Juniper Publishers | Journal of Endocrinology

Journal of Endocrinology and Thyroid Research (JETR) works mainly on the publication of the papers related to the endocrinology which is meant by study of the all glands present in human body like

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Aldosterone and Parathyroid Hormone: Evidence for a Clinically Relevant Relationship-Juniper Publishers

JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF ENDOCRINOLOGY AND THYROID RESEARCH

Introduction

A ‘new endocrine axis’, involving the bi-directional relationship between the parathyroid hormone (PTH) and the renin–angiotensin–aldosterone system (RAAS) has been established recently. Individually these have long been recognized, although it is only in recent times that we are realizing the interplay between the two and the corresponding effects this has on the physiological and pathological roles within the body. Other calciotropic hormones such as Vitamin D are also impacting on this relationship [1]. This report aims to highlight the cyclic nature of these relationships, through the physiological pathways, which will then lead into pathological disease in multiple areas such as heart failure, cardiovascular health and bone homeostasis. It is through this it is hoped to highlight this new bi-directional relationship.   

Physiological effects of Calcitrophic Hormones on the RAAS

PTH is thought to influence aldosterone secretion in the zona glomerulosa of the adrenal glands [2]. This was demonstrated by Mazzocchi et al. [3], who found that PTH exerts a significant stimulatory action on aldosterone secretion by adrenocortical cells, through the PTH/PTH-RP receptors. PTH is also thought to directly stimulate renin release in the myoepithelial cells of the preglomerular arterioles [4]. Increased activity of the RAAS, and raised aldosterone levels, have been demonstrated in patients with primary hyperparathyroidism. Parathyroidectomy, and its associated reduction in PTH, has been shown to result in normalization of the RAAS system and aldosterone levels.   

Physiological Effects of RAAS on the Calciotrophic Hormones and Calcium Homoestasis

Recent observational studies in individuals with primary hyperaldosteronism suggest that excess aldosterone may result in hyperparathyroidism. A better understanding of the normal physiologic relationship between the RAAS and PTH is of clinical relevance since inappropriate activity of both PTH and the RAAS may negatively impact cardiovascular and skeletal health [5]. Hyperaldosteronism is associated with a reversible secondary hyperparathyroidism due to increased renal and faecal calcium excretion. PTH is increased as a result of the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects, with a trend towards hypocalcemia, hypomagnesemia and the direct effects of aldosterone on parathyroid cells via binding to the MR. Moreover, the angiotensin II receptor is expressed by human parathyroid tissue, and angiotensin may therefore directly stimulate PTH secretion [6].   

RAAS and Vitamin D

Aldosterone acts through the mineralocorticoid receptor, which belongs to the same superfamily of nuclear receptors as the vitamin D receptors (VDR). Therefore, cross talk between these receptors and their agonists could potentially exist. [7]. Vitamin D has been shown to have an inverse relationship with renin levels [8]. Tomaschitz et al. [9] demonstrated that vitamin D deficient patients had significantly higher levels of renin, angiotensin 2 and aldosterone. In a subsequent study, Vaidya et al. [10] found that higher levels of Vitamin D were associated with lower plasma renin activity under both salt conditions, supporting the hypothesis that vitamin D acts as an inhibitor of renin production.   

Bi-directional interplay between PTH and RAAS in Different Systemic Diseases

Neurohormonal activation is a hallmark of chronic heart failure (HF). Low perfusion pressure due to impaired left ventricular function results in the activation of the sympathetic nervous system and the RAAS. Stimulation of adrenal aldosterone synthesis in chronic HF occurs despite sodium and fluid retention. The hyperadrenergic state leads to translocation of cations into the intracellular compartment and the increased aldosterone secretion stimulates faecal and urinary loss of cations. The resulting hypocalcemia and hypomagnesaemia stimulate PTH secretion which tends to restore extracellular calcium and magnesium homeostasis. The PTH promotes mitochondrial Ca2+ excess in the myocardium which leads to oxidative stress and necrotic cell death which, in the long term, causes or amplifies myocardial fibrosis thus aggravating systolic and diastolic HF [11].

PTH also directly stimulates aldosterone synthesis by binding to the PTH/PTH-rP receptor, voltage-gated calcium channels, and the adrenocorticotropic hormone receptor, thus triggering a vicious cycle of mutually reinforcing aldosteronism and hyperparathyroidism. Relative aldosterone excess causes sodium retention and oxidative stress, thus increasing CV morbidity and mortality [2]. PTH also contributes to the development of arterial stiffness, arterial hypertension, and cardiac hypertrophy via binding to the PTH/PTH-rP receptor, which is expressed in vascular smooth muscle cells and cardiomyocytes. In addition, aldosterone excess exerts genomic (by binding to the MR), and non-genomic profibrotic and proinflammatory effects on blood vessels and the myocardium [12].

Aldosterone-Parathyroid Hormone Interactions in Primary Hyperparathyroidism

Early evidence for a physiological and pathophysiological bidirectional link between aldosterone and PTH in humans had initially been derived mainly from case reports. Subsequent studies documented the presence of secondary-hyperaldosteronism in patients with primary-hyperparathyroidism, subsequently a marked reduction in plasma-aldosterone, angiotensin II and renin-activity was noted after parathyroidectomy [13]. Thus, in patients with hyperparathyroidism, the concomitant hyperaldosteronism can aggravate arterial-stiffness, endothelialdysfunction, blood pressure-elevation, vascular-remodelling, cardiac hypertrophy/failure and CVD.

Several studies revealed that patients with PA have alterations in calcium and increased PTH levels [14]. Treatment of PA with either MR-antagonist or adrenalectomy was found to decrease PTH levels [15]. PTH levels were significantly higher in aldosterone-producing adenomas compared to bilateral adrenal-hyperplasia, suggesting that the severity of aldosteronism correlated with severity of hyperparathyroidism. The concomitant hyperparathyroidism could contribute to skeletal diseases and compound CV-risk (beyond the CV-risk associated with PA) [2].

Aldosterone-Parathyroid Hormone Interactions in Bone Diseases

In addition to reversible elevation in PTH levels, reversible PTH mediated bone loss as evidenced by reduction in bonemineral density (BMD), osteoporosis and vertebral fractures were reported in patients with PA. Studies have demonstrated that surgery or medical treatment of PA reduced PTH levels and increased BMD on follow up. Though, bone loss is mostly mediated by PTH, additional mechanisms have been proposed, including a direct effect of aldosterone on bone (MR-expression has been identified in osteoblasts and osteoclasts). Spironolactone has been shown to lower fracture-risk in HF and RAAS-inhibitors lower PTH in CKD.   

Primary and Secondary Hyperaldosteronism

Primary aldosteronism (PA) represents a major cause of secondary hypertension with high cardiovascular morbidity and mortality. Secondary hyperaldosteronism (SA) indicates a bidirectional functional link between the adrenal and parathyroid glands. PA patients have been shown to have a significant increase of primary hyperparathyroidism (PPTH) [16]. Conversely, undetected hyper-functioning of the parathyroid gland can contribute to maintaining PA [17].

Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that correlate with each other; aldosterone regulates parathyroid hormone causing adverse skeletal complications and PTH regulates aldosterone and associates with adverse cardiovascular complications [18]. PTH stimulates in vitro the secretion of aldosterone from human adrenocortical cells in a concentration dependent manner which suggests that PTH acts as an aldosterone secretagogue that may cause human PA [3].

High aldosterone levels are associated with high PTH levels [14,19]. Brunaud L et al [13], observed that elevated aldosterone levels, positively correlated with PTH levels in patients with primary hyperparathyroidism and PTH levels >100 ng/L were an independent predictor of abnormally elevated plasma aldosterone concentration. So, primary hyperparathyroidism is associated with high aldosterone levels and primary aldosteronism is associated with high PTH levels. It is also suggested that PA contributes to secondary hyperparathyroidism [20].   

Effect of Therapeutic Interventions on the CalciCalciotrophic and Renin Angiotensin Aldosterone Systems

Role of PTH surgery on Hyperaldosteronism and CVD Risk Factors

Chronic heart failure, along with hypercalciuria, hypocalcaemia and secondary hyperparathyroidism with subsequent intracellular calcium overload is frequently found in patients with low-renin hypertension and primary aldosteronism. Interplay between the hormones regulating calcium homeostasis and the RAAS contribute to the pathogenesis of arterial hypertension. Brunaud et al. [13] reported significantly decreased aldosterone, angiotensin II, renin activity and blood pressure levels after parathyroidectomy with primary hyperparathyroidism.

Effect of RAAS Blockage and Adrenalectomy on Hyperparathyroidism and Vitamin D Levels

Drugs affecting the RAAS and surgical treatment is associated with an increase in ionised calcium and a decrease in PTH (Rossi E). Adrenalectomy or MR blockers both decrease PTH secretion, arterial blood pressure as well as bone resorption. Animal studies show strong support for vitamin D3 mediated downregulation of renin expression and RAS activity via its interaction with vitamin D receptor [21]. Appendix 1 shows the influence untreated low Vitamin D levels can have on cardiovascular health, via the RAAS and PTH pathways [22-24].   

Conclusion

As shown, increasing evidence is showing a bi-directional interplay between calciotrophic hormones, such as PTH, Vitamin D and the RAAS system. Calcitrophic hormones, particularly PTH and Vitamin D, have a cyclic nature on the RAAS system, affecting each at different receptor and cellular levels. As discussed, there are multiple pathways to consider. For example, the role of PTH’s direct stimulatory action on aldosterone, or hyperaldosteronism’s association with hyperparathyroidism. Or how Vitamin D shares the same receptor as aldosterone, and in vitamin D deficient patients the direct effect on the RAAS, through significantly higher levels of renin, angiotensin 2 and aldosterone. PTH and aldosterone both influence different pathological factors. As shown, it is this relationship between these calciotrophic hormones and the RAAS system that can adversely affect the disease states such as CVD, HF, PA & SA. It is through the recognition of this new ‘endocrine axis’ that there is a clinically relevant relationship between these hormones. From this, surgical and therapeutic interventions can be tailored with this relationship in mind, to ensure optimum treatment outcomes.

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Evaluation of Pre-Transplant Risk Factors as Independent Predictors on the New Onset of Diabetes after Renal Transplants (NODAT)-Juniper Publishers

JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF ENDOCRINOLOGY AND THYROID RESEARCH

Abstract

Background: One of the most potential complications in renal allograft recipients is post- operative impaired glucose tolerance leading to frank de novo Diabetes Mellitus known as New Onset Diabetes after Transplant (NODAT). It is multifactorial and is pathogenically similar to Type 2 Diabetes Mellitus. Having a variable incidence, it is usually associated with an increased risk of infection, cardiovascular morbidity, and graft dysfunction which can eventually cause mortality or loss of the allograft.

Methods: In this study we aimed at comparing pre-operative risk factors namely age, sex, gender, insulin resistance (estimated by HOMA-IR), ß cell function (estimated by HOMA-ß), pre-operative fasting plasma glucose, post-operative fasting plasma glucose, tacrolimus level, induction ATG and hepatitis C virus status as an implicating factor for those who developed NODAT in post-operative period versus those who maintained an euglycemic status throughout the study period (non-NODAT). The study was carried out at the renal transplant unit of NHRTIICS, Kolkata between Jan 2013 to Feb 2014.

Results: Among the 54 subjects included in the analysis, NODAT subjects (n=18) have significantly higher pre-operative insulin resistance levels (measured by HOMA-IR) than non-NODAT (n=36) subjects, p=0.021. Simultaneously, the beta cell function were significantly lower in the subjects in patients who developed NODAT compared to the non-NODAT subjects, p=0.007. Both the pre-operative and post-operative fasting plasma glucose were significantly higher in the patients who developed NODAT, p=0.032 and p<0.001 respectively. Tacrolimus levels were significantly higher in the NODAT patients, however, no significant difference was found with regards to induction ATG received (p=0.96) and hepatitis C virus status (p=0.62).

Conclusion: The incidence of NODAT is quite high in our renal transplant patients. Risk of development of post-transplant diabetes was more closely related to traditional risk factors namely age, pre-operative fasting plasma glucose, post-operative plasma glucose, pre-operative insulin resistance and immunosuppressive therapy.

Keywords: NODAT; Pre-operative risk factors; Independent predictors   

Introduction

Renal transplantation (KT) is the treatment of choice for end-stage renal disease (ESRD); nevertheless, aftermath complications are a major source of concern, one of which is development of post-transplant Diabetes Mellitus, a frequent complication that represents one of the leading causes of morbidity and mortality. Diabetes occurs in a substantial number of subjects following renal transplantation. Post-transplant diabetes mellitus (PTDM) refers to newly diagnosed diabetes in post-transplant setting, irrespective of timing or whether it was present but undetected prior to transplantation or not. However, the term PTDM should be utilized for clinically stable patients who have developed persistent post-transplantation hyperglycemia. On the other hand, new onset diabetes mellitus after transplant (NODAT) refers to the development of diabetes post-transplant in previously non-diabetic patients [1].

New onset Diabetes after transplant (NODAT) is associated with increased mortality and morbidity, and, in particular, higher rates of cardiovascular disease and infection, which are theleading causes of death in renal transplant recipients. Many of the same risk factors that predispose non-transplant subjects to diabetes mellitus have been identified as risk factors for its development after transplantation. Such common risk factors include age, obesity, African-American race and Hispanic ethnicity, family history, and impaired glucose tolerance. Risk models for NODAT have been developed and validated using pre-transplant variables alone. In addition, some risk factors are unique to the transplant population. These include specific agents used for immunosuppression, human leukocyte antigen (HLA) mismatch, donor sex, and type of underlying renal disease [2]. Impaired glucose tolerance prior to transplant and hyperglycemia in the immediate perioperative period may identify subjects at higher risk for the development of NODAT [3,4].   

