Lymphocytic hypophysitis: modern day management with limited role for surgery.

PURPOSE: We set out to describe the modern day management of Lymphocytic hypophysitis (LH) with respect to its diagnosis, treatment and long-term endocrine and visual outcomes. We deliberately included patients with a clinical diagnosis of LH and compared them with those with a histological diagnosis following surgery. METHODS: A multi-centre observational study was performed. Twenty-two patients were included and studied over a mean follow-up period of 8.6 years (range 4-26 years). RESULTS: Patients presented with headache (N = 15; 68 %), visual field disturbances (N = 7; 32 %) or a combination of these symptoms (N = 5; 23 %). The time lag between onset of symptoms and diagnosis was <1 month, 1-6 months or >6 months in approximately a third of the patients each, respectively. In two-thirds of the patients (N = 14) LH was diagnosed based on their clinical, biochemical and radiological findings. The surgical cohort (N = 8) was statistically more likely to have presented with larger lesions, with suprasellar extension and greater visual field defects. During follow-up there was improvement in headaches and visual symptoms, but the rate of hypopituitarism as reflected by the need for on-going pituitary hormone replacement persisted. At the 1, 5 and 10 year follow-up there was no significant difference between the medically and surgically managed cohorts in terms of ongoing symptomatology or need for pituitary hormone replacement. CONCLUSIONS: In the modern era, most patients with LH are diagnosed by non-surgical means and managed medically. There remains a significant time lag between the onset of symptoms and the eventual diagnosis of LH. Despite the considerable morbidity attached to LH, overall prognosis is good.

Recurrence of phaeochromocytoma in pregnancy in a patient with multiple endocrine neoplasia 2A: a case report and review of literature.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant inherited condition with a prevalence of one in 40 000 individuals. It causes the development of tumours in endocrine glands, such as medullary thyroid cancer, pheochromocytomas, as well as primary hyperparathyroidism. MEN 2A in pregnancy is very rare with only 29 cases reported in the literature. The presence of pheochromocytoma is a rare cause of hypertension during pregnancy with an incidence of 0.007% of all pregnancies. This has severe implications on both mother and the foetus. This case report describes a 22-year-old nulliparous Caucasian woman with known MEN2A syndrome, who underwent thyroidectomy for medullary thyroid carcinoma in childhood and excision of left sided pheochromocytoma at the age of 19. She was found to have a recurrence of pheochromocytoma in the right adrenal gland during pregnancy at 16 weeks of gestation and was oddly normotensive. Catecholamine effects were blocked with phenoxybenzamine and she delivered by an uneventful elective caesarean section at 36 weeks gestation. She underwent a laparoscopic right adrenalectomy six weeks postpartum, followed by lifelong corticosteroid replacement.

Adherence to the Mediterranean diet by the Greek and Cypriot population: a systematic review.

BACKGROUND: The traditional Mediterranean diet is defined as the dietary pattern in the countries of the Mediterranean basin between the 1950s and 1960s, and it is now widely accepted that has a beneficial effect on health. A debate exists from empirical and research data if the traditional Mediterranean diet remains the main dietary pattern of the region or if it has changed overtime. AIMS: This systematic review addresses whether the people of Cyprus and Greece still follow the traditional Mediterranean diet or whether the diet has become more 'Westernised'. METHODS: The MEDLINE database was searched using relevant free terms and independently reviewed by two authors. In addition, all reference lists of identified studies were hand-searched to identify additional, relevant studies. RESULTS: The review resulted in 18 research papers that met the inclusion and exclusion criteria and represented 15 independent studies. The main outcome was consistent between studies and indicated moderate adherence of the Greek, and (probably) of the Cypriot, population to the Mediterranean diet. The majority of studies found no statistically significant differences by gender. There was an observed inter-study lower adherence to the Mediterranean diet by the younger population. Few studies addressed intra-study variations by age. CONCLUSIONS: This review shows that adherence to the Mediterranean diet is moderate in Greece (and probably also in Cyprus).This suggests a continuing transition from dietary patterns in the 50 s-60 s towards a more Westernized diet.

Stress, Thyroid Dysregulation, and Thyroid Cancer in Children and Adolescents: Proposed Impending Mechanisms.

