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*Cushing's Syndrome
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3795-3800
Copyright © 2004 by The Endocrine Society

Jugular Venous Sampling: An Alternative to Petrosal Sinus Sampling for the Diagnostic Evaluation of Adrenocorticotropic Hormone-Dependent Cushing’s Syndrome

Ioannis Ilias, Richard Chang, Karel Pacak, Edward H. Oldfield, Robert Wesley, John Doppman1 and Lynnette K. Nieman

Pediatric and Reproductive Endocrinology Branch (I.I., K.P., L.K.N.), National Institute of Child Health and Human Development; Department of Radiology (R.C., J.D.) and Biostatistics and Clinical Epidemiology Service (R.W.), Warren Grant Magnuson Clinical Center; and Surgical Neurology Branch (E.H.O.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Lynnette K. Nieman, M.D., Building 10, Room 9D42 MSC 1583, 10 Center Drive, Bethesda, Maryland 20892-1583. E-mail: NiemanL{at}nih.gov.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Bilateral sampling of the inferior petrosal sinuses (IPSS) to distinguish Cushing’s disease from the ectopic ACTH syndrome is accurate but risky and technically difficult. Bilateral sampling of the internal jugular vein (JVS) is simpler and presumably safer. To compare jugular and petrosal sinus venous sampling for distinguishing Cushing’s disease from ectopic ACTH syndrome, we studied 74 patients with surgically proven Cushing’s disease, 11 with surgically confirmed, and three with occult ectopic ACTH secretion. Patients underwent JVS and IPSS with administration of CRH on separate days. Ratios of central-to-peripheral ACTH in venous samples were calculated. At 100% specificity, IPSS correctly identified 61 of 65 patients with Cushing’s disease [sensitivity, 94%; confidence interval (CI), 84–98%]. When patients with abnormal venous drainage were excluded, sensitivity was 98% (CI, 90–100%). JVS had a sensitivity of 83% (CI, 71–91%) at 100% specificity. Receiver operated characteristics plot areas under the curve were similar (0.968 ± 0.020 and 0.974 ± 0.016, area under the curve ± SE, JVS vs. IPSS). Although petrosal sampling had better diagnostic accuracy, CIs overlapped (95% CI, 90–100% vs. 86% CI, 78–94%). Centers with limited sampling experience may choose to use the simpler JVS and refer patients for IPSS when the results are negative.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ACTH-DRIVEN CUSHING’S syndrome is caused by excess ACTH secretion, either from a pituitary corticotrope tumor, termed Cushing’s disease, or from an ectopic ACTH source. Because up to 58% of pituitary microadenomas causing Cushing’s disease are not identified by magnetic resonance imaging (MRI) (1), it is important to establish the source of ACTH secretion as pituitary or ectopic. Bilateral sampling of the inferior petrosal sinus (IPSS) for ACTH levels is currently the only diagnostic test with a sensitivity for Cushing’s disease greater than the 90% pretest probability of the condition. Importantly, the test also has very high specificity for the syndrome of ectopic ACTH secretion. However, excellent diagnostic accuracy of IPSS is achieved only at centers with experienced interventional radiologists. Even then, it is technically successful only 85–99% of the time. With worldwide use of this technique, reports of false-negative and false-positive results have decreased the initially reported diagnostic accuracy of 100% to a sensitivity and specificity of about 94% (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14).

IPSS is not widely available because it is technically demanding and requires an experienced interventional radiologist. Additionally, the procedure is associated with neurological complications and venous or pulmonary thromboembolism, albeit rarely (15, 16, 17). In contrast, internal jugular vein sampling (JVS) is easier and may be safer, because the catheters are not advanced as far. In our preliminary study, JVS identified 16 of 20 patients with Cushing’s disease and one patient with ectopic ACTH secretion (18). Based on these results, the study was extended to compare the ability of JVS and IPSS to discriminate between Cushing’s disease and ectopic ACTH secretion.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study protocol