Materials and Methods

This was a single centered retrospective real world observational study of 54 subjects who underwent renal transplantation over a period of one year in a tertiary care center in eastern India. NODAT was defined according to American Diabetes Association definition with fasting glucose level equal or greater than 126mg/dl on two separate blood tastings; and/or two hours OGTT values equal or greater than 200mg/dl; and/or glycosylated hemoglobin (HbA1C) equal or greater than 6.5. The Inclusion criteria were comprised of adult subjects with end stage renal disease who underwent live donor kidney transplantation, absence of diabetes prior to kidney transplantation, defined according to American Diabetes Association guideline (not on oral hypoglycemic agents or insulin with fasting glucose <126mg/dL) and received immunosuppressive medications that include Tacrolimus. Subjects who were capable of understanding the study and given informed written consent for study participation were only included. Subjects with a diagnosis of diabetes mellitus prior to kidney transplantation based on ADA criteria for diagnosis of diabetes mellitus or those receiving anti-diabetic medications or those who were not capable of providing consent were excluded from the study.

Statistical methods

Descriptive statistical analysis has been carried out in the present study. Results on continuous measurements are presented on Mean±SD and results on categorical measurements are presented in Number (%). Significance is assessed at a level of 5%.   

Results

Among the 54 subjects included in the analysis, mean age of the subjects were 46±10.33 years and 32.14±13.67 years in NODAT (n=18) and Non-NODAT (n=36) cohort respectively. There was a statistically significant difference between two groups with respect to age. The study has a slight male preponderance with only 13 (24.07%) were females and the rest 41 (75.93) were males. However, there was no significant between the two cohorts with respect to BMI (Table 1). In our study, NODATsubjects have significantly higher pre-operative insulin resistance levels (measured by HOMA-IR) than non-NODAT subjects, p=0.021 (Table 1). Simultaneously, the beta cell function were significantly lower in the subjects in patients who developed NODAT compared to the non-NODAT subjects, p=0.007 (Table 1). Both the pre-operative and post-operative fasting plasma glucose were significantly higher in the patients who developed NODAT, p=0.032 and p<0.001 respectively (Table 1). Tacrolimus levels were significantly higher in the NODAT patients, however, no significant difference was found with regards to induction ATG received (0.96) and hepatitis C virus status (0.62) (Table 1).   

Discussion

According to International Consensus Guidelines on NODAT, 2003 recommendations, American Diabetes Association (ADA) criteria for type 2 diabetes published in 2003 should be used for diagnosis. The guidelines recommends fasting plasma glucose (FPG) ≥126mg/dL, 2-hour post-glucose ≥200mg/dL and random plasma glucose =200mg/dL), on three or more occasions [5]. Risk of diabetes increase to nine folds in solid organ transplant recipients than their age matched controls. The incidence rates are even higher in the first six months after transplantation [6].

New onset diabetes mellitus after transplantation (NODAT) is a well-known complication reported to occur in 2% to 53% of renal transplant subjects [7]. Such a wide variation may be because of lack of a universal agreement on the definition of NODAT, the duration of follow-up, and the presence of modifiable and non-modifiable risks factors [8]. From Indian studies, the incidences of NODAT were 19.12% by Prakash J et al. [9] while Sharma A et al. [10] and Bora GS et al. [11] found incidence ofNODAT was 16.75% and 54.5%, respectively. So there is wide variation among incidence. In our study the incidence of NODAT is 33.33%. Out of 18, 15 (83.33%) were male and 3 (16.67%) were female, which is asserting with the existing results. In one of the recent Indian studies by Prakash J et al. [9], mean age of NODAT was 40.4 and in non-NODAT was 31.13 [9]. Similar finding was found in our study, mean age of the subjects was 46±10.33 years and 32.14±13.67 years in NODAT (n=18) and Non-NODAT (n=36) cohort respectively. There was a statistically significant difference between two groups with respect to age.

Obesity independently correlates with the development of NODAT [12,13]. An analysis of 15,309 patients using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database found that the risk of NODAT increased 1.4-fold for those with a BMI of 25 to 30 and nearly doubled if the BMI was >30 [14]. Our study results didn’t find any significant difference in BMI between the NODAT (19.33±3.08) and non-NODAT cohort (19.99±3.45). The primary reason for not getting any significant difference is that all of the included patients had a low BMI, primarily attributable to the poor socio-economic status of our country.

According to International Consensus Guidelines on NODAT, 2003, the guidelines also recommends to preferred FPG test for diagnosing NODAT [7]. The subjects with diabetes and NODAT cohort showed increased fasting blood glucose levels, whereas normal cohort subjects were well within the normal limits [15,16]. Our study results were also providing evidence in the same line where the subjects who developed NODAThad significantly higher level of pre-operative fasting plasma glucose and post-operative fasting plasma glucose.

Consequently, high incidences of de novo hyperglycemia immediately after transplantation have been reported. This may be associated with the exposure of pancreatic β-cells to several stress factors, collectively the surgical procedure, weight gain due to physical inactivity immediately after surgery (insulin sensitivity), high doses of corticosteroids and initiation of calcineurin- inhibitor (CNIs) [17]. The underlying mechanism of development of NODAT can be classified into insulin resistance and defect in insulin secretion [7]. Preoperative impaired glucose tolerance generally identifies transplant candidates who are at higher risk for the development of NODAT. This was supported by one study in which impaired glucose tolerance was identified in 18 percent of non-diabetic patients prior to transplantation. Among 31 patients who developed NODAT after transplantation, 16 (52 percent) had impaired glucose tolerance pre-transplant [3]. In multivariate analysis, pre-transplant impaired glucose tolerance was associated with the development of NODAT (RR 2.4, 95% CI 1.1-5.3) [18,19]. Thus corroborating with the previous findings, the present study demonstrates that pre-operative insulin resistance (as measured by HOMA-IR) is significantly higher in the NODAT than non-NODAT cohort.

NODAT is consistent with type 2 diabetes and responds to the usual anti-diabetes agents. However, severe hyperglycemia during the early post-transplant period may necessitate the use of insulin. Also, high-dose glucocorticoid therapy for induction of immunosuppression (or treatment of acute rejection) may require the use of insulin therapy for glycemic control. After hospital discharge, close monitoring of blood glucose during the first month and every three months for the first year is recommended [17]. In the present study, tacrolimus levels were also significantly higher in the NODAT cohort as compared to the non-NODAT cohort. Thus from the above discussion, in the present study, tacrolimus levels, pre-operative insulin resistance levels and beta cell function were all significantly implicated in the development of NODAT.   

Conclusion

The incidence of NODAT is quite high in our renal transplant patients. Risk of development of post-transplant diabetes was more closely related to traditional risk factors namely age, pre-operative fasting plasma glucose, post-operative plasma glucose, pre-operative insulin resistance and immunosuppressive therapy.   

Limitations

The study has many limitations and the results should be interpreted in view of the limitations. As with any observational study, this study lacks the vigilance of a controlled environment and adverse events are under reported. Larger and more comprehensive trials are required to establish and further validate our findings.

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Thyroid Dysfunction During Pregnancy-Juniper Publishers

Relevance

In the first half of pregnancy, human chorionic gonadotropin (hCG) production by the placenta increases, which is similar in structure to thyroid-stimulating hormone (TSH) and has TSH-like effects, stimulating the production of thyroid hormones [1]. Therefore, the level of thyroid hormones increases, and the mechanism of “feedback” suppresses TSH. Decrease of hCG secretion during pregnancy further leads to a decrease of free T4 (fT4) and free T3 (fT3) and leads to normalization of TSH level [2,3]. Thyroid hyperfunction and presented symptoms subside with a decrease of hCG production, usually at 14–18 weeks of getation. In most cases, the cause of hyperthyroxinemia is gestational transient thyrotoxicosis, which occurs in the first half of pregnancy. This condition, which is characterized by an increased level of fT4 and a decrease of serum TSH, is diagnosed in approximately 1-3% of pregnant women [4,5].

Clinical Observation

Patient A., born in 1994, came to the RSSPMC of Endocrinology at 11.05.2018y with complaints to palpitations, nausea, vomiting 5-6 times a day, irritability, tremor, weight loss.

Endocrinological history

Patient a year ago took Iodomarin 200 1tab in the morning for the treatment of diffuse euthyroid goiter. The above complaints began to increase within a month.

Gynecological History

Menarche - from 14 years, menstruation for 4-5 days, after 28 days, regular, painless. Patient denies any gynecological diseases.

Obstetric History

First pregnancy ended with an urgent and normal birth with the birth of a full-term alive baby, second pregnancy - intrauterine death of the fetus at 4-5 weeks (patient associates this condition with SARS), third pregnancy ended with an urgent and normal birth with the birth of a full-term alive baby, fourth ended with miscarriage in 3-4 weeks [6]. Current pregnancy - occurred independently. Pregnancy flows with toxaemia from 5-6 weeks of pregnancy (vomiting 5-6 times a day). From 6 weeks of pregnancy, come out anemia of pregnant women (she does not take antianemic drugs).

Objective Data

General condition of patient is relatively satisfactory. Skin - clean, pale, palms are moist. Pulse 90 beats per minute. Blood pressure 110/80 mm Hg. On the auscultation on lungs vesicular breathing, heart sounds are clear rhythmic. On palpation abdomen is soft, painless in all areas. Thyroid gland on palpation enlarged to II st, soft elastic, painless.

Laboratory Tests

hemoglobin 95 g/L, blood glucose 4.9 mm/L, TSH 0.02 mU/L, fT4 - 4.37 ng/dl, antibodies to TPO 20.2 U/ml, antibodies to TSH receptors 0,01 U/L, ultrasound of the thyroid gland - picture of diffuse goiter.

Obtained data allowed formulating the following diagnosis:

Primary: Gestational Transient Thyrotoxicosis.

Concomitant: Pregnancy V, childbirth III, 8-9 weeks moderate severity anemia. Toxemia of pregnancy.

Considering erased complaints, the absence of thyrotoxicosis in clinical history, clinical signs of thyrotoxicosis, weight loss and low levels of antibodies to TSH receptors, to the patient recommended symptomatic treatment: beta-blockers, antianemic drugs, sedatives and hospitalization to specialized gynecology department for the treatment of toxemia of pregnant women. After re-examination in one-month patient had no complaints [7]. The skin had normal moisture. Pulse 80 beats per minute. Blood pressure 110/80 mm Hg On the auscultation on lungs vesicular breathing, heart sounds clear rhythmic. On palpation, the abdomen is soft, painless in all areas. On palpation, thyroid gland enlarged to II st, soft elastic, painless. Laboratory tests: hemoglobin 110 g/L, TSH 1.0 mU/L, fT4 2.0 ng/dl. The general condition of the patient with symptomatic treatment has improved. Tachycardia and vomiting - not observed. Indicators of thyroid hormone studies returned to normal. Monitoring continues.

Conclusion

In this observation, patient had symptoms of gestational transient thyrotoxicosis. A similar picture of gestational transient thyrotoxicosis and thyrotoxicosis often leads to several diagnostic errors and leads to incorrect treatment tactics and to prescribing unreasonable appointment of antithyroid drug. Thus, when observing symptoms of thyrotoxicosis at the beginning of pregnancy, more attention to complaints, history of thyrotoxicosis, the severity of clinical signs of thyrotoxicosis, thyroid ultrasound, low levels of TSH receptors antibodies and slightly elevated levels of free T4 and TSH. During the diagnosis of gestational transient thyrotoxicosis, antithyroid drug not recommended, more preferred symptomatic treatment. By the middle of the second trimester, patient’s clinical condition is improving, and indicators of the hormonal status are normalized due to the physiological decrease of hCG.

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Spectrum of Thyroid Abnormalities among Pregnant Women in Basrah- Juniper Publishers

Abstract

Background: Thyroid dysfunction is the second most common endocrine disorder in pregnancy coming only after diabetes mellitus.

Objective: to see the spectrum of abnormal thyroid function among apparently healthy pregnant women in Basrah (Southern Iraq).

Patients and methods: This was a cross-sectional study conducted between January 2014 and June 2015 for the screening of thyroid function in pregnant women in Basrah. Initially, we enrolled 893 pregnant women, and after applying exclusion criteria reduced to 628 pregnant women, they are divided into two groups according to anti-thyroid peroxidase (anti-TPO) antibodies status. Pregnant women sent for thyroid stimulating hormone (TSH), free thyroxine (FT4), and anti-TPO antibody tests. The samples were collected from private and public sectors in Basrah city (Southern Iraq).

Results: thyroid dysfunction was significantly higher in anti-TPO positive pregnant women, compared to those who were negative (39.6% versus 18.4% respectively). For anti-TPO negative antibody pregnant women, the following results were obtained; isolated hypothyroxinemia 5.4%, isolated hyperthyroxinemia 3.6%, subclinical hypothyroidism 4.2%, clinical hypothyroidism 0.4%, subclinical hyperthyroidism 3.9 %, and clinical hyperthyroidism 0.6%. While for anti-TPO positive antibody pregnant women the results were as follow; subclinical hypothyroidism 10.4%, isolated hypothyroxinemia 8.5%, isolated hyperthyroxinemia 5.7%, clinical hypothyroidism 7.5%, subclinical and clinical hyperthyroidism in 4.7% and 2.8% respectively.

Conclusion: Thyroid dysfunctions are common during pregnancy. Subclinical hypothyroidism and isolated hypothyroxinemia were the two most common thyroid abnormalities seen in pregnant women. Anti-TPO antibodies positivity predict an increase in thyroid diseases especially clinical and subclinical thyroid diseases.

