Selenium and the course of mild Graves' orbitopathy.

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 µg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.).

Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature.

Primary hyperparathyroidism is a heterogeneous clinical entity. In the clinical setting, the diagnosis and management of familial isolated hyperparathyroidism (FIHP) and other familial hyperparathyroidism (FHPT) forms continue to rely on clinical, laboratory, and histological findings, with careful examination of the family. In this article, we report a case series of FIHP in a four-generation Greek family, with no identifiable gene mutations. Clinical approach and long-term follow-up are discussed and a narrative review of the genetic basis of this entity has been performed.

Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts.

Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.

Propylthiouracil hepatitis: report of a case and extensive review of the literature.

Antithyroid drugs (ATDs) have been widely and effectively used for the treatment of pediatric and adult thyrotoxicosis for more than a half century. Since the very beginning of ATD use, reports of hepatic dysfunction related to propylthiouracil (PTU) therapy have been published. We describe a case of a 12-year-old girl, who, after 4 weeks of therapy for Graves disease (GD) with PTU (300 mg/day at 100 mg given three times a day), developed fatigue, fever, diarrhea, nausea, and vomiting. The initial diagnosis was "viral gastrointestinal infection". Few days after the initiation of her symptoms, the patient developed jaundice, hepatic tenderness, and dark urine. She was admitted to the hospital where, after an extensive investigation, it was found that serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were elevated (2312 and 1435 IU/L, respectively), alkaline phosphatase (ALP) was 171 IU/L and total bilirubin was 12.7 mg/dL, whereas direct bilirubin was 7.6 mg/dL and prothrombin time was 23.2 s (normal ratio, < 14.5 s). Serology for hepatitis A and B was negative. The diagnosis of PTU-induced hepatitis was established. PTU was discontinued, and a treatment with prednisone (50 mg/day) and vitamin K was initiated. Four weeks after admission, her hepatic tests returned to normal. We searched the English literature and we present details of all cases with PTU-related hepatic toxicity in children and adolescents published so far. Also, we provide information regarding the mechanisms and treatment of this appalling clinical entity. Finally, after recent recommendations from American Thyroid Association (ATA) and European Thyroid Association (ETA), PTU should be administered only in the first trimester of pregnancy and in cases of drug allergy to methimazole.

Corticosteroids in the medical treatment of thyroid ophthalmopathy: when and how? Somatostatin analogues: where we stand today.

Glucocorticoids (GCs) are used for Graves' ophthalmopathy (GO) in two different clinical settings: 1) moderately severe to severe eye disease; and 2) mild eye disease, for which radioiodine therapy is given to treat concomitant hyperthyroidism. Intravenous pulse corticosteroids have a small but statistically significant advantage in terms of response rate compared with oral corticosteroids and cause significantly fewer adverse events. Steroids should be used for as short a period of time as possible. The need for large doses of steroid over a long period of time is a hint that other treatment modalities need to be explored. Combination treatment with oral steroids and ciclosporin, another immunosuppressant, are more efficacious than use of either agent alone. The same applies to combination treatment with oral steroids and orbital radiotherapy. Somatostatin analogues (SM-as) have marginal clinical efficacy and are expensive. More potent analogues, like SOM230, could prove to be the treatment of choice in moderately severe cases of GO. The latter, in contrast to the thus far used analogues, has a rather high affinity for all SM receptors except SM receptor 4.

Orbital fat decompression for Graves' orbitopathy: a literature review.

Thyroid eye disease manifests as orbital inflammation resulting in extraocular muscle enlargement and orbital fat proliferation. This causes exophthalmos, ocular motility impairment and eyelid retraction. Numerous surgical procedures have been introduced for correction of exophthalmos by removal of bony walls. The limited success and high complication rate of the early methods lead to the evolution of an alternative procedure for reduction of retrobulbar volume by removal of intraorbital fat. The indications for this procedure extended from orbital decompression to compressive optic neuropathy with satisfactory results. The moderate complication rate and the fact that orbits with predominant muscle enlargement respond purely to this technique leads to the evolution of a combined procedure with orbital fat removal and bony wall decompression. The scattered published evidence comprising retrospective case series highlights the need for prospective controlled clinical trials in order to improve patient care and clinical practice.

