Vol 63, No 4 (2017)

Clinical endocrinology
Insulinoma: diagnostic features and treatment management
Khacimova L.S., Karonova T.L., Tsoy U.A., Ianevskaia L.G., Grineva E.N.

Background. Insulinoma is the most common functional pancreatic neuroendocrine tumor originating from β-cells, with unregulated insulin production and rarely associated with MEN-I syndrome. Diagnosis and treatment of insulinoma are a challenge in the practice of endocrinologist.

Aim. To determine on the basis of retrospective analysis the optimal approaches to the management of patients with organic hyperinsulinism.

Material and methods. Medical records of 72 patients admitted with suspected organic hyperinsulinism had been screened and medical histories of patients with a confirmed diagnosis of organic hyperinsulinism were included into the analysis. Anamnesis, results of objective, laboratory and instrumental examinations, methods and results of the treatment were analyzed.

Results. The diagnosis of insulinoma was confirmed in thirty two cases. Hypoglycemia was achieved within the first 48 hours after the start of the 72-hour fasting test in 100% of cases. Study results showed that in 50% of cases the size of the pancreatic neoplasm was more than 1.4 cm. Inverse correlation between tumor size and plasma glucose concentration at the time of hypoglycemia was found (r=–0.45; р=0.02). Surgical treatment was carried out in thirty out of 32 patients. Surgical enucleation of insulinoma was performed in 12 (40%) cases, distal pancreatectomy — in 18 (60%). Insulinoma was confirmed in 27 cases, while in three patients diagnosis of non-insulinoma pancreatogenous hypoglycemia («nesidioblastosis») was established according to histological findings. Positive clinical result was achieved after all surgeries. In postoperative period patients were discharged within 11—30 days. Patients without post-operative complications were discharged 13.0±1.4 days after surgery. Twelve (40%) patients developed post-operative complications. The duration of hospital stay in these cases was significantly longer 20.1±1.9 (р<0,01).

Conclusion. Obtained data confirmed that comprehensive approach including 72-hours fasting test, use of modern imaging techniques and application of high-tech treatment methods, is crucial for successful diagnosis and treatment of insulinoma.

Problems of Endocrinology. 2017;63(4):212-218
Evaluation of biocompatibility of an experimental membrane for glucose sensors: the results of a prospective experimental controlled preclinical study involving laboratory animals
Stanishevskiy Y.M., Sachivkina N.P., Tarasov Y.V., Philippov Y.I., Sokolov S.A., Shestakova M.V.

An increase in the accuracy of monitoring of glucose concentration indicators and an increase in the running time of glucose sensors are promising directions in the field of diabetology. One of the ways to extend the lifetime of a sensor is its complete implantation excluding direct communication with the skin surface. For effective long-term functioning in the patient’s body, the surface of an implantable sensor should be highly biocompatibile: it should not induce allergic and inflammatory reactions as well as the demarcation reaction (formation of a dense connective tissue capsule). Earlier, a group of authors developed a glucose-permeable membrane and a biocompatible coating comprising a complex of nadroparin with transesterified polyethylene glycol and γ-aminopropyl triethoxysilane, which formed a protein repellent hydrogel on the membrane surface.

Aims. To evaluate the biocompatibility of the experimental coated membrane implanted into laboratory animals.

Methods. The experimental prospective controlled study involved 60 laboratory animals (Wistar albino rats). The animals were divided into 3 groups of 20 animals each. Animals of each group were implanted with the standard, or experimental, or experimental coated membrane. After implantation, the skin condition in the implantation area was visually assessed for 90 days. After 90 days, the tissue condition around the implant was evaluated histologically.

Results. No serious allergic or inflammatory reactions in the implantation area were detected in all three groups of animals within 90 days of the follow-up period. In the case of the experimental coated membrane, a significantly low score was graded based on visual assessment of the skin reactions. In the histological analysis, the tissue condition in the implantation area of the coated membranes was characterized by significantly lower density of a connective tissue capsule and the presence of vascularization areas at the contact between of the membrane surface and the surrounding tissue.

Conclusion. In experimental animals, the tested coating significantly inhibits formation of a connective tissue capsule around the implant and reduces the intensity of skin reactions after implantation. Further clinical studies of coated membranes in humans are required to verify their biocompatibility.

Problems of Endocrinology. 2017;63(4):219-226
Case Reports
Large goiter in a patient with congenital hypothyroidism
Bolmasova A.V., Melikyan M.A., Filippova E.A., Narogan M.V., Podurovskaya Y.L., Kotova A.N.

