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/

Doctors Use Microwave Therapy on Cushing’s Patient Too Weak to Have Surgery

Microwave therapy improved the Cushing’s syndrome of a woman whose lungs had almost failed, allowing her to have the adrenal surgery needed to control her disease, a case study showed.

Lung infections had led to her near-respiratory failure.

Cushing’s syndrome stems from the pituitary gland producing excessive amounts of adrenocorticotropic hormone. Too much of the hormone leads to the adrenal glands generating excessive amounts of another hormone, cortisol — and that overproduction results in Cushing’s. The disease’s symptoms include increasing obesity, skin problems, muscle weakness, bone loss, fatigue, cognitive difficulties, and an inability to control emotions.

Doctors often remove patients’ adrenal glands to prevent cortisol production. But in this case, the patient was not in good enough condition to have the surgery. So doctors used microwave technology to reduce her cortisol levels to the point where surgeons could operate.

The case study, published in BMJ Case Reports, was titled “Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands.

Excessive pituitary gland production of adrenocorticotropic hormone is the cause of 80 percent of Cushing’s cases.

In 5 to 10 percent of cases, a tumor in another part of the body also produces the hormone, leading to excessive amounts of it in the body. When a tumor is generating the hormone, the condition is called ectopic ACTH syndrome. The patient in the case study had ACTH syndrome.

The 63-year-old woman had complained to her family doctor about weight gain, headache, weakness, and flushing. When laboratory tests led to her being diagnosed with ectopic ACTH-dependent Cushing’s syndrome, she was admitted to a hospital’s internal medicine department.

Doctors planned surgery to remove her adrenal glands, but two days before the operation was scheduled, respiratory failure sent her to the hospital’s Intensive Care Unit. There, physicians treated her for two infections in her lungs, plus infections in her blood and urinary tract. She experienced serious medical complications while in the Intensive Care Unit.

After a month, she was in good enough condition to leave intensive chair but too frail for surgery. Instead, doctors used microwaves to destroy as much of her adrenal glands as they could.

Within two weeks, her condition was better. She had been unable to leave her hospital bed while in intensive care. After the microwave treatment, she engaged in physiotherapy that led to her being able to use a two-wheeled walker to go short distances. She could also make short excursions outside the hospital with her family.

Six months later she returned to the hospital for surgical removal of her adrenal glands.

There were no complications from the operation, and doctors discharged her two days later. Her cortisol levels have been at acceptable levels since then.

“Our experience demonstrates that percutaneous ablation is a viable alternative in patients with ectopic ACTH syndrome in whom medical therapy has failed and surgical adrenalectomy is not feasible,” the researchers wrote. “Further research comparing the efficacy and complication rates between percutaneous ablation [microwave therapy] and surgical adrenalectomy is needed.” In addition, “research is needed to determine the optimal method of percutaneous intervention,” the team wrote.

From https://cushingsdiseasenews.com/2017/12/01/case-study-shows-microwave-therapy-helped-cushings-patient-who-was-too-frail-for-surgery/

Growth Hormone: Drug companies are growing less generous in helping patients pay for meds

For 14 years, Encino resident Ed Wright received an expensive prescription medication for free through a drug-industry program intended to assist people with limited or fixed incomes.

Now he’s rationing his doses after a change to the program that imposed a $1,100 deductible before he can get a refill.

“I can’t afford that,” Wright, 75, told me. “When I run out in a few weeks, that’s going to be it.”

He isn’t alone. Industry watchers say soaring drug prices have prompted many pharmaceutical companies to rethink long-standing programs to help subsidize purchases or even give meds away for free.

“More and more people have become aware of these programs, and demand has gone up,” said David P. Wilson, president of PRAM Insurance Services, a Brea firm that helps employers with prescription-drug benefits.

This means trouble for patients who, like Wright, can’t handle sticker shock at the drugstore.

He suffered a head injury 17 years ago that damaged his pituitary gland. In 2003, he was diagnosed as having an abnormally low level of growth hormone, which caused him to suddenly become overwhelmed with fatigue.

That’s a potentially life-threatening condition if an episode should occur while driving, walking down stairs or performing some other physical activity.

Wright’s doctor prescribed the self-injected human growth hormone Humatrope, manufactured by Eli Lilly & Co.

The cost, however, was out of reach for Wright, even with Medicare Part D. According to the drug-pricing website GoodRX, a 6-milligram cartridge of Humatrope — a one month’s supply — runs about $700.

Luckily, Wright’s fixed income made him eligible for a program called Lilly Cares, which made the drug available free of charge. He and his doctor would renew the paperwork annually, and for 14 years Wright had no difficulty receiving the med.

That’s no longer the case with the new $1,100 deductible, which requires Wright to spend that amount on prescription drugs before he can access his free Humatrope.

