Vol 52, No 6 (2024)
ARTICLES
Clinical and neurological specifics of the vertebrogenic lumbosacral radiculopathy course in the patients with RS1143627 polymorphism of the IL-1β gene
Abstract
Rationale: Vertebrogenic lumbosacral radiculopathy (VLSRP) is a consequence of exposure to physical exertion, back injuries, and smoking. Genetic polymorphism of the cytokine IL-1β contributes to the progression of VLSRP due to its increased production in certain genetic variants.
Aim: To establish an association between the rs1143627 polymorphism of the IL-1β gene with VLSRP, as well as with clinical and neurological specifics of VLSRP during its treatment.
Methods: The study involved 121 patients with VLSRP aged 22 to 66 years (median, 41 [35; 49] years; men, 110 (90.91%)), treated in the in-patient Department of Neurology from January 2023 to February 2024, and 100 age- and gender compatible healthy subjects. Based on the results of clinical and neurological assessments, the indices of the Digital Rating Scale, Oswestry and Roland-Morris questionnaires were determined. The rs1143627 polymorphism was identified by real-time polymerase chain reaction (IQ5 amplifier (Bio-Rad, USA)) with the SNP-express (IL-1β-31C/T) test system (Litech, Russia).
Results: VLSRP was associated with the distribution of alleles (χ2 = 3.93; p = 0.049) and genotypes according to the dominant model (χ2 = 4.7; p = 0.032) of the rs1143627 polymorphism of the IL-1β gene. The minor T allele increased the odds ratio for VLSRP (OR 1.51; 95% CI 1.004–2.26) in the dominant model; the sum of CC + CT genotypes was also associated with increased VPSRP odds ratio (OR 1.814; 95% CI 1.056–3.115). The DRS scores under treatment showed the significant predominance of pain in the T (CT + TT) allele carriers (p < 0.001). As assessed by the Oswestry and Roland-Morris questionnaires, the minor T allele in CT + TT genotypes demonstrated prevailing everyday life activities and less effective results after a treatment course (p < 0.001). In the study subjects of ≤ 41 years of age, the multiplicative model showed a higher risk of VLSRP with the minor T allele by 1.8-fold (OR 1.80; 95% CI 1.02–3.19). In the dominant model, the sum of genotypes with the minor T allele (CT + TT) was associated with a 2.23-fold higher risk of VLSRP (OR 2.23; 95% CI 1.05–4.72).
Conclusions: We were able to find the association between the rs1143627 polymorphism of the IL-1β gene with VLSRP, with a higher risk of the disease in the patients of ≤ 41 years of age, higher DRS, Oswestry, and Roland-Morris questionnaire scores, which was related to the presence of a minor T allele and CT + TT genotypes.
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Association of rs3755319 and rs4148325 of the UGT1A1 gene, rs2328136 of the NUP153-AS gene, and rs16928809 of the SLC22A18 gene with benign unconjugated hyperbilirubinemia
Abstract
Background: Benign unconjugated hyperbilirubinemia, also known as Gilbert's syndrome, is a common in the population moderate increase in total and unconjugated bilirubin concentrations in individuals without liver disease or hemolysis.
Aim: To identify associations of rs3755319, rs4148325 of the UGT1A1 gene, rs2328136 of the NUP153-AS gene, and rs16928809 of the SLC22A18 gene with benign unconjugated hyperbilirubinemia.
Methods: This case-control study included a group of individuals with benign unconjugated hyperbilirubinemia (n = 414, mean age 36.7 ± 15.9 years, 49.8% men) and a control group (n = 381, mean age 39.1 ± 15.9 years, 52.5% men). The sample was randomly selected from the participants of the MONICA project, screening of young people aged 25–44 years and a cross-sectional study of schoolchildren in Novosibirsk. DNA was isolated from venous blood by phenol-chloroform extraction or an express assay (PROBA-RAPID-GENETICS, DNA-Technology, Russia). Genotyping of the groups by rs3755319, rs4148325 of the UGT1A1 gene, rs2328136 of the NUP153-AS gene, and rs16928809 of the SLC22A18 gene was performed by polymerase chain reaction followed by restriction fragment length polymorphism analysis.
