A Case of Cushing’s Disease Presenting with Isolated Suicidal Attempt

Posted on November 2, 2021 by MaryO

Abstract

Cushing’s disease is an abnormal secretion of ACTH from the pituitary that causes an increase in cortisol production from the adrenal glands. Resultant manifestations from this excess in cortisol include multiple metabolic as well as psychiatric disturbances which can lead to significant morbidity and mortality. In this report, 23-year-old woman presented to mental health facility with history of severe depression and suicidal ideations. During evaluation, she found to have Cushing’s disease, which is unusual presentation. She had significant improvement in her symptoms with reduction of antidepressant medications after achieving eucortisolism. Cushing syndrome can present with wide range of neuropsychiatric manifestations including major depression. Although presentation with suicidal depression is unusual. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening of psychiatric symptoms The psychiatric and neurocognitive disorders improve after disease remission (the normalization of cortisol secretion), but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. The variable response of neuropsychiatric disorders after Cushing syndrome remission necessitate long term follow up.

Keywords 

Introduction

Endogenous Cushing syndrome is a complex disorder caused by chronic exposure to excess circulating glucocorticoids. It has a wide range of clinical signs and symptoms as a result of the multisystem effects caused by excess cortisol.1

The hypercortisolism results in several complications that include glucose intolerance, diabetes, hypertension, dyslipidemia, thromboembolism, osteoporosis, impaired immunity with increased susceptibility to infection as well as neuropsychiatric disorders.2,3

Cushing syndrome presents with a wide variety of neuro-psychiatric manifestations like anxiety, major depression, mania, impairments of memory, sleep disturbance, and rarely, suicide attempt as seen in this case.2,4

The mechanism of neuropsychiatric symptoms in Cushing’s syndrome is not fully understood, but multiple proposed theories have been reported, one of which is the direct brain damage secondary to excess of glucocorticoids.5

Case Report

A 23-year-old female presented to Al-Amal complex of mental health in Riyadh, Saudi Arabia with history of suicidal tendencies and 1 episode of suicidal attempt which was aborted because of religious reasons. She reported history of low mood, having disturbed sleep, loss of interest, and persistent feeling of sadness for 4 months. She also reported history of weight gain, facial swelling, hirsutism, and irregular menstrual cycle with amenorrhea for 3 months. She was prescribed fluoxetine 40 mg and quetiapine 100 mg. She was referred to endocrinology clinic at King Fahad Medical City, Riyadh for evaluation and management of possible Cushing syndrome as the cause of her abnormal mental health.

She was seen in the endocrinology clinic where she reported symptoms as mentioned above in addition to headache, acne, and proximal muscle weakness.

On examination her vital signs were normal. She had depressed affect, rounded face with acne and hirsutism, striae in the upper limb, and abdomen with proximal muscle weakness (4/5).

Initial investigations showed that 24 hour urinary free cortisol was more than 633 µg which is more than 3 times upper limit of normal (this result was confirmed on second sample with level more than 633 µg/24 hour), cortisol level of 469 nmol/L after low dose 1 mg-dexamethasone suppression test and ACTH level of 9.8 pmol/L. Levels of other anterior pituitary hormones tested were within normal range. She also had prediabetes with HbA1c of 6.1 and dyslipidemia. Serum electrolytes, renal function and thyroid function tests were normal.

MRI pituitary showed left anterior microadenoma with a size of 6 mm × 5 mm.

MRI pituitary (Figure 1).

figure

Figure 1. (A-1) Coronal T2, (B-1) post contrast coronal T1 demonstrate small iso intense T1, heterogeneous mixed high, and low T2 signal intensity lesion in the left side of anterior pituitary gland which showed micro adenoma with a size of 6 mm × 5 mm. (A-2) Post-operative coronal T2 and (B-2) post-operative coronal T1. Demonstrates interval resection of the pituitary micro adenoma with no recurrence or residual lesion and minimal post-operative changes. There is no abnormal signal intensity or abnormal enhancing lesion seen.

No further hormonal work up or inferior petrosal sinus sampling were done as the tumor size is 6 mm and ACTH level consistent with Cushing’s disease (pituitary source). She was referred to neurosurgery and underwent trans-sphenoidal resection of the tumor. Histopathology was consistent with pituitary adenoma and positive for ACTH. Her repeated cortisol level after tumor resection was less than 27 and ACTH 2.2 with indicated excellent response to surgery.

