Anaemia and thyrotoxicosis: The need to look for an alternative cause.

OBJECTIVES: Anaemia and thyrotoxicosis are both relatively common. It is unclear whether thyrotoxicosis results in anaemia in the absence of other causes. The aim of this study was to determine the prevalence and characteristics of anaemia in patients with thyrotoxicosis. DESIGN: A prospective cohort study of patients with thyrotoxicosis. PATIENTS: 353 patients referred to a regional endocrinology centre in New Zealand from March 2013 to November 2014 for new-onset thyrotoxicosis. MEASUREMENTS: Detailed assessment including thyroid function tests, full blood count, inflammatory markers, haematological parameters and coeliac serology. Anaemia was defined as a haemoglobin value <115 g/L (woman) or <130 g/L (men). RESULTS: Anaemia was present in 31 (8.7%) patients at diagnosis. Of these, pre-existing anaemia was present in 10, and a further 11 had one or more identifiable underlying cause(s) for the anaemia. Only 10 patients (2.8% of the entire cohort) had anaemia not clearly attributable to another cause. Median free thyroid hormone levels were higher in those with anaemia of unknown cause compared to patients with thyrotoxicosis alone. The median duration of anaemia was shorter in patients with thyrotoxicosis-associated anaemia compared to those with anaemia due to an underlying cause (1 vs 6 months, P = .001). In all patients with thyrotoxicosis-associated anaemia, the anaemia resolved, either prior to, or on becoming euthyroid. CONCLUSION: Anaemia coexisting with thyrotoxicosis is less common than previously reported and is mild and transient. Patients with thyrotoxicosis and significant anaemia should be investigated for other potential causes, particularly when anaemia persists.

Novel mutation in the TMEM127 gene associated with phaeochromocytoma.

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours that arise from the adrenal glands or paraganglia (paragangliomas) within the abdomen, thorax and neck. Although it was originally suggested that approximately 10% of these tumours were inherited, it is now recognised that up to approximately 30% of these tumours are associated with a germline mutation in one of the phaeochromocytoma/paraganglioma susceptibility genes. Of the 12 currently known genes predisposing to these tumours, the TMEM127 gene is one of the more recently identified and appears to be present in approximately 2% of apparently sporadic phaeochromocytomas. We report a 33-year-old man who presented with an apparently sporadic adrenal phaeochromocytoma and was identified as carrying a novel TMEM127 germline mutation, p.Gln139X. Patients harbouring a germline TMEM127 mutation most commonly present with an apparently sporadic solitary adrenal phaeochromocytoma. Testing patients who present with a phaeochromocytoma or paraganglioma for an underlying germline mutation needs to be considered in all patients due to implications for family members, but a strategy based on clinical and immunohistochemical findings would be prudent to limit costs.

Patients with RET D631Y mutations most commonly present with pheochromocytoma and not medullary thyroid carcinoma.

Multiple endocrine neoplasia type 2a results from an activating germline mutation in the RET proto-oncogene. Carriers of a RET mutation are at risk of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. Most individuals with multiple endocrine neoplasia type 2a eventually develop medullary thyroid carcinoma and as there is a strong genotype-phenotype correlation, guidelines have been established as to the age recommended for prophylactic thyroidectomy. However for rare mutations in the RET proto-oncogene there is insufficient evidence to provide guidance as to the risk of medullary thyroid carcinoma. We present a family with the rare RET mutation, D631Y in which the proband initially presented with a pheochromocytoma, and review the available literature pertaining to this mutation. In 83% of index cases, pheochromocytoma was the presenting feature and only 37% of adult germline mutation carriers have developed medullary thyroid carcinoma, none of whom have been reported to have nodal or metastatic disease. Patients with a D631Y RET mutation typically present with pheochromocytoma and medullary thyroid carcinoma appears to occur with a later onset than reported with other RET mutations. Based on the current literature we recommend performing prophylactic total thyroidectomy by age 12 years for D631Y carriers although this recommendation may need to be reviewed as additional data becomes available.

Metastatic parathyroid carcinoma initially misdiagnosed as parathyroid adenoma: the role of parafibromin in increasing diagnostic accuracy.

Parathyroid carcinoma, although a rare cause of primary hyperparathyroidism, carries a significant morbidity and mortality from severe symptomatic hypercalcaemia and related complications. We report a case where the diagnosis was not considered from the outset and review the current clinical and histopathological markers available to assist in the diagnosis of parathyroid carcinoma.

