The Relationship of Mitochondrial Dysfunction and the Development of Insulin Resistance in Cushing’s Syndrome

Authors Ježková J, Ďurovcová V, Wenchich LHansíková H, Zeman J, Hána V, Marek J, Lacinová Z, Haluzík M, Kršek M

Received 18 March 2019

Accepted for publication 13 June 2019

Published 19 August 2019 Volume 2019:12 Pages 1459—1471

DOI https://doi.org/10.2147/DMSO.S209095

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 3

Editor who approved publication: Dr Antonio Brunetti

 

Jana Ježková,1 Viktória Ďurovcová,1 Laszlo Wenchich,2,3 Hana Hansíková,3 Jiří Zeman,3Václav Hána,1 Josef Marek,1 Zdeňka Lacinová,4,5 Martin Haluzík,4,5 Michal Kršek1

1Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 2Institute of Rheumatology, Prague, Czech Republic; 3Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 4Institute of Medical Biochemistry and Laboratory Diagnostic, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Correspondence: Jana Ježková
Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 1128 02 Praha 2, Prague, Czech Republic
Tel +420 60 641 2613
Fax +420 22 491 9780
Email fjjezek@cmail.cz

Purpose: Cushing’s syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications.

Patients and methods: We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing’s syndrome and in 9 of them after successful treatment and 22 healthy control subjects.

Results: Patients with active Cushing’s syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing’s syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing’s syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing’s syndrome showed increased enzyme activity of complex I (NQR) in platelets.

Conclusion: Mitochondrial function in SCAT in patients with Cushing’s syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing’s syndrome.

Keywords: Cushing’s syndrome, insulin resistance, mitochondrial enzyme activity, gene expression

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The Incidence Of Cushing’s Disease: A Nationwide Swedish Study

In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 22, no 2, p. 179-186Article in journal (Refereed) Published

Abstract [en]

Background: Studies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.

Methods: Patients registered with a diagnostic code for Cushing’s syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.

Results: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P<0.05).

Conclusion: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

Place, publisher, year, edition, pages

SPRINGER , 2019. Vol. 22, no 2, p. 179-186

Keywords [en]

Cushing’s syndrome, Epidemiology, Incidence, Validation

National Category

Endocrinology and Diabetes

Identifiers

URN: urn:nbn:se:uu:diva-380429DOI: 10.1007/s11102-019-00951-1ISI: 000461291200010PubMedID: 30799512OAI: oai:DiVA.org:uu-380429DiVA, id: diva2:1300822

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Active Cushing’s disease is characterized by increased adipose tissue macrophage presence

Journal of Clinical Endocrinology and Metabolism — Lee IT, et al. | February 07, 2019

Using immunohistochemistry, researchers determined whether adipose tissue (AT) inflammation in humans is associated with chronic endogenous glucocorticoid (GC) exposure due to Cushing’s disease (CD).

Abdominal subcutaneous AT samples were evaluated for macrophage infiltration and mRNA expression of pro-inflammatory cytokines in 10 patients with active CD and 10 age, gender and BMI- matched healthy subjects.

The presence of AT macrophages, a hallmark of AT inflammation, increases chronic exposure to GCs due to CD. AT inflammation can, therefore, be the source of systemic inflammation in these patients, which in turn can contribute to obesity, insulin resistance and cardiovascular disease. In patients with CD, PCR showed no differences in mRNA expression of any analyzed markers.

Read the full article on Journal of Clinical Endocrinology and Metabolism

Cushing’s syndrome caused by ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis: a case report

  • Wakako Fujiwara Email author View ORCID ID profile,
  • Tomohiro Haruki,
  • Yoshiteru Kidokoro,
  • Takashi Ohno,
  • Yohei Yurugi,
  • Ken Miwa,
  • Yuji Taniguchi and
  • Hiroshige Nakamura
Surgical Case Reports20184:55

https://doi.org/10.1186/s40792-018-0459-7

Received: 28 March 2018

Accepted: 31 May 2018

Published: 11 June 2018

Abstract

Background

Ectopic ACTH-producing thymic carcinoid tumors are rare, but often behave aggressively with local invasion and distant metastasis. We herein report a case of ACTH-producing thymic typical carcinoid tumor with lymph node metastasis treated by surgery and postoperative radiation therapy.

Case presentation

A 61-year-old woman was admitted to be evaluated for hypoglycemia and hypokalemia. Laboratory data revealed elevation of serum cortisol and ACTH levels. Overnight administration of 8 mg dexamethasone did not suppress plasma ACTH. Chest CT demonstrated a tumor of 30 mm in diameter and enlargement of the lymph node at the anterior mediastinum. Ectopic ACTH syndrome was suspected and total thymectomy and lymph node dissection were performed. The histopathological examination indicated typical carcinoid tumor and mediastinal lymph node metastasis, and immunohistochemical staining was positive for ACTH. The plasma ACTH level decreased immediately after surgery. She received postoperative radiation therapy of 60 Gy.

