Cushing Patients Could Be Diagnosed, Subtyped Using Plasma Steroid Levels

Patients with different subtypes of Cushing’s syndrome (CS) have distinct plasma steroid profiles. This could be used as a test for diagnosis and classification, a German study says.

The study, “Plasma Steroid Metabolome for Diagnosis and Subtyping Patients with Cushing Syndrome,” appeared in the journal Clinical Chemistry.

A quick diagnosis of CS is crucial so that doctors can promptly give therapy. However, diagnosing CS is often complicated by the multiple tests necessary not just to diagnose the disease but also to determine its particular subtype.

Cortisol, which leads to CS when produced at high levels, is a steroid hormone. But while earlier studies were conducted to determine whether patients with different subtypes of CS had distinct steroid profiles, the methods researchers used were cumbersome and have been discontinued for routine use.

Recently, a technique called LC-MS/MS has emerged for multi-steroid profiling in patients with adrenocortical dysfunction such as congenital adrenal hyperplasia, adrenal insufficiency and primary aldosteronism.

Researchers at Germany’s Technische Universität in Dresden used that method to determine whether patients with the three main subtypes of CS (pituitary, ectopic and adrenal) showed differences in plasma steroid profiles. They measured levels of 15 steroids produced by the adrenal glands in single plasma samples collected from 84 patients with confirmed CS and 227 age-matched controls.

They found that CS patients saw huge increases in the plasma steroid levels of 11-deoxycortisol (289%), 21-deoxycortisol (150%), 11-deoxycorticosterone (133%), corticosterone (124%) and cortisol (122%), compared to patients without the disease.

Patients with the ectopic subtype had the biggest jumps in levels of these steroids. However, plasma 18-oxocortisol levels were particularly low in ectopic disease. Other steroids demonstrated considerable variation.

Patients with the adrenal subtype had the lowest concentration of dehydroepiandrosterone (DHEA) and DHEA-SO4, which are androgens. Patients with the ectopic and pituitary subtype had the lowest concentration of aldosterone.

Through the use of 10 selected steroids, patients with different subtypes of CS could be identified almost as closely as with other tests, including the salivary and urinary free cortisol test, the dexamethasone-suppressed cortisol test, and plasma adrenocorticotropin levels. The misclassification rate using steroid levels was 9.5 percent, compared to 5.8 percent in other tests.

“This study using simultaneous LC-MS/MS measurements of 15 adrenal steroids in plasma establishes distinct steroid metabolome profiles that might be useful as a test for CS,” the team concluded, adding that using LC-MS/MS is advantageous, as specimen preparation is simple and the entire panel takes 12 minutes to run. This means it could be offered as a single test for both identification and subtype classification.

From https://cushingsdiseasenews.com/2018/01/02/plasma-steroid-levels-used-screen-diagnosis-subtyping-patients-cushing-syndrome/

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

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/

ACTH-producing Lung Tumors Hard to Detect, But May Be Cured with Surgery

Ectopic Cushing’s syndrome can be challenging to diagnose, especially when it comes identifying the problem source. But appropriate hormone management protocols, used in combination with advanced imaging methods, may help physicians identify ectopic ACTH-producing tumors.

The findings in a case report of a young man with ectopic Cushing’s syndrome were published in the International Journal of Surgery Case Reports, under the title “Case report: Ectopic Cushing’s syndrome in a young male with hidden lung carcinoid tumor.”

Cushing’s syndrome is caused by high amounts of glucocoticosteroids in the blood. The most common cause is a malfunction of the glands that produce these hormones. In some cases, however, the disease may be caused by tumors elsewhere in the body that have the ability to produce adrenocorticotropic hormone (ACTH).

In half of all Cushing’s patients, ectopic ACTH is produced by small lung cell carcinomas or lung carcinoids (a type of slow-growing lung cancer). But some tumors in the thymus and pancreas also have been found to produce ACTH.

Researchers at Damascus University Hospital in Syria presented the case of a 26-year-old man who had ectopic Cushing’s syndrome due to lung carcinoids.

The patient presented with increased appetite and rapid weight gain for more than a year. These were associated with headache, fatigue, proximal muscle weakness, and easy bruising. He had no family history of hormonal disorder.

Based on the initial physical and symptom evaluation, the clinical team suspected Cushing’s syndrome. Blood analysis revealed high levels of cortisol and ACTH hormones, which supported the diagnosis.

Administration of dexamethasone, a treatment used to inhibit the production of glucocoticosteroids by the pituitary gland, reduced cortisol levels within normal range, but not ACTH levels. This led to the diagnosis of ectopic Cushing’s syndrome.

