Even in Remission, Cushing’s Patients Have Excess Mortality

Cushing’s disease patients in Sweden have a higher risk of death than the general Swedish population, particularly of cardiovascular complications, and that increased risk persists even in patients in remission, a large nationwide study shows.

The study, “Overall and disease-specific mortality in patients with Cushing’s disease: a Swedish nationwide study,” was published in the Journal of Clinical Endocrinology and Metabolism.

The outcomes of Cushing’s disease patients have improved with the introduction of several therapeutic approaches, such as minimally invasive surgery and cortisol-lowering therapies. However, mortality is still high, especially among those who do not achieve remission.

While currently patients in remission are thought to have a better prognosis, it is still unclear whether these patients still have a higher mortality than the general population. Understanding whether these patients are more likely to die and what risk factors are associated with increased mortality is critical to reduce death rates among Cushing’s patients.

A team of Swedish researchers thus performed a retrospective study that included patients diagnosed with Cushing’s disease who were part of the Swedish National Patient Registry between 1987 and 2013.

A total of 502 patients with Cushing’s disease were included in the study, 419 of whom were confirmed to be in remission. Most patients (77%) were women; the mean age at diagnosis was 43 years, and the median follow-up time was 13 years.

During the follow-up, 133 Cushing’s patients died, compared to 54 expected deaths in the general population — a mortality rate 2.5 times higher, researchers said.

The most common causes of death among Cushing’s patients were cardiovascular diseases, particularly ischemic heart disease and cerebral infarctions. However, infectious and respiratory diseases (including pneumonia), as well as diseases of the digestive system, also contributed to the increased mortality among Cushing’s patients.

Of those in remission, 21% died, compared to 55% among those not in remission. While these patients had a lower risk of death, their mortality rate was still 90% higher than that of the general population. For patients who did not achieve remission, the mortality rate was 6.9 times higher.

The mortality associated with cardiovascular diseases was increased for both patients in remission and not in remission. Also, older age at the start of the study and time in remission were associated with mortality risk.

“A more aggressive treatment of hypertension, dyslipidemia [abnormal amount of fat in the blood], and other cardiovascular risk factors might be warranted in patients with CS in remission,” researchers said.

Of the 419 patients in remission, 315 had undergone pituitary surgery, 102 had had their adrenal glands removed, and 116 had received radiation therapy.

Surgical removal of the adrenal glands and chronic glucocorticoid replacement therapy were associated with a worse prognosis. In fact, glucocorticoid replacement therapy more than twice increased the mortality risk. Growth hormone replacement was linked with better outcomes.

In remission patients, a diagnosis of diabetes mellitus or high blood pressure had no impact on mortality risk.

Overall, “this large nationwide study shows that patients with [Cushing’s disease] continue to have excess mortality even after remission,” researchers stated. The highest mortality rates, however, were seen in “patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

“Further studies need to focus on identifying best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of cardiovascular and mental health in these patients,” the study concluded.

From https://cushingsdiseasenews.com/2019/02/28/even-in-remission-cushings-patients-have-excess-mortality-swedish-study-says/

Cushing’s appears to begin its cardiovascular effects during childhood

– Cushing’s disease may begin to exert its harmful cardiovascular effects quite early, a small pediatric study has found.

Children as young as 6 years old with the disorder already may show signs of cardiovascular remodeling, with stiffer aortas and higher aortic pulse-wave velocity than do age-matched controls, Hailey Blain and Maya Lodish, MD, said at the annual meeting of the Endocrine Society.

“The study, which included 10 patients, is small, but we continue to add new patients,” said Dr. Lodish, director of the pediatric endocrinology fellowship program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Ten more children are being added to the cohort now, and she and Ms. Blain, a former research fellow at NIH, intend to grow the group and follow patients longitudinally.

Cushing’s disease has long been linked with increased cardiovascular risk in adults, but the study by Dr. Lodish and Ms. Blain is one of the first to examine the link in children. Their findings suggest that early cardiovascular risk factor management should be a routine part of these patients’ care, Dr. Lodish said in an interview.

“It’s very important to make sure that there is recognition of the cardiovascular risk factors that go along with this disease. Elevated levels of cholesterol, hypertension, and other risk factors that are in these individuals should be ameliorated as soon as possible from an early age and, most importantly, physicians should be diagnosing and treating children early, once they are identified as having Cushing’s disease. And, given that we are not sure whether these changes are reversible, we need to make sure these children are followed very closely.”

Indeed, Dr. Lodish has reason to believe that the changes may be long lasting or even permanent.

“We are looking at these children longitudinally and have 3-year data on some patients already. We want to see if they return to normal pulse wave velocity after surgical cure, or whether this is permanent remodeling. There is an implication already that it may be in a subset of individuals,” she said, citing her own 2009 study on hypertension in pediatric Cushing’s patients. “We looked at blood pressure at presentation, after surgical cure, and 1 year later. A significant portion of the kids still had hypertension at 1 year. This leads us to wonder if they will continue to be at risk for cardiovascular morbidity as adults.”

