endocrine angiography adrenal glands
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Hillman B]. Disorders of the renal arterial circulationand renal vascular hypertension. In: Pollack's clinical urography. Philadelphia: WE Saunders, 1990;2127-2187.
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4:10 pm
Endocrine AngiographyAdrenal Glands
john L. Doppman, MD
Learning objective: The participant will learn the latestangiographic and sampling techniques for localiZingendocrinal tumors.
Pheochromocytomas
COMPUTED tomography and metaiodobenzylguanidinescintigraphy have solved most of the problems of localiZing pheochromocytomas. Extra-adrenal pheos generally lie in the abdomen near the renal hilum. Pheochromocytomas in the organ of Zuckerkandl are supplied bythe inferior mesenteric artery, but arteriography is rarelyreqUired before operation. Extra-adrenal pheochromocytomas are readily visualized by screening coronalmagnetic resonance (MR) images by virtue of their highsignal intensity on T-2-weighted and short inversiontime inversion recovery images. Ectopic pheochromocytomas of the urinary bladder may be missed on MR because of the high signal intensity of the adjacent urinewithin the bladder. Arteriography is sometimes necessary.
HyperaldosteronismSome investigators have presumed that computed tomography (CT) and iodocholesterol scanning have replaced the need for venous sampling in patients with
hyperaldosteronism. As cross-sectional imaging improves with 3-mm-thick bolus-enhanced helical scans of
the adrenal glands, many patients with hyperaldosteronism tend to show multiple small adrenal nodules, even inthe presence of a single dominant aldosteronoma. Iodo
cholesterol scanning fails to resolve lesions smaller than
15 mrn. For these reasons, adrenal venous sampling isbeing resurrected as a critical study in distinguishing unilateral aldosteronomas from idiopathic hyperaldosteronism due to hyperplasia. In our experience 0,2) more
than one half the patients referred with a diagnosis ofhyperplasia based on multiple unilateral or bilateral nodules have aldosteronomas and will respond to unilateraladrenalectomy. The role of adrenal sampling is to provethat one gland is completely suppressed, because underthese circumstances resection of the contralateral glandinvariably cures hyperaldosteronism and improves control of hypertension.
Adrenal venous sampling in patients with hyperaldosteronism should always be performed before and aftercorticotropin (ACTH) stimulation. That hormone stimulates the release of both cortisol and aldosterone fromthe healthy adrenal gland. When ACTH stimulation isprolonged, as in Cushing disease, aldosterone production escapes from ACTH control; acutely, however,ACTH greatly enhances the sensitivity of adrenal veinsampling. Catheterization of the left adrenal vein is easilyperformed with an S-shaped catheter or a high-flowTracker catheter passed through a catheter with a recurred tipp, such as the Simmonds I catheter. We routinely place a Mikaellson catheter into the right adrenalvein, haVing first placed an additional hole just proximalto the tip on the superior aspect. The right adrenal veinis less than 1 cm long, and the end hole of the catheterusually is occluded when the right adrenal vein is catheterized. A small hole proximal to the tip allows aspiration of effluent from the gland.
All patients should receive anticoagulation therapy.The principle risk of this procedure is not extravasationof contrast but adrenal venous thrombosis, the cause ofthe rare adrenal infarction and, if bilateral, of addisoniancrisis. Samples are obtained before and 15 minutes aftera bolus injection of 250 pg ACTH followed by a continuous infusion of 500 mL saline containing 250 mg ACTH.The aldosterone:cortisol ratios must be calculated to correct for the varying dilution of samples from the right andleft adrenal veins. In the presence of an aldosteronoma,samples from the contralateral adrenal gland show analdosterone:cortisol ratio less than 1 and generally lowerthan the peripheral aldosterone:cortisol ratio. At the conclusion of the study, gentle retrograde injections of contrast are performed to identify the position of the catheter in the adrenal vein, but no effort is made to performa diagnostic adrenal venogram. Using this technique, our
success rate in the last 50 bilateral adrenal vein catheterizations has been 99%. In more than one half the patients
with an imaging diagnosis of hyperplasia, the presenceof an aldosteronoma has been established and confirmed by adrenalectomy (1). Rarely are aldosteronomastoo small to be seen by modern cross-sectional techniques. More common is the dilemma of multiple nodules, which, even in the presence of a dominant nodule,confirms a diagnosis of hyperplasia.
