Study links genetic mutations, Cushing syndrome

Posted on June 6, 2017 by MaryO

Researchers have determined mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.

The National Institutes of Health study findings published in Endocrine-Related Cancer found four of the 181 children and adult patient examined had mutant forms of CABLES1 that do not respond to cortisol.

The determination proved significant because normal functioning CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH).

Researchers at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) joined scientists from other institutions in the United States, France and Canada, in the evaluation.

“The mutations we identified impair the tumor suppressor function in the pituitary gland,” Constantine A. Stratakis, the study’s senior author and director of the NICHD Division of Intramural Research, said. “This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.”

Cushing syndrome symptoms include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety, officials said, adding excess cortisol found in the disorder can result from certain steroid medications or from tumors of the pituitary or adrenal glands.

Researchers maintain that more studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.

 

From https://lifesciencedaily.com/stories/21624-study-links-genetic-mutations-cushing-syndrome/

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Prednisolone May Raise Cholesterol in Adrenal Insufficiency

Posted on April 4, 2017 by MaryO

Prednisolone treatment of patients with adrenal insufficiency is associated with significantly elevated total-and low-density-lipoprotein (LDL) cholesterol levels compared with use of an alternative glucocorticoid, hydrocortisone, new data suggest.

Real-world data from the European Adrenal Insufficiency Registry (EU-AIR) were presented on April 2 here at ENDO 2017: The Endocrine Society Annual Meeting by Robert D Murray, MBBS, consultant endocrinologist and honorary associate professor at Leeds Teaching Hospitals NHS Trust, United Kingdom.

In an interview, Dr Murray told Medscape Medical News, “In addition to previous data showing that prednisolone can cause lower bone mass, we’ve now shown that it may raise cholesterol to a higher degree than hydrocortisone.”

Asked to comment, session moderator Constantine A Stratakis, MD, chief medical officer of the National Institute of Child Health & Human Development, Bethesda, Maryland, said: “These are significant findings. I think that the difference he’s seeing may be mostly due to the differences in how glucocorticoids are metabolized locally in the liver and fat tissues.”

Regarding clinical implications, Dr Stratakis said, “These data point to the need for using hydrocortisone. Clearly, at these doses anyway, you have increases in LDL and cholesterol with prednisolone.”

Indeed, the new findings support recent recommendations from the Endocrine Society to use hydrocortisone as first-line glucocorticoid replacement therapy for primary adrenal insufficiency.

But the huge cost difference between the two generic medications has led some to suggest otherwise. In 2014, the BMJ published editorials arguing both for and against the preferred use of prednisolone.

During his presentation, Dr Murray reported that in the United Kingdom, an annual supply of 5-mg prednisolone (one tablet a day) costs about £16 and 3 mg (three 1-mg tablets a day) about £48, compared with £1910 for a year’s supply of twice-daily 10-mg hydrocortisone.

(Hydrocortisone is also considerably more expensive than prednisolone in the United States, although the differential isn’t quite as dramatic.)

Dr Murray pointed out that about 75% of the patients in the database were taking 5 mg/day of prednisolone and that although that’s within the recommended range (3–5 mg/day), it might be too much. “I suspect this isn’t related to the steroid use, but that we may actually have gotten the doses wrong, and we may need a smaller dose of prednisolone. I think probably in reality the ideal dose is probably nearer to 3.5 to 4 mg. Therefore, I think we may be slightly overtreating these people and both the bone mass and the cholesterol may be a reflection of that.

“I think for now we have to stay with hydrocortisone as our mainstay of treating adrenal insufficiency, but I think more studies need to be done in patients taking 3.5 to 4.0 mg to then look at the effects on cholesterol, bone mass, and other markers….It would be quite a significant saving if we were able to move patients to prednisolone,” he added.

Dr Stratakis commented, “I have to say the price difference to me is amazing.” Asked about Dr Murray’s dose hypothesis, he responded, “It is possible we may be giving more prednisolone than we should. Also, there might be important differences in the handling of glucocorticoids at the tissue level, in fat and liver, specifically, that we don’t account for.”

Hydrocortisone vs Prednisolone

Beginning his presentation, Dr Murray noted that data on risk factors for cardiovascular disease in patients with adrenal insufficiency treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality, and so in this analysis he and his colleagues aimed to address this gap in the literature.

EU-AIR is a prospective, observational study, initiated in August 2012 to monitor the long-term safety of glucocorticoids in patients with adrenal insufficiency, and of 946 enrolled — in Germany, the Netherlands, Sweden, and the United Kingdom — 91.8% were using hydrocortisone for glucocorticoid replacement therapy compared to just 6.8% using prednisone, with marked heterogeneity in doses and frequency and timing of dosing (Endocrine Abstracts. 2015: DOI:10.1530/endoabs.37.EP39).

