Managing Co-existing Diseases May Improve Survival in Cushing’s

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by Steve Bryson, PhD |

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People with Cushing’s syndrome, a group of conditions that includes Cushing’s disease, have a three-times-higher risk of mortality compared with the general population, according to a pooled analysis of multiple studies.

Preventing and managing co-existing conditions, especially cardiovascular disease, in addition to treating Cushing’s, may benefit at least half of the patients with this rare disorder and improve their long-term survival, the researchers noted.

“Despite improved outcomes in recent years, increased mortality from [Cushing’s syndrome] persists,” the scientists wrote. “The causes of death highlight the need to prevent and manage co-morbidities [co-existing conditions] in addition to treating hypercortisolism.”

The meta-analysis, “The effect of endogenous Cushing’s syndrome on all-cause and cause-specific mortality: A systematic review and meta-analysis,” was published in the Journal of Clinical Endocrinology & Metabolism.

Cushing’s syndrome is marked by the excessive production of the stress hormone cortisol, called hypercortisolism. Its symptoms include weight gain, high blood pressure, and elevated cholesterol and sugar levels in the bloodstream — all of which can impact mortality.

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There are different forms of the syndrome, including Cushing’s disease, which is the most common and is caused by benign (non-cancerous) tumors that form in the brain’s pituitary gland. These tumors promote the excessive production of a hormone called ACTH, which in turn causes the adrenal glands sitting atop the kidneys to release too much cortisol.

Other forms of the condition include ectopic Cushing’s syndrome, caused by ACTH-producing tumors found in locations other than the pituitary gland, and adrenal Cushing’s syndrome, which is due to either benign tumors located in the adrenal glands (adrenal adenoma) or the abnormal growth of adrenal tissue (bilateral adrenal hyperplasia).

Studies suggest that people with Cushing’s syndrome have an increased risk of mortality. But given the rareness of the condition, single studies could not reliably assess patient mortality or risk of death

In this report, researchers at the University of Leeds, in the U.K., and their colleagues conducted a meta-analysis by pooling data from multiple independent studies. The goal was to investigate the long-term outcomes of individuals with Cushing’s syndrome.

“To date, no published systematic review or meta-analysis has assessed the overall mortality and specific causes of death across all the different subtypes of [Cushing’s syndrome],” the team wrote.

Attempting one “would better define our current understanding of patient outcomes and improve future treatments,” they added.

Following a search of medical databases, the team selected 14 studies, which included a total of 2,160 Cushing’s disease patients and 1,531 individuals with adrenal Cushing’s syndrome. These studies reported the standard mortality ratio (SMR) — the number of observed deaths in the patient population divided by the number of expected deaths in a standard population.

There also were 87 studies comprising 19,181 Cushing’s syndrome patients that reported the proportion of deaths from groups of adults. Among these, 53 studies reported on Cushing’s disease and 24 on adrenal Cushing’s, while 20 involved combined patient groups.

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The overall pooled analysis revealed that people with Cushing’s syndrome, including those with adrenal or Cushing’s disease, had an SMR of 3.00, meaning a threefold higher risk of mortality than the standard population. For those with Cushing’s disease, the SMR was 2.8, which was significantly lower than adrenal Cushing’s, with an SMR of 3.34.

The SMR was higher in individuals with active disease compared with patients who were in remission (5.7 vs. 2.3). It also was higher among patients with Cushing’s disease who had pituitary macroadenomas — tumors measuring more than 1 cm (.4 inches) in diameter — than in those with microadenomas, which measure less than 1 cm (7.4 vs. 1.9). SMR estimates for women and men were similar.

The overall proportion of deaths in groups of adults with Cushing’s syndrome was 0.05. For those with Cushing’s disease, the proportion was 0.04. Further, the proportion of deaths were 0.02 for adrenal adenoma, 0.09 for bilateral adrenal hyperplasia, and 0.08 for combined adrenal Cushing’s syndrome.

Based on studies published before the year 2000, the proportion of deaths was 0.1 compared with 0.03 from 2000 to 2021, representing a 71% decrease in the proportion of deaths over time. These results were consistent for all subtypes of Cushing’s syndrome, except for bilateral adrenal hyperplasia, due to the lack of publications after 2000.

Researchers noted that this finding might be related to a decrease in the overall proportion of deaths during the first 30 days after surgery to remove tumors, which dropped from 0.04 before 2000 to 0.01 after 2000.

Causes of death were reported in 68 study groups that included 592 deaths from 7,255 patients. The primary contributor to a higher mortality risk was cardiovascular disease, causing about 40% of deaths across all Cushing’s subtypes, followed by infection (about 12–16%).

For those with cardiovascular disease, the SMR was 5.52 and 8.5 for infections.

Also cited in one of the studies analyzed was a high rate of diabetes.

That “multi-centre study indicated increased mortality in [Cushing’s disease] … thought to be due to increased rates of diabetes mellitus and cardiovascular complications,” the researchers wrote.

Overall, these data suggest that “aggressive cardiometabolic management may benefit at least 50% of [Cushing’s syndrome] patients and improve long-term mortality,” the team wrote.

Malignant tumors were the third most common cause of mortality, and their cause was known in 18 of 55 cases. Undetermined causes of death accounted for 15% of deaths.