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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Screening tool accurately predicts Cushing’s syndrome in most at-risk patients

Posted on August 9, 2016 by MaryO

León-Justel A, et al. J Clin Endocrinol Metab. 2016;doi:10.1210/jc.2016-1673.

A scoring system based on clinical signs and a late-night salivary cortisol test accurately predicted Cushing’s syndrome in at-risk patients, with only one missed case, according to recent findings.

In a prospective, multicenter study, Antonio León-Justel, PhD, of the biochemistry department at the Hospital Universitario Virgen del Rocío in Seville, Spain, and colleagues analyzed data from 353 patients treated in endocrinology units in 13 university hospitals in Spain between 2012 and July 2013. All participants had at least two of five features compatible with Cushing’s syndrome, including obesity, hypertension, poorly controlled diabetes,hirsutism with menstrual disorders and osteoporosis; none of the included patients was referred to clinic with the suspicion of Cushing’s syndrome. All patients underwent late-night salivary cortisol and serum cortisol measurements after a low-dose (1 mg) dexamethasone test; those with discordant results were followed until December 2014 (mean follow-up time, 22.2 months).

Within the cohort, 26 (7.4%) patients were diagnosed with Cushing’s syndrome (20 adrenocorticotropic hormone-dependent; six of adrenal origin). In univariate logistic regression analysis, researchers found that muscular atrophy (OR = 15.2), followed by osteoporosis (OR = 4.6), dorsocervical fat pad (OR = 3.32), absence of obesity (OR = 0.21) and absence of type 2 diabetes (OR = 0.26), were associated with Cushing’s syndrome; late-night salivary cortisol values were also related (OR = 1.26). However, after multivariable adjustment, researchers found that muscular atrophy (OR = 9.04; 95% CI, 2.36-34.65), osteoporosis (OR = 3.62; 95% CI, 1.16-11.35) and dorsocervical fat (OR = 3.3; 95% CI, 1.52-7.17) remained as independent variables with Cushing’s syndrome.

“Obesity and type 2 diabetes displayed a negative association with [Cushing’s syndrome],” the researchers wrote. “These results might seem paradoxical a priori, but we want to stress that in our analyzed cohort, the prevalence of obesity and diabetes was exceedingly high (likely reflecting the reasons for referral to endocrinology units).”

In receiver operating characteristic (ROC) analysis, researchers determined that a cutoff value of 9.17 nmol/L for late-night salivary cortisol provided the best results, with an area under the curve of 0.893 (P < .001), a sensitivity of 88.5% and specificity of 83.2%.

Researchers developed a risk-scoring system, determining cutoff values from a ROC curve. The estimated area under the ROC curve was 0.93 (P < .001), with a sensitivity of 96.2% and specificity of 82.9%.

“Selecting this cutoff value of four, 271 of 327 subjects (83%) without [Cushing’s syndrome] were correctly identified, while only 1 of 26 [Cushing’s syndrome] cases was missed,” the researchers wrote. “Our model yielded 56 false positives.

“Although all the assessments were performed by specialists (endocrinologists) in our study, this scoring system could be easily tested in independent cohorts and different settings such as primary care or hypertension clinics,” the researchers wrote. “At the very least, our diagnostic prediction model could be used as a framework for future studies and potential improvements in diagnostic performance.” – by Regina Schaffer

Disclosure: Leon-Justel and another researcher report receiving a research grant from Novartis Oncology, Spain.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B50d3d398-c8fe-41e9-b815-87626bfe8a4b%7D/screening-tool-accurately-predicts-cushings-syndrome-in-most-at-risk-patients

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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 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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Long-term Cognitive Effects of Glucocorticoid Excess in Cushing’s Syndrome

Posted on June 7, 2016 by MaryO

Psychoneuroendocrinology. 2016 Mar;65:26-33. doi: 10.1016/j.psyneuen.2015.11.020. Epub 2015 Nov 30.

Forget H1, Lacroix A2, Bourdeau I2, Cohen H3.

Abstract

CONTEXT AND OBJECTIVE:

We previously found that patients with Cushing’s syndrome (CS) scored lower than controls in several domains of cognitive function and that correction of hypercortisolism is not necessarily correlated with short-term improvement in intellectual performance. Here, we examined the long-term outcome in patients treated for CS by assessing the extent to which the detrimental effects of glucocorticoid (GC) excess on cognition can be reversed three years after corrective surgery.

DESIGN:

A battery of neuropsychological tests, including tests of attention, visuospatial processing, learning and memory, and executive functioning were administered pre-treatment and 12, 24 and 36 months post-treatment.

PATIENTS AND CONTROL SUBJECTS:

We included 18 patients with endogenous CS recruited before surgical treatment and 18 controls matched for age, sex and education.

RESULTS:

CS patients performed worse than controls on tests of attention, executive functioning and nonverbal aspects of memory. Moreover, at 36 months following eucortisolism, executive function performance and, to a lesser extent, attention tasks showed limited change compared to pre-treatment testing.

CONCLUSION:

Chronic hypercortisolism is accompanied by a deleterious impact on aspects of cognitive function. This negative effect on attention, executive performance and nonverbal memory seen in patients with CS suggests a differential effect of excess GCs upon different brain areas and networks. This influence persists years after the return to normal cortisol secretion levels.

Copyright © 2015 Elsevier Ltd. All rights reserved.

KEYWORDS:

Attention; Cognitive functions; Endogenous Cushing’s syndrome; Glucocorticoids; Hypercortisolism; Memory

PMID:
26708069
[PubMed – in process]

From http://www.ncbi.nlm.nih.gov/pubmed/26708069

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