/or genetic data indicating MEN1 syndrome, a panel of genes was sequenced with subsequent analysis of the identified genetic variants and phenotypic data obtained from the medical records of patients. In one patient, an additional molecular genetic study of the «Endom» panel was performed, revealing genetic variants of coding regions of 377 genes associated with endocrine diseases.RESULTS: In 8 patients (25%, 95% CI (11%; 43%)), 9 variants of mutations were identified that were not classified as benign, at that two mutations in the TSC2 gene were detected in one patient. Frequencies of genetic variants: TSC2 — 13%, 95% CI (4%; 29%), MEN1 — 6% (1%; 21%), MLH1 — 3% (0%;16%), CDKN2A/P16INK4A — 3% (0%;16%). When comparing patients with the identified mutation, with the exception of benign (n=8), and patients without mutation or with a benign mutation (n=24), there were no differences in the Grade (degree of differentiation), Ki67 proliferation index, frequency of concomitant tumors, burdened history, multiple pancreatic lesions or recurrence of insulinoma, however, patients with germinal mutation were found at the level of statistical trend to be younger at the manifestation of insulinoma and to have bigger tumors. In a patient who underwent an additional molecular genetic study using the new «Endome» panel, previously undescribed gene variants (APC and KIF1B) associated with various sporadic tumors, including endocrine ones, were identified.CONCLUSION: A panel of 10 genes has been developed, mutations of which are associated with insulinoma. A relatively high incidence of genetically determined insulinoma was determined (25% of cases), in half of cases — against the background of tuberous sclerosis. We consider it relevant to evaluate the effectiveness of genetic testing for patients with insulinoma. We believe that, first of all, patients with a high risk of hereditary pathology should be examined: with the manifestation of the disease at a young age and with a large tumor. The identification of a genetic mutation will make it possible to determine the prognosis of the disease, optimize the monitoring algorithm in order to timely identify concomitant diseases-components of the hereditary syndrome, and conduct genetic counseling of the family.

BACKGROUND: Insulinoma is a pancreatic neuroendocrine tumor that manifests by impaired carbohydrate metabolism with the development of hypoglycemic syndrome. The instrumental methods used at the present stage do not always make it possible to identify a tumor; moreover, the data obtained often contradict each other. Thus, the search for new possibilities of visualization of insulinoma is relevant.AIM: Evaluation of diagnostic effectiveness of scintigraphy with single-photon emission computed tomography combined with X-ray computed tomography (SPECT/CT) with 99mTc-Tectrotide for insulinoma in a Russian cohort of patients.MATERIALS AND METHODS: A single-centre (Endocrinology Research Centre of the Ministry of Health of the Russia), experimental, single-stage, controlled study. In the years 2017–2021 patients with pancreatic insulinoma (group 1) and hyperinsulinemic hypoglycemia of a different genesis (group 2) with negative or contradictory results of the 1st line imaging methods (ultrasound, magnetic resonance imaging (MRI), computed tomography (CT)) were included. All participants underwent the whole-body scintigraphy and low-dose SPECT/CT with 99mTc-Tectrotide (500–900 MBq). The studies were performed on a tomograph of the SPECT/GE Discovery NM/CT 670 using low-energy high-resolution collimators (LEHR) in the «whole body» mode.RESULTS: In the group 1 (n=21), according to the results of a pathomorphological study, the presence of 26 insulin-producing tumors was confirmed. Group 2 included 9 patients. According to the SPECT/CT with 99mTc-Tectrotide, 14 tumors were diagnosed in group 1 out of 26 insulin-producing tumors of the pancreas, and negative results were obtained in group 2 in 100% of cases. Thus, the sensitivity and specificity of the method were: 54%, 95% CI [33%; 73%] and 100%, 95% CI [68%; 100%], respectively.CONCLUSION: SPECT/CT with 99mTc-Tectrotide can detect insulinoma in 54% of cases with negative or contradictory results of 1st-line imaging methods (ultrasound, MRI, CT). This study can be effectively used as an alternative to SPECT/CT with 111In-octreotide, as a 2nd-line method for topical search for an insulin-producing pancreatic tumor.

Stress induced hyperglycemia is a transient increase glucose blood level during the acute phase of ischemic stroke. Hyperglycemia enhances initiated by cerebral ischemia neuronal death, blood-brain barrier destruction, leads to hemorrhagic transformation, promotes the formation of brain edema. This increases the size of ischemic penumbra and increases the severity of neurological deficit. Stress hyperglycemia as a consequence of stress-realizing system activation is a significant pathogenetic link in ischemic stroke patients.