The study was carried out from August 1995 to May 2002 at the National Institutes of Health (NIH) Warren Grant Magnuson Clinical Center in Bethesda, Maryland, after approval by the investigational review board of the National Institute of Child Health and Human Development. Inclusion criteria for initial participation were: 1) clinical and biochemical evidence of hypercortisolism, defined as lack of suppression of cortisol after 1 mg dexamethasone, and/or elevated urine cortisol excretion; 2) plasma ACTH values greater than 10 pg/ml (2.2 pmol/liter); 3) a minimum of 4 wk of hypercortisolism before admission as shown by urine free cortisol at least 2-fold normal; and 4) lack of a definite pituitary tumor on MRI studies obtained by the local physician and reviewed by an NIH neuroradiologist. Criteria for a mass included any round, hypodense area in the sella turcica on gadolinium-enhanced T1 images with a size larger or equal to 4 mm. Patients suffering from conditions linked with pseudo-Cushing’s syndrome, such as depression, alcoholism, or marked obesity, were not included in this study without clinical features of hypercortisolism (19). Sixty-six women and 22 men (aged 20–61 yr) met these criteria and were evaluated consecutively at the NIH Clinical Center after giving informed consent. Pseudo-Cushing’s syndrome was excluded in each by history, physical examination, and a midnight cortisol level more than 7.5 µg/dl (207 nmol/liter) (20). Each patient underwent gadolinium-enhanced pituitary MRI, standard testing with ovine CRH stimulation (21), and 8 mg dexamethasone suppression (22). Patients with suspected ectopic ACTH secretion underwent computed tomography, MRI, and somatostatin receptor scintigraphy (Octreoscan; Mallinckrodt Inc., Hazelwood, MO) studies to locate the tumor. Patients with a pituitary MRI scan that showed a definite pituitary mass (>4 mm), CRH stimulation test, and dexamethasone suppression test consistent with Cushing’s disease were excluded from participation in JVS or IPSS. This decision was based on a previous observation that this combination of positive biochemical test results has a high diagnostic accuracy for Cushing’s disease (23). When these test results and an MRI suggested a pituitary tumor, we judged IPSS to be unnecessarily risky. Patients were excluded from this protocol and central venous sampling if they were not currently hypercortisolemic, as shown by a midnight cortisol level more than 7.5 µg/dl and elevated urine cortisol excretion determined within 10 d of the planned study. Of the 88 patients in the study, 74 patients had surgically proven Cushing’s disease (including nine patients with a pituitary lesion on MRI who did not undergo venous sampling and had ACTH-secreting adenomas at surgery) and 14 had presumed ectopic ACTH secretion (11 with known and three with occult ACTH-secreting tumor) (Fig. 1Go).



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  		FIG. 1. Flow diagram of the study. Gd-MRI, Gadolinium-enhanced pituitary MRI; TSS, transsphenoidal pituitary surgery; CD, Cushing’s disease; EAS Loc., localized source of ectopic ACTH secretion; EAS Occ., occult source of ectopic ACTH secretion.

 
Venous sampling and analysis

Seventy-nine patients without a visible tumor on pituitary MRI underwent JVS and/or IPSS in two sessions on different days. The sampling was performed by two experienced interventional radiologists (J.D., R.C.) as previously described, including the administration of systemic heparin (5000 U iv) to reduce the risk of thromboembolism. In general, for jugular sampling, catheters were inserted in the internal jugular vein except when sc fat in the neck did not permit venipuncture, necessitating a femoral approach, whereas petrosal sampling was usually performed via the femoral route (2, 18). For JVS, the tips of the catheters were advanced to the level of the angles of the mandible (Fig. 2Go). This level was chosen to accommodate the inferior petrosal sinuses, which occasionally enter the jugular vein at a variable distance below the jugular bulb. Venography was obtained and evaluated during IPSS to document normal venous anatomy and catheter placement (5, 24). CRH administration (1 µg/kg body weight) and blood sampling (2 and 1 min before and 3, 5, and 10 min after CRH) were the same for both procedures. Plasma ACTH was measured by RIA (Covance Laboratories, Vienna, VA) or by immunochemiluminometric assay (Nichols Institute Diagnostics, San Clemente, CA).



