ACTA ENDOCRINOLOGICA (BUC)

Background. We describe a case of denosumab-related osteonecrosis of the jaw in a 58-year-old patient with a diagnosis of osteoporosis, treated with Denosumab and a short-time course of bisphosphonates. This case illustrates that use of anti-RANKL agents can lead to a type of osteonecrosis resembling bisphosphonate-related osteonecrosis of the jaws, so this medical condition can be categorized as of antiresorptive - induced osteonecrosis of the jaw. The consensus of present day medical opinion is that the benefits of antiresorptive therapy outweigh the disadvantages. However, to provide optimal management for individual patients, the risk-benefit ratio of osteoporosis therapy must be repeatedly assessed at all stages of a patient’s treatment, and therapeutic decisions taken in the light of the ratio as it applies to the individual.

Background. Heterozygous gain-of-function mutations in the glucokinase (GCK) gene cause hyperinsulinaemic hypoglycaemia (GCK-HI), while lossof- function mutations lead to a monogenic type of diabetes (GCK-MODY). We, herein, report a heterozygous GCK gene mutation in a large family with GCK-MODY and insulinoma in one individual from the same family. Patients and methods. The proband, an 11-yearold male, was referred for asymptomatic mild hyperglycemia (fasting glucose:121 mg/dL) and HbA1c of 6.1%. Segregation analysis of the family revealed multiplex members with asymptomatic fasting hyperglycaemia or non-insulindependent diabetes and 33-year-old maternal uncle of the proband case had a history of distal pancreatectomy due to the diagnosis of insulinoma. His preoperative investigations were revealed fasting glucose of 31 mg/dL, insulin: 7μU/ mL, C-peptide: 2.6 mg/dL, and a low HbA1c(4.0%) which was suggestive for recurring hypoglycaemia episodes. Postpancreatectomy he developed mild fasting hyperglycemia (115-136 mg/dL). Results. Genetic analysis revealed heterozygous p.Ser453Leu(c.1358C> T) mutation in the GCK gene in the proband. In segregation analysis, the identical heterozygous p.Ser453Leu(c.1358C> T) GCK gene mutation was detected in all of the other affected family members for whom a DNA analysis was applicable. The maternal uncle was first diagnosed with insulinoma and underwent a pancreatectomy. He also had an identical mutation in a heterozygous state. Conclusion. We, to the best of our knowledge, firstly identified these two entirely distinct phenotypes of glucose metabolism, GCK-MODY and GCK-HI, due to an identical heterozygous p.Ser453Leu (c.1358C> T) mutation in the GCK. Further studies required to elucidate this new phenomenon and understanding the genotype-phenotype relationship of GCK gene mutations.

Background. There have been a number of reports on the relationship between the PPARγ2 Pro12Ala genotype and the development of obesity. Objective. A case-control survey was designed to investigate the potential association between a Pro12Ala polymorphism in the PPARγ2 gene and obesity and/or obesity-related phenotypes in a population from Turkey. Materials and methods. The polymerase chain reaction and restriction enzyme digestion were used to genotype the Pro12Ala polymorphism of the PPARγ2 gene in 149 unrelated obese and 105 non-obese control subjects from Turkey. The data were analyzed statistically. Results. We found that the overall minor allele frequency was 0.12 in cases and 0.095 in controls. In terms of genotype distribution and allele frequencies among the cases versus controls in the population studied, only the genderstratified analysis revealed a significantly higher frequency of Pro/Ala genotype within males. The polymorphism was associated with significantly higher weight, height, waist circumference, central adiposity (waist-to-hip ratio, WHR), lean body weight as well as dry body weight, but not overall adiposity (total body fat percentage, TBF) in cases carrying Ala allele (Pro/Ala or Ala/Ala). However, in the subjects carrying Ala allele of the control group, WHR values were found significantly lower. Conclusion. Our results showed that the Pro12Ala polymorphism in the PPARγ2 gene is associated with obesity in the studied adult population from Turkey. These data suggest that the Pro12Ala polymorphism in PPARγ2 may be a potential genetic risk factor for central obesity.

Background. Androgen receptor (AR) plays a crucial role in the homeostasis of\r\nmammary tissue. In the present study we investigated the immunohistochemical expression\r\nof AR in breast cancer and its relationships with clinico-pathological parameters of\r\nprognosis, hormone receptors status and HER2 overexpression.\r\nMethods. There were investigated 124 patients admitted with invasive breast cancer,\r\nand from these 48 had lymph node metastasis and 9 had distant metastasis. In all specimens\r\nthere were performed immunohistochemical staining for AR, estrogen receptors (ER),\r\nprogesterone receptor (PR) and HER2. Results were correlated with pathological findings\r\nand the molecular profile of the tumors.\r\nResults. The immunohistochemical expression for AR was found in 92 cases. A\r\nsignificant correlation was found between AR expression and pathological type, grade and\r\nlymph node status, but not with distant metastasis and the expression of ER, PR and HER2.\r\nAn inverse correlation was found between AR expression and triple negative breast cancers.\r\nConclusion. Our data suggest that AR is an individual factor of prognosis and is a\r\nuseful marker to stratify patients with triple negative tumors. AR could be a potential target\r\nfor specific therapy in individuals excluded from the conventional hormone therapy.