Pediatric aspects in Graves' orbitopathy.

Although pediatric Graves' disease is an uncommon condition, children have about the same (or slightly increased) risk as adults to develop Graves' ophthalmopathy (GO) once they have contracted Graves' hyperthyroidism. GO occurs in the same proportion between sexes but with a milder clinical presentation compared with adults. Lid lag, soft tissue involvement and proptosis are the commonest manifestations, whereas restricted eye muscle motility, severe strabismus and optic neuropathy are practically absent. Genetic, immunologic and environmental factors may be associated with the different appearance of GO in children and adolescents. Interestingly, manifestation of GO begins to resemble the adult findings more closely when adolescence approaches. This could be explained by increasing smoking prevalence with age as long as smoking is a proven to be a risk factor for GO, and the odds increase significantly with increasing severity of GO. Management of hyperthyroidism is essential for the control of complications and seems to offer improvement of eye changes upon restoration of euthyroidism. Antithyroid drugs are the first choice treatment. Lasting remission rates though are achieved in less than 30% of cases. Long periods of therapy are needed and risk for side effects (often serious) increases. In resistant or severe cases early radical treatment with surgery or radioiodine is needed. Both can be equally effective and safe in selected cases. Identification of subjects prone to relapses is critical for optimal management. Regarding treatment of thyroid eye disease in childhood, most physicians who are dealing with such cases prefer a 'wait-and-see' policy. Pharmacological intervention, predominantly with steroids, is considered appropriate in case of deterioration or no improvement of eye changes when the patient has become euthyroid. It has been shown that somatostatin analogs (SM-as) might be of therapeutic value in the treatment of active eye disease in adults. Newer generations of SM-as that target a wider range of somatostatin receptors may show markedly superior results in the treatment of ophthalmopathy. Surgical orbital decompression is hardly ever necessary due to the mild nature of the disease, while retrobulbar irradiation, which has been proved beneficial in adults, has no place in the treatment of juvenile GO, in view of the theoretical risk of tumor induction.

Pharmacological treatment of hyperthyroidism during lactation: review of the literature and novel data.

Antithyroid drugs (ATD) are used as a first line treatment in thyrotoxicosis. Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are available. During absorption CMZ is bioactivated to MMI. Initially, mothers were not allowed to breastfeed during treatment with ATD. Newer studies minimized the risk for mother and infant. PTU should be preferred over MMI due to its lower milk concentration. Recent studies have shown severe hepatic dysfunction for both ATD, but especially for PTU, in hyperthyroid patients. Most of those cases were idiosyncratic, not-dose related and presented a latent period of occurrence. No biomarkers could predict hepatic damage. The American Thyroid Association (ATA) has recommended that PTU should not be prescribed as the first line agent in children and adolescents. Its use might be accepted in the first trimester of pregnancy for severe thyrotoxicosis or for patients with previous MMI adverse reactions. Considering the potential harmful effects of PTU, MMI should be used instead during lactation.

Epidemiology and predisposing factors of obesity in Greece: from the Second World War until today.

Over the last 30 years overweight and obesity among adults and children have been on the rise, and since 1997 WHO has designated obesity as a major public health problem. In Greece both adult and childhood obesity is now recognized as an epidemic problem, probably more important than in other European countries. The issue is more serious in male adolescents and adults. There is also a tendency for weight increase along the last 30 years. Metabolic syndrome and type 2 diabetes mellitus are also rising rapidly in the Greek population. The reasons for this epidemic in Greece are not clear. Possible explanations could emerge from the delayed but sharp economic evolution of the country, as well as the abandonment of the traditional Mediterranean diet. Other predisposing factors in Greek children are parental obesity, frequent television viewing, low rates of breastfeeding and, in adolescent girls, smoking and alcohol consumption. Emerging measures are needed to confront this epidemic.

Recent concepts of pharmacotherapy and bariatric surgery for childhood obesity: an overview.