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  		FIG. 2. Schematic placement of the catheters for IPSS (indicated by 1) and JVS (indicated by 2). The correct position of the catheters for the sampling is verified fluoroscopically.

 
The right-to-left venous ACTH ratios for IPSS and JVS were calculated. As previously described, right-to-left venous ACTH ratio values of less than 0.7 or greater than 1.4 were considered to represent a lateralization to the left or right, respectively (2). The concordance of lateralization between IPSS and JVS, excluding cases of nonlateralization, was assessed with Cohen’s {kappa} statistic (25). We calculated the central-to-peripheral (C/P) ACTH ratios using the highest of the petrosal or jugular values at each time point. We interpreted diagnostic results using IPSS criteria that previously excluded ectopic ACTH secretion with 100% specificity [any C/P ACTH ratio >2 before or C/P of >3 after the administration of CRH (2)], as well as with the lowest C/P criteria that maintained 100% specificity. For JVS we interpreted diagnostic results with the lowest C/P criteria that maintained 100% specificity. We calculated sensitivity, negative predictive value, diagnostic accuracy, and likelihood ratio for a negative test (negative LR; defined as the probability of an individual with the condition having a negative test divided by the probability of an individual without the condition having a negative test), as well as 95% confidence intervals (CI) for each measurement (26, 27). We examined the diagnostic utility of the tests using McNemar’s test and receiver operated characteristics (ROC) plots (28), which were compared using the Hanley-McNeil statistic (29), considering a two-sided P value < 0.05 to be significant for both evaluations.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Of the 65 patients with Cushing’s disease, one had only IPSS; JVS was not performed because of bilateral groin hematomas after petrosal sampling and difficult jugular vein access in the neck. One patient with ectopic ACTH secretion due to recurrent pulmonary carcinoid had only JVS. As this patient was judged to need immediate medical therapy, the research procedure (IPSS) was cancelled. Two adverse events included transient arm numbness after anesthetic infiltration in the neck for catheter insertion during JVS and an epidural bleed without neurological sequelae during IPSS. Results presented here include 21 patients reported previously (18).

ACTH values from JVS were generally lower than those obtained with IPSS, presumably due to venous dilution (Fig. 3Go). The concordance of lateralization between IPSS and JVS was low ({kappa} = 0.46; 95% CI, 0.31–0.60).



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  		FIG. 3. Representative Bland-Altman plot of ACTH levels from right (R) IPSS and R JVS in patients with Cushing’s disease. ACTH values from JVS were generally lower than IPSS, due to venous dilution, as can also be seen in Fig. 4Go.

 
Using a C/P ratio of more than 1.6 before or a C/P ratio of more than 2.5 after CRH (the lowest values that maintained 100% specificity), IPSS correctly identified Cushing’s disease in 61 of 65 patients (sensitivity 94%; CI, 84–98%) (Table 1Go and Fig. 4Go). Using the earlier criteria (a C/P >2.0 before or >3.0 after CRH), IPSS correctly identified 60 of 65 patients with Cushing’s disease. Three of these patients had a diagnostic C/P ratio only before or after CRH administration. Four of the five patients with Cushing’s disease with a nondiagnostic ratio before and after CRH had abnormal venous drainage on venography. Their responses to CRH and dexamethasone tests suggested Cushing’s disease, and all had ACTH-staining adenomas resected at transsphenoidal exploration. IPSS identified 13 of 13 patients with ectopic ACTH secretion. Other IPSS criteria that excluded all patients with ectopic ACTH secretion had similar sensitivity for Cushing’s disease (Table 1Go). When four patients with abnormal venous drainage and a nondiagnostic ratio before and after CRH were removed, IPSS correctly identified Cushing’s disease in 60 of 61 patients (sensitivity 98%; CI, 90–100%) and had a diagnostic accuracy of 99% (CI, 96–100%).


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  		TABLE 1. Results of IPSS and JVS and corresponding diagnostic utility in excluding Cushing’s disease with 100% specificity

 


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  		FIG. 4. C/P levels of ACTH before (baseline) and after CRH administration obtained with IPSS and JVS in patients with Cushing’s disease (CD) or ectopic ACTH secretion (EAS). Closed triangles represent patients with abnormal petrosal sinus venous anatomy; closed circles represent patients with presumed occult ectopic ACTH secretion.

