24-hour Urinary Free Cortisol Excretion Research Articles

Approach to the Patient: Diagnosis of Cushing Syndrome.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

Hypercortisolism on the background of recovery of COVID-19 (сase report)

Damage to the lung tissue is a predominant complication of the viral disease COVID-19. Recently, there have been complications from other organs, including highly vascularized endocrine glands. Regarding the adrenal glands, there are reports of their damage with a decrease in their function. Сhanging the function of the adrenal glands (AG) in patients with or after COVID-19 is important. A few adrenal autopsy studies in patients have revealed vascular thrombosis, cortical lipid degeneration, ischemic necrosis, parenchymal infarcts, and other lesions leading to a decrease in AG function. The central mechanism of adrenal dysfunction through hemorrhage and necrosis of the pituitary gland is also possible. This paper presents a rare case of the development of hypercortisolism in a young woman after recovering from COVID-19. Based on high ACTH levels (157 and 122pg/ml), a negative nocturnal dexamethasone test, and high 24-hour urinary free (daily) cortisol excretion rates, we tentatively suspected Cushing’s disease. Chromogranin A was within the normal range of 21.35 (reference value <100). Other tests showed an elevated dihydrotestosterone level of 780.6 pg/ml (reference values 24–368 pg/ml). The levels of other anterior pituitary hormones tested were within the normal range. According to clinical guidelines, the drug of choice for the short-term treatment of this disease is steroidogenesis inhibitors— ketoconazole. The effectiveness of such a treatment regimen was previously brought to light by others. In our case, ketoconazole was prescribed at a dose of 400 mg 2 times a day and cabergoline (dostinex) at an initial dose of 1 mg per day. Given the low levels of vitamin D in the blood serum, it was recommended to continue taking vitamin D at a dose of 4000 IU per day. It was recommended to control blood laboratory parameters— serum cortisol, ACTH, AST, ALT, electrolytes, 25(OH)D, blood glucose level after 2 months and decide on further tactics for managing the patient.

Longitudinal Change in Cortisol Levels Across the Adult Life Span.

Cortisol is a key stress hormone implicated in the pathogenesis of many age-related diseases. Longitudinal information on cortisol exposure has been restricted to animal models and a small number of human studies. The purpose of the present study was to quantify longitudinal change in cortisol across the adult life span. We conducted a prospective longitudinal study of 24-hour urinary free cortisol excretion from ages 20 to 90 years and older. Participants were 1,814 men and women from the Baltimore Longitudinal Study of Aging who provided a total of 5,527 urine specimens for analysis. The average duration of longitudinal follow-up was 6.6 years. The primary outcome measure was 24-hour urinary free cortisol to creatinine ratio (UFC/Cr) as determined by liquid chromatography/mass spectrometry. UFC/Cr follows a U-shaped pattern across the life span with decreases in UFC/Cr in the 20s and 30s, relative stability in the 40s and 50s, and increases thereafter. This pattern of change was robust with respect to adjustment for several potential confounding factors. Age-related changes in cortisol exposure raise important questions about the potential protective or exacerbating role of cortisol exposure in predicting medical, physiological, and behavioral outcomes.

Midnight salivary cortisol for the diagnosis of Cushing's syndrome in a Chinese population.

Cushing's syndrome is defined as chronic excess free cortisol in circulation. According to recent studies, midnight salivary cortisol is an accurate and non-stress method for screening and diagnosing Cushing's syndrome. However, there is limited data on midnight salivary cortisol for diagnosing Cushing's syndrome in the Chinese population. Among 61 suspected Chinese patients, 48 patients were confirmed to have Cushing's syndrome. We evaluated the midnight salivary cortisol, midnight serum cortisol and 24-hour urine free cortisol excretion for diagnosis. Midnight salivary cortisol was collected from 21 healthy volunteers for control purposes. In the patient group, mean urine free cortisol excretion and midnight salivary cortisol levels were 296.50 ± 47.99 µg/day and 10.18 ± 1.29 ng/mL, respectively. Among the control group and normal participants, mean midnight salivary cortisol level was 0.53 ± 0.13 ng/mL and 0.50 ± 0.12 ng/mL, respectively. The cut-off value for midnight salivary cortisol was 1.7 ng/mL for diagnosing Cushing's syndrome, with a sensitivity of 98% and specificity of 100%. The diagnostic performance of midnight salivary cortisol (area under the curve [AUC] = 0.99) was superior to that of urine free cortisol (AUC = 0.89). Our study confirmed the good diagnostic performance of midnight salivary cortisol for diagnosing Cushing's syndrome in a Chinese population. Correlation between midnight salivary cortisol and either urine free cortisol or midnight serum cortisol was good. Midnight salivary cortisol is a convenient and precise tool for diagnosing Cushing's syndrome and can be the screening test of choice for Chinese populations.

Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study.

Patients with Addison's disease (AD) have increased cardiovascular mortality. To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. A cross-sectional, single-center, case-control study. Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. The mean ± standard deviation age of all subjects was 53 ± 14 years; mean BMI, 25 ± 4 kg/m2; and mean duration of AD, 17 ± 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P < 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC), >1] and vasodilatory protective marker was decreased (FC, <1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.

Psychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Carriers of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) demonstrate increased secretion of cortisol precursors following ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic corticotropin-releasing hormone (CRH) secretion. Both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression. We performed an endocrinologic and psychological evaluation in carriers of 21-OHD and matched control subjects. We recruited 29 parents of children with classic CAH (14 males, 15 females; age (mean±SD): 41.8±5.7 yr), and hence 21-OHD carriers, and 13 normal subjects (5 males, 8 females; age: 43.8±6.1 yr). All subjects underwent a formal ovine (o) CRH stimulation test with measurement of ACTH, cortisol, 17-hydroxyprogesterone (17-OHP) and androstenedione concentrations, which was preceded by determination of 24-hour urinary free cortisol (UFC) excretion. Psychometric assessment was performed by administering the State-Anxiety (STAI 1) and Trait-Anxiety (STAI 2) Inventory, Beck Depression Inventory, Symptom Checklist-90R and Temperament and Character Inventory. Carriers of 21-OHD had significantly higher 17-OHP concentrations following oCRH stimulation and higher STAI 1 (47.6±5.6 vs. 43.3±5.4, P=0.023) scores than control subjects. Mean 24-hour UFC concentrations were positively correlated with paranoid ideation (r=0.435; P=0.023) and psychoticism (r=0.454; P=0.017). Stepwise multiple linear regression analysis revealed that the single independent predictor of STAI 1 was peak stimulated 17-OHP concentrations (β: 0.055, SE: 0.023, R2: 0.290, P=0.031). Carriers of 21-OHD may be predisposed to the development of anxiety disorders.

Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion

Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. The study evaluated 60 children with mild asthma aged 5 to 12years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18mm/wk (SD, 0.55mm/wk) versus 0.45mm/wk (SD, 0.39mm/wk), with a mean difference of 0.27mm/wk (95% CI, 0.05-0.48mm/wk; P=.02). In contrast, there was no difference in 24-hour UFC excretion: 6.91nmol/mmol (SD, 4.67nmol/mmol) versus 7.58nmol/mmol (SD, 6.17nmol/mmol), with a mean difference of 0.67nmol/mmol (95% CI, -1.13 to 2.48nmol/mmol; P=.46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future.

A patient with Cushing disease lateralizing a pituitary adenoma by inferior petrosal sinus sampling using desmopressin: a case report.

A 14-year-old girl was referred for evaluation of the etiology of Cushing syndrome. During the previous 2 years, she had experienced weight gain, secondary amenorrhea, growth retardation, and back pain. Random serum cortisol level, 24-hour urinary free cortisol excretion, and overnight and low-dose dexamethasone suppression tests suggested Cushing syndrome. Midnight adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance imaging was suspicious for microadenoma. To eliminate ectopic ACTH syndrome, and lateralize the pituitary tumor, inferior petrosal sinus sampling (IPSS) was performed by desmopressin use to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to ACTH-secreting pituitary microadenoma, lateralized to the left side; subsequently underwent transsphenoidal surgery. Here we report a case of a 14-year-old girl diagnosed with Cushing disease with a pituitary tumor lateralized by IPSS using desmopressin, which is very rare in pediatric Cushing disease.

Pitfalls in the diagnosis and management of Cushing's syndrome.

Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone-secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.

Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis: Analysis of Noninvasive Coronary Angiography Using Multidetector Computerized Tomography

Observational studies show that glucocorticoid therapy and the endogenous hypercortisolism of Cushing's syndrome (CS) are associated with increased rates of cardiovascular morbidity and mortality. However, the causes of these findings remain largely unknown. To determine whether CS patients have increased coronary atherosclerosis. A prospective case-control study was performed. Subjects were evaulated in a clinical research center. Fifteen consecutive patients with ACTH-dependent CS, 14 due to an ectopic source and 1 due to pituitary Cushing's disease were recruited. Eleven patients were studied when hypercortisolemic; 4 patients were eucortisolemic due to medication (3) or cyclic hypercortisolism (1). Fifteen control subjects with at least one risk factor for cardiac disease were matched 1:1 for age, sex, and body mass index. Agatston score a measure of calcified plaque and non-calcified coronary plaque volume were quantified using a multidetector CT (MDCT) coronary angiogram scan. Additional variables included fasting lipids, blood pressure, history of hypertension or diabetes, and 24-hour urine free cortisol excretion. CS patients had significantly greater noncalcified plaque volume and Agatston score (noncalcified plaque volume [mm(3)] median [interquartile ranges]: CS 49.5 [31.4, 102.5], controls 17.9 [2.6, 25.3], P < .001; Agatston score: CS 70.6 [0, 253.1], controls 0 [0, 7.6]; P < .05). CS patients had higher systolic and diastolic blood pressures than controls (systolic: CS 143 mm Hg [135, 173]; controls, 134 [123, 136], P < .02; diastolic CS: 86 [80, 99], controls, 76 [72, 84], P < .05). Increased coronary calcifications and noncalcified coronary plaque volumes are present in patients with active or previous hypercortisolism. Increased atherosclerosis may contribute to the increased rates of cardiovascular morbidity and mortality in patients with glucocorticoid excess.

Luteinizing hormone correlates with adrenal function in postmenopausal women

In postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone-independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). Participants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women's Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson's correlation coefficient. Serum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = -0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. In postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion.

Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report

IntroductionThe diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing's syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticotropic hormone secretion.Case presentationA 37-year-old Arabian woman presented with 12 months of progressive Cushing's syndrome-like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing's syndrome. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient's pituitary gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient's favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient's 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia.ConclusionThis case report demonstrates the complexities and challenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing's syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion.

Safety of Proactive Topical Corticosteroid Therapy About Adrenal Function and Growth Velocity of Childhood Severe Atopic Dermatitis

S A T U R D A Y 129 Safety of Proactive Topical Corticosteroid Therapy About Adrenal Function and Growth Velocity of Childhood Severe Atopic Dermatitis T. Fukuie, I. Nomura, M. Futamura, M. Narita, Y. Nakagawa, T. Ohzeki, K. Matsumoto, H. Saito, Y. Ohya; National Center for Child health and Development, Tokyo, JAPAN, Hamamatsu University School of Medicine, Shizuoka, JAPAN, National Research Institute for Child Health and Development, Tokyo, JAPAN. RATIONALE:We have reported about decline of serum IgE titer by proactive treatment of atopic dermatitis (AAAAI 2009, BJD 2010 in press). But safety of long-term proactive treatment with using topical corticosteroid about adrenal and growth suppression in children with atopic dermatitis (AD) has not been enough described. METHODS: Growth measurement of the patients with severe AD who admitted to National Center for Child Health and Development (Tokyo, Japan) from April 2006 to March 2008 and continued the proactive administration of topical corticosteroid over 2 years were studied retrospectively and compared with the normal value of Japanese children. Height and annual height velocity were converted to standard deviation scores (SDS). Hypothalamic-Pituitary-Adrenal (HPA) axis function was assessed by serum cortisol and 24-hour urinary free cortisol excretion before and after receiving continuous therapy with proactive management. RESULTS: Eleven girls and 15 boys who could have continued the proactive therapy between the study periods were eligible for this study. The mean (range) agewas 4.4 yrs (0-10) and the mean baseline height SD score was -0.54. Mean baseline serum and urinary cortisol levels were once reduced significantly with everyday use of topical corticosteroids (remission-induction phase), however improved at intermittent proactive treatment phase.Mean height SD scores after 1 and 2 years were not aggravated (-0.54 and -0.47, respectively), and mean annual height velocity SD scores (height-adjusted) after 1 and 2 years were -0.23 and 0.50. CONCLUSIONS:We found that proactive intermittent application of topical corticosteroid does not have negative effects on HPA axis function and height velocity.

