Cushing’s syndrome vs simple obesity. How can a needle be found in the haystack?

Posted on April 2, 2015 by MaryO

Endocrinology Today 02/2015; 4(1):30-35.

Clinical recognition of Cushing’s syndrome should generally follow from the observation of a constellation of compatible clinical features that progress over time. Screening for Cushing’s syndrome in patients with individual features of the metabolic syndrome, such as obesity, hypertension and hyperglycaemia, is not recommended.

Early diagnosis reduces unnecessary suffering and the ultimate lifetime sequelae of Cushing’s syndrome. Confirmation involves the demonstration of biochemical hypercortisolism, and the extent of diagnostic testing needs to be based on the degree of clinical suspicion.
Read the whole article here, in PDF format

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Scientists Find Potential Therapeutic Target for Cushing’s Disease

Posted on March 2, 2015 by MaryO

Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing’s disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body’s 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing’s disease (CD). The findings were published in the May 6, 2013 early online edition of Proceedings of the National Academy of Sciences.

The diagram shows how adrenocorticotropin hormone is secreted in Cushing's disease.

“We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked,” says senior author Ronald M. Evans, a professor in Salk’s Gene Expression Laboratory and a lead researcher in the Institute’s Helmsley Center for Genomic Medicine. “TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD.”

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing’s disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing’s disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

“Pituitary tumors are extremely difficult to control,” says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. “To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone.”

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. “Our discovery,” says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, “might lead clinicians to an existing drug that could be used to treat Cushing’s disease.

Notes about this neurogenetics and Cushing’s disease research

Other researchers on the study were Li Du, Marvin Bergsneider, Leili Mirsadraei, Stephen H. Young, William H. Yong and Anthony P. Heaney of the David A. Geffen School of Medicine at the University of California, Los Angeles, and Johan W. Jonker of the University of Groningen.

The study was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, the Jonsson Comprehensive Cancer Center at UCLA, and Ipsen/Biomeasure.

Contact: Andy Hoang – Salk Institute
Source: Salk Institute press release
Image Source: The ACTH Cushing’s disease diagram is credited to NIDDK/NIH and is available in the public domain.
Original Research: Abstract for “Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease” by Li Du, Marvin Bergsneider, Leili Mirsadraei, Steven H. Young, Johan W. Jonker, Michael Downes, William H. Yong, Ronald M. Evans, and Anthony P. Heaney in Proceedings of the National Academy of Sciences. Published May 6 2013 doi: 10.1073/pnas.1306182110

From http://neurosciencenews.com/tr4-cushings-disease-acth-neurogenetics-120/

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Subclinical Cushing’s syndrome and cardiovascular disease

