The Challenge of Obesity in Diagnosing Cushing’s Syndrome and Strategies to Improve Methods

The effects of obesity on the diagnosis of Cushing’s syndrome and strategies to alter the traditional approaches have been addressed in a new review study.

The study, “Diagnosis and Differential Diagnosis of Cushing’s Syndrome,” appeared in The New England Journal of Medicine. The author was Dr. Lynn D. Loriaux, MD and PhD, and a professor of medicine at the Division of Endocrinology, Diabetes and Clinical Nutrition at the School of Medicine, Oregon Health & Science University (OHSU), in Portland, Oregon.

Traditionally, exams of patients with glucocorticoid excess focused on the presence of changes in anabolism (the chemical synthesis of molecules). Given the increase in obesity in the general population, changes in anabolism can no longer distinguish Cushing’s syndrome from metabolic syndrome.

However, analyses of anti-anabolic changes of cortisol – including osteopenia (lower bone density), thin skin, and ecchymoses (injury that causes subcutaneous bleeding) – are an effective way to make this distinction.

The worldwide prevalence of metabolic syndrome in obese people is estimated at about 10%. Conversely, the incidence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million people.

Cushing’s and metabolic syndrome share significant clinical similarities, including obesity, hypertension, and type 2 diabetes. Therefore, “making the diagnosis is the least certain aspect in the care of patients with [Cushing’s],” Loriaux wrote.

Regarding a physical examination, patients with osteoporosis, reduced skin thickness in the middle finger, and three or more ecchymoses larger than 1 cm in diameter and not associated with trauma are more likely to have Cushing’s. Researchers estimate the probability of people with all three of these symptoms having Cushing’s syndrome is 95%.

Measuring 24-hour urinary-free cortisol levels allows the assessment of excess glucocorticoid effects, typical of Cushing’s syndrome. The test, which should be done with the most stringent techniques available, averages the augmented secretion of cortisol in the morning and the diminished secretion in the afternoon and at night.

Dexamethasone suppression is one of the currently used screening tests for Cushing’s syndrome. Patients with obesity and depression should not show decreased plasma cortisol levels when dexamethasone is suppressed. However, given its low estimated predictive value (the proportion of positive results that are “true positives”), “this test should not influence what the physician does next and should no longer be used” to screen for Cushing’s, the author wrote.

Some patients may show evidence of Cushing’s syndrome at a physical examination, but low urinary free cortisol excretion. This may be due to glucocorticoids being administered to the patient. In this case, the glucocorticoid must be identified and discontinued. Periodic Cushing’s assessments that measure urinary free cortisol should be performed.

The opposite can also occur: no clinical symptoms of Cushing’s, but elevated urinary free cortisol excretion and detectable plasma levels of the hormone corticotropin. In these patients, the source of corticotropin secretion, which can be a tumor or the syndrome of generalized glucocorticoid resistance, must be determined.

The disease process can be corticotropin-dependent or independent, depending on whether the hormone is detectable. Corticotropin in Cushing’s syndrome can come from the pituitary gland (eutopic) or elsewhere in the body (ectopic).

Loriaux recommends that the source of corticotropin secretion be determined before considering surgery. Up to 40% of patients with pituitary adenomas have nonfunctioning tumors (the tumor does not produce any hormones) and the corticotropin source is elsewhere. If misdiagnosed, patients will likely undergo an unnecessary surgery, with a mortality rate of 1%.

Patients with an ectopic source of corticotropin should undergo imaging studies in the chest, followed by abdominal and pelvic organs. If these tests fail to detect the source, patients should undergo either the blockade of cortisol synthesis or an adrenalectomy (removal of adrenal glands).

However, corticotropin-independent Cushing’s is usually caused by a benign adrenal tumor that uniquely secretes cortisol.

“Such tumors can be treated successfully with laparoscopic adrenalectomy,” Loriaux wrote. If the tumor secretes more than one hormone, it is likely malignant. Surgical to remove the tumor and any detectable metastases should be conducted.

