Morton G. Burt

Low O6‐methylguanine‐DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours

Context  Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O6‐methylguanine‐DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide.

Continuous Monitoring of Circadian Glycemic Patterns In Patients Receiving Prednisolone For COPD

CONTEXT Endogenous glucocorticoid excess (Cushings syndrome) predominantly increases postprandial glucose concentration. The pattern of hyperglycemia induced by prednisolone has not been well characterized. OBJECTIVE Our objective was to define the circadian effect of prednisolone on glucose concentration to optimize management of prednisolone-induced hyperglycemia. DESIGN AND SETTING This was a cross-sectional study in a teaching hospital. PARTICIPANTS Participants included 60 consecutive consenting subjects with chronic obstructive pulmonary disease admitted to hospital: 13 without known diabetes admitted for other indications and not treated with glucocorticoids (group 1), 40 without known diabetes admitted with an exacerbation of chronic obstructive pulmonary disease and treated with prednisolone (group 2, prednisolone = 30 ± 6 mg/d), and seven with known diabetes treated with prednisolone (group 3, prednisolone = 26 ± 9 mg/d). MAIN OUTCOME MEASURE Interstitial glucose concentration was assessed during continuous glucose monitoring. RESULTS Significantly more subjects in group 2 [21 of 40 (53%), P = 0.02] and group 3 [seven of seven (100%), P = 0.003] recorded a glucose of at least 200 mg/dl (≥11.1 mmol/liter) during continuous glucose monitoring than in group 1 [one of 13 (8%)]. The mean glucose concentration between 2400-1200 h for group 3 (142 ± 36 mg/dl) was significantly greater than in the other two groups (P < 0.005), whereas mean glucose concentrations between 2400-1200 h in group 1 (108 ± 16 mg/dl) and group 2 (112 ± 22 mg/dl) were not significantly different. In contrast, the mean glucose concentrations between 1200-2400 h for group 2 (142 ± 25 mg/dl) and group 3 (189 ± 32 mg/dl) were both significantly greater than group 1 (117 ± 14 mg/dl, P < 0.05 for both comparisons). CONCLUSIONS Prednisolone predominantly causes hyperglycemia in the afternoon and evening. Treatment of prednisolone-induced hyperglycemia should be targeted at this time period.

Xanthomatous pituitary lesions: a report of two cases and review of the literature.

We describe two young men with cystic pituitary enlargement on magnetic resonance imaging (MRI) causing hypopituitarism. The first patient presented acutely unwell with headache and vomiting associated with anterior and posterior pituitary dysfunction. The second patient presented with hypopituitarism after a long history of hypogonadism. In both cases yellow/brown fluid was found at surgery and histological examination revealed inflammatory infiltrate with foamy histiocytes, lymphocytes and multinucleated giant cells containing cholesterol clefts. Full recovery of pituitary function occurred after surgery in the first but not the second patient. The first case is the first documented case of xanthomatous hypophysitis with recovery of pituitary function following surgery. The cases differed in duration of disease, as indicated by the long history of symptoms, the histological finding of marked fibrosis and the lack of recovery of pituitary function in the second. Xanthomatous pituitary lesions categorized in the literature as xanthomatous hypophysitis, xanthogranulomatous hypophysitis and xanthogranuloma of the sellar region have overlapping histological features. Our two cases revealed histological features that do not fit completely into any of the categories but share features of all three. These findings suggest that the various xanthomatous lesions of the sellar region may be a spectrum of a common inflammatory process rather than distinct pathological entities.

Characterization of the metabolic phenotypes of Cushing's syndrome and growth hormone deficiency: a study of body composition and energy metabolism

Objective  A comparison of the severity and distribution of perturbations in body composition and their relationship to energy metabolism in glucocorticoid excess and GH deficiency (GHD) has not been undertaken before. The aim of this study was to investigate the impact of Cushings syndrome (CS) and GHD on whole and regional body composition and energy metabolism.

Screening for diabetes in patients with inflammatory rheumatological disease administered long-term prednisolone: a cross-sectional study

