Mutations in Two Genes, USP48 and BRAF, Linked to Cushing’s Disease

Mutations in USP48 and BRAF genes contribute to the overproduction of adrenocorticotropin (ACTH) hormone by the pituitary gland and consequent development of Cushing’s disease, a study shows, linking these genes to the disease for a first time.

The study, “Identification of recurrent USP48 and BRAF mutations in Cushing’s disease,” published in the journal Nature Communications, also identified a possible treatment for patients with BRAF-related mutations.

Cushing’s disease is a condition characterized by excessive cortisol levels that, if left untreated, can lead to serious cardiovascular problems, infections, and mood disorders. It usually arises from benign pituitary tumors that produce too much of ACTH hormone, which in turn stimulates the adrenal glands to secrete cortisol.

It is still not clear why some people develop these tumors, but studies have pointed to mutations in the USP8 gene as a possible cause. They are present in 35%–62% of all tumor cases, and influence treatment response and long-term outcomes.

But major disease drivers in people whose tumors have no evidence of  USP8 mutations are unknown. Recognizing this gap, researchers in China examined tumor tissue samples from 22 patients with pituitary ademonas but a normal USP8 gene.

Their analysis revealed four genes that were recurrently mutated, including two — BRAF and USP48 — never before reported in this disease setting. Then, looking at 91 samples from patients, researchers found BRAF mutations in 17% of cases and USP48 mutations in 23% of patients.

These mutations were also found in patients with USP8-mutant pituitary tumors, but at a much lower rate — 5.1% for BRAF and 1.2% for USP48 mutations.

However, mutations in these two genes were not seen in patients with pituitary tumors producing other hormones, suggesting they are “unique genetic signatures of [ACTH-producing] adenomas,” the researchers wrote.

The team also found that BRAF and USP48 mutations activate signaling pathways that lead to the production of proopiomelanocortin (POMC), which is the precursor of ACTH.

“ACTH overproduction is a hallmark of Cushing’s disease and appears to be frequently induced by mutations in genes that tightly regulate POMC gene transcription in the pathogenesis of this disease,” investigators wrote.

Patients with BRAF and USP48 mutations had significantly higher levels of midnight plasma ACTH and midnight serum cortisol, compared to patients without these mutations. Tumor size, however, was similar among the two groups.

Interestingly, the team found that the BRAF inhibitor Zelboraf (vemurafenib) effectively reduced ACTH production in cells from ACTH-producing pituitary tumors. Zelboraf, marketed by Genentech, is approved in the U.S. and Europe to treat cancers with BRAF mutations, and findings suggest it may be a good therapeutic candidate for some people with Cushing’s disease.

“The mutational status of BRAFUSP8, and USP48 in corticotroph adenomas may be used in the future to characterize the molecular subtypes and guide targeted molecular therapy,” the researchers suggested.

From https://cushingsdiseasenews.com/2018/11/20/mutations-in-usp48-braf-genes-contribute-for-cushings-disease-study-finds/

Stress, cortisol and weight gain

If you’ve got your finger on the pulse of health trends, it’s likely you’ve been hearing the current buzzwords “cortisol creates belly fat” and “cortisol causes muscle wasting and fat storage.” These are the type of catch phrases that gain momentum every few years. And although some of the fads and trends showing up seasonally in fitness are myths, this caution about chronically elevated cortisol is true. Cortisol is also deeply connected with the dangers of chronic inflammation, which I described in another article, “Inflammation Creates Diseases.”

Like many hormones, cortisol has an effect on a wide variety of functions in the body. Although it’s getting particularly demonized lately, cortisol serves some very important and positive functions in the body. It’s an essential component of the flight or flight response, so it gives us energy, focus, strength, motivation and courage. But, like with sugar or caffeine, it comes with a crash that feels like an emotional, psychological and physical drain. Cortisol is important for survival, but we didn’t evolve to have high levels of it all the time.

According to hormone.org, cortisol isn’t only a stress hormone: “Because most bodily cells have cortisol receptors, it affects many different functions in the body. Cortisol can help control blood sugar levels, regulate metabolism, help reduce inflammation and assist with memory formulation. It has a controlling effect on salt and water balance and helps control blood pressure. In women, cortisol also supports the developing fetus during pregnancy. All of these functions make cortisol a crucial hormone to protect overall health and well-being.”

There are many symptoms of chronically elevated cortisol levels. With that said, the way a spike of cortisol gives you a jolt of energy is by raising blood sugar. It does this by way of gluconeogenesis. This literally means “creating new sugar,” and it happens by way of breaking protein down into amino acids that are then turned into sugar by the liver. What is a large source of protein in the body? Yep, muscles. This is what is meant by “cortisol causes muscle loss.” This in turn contributes to muscle weakness. Whereas normal levels of cortisol help to regulate blood sugar levels by breaking down only a little muscle (which can be replaced with exercise), excessive levels cause muscle wasting.

