Study Supports Midnight Salivary Cortisol Test to Diagnose Cushing’s in Chinese Population

A simple test that measures free cortisol levels in saliva at midnight — called a midnight salivary cortisol test — showed good diagnostic performance for Cushing’s syndrome among a Chinese population, according to a recent study.

The test was better than the standard urine free cortisol levels and may be an alternative for people with end-stage kidney disease, in whom measuring cortisol in urine is challenging.

The study, “Midnight salivary cortisol for the diagnosis of Cushing’s syndrome in a Chinese population,” was published in Singapore Medical Journal.

Cushing’s syndrome, defined by excess cortisol levels, is normally diagnosed by measuring the amount of cortisol in bodily fluids.

Traditionally, urine free cortisol has been the test of choice, but this method is subject to complications ranging from improper collection to metabolic differences, and its use is limited in people with poor kidney function.

Midnight salivary cortisol is a test that takes into account the normal fluctuation of cortisol levels in bodily fluids. Cortisol peaks in the morning and declines throughout the day, reaching its lowest levels at midnight. In Cushing’s patients, however, this variation ceases to exist and cortisol remains elevated throughout the day.

Midnight salivary cortisol was first proposed in the 1980s as a noninvasive way to measure cortisol levels, but its efficacy and cutoff value for Cushing’s disease in the Chinese population remained unclear.

Researchers examined midnight salivary cortisol, urine free cortisol, and midnight serum cortisol in Chinese patients suspected of having Cushing’s syndrome and in healthy volunteers. These measurements were then combined with imaging studies to make a diagnosis.

Overall, the study included 29 patients with Cushing’s disease, and 19 patients with Cushing’s syndrome — 15 caused by an adrenal mass and four caused by an ACTH-producing tumor outside the pituitary. Also, 13 patients excluded from the suspected Cushing’s group were used as controls and 21 healthy volunteers were considered the “normal” group.

The team found that the mean midnight salivary cortisol was significantly higher in the Cushing’s group compared to both control and normal subjects. Urine free cortisol and midnight serum cortisol were also significantly higher than those found in the control group, but not the normal group.

The optimal cutoff value of midnight salivary cortisol for diagnosing Cushing’s was 1.7 ng/mL, which had a sensitivity of 98% — only 2% are false negatives — and a specificity of 100% — no false positives.

While midnight salivary cortisol levels correlated with urine free cortisol and midnight serum cortisol — suggesting that all of them can be useful diagnostic markers for Cushing’s — the accuracy of midnight salivary cortisol was better than the other two measures.

Notably, in one patient with a benign adrenal mass and impaired kidney function, urine free cortisol failed to reach the necessary threshold for a Cushing’s diagnosis, but midnight salivary and serum cortisol levels both confirmed the diagnosis, highlighting how midnight salivary cortisol could be a preferable diagnostic method over urine free cortisol.

“MSC is a simple and non-invasive tool that does not require hospitalization. Our results confirmed the accuracy and reliability of [midnight salivary cortisol] as a diagnostic test for [Cushing’s syndrome] for the Chinese population,” the investigators said.

The team also noted that its study is limited: the sample size was quite small, and Cushing’s patients tended to be older than controls, which may have skewed the results. Larger studies will be needed to validate these results in the future.

From https://cushingsdiseasenews.com/2019/01/10/midnight-salivary-cortisol-test-helps-diagnose-cushings-chinese-study-shows/

Metastatic Pituitary Carcinoma Successfully Treated with Radiation, Chemo.

A man with Cushing’s disease — caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma — who later developed metastases in the central nervous system without Cushing’s recurrence, was successfully treated over eight years with radiation and chemotherapy, according to a case report.

The report, “Long-term survival following transformation of an adrenocorticotropic hormone secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma: Case report,” was published in the journal World Neurosurgery.

Pituitary carcinomas make up only 0.1-0.2% of all pituitary tumors and are characterized by a primary pituitary tumor that metastasizes into cranial, spinal, or systemic locations. Fewer than 200 cases have been reported in the literature.

Most of these carcinomas secrete hormones, with ACTH being the most common. Though the majority of ACTH-secreting carcinomas present with Cushing’s disease, about one-third do not show symptoms of the condition and have normal serum cortisol and ACTH levels. These are called silent corticotroph adenomas and are considered more aggressive.

A research team at the University of Alabama at Birmingham presented the case of a 51-year-old Caucasian man with ACTH-dependent Cushing’s disease. He had undergone an incomplete transsphenoidal (through the nose) resection of an ACTH-secreting pituitary macroadenoma – larger than 10 mm in size – and radiation therapy the year before.

At referral in August 1997, the patient had persistent high cortisol levels and partial hypopituitarism, or pituitary insufficiency. He exhibited Cushing’s symptoms, including facial reddening, moon facies, weight gain above the collarbone, “buffalo hump,” and abdominal stretch marks.

About two years later, the man was weaned off ketoconazole — a medication used to lower cortisol levels — and his cortisol levels had been effectively reduced. He also had no physical manifestations of Cushing’s apart from facial reddening.