Results: No significant differences were found between the individuals with benign unconjugated hyperbilirubinemia and the control group by the genotypes and alleles of the nucleotide sequence variants of rs16928809 of the SLC22A18 gene (p > 0.05). The CC genotype and the C allele of rs3755319 of the UGT1A1 gene were more common in the individuals with benign unconjugated hyperbilirubinemia, than in the control group (CC vs AC + AA: odds ratio (OR) = 21.1, 95% confidence interval (CI) 14.7–30.4, p < 0.001; C vs A: OR = 12.4, 95% CI 9.4–16.4, p < 0.001). The concentrations of total and unconjugated bilirubin were higher in the carriers of the CC genotype of rs3755319, compared to the carriers of the other two genotypes (p < 0.05). rs4148325 of the UGT1A1 gene was in the linkage disequilibrium with the rs3064744 UGT1A1 variant. The GG genotype and the G allele rs2328136 of the NUP153-AS gene were more common in the individuals with benign unconjugated hyperbilirubinemia than in the control group (GG vs AG + AA: OR = 1.361, 95% CI 1.002–1.848, p = 0.048; G vs A: OR = 1.33, 95% CI 1.02–1.73, p = 0.034).
Conclusion: The CC genotype and the C allele of rs3755319 of the UGT1A1 gene, the GG genotype and the G allele of rs2328136 of the NUP153-AS gene are the genotypes and alleles of risk for benign unconjugated hyperbilirubinemia. The rs16928809 of the SLC22A18 gene is not associated with benign unconjugated hyperbilirubinemia.
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Soluble galectin-4 in colorectal cancer is associated with tumor progression, but is not a predictor of the disease outcome
Abstract
Background: Galectin-4 is a member of β-galactoside-binding protein family, which is mainly expressed in gastrointestinal epithelial cells and also secreted into the extracellular environment. Studies have shown that galectin-4 is involved in the regulation of proliferation and metastasis of gastric and pancreatic cancer tumor cells. The results of studies on the clinical significance of galectin-4 in colorectal cancer (CRC) are ambiguous: some studies showed its increased expression, associated with aggressive course and unfavorable prognosis, while others showed its decrease.
Aim: To analyze the clinical significance of the soluble form of galectin-4 in CRC.
Methods: We retrospectively analyzed the medical records of 130 patients (mean age, 61 year) with a verified diagnosis of CRC, who had been examined and treated from 2016 to 2022. Galectin-4 levels were measured in serum obtained by a standard method before the start of specific treatment, by the enzyme-linked immunosorbent assay (ELISA). The control group consisted of 30 healthy donors (mean age, 53 years).
Results: The median concentration of galectin-4 in the CRC patients was higher than in the control group (531.9 [350.6–1380] pg/mL vs. 330.1 [173.0–566.4] pg/mL, p = 0.0004). The ROC analysis demonstrated maximum sensitivity and specificity of the test (66% and 67%, respectively) at a threshold value of 426.3 pg/mL (area under the curve 0.706 with 95% confidence interval 0.594–0.817; p = 0.0005). The galectin-4 levels were higher at advanced stages of the disease (p = 0.002) and in the presence of distant metastases (p < 0.0001). Cox regression analysis showed that tumor size and distant metastases were independent prognostic factors (hazard ratio (HR) = 3.87; p = 0.0439; HR = 720.4; p = 0.0062, respectively) associated with decreased survival. Galectin-4 is not a prognostic marker of CRC (HR = 2.434; p = 0.079).
Conclusion: The amounts of the soluble galectin-4 are associated with tumor progression, indicating a possible tumor-promoting function of this protein. However, its diagnostic value remains limited, as the method of serum galectin-4 determination has shown insufficient sensitivity and specificity for its routine use for the diagnosis of CRC. According to the results of univariate and multivariate analyses, serum galectin-4 is not a significant prognostic marker of CRC.
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Clinical and biochemical characteristics of patients with acromegaly and normal or increased prolactin levels
Abstract
Background: Prevalence of hyperprolactinemia in patients with acromegaly is 30 to 40%. Since recently, the necessity of screening for acromegaly in hyperprolactinemic patients with pituitary adenoma has been actively debated. The literature on this issue has been controversial, with some authors describing significant differences of clinical and biochemical parameters in acromegaly patients with normal or increased prolactin levels, while others state the absence of such differences.
Aim: To identify hallmarks of clinical and biochemical parameters in patients with acromegaly and normal or increased prolactin level.
Methods: We performed a single center, single sample retrospective, observational cohort uncontrolled non-interventional study in 306 patients (70 men and 236 women) with acromegaly examined from July 2021 to June 2024, 50 of them with a pituitary microadenomas and 256 with macroadenomas. The patients were divided into two groups: acromegaly without hyperprolactinemia (n = 234) and acromegaly with hyperprolactinemia (n = 72). The groups were compared for age, gender, clinical manifestations, insulin-like growth factor 1 (IGF1) levels, characteristics of pituitary adenomas and efficacy of the treatment. In the patients with acromegaly and hyperprolactinemia we additionally analyzed prolactin levels at disease manifestation, an association between the suprasellar adenoma growth and prolactin, and an association between prolactin levels and adenoma volume at the disease onset, before treatment.
