Ceyla Konca Degertekin

Effects of Sitagliptin on Nonalcoholic Fatty Liver Disease in Diet-Induced Obese Rats

BACKGROUND Studies investigating the effects of dipeptidyl peptidase-4 inhibitors on hepatic steatosis are lacking. We aimed to determine the effects of sitagliptin on nonalcoholic fatty liver disease (NAFLD) in rats with diet-induced obesity. METHODS A total of 24 adult female Sprague-Dawley rats, which were 24 weeks old and weighed 199-240 grams, were used. The rats were randomly separated into two groups. The control group (n=6) was fed with standard rat diet; the remaining rats (n=18) were fed with a high-fat diet (HFD) to induce NAFLD. After 12 weeks, rats that were fed with a HFD were randomly separated into two groups: (1) HFD-only group (n=8) was fed with a HFD for an additional 4 weeks, (2) HFD-sitagliptin group (n=10) received sitagliptin (3 mg/kg) for 4 weeks in addition to HFD. At the end of the study (16(th) week), blood samples were drawn from all rats to determine serum glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), and plasma insulin levels. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. Histopathologic evaluation of liver samples was undertaken. RESULTS The HFD-sitagliptin group had significantly lower serum glucose (140.8±18.8 vs. 224.7±20.6 mg/dL, P<0.001), plasma insulin (15.8±4.4 vs. 28.0±5.9 μIU/L, P<0.001), HOMA-IR index (4.9±1.8 vs. 15.9±2.3, P<0.001), serum triglycerides (199.0±108.7 vs. 468.0±370.7 mg/dL, P<0.001), and cholesterol (82.0±26.7 vs. 90.5±7.0, P<0.001) values compared to the HFD-only group. Hepatic steatosis was significantly less (mean score, 1 vs. 2; P<0.001) in the HFD-sitagliptin group compared to the HFD-only group, whereas there was no difference in hepatic inflammation (P=0.057), liver weight (P=0.068), and ALT levels (P=0.232). CONCLUSION Sitagliptin may improve hepatic steatosis by increasing insulin sensitivity and improving lipid profiles in rats.

A Case With Immunoassay Interferences in the Measurement of Multiple Hormones

CONTEXT Commonly used immunoassays are not free from interference, which can be a confounder in the interpretation of test results. We present a case with extremely high multiple hormone levels due to such interference. CASE DESCRIPTION A 33-year-old woman with no specific symptoms had markedly elevated TSH with normal free T4 and free T3 levels. Repeated measurements revealed discordantly high TSH, ACTH, FSH, PTH, IGF-1, prolactin, β-human chorionic gonadotropin, and calcitonin levels without the associated clinical pictures. The measurements were repeated with the same patient sample on four different analytical platforms using chemiluminescence immunoassays/electrochemiluminescence immunoassays, and the results were divergent on each platform. Serial dilutions of serum samples revealed nonlinearity, suggesting assay interference. All hormonal measurements were in the normal range when heterophile antibody blocking tubes were used. The serum of the patient was then subjected to polyethylene glycol precipitation. The post-polyethylene glycol recovery resulted in hormone levels in the normal range. The patient did not receive any medications and has been under follow-up without any signs and symptoms for 24 months. CONCLUSIONS This report illustrates a rare case of falsely elevated hormone levels due to assay interference caused by heterophile antibodies. We point out the importance of a close collaboration between clinicians and the laboratory to avoid unnecessary clinical investigations as well as inappropriate treatments.

The relationship between advanced oxidation protein products (AOPP) and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis

To investigate the correlation between advanced oxidation protein products (AOPP) levels and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis (NASH).