Cytokine Inhibition after Glucocorticoid Exposure in Healthy Men with Low versus High Basal Cortisol Levels

Objective: The balance between glucocorticoid (GC) release and GC sensitivity in target cells is believed to be important to maintain homeostasis in the neuroendocrine control of inflammation. We investigated the impact of in vivo exposure to adrenocorticotropic hormone (ACTH) and dexamethasone (DEX) on GC sensitivity measured in vitro in healthy individuals with high versus low baseline cortisol levels. Methods:136 healthy male volunteers were screened twice and sorted according to their 24-hour urinary free cortisol (UFC) excretion. The 10 individuals with the highest UFC (290 ± 87 nmol/24 h) and the 10 with the lowest UFC (168 ± 34 nmol/24 h) were further tested. Measurements were performed at baseline, after a low dose (0.5 μg/1.73 m²) of ACTH challenge and after 2 weeks’ exposure to DEX (0.1 mg twice daily). GC sensitivity was assessed in vitro as the ability of DEX to inhibit lipopolysaccharide-stimulated production of the cytokines interleukin 1-β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in a whole-blood assay. Results:After exposure to DEX in vivo, inhibition of IL-6 and TNF-α decreased. Also, after DEX in vivo, low-cortisol men showed lower inhibition of IL-1β and IL-6, both compared to the high-cortisol group and their own baseline levels. Conclusion: A downregulation of GC sensitivity in leukocytes after exposure to an exogenous GC seems to occur most strongly in men with low cortisol levels.

Lack of effect on adult and adolescent hypothalamic-pituitary-adrenal axis function with use of fluticasone furoate nasal spray

Intranasal corticosteroids are recommended as first-line therapy for allergic rhinitis (AR), and because of their pharmacologic class, hypothalamic-pituitary-adrenal (HPA) axis function is evaluated. To evaluate whether cortisol production was suppressed (as a measure of HPA axis function) by 6 weeks of treatment with fluticasone furoate nasal spray, 110 microg once daily, in patients with perennial AR. A double-blind, randomized, placebo- and active-controlled (prednisone), parallel-group study. Outpatients aged 12 to 65 years with perennial AR for 2 years or more were from 1 center in the United States and 1 center in Canada. Pharmacodynamic and pharmacokinetic samples were collected during 24-hour domiciled visits (overnight in clinic). Measurements included change from baseline in 24-hour serum cortisol weighted mean and 24-hour urinary free cortisol excretion, total 24-hour urinary free cortisol excretion and 6-beta hydroxycortisol excretion, and plasma concentration of fluticasone furoate. A total of 112 of 183 patients were randomized. Fluticasone furoate was noninferior to placebo with respect to the ratio from baseline in serum cortisol weighted mean (treatment ratio, 0.98; 95% confidence interval, 0.89 to 1.07). In contrast, use of prednisone, 10 mg once daily, significantly reduced the ratio from baseline compared with placebo. Change from baseline in 24-hour urinary cortisol excretion was similar in the fluticasone furoate and placebo groups. Plasma levels of fluticasone furoate were undetectable after 6 weeks of treatment. Fluticasone furoate nasal spray, 110 microg once daily, was not associated with HPA axis suppression in patients 12 years and older with perennial AR.

Tolerability of a Salmeterol Xinafoate/Fluticasone Propionate Hydrofluoroalkane Metered-Dose Inhaler in Adolescent and Adult Patients with Persistent Asthma: A 52-Week, Open-Label, Stratified, Parallel-Group, Multicenter Study

