Who’s at Risk for Cushing’s?

by Kristen Monaco
Contributing Writer, MedPage Today

Researchers have developed a new method to assess specific populations for Cushing’s syndrome, based on results from a multicenter study.

The prospective cohort study evaluated at-risk patients for Cushing’s syndrome to create a novel type of scoring system in order to better predict the development of disease, stated lead author Antonio LeĂłn-Justel, PhD,of the Seville Institute of Biomedicine in Spain, and colleagues.

Cushing’s syndrome is identified by an excess of cortisol and/or glucocorticoids in the blood, which can result in myriad negative health outcomes, including an increased risk of death and morbidity, according to the study in The Journal of Clinical Endocrinology & Metabolism.

Because Cushing’s syndrome (CS) is complex and difficult to diagnose, there is a necessity for new methods to assess at-risk populations in order to mitigate the rising prevalence of the disorder, the authors noted.

“The diagnosis of CS might pose a considerable challenge even for experienced endocrinologists since there are no pathognomonic symptoms or signs of CS and most of the symptoms and signs of CS are common in the general population including obesity, hypertension, bone loss, and diabetes,” the senior author, Alfonso Leal Cerro, MD, toldMedPage Today via email. “Routine screening for CS remains impractical due to the estimated low prevalence of the disease. However this prevalence might be higher in at-risk populations.”

The authors screened a total of 353 at-risk patients from 13 different hospitals across Spain between January 2012 and July 2013 to measure cortisol variability from saliva samples.

At-risk populations, which the authors note have a higher prevalence of Cushing’s syndrome, included individuals with type 2 diabetes, hypertension, and osteoporosis.

The patients screened in the study were each identified as having at least two of the risk factors for Cushing’s syndrome: high blood pressure (defined as taking two or more drugs and having a systolic blood pressure over 140 mmHg and/or a diastolic blood pressure over 90 mmHg), obesity (body mass index >30), uncontrolled diabetes (HbA1c>7.0%), osteoporosis (T-score ≄ -2.5 SD), and virilization syndrome (hirsutism) with menstrual disorders.

The researchers used clinical and biochemical methods of assessment. Clinical methods included inspection of physical characteristics, such as muscle atrophy, purple striae, and/or facial plethora. Biochemical methods included collecting saliva and blood samples from participants to test cortisol levels using a chemiluminescence method. Each individual was identified as either negative for hypercortisolism (late-night salivary cortisol [LNSC] ≀ 7.5 nmol/L and dexamethasone suppression test [DST] ≀ 50 nmol/L) or positive for hypercortisolism (LNSC > 7.5 nmol/L and DST > 50 nmol/L).

Univariate testing indicated the following significant characteristics to be positively correlated with the development of Cushing’s syndrome:

  • Muscular atrophy (15.2, CI 95% 4.48-51.25);
  • Osteoporosis (4.60, 1.66-12.75); and
  • Dorsocervical fat pad (3.32, 1.48-7.5).

A logistic regression analysis of LNSC values also showed significant correlation between Cushing’s syndrome and the following top three characteristics:

  • Muscular atrophy (9.04, CI 95% 2.36-34.65);
  • Osteoporosis (3.62, CI 95% 1.16-11.35); and
  • Dorsocervical fat pad (3.3, CI 95% 1.52-7.17).

Roberto Salvatori, MD, professor and medical director of the Johns Hopkins Pituitary Center, who was not involved with the study, commented to MedPage Today in an email: “Any endocrinologist would proceed with careful Cushing biochemical evaluation in the presence of the clinical features (muscular atrophy, osteoporosis, and dorsocervical fat pad) that are well known to be associated with hypercortisolism. Of notice, the odds ratio is further increased by an abnormal late-night salivary cortisol, which is already a screening test for hypercortisolism.”

The researchers used their results to develop an equation to determine the level of risk a patient has for developing Cushing’s syndrome, taking into account factors for osteoporosis, dorsocervical fat pads, muscular atrophy, and LNSC levels.

Although the study was able to develop a comprehensive risk model for the syndrome, when tested against the prevalence for Cushing’s syndrome in the subject group, the equation generated a total of 56 false-positive and 25 true-positive results. Overall, the researchers wrote, 83% of patients were accurately classified as belonging to the at-risk population when using the equation.

Because the newly developed equation for identifying at-risk individuals involved factors that are relatively easy to test for, the authors noted that clinical application is broad and cost-effective in a primary care setting.

“We would like to test the scoring system in different clinical settings such as primary care or hypertension clinics,” Leal Cerro said. “Primary care would be a particularly interesting setting since it might significantly decrease the time to diagnosis, something critical to avoid an excessive exposure to glucocorticoid excess and consequent deleterious effects.”