Congenital hypothyroidism with goiter is a rare disease. In the early neonatal period, the pathology can manifest itself as both hypothyroidism symptoms and signs of tracheal compression with a large goiter. The most common cause of this disease is antithyroid maternal therapy, which accounts for 10−15% of congenital goiter cases. In the case of an unremarkable maternal history, the main cause of goiter is thyroid hormone dyshormonogenesis. Here, we present a case of congenital hypothyroidism with a giant goiter (55 cm3). The child was intubated soon after birth due to respiratory disorders and asphyxia caused by tracheal compression. In addition, the patient had tricuspid valve insufficiency and cardiomegaly. Levothyroxine substitution therapy initiated on the first day of life led to a rapid decrease in the thyroid volume and structural changes in the heart. The patient`s DNA was analyzed using a wide genetic panel «Congenital hypothyroidism»; no mutations were found. Despite the absence of mutations in genes involved in thyroid formation, we consider dyshormonogenesis as the most likely cause of goiter in our patient.

Problems of Endocrinology. 2017;63(4):227-230
The efficacy of dopamine agonist therapy in a young man with a giant prolactinoma: case report
Tsiberkin A.I., Karonova T.L., Dalmatova A.B., Grineva E.N.

Prolactinomas are the most common of hormone secreting pituitary adenomas. Patients with prolactinomas generally have a benign prognosis. An algorithm is currently available for managing of this disease. Giant prolactinoma larger than 40 mm with severe invasive growth account for about 2—3% of the prolactin-secreting pituitary adenomas and evidence about management of such patients is limited. This case illustrates progress of a giant prolactin-secreting pituitary adenoma up to 70 mm in young male with a family history of prolactinomas in the absence of the adequate therapy for 8 years after initial diagnosis. After evaluation, it was decided to prescribe medical treatment. Cabergoline therapy started after evaluation appeared to be effective and had lead to significant decrease of serum prolactin level and shrinkage of pituitary adenoma. Described case emphasize the crucial role of identification of hyperprolactinemia among young patients on early stages of the disease. Our observation implies that treatment with dopamine agonists might be effective even in cases with giant prolactinomas.

Problems of Endocrinology. 2017;63(4):231-235
Normocalcemic primary hyperparathyroidism — «new era» in diagnosis of an old disease
Baranova I.A., Zykova T.A.

During the last century, primary hyperparathyroidism (PHPT) passed from the category of rare severe diseases to a common endocrine disorder with a prevalence of mild forms. Over the last 10—20 years, widespread screening for osteoporosis has led to the «new era» in diagnosis of PHPT when patients are diagnosed at the stage of an isolated elevated parathyroid hormone with stable normal serum calcium levels and the absence of secondary causes of hyperparathyroidism. This phenomenon was called normocalcemic primary hyperparathyroidism (nPHPT); according to the literature data, its prevalence varies from 0.4 to 16.7% due to the lack of unified diagnostic criteria. The clinical picture and natural history of the disease are poorly explored, and it is still unclear if nPHPT is a separate disease entity or if it is an early stage of hypercalcemic PHPT. A number of studies have shown that complications of nPHPT (osteoporosis and urolithiasis) are similar to those of the symptomatic form of PHPT despite stable normocalcemia. However, these patients were often referred to specialized metabolic centers due to a decrease in the bone mass or nephrolithiasis, therefore the rate of complications in them may be overestimated. There are also controversial data on an increased risk of cardiovascular diseases due to metabolic disorders in this pathology.

As a new clinical nosology, normocalcemic PHPT was first officially recognized at the Third International Workshop on Management of Asymptomatic PHPT in 2008, but there have been yet no common recommendations for its treatment. Some studies have shown a response to medical therapy and improved indicators of bone mineral density after parathyroidectomy in these patients. According to the experts of the Fourth International Workshop in 2014, nPHPT remains one of the key topics for further research.

Problems of Endocrinology. 2017;63(4):236-244
The hypoglycemic syndrome (insulinoma): pathogenesis, etiology, laboratory diagnosis (review, part 1)
Yukina M.Y., Nuralieva N.F., Troshina E.A., Kuznetsov N.S., Platonova N.M.

