ACTH-independent Cushing’s syndrome due to bilateral adrenocortical adenoma

Posted on October 2, 2021 by MaryO

https://doi.org/10.1016/j.radcr.2021.07.093

 

Abstract

The chronic excess of glucocorticoids results in Cushing’s syndrome. Cushing’s syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others.

ACTH independent Cushing’s syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas.

In this paper we report a case of a 43-year-old woman with Cushing’s syndrome due to bilateral adrenal adenoma.

Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690

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Muscle Weakness Persists in Cushing’s Syndrome Despite Remission

Posted on October 3, 2020 by MaryO

People with Cushing’s syndrome experience muscle weakness that persists even when the disorder is in remission, a new study shows.

The study, “Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission,” was published in The Journal of Clinical Endocrinology and Metabolism.

Cushing’s syndrome is characterized by abnormally high levels of the hormone cortisol. This can result in a variety of symptoms, including muscle weakness. However, it’s unclear the extent to which treatment of the underlying syndrome affects muscle weakness in the long term.

In the new study, researchers analyzed data for 88 people with endogenous Cushing’s syndrome diagnosed between 2012 and 2018 who had undergone regular muscle function tests. The data were collected as part of the German Cushing’s Registry, and the assessed group was mostly female (78%), with an average age of 49.

Of note, not all individuals had data available for every time point assessed — for example, at four years of follow-up, data were available for only 22 of the people analyzed.

Of the 88 individuals assessed, 49 had Cushing’s disease (a form of Cushing’s syndrome driven by a tumor on the pituitary gland). All 88 underwent curative surgery. The median time between diagnosis and remission was two months.

The researchers measured muscle strength in two ways: by grip strength and the chair rising test.

On average, and after statistical adjustments for age and sex, grip strength at diagnosis was 83% (with 100% reflecting the average for people without Cushing’s syndrome). Six months after surgery, average grip strength had decreased to 71%. A year after surgery, average grip strength was 77%. At all time points measured, up to four years after surgery, grip strength was significantly lowered in people with Cushing’s syndrome.

The chair rising test (CRT) involves measuring how quickly a person can rise from a seated position. Generally, being able to do so more quickly indicates greater muscle strength. People with Cushing’s syndrome showed improvement in the CRT six months after treatment (median 7 seconds), compared to the beginning of the study (8 seconds).

However, no further improvement was observed at subsequent time points up to four years, and compared to controls, CRT remained abnormal over time (7 seconds in Cushing patients at three years of follow-up vs 5 seconds in controls).

“The main finding of our study is that muscle strength remains impaired even after years in remission,” the researchers wrote.

“Another interesting finding is that at 6 months follow-up grip strength and CRT performance show opposite effects. Whereas grip strength has worsened, CRT performance has improved,” they added.

The investigators speculated that this difference is probably due to changes in body weight. Cushing’s syndrome commonly results in weight gain, and treatment resulted in significant decreases in body mass index in the analyzed group. As such, it may have been easier for individuals to stand up because there was less mass for their muscles to move, not necessarily because their muscles were stronger.

“Why patients with CS in remission showed a temporary worsening in grip strength 6 months after surgery remains unclear in terms of pathophysiology,” the researchers wrote.

They speculated that this could be due to treatment with glucocorticoids, which may affect muscle strength, but added that, “Whether the necessity of a long-term glucocorticoid replacement influences muscle strength or myopathy [muscle disease] outcome remains controversial.”

The researchers also conducted statistical analyses to determine what patient factors were associated with poorer muscle function outcomes. They found statistically significant associations between poor muscle function and older age, higher waist-to-hip-ratio, and higher levels of HbA1c (a marker of metabolic disease like diabetes).

“Influencing factors for myopathy outcome are age, waist-to-hip-ratio and HbA1c, suggesting that a consistent and strict treatment of diabetic metabolic state during hypercortisolism [high cortisol levels] is mandatory,” the investigators wrote.

The study was limited by its small sample size, the researchers noted, particularly at longer follow-up times, and by the fact that only a few measurements of muscle strength were used. Additionally, since all the data were collected at one of three centers in Germany, the analyzed population may not be representative of the worldwide population of people with Cushing’s syndrome.

Adapted from https://cushingsdiseasenews.com/2020/09/30/muscle-weakness-persists-in-cushings-syndrome-despite-remission-study-finds/

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Post-traumatic Stress Symptoms Common in Cushing’s Patients Before Surgery

Posted on June 29, 2019 by MaryO

Patients with Cushing’s disease may develop post-traumatic stress symptoms, which are generally resolved once they undergo surgery to remove the tumor, but can persist in some cases, a study shows.

The study, “Posttraumatic stress symptoms (PTSS) in patients with Cushing’s disease before and after surgery: A prospective study,” was published in the Journal of Clinical Neuroscience.

Cushing’s disease is an endocrine disorder characterized by excess secretion of the adrenocorticotropic hormone (ACTH) by a pituitary adenoma (tumor of the pituitary gland). This leads to high levels of cortisol, a condition known as hypercortisolism.

Chronic hypercortisolism is associated with symptoms such as central obesity, buffalo hump, body bruising, muscle weakness, high blood pressure, high blood sugar, and weak bones.

Additionally, patients can develop psychiatric disorders including depression, anxiety, and cognitive dysfunction, all of which contribute considerably to a lower health-related quality of life.

