Spontaneous Cushing’s Syndrome (CS) is relatively rare disorder. The estimated incidence of CS is 0.2-5 per million people per year and 66-70% of patients is due to Cushing’s Disease (CD). LODST is a tool to documentation of spontaneous CS. It is indicated for clinically suspected CS and to evaluate functional status of adrenal incidentaloma. Suppressed cortisol value excludes spontaneous CS. But there are at least two exceptions. One, when test is done during the silent period in episodic variant of CD and other one is when 1 mg dexamethasone is high dose to produce false negative in early or mild cases. There is a continued search of more sensitive biochemical and imaging tests with a trend of involving multidiscipline for more efficiently CS management. In this context, we analyzed our laboratory data of LODST to reassess its’ current role [1-22].
To assess the utility of LODST we analyzed the available data (cortisol, age and sex) of all 154 LODST done from July 2017 to
December 2019 in Endocrinology Laboratory of Bangladesh Institute for Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM). Twenty six percent of cases (n=40) were positive for CS. We analyzed the data between 2 groups in search of utility of this tool.
Test procedure and interpolation of LODST: Dexamethasone 1 mg is administered orally between 11 PM and midnight. Blood is drawn for serum cortisol levels in the next morning between 8 and 9 AM. A serum cortisol level < 50 nmol/L is considered as suppressed meaning exclusion of spontaneous hypercortisolemia.
Assay method: We used two machines for Cortisol assay 1. ARCHITECT Cortisol assay which is a delayed one-step immunoassay using CMIA technology (Chemiflex) by Abbott i2000 machine. Its detection limit of serum sample is (41.385-14484.75 nmol/L) and 2. AVIDA Centura XP assay which is a competitive immunoassay using CMIA technology by SIEMENS immunosystem. Its detection limit of serum sample is (0.20 -2069 nmol/L).
Data: Variable included are cortisol, age, sex and Age group. Population is divided into suppressed and no suppressed and groups comparison and logistic analysis to find risk factor(s) for non- suppression. Comparison between groups for continuous variable (cortisol) was done by independent sample t-test and for logical variable (sex and age group) by chi square in cross table. We used IBM SPSS statistics 20 for this purpose.
Of 154 cases, 45(29.2%) were in pediatric age group (age <19 years) and rest 109 adult; and 109 (70.8%) were female & rest 45 male. By LODST complete suppression (Cortisol < 50 nmol/L) occurred in 114 (74%) cases. So detection rate of ODST is 26% in this study population.
Cortisol of Supressed population expressed as mean + SE of mean; 95% CI & (range) innmol/L. For Total (n=114): 23.34 + 0.74; (21.87-24.80) and (6.47-48.19).
· For male (n=33): 23.67 + 1.17; (21.28 -26.06) and (12.58 -39.83).
· And for female (n=81): 23.19 + 0.93; (21.35-25.04) and (6.47- 48.19).
· For Adult (n=77): 24.27 + 0.89; (22.51-26.04) and (12.20-48.19).
· And Children (n=37): 21.38 + 01.29; (18.76 – 23.99) and (6.47- 39.83) (Tables 1 and 2).
of Not Suppressed population expressed as mean + SE of mean; 95%CI and (range)
For Total (n=40): 292.48 + 40.15; (211.27-373.69) and (51.06- 1049.88).
· For male (n=12): 286.59 + 88.03; (92.83-480.35) and (51.27- 1025.92).
· And for female (n =28): 295.00 + 44.41; (203.88 -286.13) and (51.06-1049.88).
· For Adult (n=32): 271.56 + 41.76; (186.39- 356.73) and (51.06 -1025.92).
· And Children (n=8): 376.17 + 112.96; (109.05 -643.28) and (53.70 -1049.88) (Tables 1 and 2).
In population of Suppressed cortisol (n=114) Mean Difference (MD) of cortisol between male (n=33) and female (n=81): as mean + SE of mean and (95%CI) .48+ 1.62(-3.72 – 2.77); sig. 772. And between adult (n=77) and children (n=37) 2.89+ 1.56(-.20 – 5.99) sig. 067 (Table 2). In population of Non Suppressed cortisol (n= 40) MD of cortisol between male (n12) and female (n28) as mean + SE of mean and (95%CI) 8.42 + 88.75 (-188.08 – 171.24); sig. 925 and between adult (n32) and children (n8) 104.61 + 100.26(-307.57- 89.35) sig. 303. See table 2.Therefore, there is no difference in cortisol level (sig. < .067) by age group and sex in either of the population. See table 2.MD of age between population of Supressed cortisol (n114) and Not Supressed cortisol (n40) as mean + SE of mean and (95%CI) 7.88 + 2.74 (2.46 -13.31), sig.005 (Table 1).
