Malgorzata Trofimiuk-Muldner

99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma

Introduction The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. Materials and Methods Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. Results Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). Conclusions 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma.

The development of guidelines for management of thyroid diseases in pregnancy – current status

The increasing awareness of the importance of the proper maternal thyroid function for fetal development prompted the development of guidelines on thyroid diseases in pregnancy. They have been created based on trial results as well as the personal experience of experts. The main differences between guidelines published by the Endocrine Society (ES, 2007, revised in 2012), the American Thyroid Association (ATA, 2011) and the Polish Society of Endocrinology (PSE, 2011) are further discussed. It has to be mentioned that other national guidelines also exist. Physiological changes in thyroid function during gestation influence test results, making the application of general population thyroid hormones reference values for pregnant women the most controversial. Commercially available free thyroid hormones assays tend to give values lower than the actual ones, particularly during the 3rd trimester of pregnancy. The Endocrine Society stresses a need to establish the trimester-specific reference values for each laboratory, however, the American Thyroid Association defines TSH reference values of 0.1-2.5, 0.2-3.0, and 0.3-0.3 µIU/ml for the 1st, 2nd and 3rd trimester of pregnancy, respectively, if such site-specific TSH reference is not available. The results of a multi-centre study on thyroid hormone reference values for Polish pregnant women are in press. In pregnancy, there is an approximately 50% increase in daily iodine requirement. All societies recommend daily iodine intake of 250 μg during pregnancy and lactation, which should be obtained by additional supplementation with formulas containing 150 μg of iodine. The endocrine societies are concerned with careful management of both overt and subclinical hypothyroidism in pregnant women and in women of childbearing age, especially because the number of such cases has increased significantly during the last decade. Moderate-to severe maternal hypothyreosis is associated with maternal and fetal adverse outcomes. The endocrine societies agree that a dose of L-thyroxin has to be adjusted to maintain TSH level within the trimester-specific reference range. A pregnant woman should be followed with TSH measurements every 4-6 weeks. ATA strongly recommends against therapy other than L-thyroxin preparations, including T3. After delivery L-thyroxin should be reduced to the pre-conception dose (ATA, ES, PSE) and TSH checked 4-6 weeks postponed. Consequences of mild maternal hypothyroidism, as well as the level of TSH requiring intervention, are still a matter of debate. According to current guidelines, TSH levels in hypothyroid women of childbearing age should be maintained below 2,5 µIU/ml to reduce the risk of TSH increase in early pregnancy. There is no need to monitor of the thyroid function in foetuses and newborns of hypothyroid mothers (ATA) – in Polish newborns a congenital hypothyroidism screening with TSH is routinely performed. Some issues are still debated, i.e. the necessity to treat isolated hypothyroxinemia during pregnancy or L-thyroxin administration in women with normal thyroid function and positive anti-thyroid antibodies. The lack of unequivocal data supporting the treatment of such cases during pregnancy is also stressed by the PSE. The differences in management of hyperthyroidism during pregnancy mainly concern the use of anti-thyroid drugs: according to the ATA propylothiouracyl (PTU) should be used during the first trimester and patients treated with methimazole (MMI) should be switched to PTU at the moment the pregnancy is confirmed; following the first trimester consideration should be given to switching to MMI. The Endocrine Society recommends the use of PTU as first line therapy in the first trimester as MMI is potentially responsible for congenital abnormalities; if PTU is not available or it is not tolerated MMI should be administered. Moreover, the ES states that decision which anti-thyroid drug is given should be also driven by the practitioners’ own experience. Monitoring of the liver function in patients treated with PTU is recommended by the ES only. The universal screening of asymptomatic pregnant women or women in childbearing age for thyroid dysfunction remains controversial. The ES guideline does not recommend the universal screening suggesting that aggressive case finding should be rather considered. However there was no agreement between all members of the Guideline Committee - some of them recommended screening of all pregnant women for serum TSH abnormalities by the ninth week of gestation or at the time of their first visit. The ATA does not recommend the universal screening. Routine TSH screening is recommended at the 4th-8th week of gestation (first prenatal visit) and in women planning pregnancy by the PSE. Screening for thyroid autoimmunity is not recommended but may be considered if appropriate, e.g. in recurrent spontaneous abortion or miscarriage. The frequency of nodular goitre in pregnant women is up to 20-30%, and differs between populations. The formation of new thyroid lesions during pregnancy is observed in 10-20% of women. The management of the nodular goitre in pregnancy does not differ from the general population (thyroid function assessment, a TPO in hypothyroid women, US and biopsy if needed). There are no essential differences in medullary and anaplastic thyroid cancer management in pregnant women. In case of differentiated thyroid cancer (DTC) the surgery can be performed after delivery as it is recommended by the ATA. If DTC is diagnosed before the 24th week of gestation – thyroid surgery should be considered before the end of the 2nd trimester, particularly for rapidly enlarging lesions (ES, PSE recommendation). If the patient is to be managed conservatively, L-thyroxin should be introduced to maintain the TSH level below 0.1 μIU/ml according to the PSE. The ATA recommends maintaining TSH values between 0.1-1.5 µIU/ml, and the ES – suppressed TSH and FT4 or total T4 in the upper normal range for pregnancy. Mothers with anti-TPO positivity are at increased risk of thyroid illness after pregnancy. The discussed guidelines differ slightly in screening indications for postpartum thyroiditis. The lack of evidence for anti-thyroid drug use in thyrotoxicosis phase is unquestionable. During hypothyreosis phase careful control is necessary and the treatment with l-thyroxin of all women planning next pregnancy is recommended. Summing up, it should be stressed that despite a huge progress which has been made in our understanding of thyroid physiology and pathology in pregnancy there are still important areas of uncertainty and further research is needed to optimize the management of thyroid diseases in pregnancy. The new version of the joint ATA and the ES guidelines is to be released in 2016. The Polish recommendations also need to be revised.

