Six controversial issues on subclinical Cushing’s syndrome

Abstract

Subclinical Cushing’s syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality.

The subclinical Cushing’s syndrome is not rare, being estimated to be between 0.2–2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing’s syndrome screening, diagnosis and treatment.

The Altogether to Beat Cushing’s syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing’s syndrome viewpoint regarding the following controversial issues on Subclinical Cushing’s syndrome (SCS):

(1) Who has to be screened for subclinical Cushing’s syndrome?
(2) How to screen the populations at risk?
(3) How to diagnose subclinical Cushing’s syndrome in patients with an adrenal incidentaloma?
(4) Which consequence of subclinical Cushing’s syndrome has to be searched for?
(5) How to address the therapy of choice in AI patients with subclinical Cushing’s syndrome?
(6) How to follow-up adrenal incidentaloma patients with subclinical Cushing’s syndrome surgically or conservatively treated?

Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing’s syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing’s syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing’s syndrome.

Keywords

Subclinical hypercortisolism, Adrenal incidentalomas, Hypertension, Diabetes, Osteoporosis

Pituitary Incidentaloma Treatment Guideline

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It is unclear how many people have pituitary incidentaloma, but imaging and autopsy studies indicate they are quite common and occur in up to one-third of patients. Fortunately, the vast majority of these serendipitously discovered tumors are clinically insignificant.

A management guideline in the Annals of Endocrinology brings endocrinologists up to date on current thinking about pituitary incidentaloma management.   Endocrinologists classify these tumors as micro- or macro-. Microincidentalomas are discovered in around 10% of patients, often upon CT after a fall, and are less than 1 cm in diameter. They may grow, but only 5% proceed to macroincidentaloma.

Currently, experts recommend assessing nonfunctioning (NF) microincidentaloma clinically for signs of hypersecretion (hyperprolactinemia, acromegaly or Cushing’s syndrome), with subsequent systematic prolactin and IGF-1 assay.   Pituitary incidentalomas that are larger than 1 cm at discovery—macroincidentalomas—are more likely to grow, with 25% and 24%-40% of patients having larger tumors at 4 and 8 years after diagnosis respectively.

Concerns escalate and closer surveillance is needed if a macroadenoma is in contact with the optic chiasm. With any NF macroincidentaloma, experts recommend assessing patients for signs of hormonal hypersecretion or hypopituitarism. Then, laboratory screening for hypersecretion or hormonal deficiency is needed, as is ophthalmologic assessment (visual acuity and visual field) if the lesion is near the optic chiasm (OC).   Surveillance differs by tumor size, with 5 mm the cutoff for NF microincidentaloma.

Tumors smaller than that require no surveillance, and those larger need to be monitored with MRI at 6 months and then 2 years. Endocrinologists should revisit macroincidentaloma distant from the optic chiasm with MRI at 1 year and conduct hormonal exploration (for anterior pituitary deficiency), then monitor every 2 years.   Proximity to the optic chiasm often creates a need for surgery or increased vigilance. MRI is recommended at 6 months, with hormonal and visual assessment, then annual MRI and hormonal and visual assessment every 6 months.

Specific types of pituitary incidentaloma call for surgery: evolutive NF microincidentaloma, NF macroincidentaloma associated with hypopituitarism or showing progression, incidentaloma compressing the optic chiasm, possible malignancy, non-compliant patient, pregnancy desired in the short-term, or context at risk of apoplexy.

Few guidelines are published for pituitary incidentaloma, and this one is enhanced with a decision tree that walks endocrinologist through the recommendations. –

See more at: http://www.hcplive.com/medical-news/pituitary-incidentaloma-treatment-guideline#sthash.0DqxeTru.dpuf

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

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

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

CV risk elevated in patients with adrenal incidentalomas, mild hypercortisolism

Patients with adrenal incidentalomas and mild hypercortisolism have an increased risk for cardiovascular events and mortality. This risk was evident even when clinical signs of overt hypercortisolism were not present, according to data published in The Lancet Diabetes & Endocrinology.

