Remote capillary blood collection for HbA1c measurement during the COVID-19 pandemic: A laboratory and patient perspective.

AIMS: The purpose of this study was to assess the clinical performance and user acceptance of capillary blood samples prepared remotely using the MiniCollect® capillary blood collection device as an alternative to blood collection by venepuncture for glycated haemoglobin (HbA1c ) analysis. METHODS: Following written informed consent, a cross-sectional study was conducted in individuals aged ≥18 years with any type of diabetes who routinely self-monitor their blood glucose. Eligible participants recruited whilst attending their routine clinical appointments were required to provide a venous blood sample, prepare a capillary blood sample at home (remotely) and complete a bespoke questionnaire. HbA1c in whole blood collected in ethylenediaminetetraacetic acid was determined by capillary electrophoresis on the Sebia Capillary's 3 Tera analyser following standard operating procedure. RESULTS: HbA1c results from both venous and capillary collection demonstrated good agreement. Passing-Bablok regression: y = 0 + 1x (p = 0.18), Spearman correlation r = 0.986, p < 0.0001. The Bland-Altman difference plot provided a mean difference of 0.3 mmol/mol (2.2%). Over half of the participants found the MiniCollect device easy to use. The majority of participants were in favour of the remote capillary blood collection service and would use it if routinely available. CONCLUSION: The home collection of capillary blood for HbA1c determination is a valuable and convenient alternative to standard venous blood collection as it provides an opportunity to support routine HbA1c monitoring, whilst mitigating the transmission of SARS-CoV-2. This service would additionally allow individuals to attend clinic visits with a HbA1c value, ensuring optimal continuance of patient care for individuals with diabetes.

Iodine status of teenage girls on the island of Ireland.

PURPOSE: The trace element iodine is a vital constituent of thyroid hormones. Iodine requirements increase during pregnancy, when even mild deficiency may affect the neurocognitive development of the offspring. Urinary iodine concentration (UIC) is the means of assessing iodine status in population surveys; a median UIC of 100-199 µg/L is deemed sufficient in a non-pregnant population. Milk is the main dietary source of iodine in the UK and Ireland. METHODS: We surveyed the iodine status of 903 girls aged 14-15 years in seven sites across the island of Ireland. Urine iodine concentration was measured in spot-urine samples collected between March 2014 and October 2015. Food group intake was estimated from iodine-specific food-frequency questionnaire. Milk-iodine concentration was measured at each site in summer and winter. RESULTS: The median UIC overall was 111 µg/L. Galway was the only site in the deficient range (median UIC 98 µg/L). All five of the Republic of Ireland sites had UIC ≤ 105 µg/L. In the two sites surveyed twice, UIC was lower in summer vs winter months [117 µg/L (IQR 76-165) vs 130 µg/L (IQR 91-194) (p < 0.01)]. Milk samples collected from Galway and Roscommon had a lower mean iodine concentration than those from Derry/Londonderry (p < 0.05). Milk intake was positively associated with UIC (p < 0.001). CONCLUSIONS: This is the largest survey of its kind on the island of Ireland, which currently has no iodine-fortification programme. Overall, the results suggest that this young female population sits at the low end of sufficiency, which has implications if, in future, they enter pregnancy with borderline status.

Effect of Sodium Glucose Co-Transporter-2 Inhibition on the Aldosterone/Renin Ratio in Type 2 Diabetes Mellitus.