The epidemic of childhood obesity is associated with an increased incidence of cardiovascular risk factors, adult obesity, and obesity-related comorbidity. In this review article we highlight existing data on approaches to the management of childhood obesity. There are currently three main treatment modalities for childhood obesity: a) lifestyle modifications, which include exercise, diet, counseling, and combination of these, b) pharmacotherapy, which may have a role in a select group of overweight adolescents, and c) bariatric surgery. The three main drugs currently considered for treatment of pediatric obesity are orlistat, sibutramine and metformin. Only the first two are currently approved by the Food and Drug Administration (FDA) for the long-term treatment of obesity. Safety and efficacy have not been determined beyond 4 years for orlistat and 2 years for sibutramine. Bariatric surgery in pediatric patients with morbid obesity results in sustained and clinically significant weight loss but also has the potential for serious complications. Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric binding (LAGB) are the two main surgical procedures which have been used in pediatric obesity. RYGB is considered a safe and effective option for extremely obese adolescents as long as appropriate long-term follow-up is provided. LAGB has not been approved by FDA for use in adolescents, and therefore should be considered investigational. Finally, sleeve gastrectomy, another type of weight loss surgery, which has gained significant appreciation in adults, should be also considered investigational; existing data are not sufficient to recommend widespread and general use in adolescents.

The impact of thyroid diseases starting from birth on reproductive function.

The aim of this review is to provide relevant information regarding the impact of thyroid disease, starting from birth and mainly concerning hyperthyroidism and hypothyroidism, on reproduction. Hyperthyroidism occurs much less commonly in children than hypothyroidism, with Graves' disease (GD) being the most common cause of thyrotoxicosis in children. Children born with neonatal GD have no defects in the reproductive system that could be related to hyperthyroidism. Current treatment options include antithyroid drugs (ATD), surgery, and radioactive iodine (RAI). In males, normal thyroid function seems important, at least in some parameters, for maintenance of semen quality via genomic or non-genomic mechanisms, either by locally acting on Sertoli cells, Leydig cells, or germ cells, or by affecting crosstalk between the HPT axis and the HPG axis. Sexual behavior may also be affected in thyroxic men, although many of these patients may have normal free testosterone levels. In women, menstrual irregularities are the most common reproduction-related symptoms in thyrotoxicosis, while this disorder is also associated with reduced fertility, although most women remain ovulatory. An increase in sex hormone-binding globulin (SHBG) and androgens, thyroid autoimmunity, and an impact on uterine oxidative stress are the main pathophysiological mechanisms which may influence female fertility. Thyroid hormones are responsible for normal growth and development during pre- and postnatal life, congenital hypothyroidism (CH) being the most common cause of neonatal thyroid disorders, affecting about one newborn infant in 3500. The reproductive tract appears to develop normally in cretins. Today, CH-screening programs allow for early identification and treatment, and, as a result, affected children now achieve normal or near-normal development. Hypothyroidism in males is associated with decreased libido or impotence. Although little is currently known about the effects of hypothyroidism on spermatogenesis and fertility, it has been established that sperm morphology and motility are mainly affected. In women of reproductive age, hypothyroidism results in changes in cycle length and amount of bleeding. Moreover, a negative effect on fertility and higher miscarriage rates has also been described.

Erectile dysfunction in patients with hyper- and hypothyroidism: how common and should we treat?

CONTEXT: Erectile dysfunction (ED) is associated with numerous diseases and aging. OBJECTIVE: The objective of the study was to investigate the impact of hyper- and hypothyroidism on male sexual health by using the Sexual Health Inventory for Males (SHIM). DESIGN: Seventy-one men, 27 hyper- and 44 hypothyroid and a similar number of controls were included in the study. A validated SHIM 5-item questionnaire was administered to all participants. Patients were asked to respond before and a year after initiation of treatment for thyroid dysfunction. A score between 25 and 22 is considered normal, between 21 and 11 diagnostic of mild to moderately severe ED, and 10 or less diagnostic of severe ED. RESULTS: Fifty-six men with thyroid dysfunction (78.9%; 19 hyperthyroid and 37 hypothyroid) had a SHIM score of 21 or less, compared with 24 controls (33.8%) (P < 0.0001). Twenty-one patients with ED (37.5%) had SHIM scores 10 or less, indicative of severe ED, compared with six controls (25%) (P < 0.01). ED was more prevalent in patients with hyperthyroidism and hypothyroidism, compared with controls (P < 0.001 and P < 0.0001, respectively). Positive correlation was found between SHIM scores and serum free T(4) (r = 0.413, P = 0.005) and negative for TSH (r = -0.669, P < 0.001). After treatment a significant increase of SHIM scores was noted in both hyperthyroid (P < 0.0001) and hypothyroid (P < 0.0001) patients. CONCLUSIONS: ED is extremely common in males with dysthyroidism. Treatment of the latter restores erectile function. Screening for thyroid dysfunction in men presenting with ED is recommended, whereas specific treatment for ED should be postponed in such patients for at least 6 months after achieving euthyroidism because the latter might be responsible for ED.

