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

Corcept Therapeutics Announces Partnership With Idis for Global Access to Korlym(R)

PRINCETON, NJ and MENLO PARK, CA, Jul 24, 2013 (Marketwired via COMTEX) — Corcept Therapeutics Incorporated CORT  announced today that Korlym(R) (mifepristone) 300 mg Tablets is available to patients outside of the United States through an Idis Access Program.

Idis Access Programs enable patients around the world to be prescribed investigational or approved drugs prior to their commercial launch in that country through a regulatory-compliant and ethical channel on a named-patient basis. Corcept, a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders, has been offering Korlym in the United States since April 2012 as a once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.

“We are pleased to partner with Idis so that physicians outside the United States can prescribe Korlym,” said Steven Lo, Corcept’s Vice President of Commercial Operations. “We are dedicated to meeting the needs of patients worldwide. Our partnership with Idis will help us make sure that every Cushing’s syndrome patient who could benefit from Korlym will have access to the medicine.”

Charles Simmons, President of Established Brands at Idis said of the partnership, “We are very excited to work with Corcept to provide patients around the world with access to this important treatment. Patients are at the heart of what we do at Idis and providing access to an important medicine like Korlym, creating a bridge to treatment irrespective of the number of patients involved, is one of the ways we do it”.

Licensed healthcare professionals outside the United States with patients who might benefit from Korlym should contact Idis directly:

Idis UK & Eire Enquiries Tel: +44 (0) 1932 824 100 Fax: +44 (0) 1932 824 300 Email: uk@idispharma.com

Idis Rest of the World Enquiries Tel: +44 (0) 1932 824 123 Fax: +44 (0) 1932 824 323 Email: internationalsales@idispharma.com

About Cushings Syndrome Endogenous Cushing’s syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing’s syndrome is an orphan indication that most commonly affects adults aged 20 to 50. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system in the body and can be fatal if not treated effectively.

About Corcept Therapeutics Incorporated Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. Korlym, a first generation GR-II antagonist, is the company’s first FDA-approved medication. Corcept has a phase 3 trial underway for mifepristone for treatment of the psychotic features of psychotic depression and a portfolio of selective GR-II antagonists that block the effects of cortisol but not progesterone. It owns extensive intellectual property covering the use of GR-II antagonists, including mifepristone, in the treatment of a wide variety of metabolic and psychiatric disorders. It also holds composition of matter patents for its selective GR-II antagonists. For more information about Corcept please visit: http://www.corcept.com

About Idis Idis has 25 years experience partnering with pharmaceutical and biotechnology companies to create regulatory-compliant, ethical access to medicines for healthcare professionals and their patients with unmet medical needs. Since 1987, Idis has developed and managed access to thousands of medicines from every therapeutic category, impacting the lives of hundreds of thousands of patients in countries around the world.

Idis leverages decades of experience, regulatory insight, and a thorough understanding of local and global requirements to create access to medicines at every stage of a product’s lifecycle from pre-approval to market exit, and in times of unexpected production shortages.

The company’s European headquarters are located in Weybridge, United Kingdom, and North American headquarters are located in Princeton, NJ.

For more information about Idis please visit http://www.idispharma.com.

From Marketwatch

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 Ibáñez-Costa1,#,
  3. LM López-Sánchez1,
  4. L Jiménez-Reina2,
  5. E Venegas-Moreno3,
  6. MA Gálvez4,
  7. A Villa-Osaba1,
  8. AM Madrazo-Atutxa3,
  9. MA Japón5,
  10. A de la Riva6,
  11. DA Cano3,
  12. P Benito-López4,
  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 Córdoba. Córdoba, Spain.

  3. 3Instituto de Biomedicina de Sevilla (IBiS), University Hospital Virgen del Rocío/Consejo Superior de Investigaciones Científicas/University of Seville and Endocrinology, Metabolism and Nutrition Unit, Virgen del Rocío 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 Sofía University Hospital Córdoba, Spain.
  1. Address all correspondence and requests for reprints to: Raúl 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 Córdoba, E-14014 Córdoba, Spain. Phone:(34)-957218594. Fax: (34)-957218634. E-mails: raul.luque@uco.esjusto@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)

Laparoscopic Bilateral Transperitoneal Adrenalectomy For Cushing Syndrome

Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 07/16/2013  Clinical Article

Aggarwal S et al. –

Laparoscopic adrenalectomy is well established for treatment of adrenal lesions. However, bilateral adrenalectomy for Cushing syndrome is a challenging and time–consuming operation.