Conclusion

Ectopic ACTH-producing thymic typical carcinoid tumors are rare, and it is important to consider this disease and perform appropriate treatment.

Keywords

Thymic carcinoid ACTH Cushing’s syndrome Total thymectomy

Background

Among adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome, 10–20% is due to nonpituitary tumors termed ectopic ACTH syndrome (EAS). The most common cause of EAS is small cell lung cancer, followed by thymic carcinoids. Thymic carcinoids are very rare neuroendocrine tumors that often complicate endocrine disorders. Although previously assumed to be variants of bronchopulmonary carcinoid tumors, they are generally more aggressive and difficult to treat. It is widely accepted that surgical resection is the only curative treatment for localized lesions, and the efficacy of chemotherapy and radiotherapy has not been well established.

We herein report a case of EAS caused due to a thymic typical carcinoid tumor successfully treated by surgery followed by radiation.

Case presentation

A 61-year-old woman visited her primary care doctor because of general malaise, face edema, skin pigmentation, insomnia, and polyuria. Blood examination revealed marked hypokalemia and impaired glucose tolerance. Bilateral adrenal enlargement was observed on abdominal ultrasonography, and she was referred to our hospital for further examination. Endocrine examination showed both elevated plasma cortisol (107.7 pg/mL) and ACTH levels (1100 pg/mL), and increased urinary excretion of free cortisol (6650 mcg/day) and 17-ketogenic steroids (78.7 mg/day). Plasma cortisol and ACTH levels were elevated without any diurnal rhythm. Plasma cortisol was not suppressed by the overnight 8-mg dexamethasone suppression test. There was no response of plasma ACTH or cortisol to exogenous corticotropin-releasing hormone (CRH). Other hormones of the pituitary, thyroid, and adrenal medulla were all in normal ranges. Thus, ectopic ACTH syndrome was strongly suggested.

Chest computed tomography (CT) demonstrated a tumor of approximately 30 mm in diameter and enlargement of the lymph node in the anterior mediastinum (Fig. 1). High accumulation of 18-fluorodeoxyglucose in the anterior mediastinum tumor (maximum standardized uptake value [SUV] 2.48) but not in the lymph node was observed on positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy also revealed mild uptake in the tumor. Collectively, these data were consistent with a diagnosis of EAS caused by an anterior mediastinum tumor, possibly thymic carcinoid tumor. There was no abnormal finding indicating multiple endocrine neoplasia (MEN).

Figure 1
Fig. 1

Chest CT image. A tumor (30 × 30 × 14 mm) without invasion localized in the anterior mediastinum (a). Enlargement of lymph node (b)

Before the operation, we administered 500 mg/day of metyrapone, and both ACTH and cortisol levels decreased to 68.5 pg/mL and 3.02 mcg/mL respectively. After 2 months of medical treatment, her symptoms were relieved and bilateral adrenal enlargement decreased. Under open thoracotomy by median sternotomy, she underwent total thymectomy, pericardial partial resection, dissection of the anterior regional and the right paratracheal lymph nodes, and sampling of the subcarinal lymph node. Histopathologically, the tumor consisted of round to spindle-shaped cells with high nucleus/cytoplasm ratios containing finely granular chromatin. Necrosis was absent, and mitotic figures were infrequent, with less than two per ten high-power fields (HPF). Tumor cells were positive for chromogranin A, synaptophysin, CD-56, and ACTH on immunohistochemistry (Fig. 2). The tumor had invaded the pericardium, and mediastinal lymph nodes were positive for metastasis. The final diagnosis was stage IVA (pT2N1M0) ACTH-producing thymic typical carcinoid tumor. The plasma ACTH level decreased to 14.8 pg/mL, less than normal, immediately after surgery (Fig. 3). Hydrocortisone was administered during the perioperative period and was gradually tapered, and finished 4 months after surgery. She received postoperative radiation therapy of 60 Gy. At 8 months after surgery, she showed no sign of Cushing’s syndrome or recurrence of the tumor without any medications.

Figure 2
Fig. 2

HE staining (a) indicated typical carcinoid tumor. Tumor cells were positive for synaptophysin (b), CD-56 (c), and ACTH (d) on immunostaining

Figure 3
Fig. 3

Changes in plasma ACTH levels during the clinical course

Discussion

Ectopic ACTH-producing thymic carcinoid tumor is an extremely rare clinical condition, comprising 29% of all thymic carcinoids and 5–42% of all ectopic ACTH-producing syndrome [12]. It has been reported that radical surgical resection of the ACTH source is the only effective treatment [3]. Prior to surgery, medication therapy should be done to prevent perioperative complications and perform surgery when hormone values and symptoms are controlled. Furthermore, there is a risk of postoperative adrenal insufficiency; strict perioperative management is desirable.