Overall, “the treatment for all causes of [Cushing’s syndrome], other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed,” Loriaux wrote in the study.

“This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with [Cushing’s syndrome] should be referred to such a center for treatment.”

From https://cushingsdiseasenews.com/2017/10/24/diagnosing-cushings-syndrome-amid-challenge-of-obesity-and-strategies-to-improve-methods/

Diagnosis and Differential Diagnosis of Cushing’s Syndrome

D. Lynn Loriaux, M.D., Ph.D.

N Engl J Med 2017; 376:1451-1459April 13, 2017DOI: 10.1056/NEJMra1505550

More than a century ago, Harvey Cushing introduced the term “pluriglandular syndrome” to describe a disorder characterized by rapid development of central obesity, arterial hypertension, proximal muscle weakness, diabetes mellitus, oligomenorrhea, hirsutism, thin skin, and ecchymoses.1 Cushing knew that this syndrome was associated with adrenal cancer,2 and he suspected that some cases might have a pituitary component.

On September 6, 1911, he performed a craniotomy on one of his patients (referred to as Case XLV) but found no pituitary tumor.3 In his description of the case, he goes on to say that “we may perchance be on the way toward the recognition of the consequences of hyperadrenalism.”2 With time, it became clear that the disorder could be caused by small basophilic adenomas of the pituitary gland,4 and the pluriglandular syndrome became known as Cushing’s syndrome.

Fuller Albright provided the next conceptual advance in an extraordinary report, published in the first volume of the Laurentian Hormone Conference, “The Effects of Hormones on Osteogenesis in Man”5:

It has been our concept that protoplasm in general, like the protoplasmic matrix of bone, is constantly being anabolized and catabolized at one and the same time; a factor which increases catabolism would lead to very much the same net result as a factor which inhibits anabolism, but there would be some differences; it is my belief that the “S” hormone [cortisol] is anti-anabolic rather than catabolic. . . . The anti-anabolism . . . is contrasted with the increased anabolism due to an excess of the “N” hormone [testosterone] in the adreno-genital syndrome. This anti-anabolism of protoplasm in Cushing’s syndrome accounts for not only the osteoporosis, but the muscular weakness, the thin skin, probably the easy bruisability, and possibly the atrophy of the lymphoid tissues and thymus.

Nonetheless, in the intervening years, the physical examination of patients suspected to have glucocorticoid excess focused on the anabolic changes, essentially to the exclusion of the antianabolic changes. With the rapid increase in the rate of obesity in the general population, Cushing’s syndrome can no longer be reliably separated from the metabolic syndrome of simple obesity on the basis of anabolic signs alone. However, the antianabolic changes in Cushing’s syndrome are very effective in making this distinction. This review focuses on the problems introduced into the diagnosis and differential diagnosis of Cushing’s syndrome by the obesity epidemic and on ways to alter the traditional approach, using the antianabolic changes of excess cortisol to separate patients with Cushing’s syndrome from obese patients with the insulin-resistant metabolic syndrome.

PHYSICAL EXAMINATION

Andreas Vesalius (1514–1564) published his transformational work on human anatomy, De Humani Corporis Fabrica Libri Septem, in 1543. It is the book that corrected many of Galen’s anatomical errors. The book was met with considerable hostility. As an example, Jacobus Sylvius (Jacques Dubois, 1478–1555), the world’s leading anatomist at the time and Vesalius’s former mentor, on being asked his opinion of the work, replied, “Galen is not wrong. It is man that has changed, and not for the better.”6 This was not true then, but it is true now.

Approximately one third of the U.S. population is obese. The worldwide prevalence of the metabolic syndrome among obese persons is conservatively estimated at 10%; that is, approximately 12 million people have the obesity-related metabolic syndrome.7,8 The clinical picture of this syndrome is almost the same as that of Cushing’s syndrome.9,10 The prevalence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million population, or 24,000 affected persons. On the basis of these prevalence estimates, the chance that a person with obesity, hypertension, hirsutism, type 2 diabetes, and dyslipidemia has Cushing’s syndrome is about 1 in 500. In Harvey Cushing’s era, when obesity was rare, making the diagnosis of Cushing’s syndrome was the most certain aspect of the management of this disorder. Today, making the diagnosis is the least certain aspect in the care of patients with Cushing’s syndrome.

