Vol 48, No 7 (2020)

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

Nuralieva N.F., Yukina M.Y., Troshina E.A., Malysheva N.M., Nikankina L.V.


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.

Almanac of Clinical Medicine. 2020;48(7):445-458
pages 445-458 views

The individualized statistical analysis of the continuous glucose monitoring data

Dreval' A.V., Shestakova T.P., Manukyan A.A., Brezhneva O.G.


Background: Continuous glucose monitoring (CGM) has shown its benefits in pregnant women with diabetes. Flash glucose monitoring (FGM), as one of the CGM types, has not been well assessed in this patient group. The interpretation of a  big volume of information on glycaemia obtained with various CGM devices is possible with statistical analysis according to the algorithms proposed by manufacturers. While these algorithms cannot be comprehensive, evaluation of alternative approaches to the CGM data statistical analysis and comparison of the results obtained with different devices seem reasonable. No unified algorithm for modification of antidiabetic treatment according to the CGM results has been yet developed. This study was performed in a  pregnant patient with type  1 diabetes mellitus (T1DM) to demonstrate the methods to individualized analysis of the data from various devices (CGM, FGM, glucometer) that could be used in routine clinical practice.

Aim: To evaluate the individual advantages and disadvantages of the simultaneous use of FGM, CGM and SMBG in a pregnant woman with type 1 diabetes.

Materials and methods: This was an observational case study with a retrospective assessment of the patient's data obtained with FGM, CGM and a glucometer in a 31-year female patient with T1DM of 6-year duration and 9 weeks of gestation, who had been on pump insulin therapy for one year and had an HbA1c level of 5.4%. During the study the patient continued her pump therapy and performed blood glucose self-monitoring (BGSM) and simultaneously used FGM and CGM. The following FGM data were compared with CGM and glucometer results: measurement numbers, time in range, mean daily glucose, mean absolute difference (MAD), and mean absolute relative difference (MARD).

Results: The FGM-derived mean daily glucose was lower than that measured with the glucometer: 5.1±1.9  mmol/L vs 6.4±2.2  mmol/L (p<0.001). The number of measurements with FGM was 32.0±12.9  times daily and with a  glucometer 15.1±5.5  times daily (p<0.001). MAD values were minimal in the hypoglycemic range (0.5±0.3  mmol/L) and maximal in the hyperglycemic range (1.6±1.2 mmol/L, р<0.001). The MARD values were significantly smaller in the hyperglycemic than in the normoglycemic (16.6±12.6% vs 21.3±14.0%, р=0.035). The highest MAD and MARD were observed on the Day 1 of the sensor installation. The comparison of FGM and the glucometer readings with the Clarke consensus error grid showed that 82% of the FGM readings were in zone A or B. The FGM accuracy was higher from Day 2 to Day 9 (72.5% of the FGM readings in zone A). MAD between FGM and CGM readings was not different from that between FGM and the glucometer: 1.3±1.0  mmol/L and 1.2±0.9  mmol/L, respectively (p=0.09). MARD for the FGM and CGM comparison was higher than that for FGM and glucometer comparison: 24.4±23.0% and 18.8±13.5%, respectively (р<0.001). The Pearson's correlation coefficient FGM and CGM seemed lower than that between FGM and the glucometer (0.837 and 0.889, respectively). FGM has identified more hypoglycemic events compared to CGM: time below range was 29.4% and 8.8%, respectively, p<0.001).

Conclusion: The FGM readings highly correlate with the glucometer. The FGM difference with the glucometer was lower in the hypo- and hyperglycemic ranges. FGM shows higher values for time below range than CGM. It is necessary to continue the study of the clinical acceptability of FGM in pregnant women and determination of its optimal regimen for the treatment of this patient category, as well as to develop an algorithm for treatment modification based on the results of FGM.

Almanac of Clinical Medicine. 2020;48(7):459-468
pages 459-468 views

Glucose variability in pregnant women with newly diagnosed hyperglycemia

Plekhanova M.A., Burumkulova F.F., Petrukhin V.A., Budykina T.S., Panov A.E.


Background: High-performance parallel next-generation sequencing (NGS) allows for identification of various maturity-onset diabetes of the young (MODY) subtypes also during pregnancy. As this method is expensive and time-consuming, it has proposed to use various predictors for the diagnosis of mutation in the hexokinase (GCK)/MODY2 gene, helping to select the patients for subsequent molecular genetic testing. Hyperglycemia due to MODY2 is commonly newly diagnosed during pregnancy; therefore, there is a search for factors specific to this mutation in pregnant women.