The aldosterone to renin ratio (ARR) is recommended for case detection of primary aldosteronism (PA). Several factors including medications can undermine its diagnostic accuracy. The objective was to explore the effect of Sodium Glucose Co-Transporter-2 Inhibition on the ARR in patients with type 2 diabetes mellitus (T2DM) who were prescribed a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT-2i) as part of routine clinical care. The primary outcomes were intra-individual changes in aldosterone, renin and ARR. Participants were recruited at routine diabetes outpatient visits as part of a prospective longitudinal study. Eligible participants were prescribed standard doses of empagliflozin and sampled at baseline (pre-SGLT-2i) and at their next routine outpatient visit (post-SGLT-2i). After a mean of 198 (±87) days on SGLT-2i treatment (n=20), there was a significant reduction in HbA1c, BMI, eGFR and serum triglycerides and a significant increase in serum creatinine and sodium. Compared with baseline, there was a significant increase in median direct renin concentration (mIU/l) [40.3 (6.2-249.5) vs. 70.2 (7.0, 551.0) (p=0.005)] and no significant change in median plasma aldosterone concentration (pmol/l) [296 (101, 685) vs. 273 (101, 794) (p=0.541)] with a significant reduction in median ARR (pmol/mIU) [6.9 (0.6-70.7) vs. 5.3 (0.2-39.3) (p=0.007)]. The proportion of participants with a screen positive ARR decreased from 20% (pre-SGLT-2i) to 5% (post-SGLT-2i) (p=0.248). Although performed in a relatively small cohort of medically complex patients, the study indicates that SGLT-2i therapy has the potential to cause false-negative screening for PA in the setting of T2DM. Future confirmatory studies should include patients with confirmed PA.

FOXE1 polymorphism rs965513 predisposes to thyroid cancer in a European cohort.

Objective: FOXE1 is an intronless gene on chromosome 9 which plays a significant role in thyroid morphogenesis. Mutations in FOXE1 are associated with thyroid phenotypes including congenital hypothyroidism, thyroid dysgenesis and thyroid cancer. This study aims to investigate the frequency and impact of a SNP (rs965513, G>A) at 9q22.23 in a Western European cohort of patients with differentiated thyroid cancer(DTC), compared to controls. Design: This is a candidate gene case control study. Methods: 277 patients with histologically confirmed DTC were recruited from tertiary referral centres in Ireland and France. 309 cancer-free controls were recruited from the community. DNA was extracted from buccal swabs or whole blood of control subjects and patients with DTC. Allelic and genotypic frequencies among patients were compared with controls, to assess the risk for disease conferred by homozygous and heterozygous carriers compared to WT genotypes. Genotyping was performed using Taqman-based PCR. Results: 277 patients with confirmed DTC and 309 non-cancer controls were genotyped for the variant (rs965513). The frequency of the minor allele among cases was 0.45 compared to 0.34 among controls. The genotypic odds ratio for heterozygotes was 1.66 (CI 1.16-2.39, P =0.00555), increasing to 2.93 (CI 1.70-5.05, P =0.00007) for rare homozygotes. All subjects were in Hardy-Weinberg equilibrium (±χ2, P =0.09, P =0.07 respectively). Conclusions: This FOXE1 polymorphism is a low penetrance variant associated with DTC susceptibility in this cohort. The minor allele was identified among patients with thyroid cancer significantly more frequently than controls. An allele dosage effect was observed, with rare homozygous genotypes conferring greater risk than heterozygotes.

A case of adrenal Cushing's syndrome and primary hyperparathyroidism due to an atypical parathyroid adenoma.

Cushing's syndrome is a rare disorder of cortisol excess and is associated with significant morbidity and mortality. Hypercalcaemia due to hyperparathyroidism is a common condition; however, in 10% of young patients, it is associated with other endocrinopathies and occurs due to a genetic variant [e.g. multiple endocrine neoplasia (MEN) type 1 (MEN1), MEN2 or MEN4]. We report the case of a 31-year-old woman who was referred to the endocrinology out-patient service with an 8-month history of hirsutism, amenorrhoea and weight gain. Her biochemical work up was significant for adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome. Radiological investigations revealed an adrenal adenoma. During investigation she was also found to have primary hyperparathyroidism due to a parathyroid adenoma. Pre-operatively, the patient was commenced on metyrapone and both her adrenal and parathyroid lesions were resected successfully. There were several concerning findings on initial examination of the parathyroid tumour, including possible extension of the tumour through the capsule and vascular invasion; however, following extensive review, it was ultimately defined as an adenoma. Given the unusual presence of two endocrinopathies in a young patient, she subsequently underwent genetic testing. Analysis of multiple genes did not reveal any pathogenic variants. The patient is currently clinically well, with a normal adjusted calcium and no clinical features of cortisol excess. She will require long-term follow up for recurrence of both hypercalcaemia and hypercortisolaemia.

