To test or to not test: A retrospective cross-sectional study on potentially inappropriate use of pathology testing in South Australian hospitals.

OBJECTIVES: To measure rates of potentially inappropriate pathology testing in the hospital setting. METHODS: Retrospective cross-sectional study in hospital setting from July 2021 to December 2021. We examined 3 potentially inappropriate uses: overordering, selection errors, and unnecessary repeat testing. Overordering included vitamin D and lipids (rarely required in acute hospital care). Selection error was the ratio of iron studies to standalone ferritin requests. Unnecessary repeats included any repeat vitamin D, lipids, iron, or ferritin in an episode of care or C-reactive protein (CRP) repeated within 3 days and N-terminal pro-brain natriuretic peptide (NT-proBNP) within 7 days and repeated previously abnormal CRP and NT-proBNP tests. Costs of inappropriate tests were estimated using the Australian Medicare Benefits Schedules. RESULTS: Among 55,904 test requests, 15% (n = 8120) were potentially inappropriate. Vitamin D was frequently ordered (n = 4498), as were lipids (n = 2872). Ratio of iron studies to standalone ferritin was 36. Of 19,233 repeat CRPs, 36% (n = 6947) were within 3 days and 62% (n = 179) of repeat NT-proBNPs were within 7 days of the first test. For initially abnormal tests, 89% of CRPs and 97% of NT-proBNPs remained abnormal. Inappropriate test costs accounted for 12% to 30% of costs. CONCLUSIONS: Frequent potential inappropriate use and selection of pathology tests was observed in South Australian hospitals.

Fifty years of newborn screening for congenital hypothyroidism: current status in Australasia and the case for harmonisation.

OBJECTIVES: Since its implementation 50 years ago in Quebec, Canada, newborn screening for congenital hypothyroidism has become one of the most successful public health measures worldwide. Screening programmes across Australia and New Zealand are characterised by significant commonalities in screening algorithms, and a high degree of regional cooperation in harmonisation efforts. We aimed to conduct a comprehensive survey of current performance and practices related to the total testing process for congenital hypothyroidism screening and provide recommendations for harmonisation priorities within our region. METHODS: A survey was conducted involving the six newborn screening laboratories which provide complete geographic coverage across Australasia. Approximately 360,000 newborns are screened annually. Survey questions incorporated pre-analytical, analytical, and post-analytical aspects of the screening programmes and an extensive 5-year (2016-2020) retrospective analysis of individual programme performance data. Responses from individual screening programmes were collated. RESULTS: The uptake of newborn screening was over 98% for the six major jurisdictions. All programmes have adopted a single-tier thyroid stimulating hormone (TSH) strategy using the Perkin Elmer GSP instrument. Significant similarities exist between programmes for recommended age of collection and recollection protocols for low birthweight newborns. The process for the determination of TSH cutoffs varies between programmes. TSH lower cut-offs for borderline-positive and positive notifications between 12-15 and 12-25 mIU/L blood, respectively. Recall rates vary between 0.08 and 0.20%. The case definition for congenital hypothyroidism generally includes biochemical and radiological parameters in addition to the commencement of thyroxine. All programmes reported collecting biochemical and clinical data on infants with positive screening tests, and positive predictive values vary between 23.6 and 77.3%. Variation in reported incidence (1:1,300-2,000) cannot be entirely explained by cutoff or recall rate (although one programme reporting fewer cases includes only permanent disease). CONCLUSIONS: Despite similarities between newborn screening algorithms for congenital hypothyroidism across Australia and New Zealand, differences in reported programme performance provide the basis for further harmonisation. Surveillance of a large population offers the potential for the ongoing development of evidence-based screening guidelines.

Performance of four regression frameworks with varying precision profiles in simulated reference material commutability assessment.