The metabolic syndrome caused by glucocorticoid hypersecretion can be differentiated from the obesity-associated metabolic syndrome with the use of a careful assessment of Albright’s antianabolic effects of cortisol. These effects — osteopenia, thin skin, and ecchymoses — are present in patients with Cushing’s syndrome but not in patients with simple obesity.

Patients in whom osteoporosis is diagnosed radiographically are more likely to have Cushing’s syndrome than those who do not have osteoporosis, with a positive likelihood ratio of 11.11-13 Today, a z score of −2 at the lumbar spine supports this criterion. Skinfold thickness is conveniently measured with an electrocardiographic caliper that has the points dulled with a sharpening stone and the screws tightened so that the gap is maintained when the caliper is removed from the skinfold. The skin over the proximal phalanx of the middle finger of the nondominant hand is commonly used for this measurement

 

(Figure 1 FIGURE 1Measurement of Skinfold Thickness.). A thickness of less than 2 mm is considered to be thin skin. Patients who have thin skin are more likely to have Cushing’s syndrome, with a positive likelihood ratio of 116

 

(Figure 2 FIGURE 2 Comparison of Skinfold Thickness in Patients with Cushing’s Syndrome and Those with Other Conditions Related to Insulin Resistance.).13-15 Finally, patients who have three or more ecchymoses that are larger than 1 cm in diameter and not associated with trauma such as venipuncture are more likely to have Cushing’s syndrome than are patients without such findings, with a positive likelihood ratio of 4.13,16

If we know the prevalence of undiagnosed Cushing’s syndrome in the population of persons with the obesity-related metabolic syndrome, we can begin to calculate the probability that a person has Cushing’s syndrome, using the likelihood ratios for the antianabolic features observed on physical examination. Likelihood ratios can be converted into probabilities with the use of Bayes’ theorem. This conversion is markedly facilitated by the Fagan nomogram for this purpose.17

The prevalence of undiagnosed Cushing’s syndrome is not known, but it can be estimated. Two persons per 1 million population die from adrenal cancer every year.18 The current life span for patients with adrenocortical carcinoma, after diagnosis, is between 2 and 4 years.19,20 Allowing 3 years to make the diagnosis, the prevalence of undiagnosed Cushing’s syndrome is 6 cases per million. In most case series of Cushing’s syndrome, an average of 8% of patients have adrenal carcinoma.21 If 6 per million is 8% of the group, the total Cushing’s syndrome group is 75 persons per million, or 24,000 persons. If all 24,000 patients are included in the metabolic syndrome group, comprising 12 million people, the prevalence of Cushing’s syndrome is 0.002, or 0.2%. With a probability of 0.2% and a likelihood ratio of 116 for thin skin, 18 for osteopenia, and 4 for ecchymoses, the probability that a patient with these three findings has Cushing’s syndrome is 95%.

URINARY FREE CORTISOL

The diagnosis of all endocrine diseases requires a clinical presentation that is compatible with the disease, as well as identification of the pathophysiological cause. An assessment for excess glucocorticoid effects can be made by measuring the 24-hour urinary free cortisol level.22 There are two kinds of free cortisol: plasma protein-unbound cortisol and cortisol unconjugated to sulfuric or hyaluronic acid. Protein-unbound cortisol is filtered in the glomerulus and then reabsorbed in the collecting system. About 3% of filtered cortisol ends up in the urine. This free cortisol in the urine is unconjugated. Thus, the urinary free cortisol level is a direct reflection of the free, bioactive cortisol level in plasma. The free cortisol level is quantified in a 24-hour urine sample by averaging the increased secretion of cortisol in the morning and the decreased secretion in the afternoon and at night. Urinary creatinine is also measured to determine whether the collection is complete. Creatinine levels of less than 1.5 g per day for men and less than 1 g per day for women indicate incomplete collection, and the test should be repeated in patients with these levels.

