Cushing Death Rate ‘Unacceptable,’ Triple That of General Population

Posted on April 15, 2021 by MaryO

Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population…. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet…. This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded.”

Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications…. We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest Study in Scale and Scope of Cushing Syndrome Mortality

Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome,” Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84).

This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (P = .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (P < .001).

The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing Perioperative Mortality: Consider Thromboprophylaxis

Fleseriu told Medscape Medical News that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk,” Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

From https://www.medscape.com/viewarticle/949257

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Mortality rate in Cushing’s syndrome ‘unacceptably high’

Posted on March 25, 2021 by MaryO

A large study of mortality in Cushing’s syndrome calculated a threefold higher mortality rate for these patients, with cerebrovascular and atherosclerotic vascular diseases and infection accounting for 50% of deaths, researchers reported.

“[We have seen] improvement in outcome since 2000, but mortality is still unacceptably high,” Padiporn Limumpornpetch, MD, an endocrinologist at Prince of Songkla University in Thailand and PhD student at the University of Leeds, U.K., told Healio during the ENDO annual meeting. “The mortality outcome has shown an unacceptable standardized mortality rate of 3:1, with poorer outcomes in patients with adrenal Cushing’s [and] active and larger tumors in Cushing’s disease.”

Atherosclerotic vascular disease was the top cause of death in Cushing’s disease, with infection coming in as the second-highest cause of death. Data were derived from Limumpornpetch P. OR04-4. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

For a meta-analysis and meta-regression analysis of cause of death among patients with benign endogenous Cushing’s syndrome, Limumpornpetch and colleagues reviewed data published from 1952 to January 2021 from 92 study cohorts with 19,181 patients that reported mortality rates, including 66 studies that reported causes of death.

The researchers calculated the standardized mortality rate (SMR) for Cushing’s syndrome at 3 (95% CI, 2.3-3.9). For patients with adrenal Cushing’s syndrome, SMR was 3.3 (95% CI, 0.5-6.6) — higher than for those with Cushing’s disease, with an SMR of 2.8 (95% CI, 2.1-3.7). Rates were similar by sex and by type of adrenal tumor.

Deaths occurring within 30 days of surgery for Cushing’s syndrome fell to 3% after 2000 from 10% before that date (P < .005). During the entire study period, atherosclerotic vascular disease accounted for 27.4% of deaths in Cushing’s syndrome, and 12.7% were attributable to infection, 11.7% to cerebrovascular diseases, 10.6% to malignancy, 4.4% to thromboembolism, 2.9% to active disease, 3% to adrenal insufficiency and 2.2% to suicide.

“We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population,” Limumpornpetch said.

From https://www.healio.com/news/endocrinology/20210322/mortality-rate-in-cushings-syndrome-unacceptably-high

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Largest-ever analysis of its kind finds Cushing’s syndrome triples risk of death

Posted on March 22, 2021 by MaryO

WASHINGTON–Endogenous Cushing’s syndrome, a rare hormonal disorder, is associated with a threefold increase in death, primarily due to cardiovascular disease and infection, according to a study whose results will be presented at ENDO 2021, the Endocrine Society’s annual meeting.

The research, according to the study authors, is the largest systematic review and meta-analysis to date of studies of endogenous (meaning “inside your body”) Cushing’s syndrome. Whereas Cushing’s syndrome most often results from external factors–taking cortisol-like medications such as prednisone–the endogenous type occurs when the body overproduces the hormone cortisol, affecting multiple bodily systems.

Accurate data on the mortality and specific causes of death in people with endogenous Cushing’s syndrome are lacking, said the study’s lead author, Padiporn Limumpornpetch, M.D., an endocrinologist from Prince of Songkla University, Thailand and Ph.D. student at the University of Leeds in Leeds, U.K. The study analyzed death data from more than 19,000 patients in 92 studies published through January 2021.

“Our results found that death rates have fallen since 2000 but are still unacceptably high,” Limumpornpetch said.

Cushing’s syndrome affects many parts of the body because cortisol responds to stress, maintains blood pressure and cardiovascular function, regulates blood sugar and keeps the immune system in check. The most common cause of endogenous Cushing’s syndrome is a tumor of the pituitary gland called Cushing’s disease, but another cause is a usually benign tumor of the adrenal glands called adrenal Cushing’s syndrome. All patients in this study had noncancerous tumors, according to Limumpornpetch.

Overall, the proportion of death from all study cohorts was 5 percent, the researchers reported. The standardized mortality ratio–the ratio of observed deaths in the study group to expected deaths in the general population matched by age and sex–was 3:1, indicating a threefold increase in deaths, she stated.

This mortality ratio was reportedly higher in patients with adrenal Cushing’s syndrome versus Cushing’s disease and in patients who had active disease versus those in remission. The standardized mortality ratio also was worse in patients with Cushing’s disease with larger tumors versus very small tumors (macroadenomas versus microadenomas).

On the positive side, mortality rates were lower after 2000 versus before then, which Limumpornpetch attributed to advances in diagnosis, operative techniques and medico-surgical care.

More than half of observed deaths were due to heart disease (24.7 percent), infections (14.4 percent), cerebrovascular diseases such as stroke or aneurysm (9.4 percent) or blood clots in a vein, known as thromboembolism (4.2 percent).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism and good infection control and emphasize the need to achieve disease remission, normalizing cortisol levels,” she said.

Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to put the disease in remission, other treatments are available, such as medications.

Study co-author Victoria Nyaga, Ph.D., of the Belgian Cancer Centre in Brussels, Belgium, developed the Metapreg statistical analysis program used in this study.

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The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

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From https://www.eurekalert.org/pub_releases/2021-03/tes-lao031621.php

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Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency

Posted on February 21, 2021 by MaryO
A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134).
It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor.
The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality.
The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096

Abstract

Context

Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations.

Objective

To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population.

Design

Retrospective cohort study.

Setting

UK general practitioner database (CPRD).

Participants

6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134).

Main outcome measures

All-cause and cause-specific mortality; hospital admission from adrenal crisis.

Results

With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 – 1.77]. HRs were greater in primary (1.83 [1.66 – 2.02]) than in secondary (1.52 [1.40 – 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 – 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 – 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years.

Conclusion

Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality.

PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext

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Even in Remission, Cushing’s Patients Have Excess Mortality

Posted on March 11, 2019 by MaryO

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/

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