Unlike pulmonary and other carcinoid tumors, thymic carcinoids often behave aggressively as an advanced disease with local invasion, lymph node metastasis, and distant metastasis because of the high proportion of atypical carcinoid tumors. Regarding ACTH-producing thymic tumors, Neary et al. reported three cases of well-differentiated ACTH-producing thymic neuroendocrine carcinomas, and the patients had no lymph node metastasis, recurrence, or death. On the other hand, nine cases of moderately differentiated ACTH-producing thymic neuroendocrine carcinomas almost had lymph node metastasis, and all patients had recurred [4]. However, our case was a typical carcinoid tumor with lymph node metastasis and local invasion.

As a surgical procedure, a median sternotomy approach is generally recommended because this enables excision of the entire thymus, perithymic fat, other affected mediastinal structure, and aggressive lymph node dissection. However, there is no standard for lymph node dissection in thymic epithelial tumors even though lymph node metastasis is an important prognostic factor. Hwang et al. recommended right paratracheal node dissection in addition to anterior regional lymph node dissection for TNM clinical stage II or higher diseases because they are crucial stations on the lymphatic pathway of thymic malignancies [5]. In the present case, we performed total thymectomy, followed by lymph node dissection of the anterior regional and right paratracheal nodes, and sampling of subcarinal lymph node via median sternotomy. The anterior mediastinal lymph nodes were positive for metastasis. Consequently, we considered the extent of lymph node dissection to be adequate, and radical resection was completed because the postoperative plasma ACTH level was successfully decreased. Although a good prognosis is expected by combined surgery and radiation, relatively high malignancy characteristics are observed compared with typical carcinoids, and strict follow-up is needed.

Conclusion

We report a rare case of ectopic ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis. Surgical resection was effective to control Cushing’s syndrome in this case, and nodal staging may help to guide adjuvant treatment, but systemic nodal dissection/sampling is yet to be standardized.

Abbreviations

ACTH: 

Adrenocorticotrophic hormone

CRH: 

Corticotropin-releasing hormone

CT: 

Computed tomography

SUV: 

Standardized uptake value

PET: 

Positron emission tomography

MEN: 

Multiple endocrine neoplasia

HPF: 

High-power fields

CD-56: 

Cluster of differentiation-56

Declarations

Acknowledgements

The authors thank Dr. Nosaka and Dr. Umekita for diagnostic assessment of this case.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article.

Authors’ contributions

WF and YT were the attending doctors for the patient. WF, YK, KM, YT, and HN performed the operation. WF, TH, and HN drafted this manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

No applicable.

Consent for publication

This patient consented to the reporting of this case in a scientific publication.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References

  1. Yoshikawa T, Noguchi Y, Matsukawa H, et al. Thymus carcinoid producing parathyroid hormone (PTH)-related protein: report of a case. Surg Today. 1994;24:544–7.View ArticlePubMedGoogle Scholar
  2. Alexandraki KI, Grossman AB. The ectopic ACTH syndrome. Rev Endocr Metab Disord. 2010;11:117–26.View ArticlePubMedGoogle Scholar
  3. Zhou X, Hnag J, Che J, et al. Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor. J Thorac Dis. 2016;8:888–93.View ArticlePubMedPubMed CentralGoogle Scholar
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Copyright

© The Author(s). 2018

Delayed complications after transsphenoidal surgery for pituitary adenomas

World Neurosurg. 2017 Oct 5. pii: S1878-8750(17)31710-2. doi: 10.1016/j.wneu.2017.09.192. [Epub ahead of print]

Abstract

Perioperative complications after transsphenoidal surgery for pituitary adenomas have been well documented in the literature; however, some complications can occur in a delayed fashion postoperatively and reports are sparse about their occurrence, management, and outcome.

Here, we describe delayed complications after transsphenoidal surgery and discuss the incidence, temporality from the surgery, and management of these complications based on the findings of studies that reported delayed postoperative epistaxis, delayed postoperative cavernous carotid pseudoaneurysm formation and rupture, vasospasm, delayed symptomatic hyponatremia (DSH), hypopituitarism, hydrocephalus, and sinonasal complications.

Our findings from this review revealed an incidence of 0.6-3.3% for delayed postoperative epistaxis at 1-3 weeks postoperatively, 18 reported cases of delayed carotid artery pseudoaneurysm formation at 2 days to 10 years postoperatively, 30 reported cases for postoperative vasospasm occurring 8 days postoperatively, a 3.6-19.8% rate of DSH at 4-7 days postoperatively, a 3.1% rate of new-onset hypopituitarism at 2 months postoperatively, and a 0.4-5.8% rate of hydrocephalus within 2.2 months postoperatively.

Sinonasal complications are commonly reported after transsphenoidal surgery, but spontaneous resolutions within 3-12 months have been reported. Although the incidence of some of these complications is low, providing preoperative counseling to patients with pituitary tumors regarding these delayed complications and proper postoperative follow-up planning is an important part of treatment planning.

KEYWORDS:

carotid pseudoaneurysm; cerebrospinal fluid leak; delayed complications; epistaxis; hydrocephalus; hyponatremia; hypopituitarism; pituitary; sinonasal complication; transsphenoidal surgery; tumor

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