Depression and anxiety rates are particularly high in Cushing’s disease patients, with 54% of them experiencing major depression and 79% having anxiety.

Due to the significant impact of psychological factors in these patients, they may be susceptible to post-traumatic stress symptoms (PTSS). But more information on this phenomenon in these patients is still needed.

To address this lack of data, a group of Chinese researchers conducted a prospective study to investigate the occurrence, correlated factors, and prognosis of PTSS in patients with Cushing’s disease.

A total of 49 patients newly diagnosed with Cushing’s disease who underwent transsphenoidal removal of the tumor as their first-line treatment were asked to participate in this study. Another group of 49 age- and sex-matched healthy individuals were included as controls.

PTSS was measured using the Impact of Event Scale-Revised (IES-R), depression/anxiety were measured using the Hospital Anxiety and Depression scale (HADS), and quality of life was measured using the 36-item short-form (SF-36). These parameters were measured before surgery, and then at six and 12 months after the procedure.

Before surgery, 15 patients (30.6%) had PTSS. These patients also had higher cortisol levels, worse levels of depression/anxiety, and worse quality of life scores than those without PTSS.

While most of the patients recovered after the operation, there were five (33.3%) for whom PTSS persisted for more than a year.

Additionally, one patient who had a recurrence of Cushing’s disease developed PTSS between six and 12 months after the first surgery.

PTSS severity showed consistent improvement after surgery, which was correlated with better depression/anxiety scores and psychological aspects of the SF-36. However, Cushing’s disease patients in remission still performed worse than healthy individuals concerning their physical and mental health.

Therefore, “patients with [Cushing’s disease] can develop PTSS, and they may persist for over a year even after successful surgery. Combined psychological intervention is advised for these patients,” the researchers concluded.

From https://cushingsdiseasenews.com/2019/06/25/cushings-patients-often-have-post-traumatic-stress-symptoms

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Patient’s Atypical Cushing’s Symptoms Lead to Discovery of Novel Genetic Mutations

Posted on February 14, 2018 by MaryO

New genetic mutations were found in a patient who exhibited atypical symptoms of Cushing’s syndrome, notably an abnormal protrusion of the eye, a case report shows.

The research, “Extensive ARMC5 genetic variance in primary bilateral macronodular adrenal hyperplasia that started with exophthalmos: a case report,” was published in the Journal of Medical Case Reports.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a disorder characterized by multiple lumps in the adrenal glands and excessive cortisol production. It is a rare cause of Cushing’s syndrome.

According to recent research, PBMAH is caused by mutations in the ARMC5 gene, which data suggest may act as a tumor suppressor.

Researchers presented the case of a 52-year-old Chinese woman who exhibited a protrusion of both eyes (exophtalmos), which was first thought to be Graves’ ophthalmopathy. An injection of triamcinolone acetonide, a corticosteroid, into the area behind the eye globe did not improve symptoms.

The patient later was diagnosed with diabetes, which was treated with insulin, and hypertension, treated with insulin and amlodipine. She also developed muscle weakness and bruised easily. She had no other relevant chronic illness or infectious disease, and did not smoke tobacco or drink alcohol.

Physical examination showed skin atrophy, moon face, buffalo hump (between the shoulders), and purplish abdominal striae (stretch marks), which researchers defined as a typical Cushingoid appearance. The patient also experienced elevated pressure inside the eye, and had edema, conjunctival congestion, and lid retraction. No liver, spleen, respiration, cardiac, abdominal, blood counts, urinary, sensory, or motor abnormalities were noted.

Biochemical evaluation showed elevated cortisol and reduced adrenocorticotropin (ACTH) levels. Administering  dexamethasone did not lower the level of cortisol. Abnormal responses of the hormone vasopressin also were detected.

A computed tomography (CT) scan of the adrenal glands showed bilateral multiple lobular masses, and an MRI of the eye orbits indicated bilateral exophthalmos with hypertrophy of the retro-orbital fat, which lines the orbit.

After PBMAH was diagnosed, the patient’s adrenal glands were removed. Pathological findings showed multiple, homogenous, golden-yellow-colored nodules on the glands.

The surgery successfully lowered the level of cortisol and increased that of ACTH. The patient began taking hydrocortisone and metformin for diabetes. After six months, her exophtlamos, blood glucose levels, and blood pressure had improved.

Genetic analysis revealed six specific ARMC5 mutations in five of the seven adrenal nodules analyzed. “All the mutations are novel and not found in available online databases,” the researchers wrote. The mutations may lead to resistance to cell death in the tumor cells, and cause an increase in the production of cortisol, they observed.

As a result of the ARMC5 mutations, gene expression (conversion of genetic information) of the messenger RNA (mRNA, which is converted from DNA in the first step of protein synthesis) was lower in the adrenal tumor samples, in comparison with normal adrenal cortex.

Overall, the study “highlights the importance of early recognition of atypical symptoms of Cushing’s syndrome such as exophthalmos, which would save the patient from harmful effects of excessive cortisol exposure,” the researchers said. Screening for ARMC5 mutations also would help improve diagnosis and genetic counseling, they said.

From https://cushingsdiseasenews.com/2018/02/13/odd-cushings-symptoms-linked-genetic-mutations-case-report/

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

Posted on December 30, 2017 by MaryO

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/

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