Presence and extent of estrogen receptor-alpha expression in patients with simple steatosis and NASH

Loss of estrogen receptor-alpha (ER-α) in the liver is associated with hepatic steatosis and inflammation. We conducted a study in order to investigate the presence and extent of ER-α expression in NASH, and its relationship with histological findings. Fifty-four patients with histologically confirmed NASH, 12 patients with simple steatosis (SS), and 6 patients with normal liver tissue (NLT) were included. NASH activity score and fibrosis score were calculated according to biopsy findings. Liver biopsy specimens were immunohistochemically stained for ER-α expression. Nuclear ER-α expression percentage (staining index) was calculated. Mean staining index was significantly different across the NASH, SS, and NLT groups (6.3±9.9 vs. 22.1±26.4 vs. 44.2±24.8, respectively, p<0.001 for all comparisons). Staining index was significantly higher in women than in men (19.4±22.2 vs. 7.9±15.3, respectively, p=0.003). Staining index negatively correlated with serum ALT (r=-0.240; p=0.04), fasting plasma glucose (r=-0.261; p=0.027), and fibrosis score (r=-0.312; p=0.011). As a conclusion, hepatic nuclear ER-α expression percentage (staining index) is lower in patients with NASH when compared to SS and NLT groups. Staining index is negatively correlated with serum ALT levels, plasma glucose, and fibrosis score. Further studies are required to clarify the significance of ER-α expression in NASH.

Dialysis Type May Predict Carotid Intima Media Thickness and Plaque Presence in End-Stage Renal Disease Patients

IntroductionCarotid intima media thickness (CIMT) and carotid plaques (CP) were shown to be independent predictors of mortality in end-stage renal disease (ESRD) patients. In this study, the authors aimed to compare the two dialysis modalities for CIMT and CP presence (CPP).MethodsESRD patients who had been on the same renal replacement therapy for at least 24 months were selected. CIMT, CPP, known risk factors, and laboratory parameters for atherosclerosis were determined for each patient.ResultsA total of 77 hemodialysis (HD) patients (68% male, 47.6 ± 17.0 years), 61 continuous ambulatory peritoneal dialysis (CAPD) patients (51% male, 45.3 ± 13.9 years), and 36 age- and sex-matched controls (61% male, 43.3 ± 10.6 years) were included. The mean CIMT (m-CIMT) were 0.99 ± 0.24, 0.86 ± 0.22, and 0.60 ± 0.13 mm in the HD, CAPD, and control groups, respectively (HD vs. CAPD, P = 0.001; HD vs. control, P < 0.001; and CAPD vs. control, P < 0.001). The CPP occurred more frequently in the HD group compared to the CAPD group (64% vs. 39%, respectively, P = 0.004). The backward linear and logistic regression analysis of potential confounders revealed that both m-CIMT and CPP was independently associated with dialysis type (beta = 0.249, P = 0.008; and odds ratio [OR] = 4.11, 95% CI, 1.72 to 6.73, P = 0.015, respectively).ConclusionThe authors have shown that dialysis type may be an independent predictor of m-CIMT and CPP in long-term ESRD patients.

Elevated mean platelet volume is associated with gestational diabetes mellitus

Abstract The mean platelet volume (MPV) is an indicator of the average size and activity of platelets. Elevated MPV values are associated with larger and more active platelets and perceived as a new independent cardiovascular risk factor. The aim of this study was to determine the MPV in women with gestational diabetes mellitus (GDM) and to determine the correlation of MPV with metabolic parameters in GDM. We retrospectively analyzed 30 women with GDM and 38 body mass index-matched women with healthy pregnancies as controls. MPV and platelet counts were recorded in the third trimester and at postpartum 6–12 months for GDM group and in the third trimester for control group. Third-trimester MPV was significantly higher in GDM group compared to control group (8.8 ± 1.0 versus 8.1 ± 0.7 fl, p = 0.002). In women with GDM, there was a significant decrease in MPV in the postpartum period (8.8 ± 1.0 versus 8.1 ± 0.8 fl, p < 0.001). Fasting plasma glucose levels and glucose area under the curve were positively correlated with third trimester MPV (r = 0.346, p = 0.007 and r = 0.346, p = 0.02, respectively). Our results indicate that MPV is increased in GDM. Monitoring MPV, which is widely available in clinical practice, may potentially identify women who will develop gestational diabetes during pregnancy. Chinese abstract 平均血小板体积（MPV）是测量血小板平均体积与活性的指标。MPV值升高预示着血小板体积增大、活性增加，被认为是一种新的独立心血管风险因子。本研究的目的在于测定妊娠糖尿病（GDM）女性的MPV水平，确定MPV与GDM中代谢参数的关系。我们回顾性分析了30名GDM女性，且设立对照组为38名身体质量指数相匹配的健康妊娠女性。GDM组分别在妊娠末期与产后6∼12个月记录MPV值与血小板计数，而对照组仅在妊娠末期测量。在妊娠末期，GDM组的MPV显著高于对照组（8.8±1.0 VS 8.1±0.7 fl, p = 0.002）。GDM患者的MPV水平在产后显著下降（8.8±1.0 VS 8.1±0.8 fl, p < 0.001）。空腹血糖水平与曲线下血糖面积与妊娠末期MPV密切相关（分别为r = 0.346, p = 0.007与r = 0.346, p = 0.02）。本研究的结果表明MPV水平在GDM患者中升高。MPV在临床应用中的测量十分普遍，监测MPV也许可以潜在地鉴别出有妊娠期糖尿病发病趋势的女性。

