Question of the week # 300

300) A 14 year old girl is evaluated in your office for  moderate headache of one month duration . She denies any blurred vision, neck stiffness or fever. She is accompanied by her mother who reports that her performance at school has progressively declined over the last few months and she has deepening of voice for the past 4 months. On examination, Pulse 80/min;  Temperature: 98.4F  and Blood pressure: 135/100 mm of Hg. There is excessive hair on her face. Rest of the physical is normal except for faint purplish marks on her abdomen. Laboratory investigations including complete blood count, comprehensive metabolic panel and Urine analysis are within normal limit. Which of the following is the most appropriate next step ?

A) 24 hour urinary cortisol

B) MRI brain

C) CT scan of the abdomen

D) Dexamethasone Suppression Test

E) Plasma catecholamines

F) Urine Drug Screen

19 Responses

  1. MRI of the brain

  2. B

  3. Dexamethasone suppression test.

  4. Plasma catecholamines

  5. B

  6. D

  7. dexamethasone suppression test…..

  8. 24 hours free urinary cortisol

  9. a

  10. A……..When Cushing’s syndrome is suspected, initial laboratory testing is usually directed at confirming excessive glucocorticoid production. This is best accomplished through analysis of a 24-hour urine collection for urinary free cortisol excretion.4,20 Normal values are less than 90 μg per 24 hours (250 nmol per day). Values more than 300 μg per day (830 nmol per day) are considered diagnostic for Cushing’s syndrome.4,5 The reported sensitivity of this test in detecting cortisol excess is 95 percent; the reported specificity is 98 percent.4 Ideally, the urinary free cortisol value should be confirmed with one or two additional measurements.

    Because of the difficulty in obtaining 24-hour urine collections in many outpatients, some physicians use a l-mg overnight dexamethasone suppression test. For this test, the patient takes l mg of dexamethasone orally at 11 p.m., and the plasma cortisol level is measured at 8 a.m. the following day (normal value: 5 μg per dL or less [140 nmol per L]). The reported sensitivity of this test is 98 percent; the reported specificity is 80 percent.4

    Obesity, chronic illness, chronic alcoholism and depression can cause false-positive results (pseudo-Cushing’s syndrome) on the 1-mg dexamethasone suppression test and mildly elevated free cortisol values on the 24-hour urine collection.19,21

    If the result of the dexamethasone suppression test is abnormal or the 24-hour urinary free cortisol level is mildly elevated, a confirmatory test for Cushing’s syndrome is needed. The 24-hour urine collection for urinary free cortisol excretion can be used to confirm the result of the l-mg dexamethasone suppression test. Normal findings on both tests provide strong evidence against the presence of Cushing’s syndrome.4 However, when Cushing’s syndrome is still strongly suspected based on the clinical findings, negative tests should be repeated; the tests should also be performed again in three to six months.4

    In the past, a low-dose dexamethasone suppression test was often performed to confirm the diagnosis of Cushing’s syndrome. For this test, the patient takes 0.5 mg of dexamethasone orally every six hours for two days (a total of eight doses). A 24-hour urine collection is performed before the dexamethasone administration and again during the last 24 hours of dexamethasone administration. Patients with true Cushing’s syndrome show less than 50 percent suppression of baseline urinary free cortisol excretion5 or more than 4 mg per 24 hours (11 μmol per day) of 17-hydroxysteroid excretion.4 This test is now used less often because of its low sensitivity (70 percent) and low specificity (75 percent).19

    A newer approach is to combine a CRH stimulation test with a dexamethasone suppression test. The patient takes 0.5 mg of dexamethasone every six hours for two days (a total of eight doses); two hours after the last dexamethasone dose is taken, 1 μg per kg of CRH is administered intravenously. Blood for a plasma cortisol measurement is drawn 15 minutes after the CRH injection. A plasma cortisol level exceeding 1.4 μg per L (40 nmol per L) is considered positive for Cushing’s syndrome.22 This test is nearly 100 percent sensitive and specific for Cushing’s syndrome.4

    Alternatively, if pseudo-Cushing’s syndrome is suspected, a midnight serum cortisol level of less than 7.5 μg per dL (207 nmol per L) is strongly suggestive of pseudo-Cushing’s syndrome.21

    Another approach to the patient with suspected pseudo-Cushing’s syndrome is to treat the underlying process and retest the patient in a few months.5 In this instance, the hypercortisolism of pseudo-Cushing’s syndrome should correct spontaneously if treatment of the underlying process is successful.

    If the unsuppressed 24-hour urinary free cortisol test is unequivocally positive, a confirmatory dexamethasone suppression test is usually unnecessary.20 However, elevated cortisol secretion should be confirmed with another 24-hour urinary free cortisol measurement.21

    Once hypersecretion of cortisol is confirmed, the next step is to determine whether the pathologic state is ACTH dependent or ACTH independent. This can be accomplished through measurement of the late-afternoon ACTH level. Late-afternoon (after 4 p.m.) timing is important because ACTH levels are normally low at that time.3 If the plasma ACTH level is greater than 10 pg per mL (2 pmol per L), the process is ACTH dependent. If the ACTH level is less than 5 pg per mL (1 pmol per L), the process is ACTH independent.4 Intermediate ACTH levels indicate the need for further study with, for example, a CRH stimulation test.3,4

    The CRH stimulation test is performed by administering 1 μg per kg of CRH intravenously. ACTH and cortisol levels are measured before CRH injection and 15, 30, 45, 60, 90 and 120 minutes after injection. A rise in the cortisol value of 20 percent or more above basal level or a rise in the ACTH value of at least 50 percent above basal level is considered evidence for an ACTH-dependent lesion.4,5,23

    When test results indicate that a patient has an ACTH-independent lesion, abdominal computed tomographic (CT) scanning or magnetic resonance imaging (MRI) is indicated to localize the site of the lesion.19

    If the process is ACTH dependent, a high-dose dexamethasone suppression test combined with cranial MRI studies may aid in localizing the site of ACTH overproduction.