OBJECTIVES: One approach to assessing reference material (RM) commutability and agreement with clinical samples (CS) is to use ordinary least squares or Deming regression with prediction intervals. This approach assumes constant variance that may not be fulfilled by the measurement procedures. Flexible regression frameworks which relax this assumption, such as quantile regression or generalized additive models for location, scale, and shape (GAMLSS), have recently been implemented, which can model the changing variance with measurand concentration. METHODS: We simulated four imprecision profiles, ranging from simple constant variance to complex mixtures of constant and proportional variance, and examined the effects on commutability assessment outcomes with above four regression frameworks and varying the number of CS, data transformations and RM location relative to CS concentration. Regression framework performance was determined by the proportion of false rejections of commutability from prediction intervals or centiles across relative RM concentrations and was compared with the expected nominal probability coverage. RESULTS: In simple variance profiles (constant or proportional variance), Deming regression, without or with logarithmic transformation respectively, is the most efficient approach. In mixed variance profiles, GAMLSS with smoothing techniques are more appropriate, with consideration given to increasing the number of CS and the relative location of RM. In the case where analytical coefficients of variation profiles are U-shaped, even the more flexible regression frameworks may not be entirely suitable. CONCLUSIONS: In commutability assessments, variance profiles of measurement procedures and location of RM in respect to clinical sample concentration significantly influence the false rejection rate of commutability.

Corticosteroid-Binding Globulin Deficiency Independently Predicts Mortality in Septic Shock.

CONTEXT: Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. OBJECTIVE: To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. METHODS: A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. RESULTS: 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (µg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. CONCLUSION: Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.

The BACH project protocol: an international multicentre total Bile Acid Comparison and Harmonisation project and sub-study of the TURRIFIC randomised trial.

OBJECTIVES: Multicentre international trials relying on diagnoses derived from biochemical results may overlook the importance of assay standardisation from the participating laboratories. Here we describe a study protocol aimed at harmonising results from total bile acid determinations within the context of an international randomised controlled Trial of two treatments, URsodeoxycholic acid and RIFampicin, for women with severe early onset Intrahepatic Cholestasis of pregnancy (TURRIFIC), referred to as the Bile Acid Comparison and Harmonisation (BACH) study, with the aims of reducing inter-laboratory heterogeneity in total bile acid assays. METHODS: We have simulated laboratory data to determine the feasibility of total bile acid recalibration using a reference set of patient samples with a consensus value approach and subsequently used regression-based techniques to transform the data. RESULTS: From these simulations, we have demonstrated that mathematical recalibration of total bile acid results is plausible, with a high probability of successfully harmonising results across participating laboratories. CONCLUSIONS: Standardisation of bile acid results facilitates the commutability of laboratory results and collation for statistical analysis. It may provide the momentum for broader application of the described techniques in the setting of large-scale multinational clinical trials dependent on results from non-standardised assays.

Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid-binding globulin.

Corticosteroid-binding globulin (CBG) transports cortisol and other steroids. High-affinity CBG (haCBG) undergoes proteolysis of the reactive center loop (RCL) by neutrophil elastase (NE) altering conformation to low-affinity CBG (laCBG). Elevated temperature reduces CBG:cortisol binding affinity. Surface plasmon resonance was used to determine binding profiles of 19 steroids to haCBG and laCBG at 25, 37, and 39°C mimicking pyrexia and pH 7.4 and 7.0 mimicking acidosis, pathophysiological conditions relevant to sepsis. An expected 4-8-fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone, and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion. CBG:cortisol binding affinity was further reduced 3.5-fold at 39°C relative to 37°C, binding affinity was also reduced by acidosis for both haCBG and laCBG. Using a conformational antibody generated against the RCL, we confirmed RCL antibody binding was eliminated by NE cleavage, but preserved in pyrexia and acidosis. Molecular modeling studies performed at 40°C confirmed a critical role for Trp371, positioned within the steroid-binding pocket, in ligand binding. These studies demonstrated CBG binding affinity to range of steroids is ligand specific and is reduced with NE-mediated haCBG-to-laCBG transition. Reduced CBG:cortisol binding occurs with increased temperature and in acidosis. Increased flexibility of the Trp371 side chain is proposed in the thermo-coupling mechanism of cortisol release. The synergy of NE cleavage, pyrexia, and acidosis on CBG:cortisol binding may serve to enhance cortisol delivery to the interstitial space in inflammation.

Serum prolactin overestimation and risk of misdiagnosis.

