Diagnostic pitfalls in Cushing’s disease impacting surgical remission rates; test thresholds and lessons learned in 105 patients

J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print.

ABSTRACT

CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection.

OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD.

DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD.

MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI.

RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion.

CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

PMID:34478542 | DOI:10.1210/clinem/dgab659

Metabolic profile differences in ACTH-dependent and ACTH-independent Cushing syndrome

Abstract

Background

The most common etiologies of Cushing’s syndrome (CS) are adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients.

Methods

A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009–2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups.

Results

Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, P = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, LDL-C, HDL-C, triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two.

Conclusions

Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics.

Keywords

Cushing’s syndrome
Pituitary Cushing’s
Adrenal Cushing’s
Metabolic disturbance

ACTH-independent Cushing’s syndrome due to bilateral adrenocortical adenoma

https://doi.org/10.1016/j.radcr.2021.07.093

 

Abstract

The chronic excess of glucocorticoids results in Cushing’s syndrome. Cushing’s syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others.

ACTH independent Cushing’s syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas.

In this paper we report a case of a 43-year-old woman with Cushing’s syndrome due to bilateral adrenal adenoma.

Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690

Cushing’s Found to Cause ‘Persistent Mental Health Problems’ in Patients

For years before and after their diagnosis, people with Cushing’s disease use more psychotropic medications — those that affect mood, thoughts, or perception — for mental health problems than their healthy peers, a study in Sweden found.

Notably, patients experiencing long-term disease remission still showed higher use of antidepressants and sleeping pills than healthy individuals.

These findings highlight Cushing’s persistent negative effects on mental health, according to researchers.

Additionally, the results of this study, based on prescribed medication dispenses in Sweden, support the importance of earlier diagnoses of Cushing’s disease — and the need for close and long-term monitoring of neuropsychiatric symptoms in this patient population, the researchers said.

The study, “Psychotropic drugs in patients with Cushing’s disease before diagnosis and at long-term follow-up — a nationwide study,” was published in the Journal of Clinical Endocrinology & Metabolism.

Mental health issues such as anxiety, depression, sleep disturbances, and cognitive impairments are part of the wide range of symptoms caused by the abnormally high levels of the cortisol hormone that characterize Cushing’s syndrome. Of note, Cushing’s disease is a form of Cushing’s syndrome caused by a tumor in the pituitary gland.

A “few” studies have reported the elimination or partial lessening of neuropsychiatric symptoms after successful Cushing’s treatment, according to the researchers.

But others noted that “impaired cognitive function and quality of life seemed to persist for a long time after biochemical [cortisol level-based] remission had been achieved,” the team wrote.

Now, these researchers, from several universities in Sweden, have assessed the use of psychotropic medications — reflecting mental health burden — in 372 people with Cushing’s disease. The use of such medications was assessed five years before diagnosis, at the time of diagnosis, and at five and 10 years post-diagnosis.

The patients, diagnosed between 1990 and 2018, were identified through the Swedish Pituitary Register, which covers 95% of all people with Cushing’s disease in the country. Most of the patients (76%) were women. Altogether, the patients’ mean age at diagnosis was 44 years.

For each individual with Cushing’s, four sex-, age-, and residential area-matched healthy individuals were used as controls for comparative analyses.

Data on each individual’s dispenses of medications commonly used for neuropsychiatric issues were obtained from the Swedish Prescribed Drug Register. This register, which fully covers all prescribed medications given throughout the country, also was used to determine each patient’s dispenses of other medications for Cushing’s disease symptoms, such as high blood pressure, also called hypertension, and diabetes.

The results showed that the use of antidepressants, anxiolytics — medications to lessen anxiety — and sleeping pills was at least twofold higher in Cushing’s patients than in healthy individuals during the five-year period before diagnosis, and at the time of diagnosis.

Five years after diagnosis, the proportion of patients using antidepressants (26%) and sleeping pills (22%) remained unchanged, and even individuals in remission showed significantly higher use of such medications than did controls (20–26% vs. 8.6–12%).

According to the results, one-third of the patients on antidepressants since their diagnosis were able to discontinue treatment before the five-year assessment — most having achieved disease remission. However, 47% of those receiving antidepressants at five years had initiated such treatment at a median of 2.4 years after diagnosis.

During the five-year follow-up, older age and being a woman appeared to increase the risk of antidepressant use among Cushing’s disease patients.

At 10 years of follow-up, the use of antidepressants and sleeping pills was not significantly different between groups, despite the fact that antidepressants use remained about the same among patients.

Notably, researchers conducted an analysis of 76 patients with sustained remission for a median of 9.3 years, and 292 matching controls. That analysis showed that the use of antidepressants and sleeping pills was significantly higher among patients.

The use of other medications, such as those for hypertension and diabetes, also was significantly more common among Cushing’s disease patients before, at diagnosis, and at five years post-diagnosis — although the post-diagnosis numbers dropped by half during that period.

After 10 years, only the use of anti-diabetic medications remained significantly higher in patients as compared with controls.

