The Role of Adrenal Scintigraphy in the Diagnosis of Subclinical Cushing’s Syndrome and the Prediction of Post-surgical Hypoadrenalism

Posted on March 25, 2014 by MaryO

World J Surg. 2014 Mar 11. [Epub ahead of print]

Ricciato MP1, Di Donna V, Perotti G, Pontecorvi A, Bellantone R, Corsello SM.

Author information

Abstract

BACKGROUND:

Management of subclinical Cushing’s syndrome (SCS) remains controversial; it is not possible to predict which patients would benefit from adrenalectomy. In the present study we aimed to evaluate the role of adrenocortical scintigraphy (ACS) in the management of patients with SCS.

METHODS:

The medical records of 33 consecutive patients with adrenal “incidentaloma” and proven or suspected SCS who underwent 131I-19-iodocholesterol ACS between 2004 and 2010 were reviewed. Sixteen underwent laparoscopic adrenalectomy (surgical group-S-group) and 17 were medically managed (medical group-M-group). Follow-up evaluation was obtained by outpatient consultation.

RESULTS:

Overall 25 patients (15 in the S-group and 10 in the M-group) had concordant unilateral uptake at ACS (ACS+). In the S-group, the mean follow-up duration was 30.9 ± 16.1 months and, irrespective of the presence of hormonal diagnosis of SCS, in patients who were ACS+ adrenalectomy resulted in a significant increase in HDL cholesterol and decreases in body mass index, glycemia, and blood pressure (BP). One patient reduced antihypertensive medication and three others were able to discontinue it altogether. Prolonged postoperative hypoadrenalism (PH) occurred in 14 patients in the S-group. The overall accuracy in predicting PH was 93.7 % for ACS and 68.7 % for laboratory findings. In the M-group, the mean follow-up duration was 31.5 ± 26.3 months and no patient developed overt Cushing’s syndrome, although ACS+ patients experienced a worsening in glycemia and diastolic BP.

CONCLUSIONS:

Adrenal scintigraphy seems the most accurate diagnostic test for SCS. It is able to predict the metabolic outcome and the occurrence of PH, identifying the patients who could benefit from adrenalectomy irrespective of hormonal diagnosis.

PMID:
24615601
[PubMed – as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/24615601

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Salivary cortisol performs better than urinary free cortisol to diagnose Cushing’s syndrome

Posted on March 25, 2014 by MaryO

Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing’s syndrome.

Salimetrics highlights a recent study:  Abstract

Context: The comparison of variability, reproducibility, and diagnostic performance of late-night salivary cortisol (LNSF) and urinary free cortisol (UFC) using concurrent and consecutive samples in Cushing’s syndrome (CS) is lacking.

Objectives, Patients and Methods: In a prospective study, we evaluate three simultaneous and consecutive samples of LNSF by RIA and UFC by LC-MS/MS in Cushing’s disease (CD; n=43), adrenal CS patients (n=9) and obese subjects (n=18) in order to compare their diagnostic performances. In CS patients we also performed a modified Cushing’s syndrome severity index (CSI).

Results: There was no difference in the coefficient of variation (%) between LNSF and UFC among the three samples obtained for each patient with CD (35±26vs31±24), adrenal CS (28±14vs22±14) and obesity (39±37vs48±20). LNSF confirmed the diagnosis of hypercortisolism even in the presence of normal UFC in 17.3% of CS, whereas the inverse situation was not observed for UFC. The area under the ROC curves for LNSF was 0.999 (95%CI 0.990-1.00) and for UFC was 0.928 (95%CI 0.809- 0.987). The ratio between AUCs was 0.928 (95%CI 0.810-0.988) indicating better performance of LNSF than UFC in diagnosing CS. There was no association between the severity of CSI and the degree of biochemical hypercortisolism.

Conclusion: Our data show that despite similar variability between both methods, LNSF has a superior diagnostic performance than UFC and should be used as the primary biochemical diagnostic test for Cushing’s syndrome diagnosis.

Authors Elias P, Martinez E, Barone B, Mermejo L, Castro M, Moreira A
Division of Endocrinology-Department of Medicine and Division of Statistics- Department of Social Medicine, Ribeirao Preto Medical School – University of Sao Paulo, Ribeirao Preto, SP- Brazil
LINK to Paper
Salimetrics guide to Cortisol
LINK to Salimetrics Diagnostic Salivary Cortisol Assay

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Mutations in PKA catalytic subunit associated with Cushing’s syndrome

Posted on March 18, 2014 by MaryO

1. Somatic mutations resulting in constitutive activation of PRKACA, which encodes the catalytic subunit of protein kinase A, were found in 37% of patients with Cushing’s syndrome due to an adrenal adenoma. 

2. Germline duplications of PRKACA were detected in patients with bilateral adrenal hyperplasia and overt Cushing’s syndrome. 