She was started on hydrocortisone until recovery of her hypothalamic pituitary adrenal axis documented by normal morning cortisol 3 months after surgery (Table 1).

Table

Table 1. Labs.

Table 1. Labs.

View larger version

During follow up with psychiatry her depressive symptoms improved but not resolved and she was able to stop fluoxetine 5 months post-surgery. Currently she is maintained on quetiapine 100 mg with significant improvement in her psychiatric symptoms.

Currently she is in remission from Cushing’s disease based on the normal level of repeated 24 hour urinary free cortisol and with an over-all improvement in her metabolic profile.

Discussion

Cushing syndrome is a state of chronic hypercortisolism due to either endogenous or exogenous sources. Glucocorticoid overproduction by adrenal gland can be adrenocorticotropic (ACTH) hormone dependent which represent most of the cases and ACTH independent.6 To the best of our knowledge this is the first case documented in Saudi Arabia.

There are multiple theories behind the neuropsychiatric manifestations in Cushing syndrome. These include increased stress response leading to behavioral changes, prolonged cortisol exposure leading to decreased brain volume especially in the hippocampus, reduced dendritic mass, decreased glial development, trans-cellular shift of water and synaptic loss, and excess glucocorticoid levels inhibiting neurogenesis and promoting neuronal tendency to toxic insult.3,7

In this report, the patient presented with severe depression with suicidal attempt. She had significant improvement in her symptoms with reduction of antidepressant medications but her depression persisted despite remission of Cushing disease. A similar case has been reported by Mokta et al,1 about a young male who presented with suicidal depression as initial manifestation of Cushing disease. As opposed to the present case he had complete remission of depression within 1 month of resolution of hypercortisolism.

In general, psychiatric and neurocognitive disorders secondary to Cushing syndrome improves after normalization of cortisol secretion, but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. This may be due to persistence hypercortisolism creating toxic brain effects that occur during active disease.2,8 Similar patients need to be followed up for mental health long after Cushing syndrome has been resolved.

Conclusion

Depression is a primary psychiatric illness, that is, usually not examined for secondary causes. Symptoms of depression and Cushing syndrome overlap, so diagnosis and treatment of Cushing disease can be delayed. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening psychiatric symptoms. The variable neuropsychiatric disorders associated with Cushing syndrome post-remission necessitates long term follow up.

Declaration of Conflicting Interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed Consent
Written informed consent was obtained from the patient for the publication of this case and accompanying images.

ORCID iD
Sultan Dheafallah Al-Harbi  https://orcid.org/0000-0001-9877-9371

References

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From https://journals.sagepub.com/doi/10.1177/11795476211027668

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Researchers Report Rare Case of Cushing’s Caused by Bilateral Adrenal Tumors

Posted on July 8, 2019 by MaryO

Cases of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome are often caused by unilateral tumors in the adrenal glands, but Indian researchers have now reported a rare case where the condition was caused by tumors in both adrenal glands.

Fewer than 40 cases of bilateral tumors have been reported so far, but an accurate diagnosis is critical for adequate and prompt treatment. Sampling the veins draining the adrenal glands may be a good way to diagnose the condition, researchers said.

The study, “Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing’s syndrome: A case report and review of the literature,” was published in the World Journal of Clinical Cases.

Cushing’s syndrome, a condition characterized by excess cortisol in circulation, can be divided into two main forms, depending on ACTH status. Some patients have tumors that increase the amount of ACTH in the body, and this hormone will act on the adrenal glands to produce cortisol in excess. Others have tumors in the adrenal glands, which produce excess cortisol by themselves, without requiring ACTH activation. This is known as ACTH-independent Cushing’s syndrome.

Among the latter, the disease is mostly caused by unilateral tumors — in one adrenal gland only —  with cases of bilateral tumors being extremely rare in this population.

Now, researchers reported the case of a 31-year-old Indian woman who developed ACTH-independent Cushing’s syndrome because of tumors in both adrenal glands.

The patient complained of weight gain, red face, moon face, bruising, and menstrual irregularity for the past two years. She recently had been diagnosed with high blood pressure and had started treatment the month prior to the presentation.

A physical examination confirmed obesity in her torso, moon face, buffalo hump, thin skin, excessive hair growth, acne, swollen legs and feet, and skin striae on her abdomen, arms, and legs.

Laboratory examinations showed that the woman had an impaired tolerance to glucose, excess insulin, and elevated cortisol in both the blood and urine. Consistent with features of Cushing’s syndrome, cortisol levels had no circadian rhythm and were non-responsive to a dexamethasone test, which in normal circumstances lowers cortisol production.

