The burden of Cushing’s disease: clinical and health-related quality of life aspects


Thanks to Robin Ess for the easy to read chart!

Abstract

Objective Cushing’s disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.

Design Studies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.

Methods A two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.

Results At the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.

Conclusions These findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

Introduction

Cushing’s disease (CD) is a rare condition caused by a pituitary adenoma that secretes excess ACTH (1), which promotes excess cortisol production from the adrenal glands. Excess cortisol induces a clinical phenotype that harbors all components of the metabolic syndrome, such as central obesity, diabetes mellitus, dyslipidemia, and hypertension, as well as muscle weakness, hirsutism, increased bruisability, psychological dysfunction, and osteoporosis (1234567891011).

Patients with CD experience a significant clinical burden due to comorbidities, increased mortality, and impaired health-related quality of life (HRQoL) due to prolonged exposure to elevated cortisol levels (3511121314151617181920). In particular, patients with CD often experience severe fatigue and weakness, physical changes, emotional instability, depression, and cognitive impairments, which have a profound impact on daily life (1321).

Although there have been several consensus statements published recently on the definition of remission, diagnosis, and the management of CD, the severity and diversity of the clinical scenario and associated morbidities continue to present a management challenge (12223). Additionally, there is recent evidence of persistent deleterious effects after remission, most notably persistent elevated cardiovascular risk (322). The main objective of the current literature review is to describe the current burden of the disease and to summarize data on specific aspects of this burden, which underscores the need for improved diagnostic and therapeutic approaches.

Materials and methods

Available literature were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, mortality, prevalence of comorbidities at diagnosis, reversibility of comorbidities after treatment (in particular, after disease remission), outcomes and complications of current treatment options, and HRQoL associated with CD and interventions.

The literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD. It was conducted in two stages: i) articles published between 2000 and 2012 were identified through a PubMed search using the following keywords: CD, incidence, prevalence, mortality, treatment, remission, cure, excess cortisol, outcomes, cost, QoL, morbidities, transsphenoidal surgery (TSS), adrenalectomy, radiotherapy, steroidogenesis inhibitors, ketoconazole, mitotane, aminoglutethimide, etomidate, metyrapone, pasireotide, and cortisol receptor antagonists; and ii) an additional hand search was conducted on the basis of the bibliographies of identified articles. All studies that provided data (regardless of publication year) related to these research questions were retained.

Definitions

Different criteria for defining the remission of hypercortisolism have been proposed, ranging from the occurrence of definitive or transient postoperative hypocortisolemia to the adequate suppression of cortisol after dexamethasone administration. According to a recent consensus statement (23), persistent postoperative morning serum cortisol levels of <2 μg/dl (∼50 nmol/l) are associated with remission and a low recurrence rate of ∼10% at 10 years. Persistent serum cortisol levels above 5 μg/dl (∼140 nmol/l) for up to 6 weeks following surgery require further evaluation. When serum cortisol levels are between 2 and 5 μg/dl, the patient can be considered in remission and can be observed without additional treatment for CD. A subset of patients can even develop complete adrenal insufficiency (serum cortisol levels below 2 μg/dl (∼50 nmol/l)) up to 12 weeks postsurgery (2425). Therefore, repeated evaluation in the early postoperative period is recommended. However, long-term follow-up is necessary for all patients because no single cortisol cutoff value excludes those who later experience disease recurrence, and up to 25% of patients develop a recurrent adenoma within 10 years after surgery (262728).

Results

Incidence and prevalence of CD

Although epidemiologic data on CD are limited, several population-based studies indicate an incidence of 1.2–2.4 per million (1419) and the prevalence of diagnosed cases to be ∼39 per million population (14). Lindholm et al(19) used the case definition as either the presence of a corticotroph adenoma or remission after neurosurgery, which yielded an estimated incidence rate of 1.2–1.7 per million per year. Etxabe & Vazquez (14) reported an incidence of 2.4 per million in Vizcaya, Spain. A large-scale retrospective survey carried out in New Zealand by Bolland et al(29) found the approximate prevalence of all forms of Cushing’s syndrome (CS) (the majority of these cases were of pituitary origin) to be 79 per million and the incidence to be 1.8 per million per year. Differences in epidemiologic estimates may be attributable to varying case definitions (for instance, the study by Lindholm excluded cases in which the adenoma could not be localized or those that could not achieve remission from surgery), geographical differences, and temporal effects. The prevalence of CD may be underestimated due to unrecognized patients with mild symptoms and patients with a cyclic form of CD (30).