Clinical and biochemical characteristics of patients with thyroid-stimulating hormone-secreting pituitary adenomas from one New Zealand centre.

BACKGROUND: Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas (TSHoma) are a rare cause of thyrotoxicosis and need to be distinguished from the syndrome of resistance to thyroid hormone. Patients with TSHoma may also be misdiagnosed as having primary hyperthyroidism and receive inappropriate treatment directed towards the thyroid gland. METHODS: We performed a retrospective review of patients with TSHoma who presented to one New Zealand endocrine service between 1989 and 2003. RESULTS: Six patients with TSHoma were managed during this time period. All patients had elevated free thyroid hormone levels with elevated, or inappropriately normal, TSH levels. The median age at presentation was 43 years and the median time from symptom onset to correct diagnosis was 3 years (range 0.25-12 years). Five patients had a macroadenoma at the time of diagnosis. Three had been treated elsewhere for primary hyperthyroidism prior to referral. Three patients received octreotide as primary treatment with two of these patients later undergoing transsphenoidal resection of the pituitary adenoma. CONCLUSION: With increased awareness and earlier diagnosis of TSH-secreting pituitary adenomas, management can be appropriately directed towards the pituitary.

Hypercalcaemia caused by a carcinoid tumour.

Humoral hypercalcaemia resulting from carcinoid tumours is uncommon. We report a case of hypercalcaemia because of excessive secretion of parathyroid hormone-related protein (PTHrP) in a 77-year-old woman with an advanced carcinoid tumour. Fibroblast growth factor 23 levels were also elevated. The hypercalcaemia responded to adjunctive therapy with long-acting octreotide analogue therapy, bisphosphonates and steroids. The role of PTHrP in humoral hypercalcaemia of malignancy, its association with neuroendocrine tumours, as well as the therapeutic use of somatostatin analogues are reviewed.

The safety of anaesthetising biochemically hyperthyroid patients undergoing thyroidectomy-a retrospective cohort study.

Traditionally it is recommended that hyperthyroid patients should be made euthyroid prior to thyroidectomy. However, several small observational studies have reported no increase in adverse events when hyperthyroid patients undergo thyroidectomy. The aim of this study was to assess outcomes following total thyroidectomy in patients who were biochemically hyperthyroid at the time of surgery compared to those who were euthyroid. One hundred and fifty-one eligible patients undergoing thyroidectomy for hyperthyroidism between January 2012 and February 2016 were identified, of whom 57 were hyperthyroid on perioperative blood tests and 94 were euthyroid (comparison group). Primary outcomes were 30-day mortality, increased length of postoperative hospital stay and intraoperative signs consistent with thyrotoxicosis (e.g. heart rate >100 per minute, systolic blood pressure >180 or <60 mmHg, or temperature >38°C). Secondary outcomes were intraoperative beta-blocker use and level of care required postoperatively. Thirty-day mortality was zero. The only significant difference between the two groups was a higher use of intraoperative beta-blockers amongst hyperthyroid patients (28.1% versus 8.5%, P=0.002). Our findings suggest that thyroidectomy for mild to moderate biochemical hyperthyroidism performed by an experienced thyroid surgeon and anaesthetist, is associated with increased intraoperative beta-blocker use but no statistical difference in mortality, length of postoperative stay or intraoperative signs consistent with thyrotoxicosis. While we still recommend attempting to achieve a euthyroid state whenever possible prior to thyroid surgery, mild to moderate degrees of residual biochemical hyperthyroidism when appropriately managed may not be associated with an increase in adverse outcomes.

Thyrotoxic, hypokalaemic periodic paralysis: Polynesians, an ethnic group at risk.

BACKGROUND: Thyrotoxic, hypokalaemic periodic paralysis (TPP) is a reversible cause of severe muscle weakness that occurs in a small minority of thyrotoxic patients. Most cases to date have been reported in Asian men. AIMS: To evaluate the ethnic distribution of patients with TPP. METHODS: Retrospective analysis of all patients presenting with thyrotoxicosis and hypokalaemia with paralysis to two New Zealand hospitals. RESULTS: Seventy-one per cent of the 21 patients with TPP were of Polynesian ethnicity (Maori and Pacific Islander), 24% Asian and 5% European. Based on population demographics, these figures suggest a 37-fold overrepresentation for Polynesians and 159-fold for Asians compared with New Zealand Europeans. CONCLUSION: Polynesian, in addition to Asian people, are two ethnic groups at particular risk of TPP, and this condition must be considered in the differential diagnosis for patients presenting to the emergency department with severe hypokalaemia and weakness.