BACKGROUND: Falsely elevated prolactin measurements risk overdiagnosis, and unnecessary imaging and treatment. DESIGN: We conducted a clinical audit of 18 patients who presented with hyperprolactinaemia, followed by a laboratory audit of 40 split samples across a range of serum prolactin (5-5051 mIU/L). In each case (total n = 58), serum prolactin was measured on both Roche and Siemens platforms. RESULTS: Serum prolactin as measured by Roche was higher than the corresponding Siemens value in every case, despite similar reference ranges. The mean discrepancy in serum prolactin by Roche vs. Siemens was +81% in the clinical audit and +50% in the laboratory audit. This led to unnecessary interventions in 7/18 patients (39%) in the clinical audit. CONCLUSIONS: Serum prolactin is overestimated on the Roche relative to the Siemens platform. Laboratories should review Roche reference intervals for serum prolactin, and clinicians should consider repeating serum prolactin on another platform if the serum prolactin is incongruent with the clinical scenario.

Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.

CONTEXT: Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. OBJECTIVE: To determine whether depletion of haCBG is related to mortality in septic shock. DESIGN: A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. RESULTS: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. CONCLUSIONS: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Trends in surgery, hospital admissions and imaging for pituitary adenomas in Australia.

PURPOSE: There is a paucity of epidemiological information on treatment and imaging of pituitary adenomas in Australia. METHODS: Australian data on pituitary surgery, hospital admissions for pituitary adenomas, and pituitary imaging on patients 15 years and over were obtained from administrative databases between 2000/2001 and 2014/2015. Changes over time and by age and sex were assessed. RESULTS: In 2014/15 there were 37.7 pituitary procedures/million population, corresponding to a 35.4% (p < 0.05) increase over the 2000/2001 rate. Overall, most (87.2%) procedures were partial excisions of pituitary gland via transsphenoidal surgery (TSS). Admissions for acromegaly increased from 7.1/million in 2000/2001 to 17.2/million in 2003/2004 and then decreased to 6.5/million in 2014/2015. The average age-adjusted rate of pituitary imaging over the study period was 689.6/million/year, which increased significantly (p < 0.05). There was a significant increase in pituitary MRIs (p < 0.05) and a significant decline in pituitary CTs (p < 0.05). Surgical procedure rates were correlated with the pituitary imaging rates (r = 0.62, p < 0.05). CONCLUSION: Pituitary surgery rates increased between 2000/2001 and 2014/2015. The most common procedure was partial excision of the pituitary gland via TSS. Admissions for pituitary neoplasms increased over the study while admissions for acromegaly rose to their highest rate in 2003/2004 and then decreased. There was a substantial increase in the rate of pituitary imaging, which may have resulted in increased detection of pituitary incidentalomas. The underlying reasons for the increased rate of pituitary surgery, and the non-sustained increased rate of admissions for acromegaly are unclear and warrant further investigation.

Differential Effects of Estrogen on Corticosteroid-Binding Globulin Forms Suggests Reduced Cleavage in Pregnancy.

Corticosteroid-binding globulin (CBG) is secreted as high-affinity CBG (haCBG), which may be cleaved by tissue proteases to low-affinity CBG (laCBG), releasing free cortisol. Pregnancy and the estrogen-based combined oral contraceptive pill (COCP) increase CBG concentrations twofold to threefold. The relative effects of these two hyperestrogenic states on the CBG affinity forms are unknown. We performed an observational study in 30 pregnant women, 27 COCP takers and 23 controls. We analyzed circulating total CBG, haCBG, laCBG, and free and total cortisol concentrations. In pregnancy, total CBG and haCBG were increased compared to controls (both P < 0.0001); however, laCBG concentrations were similar. In COCP takers, total CBG and haCBG were increased [802 ± 41 vs compared to controls (both P < 0.0001)], but laCBG was also increased (P = 0.03). Pregnancy and use of COCP were associated with a comparable rise in haCBG, but laCBG was lower in pregnancy (P < 0.0001). These results were consistent with an estrogen-mediated increase in CBG synthesis in both hyperestrogenemic states but with reduced CBG cleavage in pregnancy relative to the COCP, perhaps due to pregnancy-induced CBG glycosylation. Speculatively, increased circulating haCBG concentrations in pregnancy may provide an increased reservoir of CBG-bound cortisol to prepare for the risk of puerperal infection or allow for cortisol binding in the face of competition from increased circulating progesterone concentrations.

Vasculogenic hyperprolactinemia: severe prolactin excess in association with internal carotid artery aneurysms.