Other previous studies have found lower bone mass at the hip and spine with prednisolone compared with hydrocortisone-treated patients, but no quality-of-life difference between the two treatments, Dr Murray said.

The current study is the first patient-matched analysis of cardiovascular-risk-factor differences for the two glucocorticoid therapies. Patients were excluded if they were receiving more than one glucocorticoid, had congenital adrenal hyperplasia, were receiving modified-release hydrocortisone, or were receiving prednisolone or hydrocortisone doses outside the Endocrine Society’s recommended ranges.

Prior to matching, the 909 hydrocortisone patients were significantly more likely to be female, to have primary adrenal insufficiency, to be older, and to have longer disease duration. After matching three hydrocortisone patients for every one taking prednisolone, the 141 hydrocortisone and 47 prednisolone patients were similar for those factors: 62% were female, 40% had primary adrenal insufficiency, average age was around 59 years, and disease duration 23 years.

Both total cholesterol and LDL levels were significantly higher, at 6.3 and 3.9 mmol/L, respectively, in the prednisolone group compared with 5.4 and 3.2 mmol/L for hydrocortisone (both P < .05). However, there were no significant differences in rates of hypertension, diabetes (of either type), blood pressure, triglycerides, or HDL cholesterol.

In subgroup analysis, both total and LDL cholesterol were elevated among patients with primary adrenal insufficiency taking prednisolone, but among those with only secondary adrenal insufficiency, just total cholesterol was elevated with prednisolone.

Dr Stratakis told Medscape Medical News, “It is peculiar for me to see that the only difference he found from all the parameters he measured were in lipids, and specifically total cholesterol and LDL. I think the difference is tissue-specific.”

Dr Murray said it’s certainly plausible that the current prednisolone dosing is too high for two reasons: First, in the United Kingdom prednisolone comes in 1-mg and 5-mg tablets, so taking 5 mg/day is simpler than taking the lower end of the recommended range.

Second, “hydrocortisone is cortisol, so you know what the body produces and about what your levels should be, but you can’t do that with prednisone because it’s an analog. So, we’re guessing, and I think we’ve guessed too high.”

Dr Murray is a speaker and consultant to Shire. Disclosures for the coauthors are listed in the abstract. Dr Stratakis has no relevant financial relationships.   

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ENDO 2017. April 2, 2017; Orlando, Florida. Abstract OR03-5

 

From http://www.medscape.com/viewarticle/878097

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Patients with ARMC5 mutations: The NIH clinical experience

Posted on May 27, 2016 by MaryO

Screenshot 2016-05-27 13.12.55

 

Adrenal Disorders

R Correa, M Zilbermint, A Demidowich, F Faucz, A Berthon, J Bertherat, M Lodish, C Stratakis

Summary: Researchers conducted this study to describe the different phenotypical characteristics of patients with armadillo repeat containing 5 (ARMC5) mutations, located in 16p11.2 and a likely tumor-suppressor gene. They determined that patients with bilateral adrenal enlargement, found on imaging tests, should be screened for ARMC5 mutations, which are associated with subclinical Cushing’s syndrome (CS) and primary hyperaldosteronism (PA).

Methods:

  • Researchers identified 20 patients with ARMC5 mutations (germline and/or somatic) who were enrolled in a National Institutes of Health (NIH) protocol.
  • They obtained sociodemographic, clinical, laboratory, and radiological data for all participants.

Results:

  • Three families (with a total of 8 patients) were identified with ARMC5 germline mutations; the rest of the patients (13/20) had sporadic mutations.
  • The male to female ratio was 1.2:1; mean age was 48 years and 60% of patients were African American.
  • Forty percent of patients were diagnosed with CS, 20% with subclinical CS, 30% with hyperaldosteronism, and 10% had no diagnosis.
  • The mean serum cortisol (8 am) and Urinary Free Cortisol were 13.1 mcg/dl and 77 mcg/24 hours, respectively.
  • Nearly all patients (95%) had bilateral adrenal enlargement found on CT or MRI.
  • Patients underwent the following treatments: Bilateral adrenalectomy (45%), unilateral adrenalectomy (25%), medical treatment (20%), and no treatment (10%).
  • ARMC5 mutations are associated with primary macronodular adrenal hyperplasia (PMAH) and are also seen in patients with PA, especially among African Americans.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ37C4C5D3BF1A4FAE9C479A696660535B/57884/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-AACE2016&nonus=0

Filed under: 25th Annual Congress of the American Association of Clinical Endocrinologists, adrenal, Cushing's, Meetings and Conferences, Rare Diseases, Treatments | Tagged: , , , , , , , , , , , , , , , , | Leave a comment »

Day 12, Cushing’s Awareness Challenge 2016

Posted on April 12, 2016 by MaryO

In March of 1987, after the endo finally  confirmed that I had Cushing’s, I was sent to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward.

