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Research Article | DOI: https://doi.org/10.31579/2640-1045/053
CCT (London) & MRCP (UK) in Diabetes & Endocrinology, Colchester Hospital university Foundation Trust, Turner Rd, Mile End, Colchester CO4 5JL, United Kingdom
*Corresponding Author: Ahmed Imran Siddiqi (Siddiqi AI), CCT (London) & MRCP (UK) in Diabetes & Endocrinology, CCT (London) & MRCP (UK) in Internal Medicine, FRCP (Glasgow). Consultant Diabetes & Endocrinology and Internal Medicine, Colchester Hospital university Foundation Tr
Citation: Ahmed I. Siddiqi (Siddiqi AI)., (2020) Preferred screening test for Cushing’s syndrome screening J. Endocrinology and Disorders 4(1); DOI:10.31579/2640-1045/053
Copyright: © 2020 Ahmed Imran Siddiqi (Siddiqi AI), This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 10 August 2020 | Accepted: 20 August 2020 | Published: 31 August 2020
Keywords: cushing’s syndrome, cushing’s disease, pseudo-cushing’s, cushing’s screening, overnight dexamethasone suppression test, 24 hours urinary free cortisol, patient preference
Background: In our practice 24 hours urine collection for free cortisol (24Hr UFC) and overnight dexamethasone suppression test (ONDST) are initial investigations to screen patients for hyper-cortisolism. I audited our practice to find our clinicians’ and patients’ choice of first screening investigation for hyper-cortisolism.
Method & material: Electronic and paper medical records of patients who underwent 24Hr UFC and/or ONDST at our hospital over previous consecutive twenty four months were examined. 62 such patients were identified but 12 patients were excluded from analysis. We tried to contact 30 patients over consecutive 48 hours over the phone who underwent both 24Hr UFC and ONDST. We managed to contact 18 patients and asked them two study questions.
Data & results: 33 (66%) patients were female and 17 (33%) were male. 20 (40%) had 24Hr UFC alone and 30 (60%) patients had both. In total 80 such investigations completed 30 being ONDST and 50 24hr UFC. 53 (66%) of the investigations were requested by Endocrinologists, 21 (26%) by Hospital General Physicians and 6 (8%) by General practitioners (GP). For UFC 10 (20%) were true positive, 31 (62%) were false positive, 6 (12%) were true negative and 0% false negative. 3 (6%) 24Hr UFC samples were not collected properly and were not processed for results. Out of the total false positives (31 patients), 6 (19.3%) cases were of alcohol excess, 4 (13%) of dépression, 3 (9.7%) of inhaled steroids and 1 (3.2%) of sleep apnea. For the ONDST 7 (23.3%) true positive, 4 (13.3%) false positive 19 (63.4%) true negative and 0% false negative. All 18 patients contacted over the phone answered both questions. 16 preferred ONDST over 24Hr UFC, 1 patient had no preference and 1 patient preferred 24Hr UFC over ONDST.
Conclusion: Patients overwhelmingly preferred ONDST as first screening test in contrast to physician’s choice of 24Hr UFC.
Cortisol is produced and secreted by adrenal glands under stimulatory effect of adrenocorticotropin hormone (ACTH) of pituitary gland. ACTH in turn is regulated by Corticotropin releasing hormone (CRH) of hypothalamus. The stimulator effect of ACTH is balanced by negative feedback of cortisol circulating in peripheral blood (1). This state of dynamic equilibrium is often called adreno-cortical axis. Cortisol remains the main hormone with widespread systemic effects in this axis and remaining hormones of this axis have either minimal or no known systemic effects.
This dynamic equilibrium is pathologically disturbed either by uncontrolled production of ACTH which then leads to excessive cortisol production (Cushing’s disease) or ACTH independent uncontrolled production of cortisol due adrenal gland pathology (Cushing’s syndrome). At times, CRH/ACTH can be produced from sources other than pituitary gland (ectopic ACTH/CRH production) and can still stimulate adrenal glands to produce excessive uncontrolled amounts of cortisol resulting in hyper-cortisolism (2). For the sake of this manuscript I’ll use term Cushing’s syndrome to cover all of these (Cushing’s disease, ectopic CRH/ACTH production and Cushing’s syndrome).
During these pathological states usual stimulatory and inhibitory effects are no longer functional and cortisol production is increased by several folds exposing tissues to these excessively high levels of cortisol.
Clinical presentation in these patients can be variable. Pseudo-Cushing’s is the term used for patient with excessive cortisol production and clinical features of Cushing’s syndrome with potentially reversible precipitating factors. Excessive alcohol consumption, depression and sleep apnea are common precipitating factors. The excessive cortisol production is usually continuous but can be cyclical termed as cyclical Cushing’s. These episodes of excessive cortisol production are variable in duration and severity. As expected the diagnosis of this type of Cushing’s disease is even more challenging. Excessive cortisol production in these patients can lead to metabolic changes including hyperglycemia and puts patients at risk of complications of hyperglycemia like diabetic ketoacidosis and hyperosmolar hyperglycemic state (3). Patients with Cushing’s disease of pituitary origin can present with effects of pituitary adenoma affecting other hormones of pituitary gland or its mass effect on surrounding structures especially on optic chiasm affecting visual fields (4) (5).