An assessment of the effectiveness of iodine prophylaxis in pregnant women — analysis in one of reference gynaecological-obstetric centres in Poland

INTRODUCTION Iodine deficiency in pregnant women, even of a mild degree, may have adverse effects on both the mother and the foetus. Despite the obligatory model of functioning iodine prophylaxis in Poland, the iodine supply in women during pregnancy and physiological lactation is insufficient. Therefore, those groups should take additional iodine supplementation at a dose of 150-200 μg/day. The aim of this study was to examine the effectiveness of iodine prophylaxis in pregnant women in Poland. MATERIAL AND METHODS The assessment of iodine supply, urine iodine concentration (UIC) in the spot urine sample, as well as levels of TSH, fT4, thyroid antibodies, and thyroid volume, was performed at one time point in 115 women (7 in the 1st trimester, 61 in the 2nd trimester, and 47 in the 3rd trimester). RESULTS Only 45.2% of women were taking additional amounts of iodine at any time of pregnancy, and the median ioduria was 79.6 μg/L, which pointed to an insufficient supply of iodine. The percentage of women using iodine supplementation increased with the length of pregnancy, which indicates that the recommendations are implemented too late. In women who took iodine supplementation, ioduria was significantly higher than in those not applying iodine supplementation (median 129.4 μg/L vs. 73.0 μg/L; p < 0.001); however, this was still below recommended values. CONCLUSIONS The effectiveness of iodine prophylaxis in pregnant women in Poland, evaluated on the basis of the analysis of randomly chosen sample, is not satisfactory in terms of compliance with the recommendations and, possibly, the quality of supplementation.

Reference Values for TSH and Free Thyroid Hormones in Healthy Pregnant Women in Poland: A Prospective, Multicenter Study