Ms. Blaine, an undergraduate at Bowdoin College, Brunswick, Maine, worked on the study during a summer internship with Dr. Lodish and presented its results in a poster forum during meeting. She examined two indicators of cardiovascular remodeling – aortic pulse wave velocity and aortic distensibility – in 10 patients who were a mean of 13 years old. All of the children came to NIH for diagnosis and treatment of Cushing’s; as part of that, all underwent a cardiac MRI.

The patients had a mean 2.5-year history of Cushing’s disease Their mean midnight cortisol level was 18.8 mcg/dL and mean plasma adrenocorticotropic hormone level, 77.3 pg/mL. Five patients were taking antihypertensive medications. Low- and high-density lipoprotein levels were acceptable in all patients.

The cardiovascular measures were compared to an age-matched historical control group. In this comparison, patients had significantly higher pulse wave velocity compared with controls (mean 4 vs. 3.4 m/s). Pulse wave velocity positively correlated with both midnight plasma cortisol and 24-hour urinary free cortisol collections. In the three patients with long-term follow-up after surgical cure of Cushing’s, the pulse wave velocity did not improve, either at 6 months or 1 year after surgery. This finding echoes those of Dr. Lodish’s 2009 paper, suggesting that once cardiovascular remodeling sets in, the changes may be long lasting.

“The link between Cushing’s and cardiovascular remodeling is related to the other things that go along with the disease,” Dr. Lodish said. “The hypertension, the adiposity, and the high cholesterol all may contribute to arterial rigidity. It’s also thought to be due to an increase in connective tissue. The bioelastic function of the aorta may be affected by having Cushing’s.”

That connection also suggests that certain antihypertensives may be more beneficial to patients with Cushing’s disease, she added. “It might have an implication in what blood pressure drug you use. Angiotensin-converting enzyme inhibitors increase vascular distensibility and inhibit collagen formation and fibrosis. It is a pilot study and needs longitudinal follow up and additional patient accrual, however, finding signs of cardiovascular remodeling in young children with Cushing’s is intriguing and deserves further study.”

Neither Ms. Blain nor Dr. Lodish had any financial disclosures.

Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and Subclinical Cushing Syndrome

Eur J Endocrinol. 2016 Jul 22. pii: EJE-16-0465. [Epub ahead of print]

Abstract

OBJECTIVE:

Beneficial effects of adrenalectomy on cardiovascular risk factors in patients with Subclinical Cushing Syndrome (SCS) are uncertain. We sought to conduct a systematic review and meta-analysis with the following objectives: 1) determine the effect of adrenalectomy compared to conservative management on cardiovascular risk factors in patients with SCS and 2) compare the effect of adrenalectomy on cardiovascular risk factors in patients with SCS versus those with a non-functioning (NF) adrenal tumor.

METHODS:

Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial were searched on November 17th, 2015. Reviewers extracted data and assessed methodological quality in duplicate.

RESULTS:

We included 26 studies reporting on 584 patients with SCS and 457 patients with NF adrenal tumors. Studies used different definitions of SCS. Patients with SCS undergoing adrenalectomy demonstrated an overall improvement in cardiovascular risk factors (61% for hypertension, 52% for diabetes mellitus, 45% for obesity and 24% for dyslipidemia). When compared to conservative management, patients with SCS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI 4.3 – 27.8) and diabetes mellitus (RR 3.9, 95%CI 1.5- 9.9), but not dyslipidemia (RR 2.6, 95%CI 0.97 -7.2) or obesity (RR 3.4 (95%CI 0.95-12)). Patients with NF adrenal tumors experienced improvement in hypertension (21/54 patients), however, insufficient data exist for comparison to patients with SCS.

CONCLUSIONS:

Available low to moderate quality evidence from heterogeneous studies suggests a beneficial effect of adrenalectomy on cardiovascular risk factors in patients with SCS overall and as compared to conservative management.

[PubMed – as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/27450696

Six controversial issues on subclinical Cushing’s syndrome

Abstract

Subclinical Cushing’s syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality.

The subclinical Cushing’s syndrome is not rare, being estimated to be between 0.2–2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing’s syndrome screening, diagnosis and treatment.

The Altogether to Beat Cushing’s syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing’s syndrome viewpoint regarding the following controversial issues on Subclinical Cushing’s syndrome (SCS):

(1) Who has to be screened for subclinical Cushing’s syndrome?
(2) How to screen the populations at risk?
(3) How to diagnose subclinical Cushing’s syndrome in patients with an adrenal incidentaloma?
(4) Which consequence of subclinical Cushing’s syndrome has to be searched for?
(5) How to address the therapy of choice in AI patients with subclinical Cushing’s syndrome?
(6) How to follow-up adrenal incidentaloma patients with subclinical Cushing’s syndrome surgically or conservatively treated?

Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing’s syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing’s syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing’s syndrome.

