The utility of rested prolactin sampling in the evaluation of hyperprolactinaemia.

BACKGROUND AND AIMS: Serum prolactin levels may be elevated by venepuncture stress. We investigated the utility of a rested prolactin sample, obtained through an indwelling venous cannula, in preventing the overdiagnosis of hyperprolactinaemia. METHODS: Patients at our institution undergo serial prolactin sampling, usually over 40 min, when investigating hyperprolactinaemia. We retrospectively reviewed all serial prolactin sampling performed during a 3-year period. Patients with possible medication-induced hyperprolactinaemia and macroprolactin interference were excluded. We assessed the effect of venepuncture-associated stress on hyperprolactinaemia with the main outcome being normalisation of serum prolactin at the end of serial sampling. RESULTS: Ninety-three patients with documented hyperprolactinaemia (range 360-1690 mU/L) were included in the analysis. Prolactin decreased during serial sampling in 73 patients (78%), suggesting a prevalent effect of venepuncture stress. The final prolactin sample was normal in 50 patients (54%), consistent with stress hyperprolactinaemia rather than pathological hyperprolactinaemia. Patients with a referral prolactin result greater than two times the upper reference limit (URL) were less likely (15%) to have a normal prolactin result on serial sampling. Measurement of a single rested prolactin sample from an indwelling cannula showed the same diagnostic utility as serial sampling. CONCLUSION: Serum prolactin results are frequently elevated by the stress of venepuncture. Confirmation of pathological hyperprolactinaemia in a rested sample obtained from an indwelling venous cannula is recommended in patients with mild hyperprolactinaemia, particularly when the referral prolactin is less than two times the URL.

Two Cases of Adrenal Malignancy With Macroscopic Fat.

The presence of macroscopic fat on computed tomography (CT) imaging has been traditionally regarded as an indication that an adrenal lesion is likely to be a benign myelolipoma, for which further investigation is not usually required. Two cases are described where an adrenal lesion was eventually found to be malignant on histology (adrenocortical carcinoma in the first case, undifferentiated sarcoma in the second case), despite the presence of macroscopic fat on CT. In both cases there were other clinical and radiological indicators of potential malignant pathology. These cases add to increasing awareness in the literature that malignant adrenal tumors may rarely contain macroscopic fat, emphasizing a need for clinical vigilance.

Correlation of ACR TI-RADS and Patient Outcomes in a Real-World Cohort Presenting for Thyroid Ultrasonography.

Context: The American College of Radiology Thyroid Image Reporting and Data System (ACR TI-RADS) was developed to predict malignancy risk in thyroid nodules using ultrasound features. TI-RADS was derived from a database of patients already selected for fine-needle aspiration (FNA), raising uncertainty about applicability to unselected patients. Objective: We aimed to assess the effect of ACR TI-RADS reporting in unselected patients presenting for thyroid ultrasound in a real-world setting. Methods: Records for all patients presenting for thyroid ultrasonography in Canterbury, New Zealand, were reviewed across two 18-month periods, prior to and after implementation of TI-RADS reporting. Patient outcomes were compared between the 2 periods. Malignancy rates were calculated for nodules 10 mm or larger with a definitive FNA or histology result. Results: A total of 1210 nodules were identified in 582 patients prior to implementation of TI-RADS; 1253 nodules were identified in 625 patients after implementation of TI-RADS. TI-RADS category was associated with malignancy rate (0% in TR1 and TR2, 3% in TR3, 5% in TR4, 12% in TR5; P = .02); however, 63% of nodules were graded TR3 or TR4, for which malignancy rate did not meaningfully differ from baseline risk. After implementation of TI-RADS there was a small reduction in the proportion of patients proceeding to FNA (49% vs 60%; P < .01) or surgery (14% vs 18%; P < .05), with no difference in cancer diagnoses (3% vs 4%, not significant). Conclusion: TI-RADS category is associated with malignancy rate and may alter clinical decision-making in a minority of patients; however, it is nondiscriminatory in the majority of nodules. In this study of unselected patients, nodules classified as TR5 and thus considered "highly suspicious" for cancer had only a modest risk of malignancy.

TIRADS Management Guidelines in the Investigation of Thyroid Nodules; Illustrating the Concerns, Costs, and Performance.