Objectives: The diagnosis and treatment of thyroid diseases in pregnant women remains a challenge. Various medical associations recommend establishing the reference intervals for thyroid hormones by a local laboratory. Considering differences within geophysical, socioeconomic conditions, and iodine prophylaxis in various populations, it is advisable to assess reference intervals for thyroid hormones specific to a region of residence. The objective was to assess trimester-specific reference intervals for TSH, fT3, and fT4 for pregnant women in the Polish population. Methods and Results: We conducted a prospective study in 4 centers representing different regions of Poland (Krakow, Warsaw, Poznan, and Bialystok). Our study included consecutive, healthy pregnant women (172 patients), with an age range of 27-47 years. All women had a negative history for thyroid diseases, normal thyroid peroxidase antibody levels, and proper iodine prophylaxis. All newborns had TSH levels in the appropriate reference range. Serum TSH, fT3, fT4, and thyroid-peroxidase antibodies were measured in each trimester. The reference intervals were calculated using the percentile method, as recommended by the International Federation of Clinical Chemistry. The reference values calculated were 0.009-3.177, 0.05-3.442, and 0.11-3.53 mIU/L for TSH; 3.63-6.55, 3.29-5.45, and 3.1-5.37 pmol/L for fT3; and 11.99-21.89, 10.46-16.67, and 8.96-17.23 pmol/L for fT4 in consecutive trimesters of pregnancy. Reference intervals for pregnant women when compared to the general population showed a lower concentration of TSH in every trimester of pregnancy and lower fT4 in the 2nd and 3rd trimesters. Conclusions: Using appropriate trimester-specific reference intervals may improve care of pregnant women by preventing misdiagnosis and inadequate treatment.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients – results from the prospective 12-month phase of Lanro-Study

Aim of the study To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. Material and methods A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. Results 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage – 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care – 49%, hospitalization – 23%, diagnostics/laboratory tests – 28%). Conclusions These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins (Igs) and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells (PBMCs) glycosylation with AITD and the influence of genetic background. The study revealed an inverse association of IgG core fucosylation with TPOAb and PBMCs antennary α1,2 fucosylation with AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity (ADCC) associated with TPOAb levels.

How much of the predisposition to Hashimoto’s thyroiditis can be explained based on previously reported associations?

PurposeOur insight in the genetics of Hashimoto’s thyroiditis (HT) has become clearer through information provided by genome-wide association studies and candidate gene studies, but remains still not fully understood. Our aim was to assess how many different genetic risk variants contribute to the development of HT.Methods147 HT cases (10.2% men) and 147 controls (13.6% men) were qualified for the analysis. Intrinsic and environmental factors were controlled for. Polymorphisms (SNP) were chosen based on the literature and included markers of the genes PTPN22, CTLA4, TG, TPO among others, and of genomic regions pointed by GWAS studies. SNP were typed on a microarray. Variants in the HLA-DRB1 gene were identified by Sanger sequencing.ResultsMultivariate predisposition to HT was modeled. Based on the investigated group, a model of seven variables was obtained. The variability explained by this model was assessed at only 5.4821% (p = 2 × 10−6), which indicates that many dozens of factors are required simultaneously to explain HT predisposition.ConclusionsWe analyzed genetic regions commonly and most significantly associated with autoimmune thyroid disorders in the literature, on a carefully selected cohort. Our results indicated a lack of possibility to predict the risk of HT development, even with a multivariate model. We therefore conclude that strong associations of single genetic regions with HT should be interpreted with great caution. We believe that a change in the attitude towards genetic association analyses of HT predisposition is necessary. Studies including multiple factors simultaneously are needed to unravel the intricacies of genetic associations with HT.

Epidemiologia nowotworów neuroendokrynnych układu pokarmowego w Krakowie i powiecie krakowskim w latach 2007-2011.

INTRODUCTION Gastroenteropancreatic neuroendocrine neoplasms (GEPNEN) are rare and heterogeneous tumours with variable biology. The aim of this study was to evaluate the epidemiology of GEPNEN in the population of Krakow and Krakow district in 2007-2011. MATERIAL AND METHODS The Database of the Chair and Department of Endocrinology, Jagiellonian University Medical College, comprising the data on NEN cases collected from the Endocrinology Department, University Hospital in Krakow and from independent sources: surgery, pathology, and endocrinology departments located in the Krakow area, was searched for cases of GEPNEN patients living in Krakow and Krakow district, diagnosed between 2007 and 2011. Eighty-eight such patients (39 males, 49 females, median age at diagnosis 59 ± 17 years) were identified and characterised. RESULTS The mean follow-up time was 2.67 ± 1.6 years. The most frequent primary location of GEPNEN was small intestine (20%), followed by the appendix (18%), stomach (16%), pancreas (16%), rectum (15%), and colon (15%). NENG1 predominated (64%) in the analysed group. Most well-differentiated GEPNEN (63%) were diagnosed at stage I; however, 18% of them were diagnosed at stage IV. Metastases at diagnosis were found in 31% of patients. The GEPNEN incidence rate in 2007-2011 was 2.1/100000 inhabitants/year, without significant increase during the studied period. CONCLUSIONS GEPNEN incidence and epidemiology in the population of Krakow and Krakow district is similar to the incidence observed in most European countries. Registers are important tools to evaluate GEPNEN epidemiology. (Endokrynol Pol 2017; 68 (1): 42-46).