Unconjugated cortisol can be extracted directly from urine with a nonpolar lipid solvent. After extraction, the cortisol is purified by means of high-pressure liquid chromatography and then quantified with a binding assay, usually radioimmunoassay. Free cortisol also can be quantitated directly by means of mass spectroscopy. The urinary free cortisol assay of choice uses high-pressure liquid chromatographic separation followed by mass spectrometric quantitation.23 With the use of this assay, the urinary free cortisol level in healthy adults ranges from 8 to 51 μg per 24 hours (mean [±SD], 23±8). Clinical depression increases urinary free cortisol excretion, and most studies show that the level of urinary free cortisol ranges from 10 to 60 μg per day in patients with typical clinical signs and symptoms of depression. If we use 60 μg per day as the cutoff between normal values (<60 μg per day) and elevated values (≥60 μg per day), urinary free cortisol excretion of 62 μg per day or more has a positive likelihood ratio of 11.24 Thus, in a patient presenting with obesity, hypertension, type 2 diabetes, and hirsutism who has thin skin, osteopenia, ecchymoses, and an elevated urinary free cortisol level, the probability of Cushing’s syndrome is 1 (100%). For such patients, the clinician should move directly to a differential diagnostic evaluation.

DEXAMETHASONE-SUPPRESSION TEST

The dexamethasone-suppression test is commonly used in the diagnosis of Cushing’s syndrome. This test was developed by Grant Liddle in the early 1960s as a differential diagnostic test to separate corticotropin-dependent from corticotropin-independent Cushing’s syndrome. This is now done by measuring the plasma corticotropin level. Unfortunately, dexamethasone suppression has continued to be used as a screening test for Cushing’s syndrome.

The control group for this test comprises patients with obesity and depression in whom cortisol secretion is not suppressed in response to an oral dose of 1 mg of dexamethasone at midnight. Of the current U.S. population of 360 million people, approximately one third (120 million people) are obese. Of those who are obese, 10% (12 million people) have depression. In half these patients (6 million people), the plasma cortisol level will not be suppressed in response to a dexamethasone challenge. On the basis of my estimate of the current prevalence of undiagnosed Cushing’s syndrome (24,000 cases) and the estimate of the at-risk population (6 million persons), the positive predictive value of the dexamethasone-suppression test is only 0.4%. Thus, this test should not influence what the physician does next and should no longer be used for this purpose.

OUTLIERS

For patients with convincing evidence of Cushing’s syndrome on physical examination and an elevated 24-hour urinary free cortisol level, the differential diagnostic process outlined below should be initiated. However, a small group of patients will not meet these criteria.

Some patients have a strongly positive physical examination but low or zero urinary free cortisol excretion. Plasma corticotropin levels are suppressed in these patients. These patients are receiving exogenous glucocorticoids. The glucocorticoid must be identified, and a plan must be made for its discontinuation. Sometimes the glucocorticoid is being given by proxy (e.g., by a parent to a child), and no history of glucocorticoid administration can be found. Nevertheless, the glucocorticoid must be identified and discontinued.

Other patients have few or no clinical signs of Cushing’s syndrome but do have elevated urinary free cortisol excretion. Plasma corticotropin is measurable in these patients. They are usually identified during an evaluation for arterial hypertension. All such patients should undergo inferior petrosal sinus sampling to determine the source of corticotropin secretion. Ectopic sources are almost always neoplastic and are usually in the chest.25 Patients with eutopic secretion usually have the syndrome of generalized glucocorticoid resistance.26

Finally, a few patients have convincing findings on physical examination coupled with a normal urinary free cortisol level. In such cases, the clinician should make sure that urinary free cortisol is being measured with high-performance liquid chromatography and mass spectrometry, that renal function is normal, and that the collections are complete. “Periodic” Cushing’s syndrome must be ruled out by measuring urinary free cortisol frequently over the course of a month.27 If these efforts fail, the patient should be followed for a year, with urinary free cortisol measurements performed frequently. No additional tests should be performed until the situation is sorted out. More tests would be likely to lead to an unnecessary surgical procedure.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of Cushing’s syndrome is shown in Figure 3

FIGURE 3Differential Diagnosis of Cushing’s Syndrome.. If plasma corticotropin is measurable, the disease process is corticotropin-dependent. If corticotropin is not measurable, the process is corticotropin-independent.