Use of somatostatin analogues in obesity.

Obesity is a condition that results from dysregulation of energy balance. Insulin, a component of the efferent pathway of the energy-regulatory circuit, promotes storage of energy substrates in adipose tissue and is, therefore, a potential target for pharmacotherapy. Somatostatin and its analogues (octreotide and lanreotide) bind to somatostatin subtype 5 receptors on the beta-cell membrane, which limits insulin release and, consequently, may decrease adipogenesis. Somatostatin and its analogues have been used in trials in patients with paediatric hypothalamic obesity. These children have hypothalamic dysfunction, mainly due to brain tumours such as craniopharyngiomas, which are thought to generate increased vagal output, leading to hyperinsulinaemia and weight gain. Two small trials, each of 6 months' duration, in children with paediatric hypothalamic obesity showed either a minimal weight loss or stabilization of bodyweight. In children with Prader-Willi syndrome, the most common genetic hypothalamic disorder associated with hyperphagia, hyperghrelinaemia, massive obesity and other endocrine disturbances, somatostatin failed to control hyperphagia and weight gain in a small number of patients, although it lowered the levels of the anorexigenic hormone ghrelin. Long-acting release octreotide was recently used in hyperinsulinaemic obese adults without cranial pathology. Insulin suppression was associated with small decreases in the body mass indexes of obese subjects receiving the higher dosages of the drug, with an acceptable safety profile, similar to that in previous studies. In conclusion, somatostatin and its analogues, by suppressing beta-cell insulin secretion, can retard weight gain in children with hypothalamic obesity and induce a small amount of weight loss in some adults with hyperinsulinaemic obesity.

[Body composition analysis in obesity: radionuclide and non radionuclide methods].

Body composition (BC) assessment provides important information regarding the absolute or relative amount of bone, lean and fat tissue. Different somatometric techniques have been applied in numerous epidemiological and experimental studies, as well as in every day clinical practice. Traditional techniques for BC analysis include skin fold thickness measurements, radioisotope dilution methods, hydrodensitometry and underwater weighing, while newer techniques include bioelectrical impedance analysis (BIA), air displacement plethysmography (ADP), dual energy X-rays absorptiometry (DEXA), computer tomography and magnetic resonance imaging. In addition, positron emission tomography helped to the functional investigation of adipose tissue, in particular of brown tissue. All these techniques have contributed a lot to the understanding of physiological conditions such as exercise training, menopause and ageing, adolescence health parameters, as well as pathological conditions such as disorders of nutrition, cancer, obesity and diabetes mellitus. In obesity, BC contributed to diagnosis and the pathological impact of visceral adipose tissue. In addition, conditions such as pseudo- or hypermuscular obesity and sarcopenia, which are often observed in various endocrine diseases, were investigated in detail by using such methods. During weight loss, some of these methods were quite accurate in measuring changes in fat and lean mass. Apart from anthropometric measurements, a BC measurement if possible should be included in obesity assessment. Measurements of skin fold thickness combined with BIA are quite sufficient for routine clinical practice. However, in specialized clinics and in research, more sophisticated methods like ADP or DEXA are used.

Thyroid autoimmunity and miscarriage.

