Metoclopramide Can Mask Adrenal Insufficiency After Gland Removal in BMAH Patients

Metoclopramide, a gastrointestinal medicine, can increase cortisol levels after unilateral adrenalectomy — the surgical removal of one adrenal gland — and conceal adrenal insufficiency in bilateral macronodular adrenal hyperplasia (BMAH) patients, a case report suggests.

The study, “Retention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy,” was published in Therapeutics and Clinical Risk Management.

BMAH is a subtype of adrenal Cushing’s syndrome, characterized by the formation of nodules and enlargement of both adrenal glands.

In this condition, the production of cortisol does not depend on adrenocorticotropic hormone (ACTH) stimulation, as usually is the case. Instead, cortisol production is triggered by a variety of stimuli, such as maintaining an upright posture, eating mixed meals — those that contain fats, proteins, and carbohydrates — or exposure to certain substances.

A possible treatment for this condition is unilateral adrenalectomy. However, after the procedure, some patients cannot produce adequate amounts of cortisol. That makes it important for clinicians to closely monitor the changes in cortisol levels after surgery.

Metoclopramide, a medicine that alleviates gastrointestinal symptoms and is often used during the postoperative period, has been reported to increase the cortisol levels of BMAH patients. However, the effects of metoclopramide on BMAH patients who underwent unilateral adrenalectomy are not clear.

Researchers in Japan described the case of a 61-year-old postmenopausal woman whose levels of cortisol remained high after surgery due to metoclopramide ingestion.

The patient was first examined because she had experienced high blood pressure, abnormal lipid levels in the blood, and osteoporosis for ten years. She also was pre-obese.

She was given medication to control blood pressure with no results. The lab tests showed high serum cortisol and undetectable levels of ACTH, suggesting adrenal Cushing’s syndrome.

Patients who have increased cortisol levels, but low levels of ACTH, often have poor communication between the hypothalamus, the pituitary, and the adrenal glands. These three glands — together known as the HPA axis — control the levels of cortisol in healthy people.

Imaging of the adrenal glands revealed they were both enlarged and presented nodules. The patient’s cortisol levels peaked after taking metoclopramide, and her serum cortisol varied significantly during the day while ACTH remained undetectable. These results led to the BMAH diagnosis.

The doctors performed unilateral adrenalectomy to control cortisol levels. The surgery was successful, and the doctors reduced the dose of glucocorticoid replacement therapy on day 6.

Eight days after the surgery, however, the patient showed decreased levels of fasting serum cortisol, which indicated adrenal insufficiency — when the adrenal glands are unable to produce enough cortisol.

The doctors noticed that metoclopramide was causing an increase in serum cortisol levels, which made them appear normal and masked the adrenal insufficiency.

They stopped metoclopramide treatment and started replacement therapy (hydrocortisone) to control the adrenal insufficiency. The patient was discharged 10 days after the surgery.

The serum cortisol levels were monitored on days 72 and 109 after surgery, and they remained lower than average. Therefore she could not stop hydrocortisone treatment.

The levels of ACTH remained undetectable, suggesting that the communication between the HPA axis had not been restored.

“Habitual use of metoclopramide might suppress the hypothalamus and pituitary via negative feedback due to cortisol excess, and lead to a delayed recovery of the HPA axis,” the researchers said.

Meanwhile, the patient’s weight decreased, and high blood pressure was controlled.

“Detailed surveillance of aberrant cortisol secretion responses on a challenge with exogenous stimuli […] is clinically important in BMAH patients,” the study concluded. “Caution is thus required for assessing the actual status of the HPA axis.”

From https://cushingsdiseasenews.com/2019/05/07/metoclopramide-conceals-adrenal-insufficiency-after-gland-removal-bmah-patients-case-report/

Medical ID Jewelry Often Lacks Clear Instructions For Adrenal Insufficiency

Rushworth RL, et al. Clin Endocrinol. 2019;doi:10.1111/cen.13985.

Only 4.8% of patients with adrenal insufficiency who use medical identification jewelry clearly indicate on their emblem the need for urgent parenteral hydrocortisone in the event of an adrenal crisis, potentially jeopardizing the ability to receive proper assistance in an emergency, according to a cross-sectional analysis published in Clinical Endocrinology.

“Although the use of medical identification jewelry is recommended for patients with adrenal insufficiency to assist in the prevention and treatment of an adrenal crisis, the results of this study indicate that this advice is taken up by only a modest proportion of patients,” R. Louise Rushworth, MBBS, PhD, FAFPHM, an adjunct professor and medical epidemiologist at the School of Medicine, Sydney, and the University of Notre Dame Australia, told Endocrine Today. “Patients with secondary adrenal insufficiency have a lower uptake than those with primary adrenal insufficiency despite their risk of an adrenal crisis approaching that people with primary adrenal insufficiency.”

In a cross-sectional analysis, Rushworth and colleagues analyzed data from 1,955 patients with adrenal insufficiency aged at least 20 years with an active subscription to a large medical jewelry provider (MedicAlert) as of September 2018. The researchers calculated subscription rates by adrenal insufficiency subtype, geographic area, age and sex using relevant population data.

