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

Posted on August 13, 2017 by MaryO


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 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11).

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 (3, 5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). 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 (13, 21).

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 (1, 22, 23). Additionally, there is recent evidence of persistent deleterious effects after remission, most notably persistent elevated cardiovascular risk (3, 22). 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 (24, 25). 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 (26, 27, 28).

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 (14, 19) 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) (14, 15, 17, 19). 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 (15, 19, 35, 36). 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 (17, 35, 37). 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

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Study links genetic mutations, Cushing syndrome

Posted on June 6, 2017 by MaryO

Researchers have determined mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.

The National Institutes of Health study findings published in Endocrine-Related Cancer found four of the 181 children and adult patient examined had mutant forms of CABLES1 that do not respond to cortisol.

The determination proved significant because normal functioning CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH).

Researchers at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) joined scientists from other institutions in the United States, France and Canada, in the evaluation.

“The mutations we identified impair the tumor suppressor function in the pituitary gland,” Constantine A. Stratakis, the study’s senior author and director of the NICHD Division of Intramural Research, said. “This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.”

Cushing syndrome symptoms include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety, officials said, adding excess cortisol found in the disorder can result from certain steroid medications or from tumors of the pituitary or adrenal glands.

Researchers maintain that more studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.

 

From https://lifesciencedaily.com/stories/21624-study-links-genetic-mutations-cushing-syndrome/

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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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What a Hoot! Healing Cushing’s Syndrome Naturally

Posted on June 7, 2016 by MaryO

This guy must be nuts!

Healing Cushing’s Syndrome Naturally

by Dr. Paul Haider, Spiritual Teacher and Master Herbalist

Cushing’s Syndrome is the over production of cortisol by the adrenals glands and the resulting obesity, high blood pressure, fatigue, depression, muscle weakness, glucose intolerance, and more… are all part of the syndrome.

But there is hope, here are a few great herbs and other processes that can heal Cushing’s Syndrome naturally.

Read more of how you, too, can “Heal Your Cushing’s here: https://www.linkedin.com/pulse/healing-cushings-syndrome-naturally-dr-paul-haider

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Day 29, Cushing’s Awareness Challenge 2016

Posted on April 29, 2016 by MaryO

People sometimes ask me how I found out I had Cushing’s Disease.  Theoretically, it was easy.  In practice, it was very difficult.

Ladies Home Journal, 1983In 1983 I came across a little article in the Ladies Home Journal which said “If you have these symptoms…”

I found the row with my symptoms and the answer read “…ask your doctor about Cushing’s”.

After that article, I started reading everything I could on Cushing’s, I bought books that mentioned Cushing’s. I asked and asked my doctors for many years and all of them said that I couldn’t have it.  It was too rare.  I was rejected each time.

Due to all my reading at the library, I was sure I had Cushing’s but no one would believe me. My doctors would say that Cushing’s Disease is too rare, that I was making this up and that I couldn’t have it.

In med school, student doctors are told “When you hear hoofbeats, think horses, not zebras“.

According to Wikipedia: “Zebra is a medical slang term for a surprising diagnosis. Although rare diseases are, in general, surprising when they are encountered, other diseases can be surprising in a particular person and time, and so “zebra” is the broader concept.

The term derives from the aphorism “When you hear hoofbeats behind you, don’t expect to see a zebra”, which was coined in a slightly modified form in the late 1940s by Dr. Theodore Woodward, a former professor at the University of Maryland School of Medicine in Baltimore.  Since horses are the most commonly encountered hoofed animal and zebras are very rare, logically you could confidently guess that the animal making the hoofbeats is probably a horse. By 1960, the aphorism was widely known in medical circles.”

So, doctors typically go for the easily diagnosed, common diseases.  Just because something is rare doesn’t mean that no one gets it.  We shouldn’t be dismissed because we’re too hard to diagnose.

When I was finally diagnosed in 1987, 4 years later, it was only because I started bleeding under the skin. My husband made circles around the outside perimeter each hour with a marker so my leg looked like a cut log with rings.

When I went to my Internist the next day he was shocked at the size of the rings. He now thought I had a blood disorder so he sent me to a Hematologist/Oncologist.

Fortunately, that new doctor ran a twenty-four hour urine test and really looked at me and listened to me.  Both he and his partner recognized that I had Cushing’s but, of course, couldn’t do anything further with me.  They packed me off to an endo where the process started again.

My final diagnosis was in October, 1987.  Quite a long time to simply  “…ask your doctor about Cushing’s”.

Looking back, I can see Cushing’s symptoms much earlier than 1983.  But, that ‘s for a different post.

 

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