How to Read the Results of a 1mg Dexamethasone Suppression Test

Introduction

The dexamethasone suppression test (DST) is used in the evaluation of endogenous Cushing syndrome (CS), by assessing for the lack of suppression of the hypothalamic-pituitary-adrenal (HPA) axis by exogenous corticosteroids. Dexamethasone is a potent constructed corticosteroid (dexamethasone 0.75 mg = prednisone 5 mg = methylprednisolone iv mg = hydrocortisone 20 mg) with high affinity for the glucocorticoid receptors and long duration of activity (biological half-life 36 to 54 hours; plasma one-half-life 4 to 5 hours). It possesses minimal mineralocorticoid activeness and unlike other glucocorticoids, it does non interfere with cortisol measurement in the plasma, urine or saliva. It is these characteristics which make dexamethasone, the steroid of selection for the evaluation of the HPA axis.

Pathophysiology

The HPA axis, a master neuroendocrine system, helps maintain the body'shomeostatic function and stress response.[1] The neurons in the paraventricular nucleus of hypothalamus synthesize corticotropin-releasing hormone (CRH) which via the hypophysial portal claret is transported to the anterior pituitary, wherein it stimulates the production of adrenocorticotrophic hormone (ACTH). ACTH is then transported by the bloodstream to the adrenal glands and stimulates the synthesis and secretion of cortisol past zona fasciculata of the adrenal cortex. Serum cortisol, also chosen the stress hormone, in plough, exerts negative feedback on both the hypothalamus and the anterior pituitary; thus, inhibiting the secretion of CRH and ACTH, respectively. This positive/negative feedback mechanism helps regulate the torso'due south serum cortisol levels and stress response.When HPA axis is intact, exogenously administered corticosteroids exert feedback inhibition on the production of serum CRH and ACTH past binding to the hypothalamic and pituitary glucocorticoid receptors, respectively, that subsequently causes suppression of the synthesis and secretion of serum cortisol. However, in pathological hypercortisolism, the HPA axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids.

Diagnostic Tests

Types of dexamethasone suppression test (DST):

1. Low-dose DST

• Overnight, 1 mg test

• 2-twenty-four hours, 2 mg exam

two. High-dose DST

• Overnight, 8 mg test

• Two-mean solar day, 8 mg test

3. Intravenous DST

4. Dexamethasone-CRH test

Testing Procedures

1. Low-dose DST (LDDST)

LDDST helps in the initial diagnosis of Cushing syndrome, as a screening or a confirmatory test.[2] Information technology can be performed either equally an overnight or a two-twenty-four hour period test.

• Overnight, 1 mg test: Due to ease and convenience, the overnight examination is the about normally used screening test. Dexamethasone 1 mg is administered orally between 11 PM and midnight. Serum cortisol levels are drawn the next morning between 8 and 9 AM.[3][4]

• 2-solar day, 2 mg exam: Dexamethasone 0.5 mg is administered orally every 6 hours (nine AM, 3 PM, 9 PM, 3 AM) for 2 days (full dose four mg). Serum cortisol level is drawn 6 hours (9 AM) later the last administered dose.[five]

2. High-dose DST (HDDST)

Once the diagnosis of Cushing syndrome is confirmed, the adjacent stride is to categorize ACTH-independent vs. ACTH-dependent Cushing syndrome, by checking the plasma ACTH levels.  In ACTH-independent Cushing syndrome, the plasma ACTH is low or undetectable, indicating an adrenal etiology (causing pituitary suppression of ACTH). While, in ACTH-dependent Cushing syndrome, the plasma ACTH is inappropriately normal or high, suggesting either pituitary or an ectopic source.

In ACTH-dependent Cushing syndrome, HDDST tin aid distinguish pituitary (i.e., Cushing disease) from an ectopic source of ACTH overproduction. The principle behind the loftier-dose test is that overproduction of ACTH in Cushing disease (but non ectopic tumors) can undergo partial or full suppression past loftier doses of dexamethasone (approximately 8 mg). Like LDDST, information technology utilizes oral dexamethasone, either equally an overnight or 2-twenty-four hour period test.