Context. Severe hypertriglyceridemia (SH), which calls for a triglyceride (TG) level above 1000 mg/dL, remains an important health issue. While some data exist to offer combination of heparin, insulin and fenofibrate as a reasonable treatment option, safety and benefits of this therapy have not been accurately weighted, largely due to the limited sample size of the relevant studies. Aim. Assess the efficacy and safety of the heparin, insulin and fenofibrate combination in the treatment of patients with SH. Patients - Methods. Patients aged ≥18 years with TG level above 1000 mg/dL and adequate organ function were included. Triglyceride levels were measured immediately before the treatment and on the 3rd and 6th days of the treatment. Treatment dosage, duration, response and side effects were assessed. Patients with hypertriglyceridemia presenting with acute pancreatitis were treated additionally with lipid apheresis. Results. A total of 42 patients were included. Of these, 85.8% came to medical attention with some kind of secondary hypertriglyceridemia causes. The baseline median TG value of the cases was 2141.0 mg/ dL (1026-12250). There were 6 patients (14.3%) with acute pancreatitis at presentation. In patients without pancreatitis, with administration of insulin infusion, unfractionated heparin infusion and fenofibrate capsule, median TG values decreased to 921 mg/ dL (190-6400) on the 3rd day and to 437 mg/ dL (112-1950) on the 6th day of the treatment (p<0.0001, Friedman test). Potential toxicities related to insulin, heparin and fenofibrate combination treatment including hypoglycemia, hemorrhage, rise in creatine kinase levels, hepato - and nephrotoxicity were not observed. Conclusion. In this trial involving patients with SH, our data suggest that insulin, heparin and fenofibrate combination therapy was safe and effective.

Background. Alpha lipoic acid (ALA) acts as essential co-factor for mitochondrion respiratory enzymes. It has an increasing importance in diabetic neuropathy treatment. Its positive effects on weight gain and metabolic parameters have also been discussed. In this study, we aimed to search for the effect of ALA on weight, appetite, adiponectin and metabolic parameters in type 2 diabetes mellitus patients. Methods. This study is designed as a randomised, double-blind, placebo controlled, prospective study. 23 type 2 diabetes mellitus patients with peripheral neuropathy (6 normal weight, 17 obese) and 21 normal weight control group were included in the study. Patients were given 600mg/day oral ALA for 6 weeks, added to their routine therapy. Body mass index (BMI), adiponectin, fasting plasma glucose, HbA1C, lipid parameters and CRP levels were tested before and after ALA treatment. Results were evaluated using SPSS 15.0 for Windows. Results. Adiponectin levels were statistically significantly lower and CRP levels were higher in diabetes group when compared to control group. Although ALA treatment caused a slight weight loss, it was not statistically significant. Appetite scores were decreased in the diabetes group but it did not cause statistically significant weight loss. There was no significant change in metabolic parameters or adiponectin after the treatment. Conclusions. 600mg/dL ALA treatment for 6 weeks did not favor for metabolic parameters in type 2 diabetes patients. This result might be due to the dose or the duration of the treatment, genetic predisposition or dietery habits. Trial of higher doses for long terms might be needed for recovery.

Background. Unexplained high bone mass (HBM) (Bone Mineral Density-BMD Z-score at the lumbar spine or hip of ≥+3.2 SD, or a combined spine and hip Z score ≥4 SD) after routine bone densitometry occurs with a prevalence of approximately 2 out of 1.000 and is currently believed to be a mild form of skeletal dysplasia (1). Results. We present the case of a patient with unexplained HBM (Z-scores at L3, L1-L4, total hip and radius total were +3, +2.7, +2 and +1.8, respectively) and concurrent symptomatic primay hyperparathyroidism (total serum calcium 11.9 mg/dL, serum Parathyroid Hormone - PTH 189.3 pg/mL) of long duration. There were no significant BMD changes at any skeletal site after the surgical cure of hyperparathyroidism. Testing for LRP (low density lipoprotein receptor-related proteins) 5 gene mutations was negative. Conclusions. We presented an unusual case of the association of a HBM with primary hyperparathyroidism with resistance to the catabolic action of PTH. In spite of the negative result of LRP5 testing we do believe that a mutation of a gene involved in the Wnt pathway in bone is responsible.

Objective. Romania has no national guidelines for hypothyroidism treatment, nor are there any recommendations from national societies to adhere to international guidelines. Our aim was to identify the attitudes of Romanian physicians relating to hypothyroidism treatment focusing on available formulations of levothyroxine (LT4). Methods. All 748 members of the Romanian Society of Endocrinology were invited to participate in a web-based survey. A total of 316 (42.24%) members responded, of whom 222 (70.2%) completed all questions. Results. Half of the respondents recommended LT4 treatment in euthyroid patients, from 3.6% in euthyroid patients with obesity to 36.4% in euthyroid females with infertility associated with high levels of thyroid antibodies. LT4 was considered the preferred treatment for hypothyroidism (compared to combination treatment of LT4 with LT3 or LT3 alone) by 98.6% of respondents. LT4 in liquid solution was preferred over tablets if malabsorption is suspected (56.5% vs. 27.3%), for patients with unexplained poor biochemical control (52.5% vs. 22.9%) and for patients not able to adhere to ingesting LT4 fasted (74.0% vs. 9.8%). The most and least probable explanations for persistent symptoms in patients with hypothyroidism who achieve a normal TSH under medication were “psychosocial factors” and “burden of having to take medication”, respectively. Conclusion. A significant proportion of Romanian physicians would use LT4 in some groups of euthyroid patients, contrary to current evidence. The preferred treatment for hypothyroidism was LT4. Alternative LT4 formulations (liquid solution) are considered in specific clinical conditions. Diversification of available thyroid hormone formulations was readily incorporated into everyday practice.

Context. Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assayspecific reference values requires sizable representative cohort of healthy subjects. Subjects and Methods. In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. Results. IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Conclusions. Normative age-specific serum IGF- 1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Populationbased data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.