Etomidate Found Effective in Severe Cushing’s Syndrome

Etomidate — a steroid synthesis blocker — is an effective treatment for patients with severe Cushing’s syndrome who do not respond to ketoconazole, according to a new case report from Mexico.

The report, “Etomidate in the control of severe Cushing’s syndrome by neuroendocrine carcinoma,” appeared in the journal Clinical Case Reports.

The investigators reported the case of a 51-year-old woman with ectopic Cushing’s syndrome caused by a pancreatic tumor. Ectopic Cushing’s refers to cases of excess secretion of adrenocorticotropin hormone (ACTH) outside the pituitary or adrenal glands.

The patient underwent distal pancreatectomy — the surgical removal of the bottom half of the pancreas — in 2015 due to an ACTH-secreting tumor. Although she had a good initial response, liver metastasis was evident by 2016.

Compared to measurements in 2016, morning blood cortisol, 24-hour urinary-free cortisol, and ACTH levels significantly increased in 2017. The patient also showed low levels of the luteinizing and follicle-stimulating hormones, which the scientists attributed to her severe hypercortisolism (excess cortisol levels).

The woman was being treated with ketoconazole to lower her cortisol values and later received chemoembolization — a method to reduce blood supply and deliver chemotherapy directly to a tumor — for her liver metastasis.

Although ketoconazole is generally the treatment of choice for the control of hormone production in the adrenal glands, its effectiveness is often limited and is associated with side effects, clinicians noted.

In April 2017, the patient arrived at the emergency room with sepsis — a potentially life-threatening complication of an infection — that originated in the gut.

Because ketoconazole had failed to lower cortisol levels, the patient started receiving infused etomidate, an inhibitor of the enzyme 11‐beta‐hydroxylase that prevents cortisol synthesis.

This treatment was stopped one day before the bilateral removal of the adrenal glands as a definitive treatment for the elevated production of cortisol.

While the patient experienced decreased levels of potassium, calcium, and magnesium with an initial dose of 0.04 mg per kg body weight an hour of etomidate, a gradual decrease of etomidate — depending on her cortisol levels — corrected these alterations.

After surgery, the patient showed a significant improvement in her general health, including control of her sepsis. She is currently taking hydrocortisone and fludrocortisone, with treatment for liver metastasis pending.

“Etomidate is a very effective drug in severe Cushing’s syndrome that is refractory to ketoconazole,” the researchers wrote.

“Control of the serum cortisol levels in ectopic Cushing’s syndrome can be obtained with infusion rates much lower than those used in anesthesia, without respiratory side effects,” they added.

The authors recommend an initial dose of etomidate of 0.04 mg/kg per hour, daily monitoring of 24-hour urinary cortisol and cortisol levels, and a gradual decrease of the etomidate dose according to daily measurements of metabolites.

From https://cushingsdiseasenews.com/2018/05/17/severe-cushings-syndrome-case-study-finds-etomidate-effective-therapy/

Rare Malignant Tumor of Adrenal Gland Led to Cushing’s, Girl’s Death

While adrenocortical carcinoma — a malignant tumor of the adrenal gland — appears only rarely in children, the tumor may cause secondary Cushing’s syndrome in these patients, a new case report shows.

Early diagnosis of the causes of Cushing’s syndrome could improve the prognosis of these children, researchers say.

The study, “Cushing Syndrome Revealing an Adrenocortical Carcinoma,” was published in the Open Journal of Pediatrics.

Adrenocortical carcinoma is a malignant tumor that develops in the cortex of the adrenal gland. It usually is identified by increased amounts of hormones that are produced by the adrenal glands, like cortisol.

This tumor type is very rare in children, representing fewer than two in every 1,000 pediatric tumors.

Researchers at the University Hospital Center Souro Sanou, in Burquina Faso (West Africa), described the case of a 10-year-old girl who developed this rare cancer.

The patient’s first symptoms were loss of consciousness and recurrent seizures without fever. The patient also had experienced excessive weight gain in the preceding months. At admission she was in a light state of coma and showed obesity in the face and trunk.

An initial analysis of blood, urine, and cerebrospinal fluid failed to detect any alterations, with no diabetes, kidney damage, or infection identified. And, even though no lesions or alteration were seen in the pituitary gland region, brain swelling was detected.

While in the hospital, the patient’s condition continued to deteriorate. She developed fever and difficulty speaking, while showing persistent seizures.

In the absence of a diagnosis, physicians focused on the safeguard of major vital function, control of seizures, and administration of large-spectrum antibiotics. Her condition improved slightly, regaining consciousness and control of seizures.

One month later, however, the patient developed symptoms that are commonly associated with increased levels of cortisol and male sex hormones, including obesity and early development of pubic hair.

After confirming high cortisol levels, physicians examined the patient’s abdominal region,  which revealed a tumor in the left adrenal gland.

The patient received a ketoconazole treatment and a surgery to remove the tumor was planned. But her condition worsened, with development of malignant hypertension and convulsive illness, which led to her death before the tumor was removed.