When I left this hospital after a week, we didn’t know any more than we had before.

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection.

My husband asked my endo if it were his wife, if he would recommend this surgery.  The endo responded that he was divorcing his wife – he didn’t care what happened to her.  Oh, my!

I chose NIH – closest and free. After I was interviewed by the doctors there, I got a letter that I had been accepted into the clinical trial.

The night before I was admitted, I signed my will.  I was sure I was going to die there.  If not during testing, as a result of surgery.

The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Several were from Greece.

My first roommate was a nurse.  She spent the entire first night screaming in pain.  I was very glad when they moved me to a new room!

Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with – either a cure or dying. While I was at NIH, I was gaining about a pound a day!

During the time I was home the weekend  before surgery, a college classmate of mine (I didn’t know her) DID die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until reading the alumnae magazine a couple months later!  She was the same class, same major, same home-town, same disease…

We have a Scottish doctor named James Lind to thank for the clinical trial.  He  conducted the first ever clinical trial in 1747 and developed the theory that citrus fruits cured scurvy.  Lind  compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

I’d like to think that I advanced the knowledge of Cushing’s at least a little bit by being a guinea  pig in 1987-1989.

From the NIH: http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx

Hope through Research

Several components of the National Institutes of Health (NIH) conduct and support research on Cushing’s syndrome and other disorders of the endocrine system, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Center for Research Resources.

NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. Researchers continue to study the effects of excess cortisol, including its effect on brain structure and function. To refine the diagnostic process, studies are under way to assess the accuracy of existing screening tests and the effectiveness of new imaging techniques to evaluate patients with ectopic ACTH syndrome. Researchers are also investigating jugular vein sampling as a less invasive alternative to petrosal sinus sampling. Research into treatment options includes study of a new drug to treat the symptoms of Cushing’s syndrome caused by ectopic ACTH secretion.

Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy.

The NIH supports research related to Cushing’s syndrome at medical centers throughout the United States. Scientists are also treating patients with Cushing’s syndrome at the NIH Clinical Center in Bethesda, MD. Physicians who are interested in referring an adult patient may contact Lynnette Nieman, M.D., at NICHD, 10 Center Drive, Room 1-3140, Bethesda, MD 20892-1109, or by phone at 301-496-8935. Physicians interested in referring a child or adolescent may contact Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1-3330, Bethesda, MD 20892-1103, or by phone at 301-402-1998.

 

Filed under: Clinical trials, Cushing's, Cushing's Awareness Challenge 2016 | Tagged: , , , , , , , , , , , , , | Leave a comment »

Cushing’s disease associated with USP8 mutations

Posted on April 5, 2016 by MaryO

endo2016

 

April 04, 2016

Oral Session: Pituitary Patients and Outcomes

Cushing’s disease associated with USP8 mutations

RR Correa, FR Faucz, A Angelousi, N Settas, P Chittiboina, MB Lodish, CA Stratakis

Summary: In Cushing’s disease (CD), pituitary corticotroph adenomas secrete excessive adrenocorticotropic hormone (ACTH), resulting in hypercortisolism. Often, the genetic pathogenesis of CD remains unknown, but recent studies have shown that the ubiquitin-specific protease 8 gene (USP8) is frequently mutated in CD. This gene codes for a protein deubiquitinase that inhibits the lysosomal degradation of the epidermal growth factor receptor. Researchers determined that pediatric patients with USP8 mutations were predominantly female and presented with higher ACTH levels than control patients.

Methods:

  • To further study the prevalence of mutations in USP8, researchers sequenced the complete USP8-coding and surrounding intronic regions in 97 patients with diagnosed CD by Sanger sequencing of germline DNA (n=97) and tumor DNA (n=50).
  • They analuzed biochemical and clinical characteristics in all the patients with predicted (by in silico analysis) damaging USP8 mutations and it was compared to patients without the mutation (control).

Results:

  • Overall researchers identified 18 (18.5%) patients with corticotroph adenomas who had USP8mutations, 13 with germline mutation, 2 with a germline and a new somatic mutation, and 5 with somatic mutation only.
  • All the somatic mutations that were not present at the germline level were mutations in the previously described hotspot.
  • Female-to-male ratio in the patients with USP8 mutations was 3.5:1 compared to the control ratio of 1:1 (P=0.05).
  • The mean age was 13 years old (range 6-18) and 72% (13/18) were whites.
  • Three of the mutant tumors were macroadenomas (≥ 1 cm) and 15 were microadenomas (< 1 cm).
  • In cases, mean basal plasma ACTH was 53.2±28.5 pg/mL and 39.6±19.1 pg/mL in the control group (P=0.02).
  • Researchers did not note any statistically significant differences in cortisol levels between the groups.

Filed under: Clinical trials, Cushing's, Endo2016, Meetings and Conferences, pituitary | Tagged: , , , , , , , , , | Leave a comment »

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