These findings suggest that other conditions associated with Cushing’s disease, such as hypertension and diabetes, are effectively lessened with treatment. However, they also highlight that “many patients with CD [Cushing’s disease] will have persistent mental health problems,” the researchers wrote.

In addition, visits to a psychiatrist and hospital admissions for treatment of psychiatric disorders tended to be more common among Cushing’s disease patients, even before diagnosis, the team noted.

“This nationwide register-based study shows that use of psychotropic drugs in CD patients is increased from several years before diagnosis,” the researchers wrote, adding that this use “remained elevated regardless of remission status, suggesting persisting negative effects on mental health,” the researchers wrote.

These findings highlight the importance of early diagnosis of Cushing’s disease and of considering neuropsychiatric symptoms “as an important part of the disease,” they concluded.

There is a “need for long-term monitoring of mental health” in Cushing’s, they wrote.

From https://cushingsdiseasenews.com/2021/02/24/cushings-found-to-cause-persistent-negative-mental-health-effects-swedish-study/

Successful Cushing’s Surgery Leads to Better Bone Density

Biomarkers in a majority of Cushing’s syndrome patients with surgically induced disease remission showed a high rate of bone turnover and greater bone mineral density one and two years later, a study reports.

Before treatment, these patients were found to have greater bone degradation and poorer bone formation, as can be common to disease-related bone disorders.

Researchers believe their work is the first study of its kind, “and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.”

The study, “The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study,” was published in the Journal of Bone and Mineral Research.

Two common co-conditions of Cushing’s syndrome are osteopenia, a loss of bone mass, and osteoporosis, in which the body makes too little bone, loses too much bone, or both. Studies suggest up to 80% of people with Cushing’s have evidence of reduced bone mineral density affecting the entire skeleton.

However, few risk factors to predict bone health have been identified so far, and guidelines for osteoporosis management due to Cushing’s are lacking. Uncertainty as to the natural course of osteoporosis once a diagnosis of Cushing’s syndrome has been made is also still evident.

Investigators at the University of Munich, reportedly for a first time, analyzed the natural course of bone mineral density and bone turnover (recycling) in a group of people with endogenous Cushing’s syndrome — which refers to the disease caused by excess cortisol in the bloodstream, often due to a tumor in the adrenal or pituitary glands.

They examined medical records of 89 Cushing syndrome patients with a mean age of 44, of which 74% were women. Of these, 65% had pituitary Cushing’s (Cushing’s disease), 28% had adrenal, and 7% had ectopic Cushing’s, which is caused by tumors outside the adrenal or pituitary glands. A group of 71 age- and sex-matched healthy participants were included as controls.

In all patients, blood samples were collected at the time of diagnosis (baseline) and one and two years after removing one or both adrenal glands or moving tumors affecting the pituitary gland. Blood samples were analyzed for biomarkers related to bone formation and degradation (resorption).

At the study’s beginning, the mean levels of two bone formation markers, osteocalcin and intact PINP, were significantly decreased in patients compared with controls, whereas the bone formation marker alkaline phosphatase was increased.

Both markers for bone degradation — called CTX and TrAcP — were also high, which demonstrated “increased bone resorption and decreased bone formation in [Cushing’s syndrome],” the team wrote.

While bone markers were similar in participants with a reduced bone mass relative to those with a normal bone mass, bone mineral density was lower overall. Bone mineral density was significantly lower in the neck and spine compared with the femur (thigh bone). Normal bone mineral density was reported in 28 (32%) patients, while 46 (52%) had osteopenia, and the remaining 15 (17%) lived with osteoporosis.

A history of low-trauma bone fractures due to osteoporosis occurred in 17 (19%) patients, taking place shortly before diagnosis in more than half of these (58%) people, and more than two years before a Cushing’s diagnosis in the remaining group (42%).

Compared to patients without fractures, those with fractures had a significantly lower T‐score, a bone density measure that represents how close a person is to average peak bone density. While Cushing’s subtype, age, or body mass index (BMI, body fat based on height) did not differ between groups, men had a significantly higher risk of fractures than women (35% of men vs. 14% of women).

Both disease severity and duration did not contribute to fractures rates, but urinary free cortisol (a circulating cortisol measure) was significantly higher in patients with a low T‐score.

At the one year after tumor removal, which led to Cushing’s remission based on blood tests, a significant increase in bone formation markers was reported. These biomarkers decreased slightly at two years post-surgery, but remained elevated.

At the beginning of the study, bone resorption markers were mildly increased, which rose further one year after surgery before returning almost to normal levels by two years. In parallel, bone density measures conducted in 40 patients showed a matching increase in T-score, particularly in the spine.

After two years, bone mineral density improved in 78% of patients, and T-scores improved in 45% of them. No fractures occurred after Cushing’s treatment, and there was no significant correlation between bone turnover markers and better bone mineral density.

“This study analyzes for the first time in a comprehensive way bone turnover markers during the course of [Cushing’s syndrome],” the researchers wrote. “Our data suggest that the phase immediately after remission from [Cushing’s syndrome] is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients.”

These results “will influence future therapeutic strategies in patients” with Cushing’s syndrome, they added.

 

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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