Background: Many patients with asthma require an inhaled long-acting β 2-agonist (LABA) in addition to an inhaled corticosteroid to adequately control their disease. Objective: The purpose of this study was to assess the long-term tolerability of a salmeterol xinafoate/ fluticasone propionate (SFC) hydrofluoroalkane metered-dose inhaler (MDI) at 3 different doses BID. Methods: This 52-week, open-label, stratified, parallel-group study assessed SFC in patients with persistent asthma. Patients, aged ≥12 years, with a diagnosis of asthma for ≥6 months, and a percent predicted forced expiratory volume in 1 second (FEV 1) or peak expiratory flow (PEF) between 40% and 90% were enrolled between January 1999 and June 1999. The last patient completed the 12-month study in June 2000. Patients were allowed to continue their current asthma treatment during run-in, with the exception that short-acting β 2-agonists (SABAs), LABAs, and oral bronchodilators were not to be used 6, 12, and 24 hours, respectively, prior to the randomization visit. During the open-label randomized treatment period, patients were instructed to discontinue all other asthma medications with the exception of the albuterol MDI to use on an as-needed basis. Patients were assigned to treatment based on their existing asthma regimen: SABA monotherapy or LABA with or without fluticasone propionate (FP) <250 tlg/d or equivalent (group 1); FP 250 to 500 tlg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 tlg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 μg/actuation (group 1), 25/125 μg/actuation (group 2), or 25/250 pg/actuation (group 3). The primary end point was tolerability as assessed by adverse events (AEs). AEs were determined via diary cards and investigator inquiry at visits. Serious AEs were defined as death, any life-threatening event, hospitalization, disability, congenital anomaly in the patient's offspring, or other important medical events judged by the investigator to be serious. Other outcomes included clinical laboratory tests (hematology, chemistry, electrolytes), 24-hour urinary-free cortisol excretion, 12-lead electrocardiograms, oropharyn- geal examinations, vital signs, clinic visit lung function tests (FEV 1 and PEF), daily diary card entries of morn- ing PEF, and rescue medication usage. Results: Of the 372 patients assessed for eligibility, 325 from 22 centers across Canada were enrolled and randomized to treatment. Group 1 consisted of 98 pa- tients (55% women; 86% white; mean age, 37 years; mean [SD] weight, 79 [20] kg). Group 2 consisted of 109 patients (46% women; 94% white; mean age, 44 years; mean [SD] weight, 80 [17] kg). Group 3 consisted of 118 patients (47% women; 90% white; mean age, 45 years; mean [SD] weight, 80 [18] kg). A total of 15 adolescents (aged 12–17 years) comprised 11%, 2%, and 2% of groups 1, 2, and 3, respectively. Treatments were well tolerated, and 274 (84%) of the 325 patients enrolled completed the study. Upper respiratory tract infection was the most common AE reported: 52%, 37%, and 49% of patients in groups 1, 2, and 3, respectively. Twenty (6%) patients withdrew because of an AE, with worsening asthma being the most frequent reason (n = 9). None of the serious AEs (11 [3 %]) were considered drug related by the investigators. Improvements in FEV 1 and PEF and re- duction in symptomatic albuterol use occurred during the first 4 weeks and were maintained in all groups throughout the 52-week study. Conclusions: BID doses of SFC hydrofluoroalkane 50/100 pg, 50/250 pg, and 50/500 pg administered via MDI for 52 weeks were well tolerated in this population of adolescents and adults with persistent asthma.

