Hypercortisolemic Cushing’s Patients Possess a Distinct Class of Hematopoietic Progenitor Cells Leading to Erythrocytosis

Abstract

Although human cultures stimulated with dexamethasone suggest that the glucocorticoid receptor (GR) activates stress erythropoiesis, the effects of GR activation on erythropoiesis in vivo remains poorly understood.

We characterized the phenotype of a large cohort of patients with Cushing’s Disease, a rare condition associated with elevated cortisol levels. Results from hypercortisolemic patients with active Cushing’s were compared with those obtained from eucortisolemic patients after remission and from non-diseased volunteers. Active Cushing’s patients exhibit erythrocytosis associated with normal hemoglobin F levels. In addition, their blood contained elevated numbers of the GR-induced CD163+ monocytes and a unique class of CD34+ cells expressing CD110, CD36, CD133 and the GR-target gene CXCR4.

When cultured, these CD34+ cells generated similarly large numbers of immature erythroid cells in the presence and absence of dexamethasone, with raised expression of the GR-target gene GILZ. Of interest, blood from Cushing’s patients in remission maintained high numbers of CD163+ monocytes and, although their CD34+ cells had a normal phenotype, these cells were unresponsive to added dexamethasone.

Collectively, these results indicate that chronic exposure to excess glucocorticoids in vivo leads to erythrocytosis by generating erythroid progenitor cells with a constitutively active GR.

Although remission rescues the erythrocytosis and the phenotype of the circulating CD34+ cells, a memory of other prior changes is maintained in remission.

From https://haematologica.org/article/view/haematol.2021.280542

Adrenal myelolipoma(s) as presenting manifestation of subclinical Cushing’s disease (eutopic ACTH-dependent Cushing’s syndrome)

  1. Partha Pratim Chakraborty1,
  2. Shinjan Patra1,
  3. Sugata Narayan Biswas1,
  4. Rana Bhattacharjee2

+Author Affiliations


  1. 1Department of MedicineMidnapore Medical College and HospitalMidnaporeWest Bengal, India

  2. 2Department of Endocrinology and MetabolismIPGME&R/SSKM HospitalKolkataWest Bengal, India
  1. Correspondence to Dr Partha Pratim Chakraborty, docparthapc@yahoo.co.in
  • Accepted 5 August 2017
  • Published 16 August 2017

Summary

Primary adrenal myelolipomas, relatively rare benign tumours of the adrenal cortex are typically unilateral, hormonally inactive and asymptomatic, hence often diagnosed as ‘adrenal incidentaloma’. Bilateral adrenal myelolipomas, in particular, may be associated with underlying endocrinopathies associated with elevated circulating adrenocorticotropic hormone (ACTH) concentration.

Subclinical cortisol hypersecretion, irrespective of its ACTH dependency, does not manifest typical clinical phenotype of hypercortisolemia, and thus termed subclinical Cushing’s syndrome.

In this article, hormonal evaluation in a middle-aged woman with diabetes, hypertension and incidentally discovered unilateral adrenal myelolipoma revealed underlying subclinical Cushing’s disease. Abdominal CT revealed another tiny focus in the contralateral adrenal gland, probably representing incipient myelolipoma.

From (you may buy the whole article at this link) http://casereports.bmj.com/content/2017/bcr-2017-221674.short?rss=1

Ectopic Cushing’s syndrome associated with thoracic tumors

Results of a retrospective review conducted in southern India demonstrate that ectopic Cushing’s syndrome occurred most commonly in association with thoracic tumors.

Researchers added that early control over hypercortisolemia was necessary to prevent metabolic complications and infections, both of which had the potential to be life-threatening.