 
Although the basal C/P ratios during JVS overlapped considerably between the patient groups, CRH administration increased the diagnostic separation (Fig. 4Go). An arbitrary criterion set at 100% specificity (C/P >1.7 before or >2.0 after CRH) correctly identified 53 of 64 patients with Cushing’s disease (sensitivity 83%; CI, 71–91%) (Table 1Go). JVS correctly identified Cushing’s disease in all four patients with abnormal petrosal sinus anatomy and negative IPSS results. The diagnostic accuracy of JVS (86% CI, 78–94%) was lower than IPSS (94% CI, 88–99%; Table 1Go), but this difference did not reach statistical significance (P > 0.05, McNemar’s test; in this comparison the patient with Cushing’s disease who had only IPSS and the patient with ectopic ACTH secretion due to recurrent pulmonary carcinoid who had only JVS were not included). The negative LR of 0.02–0.08 for IPSS led to large changes from pre- to posttest odds ratio and the negative LR of 0.17 for JVS altered the pretest odds ratio to a moderate degree (27). The ROC plot area under the curve (AUC) was similar for JVS after CRH administration (0.968 ± 0.020, AUC ± SE) and for IPSS before (0.942 ± 0.026) and after (0.974 ± 0.016) CRH administration but was significantly lower for baseline JVS (0.820 ± 0.059; P < 0.05) (Fig. 5Go).



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  		FIG. 5. ROC plots for IPSS and JVS before (baseline) and after CRH administration. The ROC plot AUC is similar for baseline and post-CRH IPSS and for post-CRH JVS, but it is significantly lower for baseline JVS compared with baseline IPSS (P = 0.021), after CRH IPSS (P = 0.004), and after CRH JVS (P = 0.001).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study demonstrates that JVS with CRH administration can be used as the first-line invasive test to establish a diagnosis of Cushing’s disease. The study also shows the importance of venography during IPSS, because abnormal anatomy indicates that the results may be falsely negative.

Earlier studies of basal JVS were disappointing, possibly because catheter placement in the jugular bulb may have been above the entry of petrosal sinus effluent (30, 31). Undoubtedly, the lack of CRH also reduced the previous diagnostic utility of JVS. To obviate these issues, we positioned the catheters at the angle of the mandible, below the petrosal sinus inflow, and gave CRH during each procedure.

Figure 4Go illustrates that CRH administration was essential for acceptable diagnostic performance of JVS. Because of the dilution of ACTH in the jugular vein, C/P JVS ratios are lower than IPSS ratios in patients with Cushing’s disease, and there is less separation between the patient groups. Therefore, despite similarities in the ROC results, JVS values close to the diagnostic cutoff point should be viewed with skepticism, because they represent a ratio of a less robust peak central value to the peripheral result. Additionally, any result that is close to a diagnostic criterion, whether for IPSS or JVS, should be considered suspect, because tests may perform differently in different centers. For example, although current ACTH assays are relatively similar, it is possible that assay differences might lead to a different C/P result that would cross the criterion threshold. Also, this study includes only 11 patients with known and three with presumed ectopic ACTH secretion. Further experience with additional patients might result in a revision of the cutoff point that excludes all patients with this condition. We must emphasize that caution must be applied in the interpretation of results, because the cutoff criteria that work well for IPSS do not do so for JVS. These issues are illustrated by a recent report (32) that compared JVS with IPSS using the same cutoff criteria (C/P ratio >2 at baseline and >3 after CRH) for both modalities, in 32 patients with Cushing’s disease and 3 patients with ectopic ACTH secretion. The sensitivity for JVS was 81%, whereas IPSS had a sensitivity of 94% (32).

