ACTA ENDOCRINOLOGICA (BUC)

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.

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.

Context. We aimed to examine the factors affecting adverse gestational outcome in gestational diabetes (GDM) patients, who were grouped as obese and normal- weight, having only-diet, or insulin treatments. Subjects and Methods. The study included 373 patients, treated with diet or insulin. These patients were sub-grouped as obese and non-obese, and examined retrospectively. The variables affecting adverse gestational outcome in obese GDM patients having dietary and/ or insulin treatments were detected with multiple regression analysis. Results. The weight gained during pregnancy in the GDM group having insulin treatment was more than the one in only-diet treated GDM group (p=0.004). Pre-pregnancy body mass index, the weight gained during pregnancy, hemoglobin A1C levels in the second and third trimesters, caesarian rates were higher in the insulin-treated obese patients than in the other groups (p<0.001). The odds ratio for fasting blood glucose level in insulin-treated obese GDM group was 1.081 (95% CI =1.004 - 1.163) (p=0.039); and it was 0.982 (95% CI =0.924 - 1.002) (p=0.048) for the weight gained during pregnancy, in only-diet treated obese GDM patients. Conclusion. The control of weight gained during pregnancy, and of fasting blood glucose levels in obese patients having GDM, is important to decrease adverse gestational outcome.

Context. Diabetes is a serious public health problem that is increasing worldwide. Objectives. The aim of this study is to evaluate acceptance of the illness, emotional distress, depression and quality of life in individuals with type 2 diabetes mellitus. Subjects and Methods. This study was conducted in 145 individuals with type 2 diabetes mellitus, 73 males (50.3%) and 72 females (49.7%), ranging in age from 20 to 65 years old. Research data were collected using the face-to-face interview technique by the researchers. The Acceptance of Illness Scale for the determination of individuals’ acceptance of the illness, Problem Areas in Diabetes Scale for emotional distress, Beck Depression Inventory for depression and Short Form-36 scales for quality of life was used. Results. The mean score of individuals’ Acceptance of Illness Scale was 30.2±5.62. Compared to women, men had lower emotional distress, depression levels (p<0.05), higher physical, mental quality of life (p<0.001). Correlations among acceptance of illness, emotional distress, depression and quality of life were found to be significant (p<0.05). Also, models of multiple linear regression analysis were statistically significant (p=0.000). Conclusions. The main goal in the treatment of diabetes should be to eliminate complaints in patients, to reduce, prevent or delay the development of complications, to increase the quality of life, to ensure that the individual has a physically, emotionally, spiritually and mentally regular life in addition to metabolic control. For this reason, it is beneficial to carry out the treatment with a multidisciplinary approach in type 2 diabetes mellitus.

Background. Thyroid nodules are a common pathology worldwide. Fine needle aspiration biopsy (FNAB) is an important diagnostic method for the investigation of malignancy in thyroid nodules. However, according to the Bethesda System used to classify the results, patients with atypia of undetermined significance/follicular lesion of undetermined significance (AUS / FLUS) may not be classified as benign or malignant. Therefore, it may be necessary to determine some clinical risk factors to apply the best treatment in these patients. Aim. To determine the factors that increase the risk of malignancy in this patient group. Methods. A retrospective study including 138 patients with an FNAB categorized as AUS/FLUS and operated between June 2015–September 2018. Demographical, Laboratory (TSH) and Ultrasound variables (number, size and characteristics of nodules) of the patients were compared among postoperative histopathological results. Results. Hypo-echoic structure, microcalcification and irregular margin of the nodules were detected to be associated with malignancy in patients with FNAB results of AUS/FLUS (p <0.001). Conclusion. We suggest that surgical treatment should be considered if the patients have nodules with the hypo-echoic structure, microcalcification and irregular margin with an FNAB histopathological result of AUS / FLUS.

Objective. This study aims to determine the prevalence of neuropathy in the prediabetic period. Design, Subjects and Method. Informed consent was attained from the patients who volunteered to participate in the study after ethics committee approval was obtained. Patients under the age of 18, having vitamin B12 or folic acid deficiency, history of collagen tissue-rheumatological disease, chronic kidney failure, cirrhosis, ethylism, thyroid disease, autoimmune disease, malignancy, tuberculosis, type 1 or 2 diabetes mellitus and pregnant women were excluded from the study. Patients diagnosed with prediabetes were evaluated by the DN4 neuropathy complaint questionnaire. Neuropathy was diagnosed in patients having a score of four or more. For the statistical analyses Student t-test, Pearson chi-square test, and Fisher's exact test were performed using the NCSS program. Results. A total of 224 volunteers, 167 women and 57 men, were included in the study. The mean age of the participants was 51 and the mean level of hemoglobin A1C was 5.9. Neuropathy was detected in 45% of the cases. Especially in women, there was a significant increase in the frequency of neuropathy compared to men. The most common complaints found in our study were burning sensation and numbness in the extremities. Conclusions. Similar to diabetic patients, prediabetic patients also have a high rate of neuropathy. For the early diagnosis of neuropathy and to be treated promptly, screening tests such as DN4 should be performed for all prediabetic patients. According to the test results, advanced examinations such as EMG or biopsy should be performed earlier.

