Researchers Report Rare Case of Cushing’s Caused by Bilateral Adrenal Tumors

Posted on July 8, 2019 by MaryO

Cases of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome are often caused by unilateral tumors in the adrenal glands, but Indian researchers have now reported a rare case where the condition was caused by tumors in both adrenal glands.

Fewer than 40 cases of bilateral tumors have been reported so far, but an accurate diagnosis is critical for adequate and prompt treatment. Sampling the veins draining the adrenal glands may be a good way to diagnose the condition, researchers said.

The study, “Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing’s syndrome: A case report and review of the literature,” was published in the World Journal of Clinical Cases.

Cushing’s syndrome, a condition characterized by excess cortisol in circulation, can be divided into two main forms, depending on ACTH status. Some patients have tumors that increase the amount of ACTH in the body, and this hormone will act on the adrenal glands to produce cortisol in excess. Others have tumors in the adrenal glands, which produce excess cortisol by themselves, without requiring ACTH activation. This is known as ACTH-independent Cushing’s syndrome.

Among the latter, the disease is mostly caused by unilateral tumors — in one adrenal gland only —  with cases of bilateral tumors being extremely rare in this population.

Now, researchers reported the case of a 31-year-old Indian woman who developed ACTH-independent Cushing’s syndrome because of tumors in both adrenal glands.

The patient complained of weight gain, red face, moon face, bruising, and menstrual irregularity for the past two years. She recently had been diagnosed with high blood pressure and had started treatment the month prior to the presentation.

A physical examination confirmed obesity in her torso, moon face, buffalo hump, thin skin, excessive hair growth, acne, swollen legs and feet, and skin striae on her abdomen, arms, and legs.

Laboratory examinations showed that the woman had an impaired tolerance to glucose, excess insulin, and elevated cortisol in both the blood and urine. Consistent with features of Cushing’s syndrome, cortisol levels had no circadian rhythm and were non-responsive to a dexamethasone test, which in normal circumstances lowers cortisol production.

Because ACTH levels were within normal levels, researchers suspected an adrenal tumor, which led them to conduct imaging scans.

An abdominal computed tomography (CT) scan showed adrenal adenomas in both adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). A magnetic resonance imaging (MRI) scan showed that the pituitary gland (which normally produces ACTH) was normal.

To determine whether both adrenal tumors were producing cortisol, researchers sampled the adrenal veins and compared their cortisol levels to those of peripheral veins. They found that the left adrenal gland was producing higher amounts of cortisol, thought the right adrenal gland was also producing cortisol in excess.

“Our case indicates that adrenal vein [blood] sampling might be useful for obtaining differential diagnoses” in cases of Cushing’s syndrome, researchers stated. Also, they may help design a surgical plan that makes much more sense.”

The tumors were surgically removed — first the left, and three months later the right — which alleviated many of her symptoms. She also started prednisolone treatment, which helped resolve many disease symptoms.

“Bilateral cortisol-secreting tumors are a rare cause of Cushing’s syndrome,” researchers said. So when patients present bilateral adrenal lesions, “it is crucial to make a definitive diagnosis before operation since various treatments are prescribed for different causes,” they said.

The team recommends that in such cases the two tumors should not be removed at the same time, as this approach may cause adrenal insufficiency and the need for glucocorticoid replacement therapy.

From https://cushingsdiseasenews.com/2019/06/27/rare-case-of-cs-due-to-bilateral-tumors-in-the-adrenal-glands/

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Common Cushing’s Treatment, Somatostatin Analogs, May Sometimes Worsen Disease Course

Posted on December 30, 2017 by MaryO

Doctors often prescribe somatostatin analogs to manage the hormonal imbalance that characterizes Cushing’s syndrome. However, in rare situations these medicines have paradoxically made patients worse than better.

This recently happened with a 48-year-old Spanish woman whose Cushing’s syndrome was caused by an adrenal gland tumor that was producing excess adrenocorticotropic hormone (ACTH). Her case was recently reported in the study “Ectopic Cushing’s syndrome: Paradoxical effect of somatostatin analogs,” and published in the journal Endocrinología, Diabetes y Nutrición.

Cushing’s syndrome occurs when the body produces too much cortisol. This can happen for many reasons, including an oversupply of ACTH, the hormone responsible for cortisol production, due to a tumor in the pituitary gland.

But sometimes, tumors growing elsewhere can also produce ACTH. This feature, known as ectopic ACTH secretion (EAS), may also cause ACTH-dependent Cushing’s syndrome.

Two-thirds of EAS tumors are located in the thorax, and 8 to 15 percent are in the abdominal cavity. Only 5 percent of EAS tumors are located in the adrenal gland, and up to 15 percent of EAS tumors are never detected.

Doctors usually use cortisol synthesis inhibitors such as ketoconazole or Metopirone (metyrapone) to control EAS, due to their efficacy and safety profiles. But somatostatin analogs (SSAs) such as Somatuline (lanreotide) have also been used to treat these tumors. However, these drugs produce mixed results.

