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Journal of Obesity and Diabetes (ISSN: 2638-812X)

Current Status of Low Dose Overnight Dexamethasone Supression Test (LODST)

Tofail Ahmed, Hajera Mahtab, Tania Tofail, AHG Morshed, Fatema B Rahman and Shahidul A Khan

Avaliable from May, 2020

Abstract

Introduction: Low Dose Overnight Dexamethasone Supression Test (LODST) is a diagnostic tool for spontaneous Cushing’s Syndrome (CS). A LODST negative excludes CS. But there are 2 exceptions - testing during silent period of Cyclic Cushing’s Disease (CD) or a false negativity by one mg dexamethasone in mild CD. Method: We analyzed age and sex data of 154 LOSDT to see their risk association for CS.

Result: The detection rate of CS by LOSDT is 26% and with Cortisol (211.27 to 373.69 nmol/L as 95% CI). Among the cases, 29.2% are pediatric and 70.8% are female. CS group do not differ from rest in sex and age group distributions (sig.> 136) but CS is older group with a mean difference of 2.46 - 13.31 years (sig 005). Logistic equation documented CS is a different population (sig 000) and which is influence by their age (sig 021) but not by sex or age group (sig > 743). Therefore, age is an independent risk factor for CS. Conclusion: We opine to use LODST as the first tool for CS. And LODST negative cases to be evaluated by newer imaging and biochemical tests. Only in imaging positive are to be managed as per guideline(s) for incidentaloma. Both negative cases are to be enrolled in follow up if age > 30 years or symptoms score suggest CD and rest are to be excluded. Cumulative diagnostic and outcome data will then may be used to formulate cost-effective management policy for CS. 

Introduction

 

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].

 

Method

 

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.

 

Result

 

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.

Descriptive data

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).




 

Cortisol of Not Suppressed population expressed as mean + SE of mean; 95%CI and (range) innmol/L.

 

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).

 

Comparison data

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.

 

Discussion

 

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.

 
Conclusion

 

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.