The diagnostic utility of late night salivary cortisol (LNSF) and cortisone (LNSE) in Cushing's syndrome.

BACKGROUND: Measurement of late night salivary cortisol (LNSF) is useful in the identification of cyclical Cushing's syndrome (CS); the usefulness of its metabolite cortisone (late night salivary cortisone, LNSE) is less well described. AIM: The aim of this study was to determine the utility of measuring LNSE in patients with confirmed CS compared with other diagnostic tests and to analyse serial LNSF measurements for evidence of variable hormonogenesis. METHODS: This was a retrospective observational study including patients with confirmed CS in whom LNSF and LNSE were measured. RESULTS: Twenty-three patients with confirmed CS were included, 21 with Cushing's disease. LNSF had a sensitivity of 92%, LNSE 87% and combined LNSF/LNSE 94% per sample. Four patients had cyclical hormonogenesis, when the definition of one trough and two peaks was applied to LNSF measurements, and a fifth patient fell just outside the criteria. Six patients had evidence of variable hormonogenesis, defined as doubling of LNSF concentration on serial measurements. Sensitivity of 24-h urinary free cortisol (UFC) was 89% per collection. Sixteen patients had simultaneous measurements of LNSF and UFC; in three patients, they provided discordant results. CONCLUSION: LNSF appears more sensitive than LNSE and UFC in the diagnosis of CS, combining LNSF and LNSE results leads to superior sensitivity. Half of our cohort had evidence of cyclical or variable hormonogenesis. Fluctuations in LNSF did not always correlate with changes in UFC concentration, emphasising the importance of performing more than one screening test, particularly if pretest clinical suspicion is high.

Burden of chronic kidney disease and rapid decline in renal function among adults attending a hospital-based diabetes center in Northern Europe.

INTRODUCTION: This study aimed to determine the prevalence of diabetic kidney disease (DKD) and rapid renal function decline and to identify indices associated with this decline among adults attending a diabetes center in Northern Europe. RESEARCH DESIGN AND METHODS: This is a retrospective cohort study of 4606 patients who attended a diabetes center in Ireland between June 2012 and December 2016. Definition/staging of chronic kidney disease used the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification based on data from the most recently attended appointment. Relevant longitudinal trends and variabilities were derived from serial records prior to index visit. Rapid renal function decline was defined based on per cent and absolute rates of estimated glomerular filtration rate (eGFR) change. Multiple linear regression was used to explore the relationships between explanatory variables and per cent eGFR change. RESULTS: 42.0% (total), 23.4% (type 1 diabetes), 47.9% (type 2 diabetes) and 32.6% (other diabetes) had DKD. Rapid decline based on per cent change was more frequent in type 2 than in type 1 diabetes (32.8% vs 14.0%, p<0.001). Indices independently associated with rapid eGFR decline included older age, greater number of antihypertensives, higher log-normalized urine albumin to creatinine ratio (LNuACR), serum alkaline phosphatase, thyroid stimulating hormone, variability in systolic blood pressure and variability in LNuACR, lower glycated hemoglobin, high-density lipoprotein cholesterol and diastolic blood pressure, and lack of ACE inhibitor/angiotensin receptor blocker prescription. CONCLUSIONS: DKD (using the KDIGO 2012 classification) and rapid eGFR decline were highly prevalent among adults attending a hospital-based diabetes clinic in a predominantly Caucasian Northern European country. The burden was greater for adults with type 2 diabetes. Expected as well as potentially novel clinical predictors were identified.

Higher risk of vitamin D insufficiency/deficiency for rural than urban dwellers.

