Certain Comorbidities of Cushing’s Syndrome May Lead to More Complications After Remission, Study Finds

A patient’s age, urinary-free cortisol (UFC) level, fasting glucose — a measure of insulin resistance — body mass index (BMI), and the number of comorbidities at diagnosis for Cushing’s syndrome predicted the number of long-term comorbidities several years after remission, according to a study.

Specifically, older age, lower baseline UFC, and higher fasting glucose, BMI, and number of comorbidities at diagnosis are associated with more long-term comorbidities.

The research, “Factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission,” was published in the journal Endocrine.

In Cushing’s syndrome, excess levels of glucocorticoids lead to high blood pressure, and impaired insulin secretion and sensitivity, which results in diabetes. Older age and longer exposure to high amounts of glucocorticoids are associated with both diabetes and high blood pressure. Other common comorbidities are high levels of total cholesterol or triglycerides, osteoporosis, and depression.

As most Cushing’s syndrome comorbidities are also risk factors for cardiovascular disease, patients are at increased risk for cardiovascular complications even decades after disease remission. However, the baseline factors associated with long-term persistence of comorbidities in Cushing’s patients remain unknown.

Therefore, a team from the Medical University of Vienna, in Austria, studied a group of 118 patients (94 women: 52 with Cushing’s disease, 58 with adrenal Cushing’s syndrome, 8 with ectopic Cushing’s syndrome) in long-term remission.

The mean age of patients was 42.8 years at diagnosis, and diagnostic delay was 25.8 months. Patients with Cushing’s disease were younger than those with adrenal disease — 38.7 years vs. 46.4 years — and had longer exposure to excess glucocorticoids (40.5 months) than those with adrenal (26.3 months) and ectopic disease (19.9 months). They also had higher cortisol levels, as well as lower blood pressure and LDL-cholesterol than the patients with adrenal Cushing’s syndrome.

Patients were followed for a median of 7.9 years after the last surgery for their excess cortisol. The scientists evaluated the correlations between baseline body, metabolic, and hormonal parameters at diagnosis, and comorbidities — obesity, diabetes, high lipid levels, high blood pressure, osteoporosis, and depression — at the last follow-up.

Diabetes was 2.4 times more frequent in Cushing’s disease than in adrenal Cushing’s syndrome. Metabolic syndrome was present in 39.3% of patients.

A total of 98 patients (83.1%) achieved remission after a single surgery. Those with Cushing’s disease, however, needed significantly more surgeries before achieving remission. The incidence of metabolic syndrome lowered to 18.4%. Remission also resolved diabetes in 56% of cases, hypertension in 36%, hyperlipidemia in 23%, and depression in 52%.

After the follow-up period, the team found significant improvements in BMI, blood pressure, glucose and lipid metabolism, and fewer comorbidities.

Lower baseline UFC levels — suggested by the team to be linked to longer exposure time to excess glucocorticoids — correlated with a higher number of long-term comorbidities in the entire group, specifically in Cushing’s disease and adrenal Cushing’s patients. A similar negative correlation was found between serum cortisol and comorbidities in patients with adrenal Cushing’s.

A lower UFC level was also significantly associated with longer diagnostic delay, and exposure time to excess glucocorticoids. Therefore, exposure duration to excess glucocorticoids correlated with the number of surgeries, while diagnostic delay and exposure time to excess glucocorticoids were higher in patients with adrenal insufficiency at last follow-up. The data further showed that older age and lower baseline UFC levels determined low blood pressure at follow-up.

“The most remarkable novel finding presented here is the predictive value of lower baseline UFC levels for the persistence of a higher number of long-term comorbidities,” the team wrote.

However, those with higher baseline UFC achieved remission from high blood pressure at follow-up. Similar findings were observed in those with prediabetes and diabetes. Patients who maintained a normal weight at follow-up also had higher baseline UFC.

In addition, having higher baseline triglycerides was associated with increased likelihood of high lipid levels at last follow-up, and a higher BMI was associated with obesity at last follow-up. Also, higher fasting glucose at diagnosis was associated with diabetes at last follow-up.

“The high prevalence of long-term comorbidities after remission of Cushing’s syndrome underpins the importance of long-term monitoring and disease-specific therapy for reducing cardiovascular mortality,” the researchers concluded.