“Buffalo” hump in nonalcoholic fatty liver disease

I read with interest the recent article by Cheung et al.1 regarding the impact of fat distribution, as estimated by several anthropometric parameters, on the severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome in obese NAFLD patients. Notably, they found that dorsocervical lipohypertrophy (“buffalo” hump) was the single greatest predictor of the histological severity of NAFLD, whereas waist circumference was the greatest predictor of the severity of metabolic syndrome.1 Dorsocervical lipohypertrophy (DCL) was diagnosed only clinically but no quantitative measure (for example, ultrasound imaging) was used for diagnosing the “hump” at the base of the neck. Obviously, this is a major limitation of the study. Additionally, it is conceivable that the differential impact of DCL and waist circumference on the severity of NAFLD histology and metabolic syndrome is simply due to the fact that they are only indirect and crude indices of abdominal visceral fat distribution.2 A direct and more accurate measure of abdominal visceral fat, obtained by computed tomography or magnetic resonance imaging,2 would be useful to explore this issue adequately. However, the authors have interestingly shown that DCL, which is commonly seen in Cushing's syndrome, is a highly prevalent condition (28.5%) in obese NAFLD patients,1 thus suggesting an underlying subclinical hypercortisolism in NAFLD. Regarding this, recent studies have consistently shown a subclinical hypothalamo-pituitary-adrenal (HPA) axis dysfunction in NAFLD. Westerbacka et al.3 reported that obese men with higher liver fat content (as evaluated by magnetic resonance imaging spectroscopy) have a selective increase in 24-hour urinary excretion of 5-beta-reduced cortisol metabolites and a lower ratio of urinary cortisol/cortisone metabolites than men with lower liver fat content. Saruc et al.4 found that postmenopausal women with NAFLD, as assessed by ultrasound, have higher plasma dehydroepiandrosterone levels than controls. Others have shown that obese individuals5 and overweight type 2 diabetic patients6 with ultrasonographically diagnosed NAFLD have higher 24-hour urinary free cortisol excretion and postdexamethasone suppression cortisol concentrations than nonsteatotic controls. More importantly, we have recently demonstrated that overweight patients with biopsy-proven NAFLD have a subclinical, chronic HPA axis activation (as reflected by the increased, albeit still normal, 24-hour urinary free cortisol values and the blunted suppression of cortisol levels by 1.0 mg-dexamethasone with normal serum corticosteroid-binding globulin concentrations) that is correlated to the histopathological severity of NAFLD (that is, necro-inflammatory grade and fibrosis stage) independently of multiple potential confounders, including insulin resistance and metabolic syndrome components.7 Overall, therefore, the evidence from these studies,3-7 although only correlative in nature, suggests the hypothesis that overweight/obese NAFLD patients have a subtle HPA axis dysfunction that is strongly correlated with the severity of NAFLD histology, leading to subclinical cortisol overproduction that might be implicated in the development/progression of NAFLD. Future prospective and interventional (by using a cortisol inhibitor or specific 11beta-hydroxysteroid dehydrogenase-type 1 inhibitors) studies are obviously needed to validate this hypothesis and to better understand the underlying biological mechanisms linking HPA axis dysfunction to the development of NAFLD. Giovanni Targher M.D.*, * Section of Endocrinology, Department of Biomedical and Surgical Sciences, University Hospital, Verona, Italy.

Elevated Circulating Leukemia Inhibitory Factor in Patients With Extensive Burns

To investigate circulating cytokine responsiveness in major burns in association with the systemic stress response system, we tested hypothalamic-pituitary-adrenal (HPA) axis markers in extensive burn cases treated in the Department of Plastic and Reconstructive Surgery at Nagasaki University. The HPA axis is a major stress response system, and the leukemia inhibitory factor (LIF) may be a potent mediator of the HPA axis; therefore, circulating LIF levels in burn patients were studied. Twenty extensively burned patients (burn surface area, >20%), ie, 10 women and 10 men, 37 to 77 years of age (average: 59.1 +/- 12.10 years), were assessed. Circulating LIF, adrenocorticotropic hormone (ACTH), other inflammatory markers, and 24-hour urinary free cortisol excretion levels were investigated. LIF levels were greater in patients who died than in those who survived (186.1 +/- 80.41, 83.5 +/- 64.49 pg/ml, respectively, P < .001) at 36 hours after injury. ACTH levels were more significantly elevated in fatal cases than in those who survived. (41.3 +/- 8.28, 25.2 +/- 7.84 pg/ml, respectively, P < .0001). Twenty-four hour (24 to 48 hours after injury) pooled urinary free cortisol excretion levels also were significantly greater in fatal cases than in the surviving patient group (235.0 +/- 36.49 microg/day, 69.0 +/- 18.04 microg/day, respectively, P < .0001). The correlation between serum LIF and urine free cortisol was significant (r = .30; P < .01) as was the correlation of serum LIF with plasma ACTH (r = .24; P < .01). Serum LIF as well as HPA axis activity markers is a good marker of disease severity and prognosis in patients with extensive burns.