Keywords

Subclinical hypercortisolism, Adrenal incidentalomas, Hypertension, Diabetes, Osteoporosis

Endocrine Society Releases Guidelines on Treatment of Cushing’s Syndrome

To lessen the risk for comorbidity and death, the Endocrine Society’s newly published guidelines on the treatment of Cushing’s syndrome focus on surgical resection of the causal tumor with the goal of normalizing cortisol levels. Furthermore, there is increased emphasis on individualizing treatment options when choosing a second-line treatment.

In July 2015, the Endocrine Society published treatment guidelines to assist endocrinologists in appropriately initiating treatment or referring patients with Cushing’s syndrome to treatment. A task force of experts compiled evidence from systematic reviews and graded the strength of the recommendations.

“We hope that it will lead to improved treatment of comorbidities both before and after definitive treatment of the syndrome, and to increased individualization of patient treatment,” said chair of the task force Lynnette Nieman, MD, who is chief of the Endocrinology Consultation Service at the National Institutes of Health Clinical Center.

“There are two new drugs that were approved in 2012, and so I think that is what prompted the review. Still, medications are not the first line of treatment, but we have some new therapeutic options, and I think the idea was to help people understand where to use them,” Julie Sharpless, MD, assistant professor and director of the UNC Multidisciplinary Pituitary Adenoma Program, told Endocrinology Advisor.

“The primary treatment is surgical resection of the causal tumor(s). If that cannot be done (because the tumor is occult or metastatic) or is not successful, then the choice of secondary treatment should be individualized to the patient. The comorbidities of Cushing’s syndrome, for example hypertension and diabetes, should be treated separately as well,” Nieman said.

For example, the guidelines recommend surgical removal of the causative lesion, with the exception of cases which are unlikely to cause a drop in glucocorticoids or in patients who are not surgical candidates.

Likewise, in patients with benign unilateral adrenal adenoma, adrenalectomy by an experienced surgeon has a high rate of cure in children and adults. Because of the poor prognosis associated with adrenal carcinoma, the guidelines highlight the need for complete resection and possibly medical treatment to stabilize cortisol levels.

Other first-line treatment options include recommending surgical resection of ectopic ACTH-secreting tumors; referring to an experienced pituitary surgeon for transsphenoidal selective adenomectomy; treatments to block hormone receptors in bilateral micronodular adrenal hyperplasia; and surgical removal in bilateral adrenal disorders.

The elevated mortality rate seen in patients with Cushing’s syndrome is due to infection, venous thrombosis and cardiovascular disease (CVD). Appropriately lowering cortisol levels improves hypertension, insulin resistance, dyslipidemia and obesity in patients with Cushing’s syndrome. Therefore, the guidelines highlight the need for restoring cortisol levels and treating the associated comorbidities.

Nevertheless, the task force specifically recommends against treatment without an established diagnosis or when there are no signs of Cushing’s syndrome and hypothalamic-pituitary-adrenal laboratory studies are borderline.

In patients who are not surgical candidates or in cases of noncurative resection, the decision on whether to consider second-line treatment options such as medical therapy, radiation, bilateral adrenalectomy or repeat transsphenoidal surgery should be based on several factors. For instance, the guidelines recommend taking into consideration location and size of the tumor, patient desires, goals of treatment and level of biochemical control.

The guidelines note medical therapy should be based on cost, efficacy and individualization of treatment. Endocrinologists can approach medical therapy with a goal of establishing normal cortisol levels or reducing cortisol levels to very low levels and replacing to achieve desired levels.

Remission in Cushing’s syndrome is associated with notable improvement; however, long-term follow-up is recommended for osteoporosis, CVD and psychiatric conditions.

After treatment, patients may experience reductions in weight, blood pressure, lipids and glucose levels that may allow reduction or discontinuation of medications. Even so, patients with a history of Cushing’s syndrome tend to have higher rates of hypertension, hyperlipidemia and diabetes. Likewise, rates of myocardial infarction are higher in this population, further emphasizing the need for treatment and management of diabetes and hypertension.

Sharpless highlighted that Cushing’s syndrome is rare.

“There are multiple studies that have shown that patients do better when they are treated in a specialty center where people see a lot of cases of this. So in that sense, treatment is not usually going to fall to the general practitioner,” she said.

She continued that the guidelines are helpful and provide guidance to endocrinologist who “can’t readily refer their patient to a pituitary center.”

Sharpless went on to describe the multidisciplinary care involved in Cushing’s syndrome including endocrinologists, neurosurgeons, radiologists, counselors and radiation oncologist.

“When the care is complicated, you want to ensure all of your providers have reviewed your case together and figured out the best plan.”

The guidelines were co-sponsored by the European Society of Endocrinology. Nieman received salary support for her work on the manuscript from the Intramural Research Program of the Eunice Kennedy Shiver Institute of Child Health and Human Development. Members of the task force reported multiple disclosures.

Reference

  1. Nieman LK et al. J Clin Endocrinol Metab. 2015;100(8):2807-2831.

From http://www.endocrinologyadvisor.com/adrenal/cushings-syndrome-endocrine-society-guidelines/article/434307/

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