Elizaveta M. Orlova’s research while affiliated with Endocrinology Research Centre and other places

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Publications (50)


Primary Generalized Glucocorticoid Resistance: a case report
  • Article
  • Full-text available

February 2024

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11 Reads

Problemy E̊ndokrinologii

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N. V. Makazan

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K. V. Ivashchenko

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[...]

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E. A. Troshina

Primary glucocorticoid resistance (OMIM 615962) is a rare endocrinologic condition caused by resistance of the human glucocorticoid receptor (hGR) to glucocorticoids (GR) and characterised by general or partial insensitivity of target organs to GK. Compensatory activation of hypothalamic-pituitary-andrenal axis results in development of a various pathological conditions caused by overstimulation of adrenal glands. Clinical spectrum may range from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At present time, primary generalized glucocorticoid resistance has been exclusively associated with defects in the NR3C1 gene. Here, we present a case report of an adolescent patient with clinical presentation of glucocorticoid resistance confirmed by detailed endocrinologic evaluation but no confirmed mutations in the NR3C1 gene.

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FAMILIAL CASE OF AUTOSOMAL DOMINANT HYPOCALCEMIA

December 2022

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8 Reads

Autosomal dominant hypocalcemia (ADH), or familial hypocalciuric hypercalcemia (FHH) is a rare hereditary disease manifested by hypocalcemia and hypercalciuria due to a malfunction of the calcium-sensitive receptor (mutations in the CASR or GNA11 genes). A familial clinical case of ADH is presented: the disease was diagnosed in a 36 y/o female and her two male children of 11 and 1.5 y/o. The disease was detected in an older child aged 7 years on the basis of convulsive syndrome, decreased blood calcium and parathyroid hormone, increased calciuria and detection of a mutation in the CASR gene (c.344-358del TTGCTCAAAACAAAA/ p.116 120delAQNKI). The initial manifestations of the disease in the form of a convulsive syndrome were observed in a child starting his 2nd day of life and were regarded as a manifestation of epilepsy, which was then followed by a long non-convulsive period. The patient needs constant therapy with alfacalcidol and has nephrocalcinosis. Based on the diagnosis made, the disease was also confirmed in his mother as the asymptomatic hypocalcemia and a mutation in the CASR gene were found. The woman does not need drug therapy, does not have nephrocalcinosis. In the youngest child, the diagnosis was suspected at birth on the basis of convulsions, hypocalcemia and was subsequently confirmed then by the detection of a mutation in the CASR gene. The course of the disease in the youngest child is severe, aggravated by the presence of perinatal CNS lesions and epilepsy. The patient has been receiving therapy with alfacalcidol since birth, has manifestations of severe nephrocalcinosis with a decrease in the filtration function of the kidneys. To stop the convulsive syndrome the patient needs to maintain a higher level of blood calcium, which is complicated due to hypercalciuria and causes chronic kidney disease. Conclusion: the observed familial case demonstrates the polymorphism of the course of the disease, and, given the rarity of the disease and the nonspecificity of manifestations, the description of this case will improve the awareness of medical practitioners of various specialties about the disease for its timely diagnosis.


Characteristics of the type I autoimmune polyglandular syndrome (APS-1) patients and results of testing serum samples for the presence of anti-omega-interferon (IFN-ω) and anti-alpha- interferon (IFN-α) autoantibodies using microarray-based, cell-based and enzyme-linked immunosor- bent immunoassays.
Cont.
Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

November 2022

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186 Reads

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5 Citations

Journal of Personalized Medicine

Autoantibodies against type 1 interferons (IFN-I) are a highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to omega-interferon (IFN-ω) and alpha2-interferon (IFN-α2) allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon, was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies or non-autoimmune endocrine disorders, and healthy individuals were analyzed. In the APS-1 patient cohort (n = 18), there was good agreement between the results of anti-IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti-IFN-I antibody positive patients.


Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

November 2022

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19 Reads

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1 Citation

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.


Figure 1. Fluorescence images of microarrays after assay with serum samples from: an APS-1 patient (a), a patient with multiple endocrine neoplasia type 1 (b). Groups of elements with immobilized IFN-ω and IFN-α-2a are indicated by solid lines.
Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

November 2022

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38 Reads

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2 Citations

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). In this study, a comparison of three different me-thods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pa-thologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.


Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy

June 2022

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51 Reads

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23 Citations

Diabetes

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein Perilipin-1 (PLIN1) in a murine model of Autoimmune Polyendocrine Syndrome 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with controls using a specific Radioligand Binding Assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17/46; 37%) particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.


Clinical guidelines «Precocious puberty»

November 2021

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369 Reads

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7 Citations

Problemy E̊ndokrinologii

The precocious puberty is an urgent problem of pediatric endocrinology characterized by clinical and pathogenetic heterogeneity. The appearance of secondary sex characteristics before the age of 8 years in girls and 9 years in boys requires timely diagnosis and the appointment of pathogenetically justified treatment in order to achieve the target indicators of final growth and prevent social deprivation. The developed clinical guidelines are the main working tool of the practitioner. They briefly and structurally present the main information about the epidemiology and modern classification of рrecocious puberty, methods of its diagnosis and treatment based on the principles of evidence-based medicine.