• Overnight, eight mg test: Baseline morning serum cortisol is measured, and oral dexamethasone 8 mg is administered between xi PM and midnight. Repeat serum cortisol is drawn the next forenoon (between eight and nine AM).[6]

• Ii-day, viii mg test: On 24-hour interval one, a baseline morning time serum cortisol or 24-hour urinary gratis cortisol (UFC) from the day before is obtained. Then oral dexamethasone 2 mg every 6 hours ((9 AM, three PM, 9 PM, 3 AM) is given for 2 days (total dose xvi mg betwixt Day 1 and Day2) with simultaneous collection of a urine sample for UFC. Serum cortisol levels are checked six hours after the last dose (9 AM).[5]

3. Intravenous DST

This test helps in the initial diagnosis of Cushing syndrome while overcoming concerns of drug compliance and malabsorption. Additionally, it is as well useful to differentiate Cushing disease (CD) from ACTH-dependent ectopic tumor and ACTH-independent adrenal etiology. After a baseline morning time serum cortisol (viii to nine AM) is obtained, an infusion of intravenous dexamethasone at one mg/hour for 4 to vii hours is administered. Repeat serum cortisol levels are measured at the stop of the infusion (Day-i) and 23 to 24 hours later (Day-two).[vii][8][9][ten]

4. Dexamethasone – CRH Test

Based on the rationale that glucocorticoid suppression of the HPA centrality can be overcome by CRH stimulation in Cushing illness and not in pseudo-Cushing syndrome (physiologic hypercortisolism), this examination helps distinguish the two entities. Dexamethasone 0.5 mg every half-dozen hours (12 PM, six PM, 12 AM, 6 AM) is given orally for 48 hours. Two hours after the terminal dose of dexamethasone, an intravenous CRH dose of 1 mcg/kg is administered (8 AM) and serum cortisol is fatigued 15 minutes later [xi].

Interfering Factors

i. Iatrogenic hypercortisolism tin can cause exogenous Cushing syndrome. Biochemical testing shows elevated serum cortisol levels (due to cross-reactivity of most exogenous steroids with cortisol immunoassays) and depressed ACTH level as it is ordinarily seen in ACTH-independent Cushing syndrome. Information technology is crucial that the individuals receiving exogenous corticosteroids (inhaled/topical/parenteral/intraarticular) are identified, earlier pursuing a piece of work-up for pathological hypercortisolemia.

2. Pseudo-Cushing syndrome, also called physiological or non-neoplastic hypercortisolism is seen in conditions like alcoholism, obesity, insulin resistance and neuropsychiatric disorders due to HPA axis stimulation.[12] A thorough history and physical examination tin can play a pivotal role in recognizing many subjects with pseudo-Cushing syndrome. In equivocal cases, midnight serum cortisol, late-night salivary cortisol, dexamethasone-CRH, or desmopressin test tin assist in the distinction.[13]

3. In any acute illness (emotional or physical) a stress response can exist presented via the HPA centrality, resulting in elevated ACTH and cortisol levels, that'southward why the evaluation for Cushing syndrome should take place after the resolution of astute stress.

iv. Corticosteroid-binding globulin (CBG): Nigh 90% of the circulating cortisol is protein-bound and currently available assays measure the full cortisol (free and protein-bound); therefore, conditions resulting in elevated levels of CBG (pregnancy, estrogen-pill, etc.), or reduced levels of CBG (nephrotic syndrome, malnutrition, etc.) may pb to spurious results on DSTs.[xiv] In these scenarios, late-night salivary cortisol, or UFC are the preferred tests. Patients receiving estrogen therapy should finish treatment at to the lowest degree for six-weeks before DST.

5. Dexamethasone bioavailability: Malabsorption, altered metabolism, or non-compliance with taking the medication can result in variable bioavailability of dexamethasone misreckoning the results.[fifteen][16] Dexamethasone gets metabolized in the liver via CYP3A4. Thus, CYP3A4 inducers (phenytoin, carbamazepine, etc.), or CYP3A4 inhibitors (itraconazole, fluoxetine, ritonavir) may result in decreased or increased clearance of the dexamethasone, risking false positive or negative results, respectively. This mistake can be overcome by measuring serum dexamethasone levels at the same time as serum cortisol levels. Virtually laboratories that conduct this exam, provide reference ranges based on dexamethasone dose and interval of blood drawn.

6. Improper urine collection: For UFC, an inadequately collected urine sample leads to diagnostic errors. For this reason, the urine sample should include testing for 24-hour urinary creatinine excretion, in addition to cortisol. In adults less than 50 years old, 24-hour urinary creatinine excretion is approximately 15-20 mg/kg/twenty-four hour period in women and 20 to 25 mg/kg/twenty-four hours in men. In people older than 50 years of age, at that place is a progressive reject in muscle mass, hence, creatinine excretion tin exist as low as ten mg/kg/twenty-four hours.