Pancreatic Islet Cell TumorsIn our experience, only 50% of insulinomas are visualized by cross-sectional imaging (CT, MR, or ultrasound),although there may be a referral bias. Bolus-enhancedspiral CT is the best noninvasive localizing study, but inour experience it is successful in fewer than one half thepatients. When noninvasive studies are negative, pancreatic arteriography and portal venous sampling areperformed, but sampling of the portal vein has beenreplaced by stimulating the release of insulin with interarterial injection of calcium at the time of arteriography(3).
In our experience, arteriography visualizes about 50%of insulinomas. Immediately after each selective arteriogram (gastroduodenal, splenic, superior mesenteric), abolus injection of 0.025 mEq/kg calcium (l mg/kg) in theform of calcium gluconate diluted to a 5-mL bolus isinjected, and samples from the right hepatic vein areobtained before and 20, 40, and 60 seconds after calciumgluconate injection. When the vessel supplying the insulinoma is injected, a twofold or greater increase ofinsulin is measured in the right hepatic vein on the 20- or40-second samples. Insulin levels generally decline bythe 60-second sample. However, patients with historiesof frequent hypoglycemic attacks are at risk for a hypoglycemic episode at the time of calcium stimulation.O'Shea et al (4) have successfully reduced the dose ofcalcium from 0.025 mEglkg to 0.00625 mEglkg and obtained positive responses in five patients. It may turn outthat this reduced dose is equally efficacious and safer.However, hypoglycemia can always be controlled at thetime of angiography by a bolus of 500/0 glucose, whichshould be on hand during calcium stimulation studies.Patients experience a mild warm sensation in the abdomen as the only side effect of intra-arterial calcium injection. In our first 25 occult insulinomas, arteriographyyielded positive findings in 12 of 25 (48%), portal venoussampling had positive results in 6 of 9 (66%) but wassubsequently discontinued, because intra-arterial calcium stimulation was positive in 22 of 25 (88%) insulinomas. Our series now has 40 patients, and calcium gluconate stimulation has been positive in 93% of them (37of 40).
Calcium stimulation and venous sampling should beperformed in all patients with hyperinsulinism and multiple endocrine neoplasia syndromes, because such patients usually have more than one islet cell tumor, andthe larger, more readily apparent tumor at the time of
surgery may not be the adenoma responsible for the
hyperinsulinism.Intraoperative ultrasound has become so sensitive
that many surgeons now believe that once a diagnosis ofinsulinoma is established, the patient should be sent directly to the operating room if staff experienced in intraoperative ultrasound is available. At the Mayo Clinic,patients are taken directly to surgery after the diagnosis,with no attempts at preoperative localization. I have notreached this stage of confidence in intraoperative ultrasound, although its sensitivity in our last 30 patients hasbeen 100%.
A similar technique has been used extensively to localize gastrinomas. Intra-arterial secretin (30 units) is injected selectively into the gastroduodenal, proximalsplenic, and superior mesenteric arteries. Because morethan 60% of gastrinomas are malignant, secretin stimulation in the hepatic artery should be performed as well(although this is not necessary in insulinomas becausefewer than 10% are malignant). A l.5-fold increase ingastrin in the right hepatic vein after interarterial injection of secretin localizes the gastrinoma to the downstream distribution of the injected artery. A positive response in the gastroduodenal artery does not distinguishbetween lesions in the pancreatic head and the increasingly common gastrinomas in the duodenal wall. Arterialstimulation and venous sampling is the single most successful localizing study for gastrinomas (more than 90%success), although octreotide scanning is proving to be asuccessful noninvasive competitor. More than 75% ofextrahepatic and pancreatic gastrinomas are demonstrated by octreotide scanning, which is better than all ofthe noninvasive imaging modalities combined.