In May 2010, the patient reported two episodes of partial seizures, describing two spells of right arm tingling, followed by impaired peripheral vision. Imaging showed a 2.1-by-1-cm mass with an associated cyst within the brain’s right posterior temporal lobe, as well as a 1.8-by-1.2-cm mass at the cervicomedullary junction, which is the region where the brainstem continues as the spinal cord. His right temporal cystic mass was then removed by craniotomy.

A histopathologic analysis was consistent with pituitary carcinoma. Cell morphology was generally similar to the primary pituitary tumor, but cell proliferation was higher. Physical exams showed no recurrence of Cushing’s disease and 24-hour free urinary cortisol was within the normal range.

His cervicomedullary metastasis was treated with radiation therapy in July 2010. He took the oral chemotherapy temozolomide until August 2011, and Avastin (bevacizumab, by Genentech) was administered from September 2010 to November 2012.

At present, the patient continues to undergo annual imaging and laboratory draws. He receives treatment with hydrocortisone, levothyroxine — synthetic thyroid hormone — and testosterone replacement with androgel.

His most recent exam showed no progression over eight years of a small residual right temporal cyst, a residual mass along the pituitary stalk — the connection between the hypothalamus and the pituitary gland — and a small residual mass at the cervicomedullary junction. Lab results continue to show no Cushing’s recurrence.

“Our case is the first to document a patient who initially presented with an endocrinologically active ACTH secreting pituitary adenoma and Cushing’s disease who later developed cranial and spinal metastases without recurrence of Cushing’s disease and transformation to a silent corticotroph pituitary carcinoma,” the scientists wrote.

They added that the report is also the first documenting “8 years of progression-free survival in a patient with pituitary carcinoma treated with radiotherapy, [temozolomide] and bevacizumab.”

Adapted from https://cushingsdiseasenews.com/2019/01/03/successful-treatment-pituitary-carcinoma-radiation-chemo-case-report/

Vision Loss The First Sign Of Adrenal Tumour In 42-Year-Old Patient

A 42-year-old woman who presented to hospital with acute vision loss in her right eye was diagnosed with a benign tumour in her adrenal gland.

Writing in BMJ Case Reports, clinicians described how the patient presented with a visual acuity of 6/36 in her right eye and 6/6 in her left eye.

Investigations revealed an exudative retinal detachment in her right eye as well as a pigment epithelial detachment.

The patient had multifocal central serous retinopathy in both eyes.

The woman, who had hypertension and diabetes, was diagnosed with Cushing syndrome and a right adrenal adenoma was also discovered.

During a treatment period that spanned several years, the patient received an adrenalectomy followed by a maintenance dose of steroids.

The patient subsequently developed central serous retinopathy again which the clinicians believe might be related to steroid use.

The authors advised “careful deliberation” in prescribing a maintenance dose of steroids following removal of the adrenal glands because of the potential link to retinopathy.

From https://www.aop.org.uk/ot/science-and-vision/research/2018/12/17/vision-loss-the-first-sign-of-adrenal-tumour-in-42-year-old-patient

Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature

 2018 Nov 28. doi: 10.1007/s00381-018-4013-5. [Epub ahead of print]

Abstract

AIM:

Pituitary adenomas are rare in childhood in contrast with adults. Adrenocorticotropic hormone (ACTH)-secreting adenomas account for Cushing’s disease (CD) which is the most common form of ACTH-dependent Cushing’s syndrome (CS). Treatment strategies are generally based on data of adult CD patients, although some difficulties and differences exist in pediatric patients. The aim of this study is to share our experience of 10 children and adolescents with CD.

PATIENTS AND METHOD:

Medical records, images, and operative notes of 10 consecutive children and adolescents who underwent transsphenoidal surgery for CD between 1999 and 2014 in Cerrahpasa Faculty of Medicine were retrospectively reviewed. Mean age at operation was 14.8 ± 4.2 years (range 5-18). The mean length of symptoms was 24.2 months. The mean follow-up period was 11 years (range 4 to 19 years).

RESULTS:

Mean preoperative cortisol level was 23.435 μg/dl (range 8.81-59.8 μg/dl). Mean preoperative ACTH level was 57.358 μg/dl (range 28.9-139.9 μg/dl). MR images localized microadenoma in three patients (30%), macroadenoma in four patients (40%) in our series. Transsphenoidal microsurgery and endoscopic transsphenoidal surgery were performed in 8 and 2 patients respectively. Remission was provided in 8 patients (80%). Five patients (50%) met remission criteria after initial operations. Three patients (30%) underwent additional operations to meet remission criteria.

CONCLUSION:

Transsphenoidal surgery remains the mainstay therapy for CD in pediatric patients as well as adults. It is an effective treatment option with low rate of complications. Both endoscopic and microscopic approaches provide safe access to sella and satisfactory surgical results.

KEYWORDS:

Cushing’s disease; Endoscopic pituitary surgery; Pediatric; Transsphenoidal microsurgery

PMID:
30488233
DOI:
10.1007/s00381-018-4013-5

Full Text

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/

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