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24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency.
Turcu, AF, Mallappa, A, Nella, AA, Chen, X, Zhao, L, Nanba, AT, Byrd, JB, Auchus, RJ, Merke, DP
Frontiers in endocrinology. 2021;:751191
Abstract
BACKGROUND Optimal management of androgen excess in 21-hydroxylase deficiency (21OHD) remains challenging. 11-oxygenated-C19 steroids (11-oxyandrogens) have emerged as promising biomarkers of disease control, but data regarding their response to treatment are lacking. OBJECTIVE To compare the dynamic response of a broad set of steroids to both conventional oral glucocorticoids (OG) and circadian cortisol replacement via continuous subcutaneous hydrocortisone infusion (CSHI) in patients with 21OHD based on 24-hour serial sampling. PARTICIPANTS AND METHODS We studied 8 adults (5 women), ages 19-43 years, with poorly controlled classic 21OHD who participated in a single-center open-label phase I-II study comparing OG with CSHI. We used mass spectrometry to measure 15 steroids (including 11-oxyandrogens and Δ5 steroid sulfates) in serum samples obtained every 2 h for 24 h after 3 months of stable OG, and 6 months into ongoing CSHI. RESULTS In response to OG therapy, androstenedione, testosterone (T), and their four 11-oxyandrogen metabolites:11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone (11KT) demonstrated a delayed decline in serum concentrations, and they achieved a nadir between 0100-0300. Unlike DHEAS, which had little diurnal variation, pregnenolone sulfate (PregS) and 17-hydoxypregnenolone sulfate peaked in early morning and declined progressively throughout the day. CSHI dampened the early ACTH and androgen rise, allowing the ACTH-driven adrenal steroids to return closer to baseline before mid-day. 11KT concentrations displayed the most consistent difference between OG and CSHI across all time segments. While T was lowered by CSHI as compared with OG in women, T increased in men, suggesting an improvement of the testicular function in parallel with 21OHD control in men. CONCLUSION 11-oxyandrogens and PregS could serve as biomarkers of disease control in 21OHD. The development of normative data for these promising novel biomarkers must consider their diurnal variability.
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Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain.
Boluda, B, Solana-Altabella, A, Cano, I, Acuña-Cruz, E, Rodríguez-Veiga, R, Ballesta-López, O, Megías-Vericat, JE, Martínez-Cuadrón, D, Gómez, I, Solves, P, et al
Journal of clinical apheresis. 2021;(4):612-620
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BACKGROUND This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS Patients (≥18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (€22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25 319 (95% CI: €17 049-€33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (€23 120) compared with the non-ECP cohort (€27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). CONCLUSIONS ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.
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Use of Prophylactic Steroids to Prevent Hypocalcemia and Voice Dysfunction in Patients Undergoing Thyroidectomy: A Randomized Clinical Trial.