Because ACTH levels were within normal levels, researchers suspected an adrenal tumor, which led them to conduct imaging scans.

An abdominal computed tomography (CT) scan showed adrenal adenomas in both adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). A magnetic resonance imaging (MRI) scan showed that the pituitary gland (which normally produces ACTH) was normal.

To determine whether both adrenal tumors were producing cortisol, researchers sampled the adrenal veins and compared their cortisol levels to those of peripheral veins. They found that the left adrenal gland was producing higher amounts of cortisol, thought the right adrenal gland was also producing cortisol in excess.

“Our case indicates that adrenal vein [blood] sampling might be useful for obtaining differential diagnoses” in cases of Cushing’s syndrome, researchers stated. Also, they may help design a surgical plan that makes much more sense.”

The tumors were surgically removed — first the left, and three months later the right — which alleviated many of her symptoms. She also started prednisolone treatment, which helped resolve many disease symptoms.

“Bilateral cortisol-secreting tumors are a rare cause of Cushing’s syndrome,” researchers said. So when patients present bilateral adrenal lesions, “it is crucial to make a definitive diagnosis before operation since various treatments are prescribed for different causes,” they said.

The team recommends that in such cases the two tumors should not be removed at the same time, as this approach may cause adrenal insufficiency and the need for glucocorticoid replacement therapy.

From https://cushingsdiseasenews.com/2019/06/27/rare-case-of-cs-due-to-bilateral-tumors-in-the-adrenal-glands/

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Laparoscopic Removal of Adrenal Glands Safe for Obese Cushing’s Patients

Posted on March 9, 2019 by MaryO

Laparoscopic adrenalectomy — a minimally invasive procedure that removes the adrenal glands through a tiny hole in the abdomen — can be safely performed in obese patients with Cushing’s syndrome, a retrospective study reports.

The surgery resolved symptoms in 95% of cases, reducing cortisol levels, lowering blood pressure, and leading to a significant loss of weight in morbidly obese patients.

The study, “Minimally invasive approach to the adrenal gland in obese patients with Cushing’s syndrome,” was published in the journal Minimally Invasive Therapy & Allied Technologies.

Cushing’s syndrome results from the prolonged secretion of excess cortisol, the major glucocorticoid hormone. While most cases are caused by tumors in the pituitary gland, up to 27% result from tumors in the adrenal glands.

In these cases, the standard therapeutic strategy is to remove one or both adrenal glands, a surgical procedure called adrenalectomy. However, because glucocorticoids are key hormones regulating fat metabolism, Cushing’s syndrome patients are known to be prone to obesity, a feature that is often associated with post-operative complications.

In this study, researchers aimed to compare the outcomes of morbidly obese patients versus the mildly obese and non-obese who underwent a minimally invasive procedure to remove their adrenal glands.

The approach, called laparoscopic adrenalectomy, inserts tiny surgical tools through a small hole in the abdomen, along with a camera that helps guide the surgeon.

The study included 228 patients (mean age 53.4 years). Of them, 62 were non-obese, 87 were moderately obese, and 79 were considered morbidly obese. There were 121 patients with tumors in the right adrenal gland, 96 in the left gland, and 11 in both glands.

High blood pressure was the most common symptom, affecting 66.7% of the participants.

Surgery lasted 101 minutes on average, and patients remained in the hospital for a median 4.3 days afterward. Six patients had to be converted into an open surgery because of uncontrollable loss of blood or difficulties in the procedure. Post-surgery complications, most of which were minor, were seen in seven patients.

One patient had blood in the peritoneal cavity and had to have surgery again; another patient had inflammation of the pancreas that required a longer admission.

The analysis showed no statistical differences among the three groups regarding the length of surgery, length of stay in the hospital, or the rate of conversion into open surgery.

However, in obese women, surgeons chose a different surgical incision when removing the left adrenal gland, “suggesting that the distribution of visceral fat in these patients could constitute a drawback for the [standard] approach,” researchers said.

After the surgery, 95% of patients saw their symptoms resolve, including cortisol levels, high blood pressure, and glucose metabolism, and none had a worsening of symptoms in the 6.3 years of follow-up. Obese patients also showed a significant reduction in their weight — 2 kg by 18 months, and 5 kg by the end of follow-up.

Overall, “laparoscopic adrenalectomy is safe and feasible in obese patients affected with Cushing’s disease and it can lead to the resolution of the related symptoms,” researchers said.