The authors report their experience of laparoscopic bilateral adrenalectomy for this disease in 19 patients. Laparoscopic bilateral adrenalectomy for Cushing syndrome is feasible and safe. It confers all the advantages of minimally invasive approach such as less postoperative pain, shorter hospitalization, lesser wound complications, and faster recovery.

The advantages of the laparoscopic approach have led to an earlier referral for bilateral adrenalectomy by endocrinologist in patients with failed pituitary surgery.

 

This article is available on PubMed

Cushing’s Disease – Rare Disease Quick Facts

cushings-diagnosis

 

 

Cushing’s disease is a rare condition due to excess cortisol levels that result from a pituitary tumor secreting adrenocorticotropic hormone (ACTH), which stimulates cortisol secretion.  Cushing’s disease should not be confused with Cushing’s syndrome which is increased cortisol levels but that increase can be due to any number of factors. However, Cushing’s disease is the most common form of Cushing’s syndrome.

Symptoms

The symptoms related to Cushing’s disease and Cushing’s syndrome are the same, since both are related to an excess of cortisol. Also, symptoms vary extensively among patients and that, with the inherent fluctuation in hormone levels make it difficult to diagnosis both conditions.

Changes in physical characteristics of the body

  • Fullness and rounding of the face
  • Added fat on back of neck (so-called “buffalo hump”)
  • Easy bruising
  • Purplish stretch marks on the abdomen (abdominal striae)
  • Excessive weight gain, especially in abdominal region
  • Red cheeks
  • Excess hair growth on the face, neck, chest, abdomen and thighs

Changes in physiology/psychology

  • Generalized weakness and fatigue
  • Menstrual disorder
  • Decreased fertility and/or sex drive
  • High blood pressure that is often difficult to treat
  • Diabetes mellitus
  • Mood and behavior disorders

Diagnosis

The early stages of Cushing’s disease may be difficult to recognize. However, if it is suspected, diagnosis is generally a 2 stage process. First to determine if cortisol levels are high, and if so, why they are high.

Tests to confirm high cortisol levels:

  • 24-hour urine cortisol
  • Dexamethasone suppression test (low dose)

Tests to determine cause:

  • Blood ACTH level
  • Brain MRI
  • Corticotropin-releasing hormone test
  • Dexamethasone suppression test (high dose)
  • Petrosal sinus sampling

Treatment

Surgery

  • Most patients with Cushing’s disease undergo surgery to remove the pituitary adenoma offers.
  • If the tumor is isolated to the pituitary, cure rates of 80-85% are common.
  • If the tumor has spread to nearby organs, cure rates of 50-55% are common.

Medicine (approved orphan drugs)

Signifor (pasireotide)

  • Approved for patients with Cushing’s disease for whom pituitary is not an option or surgery has been ineffective.
  • Signifor is a somatostatin receptor agonist that leads to inhibition of ACTY secretion (and subsequently decreased cortisol levels).

Korlym (mifepristone)

  • Approved for patients with Cushing’s syndrome who have type 2 diabetes or glucose intolerance and have failed surgery (or not candidates for surgery).
  • Korlym is a glucocorticoid receptor antagonist which in turn blocks the effects of the high levels of cortisol in the body. Korlym is used to treat high glucose levels due to elevated cortisol.

Medicines used but not indicated for Cushing’s disease include

Mitoden

ketoconazole

Metyrapone

Etomidate

Radiation

  • Radiation therapy may be used in some patients and can be very effective in controlling the growth of these tumors.

Prognosis

In most cases, treatment can cure Cushing’s disease. If not treated properly, the chronic hypercortisolism can lead to excess morbidity and mortality due to increased cardiovascular and other risk factors.

For more information

National Library of Medicine, National Institute of Health

Cushing’s Disease Information (provided by Novartis Pharmaceuticals)

 

Images courtesy of the open access journal Orhanet Journal for Rare Diseases.  Castinetti et al. Orphanet J Rare Dis. 2012 7:41   doi:10.1186/1750-1172-7-41

– See more at: http://www.raredr.com/front-page-medicine/articles/cushings-disease-rare-disease-quick-facts-0

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