Despite Remission, Patients Have 2 Times Higher Risk of Death

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Even with biochemical remission — having normal biochemical markers for liver inflammation — patients with Cushing’s disease have a two times higher risk of mortality compared with people without the disorder, a Swedish study found.

Cardiovascular diseases and infections were the main causes of death, highlighting the importance of close monitoring and follow-up irrespective of remission status, according to the researchers. Of note, “mortality was increased in both male and female [Cushing’s disease] patients,” they wrote.

Overall, “the mortality rate was more than doubled in patients with [Cushing’s disease],” the investigators wrote, adding that “mortality continues to be increased despite biochemically successful treatment.”

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The study, “Increased mortality persists after treatment of Cushing’s disease: A matched nationwide cohort study,” was published in the Journal of the Endocrine Society. 

Cushing’s disease is caused by a tumor in the brain’s pituitary gland that triggers the excessive production of adrenocorticotropic hormone (ACTH), which in turn stimulates the production of cortisol by the adrenal glands.

Transsphenoidal surgery (TSS), the most common procedure to remove pituitary tumors, is considered the first-line treatment for Cushing’s disease. Yet, although this surgery has been associated with remission in 80% of cases, whether such biochemical remission increases patients’ life expectancy has remained unclear. Prior studies have reported differing outcomes.

To address such discrepancies, a group led by researchers at the Linköping University, in Sweden, assessed the impact of biochemical remission on mortality rates in a large group of Cushing’s patients from the Swedish Pituitary Register. All participants had been diagnosed between May 1991 and September 2018.

Patients were considered to be in biochemical remission when at least one of these criteria was met: having late-night salivary cortisol levels within a normal range; blood cortisol levels below 50 nanomoles per liter (nmol/L) following an overnight dexamethasone suppression test; 24-hour urinary free cortisol (UFC) within a normal range; or having unusually low cortisol levels (hypocortisolism) after pituitary surgery, radiotherapy, or bilateral adrenalectomy (surgical removal of both adrenal glands).

In total, 371 Cushing’s patients — including 281 women — with a median age at diagnosis of 44, were included in the study. Patients were followed for a median of 10.6 years. For each patient, four individuals matched for age, sex, and residential area were included as controls (total 1,484).

Biochemical remission was evaluated at one, five, 10, 15, and 20 years after diagnosis. The remission rates increased with time: from 80% in the first year to 97% after 20 years.

In total, 66 Cushing’s (18%) patients died during the study, compared with 139 controls (9%), corresponding to a 2.1-times higher mortality risk in the Cushing’s group.

The risk of death was lower for patients who were in remission at the last follow-up compared with those who were not (1.5 vs. 5.6 times), and similar to those who were in remission after a single pituitary surgery (1.7 times). Of note, this mortality risk was calculated in relation to controls.

Older age at diagnosis and not being in remission at the last follow-up were predictors of mortality. After adjusting for age and remission, male sex also was associated with higher mortality.

Of the 66 deaths, 32 were due to cardiovascular diseases and 12 to infections.

Overall, these results show that “mortality was increased in [Cushing’s] patients despite biochemical remission compared to matched controls,” the researchers wrote.

“Cardiovascular diseases and infections were the main causes of death, highlighting the importance of the careful follow-up of [Cushing’s] patients and the treatment of comorbidities,” they wrote.