Background: The diagnostic threshold of β-hydroxybutyrate (BHB) at the moment of hypoglycemia in insulinoma was developed for venous blood many years ago, when there were no alternative ways to measure ketones. Number of works, mainly on patients with diabetes mellitus, found differences in the measurement of this indicator in venous and capillary blood, but the results were contradictory. Moreover, this study was not previously used in the diagnosis of non-diabetic hypoglycemia (NDH) in adults on the territory of the Russian Federation.Aim: To estimate the effectiveness of the method for determining BHB in capillary blood and its place in the diagnosis of NDH.Materials and methods: We conducted an experimental, cross-sectional, comparative study and included patients with suspected NDH who underwent a standard fast test. The BHB level in capillary blood was determined every 6 hours during the fast test and at its completion.Results: Based on the results of the fast test, the participants (n=154) were divided into groups: with hyperinsulinemic variant of NDH and IFRoma (n=98; group 1), with hypoinsulinemic variant of NDH /absence of NDH (n=56; group 2). When comparing the level of BHB at the moment of fasting completion, significant differences were obtained between groups 1 and 2 (p

Rationale: In Russia, assessment of anti-P450c21 antibodies (AB) in the diagnosis of autoimmune adrenal insufficiency (AAI) has not been commonly used, and the disease screening has not been implemented.Aims: 1) To determine the sensitivity and specificity of anti-P450c21 AB determination in the AAI diagnosis; 2) To estimate the prevalence of anti-P450c21 AB carriage in patients without AAI.Materials and methods: Anti-P450c21 AB were assessed in 40 patients (group 1) with manifest AAI; 171 patients without established diagnosis of AAI, including 113 subjects with autoimmune thyroid disorders or type 1 diabetes mellitus (AID, group 2); 25 carriers of AB markers of thyroid AID and/or type 1 diabetes mellitus without any target organ dysfunctions (group 3); 33 patients with non-autoimmune endocrine disorders (group 4), and 25 healthy individuals (group 5).Results: Determination of anti-P450c21 AB for the diagnosis of AAI had 95% sensitivity, with specificity of 100%, predictive value of a positive result of 100%, and predictive value of a negative result 92.6%. Anti-P450c21 AB were inversely correlated with the duration of glucocorticoid replacement therapy (r=-0.222, p

Adrenal insufficiency (AI) is a syndrome caused by disturbance in the synthesis and secretion of hormones of the adrenal cortex, which ensure the vital activity, energy and water-salt homeostasis. The widest hormonal deficiency is observed in primary hypocorticism, when the synthesis of not only glucocorticoids (GC) and adrenal androgens, but also mineralocorticoids is disrupted. Lifelong replacement therapy with GCs for this pathology may be associated with a risk of bone loss and osteoporosis. However, at present, there are no clear guidelines for diagnosis of bone condition, including and bone mineral density (BMD) monitoring during treatment with GCs in patients with AI. This review summarizes collected data on the key pathogenetic links of glucocorticoid-induced osteoporosis, incidence of decreased BMD and fractures in patients with AI. In this review factors that influence bone metabolism in this cohort of patients are considered: the type and the dose of prescribed GCs, the type (primary, secondary, HH in congenital adrenal cortex dysfunction) and the duration of AI, age, gender, and the presence of concomitant endocrine disorders (hypogonadism, growth hormone (GH) deficiency). In addition, the review presents data on the effect of adrenal androgen replacement therapy and recombinant GH therapy on bone metabolism in secondary AI.

Vitiligo is a common polygenic autoimmune disease in which the foci of depigmentation are formed on the skin and/or mucous membranes as a result of the death of melanocytes. There are several hypotheses for the pathogenesis of the disease, the leading role among them is played the autoimmune hypothesis. This review summarizes the available literature data on the prevalence and structure of comorbid endocrine autoimmune pathology in vitiligo patients. In most studies conducted in Europe, America and Asia the prevalence of autoimmune thyroid diseases (including autoimmune thyroiditis and Graves disease), diabetes mellitus and autoimmune adrenal insufficiency was higher in vitiligo patients than in the general population. The results of some studies indicate a frequent association of vitiligo with autoimmune polyglandular syndromes. In the structure of comorbid pathology the highest prevalence was in autoimmune thyroid diseases. A number of studies have established a higher prevalence of autoimmune endocrine diseases in women, as well as in nonsegmental vitiligo patients and in cases of family history of vitiligo and/or other autoimmune diseases. In addition, it was shown that the prevalence of endocrine diseases increases with increasing area of depigmentation. The data obtained justify the advisability of conducting a timely examination of vitiligo patients with the aim of early detection of comorbid diseases and the appointment of appropriate treatment. Further studies are needed to investigate the effect of the identified associations on the course of vitiligo and comorbid endocrinopathies, as well as the effectiveness of therapy and the quality of life of patients.

