The first experience of using beta-hydroxybutyrate analysis of capillary blood in the diagnosis of non-diabetic hypoglycemia in adults

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<0.001). According to the ROC analysis, the determination of BHB for differentiation the hyper- and hypoinsulinemic variants of hypoglycemia is characterized by excellent quality of model (AUC=99,1% [98,0%; 100,0%]). The BHB determination in capillary blood has the maximum diagnostic accuracy at a cut-off point of ≤ 1.4 mmol/L (Se 98.0%, Sp 96.4%, PPV 98.0%, NPV 96.4%, Ac 97.4%). Exceeding the diagnostic threshold of BHB was first recorded after 24h of fasting; at the same point, a significant difference was determined when comparing BHB indicators between two consecutive measurements (between 18h and 24h).Conclusion: The BHB determination in capillary blood is a highly sensitive and highly specific additional method for the differential diagnosis of NDH variants. The diagnostic threshold for BHB of capillary blood, which allows differentiating hyper- and hypoketonemic variants of NDH, is ≤1.4 mmol / L. It is advisable to initiate control of BHB in the blood no earlier than 18 hours after the start of the fast test

Effect of glucocorticoids on bone metabolism in replacement therapy of adrenal insufficiency. Literature review

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

Genetic predictors of insulin-producing pancreatic tumor

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

Clinical case of factitious hypoglycemia

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

Genetically determined causes of hypoglycemic syndrome in adults without diabetes

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

Autoantibodies to 21-hydroxylase as a diagnostic marker of primary autoimmune adrenal insufficiency, including at its potential and latent stages

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<0.05). High levels of anti-P450c21 AB were found in 4 (3.5%) patients of group  2; based on the results of additional hormonal testing, 50%  cases were diagnosed with the latent stage of the disease and 50% cases with the potential stage.Discussion: The sensitivity of the anti-P450c21 AB determination for AAI diagnosis in our study was higher, than in the works by other authors. We have confirmed a  time-related reduction of anti-P450c21 AB levels, whereby the strength of the correlation was higher in the subgroups with autoimmune polyendocrine syndrome type  II and, to a greater extent, autoimmune polyendocrine syndrome type I. This might be related to their different pathogenesis, with an abnormality of central immune tolerance in autoimmune polyendocrine syndrome type I and that of peripheral immune tolerance in autoimmune polyendocrine syndrome type II. According to our data, in 50% of cases, the development of AAI was preceded by the manifestation of other AIDs (in 15% of cases being multiple). Among all patients with no AAI diagnosis at the study entry, increased anti-P450c21 AB levels were found exactly in those with pre-existing AID. Thus, we have confirmed the feasibility of AAI screening primarily in a cohort of patients with other AID (especially multiple) belonging to the risk group.Conclusion: The determination of blood anti-P450c21 AB is a highly sensitive and highly specific method to diagnose AAI. The frequency of anti-P450c21 AB detection might depend on the duration of glucocorticoid treatment. Screening for early AAI stages is relevant primarily in the risk groups with multiple autoimmune disorders

SPECT/CT with ^99mTc-Tectrotide in the diagnosis of insulinoma

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

Multiplex Autoantibody Detection in Patients with Autoimmune Polyglandular Syndromes

The diagnosis of autoimmune polyglandular syndrome (APS) types 1/2 is difficult due to their rarity and nonspecific clinical manifestations. APS-1 development can be identified with assays for autoantibodies against cytokines, and APS-2 development with organ-specific antibodies. In this study, a microarray-based multiplex assay was proposed for simultaneous detection of both organ-specific (anti-21-OH, anti-GAD-65, anti-IA2, anti-ICA, anti-TG, and anti-TPO) and APS-1-specific (anti-IFN-ω, anti-IFN-α-2a, and anti-IL-22) autoantibodies. Herein, 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies or non-autoimmune endocrine pathologies and from healthy donors were analyzed. The prevalence of autoantibodies differed among the groups of healthy donors and patients with non-, mono- and multi-endocrine diseases. APS-1 patients were characterized by the presence of at least two specific autoantibodies (specificity 99.5%, sensitivity 100%). Furthermore, in 16 of the 18 patients, the APS-1 assay revealed triple positivity for autoantibodies against IFN-ω, IFN-α-2a and IL-22 (specificity 100%, sensitivity 88.9%). No anti-cytokine autoantibodies were found in the group of patients with non-APS-1 polyendocrine autoimmunity. The accuracy of the microarray-based assay compared to ELISA for organ-specific autoantibodies was 88.8–97.6%. This multiplex assay can be part of the strategy for diagnosing and predicting the development of APS

Diffusion-weighted magnetic resonance imaging in the diagnosis of pancreatic insulinoma: a clinical case

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