Autoimmune hepatitis as the first manifestation of autoimmune polyendocrine syndrome type 1 in a 5-year-old girl

September 2021

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26 Reads

Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)

Autoimmune hepatitis is a chronic inflammatory liver disease of unknown etiology; the prevalence of juvenile autoimmune hepatitis is unknown. Autoimmune hepatitis occurs in 10–20% of patients with type 1 autoimmune polyendocrine syndrome, a rare (orphan) disease, which is characterized by a clinical triad in 70–100% of cases: chronic mucocutaneous candidiasis, hypopara thy roidismand adrenal insufficiency, as well as more 25 possible autoimmune endocrine and non-endocrine manifestations. Thisstudy describes a case of a 5-year-old girl with autoimmune hepatitis as the first clinical manifestation of the disease. The symptoms of chronic mucocutaneous candidiasis enabled us to suggest and genetically confirm the diagnosis of autoimmune poly endocrine syndrome type 1 before the lesions of endocrine organs. The girl had nonsense mutations R257 * and p.Q94* of the AIRE gene in a compound heterozygous state. Later, there appeared another autoimmune disorder – common vitiligo. Timelydiagnosisoftype1autoimmunepolyendocrinesyndromeinachildwiththefirstnon-endocrine autoimmune manifestation, initiation of therapy and further medical management made it possible to preventseve recomplications and improve the patient’s quality of life.


Figure 3. Autoantibodies to PLIN1 in sera from a patient with autoimmune AGL
Perilipin-1 autoantibodies linked to idiopathic lipodystrophy in the setting of two distinct breaks in immune tolerance

September 2021

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81 Reads

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1 Citation

Background: Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Methods: Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte specific lipid droplet protein Perilipin-1 in a murine model of Autoimmune Polyendocrine Syndrome 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with controls using a specific Radioligand Binding Assay and indirect immunofluorescence on fat tissue. Results: We identified autoantibodies to the lipid-droplet protein Perilipin-1 (PLIN1) in two human case reports including the first reported case of human APS1 with acquired lipodystrophy. Further, we extend PLIN1 autoantibodies to a second non-APS1 patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Conclusion: These data suggest that PLIN1 autoantibodies may represent a unifying marker of autoimmune lipodystrophy.


Figure 2.
Pregnancy outcome in women with APECED (APS-1) – A multicenter study on 43 females with 83 pregnancies

September 2021

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55 Reads

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11 Citations

The Journal of Clinical Endocrinology and Metabolism

Context Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED or APS-1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and setting A multicenter registry-based study including five national patient cohorts. Patients 321 females with APECED. Main outcome measure Number of pregnancies, miscarriages, and deliveries. Results Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17–39). Sixty (72%) pregnancies led to a delivery, including two stillbirths (2.4%) and five (7.1%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), eight (10%), and one (1.2%) of pregnancies, respectively. Ovum donation resulted in five (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had on average four APECED manifestations (range 0–10); 78% had hypoparathyroidism and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in one case development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from one neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from pre-conceptual care until puerperium.


Citations (17)


... Registration of fluorescent images of microarrays and calculation of fluorescent signals were performed using a microarray analyzer and software developed at the Engelhardt Institute of Molecular Biology, Moscow. Interpretation of the results of analysis on a microarray with the determination of the presence/absence of auto-Abs in blood serum were performed as described previously [16,17]. ...

Reference:

Trio-based exome sequencing and high-resolution HLA typing in families of patients with autoimmune adrenal insufficiency and autoimmune polyglandular syndrome
Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

Journal of Personalized Medicine

... Fourteen studies (5 retrospective cohort studies; 9 case reports) regarding AD-associated PAI evaluated during pregnancy were included in this systematic review [27,[32][33][34][35][36][37][38][39][40][41][42][43][44]. The 4 retrospective cohort studies and the majority of the 9 case reports included pregnant women who suffered from isolated autoimmune AD with positive or negative adrenal antibodies [27,33,35,37,41,43,44]. ...

Pregnancy outcome in women with APECED (APS-1) – A multicenter study on 43 females with 83 pregnancies