Although IPSS diagnosed more patients correctly than JVS, the procedure is technically demanding and has been associated with rare reports of cerebrovascular accident as well as thromboembolic events (15, 16, 17). Presumably, the risk of thromboembolism is similar for both JVS and IPSS because of the increased overall risk for these events in hypercortisolism (33). However, cerebrovascular accidents have been attributed to placement of a catheter in small intracranial vessels, which occurs during IPSS but not during JVS. Moreover, jugular sampling, after neck venipuncture, may entail less hemorrhagic risk, because with this procedure the patient’s head can be elevated soon after the procedure, thus having low venous pressure in the vessels through which access was obtained.

In this study the one adverse event during JVS was related to instillation of anesthetic in the neck, which temporarily reduced sensation in the arm. Transient brachial and phrenic nerve paralysis are known complications of cervical anesthetic infiltration and could occur when this site is used for either JVS or IPSS (34, 35). Thus, although serious complications from IPSS are rare, it is likely that JVS is safer.

Based on the available information, when should venous sampling be recommended for the differential diagnosis of ACTH-dependent Cushing’s syndrome, and which protocol should be used? Unfortunately, no large study evaluated responses to noninvasive and invasive biochemical and imaging tests to provide an algorithm to guide this judgment. Midgette and Aron (36) used a decision analysis approach, assuming 100% diagnostic accuracy for IPSS and 81% sensitivity and 79% specificity for the high-dose dexamethasone suppression test, to evaluate cost effectiveness in dollars per life saved. Based on these assumptions, they found that the selective use of IPSS after a negative high-dose dexamethasone suppression test was the most cost-effective approach to the differential diagnosis of ACTH-dependent Cushing’s syndrome (36). Although useful, their model does not integrate other tests, such as the CRH stimulation test or the result of imaging studies. Until an analogous study assesses JVS, its cost effectiveness remains to be proven. The cost of JVS compared with IPSS is not established; although the catheters differ and the jugular procedure is shorter, the personnel needed and other test requirements are similar.

Overall, IPSS remains the single best diagnostic test for the differential diagnosis of ACTH-dependent Cushing’s syndrome. However, in the United States and other countries without universal access to health care, factors apart from diagnostic accuracy may influence the diagnostic strategy. IPSS is costly and not widely available in the United States. If there is no experienced center nearby, or if the patient cannot afford the more expensive sampling test, clinicians may wish to rely on dexamethasone and CRH testing, in the hope that both tests will be consistent with Cushing’s disease. Although up to 98% of patients with positive results on both dexamethasone and CRH testing have Cushing’s disease, in four series, 18 to 65% of patients with Cushing’s disease lacked a response to one or both of these tests (11, 23, 37, 38, 39).

As presented in this study, JVS represents an alternative to the initial use of IPSS or testing with noninvasive agents alone. JVS can be performed easily and safely in institutions without experience in the technically more demanding and potentially more hazardous procedure of IPSS. Although this was a study of efficacy and not effectiveness in general practice, we believe that the results of this study are generalizable and that the sensitivity (83%) will not decline substantially outside a clinical research center. However, JVS needs also to be evaluated and scrutinized under conditions of everyday medical practice.

If the results of this study are confirmed elsewhere, centers with limited IPSS experience may choose to use this simpler and theoretically safer procedure. This strategy would limit the need for confirmatory IPSS to those patients with negative JVS results. Using this series as an example of that strategy, 68% of patients with normal pituitary MRI undergoing JVS would be correctly identified as having Cushing’s disease, and the remaining 32% would have required other tests.


   Acknowledgments
 
We thank the staffs of the inpatient units and Radiology Department as well as the Endocrinology and Neurosurgery Fellows for their care of these patients.


   Footnotes
 
This work was supported by the intramural division of the National Institutes of Health (Bethesda, MD).

This work was presented in part at The Endocrine Society’s 85th Annual Meeting, June 19–22, 2003, in Philadelphia, Pennsylvania.

Abbreviations: AUC, Area under the curve; CI, confidence interval; C/P, central-to-peripheral; IPSS, inferior petrosal sinus sampling; JVS, internal jugular vein sampling; LR, likelihood ratio; MRI, magnetic resonance imaging; ROC, receiver operated characteristics.

1 Deceased. Back

Received November 19, 2003.

Accepted April 16, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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