Biochemical investigations sit at the heart of diagnostic work up for Cushing’s syndrome. Imaging studies are required to localize the abnormality to help plan the management strategy. In our center twenty-four hours urine free cortisol (24Hr UFC) and overnight dexamethasone suppression test (ONDST) were the two most commonly employed tests for screening patients for hyper-cortisolism. Most patients would have only one screening test and only if it is abnormal or the results are not decisive further investigations would be carried out. Localization investigations are generally carried out if these screening tests confirm biochemical evidence of hyper-cortisolism. I audited our practice of screening such patients and also collected data on patients’ preference of a screening test. We wanted to see if clinicians’ choice matches with patients’ choice of investigation.
I retrospectively collected data from paper and electronic medical records of adult patients (over 18 years old) who underwent screening for hyper-cortisolism over previous consecutive twenty-four months at our hospital. Patients were identified by screening laboratory investigation data of all adult patients of our hospital who had any of the screening tests for hyper-cortisolism - 24Hr UFC, ONDST, MCL (midnight cortisol level) and/or SCL (Salivary cortisol level). Requesting physicians’ details were recorded from investigation request form and paper medical records. All patients above 18 years of age who had investigations sent to our Trust's laboratory (both from hospital and community) for hyper-cortisolism screening were included. Once the patients were identified their paper medical records were used to collect remaining data. Some patients underwent 24Hr UFC more than once. I included their first 24Hr UFC requests and result for this audit. Since I was auditing our Trust practice I did not include those patients who had their screening investigations completed elsewhere and then presented to our Trust for further management of their condition.
I looked at clinical notes of 62 patients who underwent the Cushing’s screening tests. I primarily looked at the laboratory investigations performed for screening these patients for hyper-cortisolism. 12 patients were excluded from this study as they underwent these investigations not for hyper-cortisolism screening.
I tried to contact those 30 patients over the phone who had both 24Hr UFC and ONDST. I managed to contact 18 patients. I completed collecting this data over phone over two days. All these patients agreed to participate in the study. 4 patients required interpreter and one of their family members helped with this. The questions were clearly read out to them and I confirmed that they understood those questions well. I did not ask the reason for them to prefer one of the tests over the other but all the patients voluntarily explained the reason while answering these two questions. Their answers were recorded on electronic pro forma straight away. I could not manage to contact the remaining 12 patients who had both 24Hr UFC and ONDST within these two days. We asked them two questions: 1) which of the two tests they found was easier for them? 2) Which of the two they would like to have done if they were to take one of these tests again?
Data Analysis and results
50 patients fulfilled the criteria for this audit. 33 (66%) patients were female and 17 (33%) were male. 20 (40%) had 24Hr UFC alone and 30 (60%) patients had both. None of the patients had any other screening tests. There were total 80 such investigations completed 30 being ONDST and 50 24hr UFC. 56 (70%) of the investigations were requested by Endocrinologists (consultants, specialist registrars, specialist nurses), 21 (26%) by Hospital General Physicians (clinicians of all grades other than Endocrinologists) and 3 (4%) by General practitioners (GP). The 1 ONDST completed by GP was advised over the phone by specialist registrar. Most of the investigations requested by clinicians other than Endocrinologists were requested in acute medical unit or Emergency department when these patients presented with other medical conditions and Cushing’s screening investigations were requested. Almost all the investigations requested by Endocrinologists were requested in clinic setting when patients were attending clinic for another Endocrinology disorder or GP had referred these patients for screening. (Table 1)
For UFC 10 (20%) were true positive, 31 (62%) were false positive, 6 (12%) were true negative and 0
A screening test is expected to pick up all the cases with a particular condition. A good screening test should have a high sensitivity. The test should be simple and easy to be performed, ideally on outpatient basis and results should be easy to interpret (6). There is no single test which fulfils all these criteria (7) however, high sensitivity is probably the most important criteria so that none of the patients with that particular condition are missed by a screening test. Both these investigations fulfil these criteria for a good screening test.
My data suggests that there was clinical bias among clinicians in choosing the first screening test for patients suspected to have hyper-cortisolism. It was encouraging to see that a significant number of screening tests were requested by clinicians who were not Endocrinologists. With an increase in number of patients with obesity and metabolic syndrome presenting to medical services it is important that such patients are screened by clinicians other than Endocrinologists so that such patients could be diagnosed as soon as possible and appropriately treated. Having said that, it is important to see that 24 Hr UFC was their investigation of choice as first line screening investigation for such patients. Only Endocrinologists selected any of the other screening tests although, they also requested 24 Hr UFC in a significant number of patients. Since all the screening tests have very high sensitivity and there is not much difference among these tests there is nothing wrong in choosing anyone of these but the patient choice survey shows an overwhelming preference for ONDST compared to 24Hr UFC. ~ 90% patients chose ONDST over 24Hr UFC. The only patient who chose 24Hr UFC was needle phobic and wanted to avoid a needle prick.
In conclusion the ONDST can be used reliably as first line screening test. It is easier to do for both patient and laboratory. Furthermore, it is more cost effective. However if Cushing’s syndrome is highly suspected clinically and ONDST is not suitable for that patient we may proceed to 24 Hr UFC test. I am not omitting the 24Hr UFC test but I am making it as second line. Patients found ONDST much easier to perform and chose that as their preferred first line investigation for screening.
I recommend that patients should have the option of selecting the screening test of their choice. Clinicians should have a discussion with patients about the available screening tests and arrange the one which patient prefers to undertake. Our survey suggests that majority of patients preferred ONDST over all other available screening tests. There should be continuous education and discussion on the subject with colleagues of other specialties and general practitioners who are actively involved in investigating patients to screen for hyper-cortisolism.
Conflict of interest: I declare I have no conflict of interest to declare in publication of this study.
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