Parathyroid LocalizationThe most common localization problem in endocrinology involves the parathyroid gland. There is an epidemicof low-grade hyperparathyroidism in middle-aged andelderly women, many of whom do not require surgerybecause the hypercalcemia is detected incidentally anddoes not threaten their well-being. Patients without previous surgery require no localization studies, because anexperienced parathyroid surgeon (one who does ten to12 operations each year) should have a cure rate at theinitial operation of more than 95%.
After a failed operation, all patients should undergononinvasive imaging studies-ultrasound, CT, MR, andSestabimi imaging. If any two procedures produce positive findings at the same site, angiography is not indicated. Localization by the noninvasive work-up is successful in our experience (5,6) in about 60% of patientshaving repeated operations. If localization is not provided by noninvasive studies, parathyroid arteriographyand venous sampling are performed. Results of arteriography are positive in about 50% of the cases and providea road map of venous drainage that has often been altered by previous unsuccessful surgery. Both internalmammary and both inferior thyroid arteries should beinjected selectively and, if negative, so should both su-
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perior thyroid arteries. Parathyroid adenomas are demonstrated as areas of diffuse opacification. When arteri
ography is negative, venous sampling will provide a localized gradient in more than 90% of patients (7).
However, this study provides regionalization, not precise localization, of abnormal parathyroid tissue, because the adenoma is not visualized.
We recently applied a technique that involved stimulating the release of parathyroid hormone at the time of
arteriography to replace parathyroid venous sampling.This technique is based on the same principle as the use
of interarterial calcium to localize insulinomas and interarterial secretin to localize gastrinomas. Initially we performed a prolonged infusion of normal saline into theselectively catheterized artery to provide a hypocalcemicstimulus, which is responsible for releasing parathyroidhormone. However, we discovered that the contrast material used for arteriography is also a powerful stimulantfor releasing parathyroid hormone.
A catheter is placed in the superior vena cava at thetime of parathyroid arteriography. Because the inferiorthyroid veins, right and left vertebral veins, and the thymic veins drain into the innominate veins, the catheter inthe superior vena cava just below the junction of theright and left innominate veins samples the entire effluent from the neck and anterior mediastinum. A baseline5-mL sample is obtained immediately before each selective arteriogram and then 20, 40, and 60 seconds after thearteriogram. A 1.5-fold elevation of parathyroid hormonein the samples after arteriography localizes the adenomato the distribution of the injected artery. Our experiencewith this technique is evolving, but it has proved successful in more than 80% of our last 20 cases and obviated the need for the more tedious and difficult parathyroid venous sampling. In at least one third of these cases,arterial stimulation with venous sampling was positive when the arteriogram failed to demonstrate the adenoma.
The two most likely sites for overlooked parathyroidadenomas are in the tracheo-esophageal grove and inthe anterior mediastinum. Recently we have seen an increasing number of glands in an undescended locationat the level of the carotid bifurcation (8). These glandsare usually supplied by the superior thyroid artery andoften cannot be reached from a standard collar incision.A less common site for ectopic glands is in the spacebetween the aorta and pulmonary artery (aortopulmonary window). We have seen eight patients with glandsat this site in the past year (9). Blood supply is from thebronchial artery. These glands can be detected readilyon CT and Sestabimi scanning if the aortopulmonarywindow is appreciated as a site for ectopic glands.