Aim: To evaluate blood glucose variability in pregnant women with newly diagnosed hyperglycemia at early gestation and to determine the threshold value of the glycemic variability coefficient for pregnant women with a mutation in the GCK/MODY2 gene.

Materials and methods: This observational single center study included 41  pregnant women with newly diagnosed early hyperglycemia (not meeting the criteria for manifest diabetes mellitus). Molecular genetic testing was performed in all of them. According to its results, they were retrospectively categorized into two groups: with early gestational diabetes mellitus (GDM, no mutations) and with hyperglycemia related to a mutation in the GCK/MODY2 gene. A comparative analysis of glycemic variability in the two groups was performed. Sensitivity and specificity of the cutoff value for the coefficient of variability as a diagnostic marker of MODY2 were also calculated.

Results: The pregnant women with GDM had significantly higher age and body mass index (BMI) than those with MODY2 (p<0.05). There were significant differences in venous fasting plasma glucose and glycated hemoglobin, with these parameters being higher in the pregnant women with MODY2 (p<0.05). In the patients with a  mutation in the GCK gene, hyperglycemia was diagnosed earlier and insulin therapy was started earlier during pregnancy than in those with GDM (p<0.05). The ROC analysis of the diagnostic accuracy of the variability coefficient showed that at the threshold CV (coefficient of variation) value of 20.8, the area under the curve was 0.742 (95% confidence intervals 0.597 to 0.888; p<0.005), with the sensitivity of 65% and the specificity of 65.4%.

Conclusion: The calculated sensitivity of 65% and specificity of 65.4% for the CV of 20.8 do not allow for its use as an independent selection criterion for subsequent confirmation of MODY2. However, its combination with the A.J. Chakera criteria (BMI<25 kg/m2 and fasting glucose≥5.5  mmol with 68%  sensitivity and 96%  specificity) allows to clarify the category of pregnant women with newly detected early hyperglycemia, to whom the search for mutations in the GCK gene should be recommended.

Almanac of Clinical Medicine. 2020;48(7):469-475
pages 469-475 views

Analysis of treatment satisfaction and adherence among patients with type 2 diabetes

Kalashnikova M.F., Bondareva I.B., Likhodey N.V., Sych Y.P.


Background: Low treatment adherence in patients with type 2 diabetes mellitus (T2DM) hinders the effective use of anti-diabetic agents and the achievement of glycemic control, reducing their quality of life and outcomes. Assessment of treatment adherence can help to identify and manage factors and barriers that affect therapy and treatment satisfaction.

Aim: To assess the treatment adherence of patients with T2DM, to identify the main barriers to adherence, and patient satisfaction with the treatment.

Materials and methods: FORSIGHT-T2DM was a  Russian multiregional, multicenter observational epidemiological study in 2014 patients with T2DM. The patients were assessed with the FORSIGHT- T2DM Patient Questionnaire, Moriski Medication Adherence Scale (MMAS), and Diabetes Treatment Satisfaction Questionnaire (DTSQ).

Results: The mean (± SD) treatment adherence estimated using the MMAS was 5.86±1.39 points. The main barriers to adherence were high treatment costs, medication side effects, forgetfulness when taking drugs, complexity of the therapy or treatment regimen. The average number of daily medications was four. There was also a lack of contact with a doctor, poor awareness of the disease and its complications. Ninety (90) per cent of the respondents trusted the recommendations from their doctors, 7.6% followed the advice of relatives or friends. The patient's choice of medication was influenced by information about its effectiveness, its cost, and reimbursement, ease of administration, and information on the absence of side effects. Seventy eight (78) per cent of the respondents were “completely” or “rather” satisfied with their treatment. About 15% of patients rated the quality of care as unsatisfactory.

Conclusion: The results of the study identified an intermediate level of treatment adherence in most patients with T2DM, as well as multiple adherence barriers, including comorbidities and the need for continuous intake of various agents. Most patients showed high treatment satisfaction, which could be due to the high availability of outpatient consultations by an endocrinologist and inpatient treatment, free access to anti-diabetic medications. However, it may also be a  result of biased assessment of problems due to insufficient patient awareness of the therapy goals and a low level of knowledge about their disease. To study the factors affecting the adherence to medical recommendations among patients with T2DM, it is necessary to develop a  specific questionnaire for this patient category, which would allow for an evaluation both drug intake and other aspects of their comprehensive treatment, including the identification and analysis of the main barriers to adherence.

Almanac of Clinical Medicine. 2020;48(7):476-486
pages 476-486 views

Basal level of luteinizing hormone as a key marker of the idiopathic central hypogonadism in women

Loktionova A.S., Ilovayskaya I.A.


