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.

Unbound vitamin D concentrations are not decreased in critically ill patients.

BACKGROUND: Free concentrations of highly protein bound hormones, such as cortisol and thyroxine, are unchanged in critical illness despite substantial decreases in total concentration. Total 25-hydroxyvitamin D (25(OH)D) concentration is decreased in critical illness, but the free concentration of 25(OH)D has had less attention. AIM: To compare total and calculated free 25(OH)D concentrations in critically ill patients with healthy controls. METHODS: In this case-control study, 38 patients with critical illness were compared with 68 healthy controls; 25(OH)D was measured by liquid chromatography tandem mass spectrometry (LCMS/MS) and vitamin D binding protein (VDBP) by direct sandwich enzyme-linked immunosorbent assay. Total and calculated free 25(OH)D concentrations were compared using unpaired t-tests. RESULTS: Total 25(OH)D concentrations were significantly lower in critically ill patients than controls (37 (95% confidence interval 31-43) vs 57 (53-60) nmol/L). Calculated free concentrations of 25(OH)D were not lower in critically ill patients than healthy controls (26 (22-29) vs 19 (18-20) pmol/L). CONCLUSIONS: Calculated free 25(OH)D concentrations are not decreased in critical illness. Measuring total 25(OH)D concentrations in patients with critical illness potentially underestimates vitamin D and overestimates the number of patients who are deficient in vitamin D.

A Volunteer Program in Maine to Transport Community Members to Health Care Appointments.

Transportation to health care appointments is a well-known barrier for many people, especially people living in rural areas. At the Kennebec Valley Community Action Program (KVCAP), 1 of 8 regional transportation centers in Maine, a robust volunteer program consisting of 93 drivers complements a staff of 45 drivers and 23 office staff members. The volunteers drive approximately 5 to 40 hours per week and have served for an average 4.4 years (range, 1-26 y); their ages range from 23 to 88. The volunteer driver program consists of a volunteer coordinator who communicates with volunteers; staff members who schedule rides; a software application (app) that serves as an interface between the agency and the volunteers as they drive clients to and from medical and social service appointments; regular training; recognition events; and incentives. Most clients have no other transportation option and indicated in informal surveys conducted by KVCAP that they would not attend appointments if the volunteer program were not available. In rural settings, volunteer driving networks provide a viable model to help meet the transportation needs of the population. Recruitment and retention of volunteers is an ongoing effort.

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.

Insulin degludec overdose in an adolescent with type 1 diabetes: proactive management including monitoring using the Freestyle Libre flash glucose monitoring system.

An adolescent with type 1 diabetes and a history of self-harm, which included intentional overdoses and insulin omission, presented with an insulin degludec overdose. She had been commenced on the ultra-long-acting insulin, degludec, with the aim of reducing ketoacidosis episodes in response to intermittent refusal to take insulin. Insulin degludec was administered under supervision as an outpatient. Because it was anticipated that she would attempt a degludec overdose at some stage, the attending clinicians implemented a proactive management plan for this (and related) scenarios. This included long-term monitoring of interstitial glucose using the Abbott Freestyle Libre flash glucose monitor. The patient took a witnessed overdose of 242 units of degludec (usual daily dose, 32 units). She was hospitalised an hour later. Inpatient treatment was guided primarily by interstitial glucose results, with capillary and venous glucose tests used as secondary measures to assess the accuracy of interstitial glucose values. Four days of inpatient treatment was required. The patient was managed with high glycaemic loads of food and also intermittent intravenous dextrose. No hypoglycaemia was documented during the admission. In summary, while a degludec overdose may require several days of inpatient management, in situations where proactive management is an option and the dose administered is relatively modest, it may be possible to avoid significant hypoglycaemia. In addition, this case demonstrates that inpatient interstitial glucose monitoring may have a role in managing insulin overdose, especially in situations where the effect of the insulin overdose on glucose levels is likely to be prolonged. LEARNING POINTS: Degludec overdoses have a prolonged effect on blood glucose levels, but if the clinical situation allows for early detection and management, treatment may prove easier than that which is typically needed following overdoses of a similar dose of shorter acting insulins.Inpatient real-time interstitial monitoring helped guide management, which in this context included the prescription of high dietary carbohydrate intake (patient led) and intravenous 10% dextrose (nurse led).Use of inpatient interstitial glucose monitoring to guide therapy might be considered 'off label' use, thus, both staff and also patients should be aware of the limitations, as well as the benefits, of interstitial monitoring systems.The Libre flash glucose monitor provided nurses with low cost, easy-to-use interstitial glucose results, but it is nevertheless advisable to check these results against conventional glucose tests, for example, capillary 'finger-stick' or venous glucose tests.

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.

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.

Is late-night salivary cortisol a better screening test for possible cortisol excess than standard screening tests in obese patients with Type 2 diabetes?

AIM: To compare the performance, in terms of specificity for cortisol excess, of late-night salivary cortisol with 24-hour urine-free cortisol (24hr UFC) and overnight 1mg dexamethasone suppression test (1mg DST) in a group of obese T2DM patients. METHODS: Forty obese patients with T2DM without clinical features of Cushing's syndrome were recruited. Plasma, urinary and salivary cortisol were measured directly by an enzyme-linked immunosorbent assay using monoclonal antibodies. The specificities of the three tests using various cutoffs were calculated and compared, employing the assumption that none of the patients had hypercortisolism. RESULTS: The patients had a mean age and BMI of 56 years (range 31-75) and 37 kg/m² (31-56) respectively. All 40 provided late-night salivary cortisol samples. Thirty-eight patients completed all three tests. Two patients only completed two screening tests. The specificities of late-night salivary cortisol (cutoff 10 nmol/L), 24hr UFC (400 nmol) and 1mg DST (50 nmol/L) were 70% (95% CI 53-83%), 90% (76-97%) and 72% (55-85%) respectively. The specificity of late-night salivary cortisol was significantly less than 24 hr UFC (P=0.039) but not 1mg DST (P>0.99). CONCLUSION: Late-night salivary cortisol has a poor specificity for cortisol excess in obese patients with T2DM with 24 hr UFC showing significantly better specificity in our population.

Four cases of autosomal dominant hypocalcaemia with hypercalciuria including two with novel mutations in the calcium-sensing receptor gene.

We present four cases with clinical and biochemical hypocalcaemia and evidence supportive of hypoparathyroidism. One case had been previously ascribed a diagnosis of idiopathic hypoparathyroidism. Following the detection of relative hypercalciuria, all cases were found to have autosomal dominant hypocalcaemia with hypercalciuria and mutations of the calcium-sensing receptor gene, of which two were novel. Increased awareness of this condition and access to genotyping enables prompt accurate diagnosis and cascade screening of first-degree relatives.

Autoimmunity predominates in a large South African cohort with Addison's disease of mainly European descent despite long-standing disease and is associated with HLA DQB*0201.

OBJECTIVE: We sought to determine whether autoimmunity is the predominant cause of Addison's disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists. DESIGN: We compiled a national registry of patients from primary care, referral centres and private practices. PATIENTS: A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45.9 years, range 2.7-88 years; mean duration of disease 13.1 years, range 0-50 years) and controls were matched for gender and ethnicity. All potential causes were investigated. RESULTS: Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21-hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X-linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0.017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0.02). CONCLUSIONS: While autoimmunity accounts for at least half of patients with Addison's disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21-hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.

FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study.

CONTEXT: Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. OBJECTIVE: Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. DESIGN, SETTING, AND PARTICIPANTS: Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. RESULTS: Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05). CONCLUSION: Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia.

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.

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.