Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

BACKGROUND: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. STUDY DESIGN AND METHODS: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. RESULTS: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11ß-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11ß-HSD2 activity. Hepatic 11ß-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11ß-HSD1 in subcutaneous adipose tissue. CONCLUSION: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Diagnosis and Management of Central Diabetes Insipidus in Adults.

Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurons in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse etiologies, although it typically develops due to neoplastic, traumatic, or autoimmune destruction of AVP-synthesizing/secreting neurons. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.

Is repeat fine needle aspiration required in thyroid nodules with initial benign cytology? Results from a large Irish series.

BACKGROUND : Fine needle aspiration (FNA) cytology is the preferred method for assessing thyroid nodules for malignancy. Concern remains about the rate of false negative results. The primary aim of this study is to investigate the malignancy rate of thyroid nodules initially classified as benign (Thy 2). METHODS: We retrospectively examined 658 nodules in 653 (429 female) patients between January 2013 to December 2017. All FNA biopsies (FNABs) were performed under ultrasound (US) guidance by a radiologist with expertise in thyroid pathology. Nodules were cytologically classified according to the UK Royal College of Pathologists guidelines. Decisions about further management were made at a regular thyroid multidisciplinary meeting. Follow up of the Thy 2 nodules was determined based on clinical and radiological criteria. RESULTS: The mean age (± SD) was 53.2 (14.6) years. Five hundred out of 658 (76.0%) nodules were classified as Thy 2 (benign) after the first FNAB. Of these thyroid nodules initially classified as benign, 208 (41.6%) underwent repeat FNAB and 9 (1.8%) were surgically removed without repeat FNAB. The remainder were followed up clinically and/or radiologically. Seven (1.4%) of nodules initially classified as Thy 2 were later shown to be or to harbor malignancy after a follow-up of 74.5 (± 19.7) months. Papillary thyroid microcarcinomas were found co-incidentally in two thyroid glands of benign nodules, giving a true prevalence of 5/500 (1.0%). CONCLUSIONS: With a well targeted FNAB, the false negative rate of an initial benign thyroid FNA is very low thus routine second FNAB is not required in patients with a thyroid nodule initially deemed benign. Multidisciplinary input is imperative in informing decision making.

ENDOCRINOLOGY IN THE TIME OF COVID-19-2021 UPDATES: The management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20-30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3-5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counseling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of the postoperative syndrome of inappropriate antidiuresis (SIAD). They should know hyponatraemia symptoms. The prevalence of hyponatraemia in patients with pneumonia due to COVID-19 is not yet known, but seems to be low. In contrast, hypernatraemia may develop in COVID-19 patients in ICU, from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance.

OBJECTIVE: Insulin resistance (IR) is associated with low adiponectin and elevated high sensitivity C-reactive protein (hsCRP). Osteoprotegerin (OPG) has been shown to be elevated in type 2 diabetes, but whether it reflects underlying IR is unclear. We aimed to compare the ability of serum OPG with adiponectin and hsCRP to act as a marker for IR in individuals with normal and abnormal glucose tolerance. MATERIALS/METHODS: 115 men underwent a 75 g oral glucose tolerance test. OPG, hsCRP and adiponectin were measured using ELISA. IR was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Men with abnormal glucose tolerance (n=38) were older (58.3±11.2 vs 47.3±11.4 years, P<.001), had higher body mass index (BMI) (31.1±2.9 vs 27.9±3.2 kg/m(2), P<.001) and were more insulin resistant (median (I.Q.) HOMA-IR 5.88 (3.38) vs 1.13 (1.14), P<.001) than those with normal glucose tolerance (n=77). After adjustment for age and BMI, OPG (6.28 (2.32) vs 5.16 (1.86) pmol/L, P<.001) and hsCRP (2.07 (5.47) vs 0.78 (1.05) mg/L, P<.001) were higher and adiponectin (3.02±1.17 vs 4.78±2.38 µg/mL, P<.001) was lower in those with AGT. After adjustment for age and BMI, adiponectin (r=-0.317, P<.001) and hsCRP (r=0.318, P<.001), but not OPG (r=0.126, P=.196) correlated with HOMA-IR. On multiple linear regression analysis, adiponectin and hsCRP but not OPG were independent predictors of HOMA-IR. CONCLUSIONS: OPG is higher in individuals with abnormal glucose tolerance, but unlike adiponectin and hsCRP, does not correlate with HOMA-IR, suggesting its elevation within this cohort of individuals is due to factors other than insulin resistance.

The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas.

BACKGROUND AND OBJECTIVES: Transsphenoidal surgery is indicated for patients with nonfunctioning pituitary adenomas (NFPAs) causing compressive symptoms. Previous studies attempting to define the rate of recurrence/regrowth of surgically treated but radiation-naïve NFPAs were somewhat limited by selection bias and/or small numbers and/or lack of consistency of findings between studies. A better understanding of the natural history of this condition could allow stratification of recurrence risk and inform future management. We aimed to define the natural history of a large, mainly unselected cohort with surgically treated, radiotherapy (RT)-naïve NFPAs and to try to identify predictors of recurrence/regrowth. DESIGN: Case-note analysis of all patients who underwent surgery for NFPA in our hospital between 1980 and 2006 was undertaken. Median follow-up was 5.7 (range 1-25) years. PATIENTS: A total of 212 patients were identified of which 159 were suitable for analysis. 93% did not receive post-operative RT. MEASUREMENT: Post-operative recurrent/regrowth was defined by any increase in tumour remnant size on serial post-operative pituitary imaging. RESULTS: Recurrence/regrowth was documented in 53 patients (33.5%). Multivariate analysis revealed size of the post-operative tumour remnant and length of follow-up to be the two major determinants of recurrence/regrowth. The presence of a tumour with an extrasellar remnant was associated with the highest risk of recurrence (odds ratio 3.73 [CI: 1.97-7.09]), while no recurrence was seen in those with no residual tumour post-operatively and regrowth risk was intermediate for those with remaining intrasellar remnant. CONCLUSION: These results indicate that patients with post-operative tumour with an extrasellar remnant should be considered routinely for adjuvant RT to reduce the risk of tumour regrowth while those with no residual tumour can be safely observed. Individualized decisions should be made for patients with an intrasellar remnant.

Risk of diabetes insipidus after pituitary surgery.

Diabetes insipidus is a common complication of pituitary surgery, occurring acutely in 18-30% of operations. Most patients recover full posterior function but a minority sustain sufficient damage to vasopressin-secreting neurons to develop permanent diabetes insipidus. The triplephase response, comprising early transient diabetes insipidus, followed by a period of antidiuresis and hyponatremia, before resolving into permanent diabetes insipidus, is an uncommon but important variant. Diabetes insipidus is more common following surgery for craniopharyngioma compared with pituitary adenoma, and craniopharyngioma patients may develop the dangerous complication of adipsic diabetes insipidus. Diabetes insipidus is also more common following pituitary surgery for Rathke's cleft cysts and possible adrenocorticotropic hormone-secreting adenomas. The data on tumor size are conflicting but our own experience would suggest that diabetes insipidus is more common after surgery for large suprasellar tumors, particularly those with hypothalamic extension. The experience and skill of the neurosurgeon also determines the likelihood of developing diabetes insipidus. The diagnosis of postsurgical diabetes insipidus depends on excluding other forms of polyuria, including diabetes mellitus, excess intravenous fluids and therapy with diuretics or mannitol. Treatment with vasopressin analogues is almost always effective in controlling renal water excretion and normalizing plasma sodium concentrations.