Time to diagnosis

Data on the time from onset of symptoms to diagnosis are also limited. In a prospective study by Flitsch et al(31) of 48 patients with pituitary adenomas, including 19 who had ACTH-secreting adenomas causing CD, the reported time from onset of symptoms to diagnosis was 4.3 years. A study by Martinez Ruiz et al(32), which was based on only four pediatric CD patients, reported the time between onset of symptoms and diagnosis as ranging from 2.5 to 5 years. Etxabe & Vazquez (14) estimated that the average time from onset of clinical symptoms to diagnosis in 49 CD patients was 45.8±2.7 months (6–144 months), thus 3.8 years. This is corroborated by the findings from a Belgian cross-sectional study on pituitary adenomas including CD, which estimated that patients experienced symptoms for an average of 45 months before diagnosis (33). However, the reliability and generalizability of these data are limited by small sample sizes and the retrospective nature of the studies. Indeed, the New Zealand data from Bolland et al(29) report that on presentation, patients experienced symptoms for a median of 2.0 years (but ranging up to 20 years) before diagnosis. On the basis of data from the prospective European Registry on Cushing’s syndrome (ERCUSYN) (total number of patients=481, of whom 66% of patients had CD), median delay in diagnosis was 2 years (34).

Mortality in patients with CD

Mortality in patients with CD has been analyzed in several small studies, with overall rates reported as standardized mortality ratio (SMR) ranging from 1.7 to 4.8 (Table 1) (14151719). In studies in which mortality was assessed among those in remission and those with persistent disease separately, patients with persistent hypercortisolemia consistently had the highest mortality risk (15193536). In addition, TSS as a first-line treatment has been an important advance as high remission rates after initial surgery have been accompanied by mortality rates that mirror those observed in the general population (173537). In a case series from the UK, it was found that the majority of deaths occurred before 1985, which was before TSS was employed as the routine first-line treatment at the center (36). In a recent retrospective study, 80 patients undergoing TSS for CD between 1988 and 2009 were evaluated, and long-term cure (defined as ongoing absence of hypercortisolism at last follow-up) was reported in 72% of patients. However, overall elevated mortality persisted in patients (SMR 3.17 (95% CI: 1.70–5.43)), including those who achieved ‘cure’ (SMR 2.47 (95% CI: 0.80–5.77)), although even higher mortality was seen in those with postoperative recurrence/persistent disease (SMR 4.12 (95% CI: 1.12–10.54) (38). Additionally, a nationwide, retrospective study in New Zealand reported significant persistently increased mortality both in macro- and microadenomas (SMR 3.5 (1.3–7.8) and 3.2 (2.0–4.8) respectively), despite long-term biochemical remission rates of 93 and 91% of patients, respectively (29).

Read more at http://m.eje-online.org/content/167/3/311.full

A Retrospective Review of 34 Cases of Pediatric Pituitary Adenoma

Abstract

Purpose

The purpose of this paper is to study invasiveness, tumor features and clinical symptoms of pediatric pituitary adenoma, and to discuss some inconclusive results in prior studies.

Methods

We retrospectively reviewed 34 cases of children (<20 year-old) who were pathologically diagnosed with pituitary adenoma and surgically treated from 2010 to 2017. Data of general information, clinical symptoms, invasive behaviors, surgery approaches, and tumor features were collected and analyzed.

Results

Sixteen boys and 18 girls aged from 12 to 19 years old were included. Prolactinoma was most suffered, followed by GH-, none- and ACTH-secreting pituitary adenoma. Invasive behaviors were observed frequently and suprasellar extensions were most found. Macroadenoma account 70% of all cases. Meanwhile, unlike prior studies, a significant raise of incidence on invasive tumor and pituitary adenoma apoplexy were observed. Craniotomy and transsphenoidal surgery were both applied with zero mortality. Nine cases occurred with transient hypopituitarism and diabetes insipidus. Three cases of tumor recurrence received secondary surgery or radiotherapy.

Conclusions

Invasive behaviors were more frequent than previous prediction. Craniotomy is worth considering for total tumor removal. Pituitary adenoma apoplexy needs further studies since its different features between children and adults in present study. Specialized care and teamwork of neurosurgeons, pediatricians, and endocrinologists are important.

Keywords

Pediatric pituitary adenoma Invasion Pituitary apoplexy Transsphenoidal surgery 

Cushing’s Syndrome, Cortisol, and Cognitive Competency: A Case Report

Abstract

Glucocorticoids are associated with immunosuppression and neuropsychiatric complications. We describe the case of a carcinoid patient with Cushing’s syndrome (CS) and neurocognitive impairment due to ectopic ACTH production who developed sepsis and died because of his family’s decision to withdraw antibiotic treatment. This report is presented to illustrate the importance of advanced-care planning in patients with CS.