There are two nonsurgical techniques to treat enlarged parathyroid glands. Adenomas can be stained byinjecting contrast material forcefully into the feeding artery. We have stained more than 50 mediastinal adenomas; in fact, we rarely perform sternotomy to removemediastinal adenomas (0). Usually, a Tracker catheter
can be inserted into the thymic branch from the internalmammary artery. A high-flow Tracker catheter is preferred because contrast material must be injected rapidlyenough to produce an intense stain of the adenoma.Staining is generally associated with mild substernalburning that patients suggest is cardiac in origin. Theyshould be warned of this sensation, which disappearswhen the injection is stopped. We repeatedly stain adenomas until a persistent stain is obtained that does notfade for 15 minutes. Often the adjacent thymic tissue isstained as well. A CT scan should be performed at 24hours to document persistent contrast in the adenoma, afinding that indicates permanent ablation in our experience. We have, however, returned to stain a recurrentadenoma, a technique not available with embolizationbecause the feeding artery is blocked. We originally usedembolic material but found that staining with contrastmedia is more effective. We do not stain adenomas ofthe neck because the surgery is generally simple.
The second technique for treating enlarged parathyroid glands is the direct injection of ethyl alcohol underCT or preferably ultrasound control OI). I do not thinkthat this is acceptable treatment for cervical adenomasbecause the risk to the recurrent laryngeal nerve andother vital structures is considerable. Local alcohol injection often renders subsequent surgical extirpation extraordinarily difficult. The intralesional injection of alcohol for well-localized cervical adenomas in patients withno previous surgery is never indicated because the potential complications are serious and the surgery issimple and extraordinarily effective. However, in patients with chronic renal failure and secondary hyperparathyroidism, often hypercalcemia can be controlledby injecting hyperplastic glands. This technique rarelyoffers a cure but often will control hypercalcemia, a satisfactory outcome in patients with chronic renal failurebut not in those with adenomas.
Petrosal Sinus SamplingPetrosal sinus sampling in patients with ACTHdependent Cushing syndrome is the most reliable technique for distinguishing pituitary from ectopic ACTHproduction and for lateralizing the microadenoma whenMR of the pituitary gland produces negative findings(2). Neuroradiologists claim petrosal sinuses as theirown, but drainage actually occurs into the jugular veinbelow the bulb and therefore outside the base of theskull (13). In many hospitals, petrosal sinus sampling isperformed by general angiographers. It should alwaysbe performed bilaterally with simultaneous sampling before and after the administration of corticotropinreleasing hormone (14), which was approved recentlyby the Food and Drug Administration in June 1996. Weperform the study with 4-Fr polyethylene catheters thathave a 20-degree hockey-stick terminal curvature. Inmost instances, inferior petrosal sinuses drain into theanteromedial aspect of the internal jugular vein belowthe base of the skull. If the patient reports ear pain, thenthe search has gone too high. In 95% of the patients, the
procedure is simple. In 5%, the petrosal sinuses are replaced by either a plexiform network of vessels (4%) ordo not connect at all with the internal jugular vein onone side 0%) (15). Tracker catheters may also fail undersuch circumstances. They can be used to cross from theavailable petrosal sinus to the contralateral cavernoussinus to obtain bilateral samples.
Tracker catheters are not necessary for successful petrosal sinus sampling and add significantly to the cost ofthe procedure. Neuroradiologists use such microcatheters very frequently and many insist that sampling beperformed in the cavernous sinuses (6). Placing Trackercatheters in the cavernous sinuses is not difficult technically, but we have published data (7) showing that it isunnecessary, expensive, and if widely applied wouldprobably be associated with more serious consequences(such as cavernous sinus thrombosis) than have beenassociated with petrosal sinus sampling. We have performed more than 1,000 petrosal sinus samples with onlyone serious complication (8).
ReferencesI. Doppman JL, Gill JG, Miller DL, Chang R, Gupta R,
Friedman TC, et al. Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: reliability of CT. Radiology1992; 184:677---682.
2. Doppman J1. The dilemma of bilateral adrenocortical nodularity in Conn's and Cushing's syndromes.Radiol Clin North Am 1993; 31:1039-1050.