CONTEXT: Ultrasound (US) risk-stratification systems for investigation of thyroid nodules may not be as useful as anticipated. OBJECTIVE: We aimed to assess the performance and costs of the American College of Radiology Thyroid Image Reporting And Data System (ACR-TIRADS). DESIGN SETTINGS AND PARTICIPANTS: We examined the data set upon which ACR-TIRADS was developed, and applied TR1 or TR2 as a rule-out test, TR5 as a rule-in test, or applied ACR-TIRADS across all nodule categories. We assessed a hypothetical clinical comparator where 1 in 10 nodules are randomly selected for fine needle aspiration (FNA), assuming a pretest probability of clinically important thyroid cancer of 5%. RESULTS: The gender bias (92% female) and cancer prevalence (10%) of the data set suggests it may not accurately reflect the intended test population. Applying ACR-TIRADS across all nodule categories did not perform well, with sensitivity and specificity between 60% and 80% and overall accuracy worse than random selection (65% vs 85%). Test performance in the TR3 and TR4 categories had an accuracy of less than 60%. Using TR5 as a rule-in test was similar to random selection (specificity 89% vs 90%). Using TR1 and TR2 as a rule-out test had excellent sensitivity (97%), but for every additional person that ACR-TIRADS correctly reassures, this requires >100 ultrasound scans, resulting in 6 unnecessary operations and significant financial cost. CONCLUSIONS: Perhaps surprisingly, the performance ACR-TIRADS may often be no better than random selection. The management guidelines may be difficult to justify from a cost/benefit perspective. A prospective validation study that determines the true performance of TIRADS in the real-world is needed.

Three-year follow up of adrenal incidentalomas in a New Zealand centre.

BACKGROUND: The international guidelines for management of adrenal incidentalomas (AI) are becoming more conservative. These changes are based on the growing body of evidence suggesting that non-functioning adenomas have a low likelihood of becoming functional or malignant over time. AIMS: To follow up at least 100 patients for 3 years who were originally found to have benign adrenal adenomas which were non-functional or had subclinical Cushing syndrome (SCS). METHODS: This study prospectively evaluated consecutive patients aged 18 years or older with benign adrenal incidentalomas (AI), not treated with adrenalectomy, which were non-functioning or had SCS. The initial and follow-up evaluation, including clinical assessment, hormonal investigations and imaging were coordinated via a standardised nurse-led AI clinic. RESULTS: Of 233 patients referred to the AI clinic, 101 patients met the inclusion criteria and completed 3-year follow up. Most of those excluded were due to incomplete initial or follow-up evaluation or were not true AI. Most AI either remained stable or decreased in size on repeat imaging, while 5% of patients had AI enlargement of >5 mm diameter. No patient developed features suggesting adrenal carcinoma. Ninety-two patients had an initial diagnosis of non-functioning adenoma and nine patients had SCS. After 3 years (range 2.9-4.7 years), five of the nine patients with SCS showed normalisation of cortisol parameters (44%), and five of the 92 non-functional AI patients developed SCS (5%). CONCLUSION: After 3 years of follow up, approximately half of patients with SCS normalised, while 5% of patients with initially non-functioning adenomas developed biochemical evidence of SCS. This study found a low likelihood of progressive hormonal excess with no evidence of malignancy developing on follow-up evaluation, providing support for the shift towards the more conservative approach to management of AI recommended in recent guidelines.

Characteristics of adrenal incidentalomas in a New Zealand centre.

BACKGROUND: Management of adrenal incidentalomas (AI) is becoming more conservative, based on international data showing a low incidence of functional or malignant lesions. The clinical characteristics of AI in New Zealand are unknown. Therefore, whether the AI guidelines apply to the New Zealand population is also unknown. AIMS: To investigate the clinical characteristics of patients with AI presenting to a tertiary-care centre in New Zealand. METHOD: This study prospectively evaluated consecutive patients aged 18 or older with AI, 1 cm or larger, diagnosed in Canterbury, New Zealand. A standardised nurse-led dedicated AI clinic was used, including clinical assessment, hormonal evaluation and imaging. RESULTS: From January 2010 to April 2016, 306 patients were referred to the AI clinic, 228 met the inclusion criteria. Most of those excluded were not true AI, due to imaging performed for known or suspected non-adrenal malignancy. The most common reason for imaging was abdominal pain (46%). Most cases were benign (96.5%) and 88.6% of all cases were non-functional. Of the functioning tumours (26 patients), 18 had subclinical Cushing syndrome, four had late-onset congenital adrenal hyperplasia, two had phaeochromocytoma and one had primary hyperaldosteronism. Three patients had primary adrenal cancer, one of whom was secreting excess cortisol. One adrenal metastasis was diagnosed. CONCLUSION: This study found a similar prevalence of functional and malignant AI as international centres, although mild cortisol excess and primary aldosteronism may be under-represented. Therefore, the conservative approach to management of AI recommended in current guidelines is likely to be applicable to New Zealand population.

Management of hypertension and heart failure in patients with Addison's disease.

Addison's disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin-angiotensin-aldosterone axis in Addison's disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addison's disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy.

Endocrine encephalopathy.