Key Words: Cushing’s syndrome, Carcinoid patient, Glucocorticoids, ACTH, Immunosuppression, Neurocognitive impairment, Advanced directives

Introduction

Cushing’s syndrome (CS) is a general term for a cluster of endocrine abnormalities characterized by chronic cortisol overproduction. Characteristic clinical comorbidities include metabolic complications (e.g., visceral obesity, diabetes mellitus, and dyslipidemia), cardiovascular complications (e.g., systemic arterial hypertension, atherosclerosis, and thromboembolism), bone complications (e.g., osteoporosis and osteoarthritis) infective complications, and neuropsychiatric disorders (e.g., major depression, mania, anxiety, and cognitive impairment) [1]. CS may be exogenous and iatrogenic due to corticosteroid administration or endogenous due to excessive ACTH secretion, most commonly from a pituitary adenoma, referred to, somewhat confusingly, as Cushing’s disease, or less commonly from a nonpituitary tumor (ectopic CS) and primary adrenal neoplasms [2]. Several studies link untreated CS to fatal infectious complications [3]. This report describes the case of a 60-year-old carcinoid patient with cognitive impairment due to hypercortisolism from CS who developed bacteremia; his condition deteriorated, and he died after a decision was made to withdraw care.

Case Presentation

A 60-year-old male with metastatic bronchopulmonary neuroendocrine tumor treated on a clinical trial for over 5 months was admitted to the hospital with complaints of fever, agitation, and weakness. His medical history was significant for newly diagnosed CS secondary to ACTH secretion; he had been hospitalized 2 weeks earlier for CS-induced hyperglycemic crisis. On admission, the patient presented with classic cushingoid habitus of facial plethora, moon facies, muscle atrophy, abdominal striae, and truncal obesity. His physical examination was significant for bilateral crackles and agitation consistent with corticosteroid psychosis. The arterial blood gas analysis on room air was pH 7.497, PaCO2 29 mm Hg, PaO2 71 mm Hg, and oxygen saturation 95%.

Laboratory data were significant for hyperglycemia, hypokalemia, and leukocytosis with bandemia. The chest CT scan showed no definite evidence of pulmonary thromboembolism.

As respiratory failure was imminent, he was transferred to the intensive care unit and mechanically ventilated. The highest positive end-expiratory pressure and FiO2 required to maintain oxygenation were 5 cm H2O and 50%, respectively. Cultures were taken from bronchial secretions directly after endotracheal intubation and from urine and blood. The patient was diagnosed with Staphylococcus aureus bacteremia, and based on susceptibility testing, he was started on vancomycin and Zosyn. In addition to antibiotics, the patient received lisinopril for CS-induced hypertension and insulin sliding scale to control hyperglycemia.

Since high circulating levels of glucocorticoids due to ectopic ACTH secretion predispose to infection and impair immune function and clearance of bacteria, the immediate plan was to start him on mifepristone (600 mg daily) as a glucocorticoid receptor antagonist to counteract the immunosuppressive and cognitive effects of the endogenous hypercortisolism. As soon as the patient’s condition improved (which would have been expected given the known reversibility of hypercortisolism), cytoreductive chemotherapy would have been restarted to reduce the paraneoplastic stimulus. However, the patient’s family with medical power of attorney refused consent and withdrew him from the ventilator. The patient died shortly thereafter.

Discussion

Advance directives are written to guarantee autonomy in the event that individual decision-making capacity is lost due to disease severity or treatment [4]. However, as a blanket statement that may contain overly broad (or overly specific) prewritten blocks of text, especially for cancer patients, the content of advance directives may or may not necessarily apply to and/or the patient’s wishes may or may not be correctly interpreted during acute, temporary and potentially reversible conditions that occur during cancer treatment such as infection due to ectopic CS.

Given the potential for cognitive impairment and other acute sequelae such as difficult-to-treat infections from the development of ectopic CS, this case illustrates the importance of revisiting the advance directive when a medical diagnosis associated with temporary cognitive impairment such as CS is made.

Statement of Ethics

The authors have no ethical conflicts to disclose.

Disclosure Statement

The authors have no conflicts of interest to declare.