Posted on May 2, 2014 by MaryO
Panagiotis Anagnostis a cEmail Address, Spyridon N Karras b, Vasilios G Athyros c, Dimitri P Mikhailidis d, Asterios Karagiannis c
Guido Di Dalmazi and colleagues1 reported that in patients with adrenal incidentalomas and either stable mild hypercortisolism or worsening of cortisol hypersecretion, all-cause and cardiovascular disease-specific mortality was higher compared with in those with adrenal incidentalomas that did not secrete cortisol, after a mean follow-up of 7·5 years. Moreover, cortisol concentrations measured after dexamethasone-suppression test were associated with all-cause mortality independent of the presence of traditional cardiovascular disease risk factors.
Subclinical Cushing’s syndrome is the most common hormonal abnormality in patients with adrenal incidentalomas (prevalence 1—29%).2 The proportion of adrenal incidentalomas that progress to subclinical Cushing’s syndrome is low (1·7%) and most are lesions of 3 cm or larger.2 Progression to overt Cushing’s syndrome is controversial (because both spontaneous normalisation of hypersecretion and stable disease have been reported during follow-up) and spontaneous normalisation of hypersecretion has been reported in 50% of cases.2 Results of the study by Di Dalmazi and co-workers1 are important because they show, for the first time, that patients with subclinical Cushing’s syndrome are at increased risk of cardiovascular disease and all-cause mortality (mainly attributable to cardiovascular disease). The association of cortisol with all-cause mortality might also be attributable to its potential role in the pathogenesis of metabolic syndrome.3
Findings of previous studies have shown an increased prevalence of cardiovascular disease risk factors in patients with subclinical Cushing’s syndrome, but data for optimum management are conflicting. Some criteria—such as large (>4—6 cm) adrenal incidentalomas, features suggestive of malignancy (eg, heterogeneity, irregular shape, calcification or necrosis, invasion to adjacent tissues), or potentially lethal hormonal hypersecretion (ie, pheochromocytomas)—support the need for adrenalectomy. However, universal surgical management of patients with subclinical Cushing’s syndrome has not been accepted.2, 4 Uncertainty about the most effective management strategy for subclinical Cushing’s syndrome is attributable to the variable definitions used, and the small sample size and retrospective nature of most studies.4 Only one prospective study has been published so far showing that laparoscopic adrenalectomy is more beneficial than is conservative management for the normalisation or improvement of cardiovascular disease risk factors, such as diabetes, dyslipidaemia, hypertension, and obesity.5
Prospective studies and registries are needed to document the effect of different approaches on the incidence of cardiovascular disease events and mortality in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Until then, individualised treatment seems prudent. Surgical management of subclinical Cushing’s syndrome can be suggested in young patients (age <50 years) and in those with cardiovascular disease risk factors or bone disease associated with hypercortisolism that are of recent onset, difficult to control with drugs, or show progression over time.4
Another message from Di Dalmazi’s study1 is that hormonal deterioration might develop even after 4—5 years, which most studies reported as a reasonable and safe follow-up.2 This possibility should be kept in mind for the management of patients with adrenal incidentalomas, especially if clinical signs of Cushing’s syndrome develop or if cardiovascular disease risk factors become evident or increase in severity (ie, hormonal hypersecretion).
We declare that we have no competing interests.

References

1 Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014. published online Jan 29 http://dx.doi.org/10.1016/S2213-8587(13)70211-0.
2 Anagnostis P, Karagiannis A, Tziomalos K, Kakafika AI, Athyros VG, Mikhailidis DP. Adrenal incidentaloma: a diagnostic challenge. Hormones (Athens) 2009; 8: 163-184. PubMed
3 Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab 2009; 94:2692-2701. PubMed
4 Terzolo M, Pia A, Reimondo G. Subclinical Cushing’s syndrome: definition and management. Clin Endocrinol (Oxf) 2012; 76: 12-18. PubMed
5 Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg 2009; 249: 388-391. PubMed
a Division of Endocrinology, Police Medical Centre, Thessaloniki, 54 640, Greece
b Department of Endocrinology and Metabolism, Agios Pavlos General Hospital, Thessaloniki, Greece
c Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
d Department of Clinical Biochemistry (Vascular Prevention Clinic) Royal Free Hospital Campus, University College London Medical School, University College London, London, UK

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Botch-up Costs Doctor an Adrenal Gland

Posted on February 7, 2014 by MaryO

Chennai, India: The state consumer forum has asked a Coimbatore hospital to pay 15 lakh to a doctor whose adrenal gland was surgically removed after a botched-up diagnosis.

In May 2006, A Indumathi, an ophthalmologist, started showing symptoms like rapid weight gain, hypertension, joint pain, puffiness of face and fatigue. She approached Kovai Medical Centre & Hospital in Coimbatore, where the consultant endocrinologist conducted various tests. Her condition was diagnosed as Cushing’s syndrome, a hormonal disorder, and she was advised to undergo surgery for removal of the left adrenal gland.

On September 18, she was operated on. However, the symptoms persisted and the doctor told her it would take some more time to get relief. She waited three more months, but when her condition worsened, she approached the doctor again. He asked her to undergo another surgery for removing her right adrenal gland.