The next step was to identify the tumor causing the syndrome. The team conducted imaging studies of the brain, chest, and abdomen, but found no tumor.

Because ectopic ACTH is commonly produced by lung cancers, the team then analyzed the patient’s lungs. Again, they failed to detect a tumor.

The patient was discharged with prescription of 200 mg of Nizoral (ketoconazole) once-daily, calcium, and vitamin D. After three months of treatment, he remained stable, with no evidence of symptom improvement.

At this point, the team decided to surgically remove both adrenal glands in an attempt to reduce the hormone levels. Treatment with prednisolone 5 mg and fludrocortisone 0.1 mg once daily was initiated, along with calcium and vitamin D.

Eighteen months later, the patient’s condition worsened and he required hospitalization.

Imaging tests targeting the neck, chest, and abdomen were conducted again. This time, physicians detected a 2 cm mass in the middle lobe of the right lung, which was removed surgically. Detailed analysis of the small tumor confirmed that it was the source of the excessive ACTH.

“ACTH secreting tumors can be very hard to detect,” the researchers stated. “Initial failed localization is common in ectopic ACTH syndrome and it is usually due to carcinoid.”

Cases where the ectopic ACTH production is caused by a carcinoid tumor can be challenging to diagnose because tumors are small and relatively slow-growing. Imaging data is often hard to analyze and the tumors can be confused with pulmonary vessels, the researchers explained.

“In such cases we should first aim to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications,” which should then “be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it, which is the definitive treatment of these patients,” the researchers concluded.

From https://cushingsdiseasenews.com/2017/12/12/case-report-ectopic-acth-producing-lung-tumors-can-hard-detect/

The Challenge of Obesity in Diagnosing Cushing’s Syndrome and Strategies to Improve Methods

The effects of obesity on the diagnosis of Cushing’s syndrome and strategies to alter the traditional approaches have been addressed in a new review study.

The study, “Diagnosis and Differential Diagnosis of Cushing’s Syndrome,” appeared in The New England Journal of Medicine. The author was Dr. Lynn D. Loriaux, MD and PhD, and a professor of medicine at the Division of Endocrinology, Diabetes and Clinical Nutrition at the School of Medicine, Oregon Health & Science University (OHSU), in Portland, Oregon.

Traditionally, exams of patients with glucocorticoid excess focused on the presence of changes in anabolism (the chemical synthesis of molecules). Given the increase in obesity in the general population, changes in anabolism can no longer distinguish Cushing’s syndrome from metabolic syndrome.

However, analyses of anti-anabolic changes of cortisol – including osteopenia (lower bone density), thin skin, and ecchymoses (injury that causes subcutaneous bleeding) – are an effective way to make this distinction.

The worldwide prevalence of metabolic syndrome in obese people is estimated at about 10%. Conversely, the incidence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million people.

Cushing’s and metabolic syndrome share significant clinical similarities, including obesity, hypertension, and type 2 diabetes. Therefore, “making the diagnosis is the least certain aspect in the care of patients with [Cushing’s],” Loriaux wrote.

Regarding a physical examination, patients with osteoporosis, reduced skin thickness in the middle finger, and three or more ecchymoses larger than 1 cm in diameter and not associated with trauma are more likely to have Cushing’s. Researchers estimate the probability of people with all three of these symptoms having Cushing’s syndrome is 95%.

Measuring 24-hour urinary-free cortisol levels allows the assessment of excess glucocorticoid effects, typical of Cushing’s syndrome. The test, which should be done with the most stringent techniques available, averages the augmented secretion of cortisol in the morning and the diminished secretion in the afternoon and at night.

Dexamethasone suppression is one of the currently used screening tests for Cushing’s syndrome. Patients with obesity and depression should not show decreased plasma cortisol levels when dexamethasone is suppressed. However, given its low estimated predictive value (the proportion of positive results that are “true positives”), “this test should not influence what the physician does next and should no longer be used” to screen for Cushing’s, the author wrote.

Some patients may show evidence of Cushing’s syndrome at a physical examination, but low urinary free cortisol excretion. This may be due to glucocorticoids being administered to the patient. In this case, the glucocorticoid must be identified and discontinued. Periodic Cushing’s assessments that measure urinary free cortisol should be performed.

The opposite can also occur: no clinical symptoms of Cushing’s, but elevated urinary free cortisol excretion and detectable plasma levels of the hormone corticotropin. In these patients, the source of corticotropin secretion, which can be a tumor or the syndrome of generalized glucocorticoid resistance, must be determined.

The disease process can be corticotropin-dependent or independent, depending on whether the hormone is detectable. Corticotropin in Cushing’s syndrome can come from the pituitary gland (eutopic) or elsewhere in the body (ectopic).