“As compared to patients with pituitary-dependent Cushing’s syndrome, patients with [ectopic Cushing Syndrome] present with a rapid progression of symptoms,” Nihal Thomas, MD, MNAMS, DNB, FRACP, professor in the department of endocrinology, diabetes and metabolism at Christian Medical College, Vellore, India, and colleagues wrote. “It is also associated with typical features of proximal muscle weakness, severe hypokalaemic metabolic alkalosis, hyperpigmentation, edema, hypertension and glucose intolerance. Early diagnosis and localization of the ectopic source of [adrenocorticotrophic hormone] is crucial, because the treatment of choice in most of these patients is complete excision of the tumor. Localizing the source of excess ACTH continues to be a challenge in most patients.”

Thomas and colleagues reviewed the records of 21 patients treated at a tertiary care center in southern India from 2006 to 2015. The researchers documented patients’ clinical features, history and images from radiological findings and PET scans, as well as details of management, follow-up and outcomes. They also compared those with ectopic Cushing’s syndrome with 20 patients who had Cushing’s disease.

Median age was 34 years. Thomas and colleagues reported that one patient demonstrated “an occult source of ACTH.” The rest had a variety of tumors: bronchial carcinoid (n = 7), thymic carcinoid (n = 7), lung malignancies (n = 3), medullary thyroid carcinoma (n = 2) and pancreatic neuroendocrine tumor (n = 1).

At presentation, muscle weakness was the most common clinical feature (95%), followed by hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%) and striae (52%). Slightly less than half (43%) showed extensive acne. Central obesity in ectopic Cushing’s syndrome was uncommon and occurred in 14% of patients (n = 3), according to Thomas and colleagues; however, it was more prevalent (n = 18) in those with Cushing’s disease.

Median cortisol at 8 a.m. was 55.5 mcg/dL, the researchers wrote, while median 8 a.m. ACTH was 207 pg/mL. The median 24-hour urinary free cortisol level was 2,484 mcg.

Compared with patients with Cushing’s disease, those with ectopic Cushing’s syndrome had “markedly higher” midnight cortisol and ACTH, as well as basal cortisol and ACTH.

During follow-up, more than half of patients (12 of 21) with ectopic Cushing’s syndrome developed life-threatening infections. Although nine patients received surgery for their tumors, only one patient achieved a complete cure during the study period, the researchers wrote.

“In our series, patients with [ectopic Cushing’s syndrome] have more profound hypokalemia, and hypercortisolemia with higher levels of ACTH,” Thomas and colleagues wrote. “The prognosis of patients with [ectopic Cushing’s syndrome] was dependent on tumor histology. The role of a timely adrenalectomy needs to be considered in patients with hypercortisolemia unresponsive to medical management, and in patients with metastatic or recurrent disease.” – by Andy Polhamus

Disclosure: Endocrine Today was unable to confirm any relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Be42c81a5-fd5b-4313-9b2b-9bcbdec7f8ce%7D/ectopic-cushings-syndrome-associated-with-thoracic-tumors

Delayed diagnosis, barriers to care increase morbidity in children with Cushing’s syndrome

Hispanic and black children diagnosed with Cushing’s syndrome are more likely to present with higher cortisol measurements and larger tumor size vs. white children, according to study findings presented at the annual Pediatric Academic Societies Meeting in Baltimore.

“Racial and socioeconomic disparities may contribute to the severity of disease presentation for children with Cushing’s [syndrome],” Alexandra Gkourogianni, MD, of the section on endocrinology and genetics at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and colleagues wrote. “Minority children from disadvantaged backgrounds present more frequently with comorbidities associated with longstanding [Cushing’s syndrome].”

Gkourogianni and colleagues analyzed data from 135 children treated for Cushing’s syndrome (transsphenoidal surgery) at the NIH between 1997 and 2015 (mean age, 13 years; 51% girls; 33% Hispanic or black). Researchers used a 10-point index for rating severity in pediatric Cushing’s syndrome based on predefined cutoffs; degree of hypercortisolemia, impaired glucose tolerance, and hypertension were graded on a 3-point scale (0-2); height, BMI z scores, duration of disease, and tumor invasion were graded on a 2-point scale (0-1).