The woman in the case study, reported by researchers at the University Hospital Vall d’Hebron in Barcelona, Spain, had an EAS tumor on the adrenal gland. She experienced s life-threatening cortisol and ACTH increase after receiving high-dose Somatuline.

The patient had been recently diagnosed with hypertension, and complained of intense fatigue, muscular weakness, easy bruising and an absence of menstruation. Laboratory analysis revealed that she had triple the normal levels of free cortisol in the urine, elevated levels of plasma cortisol, and high ACTH levels. In addition, her cortisol levels remained unchanged after receiving dexamethasone. The patient was therefore diagnosed with ACTH-dependent Cushing syndrome.

To determine the origin of her high cortisol levels, the team conducted magnetic resonance imaging (MRI). They found no tumors on the most common places, including the pituitary gland, neck, thorax or abdomen. However, additional evaluation detected a small alteration on the left adrenal gland, suggesting that was the source of ectopic ACTH production.

The team initiated treatment with 120 mg of Somatuline, but a week later, her condition had worsened and become life-threatening. Doctors started Ketoconazole treatment immediately, three times daily. The affected adrenal gland was surgically removed, and tissue analysis confirmed the diagnosis. The patient’s clinical condition improved significantly over the follow-up period.

“We highlight the need to be aware of this rare presentation of EAS, and we remark the difficulties of EAS diagnosis and treatment,”  researchers wrote.

The team could not rule out the possibility that the patient’s clinical development was due to the natural course of the disease. However, they believe “she had a paradoxical response on the basis of her dramatical worsening just after the SSAs administration, associated to an important rise in ACTH and UFC levels.”

For that reason, researchers think a new version of SSAs, such as Signifor (pasireotide) — which has improved receptor affinity — could provide better therapeutic response.

From https://cushingsdiseasenews.com/2017/11/09/paradoxical-effects-of-somatostatin-analogs-on-adrenal-ectopic-acth-tumor/

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Screening tool accurately predicts Cushing’s syndrome in most at-risk patients

Posted on August 9, 2016 by MaryO

León-Justel A, et al. J Clin Endocrinol Metab. 2016;doi:10.1210/jc.2016-1673.

A scoring system based on clinical signs and a late-night salivary cortisol test accurately predicted Cushing’s syndrome in at-risk patients, with only one missed case, according to recent findings.

In a prospective, multicenter study, Antonio León-Justel, PhD, of the biochemistry department at the Hospital Universitario Virgen del Rocío in Seville, Spain, and colleagues analyzed data from 353 patients treated in endocrinology units in 13 university hospitals in Spain between 2012 and July 2013. All participants had at least two of five features compatible with Cushing’s syndrome, including obesity, hypertension, poorly controlled diabetes,hirsutism with menstrual disorders and osteoporosis; none of the included patients was referred to clinic with the suspicion of Cushing’s syndrome. All patients underwent late-night salivary cortisol and serum cortisol measurements after a low-dose (1 mg) dexamethasone test; those with discordant results were followed until December 2014 (mean follow-up time, 22.2 months).

Within the cohort, 26 (7.4%) patients were diagnosed with Cushing’s syndrome (20 adrenocorticotropic hormone-dependent; six of adrenal origin). In univariate logistic regression analysis, researchers found that muscular atrophy (OR = 15.2), followed by osteoporosis (OR = 4.6), dorsocervical fat pad (OR = 3.32), absence of obesity (OR = 0.21) and absence of type 2 diabetes (OR = 0.26), were associated with Cushing’s syndrome; late-night salivary cortisol values were also related (OR = 1.26). However, after multivariable adjustment, researchers found that muscular atrophy (OR = 9.04; 95% CI, 2.36-34.65), osteoporosis (OR = 3.62; 95% CI, 1.16-11.35) and dorsocervical fat (OR = 3.3; 95% CI, 1.52-7.17) remained as independent variables with Cushing’s syndrome.

“Obesity and type 2 diabetes displayed a negative association with [Cushing’s syndrome],” the researchers wrote. “These results might seem paradoxical a priori, but we want to stress that in our analyzed cohort, the prevalence of obesity and diabetes was exceedingly high (likely reflecting the reasons for referral to endocrinology units).”

In receiver operating characteristic (ROC) analysis, researchers determined that a cutoff value of 9.17 nmol/L for late-night salivary cortisol provided the best results, with an area under the curve of 0.893 (P < .001), a sensitivity of 88.5% and specificity of 83.2%.

Researchers developed a risk-scoring system, determining cutoff values from a ROC curve. The estimated area under the ROC curve was 0.93 (P < .001), with a sensitivity of 96.2% and specificity of 82.9%.