Stress is a potential catalyst for thyroid dysregulation through cross-communication of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid (HPT) axes. Stress and stressors exposure motivates molecular mechanisms affecting compound feedback loops of the HPT axis. While there is evidence of connection between stress and thyroid dysregulation, the question whether this connection is implicated in the development of thyroid cancer (TC) remains unanswered. In view of the rising incidence of TC in both adults and children alongside the increasing stress in our modern society, there is a need to understand possible interrelations between stress, thyroid dysregulation, and TC. Prolonged glucocorticoid secretion due to stress interferes with immune system response by altering the cytokines, inducing low-grade chronic inflammation, and suppressing function of immune-protective cells. Chronic inflammation is a risk factor linked to TC. The role of autoimmunity has been a matter of controversy. However, there is epidemiological connection between autoimmune thyroid disease (AITD) and TC; patients with AITD show increased incidence in papillary thyroid carcinoma (PTC), and those with TC show a high prevalence of intrathyroidal lymphocyte infiltration and thyroid autoantibodies. Timing and duration-dependent exposure to specific endocrine disrupting chemicals (EDCs) has an impact on thyroid development, function, and proliferation, leading to thyroid disease and potentially cancer. Thyroid hormone imbalance, chronic inflammation, and EDCs are potential risk factors for oxidative stress. Oxygen free radicals are capable of causing DNA damage via stimulation of the mitogen-activating protein kinase or phosphatidylinositol-3-kinase and/or nuclear factor kB pathways, resulting in TC-associated gene mutations such as RET/PTC, AKAP9-BRAF, NTRK1, RAASF, PIK3CA, and PTEN. Stressful events during the critical periods of prenatal and early life can influence neuroendocrine regulation and induce epigenetic changes. Aberrant methylation of tumor suppressor genes such as P16INK4A, RASSF, and PTEN is associated with PTC; histone H3 acetylation is shown to be higher in TC, and thyroid-specific noncoding RNAs are downregulated in PTC. This review focuses on the above proposed mechanisms that potentially lead to thyroid tumorigenesis with the aim to help in the development of novel prognostic and therapeutic strategies for TC.

GLP-1 receptor agonists, polycystic ovary syndrome and reproductive dysfunction: Current research and future horizons.

Polycystic ovary syndrome (PCOS) is a disorder that involves several organ systems and cellular pathways. It is strongly influenced by environmental and epigenetic factors. The principal goal of all therapeutic approaches to individuals with reproductive abnormalities is the treatment of subfertility or the regulation of menstruation when pregnancy is not desired. Obesity is closely related to insulin resistance (IR) and subsequent hyperinsulinemia, which aggravate hyperandrogenism and impair early follicle development. Weight loss is of vital importance for overweight/obese individuals with anovulatory infertility. The GLP-1R agonists have achieved remarkable weight reduction and abdominal fat loss in patients with type 2 diabetes (T2D), as well as in overweight/obese individuals and individuals with prediabetes. They have also been shown to promote lower fasting insulin levels and insulin resistance markers. These beneficial effects have been suggested to be particularly helpful in women with PCOS, while their possible role in the hypothalamic-pituitary-gonadal axis is under intense research. This review analyzes the current evidence for GLP-1R agonists, focusing on their effects on ovarian morphology, menstrual dysfunction and fertility outcomes. It also discusses their future role in achieving targeted therapeutic approaches.

Alemtuzumab-Induced Autoimmune Thyroid Dysfunction.

Alemtuzumab, a humanized monoclonal antibody used as a disease-modifying treatment in relapsing-remitting multiple sclerosis (RRMS), frequently causes autoimmunity as its principal adverse effect. We describe a typical case of a young man treated with two courses of alemtuzumab presenting 18 months later with initial hyperthyroidism due to Graves' disease (GD) followed by persistent hypothyroidism. We discuss the pathophysiological role of stimulating and blocking thyrotropin receptor antibodies in the development of alemtuzumab-induced autoimmune thyroid dysfunction and clinical challenges posed by spontaneous, bidirectional switching between hyperthyroidism and hypothyroidism. Guidelines recommend monitoring thyroid function pre-treatment and every three months for four years following alemtuzumab treatment. Patient education is crucial for maintaining adherence to monitoring programs.

Real-world application of ATA Guidelines in over 600 aspirated thyroid nodules: is it time to change the size cut-offs for FNA?

Background: The 2015 American Thyroid Association (ATA) Guidelines recommend the following size cut-offs based on sonographic appearances for subjecting nodules to fine-needle aspiration (FNA) biopsy: low risk: 15 mm and intermediate risk and high risk: 10 mm. Objective: We conducted a 'real-world' study evaluating the diagnostic performance of the ATA cut-offs against increased thresholds, in the interest of safely limiting FNAs. Methods: We performed a retrospective analysis of prospectively collected data on 604 nodules which were sonographically risk-stratified as per the ATA Guidelines and subsequently subjected to ultrasound-guided FNA. Nodules were cytologically stratified into 'benign' (Bethesda class 2) and 'non-benign' (Bethesda classes 3-6). We obtained the negative predictive value (NPV), accuracy, FNAs that could be spared, missed 'non-benign' cytologies and missed carcinomas on histology, according to the ATA cut-offs compared to higher cut-offs. Results: In low-risk nodules, the high performance of NPV (≈91%) is unaffected by increasing the cut-off to 25 mm, and accuracy improves by 39.4%; 46.8% of FNAs could be spared at the expense of few missed B3-B6 cytologies (7.9%) and no missed carcinomas. In intermediate-risk nodules, a 15 mm cut-off increases the NPV by 11.3% and accuracy by 40.7%. The spared FNAs approach 50%, while B3-B6 cytologies are minimal, with no missed carcinomas. In high-risk nodules, low NPV (<35%) and accuracy (<46%) were obtained regardless of cut-off. Moreover, the spared FNAs achieved at higher cut-offs involved numerous missed 'non-benign' cytologies and carcinomas. Conclusion: It would be clinically safe to increase the ATA cut-offs for FNA in low-risk nodules to 25 mm and in intermediate-risk nodules to 15 mm.

