DOES GRAVES' DISEASE AFFECT ESOPHAGEAL MOTILITY?

CONTEXT: The gastrointestinal tract is one of the most affected systems in hyperthyroidism. Although thyrotoxicosis is thought to be associated with gastrointestinal dysmotility, there are limited studies focused on motility disorders in hyperthyroidism. OBJECTIVES: We aimed to investigate the manometric measurements to determine if esophageal motility is affected in Graves' disease. MATERIALS AND METHODS: Thirty patients with Graves' disease (18 female and 12 male) and 30, age and sex matched, healthy controls (22 female and 8 male) were recruited to the study between 2015 and 2016. Esophageal manometry was performed using MMS (Medical Measurement Systems bv. The Netherlands) Solar GI - Air Charged Intelligent Gastrointestinal Conventional Manometry. RESULTS: The mean lower esophageal sphincter pressure (LESP) was 16.9 ± 5.3 mmHg in hyperthyroid patients and 20.1 ± 8.8 mmHg in the control group and there was no significant difference (p>0.05). It was observed that the duration of contraction was 3.9 ± 0.7 s in healthy subjects and, significantly shorter 3.2 ± 0.5 s in hyperthyroid patients (p<0.001). Duration of contraction was negatively correlated with TSH receptor Ab titer in patients (p=0.006, r= -0.48). Also, it was observed that the duration of relaxation was negatively correlated with fT4 levels in the patient group (p<0.05, r= -0.46). CONCLUSION: In this study, we observed that esophageal motility can be affected via shortened duration of contraction in Graves' disease. The gastrointestinal symptoms due to possible motility dysfunctions should be considered in the evaluation of hyperthyroid patients.

The Correlation of Increased CRP Levels with NFKB1 and TLR2 Polymorphisms in the Case of Morbid Obesity.

Morbid obesity (MO) is associated with an increase in circulating levels of systemic acute phase proteins such as C-reactive protein (CRP). Toll-like receptor is possible candidate for inflammatory responses which is mainly mediated by NFKB1. The aim of this study was to investigate the relationship between NFKB1 and Toll-like receptor (TLR) 2 polymorphisms and the risk of MO in a Turkish population in the context of CRP serum levels which may contribute to susceptibility to the disease. We analysed the distribution of NFKB1-94 ins/del ATTG rs28362491 and TLR2 Arg753Gln rs5743708 polymorphisms using PCR-RFLP method and CRP serum levels using ELISA method in 213 MO and 200 healthy controls. The frequency of the ins/ins genotype and ins allele of rs28362491 was significantly higher in the patients compared to control group (P: 0.0309; P: 0.0421, respectively). Additionally, the frequency of GG genotype and G allele of rs5743708 was found to be statistically higher in the patient group (P: 0.0421; P < 0.0001, respectively). In addition, serum CRP levels (>20 mg/l) in MO patients with ins/ins genotype were significantly higher than in patients with del/ins genotype (P: 0.0309). Serum CRP levels were also higher in MO patients with GG genotype and G allele (P: 0.0001). According to combined analysis, the wild type of rs28362491 and rs5743708 polymorphisms (ins/ins/GG genotype) was also significantly higher in the patient group versus the control group when compared with the combined ins/ins/GA and del/ins/GA genotype (P < 0.0001). Therefore, our findings suggest that rs28362491 and rs5743708 polymorphisms were significantly associated with MO disease through acting by modulating serum CRP levels.

A novel AVP gene mutation in a Turkish family with neurohypophyseal diabetes insipidus.

