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10 Arterial Stimulation Venous Sampling forPancreatic Endocrine Tumors
a
153
Fig. 10.1 Example of ASVS results for insulinoma in the pancreatic tail. (a) Illustration showing
small hypervascular mass in the pancreatic tail. (arrow) A calcium gluconate is injected through a
microcatheter and venous sampling through a reverse-curve shaped catheter in the hapatic vein (b)
Graph of results from venous sampling after calcium stimulation. There is marked increase in
insulin levels starting at 30 seconds after calcium injection into the splenic artery
After each vessel is sampled, the catheter or microcatheter is repositioned into
the next appropriate artery. At least 5min should elapse between each calcium
injection.
When testing for insulinomas, a twofold or higher rise from baseline is the
threshold Doppman established and has been used to determine a positive result in
most published studies [4]. However, a more recent analysis suggests using a
slightly higher threshold of 2.7-fold or higher to consider the test positive for more
accurate results [45]. When testing for gastrinomas, a 50% or higher rise at 30s
after injection is the threshold used for a positive result.
154
C. T. Burke
Outcomes
Because insulinomas are rare lesions, and many of them may be identied and
treated based on cross-sectional imaging alone, there are very few large studies
evaluating this test’s effectiveness.
In one of the most extensive studies to date, Guettier etal. from the National
Institutes of Health (NIH) published a retrospective review of 45 patients who
underwent ASVS to localize insulinomas [41]. In this study, 45 patients with suspected insulinomas, based on fasting hypoglycemia, with negative cross- sectional
imaging studies underwent ASVS.All patients received 0.0125mmol Ca/kg, except
in obese patients whose dose was reduced to 0.005mmol Ca/kg. A total of 38/45
(84%) lesions were correctly localized and resected. One interesting nding from
this study was the variability in the response. While a twofold threshold was used
for a positive test, the mean increase in insulin concentration was 7.9-fold. However,
when one looks at the distribution, there was a wide range in responses, likely
reecting the difference in tumor size and/or behavior.
Overall, the NIH experience showed preoperative ASVS to be a reliable method
to localize insulinomas. There were only two false positives (4%) in which the
tumors were localized to the wrong anatomic area. There were also ve falsenegative tests (11%). One of these was attributed to a technical error related to the
catheter position. The other was associated with the reversal of ow in the GDA
from celiac stenosis in a patient with a lesion in the pancreatic head. This case illustrates the importance of ensuring the calcium is delivered to the anatomic region (in
this case, the pancreatic head) being studied.
In a recent meta-analysis and systematic review, Wang etal. studied the diagnostic value of ASVS for insulinomas [46]. The authors were able to pool ten studies
comprising 337 patients for their analysis. The authors found a sensitivity of 93%,
a specicity of 86%, a positive predictive value of 6.8, and a negative predictive
value of 0.08. These ndings support the use of ASVS as a test with high diagnostic
value inlocalizing the tumor before surgery and exceed the reported sensitivities
and specicities of cross-sectional imaging.
Most of the published studies on the value of ASVS have used the 2.0 threshold
for a positive test, though this threshold has not been validated in larger studies. One
group of investigators applied a decision tree analysis to their data and found a
slightly higher threshold of 2.7 times over baseline yielded more accurate results
[45]. Sensitivity, specicity, and accuracy improved from 100%, 69%, and 79.1%
with a twofold increase threshold to 100%, 91.4%, and 94.2%, respectively, when
using the 2.7-fold increase threshold.
As mentioned earlier, there is some evidence to suggest the ASVS may also be
useful in distinguishing between occult insulinomas and nesidioblastosis [47]. This
distinction has become more critical in recent years as the treatment for nesidioblastosis has changed from a surgical approach to a more conservative management [30,
48, 49]. While these are both rare conditions, researchers at the Mayo Clinic were
able to study 116 patients with either insulinoma or nesidioblastosis and underwent
ASVS [47]. The investigators were able to compare the two groups to see if the test
10 Arterial Stimulation Venous Sampling forPancreatic Endocrine Tumors
155
could reliably differentiate the two conditions. In this study, the researchers derived
several conclusions. First, they found that the use of the middle hepatic vein did
provide larger differences between the two patient groups than using the right
hepatic vein, though both approaches could be used. More importantly, they found
patients with insulinomas yielded much higher venous insulin levels than patients
with nesidioblastosis. When using the middle hepatic vein, an obtained insulin level
of >91.5 μIU/mL resulted in a 95% specicity for insulinoma. When the cutoff was
raised to >263.5 μIU/mL, the test was 100% specic.