“Our findings are important because they add to the previously scant information about adrenal incidentalomas, which will be of use to doctors who are seeing an increasing number of patients with these masses,” Renato Pasquali, MD, of the S. Orsola-Malpighi Hospital in Bologna, Italy, said in a press release.

The retrospective study by Pasquali and colleagues assessed the adrenal incidentalomas of 198 outpatients treated every 18 to 30 months, with a mean follow-up of 7.5 years. At the time of follow-up, 114 patients demonstrated stable non-secreting adrenal incidentalomas (<50 nmol/L), 61 had either a stable intermediate phenotype (50 nmol/L-138 nmol/L) or subclinical Cushing’s syndrome (>138 nmol/L), and 23 patients had worsening pattern of secretion.

The incidence of CV events appeared higher in patients with a stable intermediate phenotype or subclinical Cushing’s syndrome (6.7% vs. 16.7%; P=.04) and in those with worsened secreting patterns (6.7% vs. 28.4%; P=.02) compared with patients with stable non-secreting adrenal incidentalomas, according to data.

In addition, CV events were independently related to changes in cortisol concentrations after the 1-mg dexamethasone suppression test (DST; HR=1.13; 95% CI, 1.05-1.21) from baseline to follow-up.

Patients with stable intermediate phenotype adrenal incidentalomas (57%) or subclinical Cushing’s syndrome (91.2%) tended to have lower survival rates for all-cause mortality (P=.005), researchers wrote. The main risk factors for all-cause mortality were age (HR=1.06; 95% CI, 1.01-1.12) and mean concentrations of cortisol after DST (HR=1.1; 95% CI, 1.01-1.19).

The unadjusted survival for CV-related mortality was lower in patients with either a stable intermediate phenotype (97.5%) or subclinical Cushing’s syndrome (78.4%; P=.02) vs. those with stable non-secreting adrenal incidentalomas (97.5%), and patients with worsened secreting patterns (60%; P=.01).

In an accompanying comment, Rosario Pivonello, MD, PhD, Maria Cristina De Martino, PhD, and Annamaria Colao, MD, PhD, of the Federico II University of Naples, Italy, wrote that the study supports the importance of long-term hormonal follow-up for clinical management of patients with adrenal incidentalomas.

“Furthermore, clinical monitoring of cardiometabolic risks seems to be important in these patients, particularly in those with subclinical Cushing’s syndrome and intermediate phenotype adrenal incidentalomas, for whom medical or surgical intervention could be needed,” they wrote.

They suggest long-term prospective studies to determine the frequency of new CV events and mortality in this patient population.

For more information:

Di Dalmazi G. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70211-0.

Pivonello R. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70190-6.

Disclosure: The researchers report no relevant financial disclosures.

This article is from http://www.healio.com/endocrinology/adrenal/news/online/%7B85f94352-9529-4cb7-9532-9c4518f77d80%7D/cv-risk-elevated-in-patients-with-adrenal-incidentalomas-mild-hypercortisolism

 

Pituitary tumor size not definitive for Cushing’s

By: SHERRY BOSCHERT, Family Practice News Digital Network

SAN FRANCISCO – The size of a pituitary tumor on magnetic resonance imaging in a patient with ACTH-dependent Cushing’s syndrome can’t differentiate between etiologies, but combining that information with biochemical test results could help avoid costly and difficult inferior petrosal sinus sampling in some patients, a study of 131 cases suggests.

If MRI shows a pituitary tumor larger than 6 mm in size, the finding is 40% sensitive and 96% specific for a diagnosis of Cushing’s disease as the cause of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, and additional information from biochemical testing may help further differentiate this from ectopic ACTH secretion, Dr. Divya Yogi-Morren and her associates reported at the Endocrine Society’s Annual Meeting.

Pituitary tumors were seen on MRI in 6 of 26 patients with ectopic ACTH secretion (23%) and 73 of 105 patients with Cushing’s disease (69%), with mean measurements of 4.5 mm in the ectopic ACTH secretion group and 8 mm in the Cushing’s disease group. All but one tumor in the ectopic ACTH secretion group were 6 mm or smaller in diameter, but one was 14 mm.

