Surgery Preferred Option in Cushing’s Disease for Best Survival

Posted on June 21, 2016 by MaryO

Patients with Cushing’s disease who have been in remission for more than 10 years still have an increased mortality risk compared with the general population, says an international team of researchers, who found the risk of early death was particularly increased in those with Cushing’s and accompanying circulatory disease.

Richard N Clayton, MD, department of medicine, Keele University, Stoke-on-Trent, United Kingdom, showed that Cushing’s disease, which is characterized by increased secretion of adrenocorticotropic hormone by the anterior pituitary gland, is associated with an increased mortality risk of more than 60% and a median survival of around 40 years.

In patients who also had circulatory disease, the mortality risk was even higher, say Dr Clayton and colleagues.

However, patients who had undergone curative pituitary surgery had a long-term risk of death no different from that of the general population. US Endocrine Society guidelines published last August recommend that optimal treatment of Cushing’s syndrome involves direct surgical removal of the causal tumor.

But Dr Clayton and colleagues point out that even patients who undergo pituitary surgery will nevertheless “require lifelong follow-up at a center experienced in dealing with this condition, having regular checks for diabetes, hypertension, and other cardiovascular risk factors.”

The study was published online June 2 in Lancet Diabetes & Endocrinology.

In an accompanying editorial, Rosario Pivonello, MD, PhD, department of clinical medicine and surgery, section of endocrinology, University of Naples Federico II, Italy, and colleagues write that, although surgery is not suitable for all patients, “Prompt pituitary surgery might be the preferred treatment for Cushing’s disease to guarantee the best mortality outcome.”

Calling for further research to better understand why one treatment “has a better effect on mortality than another,” they state: “The results from this study might also motivate rapid interventions, cure, and long-term follow-up in patients with Cushing’s disease — even for a long time after hypercortisolism resolution.”

Studying Those Who Have Survived More Than 10 Years

Dr Clayton and colleagues explain that previous studies have explored mortality in patients with Cushing’s disease during either active disease or remission. But the outcome of patients in remission, especially long-term remission, is still a matter of debate, and assessing long-term survival has been limited by various methodological differences. To overcome some of these issues, they performed a retrospective analysis of case records from specialist referral centers in the United Kingdom, Denmark, the Netherlands, and New Zealand.

They identified 320 patients diagnosed with Cushing’s disease and cured for a minimum of 10 years at enrollment and had no relapses during the study period. The ratio of women to men was 3:1.

Median patient follow-up was 11.8 years, yielding a total of 3790 person-years of follow-up 10 years after cure. There was no difference in follow-up between countries. And as there were no significant demographic and clinical differences between men and women, the data were pooled.

During the study 16% of patients died. Median survival was 31 years for women and 28 years for men, at approximately 40 years following remission. The overall standardized mortality ratio (SMR) for all-cause mortality compared with the general population was 1.61 (P = .0001).

Patients with Cushing’s and circulatory disease had an SMR vs the general population of 2.72 (P < .0001), but deaths from cancer among those who had survived Cushing’s disease were not higher than the general population, at an SMR of 0.79 (P = .41).

Patients with Cushing’s and diabetes also had an increased mortality risk, at a hazard ratio (HR) of 2.82 (P < .0096) compared with the general population, while hypertension was not significantly associated with increased mortality, at an HR of 1.59 (P = .08).

There was also an association between mortality and number of treatments, at an HR of 1.77 for two vs one treatment (P = .08) and an HR of 2.6 for three vs one treatment (P = .02).

Pituitary Surgery Alone Associated With No Increased Risk of Death

Pituitary surgery performed as the first and only treatment was associated with an SMR vs the general population of 0.94 compared with an SMR of 2.58 for other patients (P < .0005).

Patients who had pituitary surgery only had a median survival of 31 years compared with 24 years if surgery had been required at any time (P = 0.03).

The research team states: “For patients who have been cured of Cushing’s disease for 10 years or more, treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival.”

“Pituitary surgery alone achieves a mortality outcome that is not different from the normal population and should be performed in a center of excellence,” they conclude.

However, in the editorial, Dr Pivonello and colleagues point out that the surgical approach “is not a treatment option for some patients, either because of contraindications (eg, severe clinical complications) or because of an absence of clear indication for surgery (eg, tumor is not completely removable by surgery).”

The authors and editorialist have reported no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online June 2, 2016. Abstract, Editorial

From http://www.medscape.com/viewarticle/865073#vp_2

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Bilateral adrenal myelolipoma in Cushing’s disease: a relook into the role of corticotropin in adrenal tumourigenesis

Posted on June 16, 2016 by MaryO

BMJ Case Reports 2016; doi:10.1136/bcr-2016-214965

Partha Pratim Chakraborty, Rana Bhattacharjee, Pradip Mukhopadhyay, Subhankar Chowdhury

  1. Correspondence to Dr Partha Pratim Chakraborty, docparthapc@yahoo.co.in
  • Accepted 2 June 2016
  • Published 15 June 2016

Summary

Adrenal myelolipomas are infrequently encountered benign tumours of unknown aetiology.