Results: Hyperprolactinemia was significantly less common, than acromegaly without hyperprolactinemia, associated with acromegalic enlargement of the face (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.19–0.62, р < 0.001), hands and feet enlargement (OR 0.06, 95% CI 0.03–0.12, р < 0.001), but more common with visual field derangement (OR 2.8, 95% CI 1.06–7.39, р = 0.043), menstrual cycle abnormalities in women (OR 4.11, 95% CI 2.14–7.88, р < 0.001) and breast discharge (OR 18.71, 95% CI 4–87.61, р < 0.001). The patients with acromegaly and hyperprolactinemia noticed their first symptoms of the disease at a younger age (median 37 [25; 46] years vs 41.5 [32; 51.5] years, р = 0.004) and were diagnosed with acromegaly also earlier, than the patients with acromegaly without hyperprolactinemia (45 [34.5; 55] years vs 52 [42; 61] years, р < 0.001). There were no differences in the disease latency, biochemical activity of acromegaly and gender distribution. The volume of pituitary adenomas in the patients with acromegaly and hyperprolactinemia was larger, compared to that in the patients without hyperprolactinemia (4445 [1649; 7767] mm3 vs 1242 [448; 3740] mm3, р < 0.001). No correlation was found between the pituitary adenoma volume and prolactin levels. The rates of acromegaly control in both groups were not significantly different.
Conclusion: The results of our study emphasize the importance to exclude acromegaly in patients with prolactinomas and in those with suspected pituitary stalk compression (which is characterized by moderate hyperprolactinemia and suprasellar growth of the pituitary adenoma), even in the absence of pathognomic signs of increased secretion of growth hormone. Hyperprolactinemia does not affect the treatment outcomes in acromegaly, and more frequent administration of dopamine receptor agonists does not result in an increased proportion of patients with biochemical control of the main disease.
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CLINICAL CASES
Special aspects of the clinical course and replacement therapy peculiarities in a patient with autoimmune polyglandular syndrome type 1: a clinical case
Abstract
Autoimmune polyglandular syndrome type 1 (APS-1) is an extremely rare monogenic autosomal recessive disease characterized by development of multiple organ failure with predominant endocrine glands involvement. The challenges of patient management are related to low adherence to the lifelong multicomponent therapy, high risk of complications, including pneumonia, adrenal insufficiency decompensation, necrotic colitis and other acute infectious and inflammatory diseases. Due to the rarity of this disorder, clinicians lack sufficient experience with management of such patients, which could lead to delayed medical care and patient death.
Patient A., 28 years old, was followed up for 10 years in the Endocrinology clinic with the diagnosis of “Autoimmune polyglandular syndrome type 1. Mucocutaneous candidiasis. Primary hypoparathyroidism. Primary chronic adrenal insufficiency. Primary hypothyroidism. Chronic gastroduodenitis. Chronic colitis. Autoimmune alopecia.” The onset of the disease with chronic mucocutaneous candidiasis at the age below 1 year had defined the severe course of the disease, including a wide range of consequently occurring autoimmune diseases associated with recurrent episodes of decompensation of hypoparathyroidism and adrenal insufficiency, as well as the development of acute necrotic colitis at the age of 26. As an adult, the patient admitted that he had previously been insufficiently responsible and attentive to his disease and regular medication intake, with resulting episodes of adrenal insufficiency decompensation and occurrence of the symptoms related to serum calcium fluctuations. Due to abnormalities of cellular and humoral immunity, APS-1 patients are at an extremely high risk for a critical course of COVID-associated pneumonia. In 2020, the patient contracted the coronavirus infection complicated by bilateral pneumonia, followed by respiratory failure, bacterial sepsis and acute renal failure. Despite the timely hospitalization, administration of the state-of-the-art antibacterials and antifungals and all the necessary resuscitation measures, it was not possible to save his life.
This clinical observation demonstrates the difficulties of therapeutic management of APS-1 patients with an early disease manifestation, who, due to severe genetically determined impaired immunity, are at high risk of death from an intercurrent infection. The combination of several chronic comorbidities and the need to take a large number of replacement treatments require an individual therapeutic approach, as well as psychological and social adaptation of the patients, starting from their childhood and throughout the whole life, taking into account the frequent psychological problems could lead to low treatment adherence. The timely diagnostics of the disease, understanding of pathophysiology and specifics of its course could contribute to increased qualityadjusted life years of APS-1 patients.
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