Salvatori said that while the study was a good start at shedding light on some of the unknowns about Cushing’s syndrome, more research is required. “The real question in my mind is when does a non-endocrinologist need to suspect Cushing in a general medicine, orthopedic, or other clinic? When the internal medicine residents ask me about guidelines for ‘who to screen for hypercortisolism in my clinic,’ I am unable to provide an evidence-based answer.”

The study was funded by a grant from Novartis Oncology, Spain.

LeĂłn-Justel and Leal Cerro disclosed financial relationships with Novartis Oncology, Spain.

  • Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 08.15.2016

What is the Best Approach to Suspected Cyclical Cushing Syndrome?

Strategies for Managing Cushing’s Syndrome With Variable Laboratory Data

Brew Atkinson, Karen R. Mullan

Disclosures

Clin Endocrinol. 2011;75(1):27-30.

 

Abstract

Cyclical Cushing’s syndrome is a pattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This syndrome is often associated with fluctuating symptoms and signs. It is now being increasingly recognized. The phenomenon is important because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. The techniques and criteria, protocols and dynamic biochemical tools to detect cycling in patients with hypercortisolism are discussed as are the strategies for diagnosing and managing this important subgroup of patients with hypercortisolism.

Introduction

Cyclical Cushing’s syndrome (CS) is a pattern in hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This can also be associated with fluctuating symptoms and signs. This type of case was initially thought to be rare. However, it has recently been recognized as occurring much more frequently. The phenomenon is important because, if not recognized, it can lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. All of these can have very serious clinical consequences.

As a result of reading this article, it is hoped that readers will be better able to consider more carefully the risks associated with too wide a diagnostic trawl for the diagnosis of CS and the associated chances of finding some abnormality of steroid biochemistry.

In cases where the diagnosis is being strongly considered, the risks of not considering episodic secretion when laboratory results are discordant are discussed. Readers should be able to plan strategies to assess for variable and cyclical secretion and to use these in diagnosis, differential diagnosis and treatment assessments.

Read more here: What is the best approach to suspected cyclical Cushing syndrome?

When to think Cushing’s syndrome in type 2 diabetes

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing’s disease patients: key role of AVPR1b receptor and potential therapeutic implications

Journal of Clinical Endocrinology and Metabolism, 07/25/2013  Review Article

Luque RM et al. – The study aims to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release, and to elucidate the cellular and molecular mechanisms involved in desmopressin–induced ACTH increase in Cushing’s disease (CD).

The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and post–surgery prognosis of CD.

