2-test Combo Reaches 100% Diagnostic Accuracy

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by Patricia Inacio PhD |

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A combination of two easily performed tests reached 100% accuracy for diagnosing Cushing’s disease in people with an initial negative result from an MRI scan, or who had a a small tumor in their brain’s pituitary gland, a study reports.

The study, “Indication to dynamic and invasive testing in Cushing’s disease according to different neuroradiological findings,” was published in The Journal of Endocrinological Investigation.

Excessive production of cortisol, a steroid hormone, is the hallmark of Cushing’s syndrome. Such high levels of cortisol can be caused by the regular use of corticosteroids (exogenous Cushing’s) or from certain types of tumors (endogenous Cushing’s).

The majority of patients with endogenous Cushing’s have a tumor in the pituitary gland that causes it to release large amounts of adrenocorticotropic hormone (ACTH), which increases cortisol production and leads to the onset of Cushing’s. In this case, the condition is known as Cushing’s disease.

In more rare cases, Cushing’s can be caused by a tumor located outside the pituitary gland that also produces ACTH (ectopic Cushing’s). These tumors are found most often in the lungs and thymus gland, but also have been found in the thyroid gland and spleen.

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However, it can be challenging to differentiate Cushing’s disease from ectopic Cushing’s, especially if tumors are small enough to go undetected on MRI scans.

Currently, the diagnosis is performed using a battery of tests, which include measuring urinary free cortisol (UFC), as well as cortisol levels in blood or saliva collected at night, and the overnight dexamethasone suppression test (ODST). This test measures blood cortisol levels in the morning after patients take a tablet of dexamethasone, a corticosteroid that normally blocks cortisol  production.

In this study, researchers in Italy assessed the ability of three tests at distinguishing these two types of ACTH-dependent Cushing’s syndrome: the corticotropin-releasing hormone (CRH) stimulation test; the desmopressin (DDAVP) stimulatory test; and the high-dose dexamethasone suppression test (HDDST).

The CRH test is based on the principle that pituitary tumors usually respond to CRH stimulation by increasing ACTH production, while other tumors typically do not.

Desmopressin has been used to replace CRH to stimulate ACTH release for inferior petrosal sinus sampling (IPSS), a procedure intended to measure ACTH levels in the veins that drain from the pituitary gland. Prior studies have shown that desmopressin’s sensitivity is comparable to that of CRH.

Researchers conducted a retrospective analysis of 148 patients with Cushing’s disease — 113 women and 35 men, mean age of 42.4 years — who were followed at two tertiary care centers in Italy from 2000 to 2017. All were diagnosed based on at least two abnormal results on standard diagnostic tests, including high 24-hour UFC levels, loss of diurnal (day-to-day) variation in cortisol levels in blood/saliva, and lack of cortisol suppression following ODST.

They compared their results with a group of 26 patients with a confirmed diagnosis of ectopic Cushing’s.

All 148 patients had MRI scans of the pituitary gland and were divided into three groups based on scan results. A total of 97 patients were placed in Group A, which included those in whom a tumor was not found (40 patients) or those who had a microadenoma — a small tumor measuring less than 6 mm (57 patients). A total of 29 patients were placed in Group B, which included those with a visible pituitary adenoma (tumors measuring  6–10 mm). And 22 formed Group C, which included those with a macroadenoma (tumors measuring more than 10 mm).

Among the 26 patients with ectopic Cushing’s, seven had a microadenoma, and 19 were negative for any pituitary tumor.

Patients in Group C had higher ACTH levels compared with patients who had negative MRI scans or microadenomas (Groups A and B). No differences were seen in late-night salivary cortisol levels between the different groups.

The majority of patients with Cushing’s disease (91.4%) showed a positive response in the HDSST, while only 23.1% of those with ectopic Cushing’s responded to the test. Of note, patients were considered to have a positive response to HDSST when their blood cortisol levels dropped by more than 50% after receiving dexamethasone.

Nearly all (89.4%) Cushing’s disease patients were positive for the CRH test, with patients in Groups A and B having a significantly higher response rate than those in Group C (91.7% vs. 75%). Of note, a CRH test was considered positive when it increased ACTH levels by more than 50% and cortisol levels by more than 20%.

According to the DDAVP, 70.1% of all patients showed a positive response. Patients in Group C had significantly higher responses than those in Groups A and B (90% vs. 66.3%). Of note, a DDAVP a stimulatory test was deemed positive when it increased ACTH levels by more than 30% and cortisol levels by more than 20%.

Overall, the combination of a positive response in CRH and HDDST was better than each of the two tests alone, reaching a 100% predictive power to diagnose Cushing’s disease. Moreover, a negative response in these tests was 100% reliable for the diagnosis of ectopic Cushing’s.

Similarly, positive responses in the CRH and DDAVP showed a 100% predictive power to diagnose Cushing’s disease.

Bilateral IPSS (BIPSS) confirmed the diagnosis of Cushing’s disease in 28 of 30 patients who underwent the procedure. However, these later were confirmed to be false negative at distinguishing these two types of ACTH-dependent Cushing’s syndrome. Also, one patient ended up dying within 24 hours after BIPSS due to cardiac rupture.

“All these observations point out the need for an accurate selection of patients referred to BIPSS,” the researchers wrote.

Overall, these results suggest that “CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent [Cushion’s syndrome],” they wrote.

“In patients with microadenoma … or non-visible lesion, a concordant [corresponding] positive response to noninvasive tests seems sufficient to diagnose CD [Cushing’s disease], irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests,” they concluded.