Background: Central hypogonadism (CH) is a syndrome characterized by low levels of peripheral sex steroid hormones due to the lack of central (hypothalamic-pituitary) regulation of reproductive system. In females, CH clinically manifests by amenorrhea, anovulation, and infertility. The classical diagnostic criteria of CH in the absence of organic disease of hypothalamic-pituitary region (“idiopathic” CH) include low gonadotropin levels; however, their levels within the reference ranges do not exclude CH. Moreover, reference ranges for these parameters are different between laboratories. Thus, currently no clear laboratory diagnostic criteria for female CH are available.

Aim: To determine the diagnostic value of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) basal levels for the confirmation of CH diagnosis in women and to identify cutoffs of basal gonadotropins levels, which can be considered as diagnostic criteria for female CH.

Materials and methods: This cross-sectional study included 87 women: 49 with confirmed CH, aged 18 to 36 years (median, 24 [Q21; Q29]), and 38 healthy fertile women with regular menstrual cycles aged 21 to 45 years (median, 23 [Q23; Q28]). In all subjects, LH, FSH, estradiol, testosterone, prolactin, and free thyroxin levels were measured by chemiluminiscent immunoassay.

Results: LH, FSH, estradiol, and prolactin levels in the CH patients were significantly lower than those in healthy subjects. The ROC analysis showed that LH level ≤ 1.95 ME/l indicated the central genesis of hypogonadism with sensitivity of 81.25% and specificity of 91.89%. Basal FSH level ≤ 5.075 ME/l had a 70.00% sensitivity and 77.14% specificity for CH diagnosis.

Conclusion: Basal LH level ≤ 1.95 ME/l measured by chemiluminiscent immunoassay can be considered as an idiopathic CH diagnostic criterion in female with amenorrhea due to the hypoestrogenemia with sensitivity of > 80% and specificity > 90%.

Almanac of Clinical Medicine. 2020;48(7):487-493
pages 487-493 views


A clinical case of partial androgen resistance syndrome (Reifenstein syndrome)

Dzeranova L.K., Pigarova E.A., Ivannikova E.V., Kurilo L.F., Chernykh V.B., Polyakov A.V.


In the paper we describe a clinical case and provide integrated clinical and laboratory data of a  patient with partial androgen resistance syndrome. A 25-year-old male was referred for medical evaluation for an infertile marriage. After a  comprehensive assessment, he was diagnosed with hypergonadotropic hypogonadism, coronal hypospadia, left-sided varicocele, and oligoasthenoteratozoospermia. Cytogenetic analysis showed normal male karyotype (46,XY). Molecular genetic analysis identified the c.731_736delCGGTGT mutation in the exon 1 of the androgen receptor (AR) gene, what allowed for making a diagnosis of Reifenstein syndrome. In addition, we give a brief literature review of the clinical conditions associated with abnormal androgen sensitivity and discuss the problems of testing and counseling of patients with partial androgen resistance syndrome.
Almanac of Clinical Medicine. 2020;48(7):494-499
pages 494-499 views

The role of sodium-glucose cotransporter 2 inhibitors in the treatment of type 2 diabetes: from clinical research to real practice

Misnikova I.V., Kovaleva Y.A., Gubkina V.A.


In type 2 diabetes mellitus (T2DM), the development and progression of cardiovascular diseases occurs, which allows it to be considered as a cardiorenal metabolic syndrome. This should be taken into account when choosing hypoglycemic drugs. Patients with T2DM receiving insulin therapy often have a long history of diabetes, cardiovascular disease, chronic kidney disease, obesity, and need to be prescribed high doses of insulin and/or complex insulin therapy regimens to maintain glycemic control, which does not always lead to the achievement of target levels of glycemia and glycated hemoglobin (HbA1c). Adding to any insulin therapy regimen drugs from the class of sodium-glucose cotransporter type 2 inhibitors (SGLT-2), which have proven their cardio- and renoprotective properties, seems to be a rational combination in patients with T2DM and may have a number of advantages. The article presents 4 clinical examples of dapagliflozin administration, a drug from the SGLT2 class, to patients who are on insulin therapy, having T2DM with a  long history (10–26 years), as well as cardiovascular diseases, chronic kidney disease, and obesity. Dapagliflozin administration allowed to improve glycemic control, to stabilize the insulin dose, as well as reduce body weight without increasing the frequency of serious episodes of hypoglycemia in patients who initially received large doses of insulin. In the long term, we can expect reduction of the progression of cardiovascular risks and the risks of hospitalization due to existing complications of the disease.

Almanac of Clinical Medicine. 2020;48(7):500-509
pages 500-509 views

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