    In the standard high-dose dexamethasone suppression test, a baseline 24-hour urine sample is collected. Then the patient takes 2 mg of dexamethasone every six hours for two days (total of eight doses). A 24-hour urine sample is collected during the last 24 hours of dexamethasone administration. The test is considered positive if 17-hydroxysteroid excretion is suppressed by 64 percent or urinary free cortisol excretion is suppressed by 90 percent of baseline. Using these criteria, the standard high-dose dexamethasone suppression test has been reported to be 86 percent accurate in differentiating Cushing’s disease from ectopic ACTH production.3,4,19

    Caution must be exercised in interpreting test findings. In patients with Cushing’s disease, endogenous ACTH and cortisol production should be suppressed with high-dose (8-mg) dexamethasone, but the test lacks specificity, a clear cutoff value and diagnostic accuracy.3,6,19,24,25 In fact, the pretest probability of finding a pituitary cause for ACTH-dependent Cushing’s syndrome (85 to 90 percent) may exceed the diagnostic accuracy of the test.4,25 Microadenomas are more likely to demonstrate high-dose dexamethasone suppression than macroadenomas (92 versus 56 percent in one study).26

    An 8-mg overnight dexamethasone suppression test is easier to perform than the standard high-dose dexamethasone suppression test, and it has similar accuracy and limitations. In this test, a single 8-mg dose of dexamethasone is given at 11 p.m., and the serum cortisol level is measured at 8 a.m. the next morning. Suppression of the cortisol level to less than 50 percent of baseline is considered indicative of Cushing’s disease.4,5,23

    The CRH stimulation test can also help localize the site of ACTH overproduction. A 35 percent increase in the ACTH level at 15 and 30 minutes after corticotropin administration is reported to be 93 percent sensitive and 100 percent specific for Cushing’s disease.4 The CRH stimulation test is considered to have a diagnostic accuracy similar to that of the high-dose dexamethasone suppression test, but it is more cost-effective because it can be performed in one morning in the outpatient setting.27

    Some experts recommend using the combined results of the CRH stimulation test and the high-dose dexamethasone suppression test. A diagnostic accuracy of nearly 100 percent has been noted for the combined test results.28

    Cranial MRI results must also be interpreted cautiously. MRI may not visualize small lesions (Figures 4 and 5), and incidental lesions are noted on a small percentage of MRI scans in patients with ectopic ACTH production and no pituitary hyperfunction. Cranial CT scanning is not an acceptable substitute for MRI, because CT scans only identify approximately 50 percent of pituitary lesions.

  11. D..According to the CMDT, “The easiest screening test for Cushing syndrome is the dexamethasone suppression test”

  12. ddd

  13. Ans 😀

    Imaging test is never the first test . Might lead to false fixing like incidentaloma and unnecessary removal of normal organs .
    We only do imaging after we have confirm it with lab chem .

    Dexamethasone suppresssion has higher sensitivity value than 24 hour urine test . 24 hour urine test gives specificity .

    And both of these test are required to maker the diagnosis of presence of cushing syndrome .
    If dexamethasone suppresion test is abnormal , 24 hour urine cortisol needed to confirm it .

    correct me if I’m wrong . Thanks

    • ans D

  14. The 3 standard case detection tests for CS are:

    24-hour urinary free cortisol (UFC)
    Late-night salivary cortisol
    1-mg overnight dexamethasone suppression test (DST)

    24 hr UFC test – 3-4 fold increase in cortisol level confirm CS.
    If 1mg overnight DST is positive, we still need to do 24 hr UFC test and there are more chances for false positive also.
    I will chose 24 hr UFC for most appropriate next step.

  15. “CS is confirmed when the 24-hour UFC is more than 3-fold increased above the upper limit of the reference range. The test characteristics of 24-hour UFC include sensitivities of 76% to 100% and specificities of 95% to 98%. (The variation depends on patient population, reference range, and type of assays used.) The interpretation of urinary cortisol excretion should incorporate the degree of clinical suspicion for CS.
    Another useful detection test is the 1-mg overnight DST: “If the diagnostic threshold is raised to 5 mcg/dL, the specificity increases to 95% but sensitivity declines. Interpretation of DST results can be confounded by medications that accelerate the metabolism of dexamethasone (eg, anticonvulsants) or medications that increase serum cortisol-binding globulin concentrations (eg, oral estrogens).”
    When the findings from the 3 standard case detection tests are inconclusive, there are 2 options to consider:

    One option is to reassess 3 to 6 months later. If a patient has true CS, the signs and symptoms and the levels of cortisol secretory abnormalities should progress over time.
    Another option is to perform a combined corticotropin-releasing hormone–DST (CRH-DST). The basis for the CRH-DST is that tumorous corticotroph cells respond to CRH in the presence of dexamethasone, whereas normal corticotroph cells do not respond.

  16. http://www.mayoclinic.org/medicalprofs/cushing-syndrome.html

  17. Answer A.

    http://emedicine.medscape.com/article/117365-workup
    The flow chart says to do 24h urinary cortisol first. If results are equivocal, perform DST.

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