The relation of thyroid autoimmunity to miscarriage is an important issue that has attracted the interest of many investigators. A number of papers have been published so far, which include healthy women, women with recurrent miscarriage and those undergoing assisted reproductive techniques. Most studies have shown a significant positive association between the presence of thyroid autoantibodies and miscarriage rate. It is of interest that women with high titers do not show a higher miscarriage rate when compared with women having low titers, although, there is no general agreement on this issue. There are three possible explanations for the assumed association of thyroid autoimmunity with miscarriage: 1) pregnancy loss is an epiphenomenon and not a direct effect of the thyroid autoantibodies, the presence of thyroid autoantibodies reflecting a generalized activation of the immune system; 2) delayed conception from the presence of thyroid autoantibodies; hence, when women with thyroid autoimmunity become pregnant, face a higher risk of miscarriage because of older age; and 3) the pregnancy loss is secondary to a subtle deficiency in thyroid hormone concentrations or a lower capacity of the thyroid to adequately adapt to the demands of pregnancy.

Seasonality of month of birth of patients with Graves' and Hashimoto's diseases differ from that in the general population.

OBJECTIVE: We aimed to test the viral hypothesis in the pathogenesis of autoimmune thyroid disease (AITD). DESIGN: We determined the pattern of month of birth (MOB) distribution in patients with AITD and in the general population and searched for differences between them. METHODS: A total of 1023 patients were included in this study; 359 patients had Graves' hyperthyroidism (GrH) and 664 had Hashimoto's hypothyroidism (HH). We divided the patients with HH into three subgroups according to their thyroid peroxidase (TPO) antibody titers at diagnosis: low levels (<500 IU/ml), high levels (500-1000 IU/ml), and extremely high levels (>1000 IU/ml). We used cosinor analysis to analyze the data. RESULTS: Overall, patients with GrH and HH had a different pattern of MOB distribution when compared with the general population and between groups. Furthermore, among both patients with GrH and HH, both genders had a different pattern of MOB distribution when compared with the general population and this pattern was also different between genders. Finally, only women with extremely high titers of TPO antibodies at diagnosis and men with low or extremely high TPO antibody levels showed rhythmicity in MOB, with a pattern of MOB distribution different from that in controls. CONCLUSIONS: The different MOB seasonality in both GrH and HH points towards a similar maybe even common etiology with type 1 diabetes mellitus and multiple sclerosis, namely a seasonal viral infection as the initial trigger in the perinatal period, the clinical disease resulting from further specific damage over time.

Basic endocrine products of adipose tissue in states of thyroid dysfunction.

Over the past decade it has been established that adipose tissue is capable of secreting a variety of hormones, cytokines, growth factors, and other peptides that are capable of changing adipocyte biology as well as different organ systems, like the central nervous system, liver, pancreas, and skeletal muscles. Also, it is well known that changes of thyroid function are associated with marked changes in both body weight and energy expenditure. In recent years an extensive research is under way to explore the mutual roles of different adipokines and thyroid hormones. The aim of this review is to summarize our current knowledge on the role of basic peptides of adipose tissue, such as adiponectin, interleukin-6, tumor necrosis factor-alpha, and resistin, in states of altered thyroid function.

Short-term administration of orlistat reduced daytime triglyceridemia in obese women with the metabolic syndrome.

The objective of this prospective, controlled, randomized study was to evaluate the effect of orlistat administration for 10 days on daytime capillary triglyceridemia in obese women with metabolic syndrome (MetSyn). Thirty-two obese, nondiabetic women with MetSyn were evaluated. The presence of MetSyn was defined according to the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria. Patients were randomized into 2 similar groups: group A (orlistat), mean age 50.1 -/+ 8.2 years, received a low-calorie diet combined with orlistat 120 mg tid for 10 days and group B (control), mean age 51.2 -/+ 9.1 years, received only the low-calorie diet for the same period of time. Anthropometric, lipids, and parameters of insulin resistance were measured before and after 10 days of intervention. Capillary triglycerides (TGc) were measured at 6 different time points during the day and daytime triglyceridemia was expressed as area under the curve of TGc (AUC-TGc). Most anthropometric measurements (body weight, body mass index, waist circumference, and percentage of fat mass) and most metabolic parameters (total cholesterol [TC], fasting venous triglycerides [TGfv], high-density lipoprotein cholesterol [HDL-C] levels, fasting glucose [FG], fasting insulin [FI], and homeostasis model for assessment [HOMA] for insulin resistance index) decreased significantly in both groups, while waist-to-hip ratio (WHR) and systolic (SBP) and diastolic blood pressure (DBP) did not change significantly in both groups and low-density lipoprotein cholesterol (LDL-C) levels decreased only in the orlistat group. Following minimal weight loss, TGc at most time points and AUC-TGc were significantly reduced only in group A. In group A, AUG-TGc decreased by 17% from 36.4 -/+11.8 to 30.2 -/+9.9 mmol/Lxh(-1) (p < 0.001), and this reduction was significantly greater compared with the control group (p < 0.05) and remained significant after percentage of weight loss was taken into account. This decrease of AUC-TGc significantly correlated with the decrease of HOMA index (p < 0.05, r = 0.39) and the decrease of TGfv (p < 0.001, r = 0.62). The tolerability of orlistat was very good and side effects were transient and of minimal intensity. In conclusion, short-term administration of orlistat significantly reduced daytime triglyceridemia in obese, nondiabetic women with MetSyn. This reduction could offer cardiovascular benefits in these high-risk patients. Long-term studies with more patients are needed to reach definite conclusions.