The benefits of the surgery in patients with Cushing’s syndrome “could be extended to the improvements and in some cases to the resolution of hypercortisolism related symptoms (i.e. hypertension or even morbid obesity),” the study concluded.

Adapted from https://cushingsdiseasenews.com/2019/02/07/laparoscopic-removal-of-adrenal-glands-safe-for-obese-cushings-patients/

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Adrenal Venous Sampling Helps Surgical Decisions in Type of Cushing’s

Posted on October 2, 2018 by MaryO

Cushing’s syndrome patients with tumors on both adrenal glands — which sit on top of the kidneys — could undergo adrenal venous sampling, a procedure where blood samples are taken from both adrenal glands to determine which tumors to remove, researchers suggest.

Their study, “Outcomes of Adrenal Venous Sampling in Patients with Bilateral Adrenal Masses and ACTH-Independent Cushing’s Syndrome,” was published in the World Journal of Surgery. The work was a collaboration between SUNY Upstate Medical University in Syracuse and the University of Pittsburgh.

Cushing’s syndrome, a condition characterized by excess cortisol, can be divided into two main subtypes. In some patients, the disease is dependent on tumors secreting the adrenocorticotropic hormone (ACTH), which stimulates the release of cortisol from the adrenal glands. In others, adrenal tumors are solely responsible for excess cortisol and do not require ACTH for functioning.

ACTH-independent Cushing’s syndrome (AICS), the latter subtype, constitutes about 10% to 15% of endogenous — an overproduction of cortisol within the body — Cushing’s syndrome cases, with cortisol-secreting adenomas in just one gland (unilateral) being the most common cause.

Compared to unilateral adenomas, adrenal tumors in both glands (bilateral) in patients with AICS are difficult to diagnose. Disease management in these rare cases depends on the challenging determination of the lesion’s exact location and of the functional status of the benign tumors (if they are actively secreting cortisol).

Surgical removal of both adrenal glands, also known as bilateral adrenalectomy, “ensures cure of AICS, but leads to permanent corticosteroid dependence and a lifelong risk of adrenal crisis,” investigators explained. Therefore, screening for the presence of unilateral or bilateral adenomas is essential to avoid unnecessary surgery.

“Adrenal venous sampling (AVS) has been reported in a single institutional series … to aid in successful localization of cortisol-secreting adrenal adenomas in patients with bilateral adrenal masses and AICS,” researchers wrote.

Researchers retrospectively assessed the usefulness of AVS in guiding management of patients with bilateral adrenal masses plus AICS.

Nine women (age 51-73) with bilateral adrenal masses and AICS were included in the study. All subjects had undergone AVS at the University of Pittsburgh Medical Center from 2008 to 2016. None of the patients had apparent symptoms of Cushing’s syndrome.

“Samples were obtained for testing of epinephrine [also called adrenaline] and cortisol from both [adrenal veins] and the external iliac vein. Multiple samples were obtained to ensure adequate sampling,” they wrote.

Adrenal glands produce cortisol and epinephrine, among other hormones, which are critical for maintaining good health. In AICS, there’s an overproduction of both hormones that’s independent on the release of ACTH, which is produced by the brain’s pituitary gland.

Successful adrenal venous sampling was achieved in eight women. “One patient with unsuccessful catheterization had [other additional diseases] and passed away from unrelated reasons,” researchers reported.

AVS results indicated that all patients had bilateral cortisol-secreting adenomas.

“Surgical management was strongly influenced by adrenal mass size. However, AVS may have influenced surgical decision-making in some cases, particularly when minimal difference in size was noted in adrenal mass sizes,” they reported.

Six women underwent adrenalectomy: three had the gland with larger size mass removed (unilateral type of surgery); two had both glands removed; and one had the right gland removed followed by the left one, five months later, due to continuous hormonal overproduction without experiencing symptoms of Cushing’s syndrome.

Evidence suggests that removal of the larger adrenal mass in patients with bilateral cortisol-secreting adenomas improves Cushing’s syndrome presentation.

In theory, unilateral adrenalectomy reduces cortisol production through the removal of the oversecreting mass. Because of this, unilateral adrenalectomy of the larger adrenal mass was chosen in half of this study’s surgical cases, instead of bilateral adrenalectomy.

Tissue analysis revealed multiple-lump masses, also known as macronodular adrenal hyperplasia (MAH), in all six surgical cases.