While most of the reports on ASVS have centered on localizing insulinomas,
ASVS also has diagnostic value for gastrinomas. In 1992, Thom etal. published a
report that found ASVS to have a sensitivity of 89% in this setting [50]. Other studies have conrmed similar values with sensitivities ranging between 77% and
100% [1, 2].
Complications
The primary risk of the procedure is inducing hypoglycemia in response to the
injection of calcium, resulting in a sudden release of insulin. This risk, however, is
small due to the small amounts of calcium injected [51]. Other potential complications include pancreatitis from an overzealous injection into an artery directly supplying the pancreas. There are also potential risks that are common to all
arteriograms: contrast reaction, vessel dissection, and access site hematomas.
Conclusions
Arterial stimulation venous sampling is a physiologic test that can help identify and
localize occult pancreatic endocrine tumors. While it is mostly used for insulinomas, there are other uses, including localizing gastrinomas, differentiating functional from non-functional masses and conrming diagnosis before surgery. While
the test is invasive, it is relatively straightforward to perform and has excellent diagnostic results.
References
1. Imamura M, Takahashi K, Adachi H, Minematsu S, Shimada Y, Naito M, etal. Usefulness of
selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison
syndrome. Ann Surg. 1987;205(3):230–9.
2. Doppman JL, Miller DL, Chang R, Maton PN, London JF, Gardner JD, etal. Gastrinomas:
localization by means of selective intraarterial injection of secretin. Radiology. 1990;174(1):
25–9.
156
3. Norton JA, Doppman JL, Jensen RT.Curative resection in Zollinger-Ellison syndrome. Results
of a 10-year prospective study. Ann Surg. 1992;215(1):8–18.
4. Doppman JL, Miller DL, Chang R, Shawker TH, Gorden P, Norton JA.Insulinomas: localiza-
tion with selective intraarterial injection of calcium. Radiology. 1991;178(1):237–41.
5. Pereira PL, Roche AJ, Maier GW, Huppert PE, Dammann F, Farnsworth CT, etal. Insulinoma
and islet cell hyperplasia: value of the calcium intraarterial stimulation test when ndings of
other preoperative studies are negative. Radiology. 1998;206(3):703–9.
6. Roche A, Raisonnier A, Gillon-Savouret MC.Pancreatic venous sampling and arteriography
in localizing insulinomas and gastrinomas: procedure and results in 55 cases. Radiology.
1982;145(3):621–7.
7. Gaeke RF, Kaplan EL, Rubenstein A, Starr J, Burke G.Insulin and proinsulin release during
calcium infusion in a patient with islet-cell tumor. Metabolism. 1975;24(9):1029–34.
8. Liu Y, Song Q, Jin HT, Lin XZ, Chen KM.The value of multidetector-row CT in the preopera-
tive detection of pancreatic insulinomas. Radiol Med. 2009;114(8):1232–8.
9. Gouya H, Vignaux O, Augui J, Dousset B, Palazzo L, Louvel A, etal. CT, endoscopic sonogra-
phy, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am
J Roentgenol. 2003;181(4):987–92.
10. Lin XZ, Wu ZY, Tao R, Guo Y, Li JY, Zhang J, et al. Dual energy spectral CT imaging of
insulinoma- value in preoperative diagnosis compared with conventional multi-detector
CT.Eur J Radiol. 2012;81(10):2487–94.
11. Stark DD, Moss AA, Goldberg HI, Deveney CW.CT of pancreatic islet cell tumors. Radiology.
1984;150(2):491–4.
12. Rossi P, Baert A, Passariello R, Simonetti G, Pavone P, Tempesta P.CT of functioning tumors
of the pancreas. AJR Am J Roentgenol. 1985;144(1):57–60.