Keywords:Pregnancy; Thyroid dysfunction; Subclinical hypothyroidism; Subclinical hyperthyroidism; Isolated hypothyroxinemia; Thyroid peroxidase antibodies

Introduction

Thyroid dysfunction is the second most common endocrine disorder after diabetes mellitus, affecting women in fertile age period [1]. Societies living in different geographical areas of the world may have different thyroid function tests parameters [2]. Thyroid dysfunction during pregnancy is relatively high mostly occurs in subclinical form (about 10%), while overt thyroid dysfunction occurs in 2-3% of pregnancies [3]. Some normal physiological changes during pregnancy alter thyroid function test parameters, which should be taken into consideration. The increase in estrogens induces an increase in thyroxine-binding globulin (TBG) which increases the total (bound) thyroid hormones, in addition, human chorionic gonadotropin hormone has some thyrotropic activity that induces a slight increase in free thyroxine (FT4) with a peak at the end of the first trimester, and this causes a transient decrease in thyroid stimulating hormone(TSH) [4]. Thus caution should be taken when using non-pregnant reference ranges of FT4 and TSH for pregnant woman and certain standardization required to validate their values [5].

Maintaining normal thyroid function during pregnancy is vital to both mother and baby, where hypothyroxinemia was associated with worse metabolic parameters with increased obesity, triglycerides and insulin resistance in the mother [6] while hypertension was associated with both hypo and hyperthyroidism [7]. Moreover, the fetus depends on mother thyroid hormones for his brain development in the first and second trimesters [8]. Pregnant woman with subclinical hypothyroidism in addition to hyperthyroidism and hypothyroidism have increased the risk of intrauterine growth retardation (IUGR) [9]. Overt hypothyroidism during pregnancy was also associated with several complications including increased risk of caesarian section delivery [10,11]. The adverse effects of subclinical hypothyroidism (SCH) accompanied with positive anti-thyroid peroxidase(anti-TPO) antibodies, or overt hypothyroidism on pregnancy outcome are well known. However, there is controversy over the adverse impact of SCH without autoimmunity on pregnancy outcomes [12].

Although some researchers reported no significant increase of placental abruption, preterm labor and low birth weight in pregnancy complicated by subclinical hyperthyroidism in comparison with euthyroid ones, [13] others reported that thyrotoxicosis is associated with a risk of spontaneous abortion, congestive heart failure, thyrotoxic storm, preeclampsia, preterm delivery, low birth weight, and stillbirth [14]. The objectives of this study were to see the spectrum of abnormal thyroid function among apparently healthy pregnant women in Basrah (Southern Iraq).

Methods

Setting

This study was a cross-sectional study included pregnant women selected from people attending Primary Health Centers (PHC), hospital outpatient clinic, and private gynecologic clinics in the city of Basrah (Southern of Iraq) and conducted between January 2014 and June 2015 for the screening of thyroid function in pregnant women in Basrah to established trimester specific normal thyroid values and detect thyroid dysfunctions among pregnant women in Basrah by the Faiha Specialized Diabetes Endocrine and Metabolism Center(FDEMC). The first part of the study was published previously [15]. Written informed consent was taken from all women to participate in this study, and the ethical committee of the College of Medicine in Basrah University approved the study.

Inclusion criteria: subject inclusion criteria were healthy pregnant women with uncomplicated single intrauterine gestation who gave written informed consent to participated in this study.

Exclusion criteria: any patient with a history of hyperemesis gravidarum, use of medication known to affect thyroid function, thyroid surgery, any significant acute or chronic diseases were excluded from the study.

From the total number of 893 participants, 31 excluded by history and 234 have their samples lost during processing; the remaining 628 women have accomplished sampling for TSH, FT4, and anti-TPO antibodies. (Figure 1) In this study, we use our local values of trimester-specific thyroid function in Basrah. TSH value between 0.04–3.77 μIU/mL considered normal for women in the first trimester, 0.30–3.21 μIU/mL for the second trimester and 0.60–4.5μIU/mL for the third trimester. While FT4 value between 0.8–1.53 ng/dL considered normal for the first trimester, 0.7–1.2 ng/dL considered normal for both second and third trimesters.

Pregnant women with high TSH and normal FT4 were considered as having subclinical hypothyroidism. Those with high TSH and low FT4 were considered to have overt hypothyroidism. Subclinical hyperthyroidism used in those with low TSH and normal FT4 and overt hyperthyroidism was diagnosed in those with low TSH and high FT4. Isolated hyper and hypothyroxinemia considered respectively for elevated and reduced FT4 despite normal TSH. Positive anti-TPO antibodies were considered if the level is 34 IU/mL or above. Each patient included in the study sampled for a once during pregnancy and never been tested again throughout the same pregnancy.

Biochemical Tests

All was done by an electrochemiluminescence (ECL) technique using commercially available kits from Roche Diagnostics (Germany) with cobas e 411 analyzer. The analysis was done in FDEMC laboratory. The intra-assay coefficients of variations were as follows: TSH 0.1–4 μU/mL (<5% CV), FT4 25– 100 pmol/L (<3% CV), and anti-TPO antibodies >40 IU/ML (<7% CV). The measuring range and normal values were mentioned before [15].

Statistical Analysis

For statistics, all data were computed and analyzed using SPSS, (version 15.0).

Results

The mean age was approximately 28 ± 7.2 years. The number of women according to the trimesters were 155 (24.6%), 283 (45.1%) and 190 (30.3%) for the first trimester, second and third trimesters respectively. From a total number of 628 women, the anti-TPO antibody was positive in 106 (16.9%). While the remaining 522 (83.1%) were negative. In negative anti-TPO antibodies pregnant women, 426(81.6%) were having normal thyroid function. This means that 96(18.4%) were having some abnormality in thyroid function. Isolated hypothyroxinemia was the most prevalent thyroid disorder seen in 28(5.4%). While Subclinical hypothyroidism and hyperthyroidism were observed in 22(4.2%) and 20(3.9%) respectively (Table 1) (Figure 2).

Of 106 patients with anti-TPO antibodies women, 64 (60.4%) were having normal thyroid function.For pregnant women with positive anti-TPO antibodies, subclinical hypothyroidism was the most frequent abnormality, seen in 11(10.4%) followed by isolated hypothyroxinemia observed in 9 (8.5%) of pregnant women (Table 2) (Figure 3). Clinical hypothyroidism and isolated high FT4 (isolated hyperthyroxinemia) were seen in 8 (7.5%) and 6(5.7%) respectively. Subclinical and clinical hyperthyroidism was observed in 5 (4.7%) and 3 (2.8%) pregnant women respectively. Collectively thyroid dysfunction was significantly higher in anti-TPO positive pregnant women, compared to those who were negative (39.6% versus 18.4% respectively) (Table 3).

Discussion

Subclinical hypothyroidism is the most common thyroid dysfunction during pregnancy [16]. In this study subclinical hypothyroidism in pregnant women, was lower to what has been seen in India and Congo (6.47% and 12% respectively) [10,17]. In India, they use the CLIA chemiluminescence immunoassay technique, but they use laboratory reference value for TSH 0.5- 5 μIU/mL to differentiate clinical thyroid categories. They did not measure FT4 routinely, but they use it selectively. In the Congo study the difference might be because they used median results rather than the mean as we did, in addition, they did use colorimetric method while we use electrochemiluminescent one, they did use a combination of American Thyroid Association (ATA) guidelines with manufacturer reference values as a cut limit to diagnose normal and abnormal thyroid functions. Of those diagnosed as having subclinical hypothyroidism one half were found to be positive anti-TPO antibodies. This was higher to what has been seen in Bengal-India which report about 34%. On the other hand, the Bengal study reported subclinical hypothyroidism in 32.9% of pregnant women which is significantly higher to what has been seen in our study, probably because they use a cut-off equal to 2.5 μIU/mL for TSH [18].

In our study, clinical hypothyroidism was found in about 0.4 % of negative anti-TPO antibodies, while in India it is about 13.13% which is significantly higher than in our study [19]. The Indian study was using a TSH cut off equal to 4.5 μIU/mL as the upper limit of normal. Our local study considers TSH of 3.7 μIU/ mL, 3.2 μIU/mL, and 4.5 μIU/mL as the upper limit of normal for each trimester respectively. This may explain the difference between our prevalence values. While a Mexican study gives nearer values to our results of about 1.11% [20].

Subclinical hyperthyroidism with negative anti-TPO antibodies was found in about 3.9% of our studied population; this was more than double of Casey and his colleague’s results [12]. The difference from Casey study is that they use weekly gestational age reference range for TSH, but the FT4 value was not adjusted for gestational age. While our study uses trimester specific values for both TSH and FT4.

In general hyperthyroidism during pregnancy was less frequently seen than hypothyroidism [21]. The prevalence of hyperthyroidism during pregnancy is about 0.2% in an American study [22] while in the current study in Iraq the prevalence of clinical hyperthyroidism is higher 0.6 %. Overt hyperthyroidism during pregnancy if being due to Graves’ disease could result in fetal thyroid dysfunction [23]. Isolated hypothyroxinemia may be defined by some authors as normal TSH and FT4 below the reference range [24], where others may define isolated hypothyroxinemia as a normal level of TSH with FT4 below the 2.5th, 5th, or 10th percentile of normal pregnant women [25,26]. Iron deficiency may also precipitate a state of hypothyroxinemia [27]. Isolated hypothyroxinemia was seen in about 8.5% of positive anti-TPO antibodies pregnant women. Although controversial some studies showed that isolated hypothyroxinemia in pregnancy is associated with worse metabolic parameters with increased obesity, hyperglycemia, hypertriglyceridemia, and increased insulin resistance as compared with euthyroid and subclinical hypothyroid pregnant women.

As compared to the Exeter family study of childhood health results that showed the incidence of isolated hypothyroxinemia of about 8.6 % [28] which is higher than in our study. The isolated hypothyroxinemia was considered if TSH is normal per trimester, but FT4 was below the 10th centile (0.81 ng/ dL). Exeter study was taking investigation sample in the 28 weeks of gestation, while we took it at different times during pregnancy. More significant sample size and longer duration of the study about five years for Exeter, as compared to 1.5 years and a smaller sample size for our study. Both studies used electro chemiluminescent immunoassay, (Roche) analyzer. The same definition of the isolated hypothyroxinemia but different cut levels were used for each study. We used local reference values, while Exeter used manufacturer value for FT4 and a cut value of 3 μIU/mL for TSH.

Isolated hyperthyroxinemia was seen in a small percentage in our study. Maternal euthyroid hyperthyroxinemia could have beneficial rather than harmful effect, where it may reduce the incidence of preterm delivery in multiparous women as shown by a German study [29]. Generally, in our study anti-TPO positivity confer a higher chance of thyroid dysfunctions. This was in accordance to what have been seen in the PORMETS study from Portugal [30].

Conclusion

Thyroid dysfunctions are common during pregnancy. Subclinical hypothyroidism and isolated hypothyroxinemia were the two most common thyroid abnormalities seen in pregnant women regardless of anti-TPO antibodies state. Positive anti- TPO antibodies predict an increase in the prevalence of thyroid disease especially clinical and subclinical thyroid dysfunction

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Role of Amylin in Thyroid Cancer- Juniper Publishers

Abstract

The prevalence of thyroid nodules and cancers were shown to be associated with type II diabetes mellitus (T2DM), obesity especially central obesity, and metabolic diseases. Recent studies reported that amylin, an amyloidogenic pancreatic peptide deposited in the pancreas in T2DM, theses aggregates enter the circulation and recently reported to be deposited in the brain and involved in the development of Alzheimer’s disease. These circulatory amyloid aggregates may also deposit in the thyroid gland and causes activation of some pathogenic pathways that may result in the development of thyroid nodules and cancers. This review presents some of the available data about the role of amylin in type 2 diabetes mellitus (T2DM), the association between T2DM with thyroid carcinoma, and the possible role of amylin in the pathogenies of thyroid nodules and cancers.

Keywords:Cancer, Amylin, Insulin, Diabetes, Obesity, Neurodegenerative Diseases

Introduction

Amylin and its Physiological Functions

Amylin is a 37-amino acid peptide that is co-secreted with insulin from β cells of the pancreas in response to nutrients intake, such as glucose, amino acids and lipids [1]. It is also called as islet amyloid polypeptide (IAPP) as it is found in the form of myeloid aggregates in the pancreatic islets [2]. Amylin plays a role in glucose homeostasis, reducing blood glucose level, inhibiting food intake, an action that can be mediated by the effect of amylin on leptin expression and signalling in the ventromedial nucleus of the hypothalamus [3]. The effect of amylin on food intake can be also due to the central action of amylin on the area postrema as ablation of this area abolished the inhibitory effect of amylin on food intake [4]. Amylin decreases gastric motility and delay gastric emptying, an effect that helps in delaying the entry of nutrients into the small intestine, delaying intestinal absorption and subsequently decreasing the serum levels of different nutrients especially glucose. All those effects of amylin can explain athe effectiveness of using amylin agonists in the treatment of diabetes and the potential use of amylin obesity [5]. In addition to the centrally-mediated effect of amylin in delaying gastric empting and food intake, it has been also reported that amylin mRNA and its receptors are expressed in the stomach, suggesting a direct effect of amylin on gastric emptying [6]. Amylin is a member of the calcitonin family, which includes, αcalcitonin-gene related peptides (αCGRP), βCGRP, adrenomedullin (AM) and intermedin (AM2). The effects of the calcitonin family members are mediated by calcitonin receptors (CTR) and CTR-like receptors (CLR). The specificity of those receptors for the members of calcitonin family depends on certain receptor-associated proteins called receptor-activity-modifying proteins (RAMPs) [7]. The receptors for amylin include, AMY1, AMY2, and AMY3, each consists of a combination of CTR with RAMP1, RAMP2, and RAMP3 respectively [8]. Amylin is metabolised via renal excretion and by proteolysis into less active and inactive metabolites [5]. Amylin (1-37) is the major molecular form of human amylin revealed by radioimmunoassay of the pancreatic tissue. There are two forms of circulating human amylin, the non-glycosylated form which is the biologically active form and the glycosylated form [9].