Because pituitary “incidentalomas” as large as 14 mm can be seen in patients with ectopic ACTH secretion, the presence of a pituitary tumor can’t definitively discriminate between ectopic ACTH secretion and Cushing’s disease, said Dr. Yogi-Morren, a fellow at the Cleveland Clinic.

That finding contradicts part of a 2003 consensus statement that said the presence of a focal pituitary lesion larger than 6 mm on MRI could provide a definitive diagnosis of Cushing’s disease, with no further evaluation needed in patients who have a classic clinical presentation and dynamic biochemical testing results that are compatible with a pituitary etiology (J. Clin. Endocrinol. Metab. 2003;88:5593-602). The 6-mm cutoff, said Dr. Yogi-Morren, came from an earlier study reporting that 10% of 100 normal, healthy adults had focal pituitary abnormalities on MRI ranging from 3 to 6 mm in diameter that were consistent with a diagnosis of asymptomatic pituitary adenomas (Ann. Intern. Med. 1994;120:817-20).

A traditional workup of a patient with ACTH-dependent Cushing’s syndrome might include a clinical history, biochemical testing, neuroimaging, and an inferior petrosal sinus sampling (IPSS). Biochemical testing typically includes tests for hypokalemia, measurement of cortisol and ACTH levels, a high-dose dexamethasone suppression test, and a corticotropin-releasing hormone (CRH) stimulation test. Although IPSS is the gold standard for differentiating between the two etiologies, it is expensive and technically difficult, especially in institutions that don’t regularly do the procedure, so it would be desirable to avoid IPSS if it’s not needed in a subset of patients, Dr. Yogi-Morren said.

The investigators reviewed charts from two centers (the Cleveland Clinic and the M.D. Anderson Cancer Center, Houston) for patients with ACTH-dependent Cushing’s syndrome seen during 2000-2012.

ACTH levels were significantly different between groups, averaging 162 pg/mL (range, 58-671 pg/mL) in patients with ectopic ACTH secretion, compared with a mean 71 pg/mL in patients with Cushing’s disease (range, 16-209 pg/mL), she reported. Although there was some overlap between groups in the range of ACTH levels, all patients with an ACTH level higher than 210 pg/mL had ectopic ACTH secretion.

Median serum potassium levels at baseline were 2.9 mmol/L in the ectopic ACTH secretion group and 3.8 mmol/L in the Cushing’s disease group, a significant difference. Again, there was some overlap between groups in the range of potassium levels, but all patients with a baseline potassium level lower than 2.7 mmol/L had ectopic ACTH secretion, she said.

Among patients who underwent a high-dose dexamethasone suppression test, cortisol levels decreased by less than 50% in 88% of patients with ectopic ACTH secretion and in 26% of patients with Cushing’s disease.

Most patients did not undergo a standardized, formal CRH stimulation test, so investigators extracted the ACTH response to CRH in peripheral plasma during the IPSS test. As expected, they found a significantly higher percent increase in ACTH in response to CRH during IPSS in the Cushing’s disease group, ranging up to more than a 1,000% increase. In the ectopic ACTH secretion group, 40% of patients did have an ACTH increase greater than 50%, ranging as high as a 200%-300% increase in ACTH in a couple of patients.

“Although there was some overlap in the biochemical testing, it is possible that it provides some additional proof to differentiate between ectopic ACTH secretion and Cushing’s disease,” Dr. Yogi-Morren said.

In the ectopic ACTH secretion group, the source of the secretion remained occult in seven patients. The most common identifiable cause was a bronchial carcinoid tumor, in six patients. Three patients each had small cell lung cancer, a thymic carcinoid tumor, or a pancreatic neuroendocrine tumor. One patient each had a bladder neuroendocrine tumor, ovarian endometrioid cancer, medullary thyroid cancer, or a metastatic neuroendocrine tumor from an unknown primary cancer.

The ectopic ACTH secretion group had a median age of 41 years and was 63% female. The Cushing’s disease group had a median age of 46 years and was 76% female.

Dr. Yogi-Morren reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

From Famiiy Practice News

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