PURPOSE: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare, autosomal dominant, inherited disorder which is characterized by severe polydipsia and polyuria generally presenting in early childhood. In the present study, we aimed to analyze the AVP gene in a Turkish family with FNDI. METHODS: Four patients with neurohypophyseal diabetes insipidus and ten healthy members of the family were studied. Diabetes insipidus was diagnosed by the water deprivation test in affected family members. Mutation analysis was performed by sequencing the whole coding region of AVP-NPII gene using DNA isolated from peripheral blood samples. RESULTS: Urine osmolality was low (<300 mOsm/kg) during water deprivation test, and an increase more than 50 % in urine osmolality and recovery of the symptoms were observed by the administration of desmopressin in all patients. Plasma copeptin levels were lower than expected according to plasma osmolality. Pituitary MRI revealed partial empty sella with a bright spot in index patient and a normal neurohypophysis in the other affected subjects. Genetic screening revealed a novel, heterozygous mutation designated as c.-3A>C in all patients. CONCLUSION: c.-3A>C mutation in 5'UTR of AVP gene in this family might lead to the truncation of signal peptide, aggregation of AVP in the cytoplasm instead of targeting in the endoplasmic reticulum, thereby could disrupt AVP secretion without causing neuronal cytotoxicity, which might explain the presence of bright spot. The predicted effect of this mutation should be investigated by further in vitro molecular studies.

Graves' ophthalmopathy: the role of diffusion-weighted imaging in detecting involvement of extraocular muscles in early period of disease.

OBJECTIVE: To evaluate involvement of the extraocular muscle (EOM) using diffusion-weighted imaging (DWI), to determine whether there is correlation with conventional orbital MRI and apparent diffusion coefficient (ADC) values in patients with Graves' ophthalmopathy (GO). METHODS: 35 patients known clinically with GO and 21 healthy controls were studied. Patients were assessed with clinical activity scores. All subjects underwent conventional MRI and DWI study. Involvement of the EOM was evaluated. The patients were classified as involved or uninvolved on orbital MRI and their ADC values in DWI compared. RESULTS: There was significant difference in the mean ADC value of all the EOMs in patients vs controls. The ADC values of all the EOMs were higher in patients. There were significant differences in ADC values between uninvolved muscles on conventional MRI and controls for the MR, SR and LR. There was no significant difference in ADC value between the two groups when considering the IR. ADC values of medial, lateral and superior rectus muscles were increased. CONCLUSION: Increased ADC values of the EOM in patients with GO suggest that EOM damage begins at a very early stage before being detected on routine orbital MRI. The routine MRI with DWI sequence will be a useful adjunct in the selection of a group of patients most likely to benefit from early treatment. ADVANCES IN KNOWLEDGE: This study can help to evaluate the involvement of GO in early period with MRI added DWI.

Microstructural brain changes in acromegaly: quantitative analysis by diffusion tensor imaging.

OBJECTIVE: We examined brain diffusion changes of patients with acromegaly. We searched whether there are differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values between remission and non-remission patients with acromegaly and investigated any effect of time of hormone exposure on diffusion metrics. METHODS: The values of FA and ADC were calculated in a total of 35 patients with acromegaly and 28 control subjects. Patients were subdivided into remission and non-remission groups. We looked at brain FA and ADC differences among the groups and looked for any relation between the diffusion changes and time of hormone exposure among the patients with acromegaly. RESULTS: We found decreased FA and increased ADC values in some of the growth hormone responsive areas. There were no significant brain diffusion changes between remission and non-remission groups. The most affected areas were the hypothalamus, parietal white matter and pre-motor cortex in patients with acromegaly. In terms of hormone exposure time among the patients with acromegaly, there was no effect of disease duration on brain microstructural changes. CONCLUSION: All patients with acromegaly showed increased brain diffusion with no relation to disease duration and treatment status. We suggested that in patients with acromegaly, brain damage had already occurred in the subclinical period before symptom onset. ADVANCES IN KNOWLEDGE: This study contributes to the understanding of the mechanisms in acromegaly.

The effects of long term fasting in Ramadan on glucose regulation in type 2 diabetes mellitus.