Improved Efficiency of Pulmonary Delivery of Budesonide with Respimat® Soft Mist™ Inhaler Compared with Turbohaler or pMDI

with Respimat® Soft MistTM Inhaler Compared with Turbohaler or pMDI C. C. Wood1, B. van Toor2, V. Hasselbarth2, H. Stammer2, H. Voss2; 1Respiratory and Immunology Clinical Operations, Boehringer-Ingelheim Pharmaceuticals Inc, Ridgefield, CT, 2Human Pharmacology, Boehringer Ingelheim Pharma KG, Ingelheim, GERMANY. RATIONALE: More efficient delivery of an inhaled steroid to the pulmonary target organ allows for a lower nominal, nevertheless comparable lung dose and possible reduction in systemic steroid side effects. METHODS: Seventy-one normal male volunteers (20 to 49 years) in a 21 day placebo controlled trial received budesonide via Respimat® SMI (0.2, 0.4 or 0.6 mg BID), Turbohaler (0.8 mg BID) or beclomethasonepMDI (1.0 mg BID). Plasma budesonide time course concentrations were measured along with standard safety assessments. 24-hour urinary free cortisol, serum cortisol, osteocalcin levels and a short ACTH stimulation test (0.25 mg tetrosactrin) were done. RESULTS: Pharmacokinetic and pharmacodynamic results demonstrated that Respimat® SMI delivers the substance more efficiently to the lung than Turbohaler. AUC (NG*H/ML) for Respimat® SMI was dose-linear: 0.747, 1.458 and 2.105 for the 0.2, 0.4 and 0.6 mg BID doses. Turbohaler (0.8 mg BID) AUC was 2.104. No difference in suppression of 24-hour urinary free cortisol excretion was observed between the highest dose of budesonide delivered via Respimat SMI and the Turbohaler or beclomethasone-pMDI doses. The two lower doses of budesonide delivered via Respimat SMI had less of an effect on 24-hour urinary excretion, and no significant effect on plasma cortisol or osteocalcin levels. No active treatment had any effect on serum calcium, inorganic phosphorus or ostase compared with placebo nor affected the ACTH stimulation test. S82 Abstracts J ALLERGY CLIN IMMUNOL FEBRUARY 2006 S A T U R D A Y 320 Modern Technology Making Immunotherapy Safer R. G. Houser, J. B. Hunter, S. Shaeffer, L. H. Fisher, T. J. Craig; Allergy/ Immunology, Penn State Hershey Medical Center, Hershey, PA. RATIONALE: A recent trend in allergy has been standardization to decrease the risk associated with skin testing and immunotherapy. Electronic programs further help in decreasing errors by practice standardization, charting and obliged queries. METHODS: Computerized immunotherapy with personalized scan cards was instituted in the spring of 2005. After the patient’s card is scanned, the immunotherapy records are visualized along with the patient’s picture. A printed label on each vial allows the scanner to verify that the vial is the appropriate strength for that specific individual. The electronic program shows the previous dose and how long ago it was given. It then prompts for the next scheduled dose to be given. All adverse reactions from previous injections are highlighted in red. After the injection is given, a builtin timer monitors the amount of time the patient was observed before charting the results. The program prompts for peak flow and designates peak flow values to hold immunotherapy. RESULTS: On past review the literature of immunotherapy, most errors are clerical due to inappropriate doses or to patients receiving incorrect extracts. Each error is addressed with the electronic immunotherapy program, therefore decreasing the risk associated with immunotherapy. Electronic immunotherapy has been effective in our office on improving quality of care. CONCLUSIONS: With the help of an electronic program and using the “Five Rights” (right medication, right dose, right time, right route and right patient) immunotherapy administration is now safer. Funding: Hershey Medical Center

A Case of Adrenocorticotropin-independent Bilateral Adrenal Macronodular Hyperplasia (AIMAH) with Primary Hyperparathyroidism (PHPT)

We report a rare case of ACTH-independent macronodular adrenal hyperplasia (AIMAH) with primary hyperparathyroidism (PHPT). A 57-year-old woman was admitted to our hospital for further examination of secondary hypertension and bilateral adrenal macrotumors. Midnight serum cortisol elevation with undetectable plasma ACTH, increased 24-hour urinary free cortisol excretion, and loss of the normal circadian rhythm in cortisol secretion established the diagnosis of Cushing's syndrome. Total resection of the enlarged left adrenal gland was performed with subsequent steroid replacement. Her general condition improved but serum calcium level increased 3 weeks after surgery. PHPT was diagnosed on the basis of endocrinological examination, although imaging studies failed to detect parathyroid lesion. In summary, we believe this to be the first report of a case of AIMAH with PHPT.