There are many risk factors for Vitamin D deficiency. This study aimed to compare the Vitamin D status and serum 25(OH)D concentrations of adults living in an urban area to adults living in a rural area in the West of Ireland (latitude 53.27° North). A cross-sectional retrospective analysis of clinical records was performed. Following interrogation of the electronic laboratory information system, individuals who had serum 25(OH)D concentrations measured at Galway University Hospitals between January 2011 and December 2015 were identified. Clinical demographics, setting and date of sampling were recorded. In total, 17,590 patients (urban n = 4,824; rural n = 12,766) were eligible for inclusion. Serum 25(OH)D concentrations were lower among rural compared to urban dwellers irrespective of season (spring p < 0.001, summer p = 0.009, autumn p = 0.002, winter p < 0.001). There was a significant difference in Vitamin D status between urban and rural dwellers in three of the four seasons: spring- deficiency: 16%-v-23%, insufficiency: 39%-v-43%, sufficiency: 45%-v-35% (p < 0.001); autumn- deficiency: 11%-v-10%, insufficiency: 30%-v-35%, sufficiency: 59%-v-56% (p = 0.01); winter- deficiency: 23%-v-25%, insufficiency: 35%-v-42%, sufficiency: 41%-v-33% (p < 0.001). Serum 25(OH)D concentrations were higher and the prevalence of deficiency lower in urban/rural females compared to urban/rural males (p < 0.001). Serum 25(OH)D concentrations increased sequentially from the 18-39 year age group to the 60-69 year age group in both urban (p < 0.001) and rural (p < 0.001) dwellers and then decreased progressively as age increased to ≥90 years. The odds of Vitamin D deficiency increased with age, lower daily sunshine hours, male gender, rural address and season.

Vitamin D Status of Adults in the Community, in Outpatient Clinics, in Hospital, and in Nursing Homes in the West of Ireland.

BACKGROUND: Approximately 1 billion people worldwide have Vitamin D deficiency. The aim of this study was to compare Vitamin D status and serum 25-hydroxyvitamin D (25(OH)D) concentrations among adults sampled in the community, in outpatient clinics, as hospital inpatients and in nursing homes in the West of Ireland. The secondary aim was to determine the associations between length of hospital stay (inpatients) at the time of serum 25(OH)D sampling and Vitamin D status. METHODS: A cross-sectional study was carried out. Patients who had serum 25(OH)D analysis carried out in Galway University Hospitals (January 2011-December 2015) were identified following interrogation of the electronic laboratory data system. Baseline demographics, location, and date of sample collection were recorded. Vitamin D deficiency was defined as a serum 25(OH)D concentration <25 nmol/L. RESULTS: In total, 24,302 patient samples were eligible for inclusion: community 15,319; outpatient clinics 6,371; inpatients 2,339; and nursing home residents 273. Vitamin D deficiency was more common in nursing home residents than inpatients, or those sampled in outpatient clinics or in the community (42% vs 37% vs 17% vs 13%; p < .001). Inpatients sampled further into their hospital stay (≥3 days) had greater Vitamin D deficiency than inpatients sampled on 0-2 days (p = .007). Season (p < .001), sex (p < .001), and age (p < .001) were associated with 25(OH)D concentrations. Vitamin D deficiency was more common in Winter/Spring, in males, and in those aged ≥80 years. CONCLUSIONS: Nursing home residents and inpatients are at the highest risk for Vitamin D deficiency. Season, sex, age, and day of hospital stay on which serum 25(OH)D concentrations were sampled were associated with Vitamin D status.

Biallelic CYP24A1 variants presenting during pregnancy: clinical and biochemical phenotypes.

INTRODUCTION: Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. METHODS: The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. RESULTS: The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband's brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband's daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up. CONCLUSIONS: W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

The importance of standardisation of measurement and reference intervals for detection of phaeochromocytoma and paraganglioma (PPGL).