INTRODUCTION: For Ramadan fasting, observing Muslims do not eat or drink between sunrise and sunset during Ramadan, Islam's holy month of the year according to the lunar calendar. In 2011, fasting patients with diabetes fasted for an average of 16.5 hours per day, having 2 meals between sunset and sunrise for a month. We aimed to evaluate the impact of extended fasting on glucose regulation and observe possible complications of extended fasting in type 2 diabetes mellitus patients. PATIENTS AND METHODS: We conducted a randomized, retrospective, observational study. Patients who presented at the Diabetes Clinic during the 15 days before and after Ramadan in August 2011 Istanbul, whose hemoglobin A1c, fasting plasma glucose, postprandial plasma glucose, weight and height value examinations and follow-up were completed were included in the study. FINDINGS: Seventy-six diabetes patients who fasted during Ramadan (fasting group) and 71 patients with diabetes who did not fast (non-fasting group) were included in the study. These two groups with similar demographic characteristics were compared before and after Ramadan. HbA1c, fasting and postprandial plasma glucose, body mass index, weight and adverse events were evaluated. No statistically significant difference was observed among the fasting and the non-fasting groups. There was no difference between the pre and post-Ramadan values of the fasting group. CONCLUSIONS: We could not find any negative effects of extended fasting on glucose regulation of patients with diabetes who are using certain medications. No serious adverse event was observed. We failed to demonstrate benefits of increasing the number of meals in patients with diabetes.

Elephantiasis nostras verrucosa on the abdomen of a Turkish female patient caused by morbid obesity.

Elephantiasis Nostras Verrucosa is a rare disorder of an extremity or a body region, which is associated with chronic lymphedema. There are 7 reported cases of abdominal elephantiasis in the medical literature. Here we report a morbidly obese female patient with elephantiasis nostras verrucosa on the abdominal wall.

Anti-Scl-70 antibodies in autoimmune hypothyroidism.

The relationship between autoimmune thyroiditis and systemic sclerosis is controversial. Data exist on the presence of thyroid autoantibodies in patients with systemic sclerosis but, as far as we could ascertain, anti-Scl-70 antibodies, which are highly specific for systemic sclerosis, have not been investigated in autoimmune hypothyroidism. This study compares the presence of anti-Scl-70 in females with autoimmune hypothyroidism (n = 24) and in healthy age-matched female controls (n = 26). Free thyroxine levels were similar in both groups. Thyroid stimulating hormone (TSH), antithyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg) and index values for anti-Scl-70 levels were significantly higher in patients with autoimmune hypothyroidism compared with controls, although the anti-Scl-70 test was negative in both groups. Anti-TPO, anti-Tg and TSH significantly correlated with anti-Scl-70. In conclusion, autoimmune hypothyroidism seems to be associated with a higher index level of anti-Scl-70, yet a negative anti-Scl-70 antibody test. This suggests that autoimmune hypothyroidism might have common aetiological factors with systemic sclerosis.

Is serum leptin level regulated by thyroid functions, lipid metabolism and insulin resistance in polycystic ovary syndrome?

Our aim was to determine whether serum leptin level is regulated by thyroid hormones, lipid metabolic products and insulin resistance status in women with polycystic ovary syndrome (PCOS). A prospective case-controlled study was carried out in Istanbul University, Cerrahpasa School of Medicine in 25 lean PCOS (L-PCOS) women, 19 obese PCOS (O-PCOS) women and 28 normal women. The diagnosis of PCOS was established according to the clinical, hormonal (elevated luteinizing hormone and serum androgens) and ultrasonographic findings. Fasting serum levels of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), fasting glucose, insulin, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C) and leptin were measured and compared in the three groups and the correlations between serum levels of leptin and other parameters were evaluated. Serum leptin levels were higher in the O-PCOS group, while its level was comparable between the L-PCOS and control groups. Serum levels of FT4 were significantly lower in both L-PCOS and O-PCOS groups than the control group. Women in both L-PCOS and O-PCOS groups were found to be significantly hyperinsulinemic and insulin resistant. Serum levels of TC, VLDL-C and TG were significantly higher in the O-PCOS group, while serum HDL-C level was lower. There was a poor correlation between serum leptin, and FT4, TC, TG, HDL-C and VLDL-C levels. A significant correlation was observed between serum leptin levels and both BMI and insulin resistance status in PCOS. We believe that, although thyroid hormones and lipid metabolic products do not seem to participate in the regulation of serum leptin levels, BMI and insulin resistance status may have a key role in women with PCOS.

Comparison of the effects of cabergoline and bromocriptine on prolactin levels in hyperprolactinemic patients.