The Journal of Clinical Endocrinology and Metabolism

... We recently reported that pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) underlie ∼40% of West Nile virus (WNV) encephalitis cases and ∼10% of most severe forms of tick-borne encephalitis (TBE) (Gervais et al., 2024b). Auto-Abs neutralizing type I IFNs have been shown to underlie 5-20% of cases of life-threatening pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Bastard et al., 2020(Bastard et al., , 2021a(Bastard et al., , 2021c(Bastard et al., , 2023, influenza (Zhang et al., 2022b), or Middle East respiratory syndrome (MERS) (Alotaibi et al., 2023) viruses, and about a third of severe adverse reactions to the attenuated live measles and yellow fever virus (YFV) vaccines (Bastard et al., 2021b). These findings have been replicated worldwide by many studies (Abers et al., 2021;Acosta-Ampudia et al., 2021;Akbari et al., 2023;Akbil et al., 2022;Arrestier et al., 2022;Bastard et al., 2021c;Busnadiego et al., 2022;Carapito et al., 2022;Chang et al., 2021;Chauvineau-Grenier et al., 2022;Credle et al., 2022;Eto et al., 2022;Frasca et al., 2022;Goncalves et al., 2021;Grimm et al., 2023;Hansen et al., 2023;Koning et al., 2021;Lamacchia et al., 2022;Lemarquis et al., 2021;Mathian et al., 2022;Meisel et al., 2021;Petrikov et al., 2022;Philippot et al., 2023;Pons et al., 2023;Raadsen et al., 2022;Savvateeva et al., 2021;Schidlowski et al., 2022;Saheb Sharif-Askari et al., 2023;Simula et al., 2022;Solanich et al., 2021;Soltani-Zangbar et al., 2022;Su et al., 2022;Troya et al., 2021;van der Wijst et al., 2021;Vanker et al., 2023;Vazquez et al., 2021;Wang et al., 2021;Ziegler et al., 2021). ...

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

... The presence of circulating antibodies was correlated with both a long duration of vitiligo and the onset of vitiligo at an older age, but antibody titers were not correlated with the progression, regression, or stability of vitiligo. A retrospective observational study of 700 vitiligo patients highlighted the lack of a clear difference in response to therapy or vitiligo activity in patients with other concomitant autoimmune or autoinflammatory pathologies [23] and found that forms of NSV are more commonly associated with a personal or family history of autoimmunity compared to forms of SV (segmental vitiligo) [23,38]. ...

The prevalence of autoimmune endocrine diseases in vitiligo patients

Terapevticheskii arkhiv

... Certain APECED patient cohorts carry characteristic founder variants such as the homozygous p.R257X, p.R203X, p.R139X, and p.Y85C variants seen in Finnish, Sicilian, Sardinian, and Persian Jew APECED populations, respectively 114 and primary hypoparathyroidism and developing any dyad among these three manifestations ("a classic diagnostic dyad") is used to establish the clinical diagnosis; however, a wide spectrum of other autoimmune clinical manifestations can also occur with varying frequencies including autoimmune pneumonitis, gastritis, hepatitis, enteritis, enamel hypoplasia, tubulointerstitial nephritis, Sjogren's syndrome, alopecia, nail dystrophy, vitiligo, pernicious anemia, asplenia, type-1 diabetes, thyroiditis, primary gonadal failure, growth hormone deficiency, and many others 114,115,[120][121][122][123][124][125][126] (Figure 1). Among the non-triad clinical manifestations that often occur early in the course of the disease before patients develop a classic diagnostic dyad in American APECED patients, the "APECED rash", enamel hypoplasia, and autoimmune enteritis are most prominent 115 . ...

Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1
  • Citing Article
  • July 2017

The Journal of Clinical Endocrinology and Metabolism

... An additional 4.1% of probands with homozygous variants consisted of seven children (7/169) with APECED syndrome who had a previously described hotspot variant c.769C>T (p.R257*) in the AIRE gene [21,22,23] (Fig. S1). None of their parents reported consanguinity. ...

The new immunological methods for diagnostics of type 1 autoimmune polyendocrine syndrome (the first experience in Russia)

Problemy E̊ndokrinologii

... Гораздо реже встречаются образования из остаточной надпочечниковой ткани в яичниках у женщин. Их частота менее 0,1% среди всех образований яичников [1][2][3][4]. Данные аутопсий показывают, что остаточная надпочечниковая ткань более часто встречается в чревном сплетении, яичках, широкой связке матки, нежели в яичниках, что может обусловливать редкость развития OART. Кроме того, TART чаще диагностируются у мужчин, так как могут обнаружиться пальпаторно или вызывать болевой синдром [5][6][7][8]. ...

The development of ectopic testicular adrenal rest tissue (TART) in the children and adolescents presenting with congenital adrenal cortical dysfunction

Problemy E̊ndokrinologii

... It is generally recognized that AIRE locus variability and the presence of heterozygous loss-of-function AIRE mutations can affect the presentation of self-antigens at the thymus level [19]. AIRE variants have been detected in organ-specific autoimmune conditions [20][21][22]. ...

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases
  • Citing Article
  • June 2015

Immunity

... гиперплазия надпочечников ( МикГН) -двустороннее поражение надпочечников, приводящее к избыточной продукции кортизола. МикГН является редкой патологией и составляет 0,6-1,9% АКТГ-независимого гиперкортицизма (АКТГ -адренокортикотропный гормон), из которых около 70% -семейные детерминированные формы [1,2]. По данным ретроспективных исследований, заболеваемость превалирует у лиц молодого и среднего возраста (24,2±11,0 года), патология встречается чаще у женщин, чем у мужчин, соотношение 2,3:1 [3]. ...

Carney complex - multiple endocrine neoplasia syndrome
  • Citing Article
  • June 2012

Problemy E̊ndokrinologii