13. Günther RW, Klose KJ, Rückert K, Kuhn FP, Beyer J, Klotter HJ, et al. Islet-cell tumors:
detection of small lesions with computed tomography and ultrasound. Radiology.
1983;148(2):485–8.
14. Günther RW, Klose KJ, Rückert K, Beyer J, Kuhn FP, Klotter HJ.Localization of small islet-
cell tumors. Preoperative and intraoperative ultrasound, computed tomography, arteriography, digital subtraction angiography, and pancreatic venous sampling. Gastrointest Radiol.
1985;10(2):145–52.
15. Kann PH, Rothmund M, Zielke A.Endoscopic ultrasound imaging of insulinomas: limitations
and clinical relevance. Exp Clin Endocrinol Diabetes. 2005;113(8):471–4.
16. Kann PH, Moll R, Bartsch D, Pfützner A, Forst T, Tamagno G, etal. Endoscopic ultrasound-
guided ne-needle aspiration biopsy (EUS-FNA) in insulinomas: indications and clinical relevance in a single investigator cohort of 47 patients. Endocrine. 2017;56(1):158–63.
17. Wang H, Ba Y, Xing Q, Du JL. Diagnostic value of endoscopic ultrasound for insulinoma
localization: a systematic review and meta-analysis. PLoS One. 2018;13(10):e0206099.
18. Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al.
Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas.
2013;42(4):557–77.
19. Morganstein DL, Lewis DH, Jackson J, Isla A, Lynn J, Devendra D, etal. The role of arte-
rial stimulation and simultaneous venous sampling in addition to cross-sectional imaging for
localisation of biochemically proven insulinoma. Eur Radiol. 2009;19(10):2467–73.
20. Lau JH, Drake W, Matson M.The current role of venous sampling in the localization of endo-
crine disease. Cardiovasc Intervent Radiol. 2007;30(4):555–70.
21. Monroe EJ, Carney BW, Ingraham CR, Johnson GE, Valji K.An interventionist’s guide to
endocrine consultations. Radiographics. 2017;37(4):1246–67.
22. Harness JK, Geelhoed GW, Thompson NW, Nishiyama RH, Fajans SS, Kraft RO, et al.
Nesidioblastosis in adults. A surgical dilemma. Arch Surg. 1981;116(5):575–80.
23. Laidlaw GF. Nesidioblastoma, the islet tumor of the pancreas. Am J Pathol.
1938;14(2):125–34.5.
C. T. Burke
10 Arterial Stimulation Venous Sampling forPancreatic Endocrine Tumors
24. Jabri AL, Bayard C. Nesidioblastosis associated with hyperinsulinemic hypoglycemia in
adults: review of the literature. Eur J Intern Med. 2004;15(7):407–10.
25. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd
RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N
Engl J Med. 2005;353(3):249–54.
26. Maeda Y, Yokoyama K, Takeda K, Takada J, Hamada H, Hujioka Y, etal. Adult-onset diffuse
nesidioblastosis causing hypoglycemia. Clin J Gastroenterol. 2013;6(1):50–4.
27. Toyomasu Y, Fukuchi M, Yoshida T, Tajima K, Osawa H, Motegi M, etal. Treatment of hyper-
insulinemic hypoglycemia due to diffuse nesidioblastosis in adults: a case report. Am Surg.
2009;75(4):331–4.
28. Kenney B, Tormey CA, Qin L, Sosa JA, Jain D, Neto A. Adult nesidioblastosis.
Clinicopathologic correlation between pre-operative selective arterial calcium stimulation
studies and post- operative pathologic ndings. JOP. 2008;9(4):504–11.
29. Malik S, Mitchell JE, Steffen K, Engel S, Wiisanen R, Garcia L, etal. Recognition and man-
agement of hyperinsulinemic hypoglycemia after bariatric surgery. Obes Res Clin Pract.
2016;10(1):1–14.
30. Cui Y, Elahi D, Andersen DK.Advances in the etiology and management of hyperinsulinemic
hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15(10):1879–88.