Dysregulation of Amylin with Diabetes Mellitus

Although amylin works to decrease blood glucose level, it is reported that amylin can be cytotoxic due to the formation of amylin aggregates; amyloids that associated conditions of T2DM [10]. Amylin aggregation in the pancreatic β cells induces endoplasmic reticulum stress and damage of mitochondrial membrane resulting in death of the β cells of the pancreas [8]. Normally, these aggregates once, formed, an autophagy process with be stimulated and degrade the aggregates protecting the cells from their cytotoxic effects as evidenced by the appearance of amyloids in the pancreatic β cells of mice lacking ATG-7, ATG the autophagy-related proteins [11]

Diabetes Mellitus and Thyroid Cancer

Studies over decades confirmed the association of different types of cancer with diabetes especially T2DM. Worldwide, thyroid cancer is the most common endocrine malignancy among women [12]. The increasing prevalence of thyroid carcinoma as well as diabetes suggesting a link between them [13]. In 2017, Li et al. [14] published a met-analysis of 16 cohort studies that included 10,725,884 individuals, with a total of 8032 cases of thyroid cancer reported a positive association between the diabetes mellitus and increased risk of thyroid cancer mainly among women. In addition, a recent study reported a decrease in survival among patients with thyroid carcinoma who suffer from T2DM as compared with thyroid cancer patients who are not diabetics [13]. A more recent study reported an association between the increased risk of thyroid nodules with obesity, central obesity, insulin resistance and disturbed lipid profile [15]. Based on these studies, amylin may play a role in the pathogenesis of thyroid carcinoma. Understanding the regulation of amylin can help in enhancing its uses as a treatment or even as prophylactic.

Conclusion

Amylin is physiologically important in glucose homeostasis. However, if it forms aggregates, it causes cellular stress resulting in diseases such as diabetes mellitus. Increased association between T2DM with thyroid nodules and cancers suggests a possible role of amylin in the pathogenesis of thyroid carcinoma mediated by deposition of amyloids.

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Review: Testosterone Replacement Therapy. Through 2018 Updates, should we Still Consider it a Prostate Cancer Risk Factor?- Juniper Publishers

Introduction

Testosterone Replacement Therapy (TRT) usage has great benefits on men’s health and do improve more the symptoms that could occur in those who are complaining of hypogonadism or andropause. However, it is classically known the oncological risks that may be caused due to its usage on the prostate, that’s why it was used with cautious. Recently many articles appeared in the last few years refuting this and evidencing the concept that there is no harm of their usage with those who are at risk of prostate cancer or even have treated prostate cancer. In this short review, it is aimed to review the literature that support this evidence published in 2018 on the PubMed.

Discussion

The decrease of the serum Testosterone levels causes what is known as hypogonadism which is manifested by decrease in libido, erectile dysfunction, fatigue and depression. This condition has a counted prevalence in men above the age of 50 years old. On the other side prostate cancer incidence starts to sharpen up after this age also and that’s why most of the screening programmes recommends starting the screening for men without family history at the age of 50 years old. As a historical knowledge it is known that Testosterone fuels the prostate cancer, this originally comes from 1941 when Dr Charles Huggins found that castration resulted in regression of the metastatic PCa and the debate is on since then [1].

Is it important to use it?

Restoring testosterone levels to within the normal range by using testosterone replacement therapy can improve many of the effects of hypogonadism. Most importantly, this also include beneficial effects on mood, energy levels and patients’ sense of well-being, sexual function, lean body mass and muscle strength, erythropoiesis and bone mineral density in addition to its use to improve other clinical symptoms of the metabolic syndrome, which presents as visceral obesity, hypertension, diabetes mellitus, and dyslipidaemia and are considered to be a potential risk for cardiovascular disease and cerebral apoplexy [2].

Recent Evidence of its Safety on the Prostate

Looking for the recent evidences and literature supporting that there is no correlation between the TRT and the prostate cancer which is challenging the classic opinion, Walsh TJ et al. [3] identified 56,833 men who initiated testosterone treatment for low testosterone levels and they were followed up for 3 years with PSA compared to non-treated group and a total of 1,439 prostate cancers were diagnosed; 848 were diagnosed among untreated and 591 among testosterone-treated men which was not a big statistical difference. So, they concluded that there is no much increase in the risk of prostate cancer development in those who are treated with testosterone in compared to nontreated group. However, the main pitfall of this study its short duration and it was recommended to have the same study for longer time up to 10 years.

A review by Torres et al. [4] summarized some evidences from the literature by different studies that compared patient who have a sort of treated prostate cancer and normal person and it was concluded at the end of the review that there are a lot of reassuring data that TRT doesn’t have a direct risk in causing PCa but yet there is still a small number that have a prostate cancer under TRT so a larger number studies and longer duration of follow up is recommended. Finally, a 2015 retrospective review of 98 hypogonadal men treated with TRT after radiation therapy for PCa and followed for about 40 months, they showed a rise in the levels of serum testosterone but there was no significant increase in mean PSA [5].

Conclusion

To our knowledge in 2018 there was limited published evidence on this subject. However, the new data keeping with the flow of the new evidence that there is conservative safety in TRT usage as regard its prostate cancer potential risk.

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Thanks Giving Day- Juniper Publishers

Happy Thanksgiving Day.

Juniper Publishers would like to extend warm wishes to you and yours.

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The Relationship Between Cardiometabolic Risks and Vitamin D Level with the Degree of Obesity- Juniper Publishers

Abstract

Objectives: The aim of this study was to improve the understanding of the distribution of cardiometabolic risk factors and 25 hydroxy vitamin D level according to the degree of obesity in adolescents by gender.

Methods: We performed a retrospective cross-sectional analysis of the data from overweight or obese adolescents 11 to 18 years of age who were evaluated in our clinic from January 2012 to December 2015. Degree of obesity was calculated as the body mass index standard deviation(SDS-BMI). Hypertension, dyslipidemia, hyperinsulinemia, hyperglycemia and insulin resistance were defined as cardiometabolic risk factors. Vitamin D level was recorded.

Results: Of the 319 adolescents, 85.7% had at least one cardiometabolic risk factor. As SDS-BMI increased, number of cardiometabolic risk factors were found to increase(p=0.0001); 25 hydroxy vitamin D level was found to decrease(p=0.003). In the linear regression models in which sex and age were considered as covariates, an increase of one unit in the SDS-BMI led to an increase of 6.085 mmHg in systolic blood pressure, 4.4 mmHg in diastolic blood pressure, 1.59 points in HOMA-IR, 13% in insulin level; and a decrease of 2.16 ng/ml in vitamin D level.

Conclusion: The severer the obesity, the more the number of cardiometabolic risk factors present in adolescents is. Thus, determination of the severity of obesity can help to identify who are at greater risk for higher blood pressure, and impaired glucose metabolism, and lower serum vitamin D levels. On the other hand, the degree of obesity may not reflect the presence of abnormal lipid and glucose levels.

Keywords: Adolescents; Cardiometabolic Risk Factors; Degree Of Obesity; Vitamin D Level

Introduction

The frequency of overweight and obesity is gradually increasing worldwide [1]. According to the data of World Health Organization, the prevalence of overweight and obesity among children and adolescents aged 5-19 has risen dramatically from just 4% in 1975 to just over 18% in 2016 [1]. Numerous studies showed that among overweight or obese children and adolescents cardiometabolic risk factors are more prevalent than those of normal weight peers [2-5]. It was also shown in some studies that more severe forms of obesity were associated with a greater immediate risk of complications related to weight, including abnormal lipid and blood glucose levels and increased blood pressure levels; however, definitions of severe obesity that were used in these studies were variable [3,5,6]. Also obesity during childhood increases the risk of long-term obesity, as well as the risks of substantial complications and death in adulthood [7-9].

Severe obesity at age 18 was independently associated with increased risk of diabetes, and hypertension in adulthood [10]. Thus to study the relationship between degree of obesity and cardiometabolic risk factors during adolescence is crucial. Vitamin D appears to play an important role in cardiovascular health [11-13]. It was found that in obese children and adolescents, 25 hydroxy vitamin D(25-OH vit D) concentrations were significantly associated with body mass index standard deviation (SDS-BMI) and cardiometabolic risk factors negatively [13]. Vitamin D deficient 11- 18 year old schoolchildren were found to have statistically significantly higher body mass index (BMI) than children with normal vitamin D status [14]. The aim of this study is to improve the understanding of the distribution of cardiometabolic risk factors and serum 25-OH vit D level according to the degree of obesity and to investigate the relationships between cardiometabolic risk factors and 25-OH vit D level, and the degree of obesity in adolescents by gender.

Material and Method

We obtained data retrospectively from medical records of overweight or obese adolescents 11 to 18 years of age who attended our medical faculty adolescent outpatient clinic from January 2012 to December 2015 to evaluate the association between cardiometabolic risk factors and vitamin D status with the degree of obesity. Ethical committee approval was obtained for the study: Faculty Deanship Clinical Research Ethics Committee, Date: 20.06.2016, number: 29430533-604.01.01-225233. During this period a total of 8311 new patients applied to the clinic. Among them, 363 obese or overweight adolescents who met the Cole at al. [15] overweight and obesity criteria according to age and gender, who were in puberty, who did not have a chronic disease and whose laboratory test results necessary for the initial differential diagnosis of exogenous obesity (blood cortisol level, TSH, free T4 level, etc.) were present were included in the study. Blood cortisol level, TSH and free T4 levels were not included in further analysis. Age, gender, weight, height, blood pressure, total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, fasting blood glucose, insulin and 25-OH vit D level of the participants were recorded from the patients’ files. Weight status was classified on the basis of measured height and weight obtained at the time of physical examination and BMI was calculated using the following formula: BMI=[weight/height2(kg/m2)]1. According to Cole criteria BMI values between 85th-95th persentiles were accepted as overweight and BMI values above 95th percentile were accepted as obese [15]. Degree of obesity was calculated as the SDS-BMI using age and gender specific Turkish BMI percentiles, which were generated by using LMS method, to standardise degree of obesity [15,16].

We used standard cutoff values for levels of fasting blood glucose(> 100 mg/dl), total cholesterol(≥200 mg/dl), HDL cholesterol(<40 mg/dl), LDL cholesterol(≥ 130 mg/dl) and triglycerides(≥ 130 mg/dl) to define abnormal values [17]. Homeostasis model assessment of insulin resistance was calculated using the equation: HOMA-IR=Fasting insulin(μU/mL) xFasting glucose(mg/dL)/405 [18,19]. Fasting insulin levels above 30 μU/mL was accepted as cut-off levels for hyperinsulinism and HOMA-IR cutoff point for diagnosis of insulin resistance was accepted as 3.16 [18,19].

Blood pressure(BP) was recorded as the mean value of up to three measurements or as a single measurement and auscultatory method was used in the BP measurement. We used standardized blood pressure tables in which abnormal values were determined according to age, sex, and height; abnormal values were defined as any value that was in at least the 95th percentile in those tables [20]. Vitamin D deficiency was defined as a 25- OH vit D below 20 ng/ml and vitamin D insufficiency as a 25(OH)D of 21–29 ng/ml. Vitamin D level <30ng/ml was accepted as deficient or insufficient level in this study [21].

The Statistical Package for Social Sciences version 21.0 statistical package was used for statistical analyses. Continuous variables were defined as mean±SD and categorical variables were defined as percentages. In the comparison of continuous variables by groups, Mann-Whitney U test was used. Chi-square test was used to compare categorical variables. The relationships between the number of cardiometabolic risk factors and SDS-BMI was evaluated with Spearman correlation test. In the assessment of the relationship between cardiometabolic risk factors, 25-OH vit D level and SDS-BMI, Pearson’s correlation test was used. A series of linear regressions were conducted to determine whether SDSBMI significantly contributed to the cardiometabolic risk factors and 25-OH vit D level. Sex and age were considered as covariates in the aforementioned models. Because insulin levels did not show a normal distribution, logaritmic transformation of insulin was included in looking for correlations and linear regression analysis. UCLA Institute for Digital Research and Education was used in interpreting logarithmic models [22]. A P value of <0.05 was considered statistically significant.

Results

Among 363 adolescents with a BMI at the 85th percentile or higher; 27.5% were overweight, and 72.5% were obese. In the study group, the mean age was 14.05±1.75 years and 59% of the subjects were girls. The BMI was in median 30.34±3.95 kg/m2 and SDS-BMI was in median 2.38±0.6. Of the 319 adolescents that all cardiometabolic risk factors were recorded, 85.7% had at least one cardiometabolic risk factor, and 14.3% did not have any of the risk factors studied here (Table I). Using Spearman correlation analysis, as SDS-BMI increased, number of cardiometabolic risk factors was found to increase. But this correlation was weak(r= 0.211, p= 0.0001). No significant difference was found between boys and girls in terms of number of cardiometabolic risk factors(p=0.433) (Table 1).

The frequencies of cardiometabolic risk factors are shown in Table 2. The frequency of dyslipidemia in obese and overweight adolescents did not differ significantly. Only the frequency of hypercholesterolemia was found significantly higher among obese male adolescents than overweight male adolescents (p= 0.023) (Table 3). The frequencies of hyperinsulinism and insulin resistance were found significantly higher and 25-OH D vit level was found significantly lower among obese adolescents than overweight adolescents(p in order: 0.0001, 0.001, 0.038) (Table 2). When the frequencies of cardiometabolic risk factors and 25- OH vitamin D level were analysed separately in terms of gender the frequencies of hyperinsulinism and insulin resistance were found significantly higher and 25-OH D vit level was found significantly lower only among obese female adolescents than overweight female adolescents(p in order: 0.0001, 0.0001, 0.024) (Table 2,3).