Why does cortisol cause fat gain? Remember those cortisol receptors most cells have? Fat cells have four times as many, so they are particularly responsive to cortisol. Okay, remember all that glucose the cortisol surge dumped into your blood for energy? Well, that also came with an insulin response to get your blood sugar levels back down, and insulin causes energy storage. And where do you store the energy? Yep, in those hypersensitive fat cells that cortisol just turned on. And what happens when you have too much insulin over time? Yep, diabetes. Also, another reason stress can cause emotional and/or binge eating is because cortisol also fires up your sense of purpose, as well as your appetite. So now stress has made you feel motivated…to eat.

Emotionally and psychologically, chronically high cortisol can exacerbate depression, anxiety, irritability and lack of emotional control. Cortisol triggers a release of tryptophan oxygenase. This enzyme breaks down tryptophan. Tryptophan is required for creating serotonin. Serotonin gives us the ability to feel happiness, and it also affects appetite, sleep and sexual desire. Since extended exposure to high levels of cortisol inhibits the production of serotonin, all the symptoms of low serotonin become problematic (decreased appetite, insomnia, impotence, etc.). In short, prolonged stress causes depression.

Cortisol also plays a role in the circulatory system. It manipulates blood pressure by acting as a diuretic. Excess cortisol causes an electrolyte imbalance, whereby sodium is retained, but potassium is excreted. Let me take you back to your high school biology days: Muscles fire because of the sodium potassium pump. The sodium potassium pump also effects the firing of nerves, including those impulses that cause your heart to beat and your kidneys to take in water for filtration. That sodium potassium pump is important throughout the entire body, across many of its biological functions. Because cortisol increases the concentration of sodium in your body, it has a direct impact on your blood pressure. Remember why excess salt can cause high blood pressure? Because it contains sodium. For all these reasons and more, chronically elevated cortisol also causes muscle weakness (ironic, since short bursts of it temporarily increase strength).

Cortisol has other effects on minerals. According to the Hindawi Journal of Sports Medicine, “Cortisol triggers bone mineral resorption (removal) in order to free amino acids for use as an energy source through gluconeogenesis. Cortisol indirectly acts on bone by blocking calcium absorption, which decreases bone cell growth.” As you can see, excess cortisol causes osteoporosis. It also exacerbates other bone mineral density diseases, which means cortisol can leave you literally brittle with stress.

Practically anything can become a stressor in the right conditions, and fight or flight is our only biological response to stress. Some triggers of stress include conflict, worry, alcohol and drug consumption, processed foods, excess exercise (especially prolonged and repeated sessions of low-level steady-state cardio training), sleep deprivation, thirst and hunger. As much as possible, protect yourself from stress with rest, relaxation, meditation, play time and healthy foods full of antioxidants, which reduce inflammation and thus the risks for practically all diseases.

Jack Kirven completed the MFA in Dance at UCLA, and earned certification as a personal trainer through NASM. His wellness philosophy is founded upon integrated lifestyles as opposed to isolated workouts. Visit him at jackkirven.com and INTEGRE8Twellness.com.

Adapted from https://goqnotes.com/61597/stress-cortisol-and-weight-gain/

New Phase 3 Data Further Support Recorlev’s Ability to Safely Lower Cortisol Levels in Cushing’s Patients

Strongbridge Biopharma released additional positive results from a Phase 3 trial evaluating whether the company’s investigational therapy Recorlev (levoketoconazole) is safe and effective for people with endogenous Cushing’s syndrome.

The latest results were presented in the scientific poster “Safety and Efficacy of Levoketoconazole in Cushing Syndrome:  Initial Results From the Phase 3 SONICS Study,\” at the 18th Annual Congress of the European NeuroEndocrine Association (ENEA), which took place in Wrocław, Poland, last month.

The SONICS study (NCT01838551) was a multi-center, open-label Phase 3 trial evaluating Recorlev’s safety and effectiveness in 94 patients with endogenous Cushing’s syndrome.

The trial consisted of three parts: a dose-escalation phase to determine the appropriate Recorlev dose that achieved normalization of cortisol levels; a maintenance phase in which patients received the established dose for six months; and a final extended phase, in which patients were treated with Recorlev for an additional six months, with the possibility of dose adjustments.

Its primary goal was a reduction in the levels of cortisol in the patients’ urine after six months of maintenance treatment, without any dose increase during that period. Among secondary goals was a reduction in the characteristically high risk of cardiovascular disease in these people, through the assessment of multiple cardiovascular risk markers.

Strongbridge announced top-line results of the SONICS study in August, which showed that the trial had reached its primary and secondary goals. It concluded last month.

