Cushing’s Syndrome and Skin Problems

Posted on August 22, 2016 by MaryO

By Afsaneh Khetrapal, BSc (Hons)

Cushing’s Syndrome (sometimes called hypercortisolism) is a hormonal disease caused by an abnormally high level of the hormone cortisol in the body. This may arise because of an endogenous or exogenous source of cortisol. Endogenous causes include the elevated production of cortisol by the adrenal glands, while exogenous causes include the excessive use of cortisol or other similar steroid (glucocorticoid) hormones over a prolonged period of time.

The adrenal glands are situated just above each kidney, and form part of the endocrine system. They have numerous functions such as the production of hormones called catecholamines, which includes epinephrine and norepinephrine. Interestingly, the outer layer (cortex) of the adrenal glands has the distinct responsibility of producing cortisol. This hormone is best known for its crucial role in the bodily response to stress.

At physiologically appropriate levels, cortisol is vital in maintaining normal sleep-wake cycles, and acts to increase blood sugar levels. It suppresses the immune system, regulates the effect of insulin on the metabolism of fats, proteins, and carbohydrates, and help with the homeostasis of water in the body.

Exogenous corticosteroids can also lead to Cushing’s syndrome, when they are used as a form of long-term treatment for various medical conditions. In fact, the long-term use of steroid medication is the most common reason for the development of Cushing’s syndrome.

Prednisolone is the most commonly prescribed steroid medicine. It belongs to a class of medicine that is sometimes used to treat conditions such as certain forms of arthritis and cancer. Other uses include the rapid and effective reduction of inflammation in conditions such as asthma and multiple sclerosis (MS), as well as the treatment of autoimmune conditions such as lupus erythematosus, and rheumatoid arthritis.

Overall, Cushing’s syndrome is quite uncommon and affects approximately 1 in 50,000 people. Most of them are adults between the ages of 20 and 50.  Women are 3 times more commonly affected than men. Additionally, patients who are obese, or those who have type 2 diabetes with poorly controlled blood sugar and blood pressure show a greater predisposition to the disorder.

Symptoms of Cushing’s syndrome

There are numerous symptoms associated with Cushing’s syndrome, which range from muscle weakness, hypertension, curvature of the spine (kyphosis), osteoporosis, and depression, to fatigue Specific symptoms which pertain to the skin are as follows:

  • Thinning of the skin and other mucous membranes: the skin becomes dry and bruises easily. Cortisol causes the breakdown of some dermal proteins along with the weakening of small blood vessels. In fact, the skin may become so weak as to develop a shiny, paper-thin quality which allows it to be torn easily.
  • Increased susceptibility of skin to infections
  • Poor wound healing  of bruises, cuts, and scratches
  • Spots appear on the upper body, that is, on the face, chest or shoulders
  • Darkened skin which is seen on the neck
  • Wide, red-purple streaks (at least half an inch wide) called striae which are most common on the sides of the torso, the lower abdomen, thighs, buttocks, arms, and breasts, or in areas of weight gain. The accumulation of fat caused by Cushing’s syndrome stretches the skin which is already thin and weakened due to cortisol action, causing it to hemorrhage and stretch permanently, healing by fibrosis.
  • Acne: this can develop in patients of all ages.
  • Swollen ankles: this is caused by the accumulation of fluid, called edema.
  • Hyperhidrosis (excessive sweating)

Reviewed by Dr Liji Thomas, MD

From http://www.news-medical.net/health/Cushings-Syndrome-and-Skin-Problems.aspx

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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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Experimental Drug Improves Cushing’s Disease

Posted on August 12, 2016 by MaryO

International phase 3 trial is largest study ever of rare endocrine disorder

A new investigational drug significantly reduced urinary cortisol levels and improved symptoms of Cushing’s disease in the largest clinical study of this endocrine disorder ever conducted.

Results of the clinical trial conducted at centers on four continents appear in the March 8 issue of the New England Journal of Medicine and show that treatment with pasireotide cut cortisol secretion an average of 50 percent and returned some patients’ levels to normal.

“Cushing’s disease is a rare disorder, with three to five cases per million people. It can affect all ages and both genders but is most common in otherwise healthy young women,” says Harvard Medical School Professor of Medicine Beverly M.K. Biller of the Massachusetts General Hospital (MGH) Neuroendocrine Unit, senior author of the study.

“Often misdiagnosed, Cushing’s is associated with a broad range of health problems – causing physical changes, metabolic abnormalities, and emotional difficulties – and if not controlled, significantly increases patients’ risk of dying much younger than expected,” Biller says.