Severe Cushing's syndrome due to small cell prostate carcinoma: a case and review of literature.

Cushing's syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) is associated with a variety of tumours most of which arise in the thorax or abdomen. Prostate carcinoma is a rare but important cause of rapidly progressive CS. To report a case of severe CS due to ACTH production from prostate neuroendocrine carcinoma and summarise previous published cases. A 71-year-old male presented with profound hypokalaemia, oedema and new onset hypertension. The patient reported two weeks of weight gain, muscle weakness, labile mood and insomnia. CS due to ectopic ACTH production was confirmed with failure to suppress cortisol levels following low- and high-dose dexamethasone suppression tests in the presence of a markedly elevated ACTH and a normal pituitary MRI. Computed tomography demonstrated an enlarged prostate with features of malignancy, confirmed by MRI. Subsequent prostatic biopsy confirmed neuroendocrine carcinoma of small cell type and conventional adenocarcinoma of the prostate. Adrenal steroidogenesis blockade was commenced using ketoconazole and metyrapone. Complete biochemical control of CS and evidence of disease regression on imaging occurred after four cycles of chemotherapy with carboplatin and etoposide. By the sixth cycle, the patient demonstrated radiological progression followed by recurrence of CS and died nine months after initial presentation. Prostate neuroendocrine carcinoma is a rare cause of CS that can be rapidly fatal, and early aggressive treatment of the CS is important. In CS where the cause of EAS is unable to be identified, a pelvic source should be considered and imaging of the pelvis carefully reviewed.

The effect of ovine corticotropin-releasing factor on catecholamine, vasopressin, and aldosterone secretion in normal man.

The 41-residue ovine corticotropin-releasing factor (CRF) was administered iv to five normal men. A significant rise in plasma corticotropin (ACTH), cortisol, and aldosterone was demonstrated after a dose of 200 micrograms. There was no demonstrable change in supine blood pressure, pulse rate, plasma vasopressin, renin, catecholamines, insulin, glucagon, or glucose. It is concluded that 200 micrograms ovine CRF stimulates ACTH and cortisol secretion independently of any change in peripheral plasma levels of vasopressin and catecholamines. The cortisol and ACTH responses to ovine CRF were less marked but more prolonged than those after insulin-induced hypoglycemia. The relatively small increment in plasma ACTH, which was well within the physiological range, was associated with a significant increase in plasma aldosterone. Posterior pituitary function was not affected by this dose of ovine CRF.

Effect of long-term inhibition of gonadotrophin secretion by the gonadotrophin-releasing hormone agonist, buserelin, on sex steroid secretion and ovarian morphology in polycystic ovary syndrome.

In order to investigate the effect of long-term suppression of the gonadotrophin axis in polycystic ovary syndrome, eight affected subjects were given s.c. infusions of gonadotrophin-releasing hormone (GnRH) agonist buserelin for 12 weeks. Hormone measurement and ultrasound studies were carried out weekly, from 6 weeks before to 12 weeks after administration of buserelin. An overnight dexamethasone-suppression test was carried out before and after treatment. Maximal suppression of LH to below the lower limit of that in normal subjects occurred after 6 weeks of treatment with buserelin. Plasma testosterone and androstenedione fell to normal levels during the infusion but reached pretreatment levels during the follow-up period. There was no effect of buserelin on plasma dehydroepiandrosterone sulphate or sex hormone-binding globulin. Ovarian size decreased significantly during the infusion with the disappearance of cysts in six subjects. After cessation of buserelin therapy, there was rapid and spontaneous ovulation which occurred within 3 weeks in all subjects. The results suggest that treatment with this GnRH agonist facilitates ovulation in this condition.

Changes in IGFs in cardiac tissue following myocardial infarction.