Among the subjects, 82.6% displayed increased total cholesterol, 73.3% increased triglycerides, 84.3% increased LDL- cholesterol and 76.9% decreased HDL- cholesterol(data not shown). Frequency of 25-OH vit D deficiency did not found to show seasonal variability, so vitamin D level was not corrected for season, and 25-OH vit D level did not found to change by sex. No significant correlations were found between vitamin D level and any of the cardiometabolic risk factors (data not shown), so vitamin D level was not assessed in further linear regression analysis.

Using Pearson’s correlation test, as the SDS-BMI increased, SBP, diastolic blood pressure (DBP), HOMA-IR and insulin level were found to increase; 25- OH vit D was found to decrease. Using Pearson’s correlation test, total cholesterol, HDL- cholesterol, LDL- cholesterol, triglycerides, fasting blood glucose showed no significant correlation to SDS-BMI in both genders. However, there was a negative correlation between the 25-OH vit D level and SDS-BMI only in girls, which was not apparent in further linear regression analysis (Table 4).

In the linear regression model running for determination of the contribution of the SDS-BMI to SBP, gender(β=-4.29, p= 0.0001), age(β=1.67, p= 0.0001) and SDS-BMI(β= 6.085, p= 0.0001) were the significant contributors to the model(adjusted R2= 0.131), which means that an increase of one unit in the SDSBMI led to an increase of 6.085 mmHg in SBP, an increase of one year in the age led to an increase of 1.67 mmHg in SBP, and among female participants SBP was found to be 4.29 mmHg lower than male participants(Table 5). In the linear regression model running for determination of the contribution of the the SDS-BMI to DBP, gender(β=-2,96, p= 0.014), age(β=1.076, p= 0.001) and SDSBMI( β= 4.491, p= 0.0001) were the significant contributors to the model(adjusted R2= 0.096), which means that an increase of one unit in the SDS-BMI led to an increase of 4.491 mmHg in DBP, an increase of one year in age led to an increase of 1 mmHg in DBP, and among female participants DBP was found 2.96 mmHg lower than male participants (Table 5). In the linear regression model running for determination of the contribution of the SDS-BMI to HOMA-IR, age(β=-,227, p= 0.042) and SDS-BMI(β= 1.595, p= 0.0001) were the significant contributors to the model(adjusted R2= 0.063), which means that an increase of one unit in the SDS-BMI led to an increase of 1.595 points in HOMA-IR and as age increased one year, HOMA-IR was found to decrease 0.22 points (Table 5). In the linear regression model running for determination of the contribution of the SDS-BMI to insulin level, SDS-BMI(β= .124, p= 0.0001) was the only significant contributor to the model(adjusted R2= 1.264), which means that an increase of one unit in the SDSBMI led to an 13% increase of insulin level (Table 5). In the linear regression model running for determination of the contribution of the SDS-BMI to 25-OH vit D level, SDS-BMI(β=-2.163, p= 0.008) was the only significant contributor to the model(adjusted R2= 0.022), which means that an increase of one unit in the SDS-BMI led to a decrease of 2.163 ng/ml in 25-OH vit D level (Table 5).

Discussion

In this study when we analysed 319 of 363 adolescents whose all cardiometabolic risk factors were known, 85.7% had at least one cardiometabolic risk factor, and 14.3% did not present any of the risk factors. These results indicated that overweight and obese adolescents are at increased risk for severe health complications. The results of a study from Germany showed that 70% of overweight or obese children and adolescents had at least one cardiomethabolic risk factor, and in a study conducted in Holland 80% of 80 severly obese children and adolescents were found to have at least one cardiometabolic risk factor [3,6]. Our results are similar to those of these studies. In our study, we also found that as the SDS-BMI increase the number of the cardiometabolic risk factors increase. In the German study, similar to our findings, children with four or five cardiovascular risk factors were more overweight (high SDS-BMI) than those with less than four cardiovascular risk factors. In a study conducted in USA, overweight or obese children and adolescents showed that, the greater the severity of obesity, the higher the risks of a low HDL cholesterol level, high SBP and DBP, and high triglyceride and glycated hemoglobin levels [5]. Thus, it could be stated that severe obesity might be associated with significant health problems.

In our study it also was found that as the degree of obesity increased the risk of hyperinsulinism and insulin resistance increased among both genders, but only significant difference was found in terms of hyperinsulinism and insulin resistance between obese and overweight female adolescents. Similar results were found in other studies [6,23]. In a study conducted in obese children and adolescents, participants with a higher SDS-BMI were found more than five times more likely to have a high HOMAIR than those with lower SDS-BMI [6]. In another study conducted with overweight and obese adolescents, mean fasting insulinemia and HOMA-IR values were found to increase significantly from the overweight to the extremely obese girl groups [23]. It is also known that obesity increases the risk of the development of hypertension [24-26]. The results of our study demonstrates that as the degree of obesity increased, the risk of abnormal blood pressure increased. As in our study, in another studies, it was shown that as the severity of obesity increase, the higher the risk of high blood pressure is [3,5,6].

In our study, no relationship was found between the degree of obesity and dyslipidemia, but dyslipidemia was found very frequent, for example total cholesterol level was found high among all obese males, thus dyslipidemia seems to be an early finding during the cruise of obesity and which needs further investigation. There are many possible mechanisms for lower 25-OH vit D concentrations in obese individuals, but they are not fully described [14,27,28]. There is also uncertainty as to what the health consequences of these lower concentrations of 25- OH vit D might be [28]. In our study, as SDS-BMI increased 25- OH vit D level was found to decrease after controlling for age and gender. On the other hand, in a study conducted in children and adolescents it was shown that for a unit increase in serum 25- OH vit D level, the risk of overweight and/or obesity was reduced by 5.6% suggesting a possible protective role of vitamin D against overweight and obesity [14].

This study has certain methodologic limitations. First, because this is a cross-sectional retrospective study, we could not show causality between degree of obesity, cardiometabolic risk factors, and the 25-OH vit D level. Second, although we used standard definitions of abnormal values for risk-factor variables, the cross-sectional design did not allow us to examine the effects of these abnormal values on future morbidity or mortality. Lastly in multivariate analysis, the adjusted R2 were low, so only a minor proportion of variability of dependent variable can be explained by the change in independent variable.Our findings are similar to the other studies that found some of the cardiometabolic risk factors are related to degree of obesity and these findings support the necessity of determination of degree of obesity [3,5,6,23]. Whatever the criteria for determination of severity of obesity is, an improved estimation of risk that is based on obesity severity could lower the costs of evaluation without resulting in missed diagnoses of coexisting conditions. Children with severe obesity already have increased cardiometabolic risk, which may predict the early onset of serious diseases such as hypertension and diabetes [29]. Although prevention remains the primary goal in the management of obesity, the increasing number of obese subjects confronts the healthcare professionals with the complications of obesity [1,3].

Conclusion

In conclusion, severe obesity in adolescents is associated with a high prevalence of abnormal levels of cardiometabolic risk factor variables. As the end points of obesity related co-morbidities will occur by time, appropriate predictors of outcomes after interventions have to be defined. Also additional research is necessary to determine whether low vitamin D levels may have an impact on the subsequent development of cardiovascular disease during adulthood among obese adolescents.

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SGLT2-Inhibitor-Induced Euglycemic Diabetic Ketoacidosis in a Newly Diagnosed Type 1 Diabetes Patient- Juniper Publishers

Abstract

Euglycemic Diabetic Ketoacidosis (DKA) is a medical emergency wherein the patient presents with DKA and a normal blood glucose. This can make diagnosis difficult. We report a patient with type 1 diabetes (T1D) who was prescribed the relatively new Sodium-glucose cotransporter 2 (SGLT2) inhibitor and consequently presented with euglycemic DKA.

Keywords: Euglycemic Diabetic Ketoacidosis (DKA); Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor, Type 1 Diabetes

Introduction

SGLT2 inhibitors are a relatively new class of oral hypoglycemic agents indicated for type 2 diabetes (T2D). They inhibit glucose reabsorption from urine at the proximal renal tubules by targeting SGLT2. The drugs are reported to have a relatively pronounced glucose-lowering effect with a low risk of hypoglycemia when administered as monotherapy [1]. However, when prescribed for patients with T1D, they can cause euglycemic DKA, which is DKA characterized by a normal blood glucose level at presentation.

Case Report

A 28 years old Iraqi female, known to have T2D on therapy, presented with features of DKA but with normal blood glucose (7.5mmol/L). She was diagnosed with T2D about a month before her admission to our hospital. On presentation, her Body Mass Index was 20.5kg/cm2 (Height 156cm, body weight 50kg). Family history was positive for hypothyroidism in mother, but not for diabetes in her family. She gave no history of DKA prior to this admission. At the time of diagnosis one month earlier, she had presented with a 3-week history of hyperosmolar symptoms typical of diabetes mellitus and weight loss of 7 kg. Then she had presented with a random blood glucose of 22mmol/L. Her HbA1c was 9.5%. Her physician had started her on Metformin 500 mg thrice daily. After about 2 weeks, she complained of poor glycemic control despite compliance to diet and Metformin. Glipalamide 5mg/day and dapagliflozin (10mg/day) were added after the patient refused to take insulin as recommended. Within 2 weeks of this therapy, she complained of epigastric pain for two days associated with nausea and vomiting and decreased appetite. She also complained of vaginal itching/irritation. There were no infectious diseases evidenced by chest X-ray, electrocardiogram, and urinary sediments and blood culture. Table 1 shows her laboratory findings on admission and follow up. Other investigations on follow up are presented in Table 2. Unfortunately, her initial laboratory finding at the diagnosis of T2D was not available.

Results

We stopped all her above medications. She was managed for DKA with continuous intravenous (IV) insulin and appropriate IV fluids. The patient had responded well to our management in the hospital. Her condition greatly improved after one day from admission. She was free of ketoacidosis and had resumed oral feeding with multiple daily injections of insulin (MDI). She was discharged on insulin as part 4 units thrice daily (as bolus before each meal) and insulin Glargine 4 units as basal insulin at bed time.

Discussion

SGLT2 inhibitors are a promising class of antidiabetic agents that have recently become more popular. Their main adverse effects are reported to be genital fungal infections, bacterial urinary tract infections and polyuria. Volume depletion has also been reported particularly in elderly in in patients on concurrent loop diuretics [2]. These oral antidiabetic agents can produce weight loss of about 2-3kg, secondary to the 280-320 kcal/day loss as 70-80 g of glucose is excreted in the urine [3,4]. Since patients with T2DM are usually more obese than those without diabetes, SGLT2 inhibitors may be the first choice of an oral hypoglycemic agent after metformin. However, weight loss could be a concern for patients with low body weight [3,4]. DKA is often associated with T1DM and severe hyperglycemia is a cardinal feature. Recently, there have been case reports of DKA in patients with T1DM and T2DM treated with SGLT2 inhibitors [1]. SGLT-2 inhibitor- associated DKA were also more common in patients with T1DM, rather than those with T2DM. In contrast to traditional DKA, they do not show severe hyperglycemia, and are therefore called euglycemic DKA. The absence of significant hyperglycemia in these patients made their detection and treatment delayed by physicians and patients [1]. SGLT-2 inhibitors may potentiate the generation of ketoacidosis despite achieving euglycemia through various mechanisms. Increase in glucagon in the background of an insulin deficient state, increased reabsorption of ketone with concomitant delayed clearance of ketone, shift in substrate utilization to fatty acid with concomitant increase in ketone body production, and weight loss with concomitant sarcopenia are mechanisms that could be playing complementary roles in the genesis of ketonemia. Associated dehydration, fluid loss (gastroenteritis) or poor fluid intake (vomiting) and infections, in a poor metabolic milieu, might also trigger the process of this event, making the patient ketosis prone thus precipitating a DKA with normal blood glucose levels [5]. So far, Euglycemic DKA due to SGLT2 inhibitors has been reported in patients with T1DM, and the FDA has contraindicated their routine use in such patients. Our patient also appears to have T1DM. She was later found to have positive anti GAD and anti-insulin antibodies as well as low c-peptide levels. In addition, her acute clinical presentation with DKA within one month of being diagnosed with diabetes, indicates an insulin deficient state. This case is an attestation to the FDA advice that SGLT2 inhibitors must not be routinely prescribed to patients with T1DM.

Conclusion

SGLT2 inhibitors should not be routinely used in patients with type 1 DM as add on therapy because of the adverse effect of euglycemic DKA. It poses a challenge to physicians as patients present with normal serum glucose levels and ketoacidosis may be overlooked. Despite euglycemia, ketoacidosis remains a medical emergency and must be treated quickly and appropriately [6]. Therefore, SGLT2 inhibitor should be considered as a cause in patients presenting with DKA.

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The Frequency of Diabetes among People with Dyslipidemia in Kyrgyzstan (The Steps Survey)- Juniper Publishers

Abstract

The present study examines the influence of dyslipidemia on the risk of type 2 diabetes mellitus in Kyrgyzstan.

Keywords: Type 2 diabetes mellitus; Dyslipidemia; Risk factors; Prevalence.

Abbreviations: T2DM: Type 2 Diabetes Mellitus; CVD: Cardiovascular Diseases, IR: Insulin Resistance

Introduction

Insulin resistance and T2DM are characterized by the development of dyslipidemia - the main factor of CVD. Before the development of diabetes, IR can manifest itself as dyslipidemia [1]. The recent studies have demonstrated that changes in lipids can not only be the consequence of impaired glucose metabolism but can also be its cause. The increased amount of free fatty acids damages insulin receptors and disrupts the normal functioning of β-cells [2]. Around 50% to 84% of people with diabetes have hypercholesterolemia [3]. One of the few studies conducted by Polupanov et al. in Kyrgyzstan shows that the overall incidence of hyperlipidemia in the sample was 88.4% without significant gender differences (86.8% in men and 89.6% in women [4]. Even though several studies examined the prevalence of diabetes and hypercholesterolemia, none of them analyzed the effect of high cholesterol on the risk of diabetes. Therefore, for the first time we decided to study this issue covering all regions of the country. The goals of our study were to determine the true prevalence of hypercholesterolemia and carbohydrate metabolism disorders in Kyrgyzstan, to assess the effect of high cholesterol on the development of diabetes, and to summarize the data obtained from other studies.