Cushing’s disease, one of several conditions that lead to Cushing’s syndrome, is characterized by chronically elevated secretion of the hormone cortisol. The disease is caused by a benign pituitary tumor that oversecretes the hormone ACTH, which in turn induces increased cortisol secretion by the adrenal glands.

Symptoms of Cushing’s syndrome include weight gain, hypertension, mood swings, irregular or absent periods, abnormalities of glucose processing (insulin resistance, glucose intolerance, and type 2 diabetes), and cardiovascular disease. Because those symptoms are associated with many health problems, physicians may not consider the rare possibility of Cushing’s. The diagnosis can be difficult to make and usually requires the expertise of an endocrinologist. Because cortisol levels normally fluctuate during the day, a single blood test is unlikely to identify chronic elevation, and thus the most common diagnostic test measures a patient’s 24-hour urinary output.

First-line treatment for Cushing’s disease is surgical removal of the ACTH-secreting tumor, which leads to remission in 65 to 90 percent of patients. But symptoms return in 10 to 30 percent of those patients, requiring repeat surgery, radiation therapy, or treatment with drugs that interfere with part of the cortisol control system. Until last month, there was no specific FDA-approved medical treatment for Cushing’s syndrome; the newly approved drug mifepristone should benefit some patients, but it does not affect the pituitary source of the condition or reduce cortisol levels.

The current phase 3 trial of pasireotide — the first drug that blocks ACTH secretion by binding to somatostatin receptors on the pituitary tumor — was sponsored by Novartis Pharma. The trial enrolled 162 patients at 62 sites in 18 countries. Nearly 85 percent of participants had either persistent disease that had not responded to surgery or had recurrent disease; the other 15 percent were recently diagnosed but not appropriate candidates for surgery.

Participants were randomly assigned to two groups, one starting at two daily 600-microgram injections of pasireotide and the other receiving 900-microgram doses. Three months into the 12-month trial, participants whose urinary cortisol levels remained more than twice the normal range had their dosage levels increased. During the rest of the trial, dosage could be further increased, if necessary, or reduced if side effects occurred.

At the end of the study period, many patients had a significant decrease in their urinary cortisol levels, with 33 achieving levels within normal range at their original dosage by month six of the trial. Participants whose baseline levels were less than five times the upper limit of normal were more likely to achieve normal levels than those with higher baseline levels, and the average urinary cortisol decrease across all participants was approximately 50 percent. Many Cushing’s disease symptoms decreased, and it became apparent within the first two months whether or not an individual was going to respond to pasireotide.

Transient gastrointestinal discomfort, known to be associated with medications in the same family as pasireotide, was an expected side effect. Another side effect was elevated glucose levels in 73 percent of participants, something not seen to the same extent with other medications in this family. These elevated levels will require close attention, because many Cushing’s patients already have trouble metabolizing glucose. Biller explains, “Those patients who already were diabetic had the greatest increases in blood sugar, and those who were pre-diabetic were more likely to become diabetic than those who began with normal blood sugar. However, elevations were even seen in those who started at normal glucose levels, so this is real and needs to be monitored carefully.”

Additional trials of pasireotide are in the works, and a phase 3 study of a long-acting version of the drug was recently announced. Biller notes that the potential addition of pasireotide to available medical treatments for Cushing’s disease would have a number of advantages. “It’s very important to have medications that work at different parts of the cortisol control system – which is the case for the currently used medications that work at the adrenal gland level; pasireotide, which works at the pituitary gland; and mifepristone, which blocks the action of cortisol at receptors in the body. Having more options that work in different ways is valuable because not all patients respond to one medicine and some may be unable to tolerate a specific drug’s side effects.

“As we have more drugs available to treat Cushing’s,” Biller adds, “I think in the long run we may start using combinations of drugs, which is the approach we use in some patients with acromegaly, another disorder in which a pituitary tumor causes excess hormone secretion. Ultimately, we hope to be able to give lower doses leading to fewer overall side effects, but that remains to be determined by future studies.”

Annamaria Colao, University of Naples, Italy, is the lead author of the report. Additional co-authors are Stephan Petersenn, University of Duisberg-Essen, Germany; John Newell-Price, University of Sheffield, U.K.; James Findling, Medical College of Wisconsin, Milwaukee; Feng Gu, Peking Union Medical College Hospital, Beijing; Mario Maldonado, Ulrike Schoenherr, and David Mills, Novartis Pharma; and Luiz Roberto Salgado, University of São Paulo Medical School, Brazil.

From http://dailyrecords.us/experimental-drug-improves-cushings-disease/

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New Diagnostic Criteria for Subclinical Hypercortisolism using Postsurgical Hypocortisolism

Posted on August 12, 2016 by MaryO

Clin Endocrinol (Oxf). 2016 Jun 24. doi: 10.1111/cen.13145. [Epub ahead of print]

 

Abstract

OBJECTIVE:

There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic-pituitary-adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications.