References


  1. Steffensen C, Bak AM, Rubeck KZ and Jørgensen JOL. Epidemiology of Cushing’s syndrome (2010) Neuroendocrinology 1:1-5. https://doi.org/10.1159/000314297
  2. Lindholm J, Juul S, Jørgensen JO, Astrup J, Bjerre P, et al. Incidence and late prognosis of cushing’s syndrome: a population-based study (2001) J Clin Endocrinol Metab 86: 117-23. https://doi.org/10.1210/jcem.86.1.7093
  3. http://www.ncbi.nlm.nih.gov/books/NBK470218/
  4. Stratakis CA. Cushing syndrome in pediatrics (2012) Endocrinol Metab Clin North Am 41: 793-803.
  5. https://doi.org/10.1016/j.ecl.2018.02.008
  6. Beauregard C, Dickstein G and Lacroix A. Classic and recent etiologies of Cushing’s syndrome: diagnosis and therapy (2002) Treat Endocrinol 1: 79-94.
  7. https://doi.org/10.2165/00024677-200201020-00002
  8. Nishioka H and Yamada S. Cushing’s Disease (2019) J Clin Med 12: 1-11 https://doi.org/10.3390/jcm8111951
  9. Tsigos C and Chrousos GP. Differential diagnosis and management of Cushing’s syndrome (1996) Annu Rev Med 47: 443-61. https://doi.org/10.1146/annurev.med.47.1.443
  10. Invitti C, Pecori Giraldi F, de Martin M and Cavagnini F. Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis (1999) J Clin Endocrinol Metab 84: 440-448. https://doi.org/10.1210/jcem.84.2.5465
  11. Penezić Z, Zarković M, Vujović S and Drezgić M. Diagnosis and differential diagnosis of Cushing’s syndrome (2006) Srp Arh Celok Lek 134: 558-566.
  12. Nieman LK and Ilias I. Evaluation and treatment of Cushing’s syndrome (2005) Am J Med 118:1340-1346. https://doi.org/10.1016/j.amjmed.2005.01.059
  13. Nierenberg AA and Feinstein AR. How to evaluate a diagnostic marker test. Lessons from the rise and fall of dexamethasone suppression test (1988) JAMA 259: 1699-1702.
  14. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors (2016) Eur J Endocrinol 175: 1-34. https://doi.org/10.1530/EJE-16-0467
  15. Wolthers OD, Mersmann S and Dissanayake S. A Pilot Study of the Normative Range of Overnight Urinary Free Cortisol Corrected for Creatinine in Children (2018) Clin Drug Investig. 38: 313-318. https://doi.org/10.1007/s40261-017-0609-x
  16. Valassi E, Franz H, Brue T, Feelders RA, Netea-Maier R, et al. Diagnostic tests for Cushing’s syndrome differ from published guidelines: data from ERCUSYN (2017) Eur J Endocrinol 176: 613-624. https://doi.org/10.1530/EJE-16-0967
  17. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, et al. The prevalence of pituitary adenomas: a systematic review (2004) Cancer 101: 613-619. https://doi.org/10.1002/cncr.20412
  18. Hirsch D, Shimon I, Manisterski Y, Aviran-Barak N, Amitai O, et al. Cushing’s syndrome: comparison between Cushing’s disease and adrenal Cushing’s (2008) Endocrine 62: 712-720. https://doi.org/10.1007/s12020-018-1709-y
  19. El-Farhan N, Rees DA and Evans C. Measuring cortisol in serum, urine and saliva -are our assays good enough? (2017) Ann Clin Biochem 54: 308-322. https://doi.org/10.1177/0004563216687335
  20. Pecori GF. Recent challenges in the diagnosis of Cushing’s syndrome (2009) Horm Res 71: 123-127. https://doi.org/10.1159/000178053
  21. Raff H and Findling JW. A physiologic approach to diagnosis of the Cushing syndrome (2003) Ann Intern Med 138: 980–991. https://doi.org/10.7326/0003-4819-138-12-200306170-00010
  22. Law M, Wang R, Liu C-SJ, Shiroishi MS, Carmichael JD, et al. Value of pituitary gland MRI at 7 T in Cushing’s disease and relationship to inferior petrosal sinus sampling: case report (2018) J Neurosurg 1: 1-5. https://doi.org/10.3171/2017.9.JNS171969
  23. Wiggam MI, Heaney AP, McIlrath EM, McCance DR, Sheridan B, et al. Bilateral inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome: a comparison with other diagnostic tests (2000) J Clin Endocrinol Metab 85: 1525-1532. https://doi.org/10.1210/jcem.85.4.6574
  24. Quiñones-Hinojosa A, Schmidek HH, Sweet WH. Schmidek and Sweet’s Operative neurosurgical techniques: indications, methods, and results. Philadelphia, Pa.; London: Saunders; 2012.
  25. Braun LT, Riester A, Oßwald-Kopp A, Fazel J, Rubinstein G, et al. Toward a Diagnostic Score in Cushing’s Syndrome (2019) Front Endocrinol 10: 766.
  26. https://doi.org/10.3389/fendo.2019.00766
  27. Nelson DH, Meakin JW and Thorn GW. ACTH-producing pituitary tumors following adrenalectomy for Cushing’s syndrome (1960) Ann Intern Med 52: 560-569. https://doi.org/10.7326/0003-4819-52-3-560
  28. Friedman TC, Ghods DE, Shahinian HK, Zachery L, Shayesteh N, et al. High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing’s Syndrome Suggests that the Paradigm for Diagnosis and Exclusion of Cushing’s Syndrome Requires Multiple Testing (2010) Horm Metab Re 42: 874-881. https://doi.org/10.1055/s-0030-1263128
  29. Friedman TC. An update on the overnight dexamethasone suppression test for the diagnosis of Cushing’s syndrome: limitations in patients with mild and/or episodic hypercortisolism (2016) Exp Clin Endocrinol Diabetes 114: 356-360. https://doi.org/10.1055/s-2006-924281
  30. https://linkinghub.elsevier.com/retrieve/pii/B9780128012383994
  31. Odeniyi IA, Ifedayo AO, Fasanmade OA and Olufemi AF. Urinary free cortisol in the diagnosis of Cushing’s syndrome: how useful? (2013) Niger J Clin Pract 16: 269-272. https://doi.org/10.4103/1119-3077.113445
  32. Newell-Price J, Trainer P, Perry L, Wass J, et al. Grossman A, Besser M. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing’s syndrome (1995) Clin Endocrinol (Oxf) 43: 545-550. https://doi.org/10.1111/j.1365-2265.1995.tb02918.x
  33. Direk N, Dekker MJHJ, Luik AI, Kirschbaum C, de Rijke YB, et al. The very low-dose dexamethasone suppression test in the general population: a cross-sectional study (2016) PloS One 11: e0164348. https://doi.org/10.1371/journal.pone.0164348
  34. Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E and Loli P. Bilateral inferior petrosal sinus sampling (2016) Endocr Connect 5: 12-25. https://doi.org/10.1530/EC-16-0029
  35. Chaudhary V and Bano S. Imaging of the pituitary: Recent advances (2011) Indian J Endocrinol Metab 15: S216-223. https://doi.org/10.4103/2230-8210.84871
  36. Wang F, Liu J, Zhang R, Bai Y, Li C, et al. CT and MRI of adrenal gland pathologies (2018) Quant Imaging Med Surg 8: 853-875. https://doi.org/10.21037/qims.2018.09.13
  37. Lee HB, Kim ST, Kim H-J, Kim KH, Jeon P, et al. Usefulness of the dynamic gadolinium-enhanced magnetic resonance imaging with simultaneous acquisition of coronal and sagittal planes for detection of pituitary micro adenomas (2012) Eur Radiol 22: 514-518. https://doi.org/10.1007/s00330-011-2291-3
  38. Gogas JG, Skalkeas GD, Sechas MN, Skandalakis PN. Scanning of the adrenals in Cushing’s syndrome (1987) Am Surg 53: 472-475.
  39. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors (2016) Eur J Endocrinol 175: 1–34. https://doi.org/10.1530/EJE-16-0467

*Corresponding author:


Tofail Ahmed, Department of Endocrinology, BIRDEM, Diabetic Association of Bangladesh, Bangladesh, Email: tofail.ahmed@yahoo.com

Citation:


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.


Keywords

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.