PURPOSE: Internal carotid artery (ICA) aneurysms have rarely been found in association with marked hyperprolactinemia in the absence of prolactinoma; the cause of hyperprolactinemia has never been investigated. We aimed to determine if the observed hyperprolactinemia is due to a vascular-derived or known prolactin secretagogue from the injured ICA, analogous to pregnancy-associated hyperprolactinemia putatively due to placental factors. METHODS: We conducted a case series and literature review of individuals with severe hyperprolactinemia in association with ICA aneurysms. In two affected patients at our institutions, we performed RT-PCR and ELISA of prolactin secretagogues that are produced by vascular tissue and/or upregulated in pregnancy: AGT (encoding angiotensinogen), TAC1 (encoding substance P), HDC (encoding the enzyme responsible for conversion of histidine to histamine), and prolactin-releasing hormone (PRLH). Patient blood samples were compared to pregnancy blood samples (positive controls) and middle-aged male blood samples (negative controls). RESULTS: Two men presented with serum prolactin >100-fold normal associated with cavernous ICA aneurysms and no pituitary adenoma. Aneurysm stenting in one man more than halved his serum prolactin. In both men, dopamine agonist therapy markedly reduced serum prolactin. RT-PCR and ELISA showed no differences between patients and controls in AGT, TAC1 or HDC expression or PRLH titre, respectively. Literature review revealed 11 similar cases. CONCLUSIONS: We propose the term 'vasculogenic hyperprolactinemia' to encompass the hyperprolactinemia associated with ICA aneurysms. This may be mediated by an endothelial factor capable of paracrine stimulation of lactotrophs; however, angiotensin II, substance P, histamine and PRLH appear unlikely to be causative.

Pyrexia's effect on the CBG-cortisol thermocouple, rather than CBG cleavage, elevates the acute free cortisol response to TNF-α in humans.

Corticosteroid-binding globulin (CBG) cleavage promotes local cortisol delivery in inflammation. Enzymatic cleavage of high-affinity CBG to low-affinity CBG (haCBG to laCBG) occurs at inflammatory sites and is now measurable in vivo; however, the time kinetics of haCBG depletion following an inflammatory stimulus is unknown. Hence our aim was to determine the immediate effect of the key pro-inflammatory cytokine TNF-α on CBG levels and cleavage. We performed a crossover study of 12 healthy males receiving a TNF-α versus saline infusion, measuring total CBG, haCBG, laCBG and free and total cortisol hourly for 6 h. There was no change in total CBG or haCBG levels in the first 6 h of inflammation between the groups, suggesting that CBG cleavage is not activated nor is hepatic CBG production affected by TNF-α in this time frame. There was an early increase in the ratio of free:total cortisol, in association with pyrexia. This accords with data indicating that CBG acts a thermocouple in vivo, increasing free cortisol levels independent of elastase-driven cleavage.

Corticosteroid-binding globulin cleavage may be pathogen-dependent in bloodstream infection.

OBJECTIVE: The process of enzymatic cleavage of high- to low-affinity corticosteroid-binding globulin (haCBG to laCBG) by neutrophil elastase leads to local tissue release of cortisol. Recently Pseudomonas aeruginosa was shown to instigate CBG cleavage with release of free cortisol in vitro. Hence, CBG cleavage with release of anti-inflammatory cortisol in infection may be pathogen-dependent. Our objective was to determine whether haCBG and laCBG levels are altered in infected patients compared with controls, and whether these alterations were particular to causative bacteria. DESIGN: An observational, cross-sectional study at a public pathology institution and tertiary hospital in Adelaide, South Australia. METHODS: 100 positive blood culture samples and 100 healthy control samples were analysed for serum total CBG, haCBG, laCBG, total and free cortisol, leukocyte and neutrophil count, C-reactive protein and Pitt severity score. RESULTS: Patients with infection had lower serum total CBG, haCBG and laCBG, all P<0.0001, than healthy controls. This was true in patients with and without a systemic inflammatory response and in those with culture-positive and culture-negative infections. Pseudomonas aeruginosa infection was associated with the lowest total and laCBG levels of the pathogen groups despite having the lowest inflammatory markers. CONCLUSIONS: There was evidence of CBG cleavage in early infection both in patients with and without systemic inflammation and regardless of culture status. Pseudomonas infection appeared to enhance cleavage. This observation, along with cleavage in severe neutropenia suggests mechanisms other than neutrophil elastase may be involved in CBG cleavage and local tissue cortisol release in infection.