Hypoglycemic syndrome (HGS) is a significant decrease glucose in blood, manifested by neurological symptoms, and stopped by the introduction of glucose. Among the many causes of HGS the special place is taken by the factitious hypoglycemia, as one of the variants of Munchausen syndrome. Hypoglycemia in such cases is achieved by the intentional introduction of hypoglycemic drugs. The most commonly used medications are sulfonylurea derivatives, which are affordable, inexpensive and legal. The close collaboration of clinicians with the laboratory service plays a key role in the diagnosis of factitious hypoglycemia. Since the results of biochemical and hormonal analyzes in patients with hypoglycemia due to reception of oral hypoglycemic medications and pancreatogenous HGS are identical, the only way to differentiate these conditions is by detection of insulin secretagogue substances in the blood (or urine).The determination of oral hypoglycemic medications in cases of suspicion of artificial reception is not implemented in Russia. Factitious hypoglycemia in most cases is the diagnosis of exclusion, and its confirmation if often based on detection of medications among the personal effects of patient. This is a significant difficulty given the ethical standards. However, since 2018 we conduct in our Centre the determination of 7 oral hypoglycemic medications (glibenclamide, gliquidone, gliclazide, glimepiride, glipizide, nateglinide and repaglinide) in patient’s blood using the liquid chromatography–tandem mass spectrometry (LC-MS). This article presents a clinical case of a patient without diabetes mellitus taking glibenclamide and detection of this drug using highly selective LC-MS.

Insulinoma is the most common functioning tumor of the pancreas. Approximately 5% of its cases are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), caused by mutation in the MEN1 gene. MEN1 can be manifested by pituitary and parathyroid adenomas, pancreatic neuroendocrine tumors, tumors of the thyroid gland, adrenals, intestine, carcinoids of lungs and other organs. However, in 5–10% of the patients with clinical manifestation of this syndrome, MEN1 mutations cannot be identified. Moreover, the disease can be caused by various abnormalities (mutations, polymorphisms, etc.) in other genes. More than 30 genes, associated with insulin-producing pancreatic tumors, have been described in the literature. With a known germinal mutation, the prognosis and management of patients with insulinoma can be determined by the hereditary disease with which the tumor is associated. The article emphasizes the need to search for new genetic markers that predispose to the development of insulinoma. The necessity of extended genetic testing of patients with insulinomas is discussed, primarily of young patients with multifocal lesions, family history and associated disorders.

The topical diagnosis of insulinoma continues to be an actual problem of modern medicine due to low detection rate of the tumor (about 75%) and inconsistent data on its localization when using various methods of visualization (more than in 50% of cases), as well as the lack of a single diagnostic algorithm. In the clinical practice, many different imaging assessments are conducted, including those with the administration of contrast agents and associated with radiation load, as well as invasive studies, associated with risk of various complications, high costs and duration of the examination. Thus, the search for highly sensitive and safe methods of topical diagnosis of the insulin-producing pancreatic tumor seems relevant. In the presented clinical case, the diagnosis of insulinoma is verified by diffusion-weighted magnetic resonance imaging (DW-MRI). It is an accurate and non-invasive method that does not involve exposure to ionizing radiation and does not require any administration of contrast agents. This technology, based on microstructural pathological changes, allows to identify small tumors and to make a differential diagnosis of benign and malignant neoplasms. However, at present the experience of DW-MRI use for the diagnosis of an insulin-producing neuroendocrine tumor is limited. Evaluation of its effectiveness in a large patient cohort would be necessary to assess the prospects for its introduction into clinical practice.

Hypoglycemic syndrome is a symptom complex that results from low blood sugar levels. In the endocrinologist practice, an insulinoma that is a small tumor in the pancreas that produces an excess amount of insulin is regarded as the main cause of hypoglycemia in patients without diabetes mellitus. Various molecular and genetic disorders develop in the insulinoma tissue, that lead to a change in the secretion of insulin and its precursors.There is often a situation when it is not possible to establish the cause of lowering blood glucose levels. In such cases, the development of hypoglycemia can result from various genetically determined enzyme, autoimmune and receptor disorders that cause a change in glucose metabolism or the synthesis/bioactivity of insulin. In the mild course of such congenital diseases, hypoglycemic conditions may first manifest in adulthood.The review describes various genetic predictors (mutations) that play a decisive role in the development of enzyme, autoimmune, receptor and proliferative disorders and, as a consequence, hypoglycemia.

It is known that adrenal insufficiency (AI) is a severe life-threatening disease due to the exceptional role of glucocorticoids and mineralocorticoids in the human body. At the same time, according to some reports, the deficit of androgens synthesized by the adrenal cortex (dehydroepiandrosterone - DHEA and dehydroepiandrosterone sulfate - DHEAS) is associated with an increased risk of death, including increased risk of adverse cardiovascular events, development of osteoporosis, diabetes mellitus and malignant neoplasms. The main source of DHEA and DHEAS in females are adrenal glands, so women with hypocorticism have significantly reduced (down to undetectable) levels of these hormones. However, due to lack of a reliable evidence and, accordingly, clinical recommendations, correction of androgen deficiency in patients with AI is usually not performed. The review discusses the accumulated data on the physiological significance of DHEA and DHEAS, their role in the development of various pathological conditions, as well as safety and efficacy of these drugs.