Hyperthyroidism and thyroid autoimmunity induced by sorafenib in metastatic renal cell cancer.

Dear Editor, Tyrosine kinase inhibitors (TKIs) are novel moleculartargeted agents used in the treatment of various cancers. Treatment with TKIs has been associated with changes in thyroid hormone status. While hypothyroidism had frequently been reported with the use of TKIs, thyroid-stimulating hormone (TSH) suppressing effect of TKIs is rare [1]. Here, we describe a case with metastatic renal cell cancer (RCC), who initially became hyperthyroid under sorafenib treatment and later long-term hypothyroid under sunitinib treatment. A 58-year-old male with metastatic RCC presented with the complaints of weakness, palpitations, restlessness, and trembling in his hands for 4 weeks after starting his new cancer treatment using sorafenib. He did not have any other medication or recent iodinated-contrast exposure. On examination, he had tachycardia, fine tremor, hyperactive deep tendon reflexes, and a smooth, non-tender, slightly enlarged thyroid gland. His test results were compatible with overt hyperthyroidism [TSH: 0.011 lIU/ml (0.55–4.78); free thyroxine (fT4): 8.14 ng/dl (0.89–1.76); and free triiodothyronine (fT3): 17.3 pg/dl (2.3–4.2)], and he had high titers of thyroglobulin (anti-TG) (2,500 U/ml; normal \60), thyroid peroxidase (anti-TPO) (2,723 U/ml; normal \60), and TSH-receptor (TRAb) [24.6 U/L (0–14) antibodies; however, thyroglobulin levels were not elevated [4.76 (1.6–59.9 ng/mL)]. Thyroid function tests, anti-TG and anti-TPO, were normal before sorafenib treatment. His family history was negative for Graves disease. The ultrasonography revealed heterogeneous enlargement of the thyroid gland and the Tc-99 scintigraphy showed a homogeneously increased absorption; 4 and 24 h I uptakes were 49.5 % (15–25 %) and 70.1 % (25–35 %), respectively. Graves disease, induced by sorafenib, was diagnosed based on positivity of anti-TSH receptor antibodies and high radio-iodine thyroid uptake and methimazole (20 mg/dl) and propranolol were prescribed. Completing his first cycle of sorafenib, the patient was switched to sunitinib. He had substantial improvement 1 month after the onset of antithyroid medication. Three months after starting methimazole, he developed features of hypothyroidism with low levels of fT4 (0.59 ng/dl) and fT3 (2.36 pg/dl) despite a sustained suppression of TSH (0.026 lIU/ml). Methimazole was stopped. Four weeks after, TSH increased to 11 lIU/ml and fT4 decreased to 0.47 ng/dl. Levothyroxine treatment was initiated and the patient achieved euthyroidism in 2 months. Currently, he is on follow-up with 150 mcg/day levothyroxine for the last 7 months without significant symptoms. Few cases of thyroid hormone excess have been reported with sunitinib; however, they were whether mild and self-limiting or if overt, was associated with low uptake in thyroid scan and elevated thyroglobulins suggesting destructive thyroiditis [1]. There is even fewer data on the TSH-suppressing effect of sorafenib. Miyake et al. [2] reported that 23.9 % of patients with metastatic RCC receiving sorafenib had TSH suppression before the development of hypothyroidism. One case with overt hyperthyroidism was reported after sorafenib treatment in a C. Konca Degertekin (&) F. Balos Toruner M. Akturk Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Gazi Universitesi Hastanesi, Endokrinoloji ve Metabolizma BD, 06100 Besevler, Ankara, Turkey e-mail: ceylakonca@hotmail.com