In addition, computed tomography (CT) scan findings were predictive of bilateral MAH, with scans showing evidence of one or multiple nodules on one or both adrenal glands.

“To the best of our knowledge, this is the second study to evaluate the utility of AVS in guiding management of patients with bilateral adrenal masses and AICS,” investigators said.

The first study was by Young and included 10 patients with a more severe presentation of Cushing’s syndrome and other individual characteristics, which contributed to the differences in results, compared to the current study. In Young’s study, half the subjects had unilateral adrenal masses.

Patients with bilateral cortisol-secreting masses frequently have a milder form of Cushing’s syndrome, which corroborates researchers’ findings.

Despite suggesting that adrenal venous sampling is useful in excluding a unilateral adenoma as the cause of AICS, this study’s sample size is small.

“More data are needed before AVS can be advocated as essential for management of patients with bilateral adrenal masses and AICS,” researchers concluded.

From https://cushingsdiseasenews.com/2018/10/02/adrenal-venous-sampling-helps-surgical-decisions-type-cushings-syndrome/?utm_source=Cushing%27s+Disease+News&utm_campaign=a990429aad-RSS_WEEKLY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_ad0d802c5b-a990429aad-72451321

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MEKT1 Could Be a Potential New Therapy for Treating Cushing’s Disease

Posted on August 2, 2018 by MaryO

MEKT1, a type of therapy called a PPAR-γ agonist, acts to reduce levels of the adrenocorticotropic hormone and could be a potential new therapy for Cushing’s disease, according to researchers.

Their study, “Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells,” was published in the journal PPAR Research.

Cushing’s disease is caused by a tumor in the pituitary gland — generally a type of tumor called an adenoma that produces high levels of adrenocorticotropic hormone (ACTH).

ACTH causes the adrenal glands to make too much cortisol, leading to the classic symptoms associated with Cushing’s disease.

PPAR-gamma (PPAR-γ) is a transcription factor protein (meaning it regulates the levels of certain genes by acting through other proteins), and is seen in high levels in the normal human pituitary and in ACTH-secreting pituitary adenomas.

The Pomc gene is a precursor molecule to ACTH. While it is known that PPAR-γ plays a role in regulating Pomc levels, its mechanism has not yet been clarified in pituitary cells.

PPAR-γ agonists — agents that activate PPAR-γ — include the medications rosiglitazone and pioglitazone, both of which are used to treat type 2 diabetes. Some studies have shown that rosiglitazone and pioglitazone have an effect on Pomc suppression, which would lead to lower levels of ACTH and help treat patients with Cushing’s disease.

However, the benefits of PPAR-γ agonists in the treatment of Cushing’s disease are still controversial.

Researchers examined the effects of a new PPAR-γ agonist, MEKT1, on Pomc levels and ACTH secretion using a mouse pituitary tumor-derived cell line called AtT20 cells. They also compared its effects with the well-established PPAR-γ agonists rosiglitazone and pioglitazone.

AtT20 cells were treated with either MEKT1, rosiglitazone, or pioglitazone at various concentrations ranging from 1 nM to 10 μM (micrometers) for 24 hours.

Results showed that 10 μM of MEKT1 significantly inhibited Pomc gene levels compared to rosiglitazone and pioglitazone. Additionally, ACTH secretion from AtT20 cells was also significantly inhibited by the agonist.

To see if it worked to decrease Pomc levels by acting specifically on PPAR-γ, researchers eliminated the PPAR-γ protein using a technique called siRNA knockdown. In this case, the effects of MEKT1 on Pomc levels were significantly halted.

It is known that other proteins, such as Nur77, Nurr1, and Tpit activate Pomc levels by binding to the promoter region of Pomc — the area of the gene responsible for activating gene levels.

To determine whether these proteins could be targeted by MEKT1, researchers also looked at levels of Nur77, Nurr1, and Tpit. The PPAR-γ agonist was found to significantly suppress the levels of the three genes that encode these proteins.

“Although clinical trials of MEKT1 are needed to determine its drug efficacy in the future, it can be speculated that MEKT1 is much more effective than the previously recognized PPAR-γ agonists rosiglitazone, and pioglitazone for the suppression of Pomc expression/ACTH secretion from our in vitro [laboratory] research,” they added.

Results from this study suggest MEKT1 could be a potential new therapy for the treatment of Cushing’s disease.

From https://cushingsdiseasenews.com/2018/06/12/mekt1-could-be-potential-therapy-treatment-cushings-disease/

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