Not willing to take a chance, Indumathi approached Christian Medical College, Vellore, in December, where doctors told her she was suffering from Cushing’s disease, not syndrome. After a month of treatment, she recovered.

She then approached the state commission saying she was misdiagnosed and because of the wrong surgery, she has to regularly go for blood tests for the rest of her life and could develop life-threatening complications. She said she also incurred medical expense of around 5 lakh and had to leave her medical practice for six months.

Denying the charges, the hospital said tests conducted on her showed she was suffering from Cushing’s syndrome. She, being a doctor, was aware of the test reports and gave consent for surgery, it said.

The state consumer disputes redressal commission bench comprising its president Justice(rtd )RRegupati and judicial member J Jayaram, in a recent order, said after a wrong diagnosis and surgery, the hospital should have been more diligent in reassessment but instead suggested removing the right adrenal gland. The bench said the hospital wrongly diagnosed her and removed “a precious, healthy adrenal gland.”

Stating it was a case of “gross negligence and deficiency in service,” the bench asked the hospital and two doctors to pay Indumathi 4 lakh towards medical and travelling expense, 1 lakh for loss of professional income and 10 lakh for “lifelong mental agony.”

From http://timesofindia.indiatimes.com/city/chennai/Botch-up-costs-doctor-a-gland-hospital-fined-Rs-15-lakh/articleshow/29925290.cms

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Outcome of Bilateral Adrenalectomy in Cushing’s Syndrome: A Systematic Review

Posted on October 5, 2013 by MaryO
  1. Katrin Ritzel,
  2. Felix Beuschlein,
  3. Anne Mickisch,
  4. Andrea Osswald,
  5. Harald J. Schneider,
  6. Jochen Schopohl and
  7. Martin Reincke

–Author Affiliations


  1. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 München, Germany
  1. Address all correspondence and requests for reprints to: Martin Reincke, M.D., Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 München, Germany. E-mail:Martin.Reincke@med.uni-muenchen.de.

Abstract

Background: The outcome of bilateral adrenalectomy (BADx) in patients with Cushing’s syndrome (CS) is not well characterized.

Methods: A literature search was performed with the search terms “bilateral adrenalectomy” or “total adrenalectomy” and “Cushing’s” or “Cushing.” Immediate and long-term outcomes after BADx in CS were analyzed using descriptive statistics (median [range]).

Results: From 549 screened publications, 37 studies met inclusion criteria (1320 patients, 82% having Cushing’s disease [CD], 13% having ectopic CS, and 5% having primary adrenal hyperplasia).

Surgical morbidity and mortality of BADx (23 studies, 739 patients) were 18% (6–31) and 3% (0–15), respectively. In patients with CD, surgical mortality was below 1%. Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in 3–34% (5 studies, 236 patients), less than 2% had a relapse of CS.

Symptoms of hypercortisolism (eg, hypertension, obesity, or depression) improved in the majority of the patients after BADx (7 studies, 195 patients). The number of adrenal crises per 100 patient-years was 9.3 (6 studies, 203 patients).

Nelson’s syndrome occurred in 21% (0–47) of the patients (24 studies, 768 patients). Mortality (23 studies, 690 patients) was 17% (0–88) at a follow-up of 41 months (14–294). Remarkably, 46% of the patients died in the first year after surgery. The median ages at death were 62 years (CD) and 53 years (ectopic CS).

Conclusion: BADx is relatively safe and provides adequate success. Excess mortality within the first year after surgery suggests that intensive clinical care for patients after BADx is warranted.

Footnotes

  • For editorial see page 3974

  • Abbreviations:

    BADx
    bilateral adrenalectomy
    BAH
    bilateral adrenal hypercortisolism
    CD
    Cushing’s disease
    CS
    Cushing’s syndrome
    ECS
    ectopic CS
    NS
    Nelson’s syndrome
    QOL
    quality of life
    TSS
    transsphenoidal surgery.

     

From http://jcem.endojournals.org/content/98/10/3939.abstract

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