We have studied changes in the IGF axis in an ovine model of myocardial infarction (MI), in order to determine the relationship between time-based changes in post-infarct myocardium and IGF levels. IGF localization was studied by immunocytochemistry, production by in situ hybridization, and specific binding by radioligand studies. In surviving tissue, IGF-I peptide localized to cardiomyocytes, with strongest immunostaining at 1 and 2 days post-infarct in the immediate border area adjoining the infarct, where IGF-I mRNA also increased, reaching a maximum at 2 days. Binding of radiolabelled IGF-I in surviving tissue was initially lower than that seen in cardiomyocytes in control myocardium, subsequently increasing to become significantly greater by 6 days post-infarct. In necrotic tissue, IGF-I peptide was still detectable in cardiomyocytes at 0.5 days post-infarct, but had cleared from this area by 1 day, becoming detectable again at 6 days post-infarct in macrophages and fibroblasts infiltrating the repair zone. IGF-I mRNA was not detected in necrotic tissue until 6 days, when probe hybridized to macrophages and fibroblasts. Within the necrotic zone, high levels of radiolabelled IGF-I binding to a combination of receptors and binding proteins were observed in cardiomyocytes in islands of viable tissue located close to the border. Weak immunostaining for IGF-II was observed in cardiomyocytes of the surviving tissue. IGF-II mRNA was not detected in either surviving or necrotic areas. Binding of radiolabelled IGF-II was predominantly to macrophages in both surviving and infarct areas, although as with IGF-I, high levels of binding of radiolabelled IGF-II to a combination of receptors and binding proteins were observed in islands of viable tissue close to the border within the necrotic area. We conclude that, following MI, surviving cardiomyocytes at the infarct border show marked changes in IGF-I localization, production, and specific binding, indicating that the IGF axis is directly involved in post-infarct events, possibly in the maintenance of cardiac function by the induction of hypertrophy and in cell survival by decreasing apoptotic cell death, which has been demonstrated in other cell types.

Cardiac IGF-I manipulation by growth hormone following myocardial infarction.

Evidence of a role for growth hormone (GH) in cardiac structure and function has been derived from studies of patients suffering either GH excess or deficiency, both of which may lead to reduced life expectancy. The role of GH in the ischaemic heart, however, is less than clear. We therefore investigated the effect of 30 days GH treatment in sheep with myocardial infarction. GH treatment significantly increased circulating IGF-I levels (P<0.01), heart weight (P<0.01), and cardiomyocyte cross-sectional area (P<0.001). IGF-I mRNA in peri-infarct cardiac tissue also increased significantly (P<0.05). We conclude that post-infarct GH treatment increases circulating and cardiac IGF-I levels, resulting in significant cardiomyocyte hypertrophy. This increase in cardiomyocyte size appears to correlate with local IGF-I expression rather than plasma IGF-I levels.

A prospective study of the psychological impact on patients of first diagnosis of human papillomavirus.

This study assessed the psychological impact of the first time diagnosis of human papillomavirus (HPV) in consecutive clients attending the Hamilton Sexual Health Clinic, and sought to determine whether this changed over time. Clients with a diagnosis other than HPV and those found to have no diagnosis were compared with HPV clients. All participants completed a battery of questionnaires following their initial visit and again at 4 weeks. The battery consisted of the General Health Questionnaire, Illness Attitude Scales, the International Index of Erectile Function or the Brief Index of Sexual Function for Women, and a 6-question test of the client's knowledge of HPV. One hundred and one participants completed the first questionnaires and 47 of those completed follow-up questionnaires. We found those diagnosed with first episode of HPV had considerable psychological difficulties. However these were no different to those associated with other sexually transmitted infections (STIs) or even those with no active diagnosis.

Effect of melatonin on jet lag after long haul flights.

OBJECTIVE: To determine whether doses of the pineal hormone melatonin alleviate jet lag. DESIGN: Double blind, placebo controlled crossover trial. SETTING: Long haul return flights from Auckland, New Zealand, to London and back. SUBJECTS: Twenty volunteers with experience of transcontinental flights (eight women and 12 men aged 28 to 68). INTERVENTIONS: Melatonin (or placebo) 5 mg three days before flight, during flight, and once a day for three days after arrival. END POINT: Symptoms of jet lag. MEASUREMENTS AND MAIN RESULTS: Visual analogue scale for feelings of jet lag and tiredness; profile of moods states questionnaire for vigour-activity and fatigue-inertia; and retrospective ratings 10 days after arrival of sleep pattern, energy, and daytime tiredness. Feelings of jet lag were less for subjects taking melatonin (mean score 2.15 v 3.4); these subjects took fewer days than the placebo group to establish a normal sleep pattern (2.85 v 4.15), to not feel tired during the day (3.0 v 4.6), and to reach normal energy levels (3.25 v 4.7). Results for fatigue-inertia and vigour-activity were similar. For all subjects jet lag was more severe on the return (westward) than the outward (eastward) journey. CONCLUSIONS: Melatonin can alleviate jet lag and tiredness after long haul flights.