Dhahri, AA, Ahmad, R, Rao, A, Bhatti, D, Ahmad, SH, Ghufran, S, Kirmani, N
JAMA otolaryngology-- head & neck surgery. 2021;(10):866-870
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IMPORTANCE Total thyroidectomy is associated with risks related to temporary hypocalcemia and vocal quality dysfunction. Dexamethasone has been proposed to have a physiological effect on hypocalcemia and voice quality. OBJECTIVE To assess the effect of preoperative dexamethasone used to improve hypocalcemia and postthyroidectomy voice dysfunction. DESIGN, SETTING, AND PARTICIPANTS This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted from January 15, 2014, to December 31, 2019, at the Department of Surgery, Holy Family Hospital in Rawalpindi, Pakistan. All patients with a benign thyroid condition and no preoperative corrected hypocalcemia and voice or vocal quality dysfunction were included. Patients were excluded if they had previous thyroid or neck surgery, known vocal cord dysfunction on laryngoscopy, hearing or voice problems, a history of gastroesophageal reflux, stomach ulcer disease, or contraindications to steroid use. INTERVENTIONS Corrected serum calcium levels and Voice Analog Score defined and measured preoperatively. The dexamethasone group received a 2-mL intravenous dose of 8 mg of dexamethasone 60 minutes before the induction of anesthesia. In contrast, the placebo group received 2 mL of intravenous normal saline (0.9%) 60 minutes before the induction of anesthesia. MAIN OUTCOMES AND MEASURES Evidence of hypocalcemia and voice dysfunction. Voice dysfunction was defined as a subjective score of less than 50 on a Voice Analog Score scale of 0 to 100 points. RESULTS A total of 192 patients (mean [SD] age, 38.9 [12.4] years; 156 women [81.2%]) were included in the study, with 96 patients randomized to each study group (dexamethasone group, mean [SD] age, 39.2 [12.1] years; 75 women [78.1%]; placebo group, mean [SD] age, 38.5 [12.9] years; 81 women [84.5%]). In the first 24 hours after undergoing thyroidectomy, 47 patients (24.4%) developed hypocalcemia and 18 (9.4%) were symptomatic. At 3 days postthyroidectomy, 4 of 96 patients (4.2%) in the placebo group had hypocalcemia compared with no patients in the dexamethasone group. At 24 hours postthyroidectomy, 8 of 96 patients (8.3%) in the dexamethasone group had voice dysfunction compared with 32 of 96 patients (33.3%) in the placebo group. A total of 40 patients (20.8%) reported voice dysfunction. The absolute reduction in the rate of hypocalcemia at 24 hours was 24% (95% CI, 11.9%-35.2%) and at 3 days was 4.2% (-0.44% to 10.0%). The rate of symptomatic hypocalcemia was 19% lower in the dexamethasone group than in the placebo group (95% CI, 11.1%-27.7%). The rate of voice dysfunction was 25% lower in the dexamethasone group than in the placebo group (95% CI, 13.7%-35.7%). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, a single preoperative dose of dexamethasone was safe and effective in reducing postoperative hypocalcemia and voice dysfunction rates in patients undergoing thyroidectomy. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT04752852.
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Clinical Olfactory Working Group consensus statement on the treatment of postinfectious olfactory dysfunction.
Addison, AB, Wong, B, Ahmed, T, Macchi, A, Konstantinidis, I, Huart, C, Frasnelli, J, Fjaeldstad, AW, Ramakrishnan, VR, Rombaux, P, et al
The Journal of allergy and clinical immunology. 2021;(5):1704-1719
Abstract
BACKGROUND Respiratory tract viruses are the second most common cause of olfactory dysfunction. As we learn more about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the recognition that olfactory dysfunction is a key symptom of this disease process, there is a greater need than ever for evidence-based management of postinfectious olfactory dysfunction (PIOD). OBJECTIVE Our aim was to provide an evidence-based practical guide to the management of PIOD (including post-coronavirus 2019 cases) for both primary care practitioners and hospital specialists. METHODS A systematic review of the treatment options available for the management of PIOD was performed. The written systematic review was then circulated among the members of the Clinical Olfactory Working Group for their perusal before roundtable expert discussion of the treatment options. The group also undertook a survey to determine their current clinical practice with regard to treatment of PIOD. RESULTS The search resulted in 467 citations, of which 107 articles were fully reviewed and analyzed for eligibility; 40 citations fulfilled the inclusion criteria, 11 of which were randomized controlled trials. In total, 15 of the articles specifically looked at PIOD whereas the other 25 included other etiologies for olfactory dysfunction. CONCLUSIONS The Clinical Olfactory Working Group members made an overwhelming recommendation for olfactory training; none recommended monocycline antibiotics. The diagnostic role of oral steroids was discussed; some group members were in favor of vitamin A drops. Further research is needed to confirm the place of other therapeutic options.
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Underestimated reactions and regulation patterns of adrenal cytochromes P450.