Researchers found that midnight cortisol measurements were higher among Hispanic and black children vs. white children (23.3 µg/dL vs. 16 µg/dL; P = .019), as were tumor sizes (mean 6.3 mm vs. 3.3 mm; P = .016). Height standard deviation score was more severely affected in black and Hispanic children (–1.6 vs. –1.1; P = .038), and mean Cushing’s syndrome score for Hispanic and black children was higher vs. white children (4.5 vs. 3.8; P = .033).

Researchers found that median income had an independent correlation with Cushing’s syndrome score in univariate regression analysis for covariates of socioeconomic status and demographics (P = .025). Multivariable regression analysis using race, prevalence of obesity, estimated income, access to pediatric endocrinologist, age and sex confirmed that race, along with lower socioeconomic status and older age, were predictors of a higher Cushing’s syndrome score (P = .002).

“We speculate that delayed diagnosis, barriers to access to care and poorer quality health care for these underserved patients may contribute to presentation at a later age and increased morbidity,” the researchers wrote. “Additional research is needed to identify potential modifiable factors that may improve care for these patients.” – by Regina Schaffer

Reference:

Gkourogianni A, et al. Poster #445. Presented at: Pediatric Academic Societies Meeting; April 30- May 3, 2016; Baltimore.

Disclosure: Endocrine Today was unable to determine relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7Be79d7c84-d539-4a04-a548-882b9f4caadd%7D/delayed-diagnosis-barriers-to-care-increase-morbidity-in-children-with-cushings-syndrome

Resolution of the physical features of Cushing’s syndrome in a patient with a cortisol secreting adrenocortical adenoma after unilateral adrenalectomy

A 37-year-old woman developed clinical manifestations of Cushing’s syndrome over a span of 2 years. Physical examination revealed features that best describe Cushing’s syndrome, such as wide purple striae (>1 cm) over the abdomen, facial plethora and easy bruisability.1  Other features observed were hypertension, moon facies, acne, a dorsocervical fat pad, central obesity and dyslipidaemia.

The diagnosis of hypercortisolism was confirmed using a 1 mg overnight dexamethasone suppression test (19.7 ng/dL, N: <1.8) and 24 h urine free cortisol (185.9 μg/24 h, N: 3.5–45). A suppressed adrenocorticotropic hormone (ACTH) level (4 pg/mL, N: 5–20) and a lack of hyperpigmentation suggested ACTH-independent Cushing’s syndrome. Further work up using CT with contrast of the adrenals showed a 2.4×2.3×2.4 cm right adrenal mass. The patient then underwent laparoscopic adrenalectomy of the right adrenal gland. Steroids was started postoperatively and tapered over time. Histopathology results were consistent with an adrenocortical adenoma (2.5 cm widest dimension). Six months after surgery, there was resolution of the physical features, weight loss and improvement in blood pressure.

Figure 1 is a serial photograph of the physical features seen in Cushing’s syndrome, such as moon facies, a dorsocervical fat pad and wide purple striae, taken preoperatively, and at 3 and 6 months after surgery. With treatment, physical and biochemical changes of Cushing’s syndrome both resolve through time.2 The time course of the resolution of these changes, however, is varied.2 ,3 We observed that the physical features were ameliorated at 3 months and resolved at 6 months.

Learning points

  • Physicians as well as patients should be aware that improvement of the features of Cushing’s syndrome after treatment does not occur immediately.

  • Dramatic resolution of the physical features of Cushing’s syndrome, however, can be observed as early as 6 months after surgery.

Figure 1

Physical features of Cushing’s syndrome (top to bottom: moon facies, a dorsocervical fat pad and wide purple striae (>1 cm) over the abdomen) documented before surgery, and at 3 and 6 months after surgery.

Footnotes

  • Twitter Follow John Paul Quisumbing at @jpquisumbingmd

  • Contributors JPMQ worked up the case and wrote the case report. MASS reviewed the case report and critically appraised it. JPMQ incorporated his suggestions.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

References

From http://casereports.bmj.com/content/2016/bcr-2016-215693.short?rss=1

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