3. Doppman JL, Chang R, Fraker DL, Norton JA, Alexander HR, Miller DL, Collier E, Skarulis MC, and Gorden P. Localization of insulinomas to regions ofpancreas by intra-arterial stimulation with calcium.Ann Intern Med 1995; 123(4):269-273.
4. O'Shea, D, Rohrer-Theus AW, Lynn JA, Jackson JE,Bloom SR. Localization of insulinomas by selectiveintraarterial calcium injection. J Clin EndocrinolMetab 1996; 81: 1623-1627.
5. Doppman JL, Miller D1. Localization of parathyroid tumors in patients with asymptomatic hyperparathyroidism and no previous surgery. J Bone MinRes 1991; 6(2):S153-S158.
6. Miller DL, Doppman JL, Krudy AG, Shawker TH,NortonJA, VUcichJJ, et al. Localization of parathyroid adenomas in patients who have undergone surgery. Part II. Invasive procedures. Radiology 1987;162:138-141.
7. Sugg SL, Fraker DL, Alexander R, Doppman JL,Miller DL, Chang RC, et al. Prospective evaluationof selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for primary hyperparathyroidism. Surgery1993: 114:1004-1010.
8. Doppman JL, Shawker TH, Krudy AG, Miller DL,
Marx SJ, Spiegel AM, et al. Parathymic parathyroid.CT, US, and angiographic findings. Radiology 1985;157:419-423.
9. Doppman JL, Skarulis MC, Chen CC, Chang R, PassHI, Fraker D, et al. Parathyroid adenomas in theaortopulmonary window. Radiology (In press).
10. Doherty GM, Doppman JL, Miller DL, Gee MS, MarxSJ, Spiegel AM, et al. Results of multidisciplinarystrategy for management of mediastinal parathyroidadenomas as a cause of persistent primary hyperparathyroidism. Ann Surg 1992; 215:101-106.
II. Karstrup S, Transbal I, Holm HH, Glenthoj A, Hegedus 1. Ultrasound guided chemical parathyroidectomy in patients with primary hyperparathyroidism.Br J Radiol 1989; 62:1037-1042.
12. Oldfield EH, DoppmanJL, Nieman LK, Chrousos GP,Miller DL, Katz DA, et al. Bilateral inferior petrosalvein sampling with and without corticotropin releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 1991; 325:897-905.
13. Miller DL, Doppman J1. Petrosal sinus sampling.Technique and rationale. Radiology 1991; 178:3747.
14. DoppmanJL, Oldfield E, Krudy AG, et al. Anatomical and technical considerations of inferior petrosalsinus sampling for Cushing's disease. Radiology1984; 150:99-103.
15. Miller DL, Doppman JL, Chang R. Anatomy of thejunction of the inferior petrosal sinus and the internal jugular vein. AJNR 1993; 14:1075-1083.
16. Teramoto A, Nemato S, Takakura K, et al. Selectivevenous sampling directly from cavernous sinus andCushing'S syndrome. J Clin Endocrinol Metab 1993;76:630-641.
17. DoppmanJL, Nieman LK, Chang R, YanovskiJ, Cutler GB, Chrosos GP, et al. Selective venous sampling from the cavernous sinuses is not a more reliable technique than sampling from the inferior petrosal sinuses in Cushing's syndrome. J ClinEndocrinol Metab 1995; 80:2485-3489.
18. Miller DL, DoppmanJL, Peterman SB, Nieman LK, Oldfield EH, Chang R. Neurologic complications ofpetrosal sinus sampling. Radiology 1992; 185:143147.
Part III (C302)Moderator: James F. Benenati, MD
2:30 pm
Risk Assessment and Physical Examination inVascular DiseaseJames F. Benenati, MD
Learning objectives: Physicians will be aware of riskfactors associated with peripheral vascular disease(PVD) and how these risk factors may influence the
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