Wright requires few other drugs, so the deductible is an almost insurmountable barrier to maintaining normal quality of life.

Most drugmakers offer what are known as patient assistance programs, through which the company may provide meds directly to patients at little or no cost. Or the company may assist with co-payments — the patient’s out-of-pocket expense that’s not covered by an insurer.

2009 study published in the journal Health Affairs found that most patient assistance programs run by drug companies were reluctant to disclose details of the number of people they serve or the program’s eligibility requirements.

These programs “exist to provide patients with access to a wide variety of medications,” researchers concluded. However, “many details about these programs remain unclear. As a result, the extent to which these programs provide a safety net to patients is poorly understood.”

Aaron Tidball, chief Medicare advisor for the Illinois consulting firm Allsup, which assists individuals and businesses in navigating the public insurance system, said Lilly Cares “has been more generous than some programs we’ve seen.”

He said that, until now, people who qualified for Lilly’s assistance were able to receive whatever specialty meds that were prescribed by their doctor without cost or co-pay.

It should be noted, though, that Lilly has structured its program so the company benefits as well. Rather than provide drugs directly to patients, as many companies do, Lilly donates its medications to a private foundation, the Lilly Cares Foundation, which in turn deals with the public.

This allows Lilly to deduct the value of its donated drugs from its taxes. According to the nonprofit foundation’s 2015 tax return, which by law must be made public, the Lilly Cares Foundation received more than $408 million worth of drugs from the company. That figure represented the “fair market value” of the meds.

“That’s obviously a lot more than the cost to produce the drugs,” observed Jeff Geida, a Los Angeles estate lawyer who specializes in nonprofit foundations and who examined the most recent Lilly Cares tax return at my request.

In other words, Lilly was able to reduce its taxable income for the year by $408 million, although the actual expense of manufacturing the donated drugs almost certainly was just a fraction of the deducted amount.

“It’s a very good deal,” Geida said.

To be sure, the company is still doing enormous good by making millions of dollars worth of drugs available to people in need. But the inflated figures highlight the lack of transparency surrounding the true cost of prescription meds.

Julie Williams, a Lilly spokeswoman, declined to answer my questions about the Lilly Cares Foundation. But she forwarded a statement from Steven Stapleton, the foundation’s president.

He said the foundation imposed the $1,100 deductible for Medicare Part D beneficiaries “after benchmarking our program with other similar programs, helping Lilly Cares to balance all the criteria for the program and to try to help as many people as possible.”

That’s just gibberish to my ear — and doesn’t address the fact that Lilly still helps itself to that whopping tax deduction while making it considerably harder for low-income people to receive assistance.

I called the foundation and spoke with a service rep, but she said she didn’t know why the deductible was put in place. Nor could she explain how it’s in the best interest of patients with limited incomes to have to spend $1,100 on drugs before being eligible to receive a needed medicine.

Stapleton said notifications were sent to program participants in the fall of 2015 and 2016, but Wright told me he couldn’t recall receiving any such notice. The office manager of his doctor’s practice said she too was caught by surprise.

Lilly Cares made the situation even more inexplicable when it sent a notice to Wright last month formally dropping him from the program. The only reason it gave was “inactivity,” which made no sense considering that he’s been using Humatrope steadily for 14 years.

Williams, the Lilly spokeswoman, said she couldn’t discuss an individual patient.

Wright told me that, after I started poking around, he received a call from a Lilly representative. She advised him to contact the Partnership for Prescription Assistance, an industry-sponsored service intended to help people find subsidy programs that can help cover the high cost of their meds.

Wright contacted four subsidy programs through the service. Each one turned him down.

Lilly says it’s balancing all the criteria for Lilly Cares, which undoubtedly will make the company more profitable.

Wright, and the many other patients in similar positions, are a secondary consideration.

From http://www.latimes.com/business/lazarus/la-fi-lazarus-prescription-drug-assistance-20170815-story.html

Study links genetic mutations, Cushing syndrome

Researchers have determined mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.

The National Institutes of Health study findings published in Endocrine-Related Cancer found four of the 181 children and adult patient examined had mutant forms of CABLES1 that do not respond to cortisol.

The determination proved significant because normal functioning CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH).

Researchers at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) joined scientists from other institutions in the United States, France and Canada, in the evaluation.

“The mutations we identified impair the tumor suppressor function in the pituitary gland,” Constantine A. Stratakis, the study’s senior author and director of the NICHD Division of Intramural Research, said. “This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.”

Cushing syndrome symptoms include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety, officials said, adding excess cortisol found in the disorder can result from certain steroid medications or from tumors of the pituitary or adrenal glands.

Researchers maintain that more studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.

 

From https://lifesciencedaily.com/stories/21624-study-links-genetic-mutations-cushing-syndrome/

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