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European Journal of Endocrinology (2007) 157 725–731 ISSN 0804-4643 CLINICAL STUDY Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome Srividya Kidambi1,2, Hershel Raff1,2 and James W Findling1,2 1 Endocrine Research Laboratory, Endocrine-Diabetes Center, Aurora St Luke’s Medical Center, Milwaukee, Wisconsin 53215, USA and 2Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine, Medical College of Wiscons
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  CLINICAL STUDY Limitations of nocturnal salivarycortisol and urine free cortisolin the diagnosis of mild Cushing’s syndrome Srividya Kidambi 1,2 , Hershel Raff  1,2 and James W Findling 1,2 1 Endocrine Research Laboratory, Endocrine-Diabetes Center, Aurora St Luke’s Medical Center, Milwaukee, Wisconsin 53215, USA and  2 Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA(Correspondence should be addressed to H Raff who is now at Endocrine Research Laboratory, St Luke’s Physician’s Office Building, 2801 West KK River Parkway, Suite 245, Milwaukee, Wisconsin 53215, USA; Email: hraff@mcw.edu) Abstract Objective : Cushing’s syndrome (CS) is difficult to diagnose due to its nonspecific presentation.Diagnostic tests like 24-h urine free cortisol (UFC) and the overnight 1 mg dexamethasone suppressiontest (DST) lack sufficient sensitivity and specificity. Measurement of nocturnal salivarycortisol (NSC) isan accurate and reproducible test with a high sensitivity for CS. However, its performance in mild CShas not been reported. We present 11 cases of CS with normal or mildly elevated UFC in whom NSCwas helpful in making a diagnosis. Design and methods : All patients had at least one collection of 24-h UFC and NSC and eight had anovernight 1 mg DST. The number of NSC measurements per patient was determined by the clinicalindex of suspicion and the results of initial testing. Imaging studies included magnetic resonanceimaging (MRI) of pituitary or computer tomography scan of abdomen. Results : Only four out of eleven patients had elevations in UFC and none were O 2 times the upper limitof normal. Seven out of eight had an abnormal DST. All patients had some elevated NSCs (14–100%).Out of eleven patients, six had an abnormality in the pituitary gland found by MRI and two out of eleven had adrenal masses. The remaining three had normal pituitary MRI but had inferior petrosalsinus (IPS) sampling indicating Cushing’s disease. All patients had appropriate surgery, andhistopathology of all except one was suggestive of either a cortisol-producing adrenal adenoma oran ACTH-secreting pituitary adenoma. Conclusion : Neither a normal UFC nor a normal NSC excludes mild CS. Multiple samples (urine/saliva)and DST are needed to make the diagnosis of mild CS. European Journal of Endocrinology 157 725–731 Introduction The diagnosis of Cushing’s syndrome (CS) and thedifferentiation of its causes are among the mostchallenging problems in clinical endocrinology. Thefeatures of endogenous hypercortisolism (especially,when mild) are protean and coincide with manycommon clinical conditions like the dysmetabolicsyndrome(1, 2). Screening studies in high-riskpopulations have discovered unsuspected CS in asmany as 2–5% of patients with diabetes mellitus(3–7)and suggest that mild CS is more common thanpreviously appreciated.Historically, elevation of 24-h urine free cortisol (UFC)to 2–3 times the upper limit of normal has beenconsidered the gold standard for the diagnosis of spontaneous CS(8). In addition, the overnight 1 mgdexamethasone suppression test (DST) has been used asa screening test; however, it may lack adequatesensitivity and specificity to be a stand-alone test andneeds to be complemented(9).Since the earliest biochemical abnormality in patientswith CS may be the failure to fully decrease cortisolsecretion to its nadir at night, the measurement of serumcortisol at midnight yields a high sensitivity andspecificity for the diagnosis of CS(10, 11). Themeasurement of nocturnal salivary cortisol (NSC), asurrogate for midnight serum cortisol, has proven to be amore practical means of screening for endogenoushypercortisolism and has excellent sensitivity andspecificity(1, 12–16).We present a series of 11 patients with surgicallyproven mild CS in whom the measurement of 24-h UFCwas usually normal or only slightly elevated. In thesepatients, the use of NSC measurements in combinationwith the overnight 1 mg DST provided biochemicalevidence of a pathological state of hypercortisolism. Subjects and methods The 11 patients reported here were referred to ourcenter for either first consultation or a second opinion. European Journal of Endocrinology (2007) 157 725–731 ISSN 0804-4643 q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0424Online version via www.eje-online.org  Medical records were retrospectively reviewed (Table 1)with permission from the Aurora St Luke’s MedicalCenter Institutional Review Board. None of thesepatients had florid symptoms or signs of CS; however,they had a few clinical features suggestive of CS thatprompted the work-up. Two of the eleven patients werereferred for evaluation because of an incidentallydiscovered adrenal mass. The remaining nine werereferred to for evaluation due to excessive weight gain,truncal obesity, and/or uncontrolled diabetes mellitus.UFC(1–4perpatient)andNSCsampledbetween2300 hand midnight (2–15 per patient) were measured in allpatients.WetypicallyassessatleasttwoNSCstwonightsin a row as a screening test for CS. The time betweenserial NSC measurements ranged from 1 to 23 months;and the time between serial UFC measurements rangedfrom 1 to 17 months. In some patients, large numberof NSCs were assessed because of the high clinical indexof suspicion and/or because at least one of the twoinitial NSCs sampled was abnormal or at the upperendofthereferencerange.ThereferencerangeforNSCis ! 4.3 nmol/l and is based on 73 healthy, non-obesesubjects (35 male/38 female), ages 37 G 11 ( S . D .)(17, 18).Eight patients had an overnight 1 mg DST. Aserum cortisol at 0800 h ! 50 nmol/l (1.8 mcg/dl) wasconsidered normal suppression. The two patients withadrenocorticotropin (ACTH)-independent CS had com-puterized tomography (CT) scans of the abdomen. Bothhad their scans before the clinical diagnosis of CS wasmade; one for back pain and one for presumed aorticaneurysm. Magnetic resonance imaging (MRI) of thepituitary was performed in the remainder of the ninepatients in whom ACTH-dependent CS was suspected.Sixpatients(sixoutofnine)alsohadIPSsampling(IPSS)for ACTH to differentiate between Cushing’s disease andectopic ACTH syndrome(19). CT scans and MRI scanswere performed either at the referring institution or atour institution. All radiographs were reviewed by J WFindling at the time of consultation. Laboratory evaluation UFC was measured by high performance liquid chroma-tography(HPLC)atourreferencelaboratory(ARUP)orbya variety of methods from the referring physician. Toaccountforthis,UFCdatawerenormalizedbydividingthepatient’s UFC value by the upper limit of the assayreference range(17). Serum cortisol was measured bychemiluminescence immunoassay (Siemans Centaur,Tarrytown, NY, USA). Salivary cortisol was measured byusingELISA(18).Theintra-assayimprecision(coefficient ofvariation,CV)was5.2%at3.1( S . D .,0.2)nmol/l( n Z 10)and 2.6% at10.4 (0.2) nmol/l( n Z 10).Interassay (total)imprecision (CV) was 11% at 2.8 (0.3) nmol/l ( n Z 10),11%at10.1(1.1)nmol/l( n Z 10),and6.9%at25.0(1.7)nmol/l ( n Z 10). Plasma ACTH was measured in samplesfrom IPSS by immunoradiometric assay (IRMA)(20). Allpatientsdidnothaveasimilarwork-upbecausetheywereevaluatedbydifferentphysiciansandspecialistsatvariouscentersduringthecourseofdisease.Wereporttheresultsof those patients for whom we had the minimal requiredinformation. Results All patients were female (25–79 years old) and theirbaseline clinical features are presented inTable 1. Of 11patients, 7 had consistently normal UFC and theremaining 4 had elevations in UFC between 1–2 timesthe upperlimit ofnormal (Table 1andFig. 1A). None had UFC O 2 times the upper limit of normal. Seven of eightpatients who had overnight DST were found to haveabnormal overnight 1 mg dexamethasone suppressionsuggestive of CS. All of the patients had at least somesignificantlyelevatedNSClevels;however,5outof11alsohad some NSC levels within the normal range. Thepercentageofabnormalsalivarycortisollevelsrangedfrom14(patient #3) to 100% (patients #4–8 and 11;Table 2).The two patients with adrenal gland lesions had sup-pressed ACTH levels (3.0–6.2 pg/ml (0.7–1.3 pmol/l))and underwent adrenalectomy. Histopathologyconfirmed the presence of adrenocortical adenomas inthese patients and both had secondary adrenalinsufficiency after surgery. In