OBJECTIVE The aim of the study was to assess the effect of long-term prednisolone on fasting and post-glucose load glucose concentration in patients with inflammatory rheumatological disease. We hypothesized that prednisolone would predominantly increase post-glucose load glucose concentration and that fasting glucose would have poor sensitivity as a screening test for diabetes in patients receiving chronic prednisolone therapy. METHODS In a cross-sectional study of subjects with inflammatory rheumatological disease but without known diabetes, 60 subjects [age = 70 (±10) years, 62% female] who were receiving chronic (>6 months) prednisolone [6.5 (±2.1) mg/day] (Group 1) and 58 controls [age = 70 (±11) years, 62% female] who had not received oral glucocorticoids for at least 6 months (Group 2) underwent an oral glucose tolerance test. RESULTS Fasting glucose was significantly lower [5.0 (±0.1) vs. 5.3 (±0.1) mmol/l, P = 0.02) and post-glucose load glucose concentration significantly higher [8.0 (±0.4) vs. 6.8 (±0.3) mmol/l, P = 0.02] in Group 1 than in Group 2. In a multiple regression analysis, glucocorticoid use (P = 0.004) and log CRP (P = 0.02) were independently associated with fasting glucose, while waist circumference (P = 0.01), but not glucocorticoid use, was independently associated with post-glucose load glucose concentration. A fasting glucose ≥5.6 mmol/l had 33 and 83% sensitivity for diabetes in Groups 1 and 2, respectively. CONCLUSION There is discordance between a reduced fasting and increased post-glucose load glucose concentration in rheumatological patients on long-term prednisolone. Therefore fasting glucose has poor sensitivity to screen for diabetes in prednisolone-treated patients. Treatment of prednisolone-induced hyperglycaemia should be directed at the postprandial period. Trial registration. Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/, ACTRN12607000540415.

Effects of Low-Dose Prednisolone on Hepatic and Peripheral Insulin Sensitivity, Insulin Secretion, and Abdominal Adiposity in Patients With Inflammatory Rheumatologic Disease

OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

Acute effect of calcium citrate on serum calcium and cardiovascular function.

Calcium supplements have been associated with an increased risk of cardiovascular events. However, the validity of these findings has been questioned. A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated. Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid. We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function. In an open interventional study, we recruited 25 volunteers (16 female, age 60.3 ± 6.5 years, body mass index 25.7 ± 2.7 kg/m2) from the community who were not taking calcium supplements. Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate. We assessed well‐validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry. Total and ionized serum calcium were acutely increased by 0.10 ± 0.07 and 0.06 ± 0.03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0.0001 for both comparisons). Following administration of calcium citrate there was a fall in AIx from a median of 29.7% (23.8% to 34.0%) to 26.4% (22.7% to 34.0%, p = 0.03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0.007). PWV and RHI were not significantly altered. The change in total calcium was negatively correlated with the change in AIx (r = –0.48, p = 0.02). In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion. If maintained long‐term, these changes would be expected to reduce cardiovascular risk. Acute serum calcium–mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events.

Basal–bolus insulin versus sliding-scale insulin for inpatient glycaemic control: a clinical practice comparison

Objective: To determine if the improvement in inpatient glycaemic control observed with basal–bolus insulin (BBI) over sliding‐scale insulin (SSI) in the formal study setting translates to routine clinical conditions.

Acute Effect of Increasing Glucocorticoid Replacement Dose on Cardiovascular Risk and Insulin Sensitivity in Patients With Adrenocorticotrophin Deficiency

CONTEXT Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. OBJECTIVE The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulins hemodynamic effects was responsible for this effect. DESIGN We conducted an open interventional study between 2011 and 2013. SETTING The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. PATIENTS Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. INTERVENTION Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. MAIN OUTCOME MEASURE The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. RESULTS Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. CONCLUSIONS Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.

Newer options in the management of acromegaly

Paradigms for managing acromegaly have undergone major changes in the past two decades. This has been brought about by combining surgical, pharmacological and radiotherapeutic approaches that provide tight biochemical control to reduce mortality to that of the general population. The biochemical targets for treatment are a growth hormone of <2.5 ng/mL (∼7.5 mU/L) and a normal, age‐adjusted insulin‐like growth factor‐1. Until 20 years ago, dopamine agonists were the only class of pharmaceutical agents available to control acromegaly. They have a limited adjunctive role, even with the development of second‐generation selective agonists such as cabergoline. Surgery and radiotherapy were the mainstay of acromegaly management before the advent of the effective pharmacological therapies of the modern era: somatostatin analogues and pegvisomant, a growth hormone receptor antagonist. Somatostatin analogues achieve biochemical control in approximately 60% of patients. Pegvisomant, which is available in the USA and Europe and has just been registered in Australia, normalizes insulin‐like growth factor‐1 in nearly all patients but has no effect on tumour mass. Surgery is an appropriate first‐line therapy for microadenomas as the chance of success is high. For large and/or invasive tumours where the prospect of surgical cure is remote, first‐line therapy is somatostatin analogue treatment with debulking surgery having an adjunctive role to achieve tight control or to alleviate compression of the optic chiasm. Although acromegaly remains a challenging disease to manage, the expanding range of therapeutic options is likely to result in a better outcome for patients and offers the potential to tailor therapy based on a patient’s individual requirements.