A 51-year-old male presented 25 years ago with excessive sweating and haematuria. Blood pressure was labile. CT abdomen showed a large right-sided adrenal mass. Two 24-h urine collections showed elevated urinary catecholamines. Right adrenal resection was performed; a phaeochromocytoma (PC) was confirmed histologically. Two decades later, the patient represented with excessive sweating and measured variable blood pressure readings. Measurement of plasma metanephrines (PMets) showed elevated normetanephrine (NMN) [50,250 (R.I. 0-1180) pmol/L] and metanephrine (MN) [1030 (R.I. 0-510) pmol/L] values. CT abdomen showed a 100 × 90 × 63 mm enhancing mass in the right retroperitoneum. Curative resection was undertaken confirming recurrent PC. Follow-up post-resection, plasma NMN was discordant, 1314 pmol/L (above decision threshold) at 30 min and 911 pmol/L (below decision threshold) at 40 min. Acute clinical awareness of persistent disease mandated the performance of a metaiodobenzylguanidine (MIBG) scan and CT abdomen. These confirmed residual disease in the upper right side of the retroperitoneum. Persistent disease following redo surgery could have been missed if only seated-sampling upper reference limits were applied to PMets collected at 40 min. Our experience with this patient triggered a review of our PMets sampling strategy. There was no statistically significant difference in PMets sampled at 30 and at 40 min seated-rest. Optimum diagnostic test accuracy was achieved using a supine-sampling strategy at a single time point (30 min). Our case highlights the importance of maintaining a high index of clinical suspicion for residual/recurrent disease in the face of inconclusive biochemistry, followed by appropriate targeted radiology using MIBG or PET-CT in patients with PPGL.

Differentiated Thyroid Cancer: How Do Current Practice Guidelines Affect Management?

BACKGROUND: International best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1-4 cm. A personalised approach to decision-making is recommended. OBJECTIVES: This study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1-4 cm tumour cohort on contemporary practice patterns. METHODS: Data were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed. RESULTS: Ninety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA. CONCLUSIONS: Management of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to ratio-nalise management strategies.

The Sonographic Features of the Thyroid Gland After Treatment with Radioiodine Therapy in Patients with Graves' Disease.

The aim of the study was to describe the typical sonographic features of the thyroid gland in patients with Graves' hyperthyroidism after radioiodine therapy (RIT). Thirty patients (21 female and 9 male) with a mean age of 53 y (standard deviation [SD] ± 11.3) and with previous Graves' disease who had been successfully treated with RIT were enrolled in the study. All were hypothyroid or euthyroid after treatment. The thyroid ultrasound was carried out by a single experienced operator with an 8-MHz linear transducer. Volume, vascularity, echogenicity and echotexture of the glands were noted. The presence of nodules and lymph nodes was also documented. The mean volumes of the right lobe were 2.4 mL ± 2.9 SD (0.6-14) and the left lobe were 1.8 mL ± 1.9 SD (0.4-9.1), with a mean total volume of 4.2 mL ± 4.7 SD (1.3-19.1). Of those who had a pre-treatment ultrasound (23%), the percentage reduction in volume was 87% (p < 0.05); 93% of the glands were hypovascular, with the remaining 7% showing normal vascularity. The glands were hyperechoic and of coarse echotexture. Overall, the sonographic features of the post-RIT gland included a significantly reduced mean total volume of 4.2 mL, hypovascularity, coarse echotexture and hyperechogenicity.

Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation.

CONTEXT: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner. OBJECTIVE: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL. METHODS: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications. RESULTS: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation. CONCLUSION: This study supports the value of universal genetic screening for all patients with PC/PGL.

Coeliac disease causing symptomatic hypocalcaemia, osteomalacia and coagulapathy.

A 36-year-old gentleman presented with 6 months of poor energy, tingling in fingers and weight loss with a change in bowel habit. He appeared cachectic and had clubbing, demineralisation of teeth, pectus carinatus, kyphosis, spinal tenderness, proximal muscle weakness and generalised muscle atrophy. Chvostek's and Trosseau's signs were positive. His haemoglobin (Hb) was 8.7 g/dl, MCV 64.7 fl with low iron. Calcium corrected was 1.30 nmol/l, parathyroid hormone 440.4 ng/l, vitamin D <12.5 nmol/l; INR was 2.7 with coagulation inhibitor studies negative. Radiographs of spine and pelvis commented on osteopenia with thoracic kyphosis and mild anterior wedging of thoracic vertebrae. Antitissue transglutaminase was 145 U/ml, and antiendomysial antibodies were positive. An oesophagogastroduodenoscopy was consistent with coeliac disease. A diagnosis of osteomalacia and coagulopathy secondary to coeliac disease was made. The hypocalcaemia was treated with calcium gluconate infusions with symptomatic relief. Coagulopathy was treated with vitamin K intravenously with normalisation of INR. Following treatment with coeliac diet, calcium slowly normalised.