The Role of Thyroid Hormones on Skeletal Muscle Thermogenesis.

Nowadays obesity becomes a significant global problem. Hence, recently more and more attention has been paid to substances present in the body that have a significant impact on metabolic processes and thermogenesis, in the context of their potential use in the prevention and treatment of obesity. It is well known that the relationship between thyroid hormones and obesity is multilayered, however recently, more and more information about the possible relation between thyroid hormones and muscle metabolism has been published. The aim of this review is to present the most updated information on the physiological impact of thyroid hormones on muscle tissue, as well as pathological changes related to the occurrence of various types of thyroid disorders, including hypothyroidism, hyperthyroidism and sick euthyroid syndrome. However, the data in humans still remains insufficient, and further studies are needed to fully explore the thyroid-muscle cross-talk.

Microcalcifications without a thyroid nodule as the sole sign of papillary thyroid carcinoma.

SUMMARY: Our objective is to demonstrate the importance of considering microcalcifications even without evidence of nodules as a potential sign of malignancy. Current guidelines, such as those of the British Thyroid Association, acknowledge the clinical significance of microcalcifications only when found within nodules. In this case, they are considered a suspicious feature, classifying the nodules as U5 (i.e. high risk) where fine-needle aspiration biopsy (FNAB) is warranted, following the high likelihood of cancer in these nodules. In addition, there is a dearth of evidence of ultrasound scan (USS) detection of microcalcifications in the thyroid gland outside of nodules, along with their associated clinical implications. Yet, this clinical manifestation is not so infrequent considering that we do encounter patients in the clinic showing these findings upon ultrasound examination. Three patients who presented to our clinic with thyroid-related symptoms were shown to have areas of microcalcifications without a nodule upon sonographic evaluation of their thyroid gland. These incidentally detected hyperechoic foci were later confirmed to correspond to areas of papillary thyroid carcinoma (PTC) on histopathological examination of resected tissue following thyroidectomy. Four more cases were identified with sonographic evidence of microcalcifications without nodules and given their clinical and other sonographic characteristics were managed with active surveillance instead. LEARNING POINTS: Echogenic foci known as microcalcifications may be visible without apparent association to nodular structures. Microcalcifications without nodules may not be an infrequent finding. Microcalcifications are frequently indicative of malignancy within the thyroid gland even without a clearly delineated nodule. Empirically, the usual guidelines for the management of thyroid nodules can be applied to the management of microcalcifications not confined to a nodule, but such a finding per se should be classified as a 'high-risk' sign.

Clinical Experience of the Efficacy and Safety of Low-dose Tolvaptan Therapy in a UK Tertiary Oncology Setting.

CONTEXT: In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy. OBJECTIVE: To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy. METHODS: Retrospective evaluation in a tertiary cancer center. RESULTS: Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ±â€…4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ±â€…9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01). CONCLUSION: In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.

Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus?

Pembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication.

Online health information-seeking behavior by endocrinology patients.

PURPOSE: Given that the Internet is important for health-related information (HRI) and the fact that online health information (OHI)-seeking behavior has never been studied in endocrinology, we set out to examine how and why the Internet is utilized for HRI, the frequency of such activity, its impact, future information needs, and the effect of language. METHODS: A mainly quantitative, embedded mixed-methods study was performed, employing a questionnaire survey. We included 312 patients (78.4% response rate). RESULTS: OHI-seeking was reported by 175 patients (56.1%), especially in younger (p = 0.037) and more educated (p = 0.006) patients. OHI-seekers perceived OHI to be high-quality (135, 77.1%) but 104 (59.4%) were unaware of website certification tools. Among OHI-seekers, 63 (36.6%) reported positive behavioral changes after seeking OHI. Only 45 (25.7%) OHI-seekers discussed their gathered information with their endocrinologist. If an interactive e-learning module was available, 194/312 (62.2%) patients expressed willingness to use it, especially those reporting a need for more HRI (p = 0.024). Native speakers were more likely to report that OHI did not meet their information needs (p < 0.001). CONCLUSIONS: OHI-seeking by patients attending the endocrinology outpatients is widely practiced. The availability of OHI in the native language and e-learning modules may enhance the utility of the Internet for health information.