The effect of thyroid autoimmunity on T-cell responses in early pregnancy

Thyroid autoimmunity (TAI) is common in women of reproductive age. There is a relationship between TAI and recurrent pregnancy loss and infertility. In pregnant patients with thyroid autoimmunity, the T helper-1 (Th1)/T helper-2 (Th2) ratio may shift to a Th1-type response and these activated T lymphocytes may lead to implantation failure. The aims of this study were to investigate the serum levels of Th1-, Th2-, and T-helper-17-(Th17)-associated cytokines in pregnant patients with TAI, and to evaluate how these cytokines change with l-thyroxin treatment during pregnancy. Twenty pregnant women with TAI diagnosed in the first trimester of pregnancy who were not on l-thyroxine treatment, 14 pregnant women with known TAI before pregnancy already been on l-thyroxine treatment, and 19 pregnant patients without TAI were included in this study. Thyroid function tests, thyroid autoantibodies, and cytokine levels were measured at the first and the second trimesters. In pregnant patients who were diagnosed with TAI in the first trimester, both serum IL-2 levels and IL-17 levels were significantly higher than those of the control group. There were no significant differences between groups for serum IL-4, IL-6, IL-23, IL-10, and IFNγ levels. In the second trimester, no significant differences were found between groups for all the cytokines measured. There are significant differences in Th1- and Th17-associated cytokine levels between patients with TAI and the control group in the first trimester. In the second trimester cytokine levels were similar among all groups. This pattern may be associated with the clinical benefits of l-thyroxine treatment.

Diffuse amyloid deposition in thyroid gland: a cause for concern in familial Mediterranean fever

Thyroid gland is among the many organs that could be infiltrated in systemic amyloidosis. However, diffuse infiltration of the thyroid gland secondary to systemic amyloidosis associated with Familial Mediterranean fever (FMF) is rare. Here, we present a 49-year-old woman diagnosed with FMF and systemic amyloidosis, who had a large goiter and multiple nodules that developed slowly through the years and was complicated by tracheal compression symptoms and a mild thyroid dysfunction. Multiple fine needle aspiration biopsies of the nodules and the thyroid parenchyma revealed amyloid deposits. We would like to point out that amyloidosis may have a significant impact on the thyroid gland and fine needle aspiration biopsy is a valuable tool for diagnosis.

Lack of association of hepatic estrogen receptor-alpha expression with histopathological and biochemical findings in chronic hepatitis C.

Estrogens exert a protective effect against hepatic steatosis and fibrosis. Loss of estrogen receptor-alpha (ER-α) in the liver is associated with hepatic steatosis and inflammation in animal models. We conducted a study in order to investigate the presence and extent of ER-α expression in HCV infection, and its relationship with histological and biochemical findings. Ninety biopsy-proven chronic hepatitis C (CHC) patients were enrolled in the study. Liver biopsy specimens were immunohistochemically stained for ER-α expression. Nuclear ER-α expression percentage was calculated. ER-α was positive in 69 of the patients (76%). ER-α positive and negative groups were not significantly different in terms of age, gender, necroinflammatory activity, fibrosis, steatosis, serum levels of AST, ALT, ALP, GGT, and bilirubin. ER-α expression percentage was not correlated with fibrosis, steatosis, necroinflammatory activity and biochemical findings. Although estrogens are known to be protective against fibrosis and steatosis in animal models, we did not find any significant correlation between ER-α expression and histopathological and biochemical findings in CHC patients. These findings should be verified in further large scale studies.