Bernhardt, R, Neunzig, J
Molecular and cellular endocrinology. 2021;:111237
Abstract
Although cytochrome P450 (CYP) systems including the adrenal ones are being investigated since many years, there are still reactions and regulation patterns that have been underestimated ever since. This review discusses neglected ones to bring them into the focus of investigators working in the field. Novel substrates and reactions described for adrenal CYPs recently point to the fact that different from what has been believed for many years, adrenal CYPs are less selective than previously thought. The conversion of steroid sulfates, intermediates of steroid biosynthesis as well as of exogenous compounds are being discussed here in more detail and consequences for further studies are drawn. Furthermore, it was shown that protein-protein interactions may have an important effect not only on the activity of adrenal CYPs, but also on the product pattern of the reactions. It was found that, as expected, the stoichiometry of CYP:redox partner plays an important role for tuning the activity. In addition, competition between different CYPs for the redox partner and for electrons and possible alterations by mutants in the efficiency of electron transfer play an important role for the activity and product pattern. Moreover, the influence of phosphorylation and small charged molecules like natural polyamines on the activity of adrenal systems has been demonstrated in-vitro indicating a possible regulation of adrenal CYP reactions by affecting redox partner recognition and binding affinity. Finally, an effect of the genetic background on the consequences of mutations in adrenal CYPs found in patients was suggested from corresponding in-vitro studies indicating that a different genetic background might be able to significantly affect the activity of a CYP mutant.
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Steroid use during COVID-19 infection and hyperglycemia - What a physician should know.
Sosale, A, Sosale, B, Kesavadev, J, Chawla, M, Reddy, S, Saboo, B, Misra, A
Diabetes & metabolic syndrome. 2021;(4):102167
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BACKGROUND AND AIMS The COVID-19 pandemic continues to challenge us. Despite several strides in management, steroids remain the mainstay for treating moderate to severe disease and with it arises challenges such as hyperglycemia. The review aims to enhance awareness amongst physicians on steroid use and hyperglycemia. METHODS An advisory document describing various strategies for hyperglycemia management was prepared in the public interest by DiabetesIndia. RESULTS The review provides awareness on steroids and hyperglycemia, adverse outcomes of elevated blood glucose levels and, advice at the time of discharge. CONCLUSIONS The article emphasizes enhancing awareness on effective management of hyperglycemia during COVID-19.
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Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent Adrenocortical Carcinoma.
Chortis, V, Bancos, I, Nijman, T, Gilligan, LC, Taylor, AE, Ronchi, CL, O'Reilly, MW, Schreiner, J, Asia, M, Riester, A, et al
The Journal of clinical endocrinology and metabolism. 2020;(3):e307-18
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CONTEXT Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.
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Zim CHIC: A cohort study of immune changes in the female genital tract associated with initiation and use of contraceptives.
Achilles, SL, Meyn, LA, Mhlanga, FG, Matubu, AT, Stoner, KA, Beamer, MA, Chirenje, ZM, Hillier, SL
American journal of reproductive immunology (New York, N.Y. : 1989). 2020;(3):e13287
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PROBLEM Contraceptive hormones are systemically active, potent, and likely to invoke biological responses other than known fertility regulation impacts. We hypothesized that initiation of depot medroxyprogesterone acetate (DMPA) would increase genital HIV-target-cells and soluble immune mediators compared with baseline and initiation of other contraceptive methods. METHOD OF STUDY We collected cervical cytobrushes and cervicovaginal fluid from healthy Zimbabwean women aged 18-34 to assess immune cell populations, cytokines, and innate anti-HIV activity at baseline and after 30, 90, and 180 days use of DMPA (n = 38), norethisterone enanthate (n = 41), medroxyprogesterone acetate/estradiol cypionate (n = 36), levonorgestrel implant (n = 43), etonogestrel implant (n = 47), or copper intrauterine device (Cu-IUD) (n = 45). Cells were quantified by flow cytometry, cytokines were detected by multiplex assays, and innate anti-HIV activity was assessed by in vitro HIV challenge. RESULTS Compared to baseline, the number of cervical HIV target cells (#CD4 cells P < .04 and #CD11c cells P < .04), the concentration of the inflammatory cytokine IL-1β (P < .01), and the innate in vitro anti-HIV activity (P < .001) significantly decreased following DMPA initiation. In Cu-IUD users, genital HIV target cells increased (#CD4 cells P < .001, #CD4CCR5 cells P = .02, #CD4CD69 cells P < .001, #CD8CD69 P = .01, and #CD11c cells P = .003) at day 30 and resolved by day 180. IFN-γ (P < .001), IL-1β (P < .001), IL-6 (P < .001), IL-8 (P < .001), IL-10 (P < .01), and RANTES (P < .001) were also significantly increased at day 30. Minimal alterations were observed following initiation of subdermal implantable contraceptives. CONCLUSIONS This head-to-head study compared six contraceptives and found increased HIV target cells and cervical inflammation temporally associated with Cu-IUD initiation. Use of hormonal contraception, including DMPA, did not increase cervical HIV target cells or inflammation. Clinical Trial Number: NCT02038335.