The overall subscription rate was 105.79 per million, representing approximately one-third of the estimated 300 per million patients with adrenal insufficiency in the population, according to researchers. Among subscribers, 57.4% had primary adrenal insufficiency and 15.1% had a diagnosis of congenital adrenal hyperplasia. The overall subscription rate for patients with primary adrenal insufficiency was 61.72 per million, or 61.7% of the approximately 100 per million patients with primary adrenal insufficiency in the Australian population, according to researchers.

Researchers observed considerable differences in subscription rates based on geographic region, patient age and sex. Western Australia had an overall subscription rate (247 per million) that was more than four times higher than Victoria, the state with the lowest subscription rate (60.87 per million; P < .0001). Patients aged 60 to 69 years had the highest subscription rate (165.15 per million), whereas patients aged 30 to 39 years had the lowest rate (47.23 per million; P < .001). Additionally, most subscribers reporting primary adrenal insufficiency were women (69%).

The researchers found that hydrocortisone was the most common replacement therapy (41.6%), followed by cortisone acetate (25.6%) and prednisone (16.3%). They noted that few patients — only 4.8% — clearly mentioned the need for urgent parenteral hydrocortisone in the event of severe illness.

Rushworth said most patients who used medical identification jewelry did not have clear emergency instructions inscribed on the emblem, and that this may lead to delays in administration of hydrocortisone in an emergency.

“Guidelines recommend that patients with adrenal insufficiency who are at risk for adrenal crisis should wear medical identification jewelry as a form of nonverbal communication in an emergency,” Rushworth said. “These should be recommended by the treating doctor, and adherence should be encouraged and reviewed regularly. The jewelry should be inscribed with clear instructions for emergency treatment, for example: ‘Adrenal insufficiency. Give IM 100 mg hydrocortisone.’” – by Regina Schaffer

From https://www.healio.com/endocrinology/adrenal/news/online/%7Be7eef183-09a5-46aa-96e1-1feb7c8f1e05%7D/medical-id-jewelry-often-lacks-clear-instructions-for-adrenal-insufficiency?page=2

New discoveries offer possible Cushing’s disease cure

LOS ANGELES — More than a century has passed since the neurosurgeon and pathologist Harvey Cushing first discovered the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure, according to a speaker here.

There are several challenges clinicians confront in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, FRCP, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, said during a plenary presentation. Patients who present with Cushing’s disease typically have depression, impaired mental function and hypertension and are at high risk for stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders, Melmed said. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said.

“This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”

The outlook for Cushing’s disease is now beginning to change, Melmed said. New targets are emerging for treatment, and newly discovered molecules show promise in reducing the secretion of adrenocorticotropic hormone (ACTH) and pituitary tumor size.

“Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — SST5, [epidermal growth factor] receptor, cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.”

Challenges in diagnosis, treatment

Overall, about 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average size is only about 6 mm and 40% of them are not visible, Melmed said. In patients with Cushing’s disease, surgery is effective in only about 60% to 70% of patients for initial remission, and overall, there is about a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes.

“There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said.

The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term control without recurrence.

“This is a difficult challenge to meet for all of us,” Melmed said.

Available options

Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, Melmed said, and there are several advantages, including rapid initial remission, a one-time cost and potentially curing the disease. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications.

Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said.

“The reality of Cushing’s disease — these patients undergo first surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to their demise,” Melmed said. “Medical therapy is appropriate at every step of the spectrum.”

Zebrafish clues

Searching for new options, Melmed and colleagues introduced a pituitary tumor transforming gene discovered in his lab into zebrafish, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high.

Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH.

In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said.

“Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule (that) suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.”

In a small, open-label, proof-of-principal study, four patients with Cushing’s disease who received roscovitine for 4 weeks developed normalized urinary free cortisol, Melmed said.

Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial that will evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib) in patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes.

“Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s. Hopefully, this will light the pathway for a phase 2 trial.”

 Offering optimism’

Practitioners face a unique paradigm when treating patients with Cushing’s disease, Melmed said. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life.

“Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.”

Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy.

“He was imagining this ‘elixir of youth’ (that) we could offer patients who are very ill and, in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. These Cushing’s patients are extremely ill. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer

Reference:

Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.

Disclosure: Melmed reports no relevant financial disclosures.

 

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B585002ad-640f-49e5-8d62-d1853154d7e2%7D/new-discoveries-offer-possible-cushings-disease-cure

Novel Therapy Eases Cushing’s Symptoms in Pivotal Trial

by Kristen Monaco, Staff Writer, MedPage Today

LOS ANGELES — An investigational therapy improved quality of life and reduced disease symptoms for patients with endogenous Cushing’s syndrome, according to new findings from the phase III SONICS study.

Patients taking oral levoketoconazole twice daily had significant reductions in mean scores for acne (-1.8), peripheral edema (-0.4), and hirsutism (-2.6), all secondary endpoints of the pivotal trial (P<0.03 for all), reported Maria Fleseriu, MD, of Oregon Health and Science University in Portland.