Materials and Methods

The STEPS survey was conducted in Kyrgyzstan in the period from October 2013 to November 2013. The selection of the population for the study was carried out by random sampling from all regions of the Republic in relation to the general population. A total of 2585 people were examined including 926 (35.8%) men, 1659 (64.1%) women, aged 25 to 65 years, the average age was 43.8±0.22 years (the average age of men - 44.0±0.36; women - 43.8±0.27, p>0.05). All people signed an informed consent. The survey was based on the WHO STEPS questionnaire, which ex amined the following indicators: education, work data, smoking, alcohol consumption, physical activity levels, and eating habits [5]. The next step consisted of a physical assessment that included the measurement of blood pressure (BP), heart rate (HR), height, weight, waist (WC) and hips (HC). Analysis of glucose was performed using CardioChek meter (Germany) in capillary blood. Parameters, such as fasting plasma glucose (FPG) and total cholesterol, were investigated. The measurement of glucose was carried out according to WHO criteria [6]. Total cholesterol was estimated according to the American Heart Association criteria -2013. Espino version 2007 and SPSS 11.0 versions were used for statistical processing. The processing determined mean values (M), standard deviation (δ), representativeness error (m), intensive and extensive values, and 95% confidence interval (CI). To compare the dependence of numerical series the study used Spearman’s correlation coefficient (rx,y) and determination coefficient (R,%). The main indicator of the influence of one factor to another was the method of relative risk assessment (relative risk, HR) and factor analysis. The differences with p<0.05 were considered significant.

Results and Discussion

The STEPS survey measured only fasting glycemia in plasma from capillary blood to assess carbohydrate metabolism disorders. The mean level of FPG in the examined population was 4.9±0.03mmol/l (4.8±0.05 in men, 4.9±0.04mmol/l in women, p>0.05). Because analysis was performed once and only on an empty stomach with the use of a glucometer, the diagnosis of “diabetes” was unlawful, so the following criteria for assessing glycemia were used: hyperglycemia is more or equal to 7mmol/l and hyperglycemia is more or equal to 6.1mmol/l, but less than 7mmol/l. Hyperglycemia ≥ 7mmol/l was registered in 5.4% of cases, hyperglycemia ≥ 6.1mmol/l, but < 7mmol/l - in 5.8%. The analysis determined the effect of increased total cholesterol on the risk of hyperglycemia. The level of mean total cholesterol in the population of the examined patients was 4.4±0.01mmol/l. Both men and women had the same-4.4±0.03 and 4.4±0.02 mmol/l, respectively (p>0.05). At the same time, 25.1±0.85%, i.e. a quarter of all examined patients had the level of total cholesterol more than 5mmol/l, or ypercholesterolemia (23.3±1.3% of men,26, 1±1.0% of women>0.05). The frequency of hyperglycemia ≥7mmol/l and hyperglycemia from 6.1 to 7.0 mmol/l with high confidence were higher among people with high total cholesterol (Table 1).

Note: R±m- The frequency and margin of error, RR- Relative risk, CI-95% confidence interval, P-confidence of differences between groups.

The correlation between TC and FPG was+0.18 (p<0.001), weakly positive. The degree of influence (coefficient of determination) was equal to 3.2%. The increase in TC to a small extent influenced FPG. Thus, the increase in cholesterol was a significant factor affecting the level of glycemia, and therefore, the presence of hyperglycemia in combination with hypercholesterolemia currently requires timely treatment and multi-factor approach in order to prevent these conditions.

Conclusion

Undiagnosed disorders of carbohydrate metabolism in combination with increased cholesterol levels are widespread among the population of Kyrgyzstan. The increased level of cholesterol has direct impact on the frequency of carbohydrate metabolism abnormalities. High cholesterol increases the risk of hyperglycemia 1.1-1.3 times.

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Clinical Cytology and Thyroid Pathology- Juniper Publishers

Mini Review

This review is dedicated to the results of implementation of new methods in thyroid pathology in our country.Clinical Cytology(cytopathology) is a safe, painless and simple method of morphological diagnostics for detecting various pathological conditions. In Russiafine needle aspiration (FNA)was used during many years for many sites of a human body including thyroid[1-3]. Cytopathology is a widely known method, being close to histology to detect abnormal conditions and to choose the treatment by studying individual cells, structures and clusters of cells, their surroundings, transformation etc.The accuracy of cytological diagnosis by FNA in the most cases is identical to histological.In thyroid pathology it is highly important to access not only cytological picture, but hormonal and biochemical status [4]. Nowadays, that molecular and cytogenetic studies are gradually developing it’s possible todetect and toidentify correctly various molecular targets especially in neoplastic lesions. The implementation of liquid based cytology of FNA showed that the gap between histology, cytology and molecular studies can be filledMorphological, molecular and genetic properties of cells are retained in preserve fluid. Combination of conventional smears (air-dried and MGG stained) and LBS (Papanicolaou stained) showed that both methods can and must be used together in clinical practice[5].In differential diagnostics of papillary carcinoma thyreoglobulin, TTF-1, HBME 1, galectin 3 are useful, in cases of benign lesions - CK19, p53, HBME[6]. Statistically significant difference between benign and molecular lesions has been obtained in the usage of Ki-67 (p< 0,001) and β-katenin (p< 0,05) and the combination of them allowed to telldefinitely in doubtful cases about carcinoma in 45.5%[7]. Scrapes from cytological slides, liquid-based cytology and cytoblocks (Cell blocks) can be used for molecular studies.Immunocytochemistry, flow cytometry, in situ hybridization on cytological slides (FISH. CISH, SISH), sequencing, PCR, RT-PCR (qRT-PCR), mRNA expression and other molecular studies are available nowadays[8-10]. Thus, multidisciplinary approach seems to be important, especially in difficult cases.In routine clinical practice the most often (up to 85% cases of FNA) thyroid pathology is non-toxical diffuse nodular goiter [11].FNA and intraoperative cytology can also be usefulautoimmune thyreoiditis, Graves disease and other non-neoplastic lesions[12-14].

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Insulin Resistance on The Influence of Thyroid Hormone Levels- Juniper Publishers

Introduction

Thyroid hormones (TH) are important determinants of glucose homeostasis [1,2], and in contrast, insulin is the first hormone responsible for glycemic control, and there may be an effect between T3 and insulin determining pathways of glucose and lipid metabolism [3].

In the present study, the effect of insulin on insulin secretion and insulin sensitivity on insulin sensitivity and insulin sensitivity in patients with diabetes mellitus. Lambardiari et al. [3] evaluated euthyroid subjects in the early stages of diabetes mellitus (DM) and insulin resistance (IR), investigating the association of TH levels with glucose sensitivity by insulin metabolism, and it was found that T3 and T4 levels were reduced in subjects with DM compared to the control group.

The results of T3, increased during exercise and reduced after exercise associated with caffeine, demonstrate a new context, and can be determined by fluctuations of glycemic and lipid, corticosterone and insulin, and may have characteristic effects within metabolic homeostasis. A network of adrenergic innervation in the thyroid gland stimulates the control of the activation and release of TH, influencing the thyroid stimulant hormone (TSH) stimulation response [4].

Catecholamines (corticosterone, adrenaline) increase the conversion of T4 into T3 by the specific activity of the enzyme deubiquitinase that acts on the upregulators activity of the protein deubiquitin 2, increasing T3 levels in the thyroid cell nucleus [5]. This synergism between TH and the sympathetic nervous system (SNS) may be involved in changes in stock or energy release [6]. During exercise, the adrenergic action correlates with the increase of catecholamines, which can increase the values and conversions of T4 in T3. The focus of TH on energy action as well as regulation of lipid and carbohydrate metabolism pathways describe the influence of these hormones on pathological conditions such as DM.

TH inhibits the release of glucose-stimulated insulin, associated with SNS actions, leading to increased islet glucose oxidation and utilization, thus describing a negative feedback action [7]. This stimulus is due to the adrenergic action on the thyroid gland, increasing the release and conversion of TH and consequent glycemic increase. In contrast, T3 treatment prevents deterioration and maintains β-cell structure, size and consistency of streptozotocin-induced animals [8], leading to increased insulin release. T3 treatment reversed hyperinsulinemia, but not hyperglycemia, in obese animals [9]. Thus, THs act on the maturation and development of β-cells but controlling the release of insulin due to synergistic stimulation with the SNS, maintaining glycemic homeostasis.

An important understanding has been made about the actions of TH mediating DM-related metabolic actions, acting on several glands and regulator tissues of energy substrates, as well as the actions of caffeine and physical exercise are inherent to the knowledge and treatment of DM. Some themes, such as the action of TH on the ionic regulation in cells altering actions in different pathways, as well as acting on a negative feedback by downregulations on the insulin action, but increasing the proliferation of pancreatic β cells, point out important directions in the research. The mechanisms of action related to the thyroid hormones and insulinotropic action form a counterbalance, where an imbalance (hyper or hypothyroidism) can be observed the presence of DM or IR.

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Could Hormone Remission be Achieved in Prolactinomas with Surgery?- Juniper Publishers

Abstract

We retrospectively analyzed 33 prolactinomacases. Endoscopic endonasal transsphenoidal (EET) surgery can be used as an effective method for microprolactinomastreatment to achieve rapid biochemical and clinical remission. In some macroprolactinomas (<24mm) EET surgery is effective (90% cases)

Keywords: Pituitary adenoma;Prolactinoma;Endoscopic endonasal transsphenoidal surgery;Biochemical remission

Introduction

Dopamine agonists (DA) are recognized as an effective medical treatmentsince the beginning 1970s[1,2]Normoprolactinemia was achievedin 59%when using bromocriptine[3].Normal PRL level can be achieved in 80-90%when using DA. Relevant systemic side effects, including vomiting, nausea, dizziness, headache have been reported in about one third of patients treated with DAs[ 4, 5]. DAs have a significant effect on other dopamine, serotonin androgenic receptors, which leads to severe neurological disorders such as postural hypotension or dyskinesia, psychosis, or mania, which provoke compulsive states[ 6,7]. In some cases these possible complications assume surgery over prolactinomas.

Materials and Methods

This study included 33 patients who underwent primary pituitary surgery over prolactinomas with no prior DA treatment (19 female, 14 male; age ranged, 20–67 years). Microprolactinomas10 cases, macroprolactinomas19 cases, giant prolactinoma 4 cases.endoscopic endonasal transsphenoidal (EET) surgery was performed by single neurosurgeon. Plasma PRL levels were obtained before surgery, and then on the 1st day, 1st week, 1st month, 3rd month and then every 6th months after surgery. Catamnesis1-5 yearsMRI check-up was performed before surgery and then on 3, 6 and 12month, then on yearly basis.

Results and Discussion

Median preop PRL serum level for all patients was530ng/mL (ranging, 65–1440ng/mL)Cavernous sinus invasion was ob served in 16 (48,5%) cases after surgery. Biochemical remission of PRL level back to normal wasin 10 cases withmicroprolactinomas (100%), in 10 (53%) cases of macroprolactinomas after surgery.No DA therapy after surgery in those with normal PRL serum level. Follow up lasted1-5 years. Postoperative complications such as CSF leak, meningitis, additional oculomotor disorder or visual impairment have not been established. No mortality. Biochemical and clinical remission was achieved after EET surgery with no DA therapy: microadenomas - 100% cases, macroprolactinomas– 53% (macroprolactinomas with size less then 24mm – 90% cases). Visual disturbances and visual field defects improved in all cases over macro and giant prolactinomas.

EET surgery overmicro and macroprolactinomas (tumor should be removed in capsule) achievesbiochemical and clinical remission within a short period of time. Though EET surgery over microprolactinomas gives 100% remission rate, in cases of macroprolactinomas EET surgery gives 53% remission rate. Macroadenomas give recurrence after surgery in6 months period. We noticed that the size starting from 24mm and more would likely to lead to recurrence. Meanwhile macroprolactinomas less then 24mmgive 90% remission. Cavernous sinus invasion is predicting factor over recurrence.

Foote Note

1Thorner MO, McNeilly AS, Hagan C & Besser GM. Long-term treatment of galactorrhoea and hypogonadism with bromocrip- tine. BMJ 1974 2 419–422.

2Werder K, Fahlbusch R, Landgraf R, Pickardt CR, Rjosk HK & Scriba PC. Treatment of patients with prolactinomas. Journal of Endocrinological Investigation 1978 1 47–58

3WebsterJ,PiscitelliG,PolliA,FerrariCl,IsmailI&ScanlonMF.For the Cabergoline Comparative Study Group. New England Journal of Medicine, 1994 904–909

4Molitch ME (1999) Medical treatment of prolactinomas. Endo- crinolMetab Clin North Am 28(1):143–169

5Diagnosis and treatment of hyperprolactinemia: An endocrine society clinical practice guideline, 2011

614.Noronha S, Stokes V, Karavitaki N & Grossman A. 2010. Treating prolactinomas with dopamine agonists: always worth the gamble?.Endocrine In press 10.1007/s12020-015-0727-2

716.Ali S, Klahr K &Freudenreich O. 2015. Management of psychosis associated with a prolactinoma: case and review of the literature. Psychosomatics 51 2010. 370–376. 10.1016/S0033-3182(10)70718-0.

Conclusion

Biochemical remission could be achieved surgically especially in microprolactinomas in 100% cases.

Biochemical remission might be achieved surgically in macroprolactinomas with size less then 24 mm (90% cases), cavernous sinus invasion (Knosp 0-2) is the prognostic factor.Ophthalmic symptoms regression is achieved in 100% patients and faster in cases macro and giant adenoma in comparison to DA therapy. Menses normalized in 100% cases of microprolactinomas and in 86% cases in macroadenomas with size less then 24mm.