Prevention of thyroid associated-ophthalmopathy in children and adults: current views and management of preventable risk factors.

Primary, secondary and tertiary prevention are defined according to the timing of the preventive intervention in the natural history of a disease. Secondary prevention in Graves' ophthalmopathy (GO) is challenging in the absence of reliable specific serum markers for subclinical GO that would allow an early diagnosis. Some risk factors for occurrence or progression of GO have been identified. Cigarette smoking, thyroid dysfunction and radioactive iodine (RAI) are known preventable risk factors. The list is probably much longer, and future research should be aimed at identifying more. Smoking cessation, restoration of euthyroidism by antithyroid drugs or L-thyroxine, glucocorticoid coverage after RAI or deferring RAI until the eye disease is inactive, may prevent progression of GO. Passive smoking seems to exacerbate autoimmune thyroid disease (AITD) in general, and may have a deleterious effect on childhood GO in particular, therefore avoidance of passive smoking is likely to be beneficial.

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes.

Coding synonymous single nucleotide polymorphisms (SNPs) have attracted little attention until recently. However, such SNPs located in epigenetic, CpG sites modifying exonic splicing enhancers (ESEs) can be informative with regards to the recently verified association of intragenic methylation and splicing. The present study describes the association of type 2 diabetes (T2D) with the exonic, synonymous, epigenetic SNPs, rs3749166 in calpain 10 (CAPN10) glucose transporter (GLUT4) translocator and rs5404 in solute carrier family 2, member 2 (SLC2A2), also termed GLUT2, which, according to prior bioinformatic analysis, strongly modify the splicing potential of glucose transport-associated genes. Previous association studies reveal that only rs5404 exhibits a strong negative T2D association, while data on the CAPN10 polymorphism are contradictory. In the present study DNA from blood samples of 99 Greek non-diabetic control subjects and 71 T2D patients was analyzed. In addition, relevant publicly available cases (40) resulting from examination of 110 Personal Genome Project data files were analyzed. The frequency of the rs3749166 A allele, was similar in the patients and non-diabetic control subjects. However, AG heterozygotes were more frequent among patients (73.24% for Greek patients and 54.55% for corresponding non-diabetic control subjects; P=0.0262; total cases, 52.99 and 75.00%, respectively; P=0.0039). The rs5404 T allele was only observed in CT heterozygotes (Greek non-diabetic control subjects, 39.39% and Greek patients, 22.54%; P=0.0205; total cases, 34.69 and 21.28%, respectively; P=0.0258). Notably, only one genotype, heterozygous AG/CC, was T2D-associated (Greek non-diabetic control subjects, 29.29% and Greek patients, 56.33%; P=0.004; total cases, 32.84 and 56.58%, respectively; P=0.0008). Furthermore, AG/CC was strongly associated with very high (≥8.5%) glycosylated plasma hemoglobin levels among patients (P=0.0002 for all cases). These results reveal the complex heterozygotic SNP association with T2D, and indicate possible synergies of these epigenetic, splicing-regulatory, synonymous SNPs, which modify the splicing potential of two alternative glucose transport-associated genes.