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

Posted on July 2, 2017 by MaryO
Published online 2017 Apr 6. doi:  10.1159/000470833
PMCID: PMC5422746
Neil Oronsky,a Bennett Thilagar,b,* Carolyn M. Ray,c Scott Caroen,b Michelle M.C. Lybeck,b Lindsey Ferry,b Ronald A. Voves,b and Bryan Oronskyb
Author information ► Article notes ► Copyright and License information ►

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

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Severe Trauma May Damage The Brain as Well as the Psyche

Posted on October 24, 2016 by MaryO

NOTE: This is only a portion of the article.  Read the entire post at http://www.nytimes.com/1995/08/01/science/severe-trauma-may-damage-the-brain-as-well-as-the-psyche.html?pagewanted=all

Cortisol is a major means the body uses, with adrenaline, to arouse itself so quickly; its action, for example, triggers an increase in blood pressure and mobilizes energy from fat tissue and the liver.

“The dark side of this picture is the neurological effects,” said Dr. Sapolsky. “It’s necessary for survival, but it can be disastrous if you secrete cortisol for months or years on end. We’ve known it could lead to stress-exacerbated diseases like hypertension or adult onset diabetes. But now we’re finding the hippocampus is also damaged by these secretions.”

Studies in animals show that when glucocorticoids are secreted at high levels for several hours or days, there is a detectable effect on memory, though no neuronal death. But with sustained release from repeated stress, “it eventually kills neurons in the hippocampus,” said Dr. Sapolsky. “This has been shown solidly in rats, with the cell biology well understood.”

A parallel effect has long been known among patients with Cushing’s disease, a hormonal condition in which tumors in the adrenal or pituitary glands or corticosteroid drugs used for a prolonged time cause the adrenal glands to secrete high levels of a hormone called ACTHm and of cortisol. Such patients are prone to a range of diseases “in any organ with stress sensitivity,” including diabetes, hypertension and suppression of the immune system, said Dr. Sapolsky.

Cushing’s patients also have pronounced memory problems, especially for facts like where a car was parked. “The hippocampus is essential for transferring such facts from short-term to long-term memory,” said Dr. Sapolsky.

In 1993, researchers at the University of Michigan reported that magnetic resonance imaging had shown an atrophy and shrinkage of the hippocampus in patients with Cushing’s disease; the higher their levels of cortisol, the more shrinkage.

In an apparent paradox, low levels of cortisol in post-trauma victims were found in a separate research report, also in the July issue of The American Journal of Psychiatry. Dr. Rachel Yehuda, a psychologist at Mount Sinai Medical School in New York City, found the lower levels of cortisol in Holocaust survivors who had been in concentration camps 50 years ago and who still had post-traumatic symptoms.

“There are mixed findings on cortisol levels in trauma victims, with some researchers finding very high levels and others finding very low levels,” said Dr. Sapolsky. “Biologically speaking, there may be different kinds of post-traumatic stress.”

In a series of studies, Dr. Yehuda has found that those post-trauma patients who have low cortisol levels also seem to have “a hypersensitivity in cell receptors for cortisol,” she said. To protect itself, the body seems to reset its cortisol levels at a lower point.

The low cortisol levels “seem paradoxical, but both too much and too little can be bad,” said Dr. Yehuda. “There are different kinds of cells in various regions of the hippocampus that react to cortisol. Some atrophy or die if there is too little cortisol, some if there is too much.”

Dr. Yehuda added, “In a brain scan, there’s no way to know exactly which cells have died.”

To be sure that the shrinkage found in the hippocampus of trauma victims is indeed because of the events they suffered through, researchers are now turning to prospective studies, where before-and-after brain images can be made of people who have not yet undergone trauma, but are at high risk, or who have undergone it so recently that cell death has not had time to occur.

Dr. Charney, for example, is planning to take M.R.I. scans of the brains of emergency workers like police officers and firefighters and hopes to do the same with young inner-city children, who are at very high risk of being traumatized over the course of childhood and adolescence. Dr. Pitman, with Dr. Yehuda, plans a similar study of trauma victims in Israel as they are being treated in emergency rooms.

Dr. Yehuda held out some hope for people who have suffered through traumatic events. “It’s not necessarily the case that if you’ve been traumatized your hippocampus is smaller,” she said. She cited research with rats by Dr. Bruce McEwen, a neuroscientist at Rockefeller University, showing that atrophied dendritic extensions to other cells in the hippocampus grew back when the rats were given drugs that blocked stress hormones.

Dr. Sapolsky cited similar results in patients with Cushing’s disease whose cortisol levels returned to normal after tumors were removed. “If the loss of hippocampal volume in trauma victims is due to the atrophy of dendrites rather than to cell death, then it is potentially reversible, or may be so one day,” he said.

NOTE: This is only a portion of the article.  Read the entire post at http://www.nytimes.com/1995/08/01/science/severe-trauma-may-damage-the-brain-as-well-as-the-psyche.html?pagewanted=all

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Who’s at Risk for Cushing’s?