“We’re looking forward to see the results of further studies and to add this therapy to the landscape of Cushing’s,” Fleseriu said here during a presentation of the findings at AACE 2019, the annual meeting of the American Association of Clinical Endocrinologists. “We have a newer medication and still we cannot make a dent in the outcomes of Cushing’s, especially for patient-reported outcomes.”

Free testosterone levels significantly decreased in women taking levoketoconazole (a ketoconazole stereoisomer and potent steroidogenesis inhibitor), from an average of 0.32 ng/dL down to 0.12 ng/dL (0.011 to 0.004 nmol/L, P<0.0001). Men had a non-significant increase: 5.1 ng/dL up to 5.8 ng/dL (0.177 to 0.202 nmol/L).

There were no significant changes from baseline to the end of maintenance for other secondary endpoints in the analysis: moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation, and dysmenorrhea. However, significant improvements after 6 months of therapy were seen in patient-reported quality of life compared with baseline (mean 10.6 change on the Cushing QOL questionnaire) as well as a significant reduction in depressive symptoms (mean -4.3 change on the Beck Depression Inventory II).

The open-label, multicenter SONICS (Study of Levoketoconazole in Cushing’s Syndrome) trial included 94 adult men and women with a confirmed diagnosis of Cushing’s syndrome and elevated 24-hour mean urinary free cortisol (mUFC) levels at least 1.5 times the upper limit of normal.

In the dose-titration phase of the study (weeks 2 to 21), patients were titrated up to a max dose of 600 mg levoketoconazole twice daily until mUFC normalization. A 6-month maintenance phase followed with no dose increases, but decreases were allowed if adverse events emerged. An additional 6-month extended evaluation phase followed thereafter.

The study met it’s previously reported primary endpoint, with 30% of patients achieving normalized mUFC levels after 6 months of maintenance therapy without a dose increase (95% CI 21%-40%, P=0.0154).

Levoketoconazole was well tolerated, with only 12.8% of patients discontinuing treatment due to adverse events. The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17%), and fatigue (16%), some of which were expected due to steroid withdrawal, Fleseriu said.

Serious adverse events were reported in 14 patients, including prolonged QTc interval in two patients, elevated liver function in one patient, and adrenal insufficiency in another, events similar to those seen with ketoconazole (Nizoral) therapy.

Fleseriu explained that drug-drug interaction is a problem in Cushing’s, as all of the available medications prolong QT interval.

She noted that in SONICS, QT prolongation with levoketoconazole was observed in few patients. It’s still a “concern,” said Fleseriu, especially for patients on other drugs that prolong QT.

Although not yet approved, levoketoconazole has received orphan drug designation from the FDA and the European Medicines Agency for endogenous Cushing’s syndrome. The tentative brand name is Recorlev.

The study was supported by Strongbridge Biopharma.

Fleseriu reported relationships with Strongbridge, Millendo Therapeutics, and Novartis. Co-authors also disclosed relevant relationships with industry.

From https://www.medpagetoday.com/meetingcoverage/aace/79465

Cortisol Pumps May Be Viable Option to Reduce Adrenal Crisis in Severe Adrenal Insufficiency

The use of an insulin pump to deliver continuous pulsatile cortisol may be a viable treatment option in patients with severe adrenal insufficiency who are unresponsive to oral corticosteroids, according to study results presented at the 28th Annual Congress of the American Association of Clinical Endocrinologists, held April 24 to 28, 2019, in Los Angeles, California.

According to the investigators, increasing oral steroid doses may be required to prevent adrenal crisis in patients with adrenal insufficiency. However, in light of the associated side effects of long-term use of steroids, an alternative treatment method is needed. Insulin pumps, typically used to treat patients with diabetes, can be used to deliver steroids and may provide symptom control, prevent adrenal crisis, and lower required corticosteroid dose.

The current study enrolled patients with adrenal insufficiency who could not absorb oral corticosteroid treatment or were not responding to treatment. Of 118 patients with adrenal insufficiency, 6 patients were switched to pump treatment.

The results indicated that the use of cortisol pumps was associated with a 78.5% risk reduction for adrenal crisis compared with oral corticosteroids. As hydrocortisone dose was gradually tapered using the cortisol pump, there was a mean dose reduction of 62.77 mg compared with oral corticosteroid therapy.

The researchers noted that in addition to reducing the number of adrenal crises, use of a cortisol pump was found to be associated with better symptom control and quality of life.

“Continuous pulsatile cortisol replacement via pump is an option for management of severe adrenal insufficiency in patients unresponsive to oral therapy,” concluded the researchers.

Reference

Khalil A, Ahmed F, Alzohaili O. Insulin pump for adrenal insufficiency, a novel approach to the use of insulin pumps to deliver corticosteroids in patients with poor cortisol absorption. Presented at: American Association of Clinical Endocrinologists 28th Annual Scientific & Clinical Congress; April 24-28, 2019; Los Angeles, CA.

From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2019/cortisol-pumps-may-be-viable-option-to-reduce-adrenal-crisis-in-severe-adrenal-insufficiency/

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