Low-grade inflammation persists after removing tumors
Study followed Cushing's syndrome patients for a year after surgery
Low-grade inflammation persisted in people with Cushing’s syndrome one year after surgery to remove disease-causing tumors that led to excess cortisol, the hallmark of the condition, a recent study revealed.
High levels of inflammatory markers were associated significantly with post-surgical obesity, high blood sugar levels, and worse long-term muscle function, the data showed.
These findings may explain some of the lingering symptoms that occur in patients after successful tumor removal surgery, possibly due to the reversal of immunosuppression brought on initially by excess cortisol.
Researchers also noted their findings suggest that inflammatory markers can be used to monitor patients during the post-surgical cortisol withdrawal phase.
The study, “Low-grade inflammation during the glucocorticoid withdrawal phase in patients with Cushing’s syndrome,” was published in the European Journal of Endocrinology.
Cushing’s syndrome occurs when there is too much cortisol in the body, which also is referred to as hypercortisolism.
In Cushing’s disease, a form of Cushing’s syndrome, noncancerous tumors in the brain’s pituitary gland lead to the excessive production of adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce and release too much cortisol. Tumors in the adrenal glands also can lead to hypercortisolism, as can other ACTH-producing tumors found outside the pituitary and adrenal glands, which is referred to as ectopic Cushing’s syndrome.
Surgical removal of these tumors is the first line of treatment to reduce cortisol to normal levels. However, despite successful surgery, recovery from hypercortisolism can be slow, with some symptoms persisting. However, the reasons for this incomplete recovery are unclear.
Cortisol belongs to a class of hormones called glucocorticoids that play a major role in immune function. High cortisol levels induce immunosuppression, weakening immune responses and increasing the risk of infections, which are seen commonly in Cushing’s patients.
Researchers in Germany hypothesized that, after successful surgery, prolonged recovery may be due to the reversal of immunosuppression caused by a drop in cortisol levels, triggering a state of inflammation.
80 patients studied
To find out, the team examined clinical and biochemical data from 80 Cushing’s patients who were studied before and after undergoing successful tumor removal surgery. Among them, 55 (69%) had pituitary tumors, 21 (26%) had adrenal involvement, and four (5%) had ectopic Cushing’s.
“To the best of our knowledge, this is the first study to comprehensively characterize the glucocorticoid withdrawal phase,” the team wrote.
Most patients (89%) received temporary glucocorticoid replacement therapy one month after surgery to treat adrenal insufficiency — a condition in which the adrenal glands fail to produce enough of certain hormones.
Analyses revealed that the median level of C-reactive protein (CRP), an inflammation marker, was 4.8-times higher in the early remission phase one month after surgery, than it was before surgery (0.48 vs. 0.10 mg/dL). CRP levels remained significantly high over the course of one year of follow-up.
After adjusting for age and severity of hypercortisolism, high levels of postoperative CRP correlated significantly with body composition features, such as a larger waist circumference, higher body fat percentage, and higher body mass index (BMI).
High levels of markers of insulin resistance and glucose intolerance (high blood sugar) also correlated with high CRP after adjustments.
To support these findings, researchers conducted a subgroup analysis comparing data from 25 Cushing’s patients to 25 age-, gender-, and body composition-matched control patients who had been evaluated for Cushing’s, but not diagnosed with the condition.
The median level of interleukin-6 (IL-6), an immune signaling protein, was 4.2-times higher one month after surgery — a sign of inflammatory activity — compared with the period before surgery. In Cushing’s patients, IL-6 levels were three times higher than in matched controls, and remained significantly high after follow-up visits at three and six months.
Likewise, CRP levels in the early remission phase were higher than they were before surgery. They also were higher in Cushing’s patients compared with matched controls.
Across all patients, high CRP and IL-6 levels during early remission were associated significantly with worse muscle function, as assessed by hand grip strength and standing-up tests. As evaluated with three questionnaires, lower quality of life (QoL) also correlated with high levels of these pro-inflammatory markers.
After adjustment for age and BMI, the correlation between CRP levels three months after surgery and worse muscle function remained statistically significant. The connection between CRP and QoL lost its significance after these adjustments, making age and BMI potential influencing factors in this relationship, the authors noted.
“Early remission phase after correction of hypercortisolism is characterized by low-grade inflammation up to 1 year after surgery, associated with muscular impairments,” the team wrote. “Obese and hyperglycemic patients with [Cushing’s syndrome] are especially at increased risk for elevated inflammatory markers in the postoperative period.”
“C-reactive protein and IL-6 could serve as biomarkers to monitor patients during the glucocorticoid withdrawal phase,” the researchers wrote.