Furthermore, the data indicates that AVPR1b is responsible of the direct/exclusive desmopressin–stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b–antagonists as potential therapeutic tools for CD treatment.

~~~~~~~~

Abstract

  1. RM Luque1,#,
  2. A Ibåñez-Costa1,#,
  3. LM LĂłpez-SĂĄnchez1,
  4. L Jiménez-Reina2,
  5. E Venegas-Moreno3,
  6. MA GĂĄlvez4,
  7. A Villa-Osaba1,
  8. AM Madrazo-Atutxa3,
  9. MA JapĂłn5,
  10. A de la Riva6,
  11. DA Cano3,
  12. P Benito-LĂłpez4,
  13. A Soto-Moreno3,
  14. MD Gahete1,
  15. A Leal-Cerro3,*and
  16. JP Castaño1,*

Author Affiliations


  1. 1Department of Cell Biology, Physiology and Immunology University of Córdoba, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn); 14014, Córdoba, Spain.

  2. 2Department of Morphological Sciences, University of CĂłrdoba. CĂłrdoba, Spain.

  3. 3Instituto de Biomedicina de Sevilla (IBiS), University Hospital Virgen del RocĂ­o/Consejo Superior de Investigaciones CientĂ­ficas/University of Seville and Endocrinology, Metabolism and Nutrition Unit, Virgen del RocĂ­o University Hospital, Seville, Spain.

  4. 4Service of Endocrinology and Nutrition, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC). Córdoba, Spain.

  5. 5Department of Pathology, Virgen del Rocio University Hospital, Seville, Spain.

  6. 6Service of Neurosurgery, Reina SofĂ­a University Hospital CĂłrdoba, Spain.
  1. Address all correspondence and requests for reprints to: RaĂșl M. Luque and Justo P. Castaño.Department of Cell Biology, Physiology and Immunology; Campus Universitario de Rabanales, Edificio Severo Ochoa (C6), Planta 3; University of CĂłrdoba, E-14014 CĂłrdoba, Spain. Phone:(34)-957218594. Fax: (34)-957218634. E-mails: raul.luque@uco.es; justo@uco.es.
  1. ↔# These authors have codirected this study.

Abstract

Context: Desmopressin is a synthetic agonist of vasopressin-receptors (AVPRs). Desmopressin stimulation test is employed in the diagnosis and post-surgery prognosis of Cushing’s disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in CD patients are poorly understood.

Objective: 1) To determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release, and 2) to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD.

Design: 8 normal-pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning-pituitary adenomas (NFPA), 17 somatotropinomas and 3 prolactinomas were analyzed for AVPRs-expression by qrtPCR. Primary cultures derived from corticotropinomas, NFPAs, somatotropinomas, prolactinomas and NPs were treated with desmopressin and ACTH-secretion/expression, [Ca2+]i-kinetics, AVPRs-expression and/or proliferative-response were evaluated. The relationship between AVPRs-expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin-tests was assessed.

Results: Desmopressin affects all functional parameters evaluated in corticotropinoma-cells but not in NPs or other pituitary-adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b-antagonist completely blocked desmopressin-stimulatory effects. Remarkably, only AVPR1b-expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas.

The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and post-surgery prognosis of CD. Furthermore, our data indicates that AVPR1b is responsible of the direct/exclusive desmopressin-stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b-antagonists as potential therapeutic tools for CD treatment.

Footnotes

  • ↔* These authors have codirected this study.

Full Text (PDF)

Cushing’s Syndrome is Hazardous to Your Health

morbidity

People with Cushing’s syndrome, even when treated, have higher morbidity and mortality rates that comparable controls. That is the conclusion of a new study published in the June issue of the Journal of Clinical Endocrinology Metabolism. The study by Olaf Dekkers et al, examined data records from the Danish National Registry of Patients and the Danish Civil Registration System of 343 patients with benign Cushing’s syndrome of adrenal or pituitary origin (i.e., Cushing’s disease) and a matched population comparison cohort (n=34,300).  Due to the lengthy delay of many patients being diagnosed with Cushing’s syndrome, morbidity was investigated in the 3 years before diagnosis while  morbidity and mortality were assessed during complete follow-up after diagnosis and treatment.

The study found that mortality was twice as high in Cushing’s syndrome patients (HR 2.3, 95% CI 1.8-2.9) compared with controls over a mean follow-up period of 12.1 years. Furthermore, patients with Cushing’s syndrome were at increased risk for:

  • venous thromboembolism (HR 2.6, 95% CI 1.5-4.7)
  • myocardial infarction (HR 3.7, 95% CI 2.4-5.5)
  • stroke (HR 2.0, 95% CI 1.3-3.2)
  • peptic ulcers (HR 2.0, 95% CI 1.1-3.6)
  • fractures (HR 1.4, 95% CI 1.0-1.9)
  • infections (HR 4.9, 95% CI 3.7-6.4).

The study also found that this increased multimorbidity risk was present before diagnosis indicating that it was due to cortisol overproduction rather than treatment.

Many of the Cushing’s syndrome patients underwent surgery to remove the benign tumor. For this group, the investigators performed a sensitivity analysis of the  long-term mortality and cardiovascular risk in this  subgroup (n=186)  considered to be cured after operation (adrenal surgery and patients with pituitary surgery in combination with a diagnosis of hypopituitarism in the first 6 months after operation).  The risk estimates for mortality (HR 2.31, 95% CI 1.62-3.28), venous thromboembolism (HR 2.03, 95% CI 0.75-5.48), stroke (HR 1.91, 95% CI 0.90-4.05), and acute myocardial infarction (HR 4.38, 95% CI 2.31-8.28) were also increased in this subgroup one year after the operation.

The standard treatment for endogenous Cushing’s syndrome is surgery. This past year, Signifor (pasireotide) was approved for treatment of adults patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.  Cushing’s disease, which accounts for the majority of Cushing’s syndrome patients, is defined as the presence of an ACTH producing tumor on the pituitary grand. In the study by Dekker’s et al, the percentage of patients with Cushing’s disease is not known. We look forward to reexamination of this dataset in a few years following the introduction of more treatment options for Cushing’s disease as well as an analysis that explores the differences in mortality/morbidity rates in the different subsets of patients that make of Cushing’s syndrome (Cushing’s disease, ectopic Cushing’s syndrome, Exogenous Cyshing’s syndrome).

References

Dekkers OM, Horvath-Pujo, Jorgensen JOL, et al, Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 2013 98(6): 2277–2284. doi: 10.1210/jc.2012-3582

– See more at: http://www.raredr.com/medicine/articles/cushing%E2%80%99s-syndrome-hazardous-your-health-0

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