DESIGN:

Prospective and cross-sectional, observational, multicentre study in Korea.

METHODS:

After exclusion of overt Cushing’s syndrome, adrenal incidentaloma (AI) patients who underwent unilateral adrenalectomy (n = 99) and AI patients (n = 843) were included. Primary outcome was defined as the presence of postsurgical hypocortisolism; secondary outcome was the presence of ≥4 complications (components of the metabolic syndrome and low bone mass). Postsurgical hypocortisolism was determined on the fifth postsurgery day using the ACTH stimulation test.

RESULTS:

Thirty-three of the 99 patients developed postsurgical hypocortisolism. Analysis of the presurgery overnight 1-mg dexamethasone suppression test (1-mg DST) showed that all patients with cortisol levels of >138 nmol/l experienced postsurgical hypocortisolism, whereas those with levels of ≤61 nmol/l did not. The models of (i) 1-mg DST >138 nmol/l or (ii) >61 nmol/l with the presence of one among low levels of ACTH and dehydroepiandrosterone-sulphate had the highest accuracy (89·9%, P < 0·001) and odds ratio [OR 111·62, 95% confidence interval (CI) 21·98-566·74, P < 0·001] for predicting postsurgical hypocortisolism. Finally, patients with the same criteria in the 843 AI patients showed the highest risk for having ≥4 complications (OR 3·51, 95% CI 1·84-6·69, P < 0·001), regardless of gender, age, body mass index and bilaterality.

CONCLUSIONS:

Our proposed model is able to accurately predict subtle cortisol excess and its chronic manifestations in AI patients.

© 2016 John Wiley & Sons Ltd.

PMID:
27341314
DOI:
10.1111/cen.13145

From http://www.ncbi.nlm.nih.gov/pubmed/27341314

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Cushing’s Syndrome Masquerading as Treatment Resistant Depression

Posted on July 4, 2016 by MaryO
Indian J Psychol Med. 2016 May-Jun; 38(3): 246–248.
PMCID: PMC4904762
B. N. Anil Kumar and Sandeep Grover1
Author information ► Copyright and License information ►

Abstract

Treatment resistant depression (TRD) is a common clinical occurrence among patients treated for major depressive disorder. A significant proportion of patients remain significantly depressed in spite of aggressive pharmacological and psychotherapeutic approaches. Management of patient with treatment resistant depression requires thorough evaluation for physical causes. We report a case of recurrent depressive disorder, who presented with severe depressive episode without psychotic symptoms, not responding to multiple adequate trials of antidepressants, who on investigation was found to have Cushing’s syndrome and responded well to Ketoconazole.

Keywords: Antiglucocorticoid drugs, Cushing’s syndrome, treatment-resistant depression

INTRODUCTION

The main aim of management of depression is remission of the episode. However, in a proportion of the patients with major depression, despite the use of adequate antidepressant doses for the adequate duration, clinical remission is not achieved. Although there is no consensus, but in general it is accepted that those patients with major depression who do not respond to 2-3 adequate trials of antidepressants are considered to have treatment-resistant depression (TRD).[1] Some of the authors[2] have suggested staging for TRD and based on the level of nonresponse the patient is allocated to different stages of TRD. The prevalence of TRD varies depending on the stage.[1] It is suggested that whenever a patient present’s with TRD, a thorough evaluation needs to be done to evaluate the underlying organic and psychosocial causes.[1] We here, report a case of recurrent depressive disorder, current episode severe depressive episode without psychotic symptoms, who did not respond to adequate trials of antidepressants and showed minimal response to electroconvulsive therapy (ECT). In view of the lack of remission, on investigation she was found to have adrenal adenoma and raised cortisol levels. She was managed with ketoconazole 400 mg/day along with the continuation of antidepressants with which she achieved remission.

CASE REPORT

Mrs. A, 40-year-old, known case of recurrent depressive disorder, with first episode occurring at the age of 36 years, with two episodes in the past which responded to antidepressant treatment, presented with severe depressive episode without psychotic symptoms of 18 months duration. For the current episode, the onset was insidious with the evolution of symptoms over the period of 1-month, without any precipitating event and the course was continuous for the current episode. Her clinical presentation was characterized by persistent sadness of mood with morning worsening, poor interaction, anhedonia, lethargy, psychomotor retardation, sleep disturbance in the form of difficulty in falling asleep with frequent midnight awakenings, reduced appetite associated with weight loss of 3 kg, reduced libido, ideas of guilt, suicidal ideations, suicidal planning with one unsuccessful attempt and off and on anxiety symptoms. Her treatment history revealed that during the current episode she was treated with tablet paroxetine 12.5-37.5 mg/day for 4 months, tablet mirtazapine 15-30 mg/day for 3 months, tablet imipramine up to 175 mg/day for 5 months, C. venlafaxine up to 300 mg/day for 2 months with no response. Later she was treated with C. venlafaxine 300 mg/day along with thyroxine 75 µg/day (for 2 months) and C. venlafaxine 300 mg/day and lithium 600 mg/day for a period of 2 months but with minimal improvement. Her compliance with the medication throughout was satisfactory.

Her general physical examination and systemic examination were normal. On mental status examination, she had sadness of mood, psychomotor retardation, ideas of hopelessness, worthlessness, guilt, and suicidal ideas. Investigations in the form of hemogram, liver function test, renal function test, serum electrolytes, thyroid function test, serum vitamin B12 levels were did not reveal any abnormality. Her magnetic resonance imaging (MRI) scan of the brain did not show any abnormality. Her psychosocial history did not reveal any evidence of chronic stressors and her family was very supportive. There was no history suggestive of mania, psychotic symptoms, alcohol or drug abuse, seizure, head injury, and cognitive decline. Her Hamilton Depression Rating scale (HDRS) score was 35.

She was continued on C. venlafaxine 300 mg/day along with tablet lithium carbonate 300 mg/day (with serum levels in the therapeutic range). In addition, due to lack of response to adequate doses of antidepressants she was treated with 14 sessions of modified ECT over the period of 6 weeks with minimal improvement (HDRS score reduced to 32). In view of the lack of response to ECT, further investigations were done for Cushing’s syndrome although her physical examination was not suggestive of the same. Workup for Cushing’s syndrome revealed raised plasma cortisol level (722.7 nmol/L [normal range 193-634 nmol/L]), dexamethasone nonsuppression and reduced plasma adreno corticotrophin hormone. MRI scan of the abdomen revealed small homogenous, well-defined lesion measuring 2 cm in the adrenal cortex with clear margins suggestive of an adrenal adenoma. She was advised surgical intervention for the same. However, she was reluctant for the same. As a result, she was started on tablet ketoconazole 200 mg/day and increased to 400 mg/day over next 15 days along with the continuation of C. venlafaxine 300 mg/day. Patient improvement was monitored clinically and using HAM-D score. Over a period of next 4 weeks, the patient showed significant improvement in her depressive symptoms with no associated side effects. Her HDRS score reduced from 32 to 5. After remission she was clinically monitored. She has been maintaining well on tablet ketoconazole 400 mg/day and of C. venlafaxine 225 mg/day for the last 4 years. Her adrenal mass has been monitored with no increase in the size of the tumor.

DISCUSSION

According to the staging of TRD by Thase and Rush,[2] the index case can be considered as stage-5 TRD, that is, patient who has not responded to antidepressants of two different classes, tricyclic antidepressants and ECT. In addition, the patient had also not responded to augmentation with thyroxine and lithium. It is suggested that whenever a patient presents with TRD, first there is a need to evaluate the patient for pseudo-resistance. The factors that contribute to pseudo-resistance include poor compliance, inadequate dosing, and discontinuation of antidepressant before adequate duration.[3] The history of the index case did not reveal the same. In view of the stage-5 nonresponse, she was empirically evaluated for Cushing’s syndrome and was found to have positive evidence for the same. Addition of ketoconazole led to remission of the episode.

Due to the role of stress and involvement of cortisol in understanding the etiopathogenesis of depression, researchers have used antiglucocorticoid drugs such as metyrapone, aminoglutethimide, ketoconazole, and Mifepristone in the management of TRD. In a review, which included 11 studies, authors reported that 67-77% of the patients show at least a partial antidepressant response and largest two series documenting response rates of 70-73%.[4]

Our case highlights the fact that while dealing with patients with TRD, psychiatrists should look into all possible medical causes for depression. Further, our case suggests that antiglucocorticoid medications can be considered in patients with TRD who do not respond to conventional treatments.

Footnotes

Source of Support: Nil

Conflict of Interest: None.

REFERENCES

1. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(Suppl 8):17–25. [PubMed]
2. Thase ME, Rush AJ. When at first you don’t succeed: Sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(Suppl 13):23–9. [PubMed]
3. Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry. 2006;67(Suppl 6):16–22. [PubMed]
4. Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosom Med.1999;61:698–711. [PubMed]
Articles from Indian Journal of Psychological Medicine are provided here courtesy of Medknow Publications
From http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904762/

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