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Intravitreal steroids for macular edema in diabetes.
Rittiphairoj, T, Mir, TA, Li, T, Virgili, G
The Cochrane database of systematic reviews. 2020;(11):CD005656
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BACKGROUND Diabetic macular edema (DME) is secondary to leakage from diseased retinal capillaries with thickening of central retina, and is an important cause of poor central visual acuity in people with diabetic retinopathy. Intravitreal steroids have been used to reduce retinal thickness and improve vision in people with DME. OBJECTIVES To assess the effectiveness and safety of intravitreal steroid therapy compared with other treatments for DME. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on 15 May, 2019. We also searched reference lists, Science Citation Index, conference proceedings, and relevant trial registers. We conducted a top up search on 21 October, 2020. SELECTION CRITERIA We included randomized controlled trials that evaluated any type of intravitreal steroids as monotherapy against any other intervention (e.g. observation, laser photocoagulation, anti-vascular endothelial growth factor (antiVEGF) for DME. DATA COLLECTION AND ANALYSIS Two review authors independently assessed study eligibility and risk of bias and extracted data. Where appropriate, we performed meta-analyses. MAIN RESULTS We included 10 trials (4348 participants, 4505 eyes). These trials compared intravitreal steroid therapies versus other treatments, including intravitreal antiVEGF therapy, laser photocoagulation, and sham injection. Most trials had an overall unclear or high risk of bias. One trial (701 eyes ) compared intravitreal dexamethasone implant 0.7mg with sham. We found moderate-certainty evidence that dexamethasone leads to slightly more improvement of visual acuity than sham at 12 months (mean difference [MD] -0.08 logMAR, 95% confidence interval [CI] -0.12 to -0.05 logMAR). Regarding improvement of three or more lines of visual acuity, there was moderate-certainty evidence in favor of dexamethasone at 12 months, but the CI covered the null value (risk ratio (RR) 1.39, 95% CI 0.91 to 2.12). Regarding adverse events, dexamethasone increased by about four times the risk of cataract progression and the risk of using intraocular pressure (IOP)-lowering medications compared to sham (RR 3.89, 95% CI 2.75 to 5.50 and RR 4.54, 95% CI 3.19 to 6.46, respectively; moderate-certainty evidence); about 4 in 10 participants treated with dexamethasone needed IOP-lowering medications. Two trials (451 eyes) compared intravitreal dexamethasone implant 0.7mg with intravitreal antiVEGF (bevacizumab and ranibizumab). There was moderate-certainty evidence that visual acuity improved slightly less with dexamethasone compared with antiVEGF at 12 months (MD 0.07 logMAR, 95% CI 0.04 to 0.09 logMAR; 2 trials; 451 participants/eyes; I2 = 0%). The RR of gain of three or more lines of visual acuity was inconsistent between trials, with one trial finding no evidence of a difference between dexamethasone and bevacizumab at 12 months (RR 0.99, 95% CI 0.70 to 1.40; 1 trial; 88 eyes), and the other, larger trial finding the chances of vision gain were half with dexamethasone compared with ranibizumab (RR 0.50, 95% CI 0.32 to 0.79; 1 trial; 432 participants). The certainty of evidence was low. Cataract progression and the need for IOP-lowering medications increased more than 4 times with dexamethasone implant compared to antiVEGF (moderate-certainty evidence). One trial (560 eyes) compared intravitreal fluocinolone implant 0.19mg with sham. There was moderate-certainty evidence that visual acuity improved slightly more with fluocinolone at 12 months (MD -0.04 logMAR, 95% CI -0.06 to -0.01 logMAR). There was moderate-certainty evidence that an improvement in visual acuity of three or more lines was more common with fluocinolone than with sham at 12 months (RR 1.79, 95% CI 1.16 to 2.78). Fluocinolone also increased the risk of cataract progression (RR 1.63, 95% CI 1.35 to 1.97; participants = 335; moderate-certainty evidence), which occurred in about 8 in 10 participants, and the use of IOP-lowering medications (RR 2.72, 95% CI 1.87 to 3.98; participants = 558; moderate-certainty evidence), which were needed in 2 to 3 out of 10 participants. One small trial with 43 participants (69 eyes) compared intravitreal triamcinolone acetonide injection 4 mg with sham. There may be a benefit in visual acuity at 24 months (MD -0.11 logMAR, 95% CI -0.20 to -0.03 logMAR), but the certainty of evidence is low. Differences in adverse effects were poorly reported in this trial. Two trials (615 eyes) compared intravitreal triamcinolone acetonide injection 4mg with laser photocoagulation and reached discordant results. The smaller trial (31 eyes followed up to 9 months) found more visual acuity improvement with triamcinolone (MD -0.18 logMAR, 95% CI -0.29 to -0.07 logMAR), but a larger, multicenter trial (584 eyes, 12-month follow-up) found no evidence of a difference regarding change in visual acuity (MD 0.02 logMAR, 95% CI -0.03 to 0.07 logMAR) or gain of three or more lines of visual acuity (RR 0.85, 95% CI 0.55 to 1.30) (overall low-certainty evidence). Cataract progression was about three times more likely (RR 2.68, 95% CI 2.21 to 3.24; moderate-certainty evidence) and the use of IOP-lowering medications was about four times more likely (RR 3.92, 95% CI 2.59 to 5.96; participants = 627; studies = 2; I2 = 0%; moderate-certainty evidence) with triamcinolone. About 1 in 3 participants needed IOP-lowering medication. One small trial (30 eyes) compared intravitreal triamcinolone acetonide injection 4mg with intravitreal antiVEGF (bevacizumab or ranibizumab). Visual acuity may be worse with triamcinolone at 12 months (MD 0.18 logMAR, 95% CI 0.10 to 0.26 logMAR); the certainty of evidence is low. Adverse effects were poorly reported in this trial. Four trials reported data on pseudophakic participants, for whom cataract is not a concern. These trials found no decrease in visual acuity in the second treatment year due to cataract progression. AUTHORS' CONCLUSIONS Intravitreal steroids may improve vision in people with DME compared to sham or control. Effects were small, about one line of vision or less in most comparisons. More evidence is available for dexamethasone or fluocinolone implants when compared to sham, and the evidence is limited and inconsistent for the comparison of dexamethasone with antiVEGF treatment. Any benefits should be weighed against IOP elevation, the use of IOP-lowering medication and, in phakic patients, the progression of cataract. The need for glaucoma surgery is also increased, but remains rare.
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Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study.
Bancos, I, Taylor, AE, Chortis, V, Sitch, AJ, Jenkinson, C, Davidge-Pitts, CJ, Lang, K, Tsagarakis, S, Macech, M, Riester, A, et al
The lancet. Diabetes & endocrinology. 2020;(9):773-781
Abstract
BACKGROUND Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.