Posted on August 16, 2016 by MaryO

by Kristen Monaco
Contributing Writer, MedPage Today

Researchers have developed a new method to assess specific populations for Cushing’s syndrome, based on results from a multicenter study.

The prospective cohort study evaluated at-risk patients for Cushing’s syndrome to create a novel type of scoring system in order to better predict the development of disease, stated lead author Antonio León-Justel, PhD,of the Seville Institute of Biomedicine in Spain, and colleagues.

Cushing’s syndrome is identified by an excess of cortisol and/or glucocorticoids in the blood, which can result in myriad negative health outcomes, including an increased risk of death and morbidity, according to the study in The Journal of Clinical Endocrinology & Metabolism.

Because Cushing’s syndrome (CS) is complex and difficult to diagnose, there is a necessity for new methods to assess at-risk populations in order to mitigate the rising prevalence of the disorder, the authors noted.

“The diagnosis of CS might pose a considerable challenge even for experienced endocrinologists since there are no pathognomonic symptoms or signs of CS and most of the symptoms and signs of CS are common in the general population including obesity, hypertension, bone loss, and diabetes,” the senior author, Alfonso Leal Cerro, MD, toldMedPage Today via email. “Routine screening for CS remains impractical due to the estimated low prevalence of the disease. However this prevalence might be higher in at-risk populations.”

The authors screened a total of 353 at-risk patients from 13 different hospitals across Spain between January 2012 and July 2013 to measure cortisol variability from saliva samples.

At-risk populations, which the authors note have a higher prevalence of Cushing’s syndrome, included individuals with type 2 diabetes, hypertension, and osteoporosis.

The patients screened in the study were each identified as having at least two of the risk factors for Cushing’s syndrome: high blood pressure (defined as taking two or more drugs and having a systolic blood pressure over 140 mmHg and/or a diastolic blood pressure over 90 mmHg), obesity (body mass index >30), uncontrolled diabetes (HbA1c>7.0%), osteoporosis (T-score ≥ -2.5 SD), and virilization syndrome (hirsutism) with menstrual disorders.

The researchers used clinical and biochemical methods of assessment. Clinical methods included inspection of physical characteristics, such as muscle atrophy, purple striae, and/or facial plethora. Biochemical methods included collecting saliva and blood samples from participants to test cortisol levels using a chemiluminescence method. Each individual was identified as either negative for hypercortisolism (late-night salivary cortisol [LNSC] ≤ 7.5 nmol/L and dexamethasone suppression test [DST] ≤ 50 nmol/L) or positive for hypercortisolism (LNSC > 7.5 nmol/L and DST > 50 nmol/L).

Univariate testing indicated the following significant characteristics to be positively correlated with the development of Cushing’s syndrome:

  • Muscular atrophy (15.2, CI 95% 4.48-51.25);
  • Osteoporosis (4.60, 1.66-12.75); and
  • Dorsocervical fat pad (3.32, 1.48-7.5).

A logistic regression analysis of LNSC values also showed significant correlation between Cushing’s syndrome and the following top three characteristics:

  • Muscular atrophy (9.04, CI 95% 2.36-34.65);
  • Osteoporosis (3.62, CI 95% 1.16-11.35); and
  • Dorsocervical fat pad (3.3, CI 95% 1.52-7.17).

Roberto Salvatori, MD, professor and medical director of the Johns Hopkins Pituitary Center, who was not involved with the study, commented to MedPage Today in an email: “Any endocrinologist would proceed with careful Cushing biochemical evaluation in the presence of the clinical features (muscular atrophy, osteoporosis, and dorsocervical fat pad) that are well known to be associated with hypercortisolism. Of notice, the odds ratio is further increased by an abnormal late-night salivary cortisol, which is already a screening test for hypercortisolism.”

The researchers used their results to develop an equation to determine the level of risk a patient has for developing Cushing’s syndrome, taking into account factors for osteoporosis, dorsocervical fat pads, muscular atrophy, and LNSC levels.

Although the study was able to develop a comprehensive risk model for the syndrome, when tested against the prevalence for Cushing’s syndrome in the subject group, the equation generated a total of 56 false-positive and 25 true-positive results. Overall, the researchers wrote, 83% of patients were accurately classified as belonging to the at-risk population when using the equation.

Because the newly developed equation for identifying at-risk individuals involved factors that are relatively easy to test for, the authors noted that clinical application is broad and cost-effective in a primary care setting.

“We would like to test the scoring system in different clinical settings such as primary care or hypertension clinics,” Leal Cerro said. “Primary care would be a particularly interesting setting since it might significantly decrease the time to diagnosis, something critical to avoid an excessive exposure to glucocorticoid excess and consequent deleterious effects.”

Salvatori said that while the study was a good start at shedding light on some of the unknowns about Cushing’s syndrome, more research is required. “The real question in my mind is when does a non-endocrinologist need to suspect Cushing in a general medicine, orthopedic, or other clinic? When the internal medicine residents ask me about guidelines for ‘who to screen for hypercortisolism in my clinic,’ I am unable to provide an evidence-based answer.”

The study was funded by a grant from Novartis Oncology, Spain.