“The delay in the diagnosis and the insufficiency of the therapeutic means darken the prognosis in our context,” the researchers wrote.

“[Adrenocortical carcinoma] diagnosis should be considered in presence of virilization and early signs of puberty,” the researchers suggested. “Early diagnosis and multidisciplinary management of adrenocortical carcinoma could improve the prognosis in children.”

From https://cushingsdiseasenews.com/2018/05/04/rare-malignant-tumor-adrenal-gland-caused-cushings-case-report/

Cushing’s Patient Exhibits Cortisol-Secreting Lesions in Both Adrenal Glands

In rare cases, Cushing’s syndrome may be caused by cortisol-secreting masses in both adrenal glands, a case report shows.

The study with that finding, “ACTH-independent Cushing’s syndrome with bilateral cortisol-secreting adrenal adenomas: a case report and review of literatures” was published in BMC Endocrine Disorders.

Cushing’s syndrome results from the prolonged secretion of excess cortisol. While most cases are caused by tumors in the pituitary gland, up to 20 percent result from tumors in the adrenal glands.

Occasionally, Cushing’s syndrome is caused by masses in both adrenal glands, which may be similar or display different properties. “Determining the nature and function of bilateral adrenal masses is always a challenge in clinical practice,” researchers said.

Now, physicians at Sichuan University in China, reported the case of a 55-year-old woman who complained of difficulty breathing for more than 10 years.

The patient had developed obesity of the trunk and face over the past two years, and had been diagnosed with hypertension 10 years before. She also had high lipid levels for the past five years.

The patient was taking Avapro (irbesartan), Lopressor (metoprolol), Procardia XL (nifedipine), and statins for these disorders. No other health conditions or treatments were reported.

Physical examination showed a moon-shaped face, truncal obesity, and accumulation of fat in the back of the neck and upper back (aka buffalo hump). She also had discoloration of the lower limbs, with slight fluid accumulation and muscle weakness.

Routine blood analysis did not reveal significant changes, but hormone analysis showed high cortisol levels and low adrenocorticotropic hormone (ACTH) was low.

The amount of 24-hour urine-free cortisol was almost five times higher than the upper normal limit. Also, the patients had reduced response to corticosteroids treatment, showing even higher cortisol levels upon treatment with 1 mg dexamethasone. Additional evaluations revealed reduced bone mineral density, indicative of osteoporosis.

Together, the findings led to a diagnosis of ACTH-independent Cushing’s syndrome.

To identify what was causing Cushing’s syndrome, the team looked at the adrenal glands. They detected three lesions, one on the right side measuring 2.5 centimeters, and two on the left side, with 2.3 cm and 0.6 cm respectively. The masses in both sides were actively producing cortisol in similar proportions.

These results confirmed that the patient had Cushing’s syndrome induced by bilateral adrenal excessive cortisol secretion.

Because the patient had poor cardiac function, researchers planned a two-step operation. First, they removed the right adrenal gland laparoscopically, followed by the left adrenal gland two months later. The patient started replacement therapy with hydrocortisone, and her cortisol levels improved significantly, returning to normal levels. She also lost 4 kilograms (8.8 pounds) of body weight in the following year.

“The optimal treatment for patients with bilateral cortisol-secreting adenomas remains uncertain,” the researchers wrote. Although there are no reports of recurrence after surgical treatment, the long-term outcome of these patients remains unclear, and “lifelong follow-up of the patient is required,” they added.

Bilateral cortisol-secreting adrenal adenomas are rare, having been reported in only 15 other studies, the team wrote. Interestingly, some features reported in this study also were identified by other researchers, including the fact that bilateral cortisol-secreting adrenal lesions are more predominantly found in females during adulthood. Also, the size of the lesions commonly range between 1 to 5 centimeters when detected, and appear at approximately the same time in both adrenal glands.

Although there are no treatment guidelines for these cases, surgical removal of the lesions or adrenal glands, plus glucocorticoid replacement therapy, is the mostly used therapeutic approach. Importantly, the researchers noted that patients who underwent partial gland removal were able to withdraw from glucocorticoid replacement therapy during follow-up.

From https://cushingsdiseasenews.com/2018/05/03/cushings-patient-has-cortisol-secreting-lesions-in-both-adrenal-glands/

Blood Lipid Levels Linked to High Blood Pressure in Cushing’s Disease Patients

High lipid levels in the blood may lead to elevated blood pressure in patients with Cushing’s disease, a Chinese study shows.

The study, “Evaluation of Lipid Profile and Its Relationship with Blood Pressure in Patients with Cushing’s Disease,” appeared in the journal Endocrine Connections.

Patients with Cushing’s disease often have chronic hypertension, or high blood pressure, a condition that puts them at risk for cardiovascular disease. While the mechanisms of Cushing’s-related high blood pressure are not fully understood, researchers believe that high levels of cortisol lead to chronic hypertension through increased cardiac output, vascular resistance, and reactivity to blood vessel constrictors.