References

1. Pivonello R, Simeoli C, De Martino MC, Cozzolino A, De Leo M, Iacuaniello D, Pivonello C, et al. Neuropsychiatric disorders in Cushing’s syndrome. Front Neurosci. 2015;9:129. [PMC free article][PubMed]
2. Tsigos C, Chrousos GP. Differential diagnosis and management of Cushing’s syndrome. Annu Rev Med. 1996;47:443–461. [PubMed]
3. Bakker RC, Gallas PR, Romijn JA, Wiersinga WM. Cushing’s syndrome complicated by multiple opportunistic infections. J Endocrinol Invest. 1998;21:329–333. [PubMed]
4. Halpern NA, Pastores SM, Chou JF, Chawla S, Thaler HT. Advance directives in an oncologic intensive care unit: a contemporary analysis of their frequency, type, and impact. J Palliat Med. 2011;14:483–489.[PMC free article] [PubMed]

Articles from Case Reports in Oncology are provided here courtesy of Karger Publishers

Grading system may predict recurrence, progression of pituitary neuroendocrine tumors

The risk for recurrence or progression of pituitary neuroendocrine tumors in adults is significantly associated with age and tumor type, according to findings published in The Journal of Clinical Endocrinology & Metabolism.

Gérald Raverot, MD, PhD, of Hospices Civils de Lyon, Federation d’Endocrinologie du Pole Est in France, and colleagues evaluated 374 adults (194 women) who underwent surgery for a pituitary neuroendocrine tumor (mean age at surgery, 51.9 years) between February 2007 and October 2012 to test the value of a new classification system on prognostic relevance.

Tumors were classified using a grading system based on invasion on MRI, immunocytochemical profile, Ki-67 mitotic index and p53 positivity. Noninvasive tumors were classified as grade 1a, noninvasive but proliferative tumors were grade 1b, invasive tumors were grade 2a, invasive and proliferative tumors were grade 2b and metastatic tumors were grade 3.

Macroadenomas were the most common type of tumor based on MRI classification (82.1%), followed by microadenoma (13.6%) and giant adenoma (4.3%).

Information on grade was available for 365 tumors; grade 1a was the most common (51.2%), followed by grades 2a (32.3%), 2b (8.8%) and 1b (7.7%).

The progression-free survival analysis included 213 participants from the original cohort during a mean follow-up of 3.5 years. A recurrent event occurred in 52 participants, and progression occurred in 37 participants. The risk for recurrence and/or progression was associated with age (P = .035), tumor type (P = .028) and grade (P < .001). The risk for recurrence and/or progression was increased with grade 2b tumors compared with grade 1a tumors (HR = 3.72; 95% CI, 1.9-7.26) regardless of tumor type. Invasion was significantly associated with recurrence in grade 2a tumors (HR = 2.98; 95% CI, 1.89-4.7), whereas proliferation was not significantly associated with prognosis for grade 1b (HR = 1.25; 95% CI, 0.73-2.13).

“This prospective study confirms the usefulness of our previously proposed classification and may now allow clinicians to adapt their therapeutic strategies according to prognosis, but may also be used to stratify patients and evaluate therapeutic efficacy in future clinical trials,” the researchers wrote. “Further progress can be expected, in particular if an improved understanding of molecular abnormalities associated with pituitary tumorigenesis generates better biomarkers.” – by Amber Cox

Disclosures: The researchers report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B4dbd524c-4534-42e3-a1dc-4e3a0d82a0f1%7D/grading-system-may-predict-recurrence-progression-of-pituitary-neuroendocrine-tumors

A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery

Abstract.

Background

Pituitary adenoma is one of the most common intracranial neoplasms, and its primary treatment is endoscopic endonasal transsphenoidal tumorectomy. Postoperative hypokalemia in these patients is a common complication, and is associated with morbidity and mortality. This study aimed to analyze the etiopathology of postoperative hypokalemia in pituitary adenomas after endoscopic transsphenoidal surgery.

Methods and Materials

This retrospective study included 181 pituitary adenomas confirmed by histopathology. Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Repeated measures ANOVA was used to analyze change in serum potassium levels at different time points.

Results

Multiple Logistic regression analysis revealed that only ACTH-pituitary adenoma (OR = 4.92, 95% CI [1.18–20.48], P = 0.029) had a significant association with postoperative hypokalemia. Moreover, the overall mean serum potassium concentration was significantly lower in the ACTH versus the non-ACTH group (3.34 mmol/L vs. 3.79 mmol/L, P = 0.001). Postoperative hypokalemia was predominantly found in patients with ACTH-pituitary adenoma (P = 0.033).

Conclusions

ACTH-pituitary adenomas may be an independent factor related postoperative hypokalemia in patients despite conventional potassium supplementation in the immediate postoperative period.

Cite this as

You L, Li W, Chen T, Tang D, You J, Zhang X. (2017) A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery. PeerJ5:e3337 https://doi.org/10.7717/peerj.3337

Read the entire article at https://peerj.com/articles/3337/
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