Corticotropin-dependent causes of Cushing’s syndrome are divided into those in which the corticotropin comes from the pituitary (eutopic causes) and those in which the corticotropin comes from elsewhere (ectopic causes). This differentiation is made with the measurement of corticotropin in inferior petrosal sinus plasma and the simultaneous measurement of corticotropin in peripheral (antecubital) plasma immediately after corticotropin-releasing hormone stimulation of pituitary corticotropin secretion. In samples obtained 4, 6, and 15 minutes after stimulation with corticotropin-releasing hormone, eutopic corticotropin secretion is associated with a ratio of the central-plasma corticotropin level to the peripheral-plasma corticotropin level of 3 or more. Ectopic corticotropin secretion is associated with a central-to-peripheral corticotropin ratio of less than 3. The positive predictive value of this test is 1 (Figure 4

FIGURE 4Maximal Ratio of Corticotropin in Inferior Petrosal Sinus Plasma to Corticotropin in Peripheral Plasma in Patients with Cushing’s Syndrome, Ectopic Corticotropin Secretion, or Adrenal Disease.).28

Although some authorities suggest that inferior petrosal sinus sampling can safely be bypassed in patients with corticotropin-dependent Cushing’s syndrome and a well-defined pituitary adenoma, I disagree. The incidence of nonfunctioning pituitary microadenomas is between 15% and 40%.29 This means that up to 40% of patients with ectopic secretion of corticotropin have an incidental pituitary abnormality. If it is assumed that the pituitary abnormality is responsible for corticotropin secretion, 15 to 40% of patients with ectopic secretion of corticotropin will be misdiagnosed and submitted to a transsphenoidal exploration of the sella turcica and pituitary gland. The prevalence of ectopic corticotropin secretion in the population of patients with undiagnosed Cushing’s syndrome is about 10%, accounting for 2400 patients. Up to 40% of these patients, or 960, have an incidental pituitary tumor. The mortality associated with transsphenoidal microadenomectomy is 1%.30 If all 360 to 960 patients undergo this procedure, there will be up to 10 deaths from an operation that can have no benefit. For this reason alone, all patients with corticotropin-dependent Cushing’s syndrome should undergo inferior petrosal sinus sampling to confirm the source of corticotropin secretion before any surgical intervention is contemplated.

Patients with eutopic corticotropin secretion are almost certain to have a corticotropin-secreting pituitary microadenoma. An occasional patient will have alcohol-induced pseudo–Cushing’s syndrome. The slightest suggestion of alcoholism should lead to a 3-week abstinence period before any surgery is considered.31

Patients with ectopic corticotropin secretion are first evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. In two thirds of these patients, a tumor will be found.25 If nothing is found in the chest, MRI of the abdominal and pelvic organs is performed. If these additional imaging studies are also negative, there are two options: bilateral adrenalectomy or blockade of cortisol synthesis. If blockade is chosen, the patient should undergo repeat scanning at 6-month intervals.32 If no source is found by the end of the second year, it is unlikely that the source will ever be found, and bilateral adrenalectomy should be performed for definitive treatment (Doppman JL: personal communication).

Corticotropin-independent Cushing’s syndrome is usually caused by an adrenal neoplasm. Benign tumors tend to be small (<5 cm in diameter) and secrete a single hormone, cortisol. The contralateral adrenal gland is suppressed by the cortisol secreted from the tumorous gland. If the value for Hounsfield units is less than 10 and the washout of contrast material is greater than 60% at 15 minutes, the tumor is almost certainly benign.33 Such tumors can be treated successfully with laparoscopic adrenalectomy.