In children and adults with Cushing’s syndrome, the relationship between increased cortisol levels and higher blood pressure has also been reported. Patients with Cushing’s syndrome may remain hypertensive even after surgery to lower their cortisol levels, suggesting their hypertension is caused by changes in blood vessels.

Studies have shown that Cushing’s patients have certain changes, such as increased wall thickness, in small arteries. The renin-angiotensin system, which can be activated by glucocorticoids like cortisol, is a possible factor contributing to vascular changes by increasing the uptake of LDL-cholesterol (LDL-C) — the “bad” cholesterol — in vascular cells.

Prior research showed that lowering cholesterol levels could benefit patients with hypertension and normal lipid levels by decreasing the stiffness of large arteries. However, the link between blood lipids and hypertension in Cushing’s disease patients is largely unexplored.

The study included 84 patients (70 women) referred to a hospital in China for evaluation and diagnosis of Cushing’s disease. For each patient, researchers measured body mass index, blood pressure, lipid profile, and several other biomarkers of disease.

Patients with high LDL-cholesterol had higher body mass index, blood pressure, cholesterol, triglycerides, and apolipoproteinB (apoB), a potential indicator of atherosclerosis and cardiovascular disease.

Data further revealed an association between blood pressure and lipid profile, including cholesterol, triglycerides, apoB and LDL-c. “The results strongly suggested that CHO (cholesterol), LDL-c and apoB might predict hypertension more precisely in [Cushing’s disease],” the scientists wrote.

They further add that high cholesterol, LDL-cholesterol, and apoB might be contributing to high blood pressure by increasing vessel stiffness.

Additional analysis showed that patients with higher levels of “bad” cholesterol — 3.37 mmol/L or higher — had higher blood pressure. This finding remained true, even when patients were receiving statins to lower their cholesterol levels.

No association was found between blood pressure and plasma cortisol, UFC, adrenocorticotropic hormone, or glucose levels in Cushing’s disease patients.

These findings raise some questions on whether lipid-lowering treatment for high blood pressure and cardiovascular disease would be beneficial for Cushing’s disease patients. Further studies addressing this question are warranted.

Adapted from https://cushingsdiseasenews.com/2018/04/24/blood-pressure-linked-lipid-levels-cushings-disease-study/

Mild Cortisol Increases Affect Cardiovascular Changes Linked to Heart Disease in Cushing’s

Increases in cortisol secretion, even if mild, induce early heart and blood vessel changes that may increase the risk for cardiovascular disease, according to Italian researchers.

The findings continue to support the role of the hormone cortisol in heart disease, and demonstrate the need for carefully monitoring cardiovascular risk in patients with high levels of the hormone, including those with Cushing’s disease.

The study, “Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas,” was published in the European Journal of Endocrinology.

While most patients with adrenal incidentalomas don’t have symptoms, nearly half have excess cortisol production. Adrenal incidentalomas are masses in the adrenal glands discovered only when a patient undergoes imaging tests for another unrelated condition.

These asymptomatic, mild cortisol-producing cases are defined as possible autonomous cortisol secretion (pACS), according to the European Society of Endocrinology Guidelines.

Excess production of the hormone, seen in Cushing’s disease patients, is associated with increased mortality, mainly due to heart diseases. Patients with asymptomatic adrenal adenomas and mild cortisol secretion also have more cardiovascular events and generally die sooner than those with normal cortisol levels.

But little is known about the causes behind cardiac and vessel damage in these patients.

To shed light on this matter, a research team at Sapienza University of Rome evaluated the cardiovascular status of patients with pACS. This allowed them to study the impact of cortisol in the heart and blood vessels without the interference of other hormone and metabolic imbalances seen in Cushing’s disease.

The ERGO trial (NCT02611258) included 71 patients. All had been diagnosed with adrenal incidentalomas, 34 of which were pACS with mildly increased levels of the hormone and 37 were defined as nonfunctioning adenoma (NFA) — adrenal masses with normal hormone levels.

The two groups were very similar, with no significant differences in metabolic and cardiovascular risk factors. Adrenal lesions in the pACS group, however, were significantly bigger, which was linked to cortisol levels.

Looking at the heart morphology, researchers found that pACS patients had a significantly higher left ventricular mass index (LVMI), which is a well-established predictive measure of adverse cardiovascular events.

Further analysis revealed that LVMI scores were associated with levels of the hormone, suggesting it has an “independent effect of cortisol on cardiac function,” the researchers wrote.

Slightly more than half of pACS patients (53%) also had a thicker left ventricle, a feature that was seen only in 13.5% of NFA patients. The performance of the left ventricle during diastole (muscle relaxation) was also affected in 82.3% of pACS patients, compared to 35.1% in those with NFA.

Patients with pACS also had less flexible arteries, which may contribute to the development of vascular diseases.

The results show that “mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling” in patients who appear apparently healthy, the researchers said.

“The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition,” they added.

From https://cushingsdiseasenews.com/2018/03/13/cushings-disease-increased-cortisol-affects-cardiovascular-changes-heart-disease/

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