7. Others: Circadian Cushing syndrome and glucocorticoid receptor polymorphisms are a few rare causes of false test results.[17][18]

Results, Reporting, Critical Findings

1. LDDST

In either of the LDDST (overnight, or 2-day), serum cortisol level of ane.8 mcg/dl (50 nmol/L) is the recommended cut-off value that increases the diagnostic sensitivity of the test to approximately 95%.[19][20] Nonetheless, at this cut-off value, the specificity of the two-twenty-four hour period exam is better compared to that of the overnight exam (97 to 100% versus 86%). A recent meta-analysis showed that for the 1 mg overnight test, abnormal and normal results possessed a positive and negative likelihood ratio (LR) of 11.6 and 0.09, respectively. On the other hand, for the two-twenty-four hours 2 mg examination, abnormal and normal results had a positive and negative LR of vii.iii and 0.8, respectively.[21] Serum cortisol level nether 1.8 mcg/dl suggests adequate HPA axis suppression by dexamethasone and excludes CS. Levels over ane.8 mcg/dl should exist verified with a 2nd test (24-hr urinary costless cortisol, or late-nighttime salivary cortisol), earlier establishing a confirmed diagnosis of CS.[four]

two. HDDST

Reduction in UFC, or serum cortisol greater than 50% in the overnight, or two-day HDDST makes Cushing disease (CD) the probable source of ACTH-dependent Cushing syndrome. At a cut-off value of 50% suppression, HDDST provides a sensitivity and specificity of lx to 100%. Increasing the cut-off to in a higher place 90% cortisol suppression increases the specificity of diagnosing Cushing affliction to almost 100%, albeit at a much-reduced sensitivity.[22] Considering of this limitation, HDDST is not the recommendation, unless, both the pituitary MRI and bilateral junior petrosal venous sampling are negative or logistically challenging. Fifty-fifty in this scenario, HDDST is performed in conjunction with a CRH stimulation test, to enhance diagnostic accurateness.[23]

iii. Intravenous DST

The diagnosis of Cushing syndrome is fabricated if the mean solar day-ii serum cortisol level is to a higher place 20% of baseline [or greater than 4.7 mcg/dl (130 nmol/L)] with sensitivity 100% and specificity 96%.[7][8] Additionally, in Cushing disease as opposed to other etiologies of Cushing syndrome, the day-1 (i.east., the end of infusion) serum cortisol level shows greater than 70% suppression from the baseline, followed by rebound hypercortisolism in 24 hours.[8][9][ten]

4. Dexamethasone - CRH

Serum cortisol levels over 1.iv mcg/dl (39 nmol/L) at 15 minutes suggest CD with a 90 to 100% sensitivity and 50 to 100% specificity.[11][24][25] Raising the cut-off value to over 3.viii mcg/dl (87 nmol/L) increases the specificity to 100%, at the cost of slightly reduced sensitivity (94%).[26] The cumbersomeness of this test limits its extensive application in the convalescent setting.[27]

Clinical Significance

Iatrogenic hypercortisolism is the most mutual crusade of Cushing syndrome; and information technology should exist recognized earlier these individuals are subject to further diagnostic workup; instead, the focus should be on titrating down (or discontinuing, if viable) the prescribed steroid dosages. It is crucial that the dexamethasone suppression test is performed and interpreted in the calorie-free of pretest probability that should exist based on a thorough history and physical exam. Additionally, clinicians should exist mindful of all the tests' diagnostic accuracy, limitations, and interfering factors. In subjects with high clinical suspicion of Cushing syndrome but equivocal or negative test results, echo testing should take identify in 3 to half dozen months, as untreated hypercortisolemia has detrimental consequences.

Enhancing Healthcare Team Outcomes

Principal intendance providers initially evaluate the patients with suspected Cushing syndrome and they refer to an endocrinologist for further work-upwards. Clear communication and care coordination between physician, patient, and nurse are of paramount importance as the correct implementation of DST and sample collection tin can have a dramatic touch on of these factors on subsequent results.

Review Questions

Figure

Dexamethasone Suppression Test - Types & Indications. Contributed by Prerna Dogra, Doc

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Source: https://www.ncbi.nlm.nih.gov/books/NBK542317/

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