Logistic analysis data
Binary logistic regression equation with age, sex & age group distribution as covariate document that the suppressed and non- suppressed populations are different (sig.000) and such deference is influence by their age (sig..021) but not by sex (sig.821) or age group (sig.743) (Figures 1 and 2).
Figure 1: Cortisol levels during LODST.
Figure 2: Comparison of sex and age group data during LODST. Therefore, advancing age is an independent risk factor for CS.
Like other aspects of endocrinology, the spectrum of CS is constantly under evolution. And it is in fact due to multidisciplinary involvement in its management. We observed there are already some changes of frequencies of its different symptom. This shifted the Cushing’s appearance of CS to a minimum or early feature of hypercortisolema. This is the result of increased early delectation of adrenal incidentaloma and they are mostly asymptomatic cases if identified as CS. Moreover, due to involvement of neurosurgery and imaging specialist more and more CD cases are being detected and treated. Our study documented the detection rate of Cushing Syndrome by LODST is 26% in a mixed population of symptomatic and or asymptomatic (adrenal incidentaloma) for CS. Considering the availability, detection rate and cost we opine the LODST should remain as the initial screening tool of investigation CS has it has been supported by other studied [23-27].
The newer, more sophisticated and sensitive tools like free cortisol in urine or saliva, lower dose suppression test(30); CRF stimulated inferior petrosal sinus sampling etc. should be in practice in specialized units in negative ODST cases. An imaging at pituitary is need for all LODST negative cases. CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas. Scintigraphy of the adrenal gland with iodocholesterol scan is now may be needed (35). Petrosal sinus sampling and ACTH assay is necessary for cases of Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging.
Conventional MRI (CMRI) are now being replaced by Dynamic Contrast-Enhanced MRI (DMRI) and Spoiled Gradient–Recalled Acquisition (SPGR) which have the potentiality to increase value of MRI for CD due to micro adenoma will increase in the days to come. When imaging is positive but biochemical test is/are negative than we can follow a guideline for incidentoloma. Recent trend of shifting symptomatic (Cushingoid) to asymptomatic (minimum symptoms presentation of CS is supported by the raised prevalence of CD. An involvement of neuroradiology and neurosurgery with endocrinology has definite contribution in this challenging area of endocrinology [28-36].
In the present study we have documented age as an independent risk factor for CS so we proposed when standard imaging and biochemical tools are negative but age is > 30 years they need to be enrolled in follow-up protocols along with cases clinically suspected to be in silent phase of episodic variant of CD. Newer biochemical and imaging tests for CS/CD should be done in specialized center. Analysis of diagnostic and outcome data together has potential to develop simpler and cost-effective management policy for CS.
We opine to use LODST as the screening tool for Cushing Syndrome because of its good detection rate and availability for long time. Then all LODST negative cases should be subjected to dual diagnostic tools - imaging (the pituitary and adrenal) plus at least one newer biochemical test (UFC/ Salivary/ other). Negative cases for both the tools need to be enrolled in follow up protocols if age > 30 years or if symptoms score suggest episodic variant of CD and rest can be excluded from follow up. Positive in imaging tool but negative in biochemical tool(s) should be managed according to guideline (s) for incidentaloma (Table 3).
Note: Biochemical tools are urinary or salivary cortisol or others such as very low dose dexamethasone suppression, Inferior petrosal sinus sampling combining CRF stimulation etc. Imaging tools MRI of Pituitary (preferably newer version) or CT of adrenals etc.
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Tofail Ahmed, Department of Endocrinology, BIRDEM, Diabetic Association of Bangladesh, Bangladesh, Email: firstname.lastname@example.org
Ahmed T, Mahtab H, Tofail T, Morshed AHG,
Rahman BR and Khan AS. Current status of low dose overnight dexamethasone
supression test (LODST) (2020) J Obesity and Diabetes 4: 5-8.
Low dose Overnight Dexamethasone Suppression Test,
Cushing’s syndrome, Cushing’s disease, Cortisol and detection rate of CS.
Abbreviations: LODST-Low dose Overnight Dexamethasone Suppression Test, CS-Cushing’s syndrome, CD-Cushing’s disease, DMRI-Dynamic Contrast-Enhanced MRI, BIRDEM- Bangladesh Institute for Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders.