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Cushing?s syndrome might be underappreciated in patients seeking

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I blogged about this newly published research at Bariatric surgery: Not the answer for obesity and "hidden" Cushing's syndrome


I'll try to paste the text of the article here:


Case report

Cushing?s syndrome might be underappreciated in patients seeking

bariatric surgery: a plea for screening

Maria Fleseriu, M.D.a,d, William H. Ludlam, M.D., Ph.D.b, Swee H. Teh, M.D.c,


Chris G. Yedinak, F.N.P.d, Clifford Deveney, M.D.c, Brett C. Sheppard, M.D.c,*

aPituitary Center, Department of Medicine, Oregon Health & Science University, Portland, Oregon

bSeattle Pituitary Center, Neuroscience Institute, Swedish Medical Center, Seattle, Washington

cDepartment of Surgery, Oregon Health & Science University, Portland, Oregon

dDepartment of Neurosurgery, Oregon Health & Science University, Portland, Oregon


Received April 24, 2008; revised September 3, 2008; accepted September 8, 2008

Keywords: Cushing?s syndrome; Hypercortisolism; Adrenocorticotropic hormone; ACTH; Bariatric surgery; Urine free cortisol; Dexamethasone suppression test; Midnight salivary test


Morbid obesity is increasing in developed countries. Nonoperative therapy remains the mainstay of management. However, the results are often not satisfactory [1]. Bariatric surgery is an effective therapy and results in long-term weight loss. Thus, the number of patients undergoing bariatric surgery is increasing.


Morbid obesity can sometimes be caused by unidentified co-morbid conditions [2]. For instance, Cushing?s syndrome (CS) is a potentially reversible cause of obesity and is often characterized by rapid weight gain. However, CS can also have a more gradual onset of physical features, making diagnosis difficult. The clinical expression of CS is not always florid, and mild hypercortisolism can present as weight gain, diabetes, and/or hypertension (HTN).


We report on 2 patients who underwent bariatric surgery before we diagnosed their CS. Both had adverse sequelae from undiagnosed CS. One patient had progression of obe?sity, multiple vertebral compression fractures, poorly con?trolled diabetes and HTN during a 10-year period, and the second patient ultimately died.


Case report

Case 1

A 50-year-old obese woman (body mass index [bMI] 39 kg/m2) presented with hypertension and hyperglycemia. Sixteen years previously she had undergone open vertical banded gastroplasty followed by 2 revisional gastroplasties for weight loss failure. At presentation to our institution she had clinical features strongly suggestive of Cushing?s syn?drome. These included facial plethora and rounding, a dor?socervical hump, supraclavicular fat pad filling, increased central obesity, proximal muscle weakness, and easy bruis?ing. All these clinical features, with the exception of muscle weakness, had been present, but much less obvious, 16 years earlier and before she had undergone vertical banded gastroplasty. Biochemical testing confirmed hypercorti?solism. The test results included a urine free cortisol (UFC) level of 2400 �g/d (normal �50), a random adrenocortico?tropin hormone (ACTH) level of 70 pg/mL (normal �46), and a midnight serum cortisol (MNSC) level of 12 �g/dL (normal �5).

Pituitary magnetic resonance imaging revealed a 1.0-cm neoplasm. Two attempts to resect the pituitary tumor did not cure her hypercortisolemia. She was successfully treated with laparoscopic bilateral adrenalectomy (BLA). At the last follow-up visit, 3 years after adrenalectomy, she was taking physiologic doses of glucocorticoid and mineralocor?ticoid replacement. Her glucose management has substantially improved, and she has lost 50 lb since undergoing BLA.


Case 2

A 27-year-old man developed rapid weight gain at 20 years of age. He became morbidly obese (BMI 53 kg/m2) and developed hypertension, hyperlipidemia, and obstruc?tive sleep apnea. Three years before presentation he had undergone Roux-en-Y gastric bypass. He lost 170 lb but continued to complain of persistent nausea and abdominal pain. He underwent laparoscopic exploration, but no me?chanical cause of his complaints was found. On presentation to our institution, he had a BMI of 20 kg/m2. He described symptoms suggestive of hypercortisolism. These included lower extremity edema, facial plethora, facial rounding, a dorsocervical hump, acne, proximal muscle weakness, and neuropsychiatric symptoms. These symptoms had all been present before the initial bariatric surgery but had been of a lesser magnitude. Biochemical testing confirmed hypercor?tisolism. The test results included a UFC of 193 �g/d, multiple ACTH tests that were in the normal range (i.e., not suppressed), a dexamethasone/corticotropin-releasing hor?mone stimulation test of 2.0 �g/dL at 15 minutes after corticotropin-releasing hormone stimulation (serum dexa?methasone level 1114 ng/dL), an overnight low-dose (1-mg) dexamethasone suppression test result of 9.5 �g/dL, and a cavernous sinus sampling test that indicated the inappropri?ate ACTH source was on the right side of the pituitary. Magnetic resonance imaging demonstrated a 2-mm right-sided pituitary microadenoma. He underwent transsphenoi?dal resection that was not curative. Because of the malnu?trition, we considered reversing his Roux-en-Y divided gastric bypass before BLA. However we believed control of his hypercortisolism first would help manage his other symptoms. Four weeks after his pituitary surgery, he devel?oped gallstone pancreatitis with necrosis and hemorrhage and died of progressive multiorgan failure.




The metabolic effect of prolonged hypercortisolism re?sults in the classic features of CS, characterized by supra?clavicular fat pad deposition, a dorsocervical hump, central obesity, viloaceous stria, facial plethora, facial rounding, sleep disturbances, proximal muscle wasting, hypertension, and diabetes. These patients can be differentiated from pa?tients with indigenous obesity by meticulous clinical exam?ination and biochemical investigation. Clinical suspicion is more challenging when obesity and early/mild hypercorti?solism co-exist because these 2 medical conditions share common clinical features. Because the incidence of obesity is much greater than that of hypercortisolism, the diagnosis of CS can be overlooked. The purpose of this report was to highlight the potential for CS in patients with obesity. In our series of patients undergoing BLA with persistent CS after pituitary ablation, the average BMI was 35 kg/m2 [3].

For both of our index patients, undiagnosed CS led to unindicated bariatric surgery. In the first case, this was followed by several attempts at revisional surgery owing to weight gain and progression of the metabolic syndrome. These well-intentioned therapeutic interventions were pre?dictably unsuccessful because of the underlying CS. This patient had 16-year delay in the diagnosis of her CS and underwent 3 nontherapeutic bariatric surgical procedures.


The case of the second patient demonstrates the risk of severe malnutrition in patients with undiagnosed CS who undergo bariatric surgery. Unlike the first patient, who had undergone a less-effective weight loss procedure (vertical banded gastroplasty), the second patient had undergone Roux-en-Y divided gastric bypass. When combined with the metabolic effects of unidentified CS, this resulted in signif?icant malnutrition. This patient?s symptom complex led to additional negative explorations to evaluate for kinking of his Roux limb. The development of gallstones and gallstone pancreatitis was a lethal event, given his associated co?morbidity from malnutrition.


CS results from prolonged exposure to elevated levels of systemic glucocorticoid. ACTH-dependent CS (70 ?80% of cases) is caused by inappropriate ACTH production by a pituitary adenoma (Cushing?s disease) or, less commonly, by ectopic tumors secreting ACTH or, rarely, corticotropin-releasing hormone-producing tumors. ACTH-independent CS is caused by adrenocortical tumors or hyperplasia.

CS is a rare disease, with an incidence of 2.5?3 cases/1 million persons annually. CS is more prevalent in high-risk populations such as the obese with poorly controlled diabe?tes mellitus and was reported to have an incidence of 3.3% in 1 series [4] and 5.8% in another [5]. Although florid CS is characterized by the classic physical features, many of these features can be less pronounced in early CS, making it difficult to distinguish CS from ?simple? obesity. More?over, some patients have episodic cortisol hypersecretion and have varied clinical presentations [6,7]. Subclinical CS is present in �30% of adrenal incidentalomas. These indi?viduals are at increased risk of diabetes, obesity, HTN, and osteoporosis [8]. With careful attention to the history and physical examination findings, most individuals with CS can be diagnosed [9].


Several tests are used to screen for CS. However, no single screening test is available that is able to distinguish CS from indigenous obesity. The 24-h UFC test is the most commonly used test to evaluate for CS. It is less useful as a screening test when a patient is morbidly obese, because it may result in mild false-positive values. The sensitivity of the UFC test in detecting CS is 45?71% [10]. An overnight low-dose dexamethasone suppression test is an excellent alternate screening test for CS in the context of obesity and hyperglycemia. Patients receive 1 mg of dexamethasone the evening before testing. A low 8:00 AM cortisol level (�1.8 mg/dL) effectively rules out CS, with a sensitivity of 98%

[4]. However, the overnight low-dose dexamethasone sup?pression test has a lower specificity (87%), making it less useful for confirming the presence of CS [6]. The MNSC test is an appealing screening test. It can be collected by the patient at home and is a valid indicator of the plasma-free cortisol concentration. Putignano et al. [11] compared the MNSC levels in 199 obese subjects (average BMI 40 kg/ m2) with those in 41 patients with CS and 27 normal controls. The patients with CS had significantly greater MNSC levels compared with the other 2 groups. They concluded that MNSC measurement can be used as a first-line test for CS screening in those with simple obesity owing to its high sensitivity (92.7%) [11]. A similar study compared 63 patients with CS with a control group of 54 obese patients (average BMI 38.3 kg/m2). A single MNSC level �2.0 mg/mL provided a sensitivity of 100% and a specificity of 96% for the diagnosis of CS compared with simple obesity [12].


The individual benefit of CS screening in patients seek?ing bariatric surgery is substantial. Undiagnosed CS with florid hypercortisolism has a 5-year survival rate of about 50%. More commonly, undiagnosed and slowly progressive CS relentlessly erodes the patient?s quality of life owing to progressive morbidity and shortens the lifespan from the increased risk of death from cardiovascular disease [13]. Owing to the complications of CS, undiagnosed patients have a mortality 4 times greater than age-and gender-matched controls. Delay in diagnosis is also associated with irreversibility of the adverse metabolic, osteoporotic, car?diovascular, and cognitive sequelae of CS.

Undiagnosed CS can also increase the risk of complica?tions and death for patients undergoing surgery for other causes. CS is associated with increased circulating levels of factor VII and von Willebrand factor, which include a hy?percoagulable state. Untreated patients undergoing surgery have a thromboembolic morbidity rate of 20% and a 10% mortality rate. When treated with appropriate long-term perioperative anticoagulation, the morbidity rate decreases to 6.0% and the mortality rate to .4% [14]. Moreover, for reasons that are not yet clear but are likely related to the irreversible intensive biologic changes from the hypercor?tisolism, patients with CS have 2.4-fold increased risk of dying compared with patients without CS undergoing a similar surgical procedure [15].


Undiagnosed CS can also cause significant specific com?plications in the postoperative bariatric patient. The additive adverse effects of an effective weight loss procedure combined with the metabolic effects of CS (hyperlipidemia, impaired glucose tolerance, decreased growth hormone lev?els, hypothyroidism) can result in profound malnutrition. Hypercortisolism also profoundly alters the bone and cal?cium metabolism. Osteoporosis occurs in close to 40% of adults with CS. Patients with undiagnosed CS who undergo bariatric surgery are already at a substantial risk of loss of bone mineral density. The early adverse sequelae of vitamin D malabsorption after bariatric surgery, combined with the pre-existing alteration of bone and calcium metabolism in CS, can result in rapid and profound osteoporosis [16,17].


Although the benefit of screening is clear, the question of which group of preoperative bariatric surgery patients to screen is less so. This is made more complex by the overlap of symptoms of mild CS and simple obesity (weight gain, diabetes, HTN), the low incidence of CS, and the lack of an ideal screening test. However, once iatrogenic causes of hypercortisolism are excluded by history, we recommend the following patients be screened.


1 All patients with a known adrenal incidentaloma should be screened for CS. Patients with ?subclinical? CS might lack the florid manifestations of CS but are often obese and have HTN and type 2 diabetes. Adrenalectomy in this setting may be beneficial [18,19].


2 Guidelines for the diagnosis of CS have recently been published [20]. The features that are discriminating and offer the greatest chance of a positive pretest probability are a history of easy bruising, evidence of proximal muscle weakness, the presence of reddish-purple striae �1 cm wide, and facial plethora. Such patients should always be screened.


3 In addition, we recommend screening younger pa?tients with atypical osteoporosis, HTN, unexplained multiple infections, or kidney stones. Rapid weight gain in previously normal and active young patients should also prompt consideration for screening.


4 The referral for screening should always be consid?ered for patients who have a constellation of multiple features suggestive of CS and whose medical history prompts concern [20].


Which screening test to consider will depend on the patient, local expertise, and available resources. At our institution, we prefer 2 measurements of either UFC or MNSC for screening. These tests are accurate, can be done on an outpatient basis, and are of lower cost. At least 2 samples are necessary because a solitary normal UFC or MNSC will not exclude the presence of mild CS [21]. Screening and confirmation of CS is a complex investiga?tive diagnosis. For this reason, we recommend referral to a specialist in endocrinology.




We gratefully recognize the mother of our second patient. It was her wish that this report be published to help future patients.



[1] Douketis JD, Macie C, Thabane L, Williamson DF. Systematic re?view of long-term weight loss studies in obese adults: clinical signif?icance and applicability to clinical practice. Int J Obes (Lond) 2005; 29:1153?67.

[2] Stocker DJ. Management of the bariatric surgery patient. Endocrinol Metab Clin North Am 2003;32:437?57.

[3] Thomspon SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux L, Sheppard BC. Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing?s disease: a 10-year experience. Ann Surg 2007;245:790?4.

[4] Leibowitz G, Tsur A, Chayen SD, et al. Pre-clinical Cushing?s syn?drome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients. Clin Endocrinol (Oxf) 1996;44:717?22.

[5] Catargi B, Rigalleau V, Poussin A, et al. Occult Cushing?s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003;88:5808?13.

[6] Boscaro M, Barzon L, Fallo F, Sonino N. Cushing?s syndrome. Lancet 2001;357:783?91.

[7] Velez DA, Mayberg MR, Ludlam WH. Cyclic Cushing syndrome: definitions and treatment implications. Neurosurg Focus 2007;23: 1?3.

[8] Sippel RS, Chen H. Subclinical Cushing?s syndrome in adrenal inci?dentalomas. Surg Clin North Am 2004;84:875?85.

[9] Findling JW, Raff H. Cushing?s syndrome: important issues in diag?nosis and management. J Clin Endocrinol Metab 2006;91:3746?53.

[10] Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing?s syndrome and pseudo-Cushing?s states. Endocr Rev 1998;19:647?72.

[11] Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cush?ing?s syndrome. J Clin Endocrinol Metab 2003;88:4153?7.

[12] Yeneva M, Mosnier-Pudar H, Dugue MA, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing?s syndrome. J Clin Endocrinol Metab 2003;88: 4153?7.

[13] Pivonello R, Faggiano A, Lombardi G, Colao A. The metabolic syndrome and cardiovascular risk in Cushing?s syndrome. Endocriol Metab Clin North Am 2005;34:327?39.

[14] Boscaro M, Sonino N, Scarda A, et al. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing?s syn?drome. J Clin Endocrinol Metab 2002;87:3662?6.

[15] Dekkers O, Biermasz N, Pereira, A, et al. Mortality in patients treated for Cushing?s disease is increased compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrin Metab 2007:92:2006?112.

[16] Armaldi G, Angeli A, Atkinson A, Bertagna X. Diagnosis and com?plications of Cushing?s syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593?602.

[17] Johnson J, Maher J, Samuel I, Heitshusen D, Doherty C, Downs R. Effects of gastric bypass procedures on bone mineral density, cal?cium, parathyroid hormone, and vitamin D. J Gastrointest Surg 2005; 9:1106?11.

[18] Sippel R, Chen H. Subclinical Cushing?s syndrome in adrenal inci?dentalomas. Surg Clin North Am 2004:84:875?85.

[19] Mitchell I, A. R, Juneja K, et al. ?Subclinical Cushing?s syn?drome? is non subclinical: improvement after adrenalectomy in 9 patients. Surgery 2007;142:900?5.

[20] Nieman L, Biller B, Findling J, et al. The diagnosis of Cushing?s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526 ?40.

[21] Kidambi S, Raff H, Findling J. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing?s syndrome. Eur J Endocrinol 2007;157:725?31.




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