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Influence of rs1137101 gene polymorphism of leptin receptor on the development of diabetes mellitus type 2 and obesity- Juniper Publishers

Abstract

Influence of polymorphism rs1137101 of the leptin receptor gene on diabetes mellitus 2 types development. The aim of this research was a study of gene LEPR polymorphism rs1137101 role in diabetes mellitus 2 type development and his influences on the clinical and laboratory data, related to obesity for these patients. 103 patients are inspected, that had the clinically expressed complications. A control group was made by 100 practically healthy persons of corresponding age. The analysis of polymorphic DNA-loci was carried out by the method of polymerase chain reaction in real time (TaqMan® SNP Genotyping Assay). Results showed that allelic polymorphism of rs1137101 (223Gln>Arg) had been associated with diabetes mellitus 2 types development: allele Gln promotes, while allele Arg – reduces (OR=1,5; p=0,039) the risk of its development. Presence allele Gln for diabetic patients assists development of obesity and his displays, namely – to the higher values of body mass index and HOMA-IR, and to the greater leptin and triglycerides blood levels on a background reduction of high-density lipoproteides maintenance.

Keywords: Diabetes mellitus 2 types;Leptin receptor gene; rs1137101

Introduction

Despite the adoption of national programs for the control of diabetes in most countries of the world, its prevalence and morbidity continue to increase, mainly due to type 2 diabetes mellitus (DM2) [1]. Comparable trend is typical for Ukraine, where today more than 1.3 million patients are counted. In fact, these data are substantially understated, since over 50% of patients with DM2, with pre-diabetes and the latent course of the disease remain undiagnosed [2].

It was established that the main link of the pathogenesis of DM2 is chronic hyperglycemia, which develops on background of insulin resistance and progressive functional activity decreament of β-cells of the pancreas [3,4]. In this setting, in most cases, DM2 is combined with abdominal-visceral obesity [2,1], and has a dependence on some genetic polymorphisms[5].It is shown that the degree of obesity directly affects the rate of development, and, accordingly, the severity of hyperglycemia and cardiovascular complications, which are one of main causes of early disability and high mortality of patients [1].Key role in the regulation of lipogenesis and oxidation of fatty acids is given to leptin, which, being integrated into the feedback system with the participation of hypothalamic neuropeptides, participates in the system of regulation of hunger and satiation. It was established that, in case of DM2 phenomenon of leptin resistance develops, in which hyperleptinemia, that directly depends on amount of adipose tissue, is accompanied by loss of the physiological properties of the hormone. Leptin resistance contributes significantly to the formation and progression of obesity, angiopathy and insulin resistance [3,4].

Some causes of leptin sensibility loss are described. Among them leading role is issued to disorders of structure of specific receptors LepRa-LepRf which are present in the hypothalamus, peripheral organs and tissues (fat, liver, skeletal muscles, pancreas, testicles, prostate, placenta, kidneys, lungs) and are coded by the gene LEPR (chromosomal localization 1p31, exon 24) [3,6]. Product of this gene – protein gp130 belongs to the family of cytokinereceptors, which stimulate transcription of genes through activation of cytosol proteins STAT [6]. Some LEPR polymorphisms are described, but rs1137101 is the most investigated among them. The point of single-nucleotide polymorphism is change of adenine (A) for guanine (G) in the position 668 of the gene (668A>G), that leads to change of glutamine for arginine in the 223rd position of protein receptor (Gln223Arg) [7]. Research results, which are dedicated to influence of rs1137101 polymorphismof LEPR gene to the development of DM2 are contradictory and in Ukrainian population are not defined at all.

The aim of the study is to define role of rs1137101 polymorphism of LEPR gene in the pathogenesis of the DM2 and its influence on clinical laboratory indices which are connected with obesity among patients with the DM2.

Materials and Methods

Data from 103 patients with DM2, that had clinically apparent complications of main illness, were investigated. The age of patients was from 33 to 79 years, mean age 53±8 years. 38 were men (37%), 65- women (63%). All patients had complications like diabetic polyneuropathies (88%), microangiopathies (84%),ophtalmopathies (40%), encephalopathies (27%), and nephropathies (20%). Durations of disease were from 1 to 25 years. 23% of patients had close relatives with DM2. Control group consisted from 100 healthy people with according age and sex distribution.

Analysis of polymorphous DNA-locuses was performed by method of polymerase chain reaction (PCR) in real-time with use of TaqMan® SNP Genotyping Assay system (USA) on the amplificatory Applied Biosystems 7500 RealTime PCR System (USA). Blood biochemical parameters of lipid metabolism were evaluated with spectrophotometry, body mass index (BMI) and insulin resistance index (HOMA) were also calculated. Influence of polymorphic markers on the development of disease was evaluated with ANOVA and contingency tables. Degree of disease association was evaluated with odd ratio calculation. Statistical calculations were performed inStatistica 10 application program (StatSoft, Inc, USA).

Results

Frequencies of genotypes of rs1137101polymorphism of LEPR gene in the experimental and control groups were distributed in the following way (Figure 1)Gln/Gln – 0,282 and 0,170; Gln/Arg – 0,582 and 0,600; Arg/Arg – 0,136 and 0,230.

Analysis of genotype frequencies revealed significant increase (1.65 fold; p=0.041) of Gln/Gln genotype in the experimental group in comparisonwith control group. Other genotypes frequencies did not differ significantly. Need to be said, that received data corresponded with the Hardy–Weinberg principle for cases (χ2=3.730, df=1, р=0.162) and controls (χ2=4.175, df=1, р=0.129).Allelic frequencies of rs1137101polymorphism of LEPR gene were distributed in experimental and control groups in accordance: Gln – 0.573 and 0.470; Arg – 0.427 and 0.530(Figure 2).

The analysis of contingency tables (3×2) didn’t show significant association of genotypes of rs1137101 polymorphism of LEPR gene with DM2 development in both groups: χ2=5.276; df=2; р=0.074 (Table 1).

Significant association between allele Gln and the presence of DM2 was revealed by analysis of influence of alleles of rs1137101 polymorphism of LEPR gene on the development of DM2 by 2×2 tables: χ2=4.299; df=1; р=0.039 (Table 2).It was revealed, that carriers of Gln allele had 1.5 times higher degree of association with DM2 (OR=1.512; CI 1.022-2.237; p=0.039). In case of presence of Arg allele degree of association with DM2 was 1.5 times lower.ANOVA showed influence of Gln allele of rs1137101 polymorphism of LEPR gene (Table 3)to higher BMI in comparison to Arg allele (26.29±0.81kg/m2 and 30.32±0.68kg/m2; F=7.51; p=0.003); higher blood leptin concentration (87.27±7.52ng/ ml and 105.58±10.25ng/ml; F=6.59; p=0.006); higher level of triglyceride (4.48±0.41mmol/L and 5.52±0.48mmol/L; F=5.27; p=0.015); and higher HOMA (7.66±0.75 and 9.47±0.99; F=3.64; p=0.040); and decrease of high-density lipoprotein (HDL) blood concentration (2.01±0.09mmol/L and 1.57±0.11mmol/L; F=4.90; p=0.019).

Listed changes are traditionally linked with obesity in patients with DM2 [8,9] and presented in the Table 3 according to decrease of influence degree of alleles of rs1137101 polymorphism of LEPR gene: increase of BMI > hyperleptinemia > dyslipidemia (increase of triglycerides and decrease of protective HDL), which were on the background of increase of insulin resistance.Numeral data [8-10] shows that rs1137101 polymorphism of LEPR gene leads to disorder of structure and function of leptin receptor and blocks its expression with alteration of hormonal signal. We suggest that presence of allele Gln in genotype contributes increase of BMI, HOMO, leptin and triglyceride level, and decrease protective HDL.

For evaluation of influence of rs1137101 polymorphism of LEPR gene on obesity in patients with DM2 the distribution of genotypes and alleles was analyzed in cases, where BMI>30kg/ m2 (obesity) and BMI≤30kg/m2(normal weight and overweight). As it shown in the Table 4 obesity patients with DM2 had 2 times higher frequency of Gln223Gln genotype than patients without obesity (36.5% and 19.6% respectively, p=0.045).

Frequencies of heterozygous genotype Gln223Arg didn’t differ significantly and frequency of the minor homozygous genotype Arg223Arg in patients with obesity was 2.5 times rarely (7.7% against 19.6% in patients without obesity; p=0.025). Dependence of distribution of genotypes from presence or absence of obesity was not revealed (p=0.069) on condition of accordance of data in groups by BMI to the Hardy–Weinberg principle (χ2=2.404; df=1; р=0.308 for group with BMI > 30 and χ2=2.373; df=1, р=0.319 for group with BMI≤30).

There was significant difference between groups with different BMI by frequency of alleles of rs1137101 polymorphism of LEPR gene. In the group with BMI>30 allele 223Gln was present in 64.4% cases and in the group with BMI≤30– in 50% of cases. For allele 223 Arg distribution was opposite: group with BMI >30–35.6%, group with BMI≤30–50% (p=0.038). In presence of obesity in patients with DM2 223Gln allele occurred 1.3 times more and minor 223Arg allele 1.4 times rarely. Thereby we suggest that 223Gln allele is associated with obesity (BMI>30) in DM2 and risk of obesity development is 1.8 times increased (OR=1.811; CI 1.036-3.165; p=0.038).

Thus, rs1137101 polymorphism (223Gln>Arg) of LEPR gene is a risk factor for DM2 and contributes to obesity in these patients. DM2 could be related to diseases with inherited predisposition which has high risk of development in persons with respective rs1137101 polymorphism of LEPR gene according to multiplicative model of inheritance under the provocative influence of modified risk factors.

Conclusion

1. Higher rate of Gln/Gln genotype was revealed in patients with DM2 in comparison to the control group (1.65 times more; p=0.041)

2. Gln allele was presentmore often and Arg allele-more rarely in patients with DM2 (1.2 times in comparison to the control group; p=0.024). Carriers of Gln allele had 1.5 times higher risk of DM2 development and presence of Arg allele-1.5 times lower risk of disease (p=0.039).

3. Presence of Gln allele in patients with DM2 contributes to progression of obesity and insulin resistance, more pronounced hyperleptinemia and dyslipidemia (increase of triglyceride and decrease of HDL). The risk of obesity development was 1.8 times higher among these patients.

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Largest Reported 3 month drop in HbA1c for a Newly Diagnosed Patient with Type 2 Diabetes- Juniper Publishers

Short Communication

Diabetes mellitus is a leading cause of morbidity and mortality worldwide [1]. The causes of type-2 diabetes are multi-factorial, and supplements can play an important role on its’ incidence, severity and management [2]. Hence studies have frequently focused on dietary components beneficial in the prevention and treatment of diabetes. Recent studies have demonstrated that numerous herbal and nutraceutical products have beneficial effects in patients by improving glucose and lipid metabolism, antioxidant status, disease progression and capillary function [3].

Lysulin™ is a new supplement for people with Type 2 diabetes and prediabetes and those atrisk of developing diabetes and metabolic syndrome [4]. Lysulin is a nutritional supplement tablet manufactured in the USA which contains the essential amino acid Lysine, a micronutrient Zinc and Vitamin C as the active ingredients, together with other standard excipients (Lysulin Inc, San Diego, CA) (www.lysulin.com). The patent pending Lysulin formulation contains the essential amino acid, lysine, a mineral, zinc, and vitamin C. All of these ingredients have been shown in over 20 years of R&D and clinical studies to lower blood glucose, lower glycated proteins and improve the lipid profile by lowering cholesterol and LDL and raising HDL. Daily use of Lysulin™ may slow or halt the progression of prediabetes to diabetes and slow or halt the progression of diabetes complications by lowering protein glycation.

We wish to report the largest documented three month drop in HbA1c in a newly diagnosed patient with Type 2 diabetes. MR was diagnosed with Type 2 diabetes as a result of an HbA1c of 12.8. He immediately was prescribed 2000mg Metformin and 2mg Lisinopril a day. He also started self-treatment with 2 servings a day of Lysulin, a nutritional supplement for people with diabetes and prediabetes. The following drop in HbA1c was observed:

As seen, a dramatic drop is HbA1c was observed after just one month and by 3 months the HbA1c had dropped from 12.8% down to 5.4%. Several new double blind, placebo-controlled studies are underway and we plan to report on the finding that the drop in HbA1c can be seen is as little as 1 month following treatment with Lysulin and also that the use of continuous glucose monitoring shows improvement in glycemic control is as little as one week following the initiation of use of Lysulin (manuscript in preparation). Such observations may mean that home testing for HbA1c on a monthly basis may lead to more effective diabetes management. This report of a large drop in HbA1c is extraordinary and shows the promise of adding Lysulin to other oral diabetes medicines to achieve outstanding glycemic control.

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Small Pheochromocytomas: Clinical, Diagnostic and Perioperative Issues of Disease- Juniper Publishers

Abstract

Small Pheochromocytomas: Clinical, Diagnostic and Perioperative Issues of Disease

Introduction: Pheochromocytoma (P) is considered as relatively rare adrenal tumor with clinical manifestation after reaching the size of 4-6cm. Meanwhile, it’s supposing that small P can be not rare found within different diagnostic imagination. Some of these, being clinically silent, can cause serious cardio-vascular risk undergoing unrelated medical procedures. We compared clinical course, peculiarities of diagnostics and treatment of small P (less than 3cm) and bigger P on the basement of own clinical experience among patients underwent adrenalectomy on proven or suspected P.

Material and methods: Group of small P was comprised by 14 patients aged from 21 to 62 years with mean size of tumor 23mm (range: 4-29mm). Control group consisted of 35 patients corresponded on age (23-75 years) with mean P diameter of 56mm (range: 30-127mm). Small P comprised 8% of all 175 patients with P operated on during the last 19 years in endocrine surgery hospital from the whole group of 967 adrenalectomies. Prevalence of women and right side lesions characterized both groups.

