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.

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.

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%.

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.

Intraosseous lipoma of the body of the sphenoid bone.

A case of intraosseous lipoma arising from the body of the sphenoid bone with intrasellar and suprasellar components is reported. This is the first report of this uncommon tumour occurring in an atypical intracranial site, producing the locally invasive and pressure effects of visual failure and hypopituitarism. The diagnosis was based on computed tomographic (CT) and magnetic resonance (MR) imaging with histological confirmation following frontal craniotomy.

Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management.

Patients undergoing surgical resection of pituitary adenomas are frequently given perioperative glucocorticoid therapy. There are no randomized controlled studies assessing the need for such steroids; however, several studies have documented changes in the hypothalamic-pituitary-adrenal (HPA) axis associated with pituitary surgery. Based on the evidence available, this article details recommendations for the perioperative management of glucocorticoid therapy in patients with pituitary tumors. For patients with proven ACTH deficiency preoperatively [usually based on response to a short ACTH 1-24 (Synacthen) test], 48 hours of supraphysiological glucocorticoid therapy should be administered perioperatively (e.g. hydrocortisone, 50 mg every 8 hours on day 0, 25 mg every 8 hours on day 1, and 25 mg at 0800 h on day 2). For patients with intact HPA function preoperatively, and in whom selective adenomectomy is possible, perioperative glucocorticoids are not necessary. Early postoperative assessment depends on daily clinical assessment of the patient and 0800 h plasma cortisol levels. Cortisol levels over 450 nM (16 microg/dl) reflect normal HPA function, and levels less than 100 nM (3.6 microg/dl) are consistent with ACTH deficiency. Cortisol levels between 100 and 250 nM (3.6-9 microg/dl) may be ACTH deficient and should receive morning hydrocortisone replacement until definitive HPA axis testing. Cortisol levels between 250 and 450 nM (9-16 microg/dl) are unlikely to be ACTH deficient but should receive additional steroids for stress until a definitive test is performed. For those requiring definitive testing, the insulin tolerance test, the overnight metyrapone test, or the glucagon stimulation test are appropriate and may be performed as early as d 7-10 or, if more convenient, wk 4-6. Following the guidelines suggested here should reduce the use of unnecessary glucocorticoids, while ensuring the safety of patients is not compromised.

The deleted in colorectal carcinoma (DCC) gene 201 R --> G polymorphism: no evidence for genetic association with autoimmune disease.

The product of the deleted in colorectal carcinoma (DCC) gene has a role in apoptosis and is a positional candidate for IDDM6, the putative chromosome 18q12-q23 autoimmune disease locus. We hypothesised that a nonconservative substitution (DCC 201 R --> G; nucleotide (nt) 601 C --> G), located in an extracellular immunoglobulin-like domain of DCC, is an aetiological determinant of autoimmunity. We tested this hypothesis by genetically testing the nt 601 C --> G polymorphism for association with three autoimmune phenotypes in a large population-based case-control study. There was no evidence for association of DCC nt 601 C --> G with autoimmune disease in cohorts comprising 2253 subjects with rheumatoid arthritis, type I diabetes and Graves' disease, and 2225 control subjects, from New Zealand and the United Kingdom. Furthermore, using the transmission disequilibrium test, there was no significant evidence for biased transmission of the nt 601 C --> G polymorphism to probands within a 382 family type I diabetes affected sibpair cohort from the United Kingdom. Thus, the DCC 201 R --> G polymorphism does not appreciably influence risk of developing the autoimmune diseases tested.

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.

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.