In the majority of cases they are unilateral, and clinically and hormonally silent, only requiring periodic follow-up. However, bilateral adrenal myelolipomas are sometimes associated with endocrine disorders and warrant appropriate evaluation.

Though the understanding of the pathophysiology of adrenal myelolipomas has long been elusive, adrenocorticotropic hormone (ACTH) has been proposed as the main tropic factor in a number of studies. Cushing’s disease is rarely associated with bilateral and sometimes giant myelolipomas.

In this article, the association of bilateral adrenal myelolipomas with Cushing’s disease has been discussed and the role of ACTH in the tumourigenesis has been reviewed.

From http://casereports.bmj.com/content/2016/bcr-2016-214965.short?rss=1#content-block

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Resolution of the physical features of Cushing’s syndrome in a patient with a cortisol secreting adrenocortical adenoma after unilateral adrenalectomy

Posted on May 1, 2016 by MaryO

A 37-year-old woman developed clinical manifestations of Cushing’s syndrome over a span of 2 years. Physical examination revealed features that best describe Cushing’s syndrome, such as wide purple striae (>1 cm) over the abdomen, facial plethora and easy bruisability.1  Other features observed were hypertension, moon facies, acne, a dorsocervical fat pad, central obesity and dyslipidaemia.

The diagnosis of hypercortisolism was confirmed using a 1 mg overnight dexamethasone suppression test (19.7 ng/dL, N: <1.8) and 24 h urine free cortisol (185.9 μg/24 h, N: 3.5–45). A suppressed adrenocorticotropic hormone (ACTH) level (4 pg/mL, N: 5–20) and a lack of hyperpigmentation suggested ACTH-independent Cushing’s syndrome. Further work up using CT with contrast of the adrenals showed a 2.4×2.3×2.4 cm right adrenal mass. The patient then underwent laparoscopic adrenalectomy of the right adrenal gland. Steroids was started postoperatively and tapered over time. Histopathology results were consistent with an adrenocortical adenoma (2.5 cm widest dimension). Six months after surgery, there was resolution of the physical features, weight loss and improvement in blood pressure.

Figure 1 is a serial photograph of the physical features seen in Cushing’s syndrome, such as moon facies, a dorsocervical fat pad and wide purple striae, taken preoperatively, and at 3 and 6 months after surgery. With treatment, physical and biochemical changes of Cushing’s syndrome both resolve through time.2 The time course of the resolution of these changes, however, is varied.2 ,3 We observed that the physical features were ameliorated at 3 months and resolved at 6 months.

Learning points

  • Physicians as well as patients should be aware that improvement of the features of Cushing’s syndrome after treatment does not occur immediately.

  • Dramatic resolution of the physical features of Cushing’s syndrome, however, can be observed as early as 6 months after surgery.

Figure 1

View larger version:

Figure 1

Physical features of Cushing’s syndrome (top to bottom: moon facies, a dorsocervical fat pad and wide purple striae (>1 cm) over the abdomen) documented before surgery, and at 3 and 6 months after surgery.

Footnotes

  • Twitter Follow John Paul Quisumbing at @jpquisumbingmd

  • Contributors JPMQ worked up the case and wrote the case report. MASS reviewed the case report and critically appraised it. JPMQ incorporated his suggestions.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

References

  1. ↵
    1. Ross EJ,
    2. Linch DC

    . Cushing’s syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis.Lancet 1982;2:646–9. doi:10.1016/S0140-6736(82)92749-0

    [CrossRef][Medline][Web of Science]
  2. ↵
    1. Sippel RS,
    2. Elaraj DM,
    3. Kebebew E, et al

    . Waiting for change: symptom resolution after adrenalectomy for Cushing’s syndrome. Surgery2008;144:1054–61. doi:10.1016/j.surg.2008.08.024

    [CrossRef][Medline][Web of Science]
  3. ↵
    1. Mishra AK,
    2. Agarwal A,
    3. Gupta S, et al

    . Outcome of adrenalectomy for Cushing’s syndrome: experience from a tertiary care center. World J Surg2007;31:1425–32. doi:10.1007/s00268-007-9067-6

    [CrossRef][Medline]

From http://casereports.bmj.com/content/2016/bcr-2016-215693.short?rss=1

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Morning Cortisol Rules Out Adrenal Insufficiency

Posted on April 7, 2016 by MaryO

endo2016

 

Key clinical point: Skip ACTH stimulation if morning serum cortisol is above 11.1 mcg/dL.

Major finding: A morning serum cortisol above 11.1 mcg/dL is a test of adrenal function with 99% sensitivity.

Data source: Review of 3,300 adrenal insufficiency work-ups.

Disclosures: There was no outside funding for the work, and the investigators had no disclosures.

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

In short, “basal serum cortisol as a screening test … offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

aotto@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com/specialty-focus/pituitary-thyroid-adrenal-disorders/single-article-page/morning-cortisol-rules-out-adrenal-insufficiency/af59bab2bb014ca9d352c792f9d41653.html

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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, Meetings and Conferences, pituitary | Tagged: , , , , , , , , , | Leave a comment »

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