“Selecting this cutoff value of four, 271 of 327 subjects (83%) without [Cushing’s syndrome] were correctly identified, while only 1 of 26 [Cushing’s syndrome] cases was missed,” the researchers wrote. “Our model yielded 56 false positives.

“Although all the assessments were performed by specialists (endocrinologists) in our study, this scoring system could be easily tested in independent cohorts and different settings such as primary care or hypertension clinics,” the researchers wrote. “At the very least, our diagnostic prediction model could be used as a framework for future studies and potential improvements in diagnostic performance.” – by Regina Schaffer

Disclosure: Leon-Justel and another researcher report receiving a research grant from Novartis Oncology, Spain.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B50d3d398-c8fe-41e9-b815-87626bfe8a4b%7D/screening-tool-accurately-predicts-cushings-syndrome-in-most-at-risk-patients

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Polycystic ovarian syndrome and Cushing’s syndrome: A persistent diagnostic quandary

Posted on February 10, 2014 by MaryO
European Journal of Obstetrics & Gynecology and Reproductive Biology, 02/10/2014  Clinical Article

Brzana J, et al. – This study aims to retrospectively review institutional records of female patients of reproductive age with Cushing’s disease (CD) and determine if and how many had been previously diagnosed as having solely PCOS. To determine whether clinical patterns might be useful in identifying appropriate candidates for hypercortisolism screening in women suspected of PCOS. Prolonged exposure to hypercortisolism has been linked with increased mortality and morbidity. Tests for hypercortisolism in all the PCOS cases authors report led to an appropriate CD diagnosis. Future research should focus on when and which (if not all) women with suspected PCOS should be tested for hypercortisolism.

Methods

  • The study included 50 patients with pathologically proven CD at Oregon Health & Science University, Northwest Pituitary Center between 2006 and 2011.
  • Physical, clinical, and biochemical features for hypercortisolism were compared.

Results

  • Of 50 patients with pathologically proven CD, 26 were women of reproductive age.
  • Of these, half had previously been diagnosed with and treated initially solely for PCOS.
  • Hirsutism and menstrual abnormalities were more common in the group with an initial PCOS diagnosis than in the group with an initial CD diagnosis.

From http://www.mdlinx.com/endocrinology/newsl-article.cfm/5055779/ZZ4747461521296427210947/?news_id=2364&newsdt=021014&subspec_id=1509&utm_source=Focus-On&utm_medium=newsletter&utm_content=Top-New-Article&utm_campaign=article-section

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FDA Puts Strict Limits on Oral Ketoconazole Use

Posted on August 3, 2013 by MaryO

By John Gever, Deputy Managing Editor, MedPage Today

SILVER SPRING, Md. — Oral ketoconazole (Nizoral) should never be used as first-line therapy for any type of fungal infection because of the risk of liver toxicity and interactions with other drugs, the FDA said Friday.

The agency ordered a series of label changes and a new medication guide for patients that emphasize the risks, which also include adrenal insufficiency. It noted that the restrictions apply only to the oral formulation, not topical versions.

Late Thursday, the chief advisory body for the FDA’s European counterpart went further. The EU’s Committee on Medicinal Products for Human Use (CHMP) recommended that member nations pull oral ketoconazole from their markets entirely.

Both the FDA and the CHMP cited studies indicating high risks of severe, acute liver injury in patients taking the drug. Studies using the FDA’s adverse event reporting system and a similar database in the U.K. indicated that liver toxicity was more common with oral ketoconazole than with other anti-fungals in the azole class.

The FDA also said that oral ketoconazole “is one of the most potent inhibitors” of the CYP3A4 enzyme. This effect can lead to sometimes life-threatening interactions with other drugs metabolized by CYP3A4, and also to adrenal insufficiency, since the enzyme also catalyzes release of adrenal steroid hormones.

“This accounts for clinically important endocrinologic abnormalities observed in some patients (particularly when the drug is administered at high dosages), including gynecomastia in men and menstrual irregularities in women,” the FDA said.

The only indication for oral ketoconazole still supported by the FDA is for use in life-threatening mycoses in patients who cannot tolerate other anti-fungal medications or when such medications are unavailable.

In such instances, the FDA said, physicians should assess liver function before starting the drug. It is contraindicated in patients with pre-existing liver disease, and patients should be instructed not to drink alcohol or use other potentially hepatotoxic drugs.

Adrenal function should also be monitored in patients using the drug.

The CHMP also indicated the topical formulations of ketoconazole should stay on the market, but it found no basis for keeping the oral form available for any purpose.

“Taking into account the increased rate of liver injury and the availability of alternative anti-fungal treatments, the CHMP concluded that the benefits did not outweigh the risks,” the panel indicated in a statement.

It recommended that physicians stop prescribing oral ketoconazole and that they should review alternatives in patients currently receiving the drug. The committee also said that patients now taking oral ketoconazole “make a non-urgent appointment” with their physicians to discuss their treatment.

From MedPage Today

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