The effect of high dose rate brachytherapy in combination with external beam radiotherapy on men's health-related quality of life and sexual function over a 2 year time span.

AIM: To investigate changes in health-related quality of life and sexual function in men after high dose rate (HDR) brachytherapy and external beam radiotherapy (EBRT), with or without androgen deprivation therapy, for localised prostate cancer. MATERIALS AND METHODS: Eligible men who had undergone HDR brachytherapy/EBRT for their prostate cancer completed questionnaires before any treatment (baseline) and at 3 monthly intervals. The European Organization for Research and Treatment of Cancer (EORTC) C30 quality of life measure (QLQ-C30), the PR25 prostate-specific supplement and the International Index of Erectile Function-Short Form (IIEF-SF) were completed. An analysis of changes from baseline to 2 years, for the 87 men who completed surveys, was carried out. RESULTS: The mean EORTC QLQ-C30 quality of life scores, urinary, bowel and sexual symptoms had all improved. However, improvements did not return men to baseline levels at 2 years. Sexual function as measured by both scales was least likely to recover. There were no differences due to androgen deprivation therapy. Minimally important differences were still reported by men at 2 years as follows: urinary (36%), bowel (24%), hormone treatment side-effects (40%), IIEF-SF (55%). Discrepancies between mean and minimally important differences changes are explained by some men remaining more affected by their therapy than others. CONCLUSION: The findings do not support our first hypothesis that urinary, bowel and sexual problems in these men will return to baseline levels once therapy is completed and 2 years have elapsed. Our findings indicate the changes men experience are significant, do occur early, and many do not resolve in the longer term.

Duration of cortisol suppression following a single dose of dexamethasone in healthy volunteers: a randomised double-blind placebo-controlled trial.

The synthetic glucocorticoid dexamethasone is administered to many patients receiving a general anaesthetic to reduce the risk of postoperative nausea and vomiting. Dexamethasone is known to suppress the hypothalamic-pituitary-adrenal axis; however, the duration of this suppression following the standard anti-emetic intravenous dose of 4 to 8 mg used with anaesthesia is unknown. A randomised controlled double-blind crossover trial assessing the effects of 8 mg intravenous dexamethasone versus saline control was performed in ten healthy male volunteers. The adrenal, thyroid and gonadal axes and glucose levels were assessed over a four-day period after dexamethasone administration. All participants had normal baseline hypothalamic-pituitary-adrenal axis function. No difference in cortisol levels was demonstrated at four or eight hours after dexamethasone administration compared with placebo. At 24 hours post dexamethasone, the cortisol had dropped to less than 5% of baseline and returned to normal during the subsequent day. Increased plasma glucose levels were also observed in the dexamethasone group as compared with placebo. A dose of 8 mg of dexamethasone results in significant suppression of the hypothalamic-pituitary-adrenal axis and elevated plasma glucose levels. The cortisol suppression is maximal at approximately 24 hours post dose.

An investigation of sexual dysfunction in female partners of men with erectile dysfunction: how interviews expand on questionnaire responses.

Using the Female Sexual Function Index (FSFI) for investigating female sexual function has become widespread. A score of 26.5 has been suggested as delineating 'functional' from 'dysfunctional' women. This study aimed to understand in greater detail what contributes to changes in women's FSFI scores while their partners are taking oral erectile medications for erection problems. Couples randomized to receive two erectile medications for two 3-month phases, completed questionnaires. FSFI scores were augmented by individual interviews at baseline, 3 and 6 months, in order to better understand what the scores meant in the context of ED medication use. In all, 50% of the women scored <26.5 at baseline; of these 56% recovered by 6 months. A number of 'dysfunctional' women recorded low FSFI scores solely as a result of their partner's ED. Overall, 22% were still 'dysfunctional' at 6 months, but one third of these appeared 'functional' at 3 months. A further group of women continued to record low scores despite reporting much improved sexual satisfaction. The women's interviews elaborate on their FSFI results, with five themes emerging to provide more clarity about the relative changes seen in a prospective study situation, and potentially in clinical practise contexts. The increasing use of questionnaires to determine sexual function should be supplemented with good clinical interviewing. The interview details explain how FSFI fluctuations occurred and contain clinical implications for research and practise in the area of couple's sexuality.