Reduced corticosteroid-binding globulin cleavage in active rheumatoid arthritis.

OBJECTIVE: Corticosteroid-binding globulin (CBG), the cortisol transport protein, is cleaved from high-affinity (haCBG) to low-affinity (laCBG) CBG at sites of inflammation releasing bioavailable, anti-inflammatory cortisol. Rheumatoid arthritis (RA) is a glucocorticoid-responsive disorder, with paradoxically normal cortisol levels despite elevated inflammatory mediators. Our objective was to determine whether CBG cleavage relates to RA disease activity. We hypothesized that impaired CBG cleavage may limit delivery of free cortisol to inflamed joints in RA. DESIGN: Prospective, cross-sectional observational study. SETTING AND PARTICIPANTS: Fifty-three patients with RA recruited from a Rheumatology outpatient clinic at a tertiary referral centre in Adelaide, Australia, and 73 healthy controls. MEASUREMENTS: Total CBG, haCBG and laCBG, total, free and salivary cortisol, inflammatory markers including interleukin-6 soluble receptor (IL-6sR) and macrophage migration inhibitory factor and clinical measures of disease activity. RESULTS: Among patients with RA, a wide range of disease activity scores was observed (DAS28: range 1·2-6·4). laCBG was lower in patients with RA (mean ± SEM); 153 ± 9, compared with healthy controls; 191 ± 8 nmol/l, P = 0·003. Levels of total and haCBG were higher in patients with more severe RA disease activity. Free and total cortisol, free cortisol:IL-6sR ratio and total cortisol:IL-6sR ratio correlated negatively with disease activity. CONCLUSIONS: These results suggest that patients with RA have reduced CBG cleavage compared to healthy controls and that cleavage is reduced further with higher RA disease activity. Hence, impaired CBG-mediated delivery of endogenous cortisol may perpetuate chronic inflammation in RA.

Corticosteroid-binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: Implications for cortisol homeostasis.

High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase-antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210-551] vs. 250 [175-365] nmol/L; P<0.005, and laCBG lower; 174 [68-229] vs. 220 [119-348] nmol/L; P=0.016 in the AATD group, compared with controls. The ratio of haCBG:total CBG was also higher in AATD; 72 [53-83] vs. 54 [41-72] %; P=0.0001). There was a negative correlation between haCBG:total CBG and AAT levels (P<0.05, R=-0.64). Paradoxically, proteolytic cleavage of CBG was reduced in AATD, despite the recognized increase in NE activity. This implies that NE activity is not the mechanism for systemic CBG cleavage in basal, low inflammatory conditions. Relatively low levels of laCBG may have implications for cortisol action in AATD.

Anti-obesity drugs.

PURPOSE OF REVIEW: The prevalence of obesity across the world continues to climb, bringing with it otherwise preventable obesity-related comorbidities including type 2 diabetes, hypertension and cardiovascular disease. Weight loss is difficult to achieve and maintain through lifestyle interventions alone, leading to intense efforts to develop adjunctive pharmacological approaches. Herein, we examine recent advances in this field and limitations of currently available and emerging agents. RECENT FINDINGS: Liraglutide, lorcaserin and combination of phentermine-topiramate and bupropion-naltrexone have all been the subject of recent studies examining their efficacy as weight-loss agents. Although each effectively induces weight loss over and above placebo, significant concerns exist regarding side-effect profiles and safety, along with their ability to achieve sustained effects. Dropout rates in all examined studies were up to 50% or more, usually a result of intolerable side-effects. Recruitment of a high proportion of women of European descent also casts doubt on the generalizability of trial data. SUMMARY: Pharmacological interventions for weight loss remain limited, with side-effects often outweighing efficacy. Interestingly, substantial early weight loss was associated with sustained loss, suggesting a responsive phenotype and future trials might best be targeted in identifying responsive subpopulations.

Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial.