Discussion: Principal differences between groups were less prominent clinical activity (any symptoms were detected in half of small P) with less level of catecholamines and metanefrines in lab examination of serum and urea of small P patients. Computed tomography was often the first but not targeted diagnostic step. Silent clinical course was the main reason that small P have been discovered predominantly incidentally with no blockage of alpha-adrenergic receptors before surgery in 6 of 14 patients. Most of them had a critical elevation of blood pressure during operation (43% against 9% in control group; p<0.05). Despite small size and mild catecholamine excess in small P group, 4 from 14 patients (29%) experienced episodes of potentially harmful hypertensive crisis during unrelated medical procedures in the past. All small P were treated successfully by laparoscopic adrenalectomy. Most of patients became free from hypertension.

Conclusion: Small P may carry actual risk of unexpected hypertensive crisis during any unrelated medical procedures. The clinical course of small P is hidden in half of patients and laboratory investigations are interfered with mild elevation of biochemical markers. Laparoscopic adrenalectomy is safe mode of treatment of small P in case of adequate preparation.

Keywords: Pheochromocytoma; Small size; Diagnostics; Peculiarities; Laparoscopic adrenalectomy

Introduction

Pheochromocytoma (P) is considered as relatively rare adrenal tumor which typically demonstrates clinical manifestation after reaching the size of 4-6cm. The rate of P among adrenal incidentalomas is about 5 %, and on autopsy among died from all causes 1:1000 [1]. Meanwhile, it’s supposing that small P can be not rare found within different diagnostic imagination. Some of these, being clinically silent, can cause serious cardio-vascular risk undergoing unrelated medical procedures [2].

Half of P are discovered only at autopsy despite most of them demonstrated bright clinical symptoms [2,3]. From this point of view the case of 34th USA President Dwight David Eisenhower, whose diagnosis of small P was revealed only postmortem, is a very illustrative example. He suffered from poor controlled arterial hypertension for a long time and sustained 4 myocardial infarction [4].

Purpose

To compare clinical course, peculiarities of diagnostics and treatment of small P (less than 3cm) and bigger P on the basement of own clinical experience among patients underwent adrenalectomy due proven or suspected diagnosis.

Material and Methods

There was a retrospective study with randomized historical control group. All together during 1.01.1997-1.08.2016 years in Department of Endocrine Surgery of Ukrainian Research Center for Endocrine Surgery of Public Health Ministry 967 adrenalectomies have been performed. Tumors arisen from adrenal medulla comprised 18.1% (175 cases). Patients were aged from 8 to 75 years with female prevalence (74.3%). Size of P mostly exceeds 30mm ranged from 3.8mm to 127mm (mean 47.99±2.93mm). Adrenalectomy was performed initially through open conventional lumbotomy, but during last decade predominantly by laparoscopic methodic (71.4% among all cases).

The group of small P was comprised by 14 patients aged from 21 to 62 years with mean size of tumor 23 mm (range: 4-29mm). Control group consisted of 35 patients corresponded on age (23-75 years) with mean tumor diameter of 56mm (range: 30-127mm). Small P comprised 8% of all 175 patients with P operated on during the last 19 years in endocrine surgery hospital from the whole group of 967 adrenalectomies. Prevalence of women and right side lesions characterized both groups. We excluded from both groups all cases of malignant P, family forms, bilateral P, children and pregnant.

After laboratory confirmation of diagnosis patients were prepared by alpha-adrenoblockers till stable normalization of BP. Computed tomography was the main method of visualization (in most cases – on «Toshiba Aquilion 64» CT). Laparoscopic adrenalectomy was performed by well known traditional methodic of M. Gagner [7] with authors modification [8]. Statistics for compared groups of study based on paired “t” test. Difference considered significant if P was less than 0.05.

Results and Discussion

Typical presentation of P in group of small P was the incidentally discovered on CT adrenal tumor of high native attenuation (mean - +31.06±3.52HU) – Figure 1. Macroscopically small P looks like homogenous solid tumor of grey or grey-cherry color defined by thin capsule (Figure 2). Clinical and laboratory data of studied groups are presented in Table 1.

The less prominent clinical activity (any symptoms were detected in half of small P) with less level of catecholamines and metanefrines in lab examination of serum and urea of small P patients represented the principal difference between groups. Computed tomography was often the first but not targeted diagnostic step. Silent clinical course was the main reason that small P have been discovered predominantly incidentally with no blockage of alpha-adrenergic receptors before surgery in 6 of 14 patients. Most of them had a critical elevation of blood pressure during operation (43% against 9% in control group).

Despite small size and mild catecholamine excess in group of small P, 4 from 14 patients (29%) experienced some episodes of potentially harmful hypertensive crisis during unrelated medical procedures in the past. All small P were treated with successful laparoscopic adrenalectomy. Most of patients became free from arterial hypertension.

Discussion

Our study confirmed opinion of some authors that even small P can bring significant risk for patients in case of stressful situation or unrelated medical procedures [5,6]. Despite existing information about significant rate of “hidden” P in population [1,9], targeted screening of P among patients with elevated BP or sympathetic crisis is not recommended routinely. Yu R et al. [5] supposed that small P could carry the 17% cardio-vascular risk in case of unrelated surgical or dentistry manipulation, that is equal to P of regular size. We found two fold differences in such risk for small and bigger P (29% against 69%), but it even more than found previous authors and allow us strongly recommend surgical operation for all such patients, as it sounds from other investigators [5,6]. Some authors recommend adrenal venous sampling with glucagon stimulation test in patients with negative visualization but clinical suspicion to catecholamine producing tumor, that prove presence of P in 36 from 41 patients[6]. Mere than half of those patients became normotensive after operation. We also observed normalization of BP in ¾ of operated patients within first months after adrenalectomy. Laparoscopic methodic of adrenalectomy for patients with P is well recognized type of surgery all around the world [1,7,8], all the more for small tumors, and we confirm it one more time on our clinical series [9].

Conclusion

Pheochromocytomas of size less than 3cm is not exclusive catecholamine producing tumors and comprise 8 % of operated on P in large clinical series. Small P may carry actual risk of unexpected hypertensive crisis during any unrelated medical procedures. The clinical course of small P is hidden in half of patients and laboratory investigations are interfered with mild elevation of biochemical markers. Laparoscopic adrenalectomy is reliable and safe mode of treatment of small P in case of adequate preparation with alpha-blockers.

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Familial Nonmedullary Thyroid Carcinoma (Fnmtc): Molecular Advances with the New Sequencing Technologies- Juniper Publishers

Introduction

Approximately 3-9% of the thyroid neoplasms are hereditary. Familial non-medullary thyroid cancer (FNMTC) is diagnosed when three or more first-degree relatives are affected and is classified into Syndromic familial adenomatous polyposis, Gardner’s syndrome, Cowden’s disease, Carney’s complex type 1, Werner’s syndrome) and Nonsyndromic (thyroid cancer). Several candidate chromosomal loci and susceptibility genes have been reported but these results are not replicated in subsequent studies. As the Next Generation Sequencing (NGS) now offers a powerful new diagnostic approach of the goal of this article was to review the current knowledge the new approaches used for the molecular characterization of FNMTC cases.

Familial predisposition of nonmedullary thyroid carcinoma (FNMTC) is diagnosed when three or more first-degree relatives are affected. It occurs in about 3-9% of the follicular cell-derived neoplasms and is classified into Syndromic and Nonsyndromic because encompasses a heterogeneous group of diseases [1]. The Syndromic group is characterized by a predominance of non-thyroidal tumors. Some syndromes are more frequently observed, such as familial adenomatous polyposis (FAP), Cowden syndrome, Werner syndrome and Carney complex, with thyroid cancer prevalence of 2-12%, 35%, 18% and 15%, respectively. Except for Werner’s syndrome, all syndromes related with FNMTC are autosomal dominant. Several driver-genes have been identified, APC gene was associated to FAP and PTEN, SDH, PIK3CA, AKT1 and KLLN were related to Cowden syndrome; PRKAR1α was related to Carney complex and WRN gene was associated to Werner’s syndrome [1].

The Nonsyndromic form accounts for 95% of all FNMTC cases and is characterized by the presence of thyroid cancer and the absence of other known associated syndromes [2]. The Papillary Thyroid Carcinoma (PTC) subtype is the most commonly observed and may or may not be associated with benign thyroid neoplasms (multinodular goiter) or autoimmunity thyroid disease (Hashimoto’s thyroiditis). Several candidate chromosomal loci and susceptibility genes have been reported (1q21, 2q21, 6q22, 8p23.1-p22 and 19p13.2, NKX2‐1, FOXE1, SRGAP1, TERT, HABP2 and C14orf93) suggesting that it is a polygenic familial cancer syndrome [1,3-5]. As subsequent studies failed to identify segregation of these candidates with the disease and due to the clinical variability of the patients, the molecular profile of each FNMTC family may be unique [6-9]. Furthermore, important cancer-related genes (APC, PTEN, TSHR, RET, TRK, c‐MET, BRAF and H‐K‐N‐RAS) were also excluded as the cause of FNMTC [10]. In the last decade, techniques for single-target detection have been replaced by the Next Generation Sequencing (NGS), which allows simultaneous analysis of a large group of genes generating a large volume of data in parallel [11-13]. The NGS high-throughput platforms are more efficient, less expensive and provides information that is not provided by Sanger DNA sequencing analysis or by hot spot mutation gene targeted assays (MLPA - Multiplex Ligation Probe-dependent Amplification or Taqman Genotyping) [10–12]. Analysis of the generated data is a complex process. In familial diseases with clinical heterogeneity, as observed in FNMCT, a careful selection of the individuals to be submitted to the NGS is necessary. The inclusion of unaffected individuals improves diagnostic rates by facilitating variants selection and mutations identification due to the exclusion of regional polymorphisms. The definition of a suitable pipeline for the identification and classification of the variants is also an essential step [11,12]. In silico predictive analysis provided by specific programs such as Polyphen2, SIFT, Mutation Assessor and Mutation Taster is a valuable tool to distinguish between the pathological and benign variants associated with the phenotype, taking into account the evolutionary conservation of the amino acid or nucleotide residue, biochemical impact of the amino acid substitution considering the physicochemical properties, and the variant localization [11,12]. As there is no rule, the use a more stringent filtering criterion are more appropriate as the first approach while less strict selection may be adequate when no candidate variant was identified [13-16]. It is noteworthy that a consensus among the prediction results leads to a better accuracy, as in CONDEL, PON-P and Meta-SNP algorithms [11,17,18]. Information obtained from population databases (1000 Genomes Project, ExAc and Exome Variant Server (EVS)) are frequently used to exclude variants that are deemed polymorphic/benign based on a global minor allele frequency (MAF) cut off of ~1% (0.01).

However, it is important to consider ethnicity-specific MAFs that depend on the ethnic background of the population, particularly in populations with high miscegenation as observed in Brazilians, underrepresented in most of the genomic databases, however data made available by local consortiums as ABraOM [19] and EPIGEN-BRAZIL [20] unravel this problem. In the literature, it is already possible to observe the benefits of new generation sequencing in the FNMTC. Recently, a group sought to identify previously undescribed cancer-predisposing gene(s) in a Cowden Syndrome family enriched for thyroid cancer across 4 generations, who had tested negative for PTEN, SDHB-D and KLLN, via an approach combining exome sequencing and family study. They found a variant in SEC23B gene and suggested that this germline heterozygous variant is associate with cancer predisposition [21]. Moreover, when whole-genome approach was conducted in sporadic FAP patient in which any pathogenic APC mutations was found by the conventional Sanger sequencing, a mosaic mutation in ~12% of his peripheral leukocytes was identified. Demonstrating that NGS is an effective tool to identify genetic mosaicism in hereditary diseases [22]. A variant on WRN gene was identified by exome-wide sequencing in a 16-year-old girl with an atypical syndrome without diagnosis after 10 years of the first symptoms. The variant has been previously reported in Werner’s syndrome (WS) and when the patient was re-evaluated several features of WS were detected, allowing the early diagnosis of a recessive disease and the early use of adequate therapies and interventions [23]. Using Whole Exome Sequencing (WES) a germline variant in the HABP2 gene was identified in a family with seven PTC patients of a FNMTC kindred and in 4.7% of 423 sporadic PTC cases. This variant increased protein expression in the tumor samples and functional studies showed that the loss of function p.G534E rs7080536 variant leads to increased colony formation and cell migration, characteristics of malignant transformation, suggesting that the HABP2 gene may be involved in susceptibility to thyroid cancer [4]. Because the authors did not report the ethnicity of the family and for having used only one database to determine MAF (1000 Genomes), this result was questioned by others groups [24]. Furthermore, this variant was considered a polymorphism in other populations (United Kingdom, USA, Saudi Arabia, Colombia, Spain, Italy, Australia and Brazil) [24].

Only Zhang et al identified the rs7080536 variant in 4/29 (13.8%) of unrelated FNMTC kindreds [25]. In other study, through linkage analysis and exome-sequencing the genes C14orf93 (RTFC), PYGL and BMP4 were identified as candidate genes in a FNMTC family with 5 cases of PTC. However, the functional studies showed that only the p.V205M mutation of the C14orf93 gene led to increased migration rate and colony formation in a PTC cell line [5]. Next Generation Sequencing allied to capture of expressed sequences from genomic DNA now offers a powerful new diagnostic approach. Barriers to use this technology still include cost and the complexity of interpreting results arising from simultaneous identification of large numbers of variants. Thus, cost reductions and new friendly analysis of this big data are necessary. Even so, the results obtained through this new generation sequencing technology have opened doors to new possibilities in the search for the molecular bases of thyroid familial cancer.

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