After six months of maintenance therapy, Recorlev successfully lowered to normal the levels of cortisol in 30% of patients without a dose increase. It also led to statistically and clinically significant reductions in cardiovascular risk biomarkers, including blood sugar, cholesterol levels, body weight, and body mass index.

Maria Fleseriu, MD, director of the Oregon Health Sciences University Northwest Pituitary Center, presented additional and detailed results of SONICS at the congress.

Additional analyses showed that among the 77 patients who completed the dose-escalation phase and entered the study’s maintenance phase, 81% had their cortisol levels normalized.

At the end of the six months of maintenance treatment, 29 (53%) of the 55 patients who had their cortisol levels assessed at the beginning of the study and at the end of the maintenance phase had achieved normalization of cortisol levels, regardless of dose increase.

Among all patients who completed maintenance treatment (including patients with some missing data) and regardless of dose increase, 38% had achieved normalization of cortisol levels and 48% recorded a 50% or more decrease or normalization.

The results also highlighted that Recorlev substantially reduced patients’ cortisol levels regardless of their levels at the study’s beginning (which were on average about five-fold higher than the upper limit of normal). In those patients with the highest levels of cortisol in their urine, Recorlev led to a median reduction of more than 80%.

As previously reported, Recorlev was found to be generally well-tolerated, with no new safety concerns, and only 12 participants (12.8%) stopped treatment due to adverse events.

Ten patients had three- or five-fold increased levels of alanine aminotransferase — a liver enzyme used to assess liver damage — which were fully resolved without further complications. These liver-related adverse events “were all noted in the first 60 days, thus suggesting a timeline interval for monitoring,” Fleseriu said in a press release.

“We continue to be encouraged by the positive efficacy results of SONICS and the overall benefit-to-risk profile of Recorlev and look forward to sharing additional planned analyses from the study in the near future,” said Fredric Cohen, Strongbridge’s chief medical officer.

From https://cushingsdiseasenews.com/2018/11/01/new-data-from-phase-3-trial-supports-recorlev-ability-to-safely-treat-cushings-syndrome/

Rare Case of Cushing’s Disease Diagnosed in 7-year-old Boy

A recent case report describes a 7-year-old boy with Cushing’s disease who had an unusual clinical presentation, which significantly delayed his diagnosis.

The study, “A variable course of Cushing’s disease in a 7 year old: diagnostic dilemma,” was published in the Journal of Pediatric Endocrinology and Metabolism.

Rare in children and adolescents, Cushing’s disease refers to overproduction of cortisol caused by excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor. In pediatrics, early symptoms of excess cortisol include weight gain and delayed growth.

Despite being extremely unlikely in children younger than 7, some cases of Cushing’s disease in infancy have been reported.

“If undiagnosed or untreated it can lead to considerable morbidity and mortality, and the inability to detect a microadenoma [tumors smaller than 10 mm in diameter] on magnetic resonance imaging (MRI) can lead to a diagnostic dilemma leading to unnecessary delays in treatment initiation,” the researchers wrote.

Researchers from the Indraprastha Apollo Hospital in New Delhi, India, described a 7-year-old boy who complained of excessive appetite and weight gain in the previous five months. The child weighed 46.8 kg, was 127 cm tall, and had a body mass index (BMI) of 29, indicating he was overweight.

The child’s excess fat was mainly in his abdomen plus he had a round, red, puffy face, which are both common features of Cushing’s disease. He had no history of acute or chronic steroid intake, mood swings, sleep disorders, or issues with eyesight.

Given his clinical presentation, the investigators suspected the boy had Cushing’s disease or pseudo-Cushing’s disease, which refers to situations where the overproduction of cortisol is caused by something unrelated to the disease, such as stress or uncontrolled diabetes mellitus.

Biochemical testing showed the patient had high levels of cortisol, which remained unchanged after a dexamethasone suppression test. In addition, his levels of “bad” cholesterol, referring to low-density lipoprotein, were extremely elevated at 194 mg/dL, where a normal range is defined as less than 110 mg/dL.

Imaging revealed no lesions in the pituitary gland.

The boy was sent home with dietary recommendations. Eight weeks later, he had lost 4 kg, while his height remained the same; he also complained of headaches and various episodes of double vision.

This confused the clinical team as hallmarks of Cushing’s disease include short stature and weight loss triggered by pharmacological therapy. Despite having lost weight, he did not take any medications to help him with it, plus the boy’s height was normal for his age.

Nonetheless, the patient was complaining of neurological symptoms, suggesting progression of Cushing’s disease.

An ophthalmologist did not observe anything abnormal with the child’s eyes that could explain his double vision episodes.

A new series of tests revealed slightly elevated 24-hour urinary cortisol levels, decreased concentration of ACTH, and mildly increased cortisol levels after a two-day dexamethasone suppression test.