six out of nine patientswho had MRI, there were unequivocal pituitaryadenomas and they underwent pituitary surgery. Fiveof these six patients had pituitary tumor removal withdevelopment of post-operative adrenal insufficiency. Theremaining patient (patient #7) had a hemihypophy-sectomy and was found to have a pituitary adenomawhich was, however, negative for ACTH by immuno-histochemistry. However, she developed prolongedsecondary adrenal insufficiency post-operatively. Theremaining three of nine patients (#2, 6, and10), whounderwent MRI imaging had no pituitary lesions. Thesepatients had IPSS for ACTH which indicated Cushing’sdisease. All three of these patients underwent pituitarysurgery with resection of pituitary microadenoma thatstained for ACTH. IPSS was also performed in threepatients in whom there were known pituitary lesions(#3, 7, and 9) either at treating physician’sdiscretion orlarge/undefined pituitary lesions which are atypical forACTH-secreting adenomas. Discussion We describe 11 patients with mild spontaneous CS witheither normal or only slightly elevated levels of UFC.Establishing the diagnosis of hypercortisolism in thisgroup of patients required a high index of clinicalsuspicion and multiple measurements of NSC and UFC,in addition to low-dose DST in some patients. The726 S Kidambi and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 www.eje-online.org  measurement of UFC in a 24-h collection has beenconsidered the gold standard for the diagnosis of CS.However, UFC may not accurately reflect the cortisolsecretory state in patients with even the modestimpairment of renal function(8).In addition, most of  the cortisol secreted during a 24-h period is between0400 h and 1600 h. Subtle increases in nighttimesecretion,asmaybeseeninmildCS,maynotbedetectedoronlyintermittentlydetectedin a24-h urine collection(21, 22). Other potential problems with UFC are thedifferent analytical methods used and differing potentialinterferingsubstances(23–25).Sincerepeatedmeasure-ments are usually needed to determine the presence orabsence ofmildorintermittent hypercortisolism, the useof 24-h urine collections can be impractical.Seven of the eleven patients reported here did nothave an elevation of UFC. The high false negative rate inour series may be because we did not obtain as manyUFC as NSC samples. This reflects the practical aspectsof clinical medicine. If the only measurement availablein these patients had been UFC, the diagnosis wouldprobably have been overlooked in many, when a normalUFC was measured the first time.NSC is a sensitive and specific means of determiningthe presence or absence of endogenous hypercortiso-lism. Numerous studies have validated this approachwhich yields a remarkable 93% sensitivity at 100%specificity(17, 26–29). The test is useful in cyclic CSand in children(30, 31), and may be able to distinguishpseudo-Cushing states from CS with 95% diagnosticaccuracy(16, 32).Although NSC measurement is not without fault, the ease with which it can be repeatedmakes it ideal in certain situations.Even though a majority of these patients had NSClevels above the upper limit of normal (4.0 nmol/l(0.15 mcg/dl)), six had NSC levels in the normal rangeon several occasions. For example, patient #3 actuallyhad 14 NSC samples measured over 2 years, becauseseveral of the initial NSCs were at or slightly above theupper limit of the reference range. Careful examinationby an experienced endocrinologist revealed subtle butspecific symptoms and signs of CS, which made it hardto ignore these slightly abnormal NSCs even thoughUFC was normal. Although most of the NSCs were ! 4.0 nmol/l (0.15 mcg/dl), the majority of the levelswere O 3.0 nmol/l (0.11 mcg/dl), suggesting thepotential for very mild, but significant hypercortisolism.Patient #2 had a similar NSC profile. We do not knowthe reason for these variable NSC measurements, butcan only speculate that it might be secondary to cyclicCS(22)or normal biological variability around a mildlyelevated set point. Obviously, both of these studies, NSCand UFC, may need to be performed several times beforethe suspected diagnosis of endogenous hypercortisolismcan be correctly identified.The overnight 1 mg DST is also widely used forscreening test(1, 33), although some patients with CSretain their ability to suppress the cortisol. 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