The syndromes of micronodular and macronodular adrenal dysplasia usually affect both adrenal glands. The nodules secrete cortisol. Corticotropin is suppressed, as is the internodular tissue of the adrenal glands. Percutaneous bilateral adrenalectomy, followed by glucocorticoid and mineralocorticoid treatment, is curative.

Adrenal tumors secreting more than one hormone (i.e., cortisol and androgen or estrogen) are almost always malignant. Surgical removal of all detectable disease is indicated, as is a careful search for metastases. If metastases are found, they should be removed. This usually requires an open adrenalectomy. It goes without saying that adrenal tumors, nodules, and metastases should be treated by the most experienced endocrine cancer surgeon available.

If the plasma cortisol level on the morning after a transsphenoidal microadenomectomy is 0, the operation was a success. The patient should be treated with oral hydrocortisone, at a dose of 12 mg per square meter of body-surface area once a day in the morning, and a tetracosactide (Cortrosyn) stimulation test should be performed at 3-month intervals. When the tetracosactide-stimulated plasma cortisol level is higher than 20 μg per deciliter (551 μmol per liter), cortisol administration can be stopped. The same rule applies in the case of a unilateral adrenalectomy. If the adrenalectomy is bilateral, cortisol, at a dose of 12 to 15 mg per square meter per day, and fludrocortisone (Florinef), at a dose of 100 μg per day, should be prescribed as lifelong therapy.

SUMMARY

The obesity epidemic has led to necessary changes in the evaluation and treatment of patients with Cushing’s syndrome. The most dramatic change is the emphasis on the antianabolic alterations in Cushing’s syndrome, which can provide a strong basis for separating patients with Cushing’s syndrome from the more numerous patients with obesity and the metabolic syndrome. More can be done along these lines. Likelihood ratios are known for proximal muscle weakness and can be known for brain atrophy and growth failure in children.

The dexamethasone-suppression test, although still very popular, no longer has a role in the evaluation and treatment of patients with Cushing’s syndrome. Only three biochemical tests are needed: urinary free cortisol, plasma corticotropin, and plasma cortisol measurements. Urinary free cortisol excretion is the test that confirms the clinical diagnosis of Cushing’s syndrome. To be trustworthy, it must be performed in the most stringent way, with the use of high-pressure liquid chromatography followed by mass spectrometric quantitation of cortisol. Measurement of plasma corticotropin is used to separate corticotropin-dependent from corticotropin-independent causes of Cushing’s syndrome and to separate eutopic from ectopic secretion of corticotropin. Inferior petrosal sinus sampling should be performed in all patients with corticotropin-dependent Cushing’s syndrome because of the high prevalence of nonfunctioning incidental pituitary adenomas among such patients. Measurement of plasma cortisol has only one use: determining the success or failure of transsphenoidal microadenomectomy or adrenalectomy. If the plasma cortisol level is not measurable on the morning after the operation (<5 μg per deciliter [138 μmol per liter]), the procedure was a success; if it is measurable, the operation failed. The surgeon must not administer intraoperative or postoperative synthetic glucocorticoids until the plasma cortisol level has been measured.

Successful evaluation of a patient who is suspected of having Cushing’s syndrome requires an endocrinologist who is skilled in physical diagnosis. Also required is a laboratory that measures urinary free cortisol using high-performance liquid chromatography and mass spectrometry and that can measure plasma cortisol and plasma corticotropin by means of radioimmunoassay.

Inferior petrosal sinus sampling is performed by an interventional radiologist. The treatment for all causes of Cushing’s syndrome, other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed. This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with Cushing’s syndrome should be referred to such a center for treatment.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

From the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland.

Address reprint requests to Dr. Loriaux at the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., L607, Portland, OR 97239-3098, or at .

From http://www.nejm.org/doi/full/10.1056/NEJMra1505550

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

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

Table thumbnail

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

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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]
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10. Assie G, Bahurel H, Bertherat J, et al. The Nelson’s syndrome … revisited. Pituitary. 2004;7:209–215. [PubMed]
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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