The diagnosis of Hashimoto's encephalopathy is made when no other cause is found for an acute encephalopathic illness, in the presence of positive thyroid autoantibodies, and is supported by a response to steroid therapy. A 59-year-woman developed an encephalopathic illness with mixed aphasia, global weakness and generalised seizures requiring intubation and ICU admission. Extensive imaging and laboratory investigations looking for an underlying cause for the encephalopathy were unremarkable. Thyroid autoantibodies were strongly positive, raising the possibility of Hashimoto's encephalopathy. Thyroid function testing showed profound primary hypothyroidism. The patient was commenced on high-dose methyprednisolone, with prompt cessation of seizure activity. Thyroxine replacement was commenced, with the methyprednisolone switched to oral prednisone and slowly weaned. The patient had no further seizures and ultimately made a full recovery.

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe.

CONTEXT: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life. OBJECTIVE: Month of birth effects were investigated in three independent European Caucasian AITD datasets. DESIGN: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test. SETTING: The study was conducted at a research laboratory. PATIENTS: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent). MAIN OUTCOME MEASURES: Case-control and family-based association studies were measured. RESULTS: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort. CONCLUSION: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Mortality and morbidity in Cushing's syndrome in New Zealand.

OBJECTIVE: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population-based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand. DESIGN: A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services. PATIENTS: A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS. MEASUREMENTS; The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow-up. Secondary outcomes were the change in prevalence of co-morbidities at presentation and at final follow-up. RESULTS: The approximate prevalence and incidence of CS was 79/million and 1·8/million/y. The mean age at presentation was 39 year, and median duration of follow-up was 6·4 year (range 0-46). Overall, 89% achieved biochemical cure at last follow-up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty-six patients died during follow-up compared with 8·8 expected deaths (SMR 4·1, 95%CI 2·9-5·6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow-up. CONCLUSION: CS is associated with both high mortality and a high prevalence of co-morbidities, even when biochemical cure rates are between 80% and 90%.

Juvenile thyrotoxicosis--a South Island, New Zealand experience with long-term outcome.

AIM: To assess our experience in the management of juvenile thyrotoxicosis. METHOD: Retrospective review of thyroid clinic records of juvenile (<16 y) thyrotoxic (JT) patients treated at thyroid clinic between 1972 and 1999. Long-term (>8 y) treatment outcome was assessed. RESULTS: During the 28-year period, 34 JT patients were diagnosed and treated--30 girls and 4 boys, median age 13 years (5.6-15.9 y). Thirty-two children had Graves' disease and two had toxic nodular goitre. All patients were initially treated with carbimazole, and no major adverse reactions occurred. One Graves' disease child later developed severe ophthalmopathy. During long-term follow-up, 12 of the 32 Graves' patients remain in remission after antithyroid drug treatment alone, but 4 of these 12 patients are currently receiving thyroxine replacement. Fifteen patients were surgically treated (median age 16 y), and six patients received radioiodine therapy (median age 18 y) including one patient with post-thyroidectomy relapse. The two patients with toxic nodular goitre were treated by thyroidectomy. CONCLUSION: Juvenile thyrotoxicosis is relatively rare and not always due to Graves' disease. More than a third of children with Graves' disease achieved long-term remission following antithyroid drug therapy, and remaining patients required definitive therapy.

Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease.

Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

Intermittent severe, symptomatic hyponatraemia due to the nephrogenic syndrome of inappropriate antidiuresis.

A 20-year-old fit male soldier presented on two separate occasions 16 months apart with severe, symptomatic hyponatraemia and a clinical and biochemical picture consistent with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In the intervening period, repeated plasma sodium values were in the reference range. Intensive investigation failed to reveal a cause for SIADH that was initially considered idiopathic. The description of a family comprising several adults with intermittent or water load induced-hyponatraemia associated with an activating mutation in the arginine vasopressin (AVP) receptor type 2 (AVPR2) raised the question of whether our patient could have a similar 'nephrogenic syndrome of inappropriate antidiuresis'. Mutational screening of AVPR2 in our patient revealed a single missense mutation (R137C) in the second intracellular loop, which has been associated with constitutive activation of the AVPR2. In conclusion, adults with intermittent, severe hyponatraemia may have a constitutively activating mutation in the AVPR2 with resultant nephrogenic syndrome of inappropriate antidiuresis. Patients with idiopathic SIADH, particularly those with unmeasurable circulating AVP concentrations, should be considered for mutational screening of AVPR2.

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

OBJECTIVE: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.

Association of the TSHR gene with Graves' disease: the first disease specific locus.

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD 'blocks' and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1,059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 x 10(-6), OR 1.7) with Graves' disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1,366 AITD cases and 1,061 controls (GD, P=2 x 10(-6), OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.