OBJECTIVE: It is well known that bromocriptine has a suppressive effect on the prolactin release in hyperprolactinemic patients. But it also has some adverse effects. The new, long-acting dopaminergic drug, cabergoline, has been reported to be an effective agent in these patients. However, there are relatively few reports comparing the beneficial and adverse effects of these drugs in the treatment of hyperprolactinemic patients. Therefore, here we studied and compared the efficacy and tolerability of cabergoline with bromocriptine in hyperprolactinemic patients. PATIENTS: Seventeen patients (7 with microprolactinoma, 4 with macroprolactinoma, 6 with idiopathic hyperprolactinemia) were given bromocriptine at a dose of 2.5 mg (or 5 mg for macroprolactinomas) twice daily, and 17 patients (8 with microprolactinoma, 4 with macroprolactinoma, 5 with idiopathic hyperprolactinemia) were given cabergoline at a dose of 0.5 mg twice weekly for 12 weeks. RESULTS: At the end of the study, the prolactin reduction was significantly greater in the cabergoline group than in the bromocriptine group (-93 vs. -87.5 %, respectively, p < 0.05). Normalization of prolactin levels was achieved in 10 of 17 patients (59%) in the bromocriptine group, and in 14 of 17 patients (82%) in the cabergoline group (p = 0.13). Two patients (50%) with macroprolactinoma in the bromocriptine group and three patients (75%) with macroprolactinoma in the cabergoline group demonstrated a normalization of their serum prolactin levels. Adverse events were noted in 53% of bromocriptine patients and in 12% of cabergoline patients (p < 0.01). CONCLUSION: These data indicate that cabergoline is a very effective agent for lowering the prolactin levels in hyperprolactinemic patients and that it appears to offer considerable advantage over bromocriptine in terms of efficacy and tolerability.

Early changes in parameters of bone and mineral metabolism during therapy for hyper- and hypothyroidism.

The effects of thyroid hormones on various organs and metabolic systems have been the focus of intensive research. In this study we investigated the mechanisms of the changes in some parameters of bone and mineral metabolism before and during treatment of hyper- and hypothyroidism. Our study groups were as follows; 1) Untreated hyperthyroid patients (n= 38), 2) Hyperthyroid patients treated for three months (n=21), 3) Untreated hypothyroid patients (n=27), 4) Hypothyroid patients treated for three months (n= 20), and 5) Euthyroid control subjects (age, weight, sex and menopausal status matched) (n = 47). As expected, the mean serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and urinary Ca/creatinine and deoxypyridinoline (D-Pyr)/creatinine levels were higher in group-1 than in the control group. Serum PTH level was lower in group-1 than in group-5. However, after treatment for three months (group-2) we found that the serum and urinary levels of these parameters (except ALP) were not different than in the control group. Group-3 and group-4 did not show any differences in these parameters compared with group-5. Covariance analysis showed that urinary D-Pyr excretion had a positive, independent relationship to the serum free T3 level and age (P < 0.001 and P = 0.02, respectively). These results suggest that both bone formation and resorption markers increase in hyperthyroid patients, and with the treatment, particularly, in the period of first three months the bone resorption markers decrease rapidly. If the treatment is maintained the decrease slows, becoming more gradual. However, bone formation markers like ALP remain high in hyperthyroid patients during the treatment. In the light of this data, it is possible to conclude that osteoblastic activity lasts longer in hyperthyroidism. On the other hand, we demonstrated that these bone formation and resorption markers do not seem to be different in hypothyroid patients, even during the treatment, compared to the euthyroid controls.

The impact of propylthiouracil therapy on lipid peroxidation and antioxidant status parameters in hyperthyroid patients.