Weight gain following treatment of hyperthyroidism-A forgotten tale.

Hyperthyroidism causes weight loss in the majority, but its effect is variable and 10% of patients gain weight. Its treatment usually leads to weight gain and some studies have reported an excess weight regain. However, there is considerable inter-individual variability and a differential effect on body weight by different treatments, with some studies reporting more weight increase with radioiodine, and perhaps surgery, compared with anti-thyroid drugs. The excess weight regain may relate to treatment-induced hypothyroidism. Furthermore, the transition from hyperthyroidism to euthyroidism may unmask, or exacerbate, the predisposition that some patients have towards obesity. Other risk factors commonly implicated for such weight increase include the severity of thyrotoxicosis at presentation and underlying Graves' disease. Conflicting data exist whether lean body mass or fat mass or both are increased post-therapy and whether such increments occur concurrently or in a sequential manner; this merits clarification. In any case, clinicians need to counsel their patients regarding this issue at presentation. Limited data on the effect of dietary interventions on weight changes with treatment of hyperthyroidism are encouraging in that they cause significantly lesser weight gain compared to standard care. More research is indicated on the impact of the treatment of hyperthyroidism on various anthropometric indices and the predisposing factors for any excessive weight gain. Regarding the impact of dietary management or other weight loss interventions, there is a need for well-designed and, ideally, controlled intervention studies.

Florid hyperandrogenism due to a benign adrenocortical adenoma.

A 26-year-old woman with a history of polycystic ovarian syndrome presented with secondary amenorrhea, worsening hirsutism, acne, deepening of voice and unexplained 10-20 kg weight gain. Her Ferriman-Gallway hirsutism score was 12 with cystic facial acne and increased masculine phenotype. Urine Beta-Human Chorionic Gonadotropins (bHCG) was negative. She had elevated serum testosterone of 551 ng/dL, androstenedione at 7.46 ng/mL and dehydroepiandrosterone sulfate (DHEAS) at 4243 µg/L. Overnight dexamethasone suppression test showed mildly unsuppressed cortisol (2.89 µg/dL). Urinary free cortisol along with paired serum cortisol and adrenocorticotrophic hormone (ACTH) tests were normal (55.4 µg/24 hours, 13.44 mcg/dL, 30.4 pg/mL respectively). Her leutinizing hormone (LH) was low(<0.1 mIU/mL), follicle stimulating hormone (FSH) low/normal (1.41 mIU/mL) with sex hormone binding globulin (SHBG) level 45nmol/L and the rest of the pituitary and adrenal workup was unremarkable. Thyroid stimulating hormone (TSH) was 2.15mU/mL. MRI revealed a 3.1 cm, indeterminate but well-defined left adrenal lesion and polycystic ovaries without abdominal lymphadenopathy. Given radiological appearances and despite biochemical concerns for adrenocortical malignancy, a multidisciplinary team meeting decision was made to proceed with laparoscopic adrenalectomy. Histology was consistent with a benign adenoma. Postoperatively, there was clinical and biochemical resolution of the disease.

Clinical diagnosis of Graves' or non-Graves' hyperthyroidism compared to TSH receptor antibody test.

BACKGROUND: TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves' disease (GD), which is commonly diagnosed clinically. AIM: To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test. SETTING: University teaching hospital in North West England. PARTICIPANTS: Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015. METHODS: Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables. RESULTS: We identified 316 patients with a mean age of 45 (range, 17-89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001). CONCLUSIONS: Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism.

Intractable hypoglycaemia in a patient with advanced carcinoid syndrome successfully treated with hepatic embolization.

A male patient presented at the age of 54 years with metastatic pancreatic neuroendocrine tumour (NET). He was managed with interferon and multiple courses of MIBG therapy which controlled his disease for about seven years. He then developed symptomatic hypoglycaemia which resolved with the introduction of somatostatin analogue treatment and further therapeutic MIBG. However, three years later he was admitted to hospital with severe and intractable hypoglycaemia, which persisted despite treatment with dietary manipulation, diazoxide, long-acting octreotide injections, intravenous infusion of dextrose and octreotide and everolimus. Bland hepatic embolization was attempted as a last resort and resulted in prompt and dramatic improvement of his condition with no hypoglycaemia for five months. We recommend that hepatic embolization should be considered in patients with advanced and metastatic NETs accompanied by refractory hypoglycaemia, with the aim of symptomatic relief and palliation, and possibly some survival benefit.