Study Rundown: This study found that 37% of patients with overt Cushing’s syndrome due to an adrenal adenoma have a somatic mutation in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase A (PKA), present in their tumor cells. The most commonly identified variant, Leu206Arg, results in impaired interaction between the catalytic and regulatory subunits of PKA, thereby causing constitutive activation of PKA. Additionally, a subset of patients with cortisol-producing bilateral adrenal hyperplasia harbored germline duplications of PRKACA.

This is the first study to identify an association between genetic alterations of the catalytic subunit of PKA and Cushing’s syndrome. It is significant that 37% of patients with overt Cushing’s syndrome were found to have tumors with PRKACA mutations; previous research had revealed only very rare mutations. Of note, this study did not find PRKACA mutations in any patients with subclinical Cushing’s syndrome or inactive adenomas. This suggests that Cushing’s syndrome and subclinical Cushing’s are distinct entities. Patients involved in this study were recruited from only three centers; the frequency of PRKACA mutations in Cushing’s syndrome may be different in other study populations. Further research will be needed to identify biochemical causes of overt Cushing’s syndrome in patients without PRKACA mutations.

Relevant Reading: Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing’s syndrome despite the absence of mutations in known genes

In-Depth: In this study, exome sequencing of tumor specimens from 10 patients with unilateral cortisol-producing adenomas and overt Cushing’s syndrome was performed. Eight of 10 adenomas had somatic mutations in PRKACA; 7 of these patients had the same mutation (p.Leu206Arg). Subsequently, PRKACA was sequenced in 129 additional patients with adrenal adenomas. Patients were classified as having overt Cushing’s syndrome (at least three abnormal biochemical tests or catabolic features plus two abnormal tests), subclinical Cushing’s (at least one abnormal biochemical test without catabolic signs) or as having an inactive adenoma. The Leu206Arg variant was identified in tumor tissue of 14/129 patients and all 14 had overt Cushing’s syndrome. Overall, 37% (22/59) of patients with overt Cushing’s syndrome due to an adenoma had a PRKACA mutation; in contrast, PRKACA mutations were not found in any patients with subclinical Cushing’s or an inactive adenoma. Of 35 patients with overt Cushing’s syndrome due to cortisol-secreting bilateral adrenal hyperplasia, 5 patients had copy-number gains of a region on chromosome 19p that contains PRKACA.

Analysis of holoenzyme structure revealed that the Leu206Arg mutation is located in the active-site cleft of the catalytic subunit of PKA. To evaluate the functional consequences of this mutation, cells were transfected with either nonmutant or variant C-alpha, which encodes the catalytic subunit of PKA. Investigators determined that the mutation causes constitutive activation of the catalytic subunit by impairing interaction with the regulatory subunit of PKA.

From http://www.2minutemedicine.com/mutations-in-pka-catalytic-subunit-associated-with-cushings-syndrome/

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Genetic variations associated with hyperplasias, adenomas of adrenal cortex

Posted on February 27, 2014 by MaryO

Beuschlein F. N Engl J Med. 2014;doi:10.1056/NEJMoa1310359.

Genetic variations of the catalytic subunit of cyclic protein kinase A, or PKA, were linked to the development of bilateral adrenal hyperplasias and unilateral cortisol-producing adrenal adenomas. These effects may activate corticotropin-independent Cushing’s syndrome, according to data published in The New England Journal of Medicine.

“The current study suggests that more than one-third of cortisol-producing adenomas associated with overt Cushing’s syndrome have unique somatic mutations in PRKACA (which encodes the main catalytic subunit of PKA), resulting in constitutive PKA activation,” Felix Beuschlein, MD, of the University of Munich, and colleagues wrote.

The researchers performed an exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated their recurrent mutations in candidate genes in 171 additional patients with adrenocortical tumors, according to data.

Somatic mutations in PRKACA were discovered in eight of 10 adenomas. These somatic mutations also were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing’s syndrome; mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors, according to data.

Five of the 35 patients with cortisol-producing hyperplasias appeared to be carriers of the germline duplication of the genomic region on chromosome 19 that includes PRKACA, researchers wrote.

In vitro study data indicated that PKA catalytic subunit genetic mutations impaired inhibition by the PKA regulatory subunit, and cells from patients with germline chromosomal gains appeared to increase the protein levels of the subunit.

“Because PRKACA mediates most of the effects of inactivating PRKAR1A mutations and because mutations of PRKAR1 are associated with a variety of tumors in humans and mice, we would speculate that somatic PRKACA defects might also play a role in other forms of endocrine and nonendocrine tumors,” researchers wrote.

Disclosure: Beuschlein reports financial ties with the European Community, HRA Pharma, Novartis, Viropharma, and Wilhelm-Sander Stiftung.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B22954d9a-0fc9-4e80-b80a-d74bbdfea1a9%7D/genetic-variations-associated-with-hyperplasias-adenomas-of-adrenal-cortex

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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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