Abnormal blood proteins in remission suggest lasting Cushing’s risks
Not all alterations normalize when disease activity resolves, study finds
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Abnormal protein levels in the blood that develop during Cushing’s disease may somewhat, but not entirely, normalize when disease activity resolves, a new study reports.
These “distinct [blood] protein profiles” could potentially indicate an “increased risk for thrombosis [formation of a blood clot inside a blood vessel] and metabolic complications” for people whose Cushing’s is in remission, the researchers wrote. Metabolic complications are health issues arising from impaired metabolism.
Previous research has shown that levels of several proteins, including some involved in blood clotting and transporting the hormone cortisol, are altered in Cushing’s disease. The results of this study suggest that these changes may remain despite long-term remission, according to the researchers. Remission is defined as a state of low disease activity,
“These findings provide new insights into the long-term effects of Cushing’s disease, and suggest that persistent protein changes may contribute to ongoing health risks,” the researchers wrote. “Understanding these biochemical changes could help improve patient monitoring and therapeutic management after remission.”
The study, ”Distinct plasma protein profiles after long-term remission of Cushing’s disease,” was published in JCEM, The Journal of Clinical Endocrinology & Metabolism.
Cushing’s disease occurs when tumors form in the pituitary gland, a part of the brain that releases hormones. These tumors can cause excessive secretion of cortisol, a hormone that helps regulate various processes throughout the body. High cortisol levels, in turn, can lead to a variety of symptoms.
As cortisol levels shift in Cushing’s, so do levels of certain proteins in plasma, the liquid component of blood. However, data about how these plasma proteins change during Cushing’s remission, as cortisol levels return to normal, remain limited.
Scientists focus on blood proteins in long-term remission
To fill that knowledge gap, a research team in the Netherlands designed a study to test this question, with a focus on remission lasting several years.
“Given the systemic effects of cortisol, a comprehensive evaluation of these plasma proteins may provide further insight into the long-term consequences of [Cushing’s disease] remission,” the team wrote.
Their study involved 26 adults with Cushing’s disease, with a median age at diagnosis of 45. The researchers measured plasma proteins during active disease and again a median of 5.6 years later. At the second time point, participants had been in remission for a median of 4.4 years.
Most participants entered remission after surgical interventions or the use of medications to reduce cortisol production.
During the active disease state, 78 of 159 measured plasma proteins differed significantly between Cushing’s patients and controls without the condition. In remission, 22 of these remained abnormal. There were also nine proteins that were significantly different from controls during remission, but not during active disease.
“Our findings indicate that remission results in substantial, but incomplete normalization of the plasma protein profile,” the team wrote.
Cushing’s participants tended to show excessive activity of proteins that promote blood clotting and prevent clot breakdown. These results are consistent with a known risk of blood clotting complications in Cushing’s, the researchers noted.
While this danger remains present for many people with Cushing’s during long-term remission, the researchers found that levels of most clotting proteins had returned to normal at the second measurement. This suggests that other aspects of the disease may also contribute to the ongoing risk.
Cortisol levels may play a role
Another area of change was in proteins that facilitate cortisol’s movement through the body. Two notable proteins, called cortisol-binding protein (CBG) and albumin (ALB), had significantly lower levels during active disease. This could contribute to elevated cortisol levels in the bloodstream by reducing the amount of the hormone that can bind to proteins stably.
As with clotting proteins, transport proteins largely normalized during remission. “The restoration of CBG and ALB levels after remission indicates recovery of cortisol transport capacity, which may contribute to normalization of cortisol homeostasis [balance],” the researchers noted.
An unexpected protein that stood out in the analysis was extracellular matrix protein 1 (ECM1). ECM1 helps support the integrity of tissues such as the skin and plays an important role in liver health. During both active disease and remission, ECM1 levels were significantly lower in patients than in control participants.
“Reduced ECM1 levels have previously been linked to fibrosis [scarring] and tissue remodeling, indicating that its persistent decrease in [Cushing’s disease] may reflect lasting structural tissue alterations that do not resolve after remission,” the team wrote.
People with higher levels of cortisol during active Cushing’s disease had more proteins that differed significantly from those of the controls. The differences between active disease and remission were also more pronounced in the more severe group. This may mean that there was more room for change for these individuals, the team noted.
Other factors, including coexisting diseases and treatment types, did not significantly influence changes in protein levels. However, the researchers suggested this could have been because the participant group was too small to detect differences.
Another potential limitation of the study was the variability in the timing of data collection. “Remission samples were collected during routine clinical follow-up rather than at a standardized time interval, resulting in variability in follow-up time and remission duration between patients,” the team wrote. This could have influenced the degree of change in protein levels.”
Future studies could continue exploring long-term protein changes, potentially linking these to continued health risks during remission, the researchers noted.