Loriaux recommends that the source of corticotropin secretion be determined before considering surgery. Up to 40% of patients with pituitary adenomas have nonfunctioning tumors (the tumor does not produce any hormones) and the corticotropin source is elsewhere. If misdiagnosed, patients will likely undergo an unnecessary surgery, with a mortality rate of 1%.

Patients with an ectopic source of corticotropin should undergo imaging studies in the chest, followed by abdominal and pelvic organs. If these tests fail to detect the source, patients should undergo either the blockade of cortisol synthesis or an adrenalectomy (removal of adrenal glands).

However, corticotropin-independent Cushing’s is usually caused by a benign adrenal tumor that uniquely secretes cortisol.

“Such tumors can be treated successfully with laparoscopic adrenalectomy,” Loriaux wrote. If the tumor secretes more than one hormone, it is likely malignant. Surgical to remove the tumor and any detectable metastases should be conducted.

Overall, “the treatment for all causes of [Cushing’s syndrome], other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed,” Loriaux wrote in the study.

“This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with [Cushing’s syndrome] should be referred to such a center for treatment.”

From https://cushingsdiseasenews.com/2017/10/24/diagnosing-cushings-syndrome-amid-challenge-of-obesity-and-strategies-to-improve-methods/

Ectopic Cushing’s syndrome associated with thoracic tumors

Results of a retrospective review conducted in southern India demonstrate that ectopic Cushing’s syndrome occurred most commonly in association with thoracic tumors.

Researchers added that early control over hypercortisolemia was necessary to prevent metabolic complications and infections, both of which had the potential to be life-threatening.

“As compared to patients with pituitary-dependent Cushing’s syndrome, patients with [ectopic Cushing Syndrome] present with a rapid progression of symptoms,” Nihal Thomas, MD, MNAMS, DNB, FRACP, professor in the department of endocrinology, diabetes and metabolism at Christian Medical College, Vellore, India, and colleagues wrote. “It is also associated with typical features of proximal muscle weakness, severe hypokalaemic metabolic alkalosis, hyperpigmentation, edema, hypertension and glucose intolerance. Early diagnosis and localization of the ectopic source of [adrenocorticotrophic hormone] is crucial, because the treatment of choice in most of these patients is complete excision of the tumor. Localizing the source of excess ACTH continues to be a challenge in most patients.”

Thomas and colleagues reviewed the records of 21 patients treated at a tertiary care center in southern India from 2006 to 2015. The researchers documented patients’ clinical features, history and images from radiological findings and PET scans, as well as details of management, follow-up and outcomes. They also compared those with ectopic Cushing’s syndrome with 20 patients who had Cushing’s disease.

Median age was 34 years. Thomas and colleagues reported that one patient demonstrated “an occult source of ACTH.” The rest had a variety of tumors: bronchial carcinoid (n = 7), thymic carcinoid (n = 7), lung malignancies (n = 3), medullary thyroid carcinoma (n = 2) and pancreatic neuroendocrine tumor (n = 1).

At presentation, muscle weakness was the most common clinical feature (95%), followed by hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%) and striae (52%). Slightly less than half (43%) showed extensive acne. Central obesity in ectopic Cushing’s syndrome was uncommon and occurred in 14% of patients (n = 3), according to Thomas and colleagues; however, it was more prevalent (n = 18) in those with Cushing’s disease.

Median cortisol at 8 a.m. was 55.5 mcg/dL, the researchers wrote, while median 8 a.m. ACTH was 207 pg/mL. The median 24-hour urinary free cortisol level was 2,484 mcg.

Compared with patients with Cushing’s disease, those with ectopic Cushing’s syndrome had “markedly higher” midnight cortisol and ACTH, as well as basal cortisol and ACTH.

During follow-up, more than half of patients (12 of 21) with ectopic Cushing’s syndrome developed life-threatening infections. Although nine patients received surgery for their tumors, only one patient achieved a complete cure during the study period, the researchers wrote.

“In our series, patients with [ectopic Cushing’s syndrome] have more profound hypokalemia, and hypercortisolemia with higher levels of ACTH,” Thomas and colleagues wrote. “The prognosis of patients with [ectopic Cushing’s syndrome] was dependent on tumor histology. The role of a timely adrenalectomy needs to be considered in patients with hypercortisolemia unresponsive to medical management, and in patients with metastatic or recurrent disease.” – by Andy Polhamus

Disclosure: Endocrine Today was unable to confirm any relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Be42c81a5-fd5b-4313-9b2b-9bcbdec7f8ce%7D/ectopic-cushings-syndrome-associated-with-thoracic-tumors

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