This study was performed on 17 hyperthyroid patients and 15 healthy controls. The patients were under propylthiouracil (PTU) therapy at a dosage of 3 x 100 mg/day for one month. Blood samples, taken at the beginning and on the 30th day of therapy, were analyzed for hormonal parameters (T3, T4, TSH), lipid peroxidation endproduct [thiobarbituric acid reactive substances (TBARS)] and antioxidant status parameters: glutathione (GSH), glutathione peroxidase (GSH-Px) and CuZn superoxide dismutase (CuZn SOD). Hyperthyroid patients were observed to have significantly higher TBARS, GSH and CuZn SOD levels than controls (P < 0.05, P < 0.001, P < 0.001, respectively). PTU therapy caused a relief in oxidative stress as reflected by significantly decreased TBARS levels (P < 0.001) and a selective modification in the antioxidant status parameters: significant decreases in GSH and CuZn SOD levels (P < 0.001) and a significant increase in GSH Px (P < 0.01) activity. Our findings suggest a selective modification of the antioxidative profile in hyperthyroidism. PTU should also be considered as an in vivo antioxidant, in addition to its antithyroid action.

Biochemical evaluation of oxidative stress in propylthiouracil treated hyperthyroid patients. Effects of vitamin C supplementation.

In this study the impact of vitamin C supplementation on oxidative damage as assessed by thiobarbituric acid reactive substances and markers of antioxidant status: namely Cu/Zn superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione were investigated in 24 hyperthyroid patients under propylthiouracil therapy (3x100 mg/day) for five days and in 15 healthy controls. Ascorbic acid (1000 mg/day) was given as a supplement for 1 month to both the patients and controls during the study period. Heparinised blood samples were taken at the beginning and the end of one month ascorbic acid supplementation. Comparison of the hyperthyroid patients with the controls revealed higher lipid peroxidation (p<0.001), higher Cu/Zn superoxide dismutase activity (p<0.001), higher glutathione level (p<0.001) and lower glutathione reductase activity (p<0.001). Vitamin C supplementation to hyperthyroid patients caused significant increases in glutathione concentration (p<0.001) and glutathione peroxidase activity (p<0.001), whereas there were significant decreases in glutathione reductase (p<0.001) and Cu/Zn superoxide dismutase activities (p<0.01). Thiobarbituric acid reactive substances and thiobarbituric acid reactive substances/glutathione ratio were significantly decreased (p<0.01). Vitamin C supplementation to euthyroid controls caused significant increases in glutathione concentration (p<0.001) and glutathione peroxidase and Cu/Zn superoxide dismutase activities (p<0.001), whereas there was a significant decrease in glutathione reductase (p<0.001). The thiobarbituric acid reactive substances/glutathione ratio was significantly decreased (p<0.05). Our findings reveal the potentiation of antioxidant status and a relief in oxidative stress in both propylthiouracil treated hyperthyroid patients and controls in response to vitamin C supplementation.

The modulation of glucocorticoid receptor content by 3-O-methyl-D-glucose transport in human mononuclear leukocyte in obesity.

Glucocorticoid receptors (GR) and 3-O-methyl-D glucose (3-O-MG) transport were determined in mononuclear leukocytes (MNL) from 11 abdominal obese subjects, 10 pituitary-dependent Cushing's syndrome (Cushing's disease) and 10 healthy controls. Using a whole-cell competitive binding assay and 3H-dexamethasone as tracer, MNL of abdominal obese subjects were found to have 4855 +/- 1389 sites/cell which was significantly lower (p < 0.05) than controls (6234 +/- 1568 sites/cell), although no significant difference was found in the mean serum cortisol level. Their mean Kd (affinity) was also significantly lower than that found in the healthy controls (obese Kd:2.92 +/- 0.84 nmol/l, control Kd: 4.55 +/- 0.67 nM, p < 0.05). On the other hand, the receptor characteristics in Cushing's disease patients were within the normal range. At the same time, 3-O-MG transport was determined in the same subjects. In Cushing's disease, 3-O-MG transport was within the normal range, whereas in abdominal obesity this value was significantly lower than the healthy controls (abdominal obese: 31.90 +/- 8.20; control: 46.26 +/- 12.91 fmol/10(6) cell, min, p < 0.05). We also found a positive correlation between 3-O-MG transport and GR binding capacity in abdominal subjects (r = 0.89, p < 0.001), however we did not find such a correlation in Cushing's disease (r = 0.60, p > 0.05). These results indicated that, in abdominal obesity, the GR binding capacity in MNL is influenced by the changes in glucose transport.