Hypoglycemic syndrome is a cluster of symptoms developing due to imbalance in the glucose homeostasis system leading to hypoglycemia and that is corrected by glucose administration. A rapid and significant drop of glucose blood level may lead to life-threatening condition, hypoglycemic coma. Chronic hypoglycemia leads to irreversible changes in the central nervous system, while forced frequent meals with high carbohydrate content in order to correct hypoglycemia significantly increases body weight, until morbid obesity develops. Hence, the hypoglycemic syndrome is a topical problem of contemporary medicine. Insulinoma is the most common cause of pancreatogenous hypoglycemia in patients without diabetes mellitus. Exogenous administration of hypoglycemic agents, severe multiple organ and tumor pathologies, sequelae of bariatric surgery, deficiency of contrainsular hormones, genetically determined enzyme disorders and autoimmune diseases may also cause the hypoglycemic syndrome. The primary diagnostic tasks determining the choice of the treatment approach involve confirming the hypoglycemic syndrome and determining its etiology. The test after 3-day-long fasting and other tests are used for this purpose. In this review, we discuss the main causes and features of pathogenesis of the hypoglycemic syndrome, as well as criteria of differential diagnosis and the possibility of introducing new diagnostic tests and markers.

Problems of Endocrinology. 2017;63(4):245-256
Insulin glargine 300 U/ml in type 2 diabetes mellitus patients: results of the EDITION program (review)
Shestakova M.V., Galstyan G.R.

Unmet medical needs in basal insulin therapy include late initiation of therapy, hypoglycemia, and low patient compliance. Introduction of new basal insulin may cater to these unmet medical needs.

New insulin glargine 300 U/mL (Gla-300) (Toujeo) is a long-acting basal insulin with a more even and prolonged PK/PD profile compared to those of insulin glargine 100 (Lantus). The glucose infusion rate profiles and insulin concentration of Gla-300 were more constant and more evenly distributed over 24 h compared to those of glargine 100 U/mL. Stable blood glucose control (≤ 5.5 mmol/L) was maintained approximately 5 h longer with glargine 300 U/mL compared to glargine 100 U/mL. The difference in PK/PD profiles of glargine 300 U/mL and glargine 100 U/mL may be a key to explanation of the Toujeo® clinical features demonstrated in the EDITION program.

This review discusses the EDITION clinical program results in type 2 diabetes mellitus (T2MD) patients, except EDITION JP2: on previous basal-bolus therapy (EDITION 1, n=807), previous basal insulin in combination with oral anti-diabetic drug (EDITION 2, n=811), and insulin naive patients (oral anti-diabetic drug excl. SU) (EDITION 3, n=878). The EDITION program was aimed to assess the efficacy and safety of Gla-300 compared to those of glargine 100 U/mL. EDITION programs were multicenter, 1:1 randomized, open-label, parallel group, phase III, and non-inferiority studies, with similar designs and endpoints. The primary endpoint was the non-inferiority of Gla-300 vs glargine 100 U/mL, which was estimated as a HbA1c reduction at 6 months. The main secondary endpoint was the percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L) or severe hypoglycemic events from week 9 to month 6 of treatment. Patients were randomized to glargine 300 U/mL or glargine 100 U/mL once a day, with dose titration seeking fasting plasma glucose of 4.4—5.6 mmol/L.

Non-inferiority of glargine 300 U/mL in the HbA1C reduction vs glargine 100 U/mL was confirmed in EDITION 1, EDITION 2, and EDITION 3 studies. According to the results of a pool analysis of these three trials, annualized rates of confirmed (≤3.9 mmol/L) or severe hypoglycemia were lower with glargine 300 U/mL than with glargine 100 U/mL during the night (31% difference in the rate ratio over 6 months, p=0.0002) and at any time (24 h, 14% difference, p=0.0116). Severe hypoglycemia at any time was rare (glargine 300 U/mL: 2.3%; glargine 100 U/mL: 2.6%). Weight gain was low (<1 kg) in both groups, with the gain being less with glargine 300 U/ml [LS mean difference —0.28 kg (95% CI –0.55 to –0.01); p=0.039]. Both treatments were well tolerated, having similar rates of adverse events.

In conclusion, glargine 300 U/mL was characterized by the non-inferior efficacy compared to glargine 100 U/mL, a better safety profile (reduced hypoglycemia), and lower weight gain. These advantages may allow for more active insulin dose titration in real clinical practice, contribute to better-sustained glycemic control and patient compliance, and, consequently, improve the prognosis and clinical outcome.

Problems of Endocrinology. 2017;63(4):257-268

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