UNLABELLED: Long-term opioid therapy has been associated with low cortisol levels due to central suppression of the hypothalamic-pituitary-adrenal axis. The implications of hypocortisolism on wellbeing have not been established. Our aim was to determine whether intervention with physiologic glucocorticoid replacement therapy improves wellbeing and analgesic responses in patients with chronic non-cancer pain on long-term opioid therapy with mild cortisol deficiency. We performed a pilot randomized, double-blind, placebo-controlled crossover study of oral hydrocortisone replacement therapy in 17 patients recruited from a Pain Clinic at a single tertiary center in Adelaide, Australia. Patients were receiving long-term opioid therapy (≥ 20 mg morphine equivalents per day for ≥ 4 weeks) for chronic non-cancer pain with mild hypocortisolism, as defined by a plasma cortisol response ≤ 350 nmol/L at 60 min following a cold pressor test. The crossover intervention included 28-day treatment with either 10mg/m(2)/day of oral hydrocortisone in three divided doses or placebo. Improvement in wellbeing was assessed using Version 2 of the Short Form-36 (SF-36v2), Brief Pain Inventory-Short Form, and Addison's disease quality of life questionnaires; improvement in analgesic response was assessed using cold pressor threshold and tolerance times. Following treatment with hydrocortisone, the bodily pain (P=0.042) and vitality (P=0.013) subscales of the SF-36v2 were significantly better than scores following treatment with placebo. There was also an improvement in pain interference on general activity (P=0.035), mood (P=0.03) and work (P=0.04) following hydrocortisone compared with placebo. This is the first randomized, double-blind placebo-controlled trial of glucocorticoid replacement in opioid users with chronic non-cancer pain and mild hypocortisolism. Our data suggest that physiologic hydrocortisone replacement produces improvements in vitality and pain experiences in this cohort compared with placebo. TRIAL REGISTRATION: Therapeutic Goods Administration Clinical Trials Notification Scheme (Drugs), Trial Number 2012/0476.

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment.

We describe a case of development of painful periostitis deformans in a 39-year-old woman who was receiving long-term voriconazole treatment for Aspergillus infection as a complication of orthotopic liver transplant. Measurement of fluoride levels strongly supports fluorosis to be the mechanism of the voriconazole-induced periostitis deformans and supports the concept that such measurements might be of use in predicting this complication of long-term voriconazole treatment.

Continuous subcutaneous hydrocortisone infusion therapy in Addison's disease: a randomized, placebo-controlled clinical trial.

CONTEXT: Patients with Addison's disease (AD) report impaired subjective health status (SHS). Since cortisol exhibits a robust circadian cycle that entrains other biological clocks, impaired SHS may be due to the noncircadian cortisol profile achieved with conventional glucocorticoid replacement. Continuous subcutaneous hydrocortisone infusion (CSHI) reproduces a circadian cortisol profile, but its effects on SHS have not been objectively evaluated. OBJECTIVE: The aim of this study was to determine the effect of CSHI on SHS in AD. SETTING AND DESIGN: This was a multicentre, double-blind, placebo-controlled trial of CSHI vs oral glucocorticoid therapy. Participants received in random order 4 weeks of: CSHI and oral placebo, and subcutaneous placebo and oral hydrocortisone, separated by a 2-week washout period. SHS was assessed using the Short-Form 36 (SF-36), General Health Questionnaire (GHQ-28), Fatigue Scale (FS), Gastrointestinal Symptom Rating Scale (GSRS); and Addison's Quality of Life Questionnaire (AddiQoL). Participants were asked their (blinded) treatment preference. Twenty-four hour urine free cortisol (UFC) and diurnal salivary cortisol collections compared cortisol exposure during each treatment. RESULTS: Ten participants completed the study. Baseline SHS scores (mean ± SE) were consistent with mild impairment: SF-36 physical component summary 48.4 (± 2.4), mental component summary 53.3 (± 3.0); GHQ-28 18.1 (± 3.3); GSRS 3.7 (± 1.6), and AddiQoL 94.7 (± 3.7). FS was similar to other AD cohorts 13.5 (± 1.0) (P = 0.82). UFC between treatments was not different (P = 0.87). The salivary cortisol at 0800 h was higher during CSHI (P = 0.03), but not at any other time points measured. There was no difference between the treatments in the SHS assessments. Five participants preferred CSHI, four oral hydrocortisone, and one was uncertain. CONCLUSIONS: Biochemical measurements indicate similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD.