Mild Cases of Cushing’s Syndrome Present Diagnostic Challenges

Posted on August 16, 2017 by MaryO

By Tori Rodriguez, MA, LPC

 

In the early 20th century, the term “pluriglandular syndrome” was coined by Harvey Cushing to describe the disorder that results from chronic tissue exposure to excessive levels of glucocorticoids.1 Now called Cushing’s syndrome, the condition affects an estimated 10-15 million people annually, most often women and individuals between the ages of 20 and 50 years.2 Risk factors and common comorbidities include hypertension, obesity, osteoporosis, uncontrolled diabetes, depression, and anxiety.3

Presentation

The clinical presentation of the disorder is heterogenous and varies by sex, age, and disease severity. Common signs and symptoms include central adiposity, roundness of the face or extra fat around the neck, thin skin, impaired short-term memory and concentration, irritability, hirsutism in women, fatigue, and menstrual irregularity.4 Because each of these features may be observed in a wide range of other conditions, it may be difficult to diagnose cases that are not severe.

“It can be challenging to differentiate the milder forms from pseudo-Cushing’s states,” which are characterized by altered cortisol production and many of the same clinical features as Cushing’s syndrome, according to Roberto Salvatori, MD, the medical director of the Johns Hopkins Pituitary Center, Baltimore, Maryland. These may include alcoholism, obesity, eating disorders, and depression. “Because Cushing’s can cause depression, for example, it is sometimes difficult to determine which came first,” he says. In these states, however, hypercortisolism is believed to be driven by increased secretion of hypothalamic corticotropin-releasing hormone, which is suppressed in Cushing’s syndrome.5

Causes and Diagnosis

If Cushing’s syndrome is suspected on the basis of the patient’s physical appearance, the diagnostic workup should include a thorough medical history, physical exam, and 1 or more of the following tests to establish hypercortisolism: the 24-hour urinary cortisol test, the low-dose dexamethasone suppression test, or the late-night salivary cortisol test. “We sometimes use 2 or 3 of these tests since 1 may not accurately reflect cortisol production in a particular patient,” Dr Salvatori notes. The next step is to determine the source of the hypercortisolism, which may involve the high-dose dexamethasone suppression test, magnetic resonance imaging, or petrosal sinus sampling.2

Medication is the most common cause of Cushing’s syndrome. These iatrogenic or exogenous cases typically result from corticosteroids administered for conditions such as asthma, allergies, and autoimmune disorders.6 More rarely, the disorder can be caused by the use of medroxyprogesterone. In these cases, corticosteroids should be reduced or discontinued under medical care, if possible.

Endogenous Cushing’s syndrome results from the presence of benign or malignant tumors on the adrenal or pituitary glands or elsewhere in the body. These tumors can interfere with the adrenal glands’ production of cortisol that is usually prompted by the adrenocorticotropic hormone (ACTH) released by the pituitary gland.6 There are 3 different mechanisms by which the process can occur.

  • Pituitary adenomas, which account for approximately 70% of endogenous cases of Cushing’s syndrome, secrete ACTH and stimulate additional cortisol production. Because of the large proportion of cases this condition represents, it is specifically referred to as Cushing’s disease. It is more common in women than men (with a ratio of 3 to 4:1), although in pediatric patients, it occurs more frequently in boys vs girls.5
  • Adrenal tumors (adenomas, malignant tumors, or micronodular hyperplasia) produce cortisol in their own tissue in addition to the amount produced by the adrenal glands. These tumors, which cause approximately 15% of endogenous Cushing’s syndrome cases, are more common in children vs adults and in women vs men.
  • Benign or malignant tumors elsewhere in the body, most often the lungs, thyroid, thymus, and pancreas, secrete ACTH and trigger the excessive release of cortisol. An estimated 15% of endogenous cases are attributed to these types of tumors.

Treatment

Surgery is the first-line treatment for Cushing’s syndrome. “We first want to try to figure out the cause of the disorder,” Dr Salvatori says. “Ideally, treatment involves surgery to remove the tumor that is causing it.”

When surgery is unsuccessful, contraindicated, or delayed, other treatment options include radiation or medications that inhibit cortisol, modulate the release of ACTH, or inhibit steroidogenesis.5 Bilateral adrenalectomy may be indicated for patients who do not respond to medication or other surgery.

If surgical resection of the tumor is successful, then “all of the comorbidities reverse, but if it is unsuccessful or must be delayed, you would treat each comorbidity” with the appropriate medication; for example, antihypertensives for high blood pressure and antidiabetic medications for diabetes, Dr Salvatori advises. In severe cases, prophylactic antibiotics may be indicated for the prevention of severe infections such as pneumonia.

It is also important to inquire about and address psychiatric symptoms related to Cushing’s syndrome, even in patients who are in remission. It has been proposed that the chronic hypercortisolism and dysfunction of the HPA axis may “lead to structural and functional changes in the central nervous system, developing brain atrophy, particularly in the hippocampus, which may determine the high prevalence of psychiatric disorders, such as affective and anxiety disorders or cognitive dysfunctions,” according to a recently published paper on the topic.7 Patients should be screened with self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale, and management of psychiatric symptoms may include patient education, psychotropic medications, and referral to a mental health professional.

Future Directions

Several trials are currently planned or underway, including a phase 2 randomized, double-blind, placebo-controlled study of an oral medication called ATR-101 by Millendo Therapeutics, Inc. (ClinicalTrials.gov identifier: NCT03053271). In addition to the need for novel medical therapies, refined imaging techniques could improve surgical success rates in patients with Cushing’s disease in particular, according to Dr Salvatori. “A significant portion of these patients have tumors too small to be detected by MRI, and the development of more sensitive MRI could improve detection and provide a surgical target” for neurosurgeons treating the patients, he says.

Summary

Milder cases of Cushing’s syndrome present diagnostic challenges are a result overlapping features with various other conditions. Diagnosis may require careful observation as well as biochemical and imaging tests.

RELATED ARTICLES

References

  1. Loriaux DL. Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med. 2017;376:1451-1459. doi:10.1056/NEJMra1505550
  2. American Association of Neurological Surgeons. Cushing’s syndrome/disease. http://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Cushings-Disease. Accessed August 1, 2017.
  3. León-Justel A, Madrazo-Atutxa A, Alvarez-Rios AI, et al. A probabilistic model for cushing’s syndrome screening in at-risk populations: a prospective multicenter study. J Clin Endocrinol Metab. 2016;101:3747-3754. doi:10.1210/jc.2016-1673
  4. The Pituitary Society. Cushing’s syndrome and disease–symptoms. https://pituitarysociety.org/patient-education/pituitary-disorders/cushings/symptoms-of-cushings-disease-and-cushings-syndrome. Accessed August 1, 2017.
  5. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281-293. doi:10.2147/CLEP.S44336
  6. National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development. What causes Cushing’s syndrome?https://www.nichd.nih.gov/health/topics/cushing/conditioninfo/pages/causes.aspx. Accessed August 1, 2017.
  7. Santos A, Resmini E, Pascual JC, Crespo I, Webb SM. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs. 2017;77:829-842. doi:10.1007/s40265-017-0735-z

From http://www.endocrinologyadvisor.com/adrenal/cushings-syndrome-diagnosis-treatment/article/682302/

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Cataloging Cushing’s Patients

Posted on June 3, 2017 by MaryO

The Cushing/Whitney Medical Library is pleased to announce the completion of a grant funded to catalog 2,600 glass plate negatives from the Cushing Brain Tumor Registry.  The grant proposal, “Rethinking Early Neurosurgery: The Harvey Cushing Collection,” was funded through a National Network of Libraries of Medicine-New England Region Knowledge/Data Management Award.  From mid-February through April 30th 2017,  a team of graduate and undergraduate students carefully inputted information on over 3,000 glass plate negatives into the Cushing Center database, exceeding the estimated amount in the grant. The negatives depict Dr. Harvey Cushing’s patients, including histology.

Harvey Cushing, the pioneer and father of neurosurgery, was born on April 8, 1869 in Cleveland, Ohio. He graduated from Yale University in 1891, studied medicine at Harvard Medical School and received his medical degree in 1895. In 1896, he moved to Johns Hopkins Hospital where he trained to become a surgeon under the watchful eye of William S. Halstead, the father of American surgery. By 1899 Cushing became interested in surgery of the nervous system and began his career in neurosurgery. During his tenure at Johns Hopkins, there were countless discoveries in the field of neuroscience.

In 1913, Cushing relocated to Harvard as the surgeon-in-chief at the new Peter Bent Brigham Hospital. Cushing continued to operate on several hundred patients a year with remarkable results.  In addition he was relentless in his recording of patient histories and continued his careful attention to the details and documentation of each surgery.

In 1932 Harvey Cushing retired and in 1933 he agreed to join the staff at Yale University, his alma mater, as the Sterling Professor of Medicine in Neurology.  Cushing died in 1939.

The negatives are undergoing rehousing and digitization, and will be made available for research through the Cushing Center database, which brings multiple parts of Harvey Cushing’s work together in one place.  The database, still in development, will allow researchers to explore Cushing’s medical work and patients.  Please contact Terry Dagradi, Cushing Center Coordinator, for details.

 

From http://library.medicine.yale.edu/blog/cushing-center/cataloging-cushings-patients

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Differences Between Cushing’s Syndrome and Cushing’s Disease

Posted on August 28, 2013 by MaryO

What’s the difference between Cushing’s Disease and Cushing’s Syndrome?

disease-syndrome

Cushing’s syndrome is a hormonal disorder

Cortisol is a normal hormone produced in the outer portion of the adrenal glands. When functioning normally, cortisol helps the body respond to stress and change. It mobilizes nutrients, modifies the body’s response to inflammation, stimulates the liver to raise blood sugar, and helps control the amount of water in the body. Cortisol production is regulated by the adrenocorticotrophic hormone (ACTH), produced in the pituitary gland. Spontaneous overproduction of cortisol in the adrenals is divided into two groups – those attributed to an excess of ACTH and those that are independent of ACTH.

Cushing’s syndrome is the term used to describe a group of symptoms that occur when a persons’ cortisol levels are too high (known as hypercortisolism) for too long. The majority of people have Cushing’s syndrome because they are regularly taking certain medicine(s) that continually add too much cortisol to the body. Doctors call this an “exogenous” (outside the body) cause of Cushing’s syndrome. Other people have Cushing’s syndrome because something is causing the adrenal gland(s) to overproduce cortisol. Doctors call this an “endogenous” (inside the body) cause of Cushing’s syndrome.

Cushings-causes.png

Cushing’s disease is a form of Cushing’s syndrome

Cushing’s disease is the most common form of endogenous Cushing’s syndrome. It is caused by a tumor in the pituitary gland that secretes excessive amounts of a hormone called Adrenocorticotropic hormone, or ACTH. Fortunately, this type of tumor is typically benign. Unlike a cancerous (malignant) tumor, a benign tumor stays in its original location and will not spread. After you are diagnosed with Cushing’s syndrome, it is important that your doctor continues the diagnostic process to determine the cause of hypercortisolism.

From the message boards It is not only a tumor that causes Cushings Disease—many of us have the rarer form of this rare disease which is Pituitary Hyperplasia. It also causes CD and may be nodular (shown on MRI s a tumor) or dispersed (meaning spread throughout the gland).

How a pituitary tumor causes Cushing’s disease

Pituitary.jpg

ACTH is a hormone produced in your pituitary gland. ACTH travels to your adrenal glands and signals them to produce cortisol.

Pituitary adenomas are benign tumors of the pituitary gland which secrete increased amounts of ACTH, causing excessive cortisol production. Most patients have a single adenoma. First described in 1912 by neurosurgeon Harvey Cushing in his book The Pituitary Body and its Disorders, Cushing’s disease is the most common cause of spontaneous Cushing’s syndrome, accounting for 60 to 70 percent of cases.

If a person has Cushing’s disease, it means that a group of abnormal cells has built up in the pituitary gland to form an ACTH-producing pituitary tumor. These abnormal cells produce ACTH, just as normal pituitary gland cells do—only far too much. The excess ACTH travels to adrenal glands. The adrenal glands are then bombarded with signals to produce more and more cortisol. As a result, the adrenal glands continuously secrete too much cortisol.

Ectopic ACTH Syndrome

Some benign or malignant (cancerous) tumors that arise outside the pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Lung tumors cause more than 50 percent of these cases. Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.

Adrenal Tumors

Adrenal glands.jpg

An abnormality of the adrenal glands such as an adrenal tumor may cause Cushing’s syndrome. Most of these cases involve non-cancerous tumors called adrenal adenomas, which release excess cortisol into the blood.

Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing’s syndrome. Cancer cells secrete excess levels of several adrenal cortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas often cause very high hormone levels and rapid onset of symptoms.

Familial Cushing’s syndrome

Most cases of Cushing’s syndrome are not genetic. However, some individuals may develop Cushing’s syndrome due to an inherited tendency to develop tumors of one or more endocrine glands. In Primary Pigmented Micronodular Adrenal Disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. In Multiple Endocrine Neoplasia Type I (MEN I), hormone secreting tumors of the parathyroid glands, pancreas and pituitary occur. Cushing’s syndrome in MEN I may be due to pituitary, ectopic or adrenal tumors.

Risk factors

Obesity, type 2 diabetes, poorly controlled blood glucose (blood sugar levels), and high blood pressure may increase the risk of developing this disorder.

Adapted from http://www.cushiewiki.com/index.php?title=Cushing%27s_Disease_or_Syndrome

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Improved Quality of Life After Bilateral Laparoscopic Adrenalectomy for Cushing’s Disease

Posted on August 11, 2013 by MaryO
Ann Surg. 2007 May; 245(5): 790–794.
A 10-Year Experience
Sarah K. Thompson, MD,* Amanda V. Hayman, MD, MPH,* William H. Ludlam, MD, PhD,† Clifford W. Deveney, MD,* D Lynn Loriaux, MD, PhD,† and Brett C. Sheppard, MD*

Objective:

To determine long-term quality of life after bilateral adrenalectomy for persistent Cushing’s disease after transsphenoidal pituitary tumor resection.

Summary Background Data:

Bilateral adrenalectomy for symptomatic relief of persistent hypercortisolism appears to be an effective treatment option. However, few studies have examined long-term outcomes in this patient population.

Methods:

Retrospective review of 39 patients treated by bilateral laparoscopic adrenalectomy for Cushing’s disease from 1994 to 2004. Patients completed a follow-up phone survey, including our Cushing-specific questionnaire and the SF-12v2 health survey. Patients then refrained from taking their steroid replacement for 24 hours, and serum cortisol and ACTH levels were measured.

Results:

Three patients died at 12, 19, and 50 months following surgery from causes unrelated to adrenalectomy. The remaining 36 patients all responded to the study questionnaire (100% response rate). Patients were between 3 months and 10 years post-adrenalectomy. We had zero operative mortalities and a 10.3% morbidity rate. Our incidence of Nelson’s syndrome requiring clinical intervention was 8.3%; 89% of patients reported an improvement in their Cushing-related symptoms, and 91.7% would undergo the same treatment again. Twenty of 36 (55%) and 29 of 36 (81%) patients fell within the top two thirds of the national average for physical and mental composite scores, respectively, on the SF-12v2 survey. An undetectable serum cortisol level was found in 79.4% of patients.

Conclusions:

Laparoscopic bilateral adrenalectomy for symptomatic Cushing’s disease is a safe and effective treatment option. The majority of patients experience considerable improvement in their Cushing’s disease symptoms, and their quality of life equals that of patients initially cured by transsphenoidal pituitary tumor resection.

harvey-cushing-memorial

Harvey Cushing first described Cushing’s disease (hypercortisolism caused by an ACTH-secreting pituitary adenoma) in 1912 in his book entitled: The Pituitary Body and its Disorders. Endogenous glucocorticoid excess causes devastating sequelae in the patient, including marked central obesity, facial fullness, proximal muscle weakness, hypertension, diabetes, hypogonadism, osteoporosis, mood disorders, and cognitive impairment.1–4 Transsphenoidal pituitary tumor resection is without dispute the best first line treatment option for these patients. Unfortunately, 10% to 30% of patients will fail to achieve long-term remission of their Cushing’s disease.5 Four treatment options exist for these patients: 1) repeat transsphenoidal resection, 2) medical therapy, 3) radiation therapy, and 4) bilateral laparoscopic adrenalectomy. Optimum treatment or sequence of different treatments has not yet been established in the literature and often presents a considerable challenge to both the patient and the physician.5

Few studies examine long-term outcomes, including quality of life, in patients requiring additional therapy for persistent Cushing’s disease.6,7 At our institution, patients who fail repeated transsphenoidal adenomectomy are offered bilateral laparoscopic adrenalectomy in the hopes of minimizing the adverse effects caused by chronic hypercortisolism.

The purpose of this study was to determine the safety, efficacy, and long-term outcomes in patients who underwent bilateral laparoscopic adrenalectomy for persistent Cushing’s disease. We assessed all patients for biochemical cure of their Cushing’s disease and evaluated their quality of life with both a general and a Cushing-specific questionnaire.

METHODS

Selection of Patients and Variables

After approval from our Institutional Review Board, all patients who underwent a bilateral laparoscopic adrenalectomy for persistent Cushing’s disease were identified from Oregon Health & Science University (OHSU)’s centralized administrative hospital discharge database. As the first laparoscopic adrenalectomy was reported in 1992 by Gagner et al,8 our first patient dates back to November 1994. OHSU is an ideal setting for a study of this nature as there are large neuroendocrine and neurosurgical units subspecializing in Cushing’s disease management. Therefore, patients in this study were accrued from direct referral from these 2 units, and include patients from adjacent and remote states as well as from Oregon. Inclusion criteria included: confirmed diagnosis of Cushing’s disease, minimum of 3 months follow-up, and bilateral laparoscopic adrenalectomy (BLA) done at OHSU. Our surgical technique has been previously reported6 and is the standard transperitoneal approach in lateral decubitus position. Medical records were reviewed to obtain patient demographics, operative reports, pathologic data, and postoperative events.

A total of 39 patients qualified for our study. Their characteristics at study entry are listed in Table 1. The majority of patients were female (34 of 39), and mean age at time of BLA was 41.5 years. Our follow-up ranged from 3 months to 10 years, with a mean follow-up of 3.6 years following BLA. Three patients died at 12, 19, and 50 months after BLA from cardiac failure (1), pneumonia (1), and stroke (1) as reported by Hawn et al.6 These patients were more than 65 years of age at the time of BLA, and their deaths occurred well outside of the perioperative time period. Patients with Cushing’s disease have a high prevalence of atherosclerosis and maintain increased cardiovascular risk even 5 years after cure.2–4

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TABLE 1. Patient Characteristics

The remaining 36 patients all responded to our phone questionnaire (100% response rate). We achieved a 100% response rate by contacting patient’s primary physician, their endocrinologist, and/or their next-of-kin contact (in case of emergency) if a patient was not available at their listed phone number. Thirty-five of 36 patients complied with biochemical testing (97.2% of available study sample). All patients had undergone at least one transsphenoidal pituitary tumor resection, with the mean number of resections calculated at 1.5. Most patients had a time interval of at least 2 years between their last pituitary tumor resection and BLA. Four patients had had failed pituitary irradiation (10.3%).

Study Protocol

Once consented, patients were submitted to a two-step study:

Clinical Study

Patients were asked to complete a two-page phone questionnaire by an independent investigator (A.V.H.) that identified patient’s preoperative and postoperative body mass index (BMI), comorbidities, preoperative and postoperative Cushing’s disease symptoms, and satisfaction with surgery. Cushing’s disease-specific symptoms were subcategorized into 4 categories: physical appearance (9 items), hematologic/immunologic (3 items), comorbidities (3 items), and neuropsychiatric (10 items) (questionnaire available upon request). Patients were asked to describe their symptoms both preoperatively and currently on a linear scale from 1 point (no symptom) to 5 points (extreme symptom). We then calculated the increase or decrease in number of points from preoperatively to the present time. This was reported as a mean increase or decrease in the overall number of points for each category of symptoms. The SF-12v2 questionnaire (QualityMetric Inc, Lincoln, NE) was also administered during the same interview.

Biochemical Study

Patients were instructed to cease their steroid replacement for 24 hours, and then have a morning serum cortisol level drawn to confirm biochemical cure. A serum cortisol level less than 1 μg/dL was considered a “cure.” Any patient who had a level over 1 μg/dL was asked to change their steroid replacement regimen to dexamethasone (0.5 mg orally once a day) and to undergo repeat cortisol level testing. If their serum cortisol levels were still detectable (>1 μg/dL) after continuing on dexamethasone replacement for 3 days, the patients were deemed to have endogenous cortisol production.

Statistical Analysis

SPSS for Windows, version 11.0 (SPSS Inc., Chicago, IL) was used to perform data analysis. Data were expressed as mean (range) or mean ± SD as appropriate. Results from the SF12v2 health survey were compared with published values for the U.S. population using t tests. Postoperative variables associated with an elevated cortisol level were evaluated by bivariate logistic regression.

RESULTS

Surgical outcomes are listed in Table 2. We had no surgical mortalities, and 4 of 39 (10.3%) patients had significant complications, including urosepsis, distal pancreatitis, and 2 conversions to an open procedure. One patient was converted for bleeding from a splenic injury, and the second patient was converted to an open procedure for hepatomegaly and inability to visualize the adrenal vein safely. One patient had a minor vena caval injury requiring only pressure to control. Mean operating time was 273 minutes (excluding 35 minutes of repositioning time), and estimated blood loss was less than 100 mL for 25 of 39 (75.8%) patients. Mean length of stay was 4.2 days. Twenty-seven of 39 (69%) adrenal glands showed diffuse or nodular hyperplasia on pathology, while 9 of 39 (25%) adrenal glands were hypertrophic only. Three adrenal glands (8.3%) were normal on pathology. More than 50% of patients had never experienced an adrenal crisis. Approximately 20% had had one adrenal crisis, and the rest had had more than one episode of cortisol insufficiency.

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TABLE 2. Surgical Outcomes

Nelson syndrome is characterized by: 1) growing residual pituitary adenoma, 2) ACTH concentration >300 mg/dL, and 3) hyperpigmentation of the skin following bilateral adrenalectomy.9,10 Twenty-six of 35 patients (74.3%) had a serum ACTH level less than 300 pg/mL and 9/35 patients (25.7%) had an elevated ACTH level (Table 3). Three of 35 patients (8.6%) had MRI evidence of growing residual pituitary adenoma, and 4 of 36 patients (11.1%) complained of significant skin darkening (and an additional 7 of 36 patients, 19.4%, noted mild skin darkening). In our patient population, 3 of 36 (8.3%) required further pituitary surgery or irradiation for some or all of these components of Nelson syndrome.

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TABLE 3. Nelson’s Syndrome

Postoperative Cushing’s disease symptom resolution postadrenalectomy is listed in Table 4. Thirty-three of 36 patients (92%) experienced weight loss following BLA, with a mean decrease in BMI from 35 to 29.6. The highest mean points improvement in Cushing symptoms was reported for physical appearance and neuropsychiatric complaints, 11.1 and 9.8 points, respectively. Patients also reported some improvement in their hematologic/immunologic complications and systemic comorbidities, 2.8 and 3.1 points, respectively. Twenty-eight of 36 patients (78%) reported a moderate or significant improvement in their symptoms, while 4 of 36 (11.1%) experienced only mild improvement, and 4 of 36 (11.1%) had no improvement or were worse.

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TABLE 4. Postoperative Symptom Resolution

Thirty-one of 36 patients (86.1%) were either satisfied or very satisfied with their BLA (Table 5). Four patients (11.1%) were dissatisfied or very dissatisfied with BLA. An overwhelming 33 of 36 patients (91.7%) said they would undergo the same treatment again if needed. The mean Physical Composite Score for the SF-12v2 was 36 (range, 16–60) compared with 48 for U.S. women 45 to 54 years of age. The mean Mental Composite Score was 45 (range, 14–64) compared with 49 for U.S. women 45 to 54 years of age. Six of 36 patients (16.7%) were above the 50th percentile for U.S. population in physical categories, while 16 of 36 patients (44.4%) were above the 50th percentile in mental categories. Twenty of 36 (56%) and 29 of 36 (81%) patients fell within the top two thirds of the national average for physical and mental composite scores, respectively. By comparison with another chronic disease, namely diabetes, 23 of 36 (64%) and 28 of 36 (78%) of the BLA patients fell within the top two thirds of the diabetic patient average for physical and mental composite scores, respectively.

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TABLE 5. Postoperative Quality of Life

Postoperative biochemical results are listed in Table 6. Twenty-seven of 34 patients (79.4%) had no detectable endogenous cortisol after ceasing exogenous steroids for 24 hours. Seven of 34 patients (20.6%) were confirmed to have endogenous cortisol production with a detectable serum cortisol level after both cessation of steroids for 24 hours and after 3 days of dexamethasone.

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TABLE 6. Postoperative Biochemical Outcomes

DISCUSSION

The main objective of this study was to evaluate quality of life (QOL) after bilateral laparoscopic adrenalectomy for persistent Cushing’s disease. Thirty-nine patients have had this therapy for chronic hypercortisolism over the past 10 years at OHSU and, of those patients still alive, we had a 100% response rate. To our knowledge, this is the largest series of long-term follow-up of patients with persistent Cushing’s disease treated by BLA. The degree of willingness of this patient group to assist the medical community in studying this disease likely reflects the impact Cushing’s disease has had on these patients and the enormity of the decisions they have had to make regarding their health over the course of their disease.

Our center published preliminary QOL results on our initial 18 patients.6 In this study, there was a 66% response rate, and scores on all 8 parameters of the SF-36 were significantly reduced from general population values. We significantly improved our response rate by doing telephone surveys as opposed to mail-out questionnaires, and by contacting all those necessary to locate a “missing patient.” In the present study, we though it would be more representative to compare our patient’s SF-12 values to U.S. women 45 to 54 years of age as well as to patients with diabetes (a patient population also with a chronic disease). In both cases, Cushing’s disease patients that are treated with BLA have significant improvement in their Cushing-related problems and most have regained a relatively normal QOL. Furthermore, we created a Cushing-specific symptom questionnaire as there is no disease-specific QOL questionnaire available for Cushing’s disease. This Cushing-specific questionnaire shows that 89% of patients experience improvement in their symptoms after BLA and, consequently, marked improvement in their QOL.

The results of this study show that, while the mean physical composite score was significantly lower than that of age- and gender-matched U.S. citizens (36 vs. 48), the mean mental composite score was close to that of U.S. women 45 to 54 years of age (45 vs. 49). A recent paper by van Aken et al7 reports similar findings in patients successfully treated by transsphenoidal surgery. They found, using 4 different questionnaires including the SF-36, that several aspects of QOL are reduced, particularly in areas of physical ability. It would seem, therefore, that patients who undergo BLA for persistent Cushing’s disease have, at the very least, an equal QOL to those patients who are successfully treated by initial transsphenoidal pituitary tumor resection.

Two other findings are worthy of discussion in this study. First, the surgical outcomes for these patients were favorable, with zero mortalities, and a 10% morbidity rate. Our operative times (mean, 273 minutes), and length of stay (mean, 4.2 days) were longer than most other series of laparoscopic adrenalectomies.11,12 However, this can be explained by a Canadian study that compared surgical outcomes in 3 different categories of patients13: 1) Cushing’s disease, 2) pheochromocytoma, and 3) unilateral adrenalectomy for nonpheochromocytoma. Poulin et al13found that patients in the first group had longer operating time (median, 255 minutes) and a long postoperative stay (median, 4 days). This is likely secondary to the high BMI of this patient population and the added operative time inherent in repositioning the patient. The extended postoperative stay is in part due to the need to establish homeostasis in fluids and electrolytes following removal of both adrenal glands. It is also due to the need for steroid taper and regulation, as well as the delayed healing these patients experience due to the catabolic nature of cortisol. Our results show that this is a safe, effective option for patients with persistent Cushing’s disease after transsphenoidal pituitary tumor resection.

Second, approximately 20% of our study sample had evidence of endogenous cortisol production following BLA. Evidence of detectable cortisol levels after BLA is reportedly rare; however, there is a paucity of literature on this subject. Possible etiologies include incomplete adrenal resection or functional ectopic adrenal remnants in the adrenal fossa or elsewhere. In 2 patients undergoing BLA for Cushing’s disease (from this current series), we have documented extracortical adrenal tissue remote from the adrenal gland in the retroperitoneal fat. Since then, we have changed our operative conduct to include complete removal of the retroperitoneal fat in the adrenal bed to avoid inadvertently leaving behind extracortical adrenal tissue. Since changing our technique, we have identified one other patient with an extracortical adrenal rest in the left adrenal fossa.

We have also done reoperative laparoscopic explorations in 2 of 7 patients with detectable serum cortisol levels, clinical evidence of hypercortisolism (and subsequent loss of postoperative need for steroid replacement), and positive NP-59 radioscintigraphy scans. The source of alleged endogenous cortisol production, as directed by NP-59 scanning, was in the adrenal fossa in one patient and on the left ovary in the second patient. Pathology demonstrated only fibrous tissue. The source of cortisol production following BLA remains to be determined and will be the subject of future investigation. We currently do not advise routine reexploration for symptomatic endogenous cortisol production without a positive NP-59 scan.

The present study does have one important limitation. We do not have preoperative QOL surveys on the majority of our patients. Therefore, we are relying on patients to remember their preoperative status and compare it with their current state of health. However, bias toward the patient feeling obliged to report a positive outcome was avoided by using an independent investigator (A.V.H.) with no involvement in the patient’s perioperative care to complete all telephone questionnaires. As well, there was no variation in response according to time interval between BLA and our study or between number of preoperative transsphenoidal treatments and BLA, suggesting that memory (or lack thereof) is not an independent predictor of postoperative improvement.

CONCLUSION

Our study shows that BLA for persistent Cushing’s disease provides patients with considerable improvement in their Cushing-related symptoms with concordant increase in their quality of life. After BLA, patients may attain the same (or better) quality of life as patients initially cured by transsphenoidal pituitary tumor resection. We think that BLA is a safe and effective treatment of the 10% to 30% of patients who fail initial therapy for Cushing’s disease, and should be considered preferentially over other available therapies.

ACKNOWLEDGMENTS

The authors thank Karin Miller and Chris Yedinak for all their help in coordinating and collecting biochemical data on our patients.

Footnotes

Reprints: Brett C. Sheppard, MD, Department of Surgery, Oregon Health & Science University, Mail Code: L223A, Portland, OR 97239. E-mail: sheppard@ohsu.edu.

REFERENCES

1. Di Somma C, Pivonella R, Loche S, et al. Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing’s disease: a prospective study. Clin Endocrinol. 2003;58:302–308. [PubMed]
2. Colao A, Pivonello R, Spiezia S, et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab. 1999;84:2664–2672. [PubMed]
3. Faggiano A, Pivonello R, Spiezia S, et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab. 2003;88:2527–2533. [PubMed]
4. Albiger N, Testa RM, Almoto B, et al. Patients with Cushing’s syndrome have increased intimal media thickness at different vascular levels: comparison with a population matched for similar cardiovascular risk factors. Horm Metab Res. 2006;38:405–410. [PubMed]
5. Locatelli M, Vance ML, Laws ER. The strategy of immediate reoperation for transsphenoidal surgery for Cushing’s disease [Clinical Review]. J Clin Endocrinol Metab. 2005;90:5478–5482.[PubMed]
6. Hawn MT, Cook D, Deveney C, et al. Quality of life after laparoscopic bilateral adrenalectomy for Cushing’s disease. Surgery. 2002;132:1064–1069. [PubMed]
7. van Aken MO, Pereira AM, Biermasz NR, et al. Quality of life in patients after long-term biochemical cure of Cushing’s disease. J Clin Endocrinol Metab. 2005;90:3279–3286. [PubMed]
8. Gagner M, Lacroix A, Prinz RA, et al. Early experiences with laparoscopic approach for adrenalectomy. Surgery. 1993;114:1120–1124. [PubMed]
9. van Aken MO, Pereira AM, van den Berg G, et al. Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson’s syndrome compared with Cushing’s disease. Clin Endocrin. 2004;60:765–772. [PubMed]
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11. Zeh HJ, Udelsman R. One hundred laparoscopic adrenalectomies: a single surgeon’s experience. Ann Surg Oncol. 2003;10:1012–1017. [PubMed]
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Articles from Annals of Surgery are provided here courtesy of Lippincott, Williams, and Wilkins

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Know Your Number

Posted on April 29, 2013 by MaryO
English: "Dr. Harvey Cushing," oil o...

English: “Dr. Harvey Cushing,” oil on canvas, by the American artist Edmund Tarbell. Courtesy of the Dittrick Medical History Center. (Photo credit: Wikipedia)

From my email:

As an advocate for patients with Cushing’s disease and their supporters, you certainly understand the importance of continually monitoring cortisol.

April 8th marks Cushing’s Awareness Day and the birthday of Dr. Harvey Cushing, who first described the disease in 1912. We want to use the month of April to bring attention to this disease. In honor of this day, Novartis Pharmaceuticals Corporation is kicking off “Know Your Number,” an important new program emphasizing the importance of cortisol regulation.

Being an advocate for those with Cushing’s disease and for those who care for them, you know that even after a successful pituitary surgery, where cortisol levels return to normal, there is still up to a 35% risk the pituitary tumor could begin to grow again, thus causing hypercortisolism. This potential rise in cortisol is also true for patients who are currently taking medication to control their Cushing’s disease. Over time, this control may begin to diminish. These important facts make it essential that your members are aware of the need to monitor their cortisol level.

Novartis Pharmaceuticals Corporation is initiating an important new program, and we would like to partner with Cushing’s Help and Support to bring this information to your membership and to all patients with Cushing’s disease. “Know Your Number” reminds both endocrinologists and patients that hypercortisolism can have devastating consequences on a patient’s body and emotions. “Know Your Number” promotes follow-up cortisol testing to help identify those patients whose cortisol levels have increased.

Please reach out to your membership with this message during the month of April as we celebrate Dr. Harvey Cushing’s birthday.

To learn more about this program and Cushing’s disease, and to download a discussion guide, please visit www.CushingsDisease.com

Know Your Number.

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