León-Justel and Leal Cerro disclosed financial relationships with Novartis Oncology, Spain.

  • Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 08.15.2016

From http://www.medpagetoday.com/endocrinology/generalendocrinology/59688

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Cushing’s Syndrome Epidemiology

Posted on August 3, 2016 by MaryO

By Yolanda Smith, BPharm

Cushing’s syndrome is considered to be a rare disorder that results from prolonged exposure to glucocorticoids. However, there are few epidemiological studies to provide adequate data to describe the incidence and prevalence of the condition accurately. Most cases are diagnosed between the ages of 20 and 50, although any individual may be affected at any age.

The presentation of the symptoms of Cushing’s syndrome can vary greatly. In addition, many of the symptoms overlap with those caused by other health conditions, such as metabolic syndrome and polycystic ovary syndrome. This can make the diagnosis of the condition difficult. It is also difficult to establish epidemiological trends in Cushing’s syndrome, because not all cases of the disease are diagnosed. However, it is important that diagnosis is made as soon as possible, because early diagnosis and treatment of the condition are associated with improved morbidity and mortality rates.

Population-based Studies

There are several population-based studies that have reported the incidence and mortality rates of Cushing’s syndrome in certain populations over a discrete period of time.

A study in Denmark followed 166 patients with Cushing’s syndrome for 11 years, finding an incidence of 2 cases per million population per year. Of the 166 patients, 139 had benign disease. There was a mortality rate of 16.5% in the follow-up period of 8 years, with most deaths occurring in the year after the initial diagnosis, often before the initiation of treatment. The causes of death of patients with Cushing’s syndrome in the study included severe infections, cardiac rupture, stroke and suicide.

A study in Spain found 49 cases of Cushing’s syndrome over a period of 18 years, with an incidence of 2.4 cases per million inhabitants per year and a prevalence of 39.1 cases per million. The standard mortality ratio in this study was 3.8, in addition to an increase in morbidity rates.

Incidence

A low incidence of endogenous Cushing’s syndrome was established by the population-based studies outlined above, corresponding to approximately 2 cases per million. Some studies have an estimated incidence as low as 0.7 people per million.

However, the incidence of subclinical Cushing’s syndrome may be underestimated in certain population groups, such as those with osteoporosis, uncontrolled diabetes mellitus or hypertension. For example, of 90 obese patients with uncontrolled diabetes mellitus in one study, three had Cushing’s syndrome. This yielded a prevalence of 3.3%, which is considerably higher than the incidence reported in the population-based studies. However, these findings should be supported by larger studies.

Females are more likely to be affected by Cushing’s syndrome than males, with a risk ratio of approximately 3:1. There does not appear to be a genetic link that involves an ethnic susceptibility to the condition.

Treatment Outcomes

Surgery is the first-line treatment option for most cases of overt disease and remission is achieved in the majority of patients, approximately 65-85%. However, for up to 1 in 5 patients the condition recurs, and the risk does not appear to level off, even after 20 years of follow-up.

The risk of mortality for individuals with Cushing’s syndrome is estimated to be 2-3 times higher than that of the general population, based on epidemiological studies.

Reviewed by Dr Liji Thomas, MD.

From http://www.news-medical.net/health/Cushings-Syndrome-Epidemiology.aspx

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Cushing’s: Update on signs, symptoms and biochemical screening

Posted on October 11, 2015 by MaryO

10.1530/EJE-15-0464

  1. Lynnette Nieman⇑

+Author Affiliations


  1. L Nieman, RBMB, NIH, Bethesda, 20817-1109, United States
  1. Correspondence: Lynnette Nieman, Email: niemanl@mail.nih.gov

Abstract

Endogenous pathologic hypercortisolism, or Cushing’s syndrome, is associated with poor quality of life, morbidity and increased mortality. Early diagnosis may mitigate against this natural history of the disorder.

The clinical presentation of Cushing’s syndrome varies, in part related to the extent and duration of cortisol excess. When hypercortisolism is severe, its signs and symptoms are unmistakable. However, most of the signs and symptoms of Cushing’s syndrome are common in the general population (e.g. hypertension and weight gain) and not all are present in every patient.

In addition to classical features of glucocorticoid excess, such as proximal muscle weakness and wide purple striae, patients may present with the associated co-morbidities that are caused by hypercortisolism. These include cardiovascular disease, thromboembolic disease, psychiatric and cognitive deficits, and infections. As a result, internists and generalists must consider Cushing’s syndrome as a cause, and endocrinologists should search for and treat these co-morbidities.

Recommended tests to screen for Cushing’s syndrome include 1 mg dexamethasone suppression, urine free cortisol and late night salivary cortisol. These may be slightly elevated in patients with physiologic hypercortisolism, which should be excluded, along with exogenous glucocorticoid use. Each screening test has caveats and the choice of tests should be individualized based on each patient’s characteristics and lifestyle.

The objective of this review was to update the readership on the clinical and biochemical features of Cushing’s syndrome that are useful when evaluating patients for this diagnosis.

Read the entire manuscript at http://www.eje-online.org/content/early/2015/07/08/EJE-15-0464.full.pdf+html

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