Proprotein convertase 1/3 (PC 1/3) deficiency is a rare, autosomal recessive disorder caused by mutations in the PCSK1 gene. The disease is characterized by earlyonset chronic diarrhea/malabsorption, followed by severe obesity and hormonal deficiencies such as hypocortisolism, hypothyroidism, diabetes insipidus, hypogonadism, growth deficiency, and diabetes mellitus. Ewing’s sarcoma is a rare tumor, usually of small dimensions of neuroectodermal origin that is difficult to distinguish pathologically from a primitive neuroectodermal tumor. A 22-year-old female patient with PC 1/3 deficiency was admitted to our clinic with recurrent urinary tract infections. Magnetic resonance imaging (MRI) revealed an 11x12 cm pelvic mass displacing the uterus. A core-needle biopsy was performed on the pelvic mass. As a result of the pathological evaluation, ıt was diagnosed with pelvic Ewing’s sarcoma. The patient was started on the VAC-IE chemotherapy protocol. We report a case of pelvic Ewing’s sarcoma in a patient with PC 1/3 deficiency. Further research is needed to assess malignancy risk in metabolic disorders including very rare disorders like PC 1/3 deficiency.

Context. Diabetes is a chronic disorder with a complex pathogenetic background including monogenic, polygenic, and environmental causes. Objective. The aim of the present paper is to share the information related to genetic and clinical data of large pediatric diabetes cohort. Design. The present study retrospectively analyzes genetic and clinical findings of subjects diagnosed with diabetes under the age of 18 year and are in follow-up in a pediatric diabetes referral center. Subjects and Methods. Out of 1205 children with diabetes (902 treated with insulin) 246 underwent genetic tests on the basis of clinical selection criteria since 2007. Results. One hundred and ten variants related to diabetes were found in 89 of them. Age at presentation was 9.5±4.02 years (F/M 44/45). In total 49 pathogenic and likely pathogenic, 11 “hot and warm” of unknown significance variants were found in fourteen MODY and fifteen non- MODY genes according to criteria developed by American College of Medical Genetics. Thirty novel mutations were found. GCK (26.6%) and ABCC8 (10%) were two most frequently affected genes. Antibody testing revealed negative results in 80% of cases. Conclusions. Genetic interpretation in selected cases is important to understand the nature of the disease better. Improvement in testing opportunity and awareness might increase the prevalence of genetically explained diabetes cases. The distribution of subtypes differs between countries and even regions of the same country.

Objective. The non-effectiveness of levothyroxine administration in hypothyroidism depends on many factors and mechanisms influencing its absorption in small intestins or bounding of circulating hormone with different active molecules. Methods. Thyroid hormones, TSH, rT3, TGl, TPOAb, TG-Ab, were measured using commercially available assays. For anti-T4ab, radioiodine-labeled T4 was added to the patient’s serum and the IgG fraction subsequently precipitated by addition of 15% polyethylene glycol. Background was determined by testing 100 control sera from individuals without autoimmune thyroid disease. Results. A 42-year old woman (71.5 kg) with Hashimoto thyroiditis receiving levothyroxine (L-T4) 150 μg and liothyronine (L-T3) 37.5 μg was admitted to the hospital with clinical data of hypothyroidism, TSH-23.8 mU/L, FT4- 6.18 pmol/L (n.range 9-19 pmol/L), TPO-Ab 696 IU/mL, TGAb 818 IU/mL, circulating T4- antibodies positive. She has a good adherence to medication, malabsorption or administration of other drugs were excluded. L-T4 absorption test revealed 44% increase of serum FT4 at 120 min after ingestion of 150 mcg L-T4 (2.1 mcg/kg). Methylprednisolone pulses of 500 mg i.v. administered in three consecutive days at equal doses of L-T4/L-T3 resulted in a rapid increase of FT4 to 14.5 pmol/L, fall of TSH to 0.18 mU/L and decrease of anti-T4 antibodies to referent range; TPO-Ab and TG-Ab also decreased significantly. Monotherapy by 150 mcg L-T4 was continued in the next three months. A recurrence of hypothyroidism with increase of circulating T4-Ab was observed 100 days later. New administrations of methylprednisolone two pulses of 500 mg revealed a similar normalization of thyroid hormones and anti-T4 antibodies. Conclusion. The data showed that T4-antibodies might be a cause of insufficient effects of levothyroxine therapy in autoimmune hypothyroidism. This could be overcome by glucocorticoid administration probably resulting in FT4 release from circulating immune complexes.

Background. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. Antibodies directed against programmed cell death receptor 1 (PD-1) interrupt the ability of the cancerous cell to depress the immune system. Methods and results. We report three patients who developed different endocrine abnormalities after treatment with nivolumab, a monoclonal antibody directed against PD-1. First, we report a 76-year-old male presenting with generalized fat loss after treatment with nivolumab which predominantly affected his face and trunk. Second, we described the development of thyroiditis that presented with thyrotoxicosis and the expression of thyroid-stimulating hormone receptor antibodies (TRAb). Finally, we observed the emergence of adrenal insufficiency due to hypophysitis in another case. Conclusion. Although immune checkpoint inhibitors are an effective anticancer treatment modality, adverse effects are evident that can affect the endocrine system. These adverse events may relate to different endocrine systems that include the thyroid and pituitary glands. Also, acquired generalized lipodystrophy should be suspected in patients developing unusual fat loss after treatment with ICIs.