The relation of pituitary adenomas invasiveness and the proliferative index measured by immunoexpression of topoisomerase IIα

INTRODUCTION Cavernous sinus invasion by pituitary adenoma affects surgical procedure radicality and consequently the postoperative course and prognosis in pituitary adenoma treatment. The search for pituitary adenoma aggressive behaviour markers is still a matter of debate. MATERIAL AND METHODS This study evaluates the relation of pituitary adenoma invasiveness to the expression of topoisomerase IIα in 72 patients who underwent transsphenoidal pituitary surgery. The assessment of tumour growth was conducted according to the Hardy scale as modified by Wilson and the Knosp scale. Topoisomerase IIα expression in tumour specimens was evaluated using immunohistochemical staining. RESULTS There was a correlation between the Knosp scale degree and the topoisomerase IIα expression (Spearman R = 0.3611, p < 0.005). The Kruskal-Wallis H test (p = 0.0034) showed that there was a statistically significant topoisomerase IIα expression increase in tumours classified as grade E on the Hardy scale. The topoisomerase IIα expression correlated also with tumour size (Spearman R = 0.4117, p < 0.001). Higher levels of expression were observed in macroadenomas, as compared to microadenomas (p < 0.05, Mann-Whitney test). Topoisomerase IIα expression correlated with cavernous sinus invasion. CONCLUSIONS The topoisomerase IIα expression correlated more with invasiveness than with extensiveness, which might make it an eminently useful marker in the assessment of aggressive pituitary adenoma behaviour.

Topoisomerase IIα as a prognostic factor in pituitary tumors.

INTRODUCTION There is an ongoing search for markers of pituitary tumor proliferation and progression that could facilitate further treatment and patient monitoring. OBJECTIVES We studied topoisomerase IIα (topo IIα) expression in different types of pituitary adenomas to evaluate its prognostic value. PATIENTS AND METHODS In a retrospective study of 60 patients (mean age, 46.7 ±17.6 y) who underwent pituitary tumor surgery, expression of topo IIα was assessed by immunohistochemistry and compared with histopathological tumor features, clinical symptoms, magnetic resonance imaging, and postoperative tumor recurrence or progression. RESULTS Expression of topo IIα was observed in 44 of 60 pituitary adenomas (73%). The highest topo IIα index was observed in adrenocorticotropic hormone (ACTH)-secreting tumors (median, 1.13% [0.37-1.21]), followed by silent-ACTH tumors (0.94% [0.89-1.0]), and hormone immunonegative adenomas (0.8% [0.65-1.55]). There were no differences in topo IIα expression with respect to age or sex. Significant correlations were observed between the topo IIα index and tumor size, its invasiveness, abnormal ocular test results, and postoperative tumor recurrence. In patients with a topo IIα index exceeding 1%, we observed a 3.5-fold higher relative risk of tumor recurrence as compared with patients with a topo IIα index lower than 1% (95% confidence interval: 1.8-6.9; P <0.001). Patients with acromegaly who received somatostatin analogues before the surgery had a lower median topo IIα index compared with untreated patients (0%[0-0.22] vs. 0.71% [0.17-1.0]; P <0.05). CONCLUSIONS In our study group, a topo IIα index exceeding 1% was a prognostic factor for tumor recurrence or progression, especially in patients with hormonally inactive adenomas, which facilitates patient selection for intensive postoperative treatment. Use of somatostatin analogues in acromegaly inhibits topo IIα expression, providing molecular evidence for the effectiveness of these analogues.