Magnetic resonance imaging (MRI) showed a small microadenoma in the right lobe of the pituitary gland.

Using Gamma Knife radiation therapy, a kind of high-precision radiation therapy, and surgery, doctors successfully removed the boy’s microadenoma. Six weeks post-procedure, his cortisol and ACTH concentrations returned to normal.

“MRI findings of the pituitary may be inconclusive in the beginning of the disease process and should be borne in mind during further follow-up. In cases where a clear-cut diagnosis may be difficult, a diligent follow-up is required to ascertain the course of the disease and to make timely diagnosis,” the investigators concluded.

From https://cushingsdiseasenews.com/2018/10/25/rare-case-cushings-disease-diagnosed-7-year-old-boy-case-study/

Pregnancy Could Be Linked to Onset of Cushing’s Symptoms

More than 25 percent of women with Cushing’s disease experienced their first symptoms within one year of giving birth, a small study by the Pacific Neuroscience Institute found.

The findings suggest a possible causal relationship between the biological stress of pregnancy and Cushing’s disease (CD), with more than a two-fold risk of women developing the disease within one year of pregnancy.

The study, “Pregnancy-associated Cushing’s disease? An exploratory retrospective study,” was published in the journal Pituitary.

Eighty percent of Cushing’s disease cases are women, and most are of reproductive age.

Levels of the body’s main stress hormone, cortisol, normally increase during pregnancy. In the last weeks before birth, cortisol levels are two to three times higher than normal, similar to Cushing’s disease.

Because cortisol levels gradually increase during pregnancy, a diagnosis of Cushing’s disease within the gestation period is problematic.

Circumstantial “evidence suggests a higher incidence of CD immediately following pregnancy, in the peripartum period [a few weeks after childbirth],” the study’s authors wrote.

To shed additional light on the matter, researchers retrospectively investigated the frequency of Cushing’s disease onset related to pregnancy.

A total of 64 women with biochemically-diagnosed Cushing’s disease and treated at Providence Saint John’s Health Center in Santa Monica, California, from July 2007 to December 2017 were included in this study.

For the analysis, patients were divided into three groups:

  1. Women with pregnancy-associated CD: “defined as symptom-onset within 1 year of pregnancy that was explicitly linked to the pregnancy by the patient’s own recollection of her pregnancy and subsequent symptoms related to CD”;
  2. Women of reproductive age: “defined as age 15–45 years, in whom CD onset was not associated temporally with pregnancy within the past year”;
  3. Women not of reproductive age at the time of CD onset.

Results showed that 64 percent of the patients were of childbearing age at the time of diagnosis. Of these, 27 percent (11 women) had pregnancy-associated Cushing’s disease. This might be due to small, slow-growing or dormant corticotroph pituitary adenomas that were stimulated by pregnancy-related hormonal changes; however, this hypothesis was not confirmed by the researchers.

On average, patients in group 1 had two pregnancies prior to Cushing’s disease onset, compared to zero for 30 other women with disease onset during reproductive age. This suggests that undergoing the biological stress of pregnancy more than once could play a role in Cushing’s development.

“Another possible explanation of the association between CD and pregnancy is simply that patients are more likely to remember the onset of their CD symptoms in relation to a landmark life event such as pregnancy and childbirth, which leads to long-term physical changes in most women, irrespective of Cushing’s status,” the researchers noted.

In contrast, 19 of the 30 patients at reproductive age without pregnancy-associated disease had no pregnancies before being diagnosed, which weakens the association between pregnancy and Cushing’s and draws attention to various other factors that may also be involved in disease onset, apart from gestation-related hormonal changes.

The time from the onset of symptoms to diagnosis for women with pregnancy-related disease varied from two to six years.

“It was in fact weight gain or failure to lose weight post-pregnancy, which was the most frequent complaint and presentation in our patients with pregnancy-associated CD, and which often lead to an eventual diagnosis of CD,” the researchers stated.

“As such, appropriate biochemical testing may be indicated in women who 6–18 months after pregnancy, are still unable to lose the weight of pregnancy, continue to gain weight, have new, persistent or more [treatment-resistant] hypertension and diabetes mellitus, and/or other classical stigmata of CD,” they suggested.

All patients with biochemically-confirmed Cushing’s disease underwent surgery to remove pituitary adenoma. Sustained surgical remission rates for groups 1, 2, and 3 were 91%, 80%, and 83%, respectively.

“This possible association suggests a heightened degree of clinical suspicion and biochemical testing for CD may be warranted after childbirth. Further study of this possible link between pregnancy and CD is warranted,” the team concluded.

From https://cushingsdiseasenews.com/2018/09/21/cushings-disease-symptoms-onset-pregnancy-could-be-linked-study-suggests/

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