31. Okauchi Y, Nammo T, Iwahashi H, Kizu T, Hayashi I, Okita K, etal. Glucagonoma diagnosed
by arterial stimulation and venous sampling (ASVS). Intern Med. 2009;48(12):1025–30.
32. Eguchi H, Tanemura M, Marubashi S, Kobayashi S, Wada H, Okita K, etal. Arterial stimu-
lation and venous sampling for glucagonomas of the pancreas. Hepato-Gastroenterology.
2012;59(113):276–9.
33. Bertelli E, Di Gregorio F, Bertelli L, Mosca S.The arterial blood supply of the pancreas: a
review. I. The superior pancreaticoduodenal and the anterior superior pancreaticoduodenal
arteries. An anatomical and radiological study. Surg Radiol Anat. 1995;17(2):97–106, 1–3.
34. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S.The arterial blood supply of the
pancreas: a review. II.The posterior superior pancreaticoduodenal artery. An anatomical and
radiological study. Surg Radiol Anat. 1996;18(1):1–9.
35. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S.The arterial blood supply of the
pancreas: a review. III.The inferior pancreaticoduodenal artery. An anatomical review and a
radiological study. Surg Radiol Anat. 1996;18(2):67–74.
36. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A.The arterial blood supply of the
pancreas: a review. IV.The anterior inferior and posterior pancreaticoduodenal aa., and minor
sources of blood supply for the head of the pancreas. An anatomical review and radiologic
study. Surg Radiol Anat. 1997;19(4):203–12.
37. Bertelli E, Di Gregorio F, Mosca S, Bastianini A.The arterial blood supply of the pancreas:
a review. V. The dorsal pancreatic artery. An anatomic review and a radiologic study. Surg
Radiol Anat. 1998;20(6):445–52.
38. Uacker R. Atlas of vascular anatomy: an angiographic approach. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 2007. xiv, 905 p.
39. Sakuhara Y, Kodama Y, Abo D, Hasegawa Y, Shimizu T, Omatsu T, etal. Evaluation of the
vascular supply to regions of the pancreas on CT during arteriography. Abdom Imaging.
2008;33(5):563–70.
40. Wiesli P, Brändle M, Schmid C, Krähenbühl L, Furrer J, Keller U, et al. Selective arterial
calcium stimulation and hepatic venous sampling in the evaluation of hyperinsulinemic hypoglycemia: potential and limitations. J Vasc Interv Radiol. 2004;15(11):1251–6.
41. Guettier JM, Kam A, Chang R, Skarulis MC, Cochran C, Alexander HR, etal. Localization of
insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94(4):1074–80.
42. Thompson SM, Vella A, Service FJ, Grant CS, Thompson GB, Andrews JC.Impact of variant
pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selec-
157
158
tive arterial calcium stimulation with hepatic venous sampling for preoperative localization of
occult insulinoma. Surgery. 2015;158(1):162–72.
43. Tseng LM, Chen JY, Won JG, Tseng HS, Yang AH, Wang SE, etal. The role of intra-arterial
calcium stimulation test with hepatic venous sampling (IACS) in the management of occult
insulinomas. Ann Surg Oncol. 2007;14(7):2121–7.
44. Defreyne L, König K, Lerch MM, Hesse UJ, Rottiers R, Feifel G, etal. Modied intra-arterial
calcium stimulation with venous sampling test for preoperative localization of insulinomas.
Abdom Imaging. 1998;23(3):322–31.
45. Kajiwara K, Yamagami T, Toyota N, Kakizawa H, Urashima M, Hieda M, etal. New diagnos-
tic criteria for the localization of insulinomas with the selective arterial calcium injection test:
decision tree analysis. J Vasc Interv Radiol. 2018;29(12):1749–53.
46. Wang H, Ba Y, Xing Q, Cai RC.Diagnostic value of ASVS for insulinoma localization: a
systematic review and meta-analysis. PLoS One. 2019;14(11):e0224928.
47. Thompson SM, Vella A, Thompson GB, Rumilla KM, Service FJ, Grant CS, etal. Selective
arterial calcium stimulation with hepatic venous sampling differentiates insulinoma from
nesidioblastosis. J Clin Endocrinol Metab. 2015;100(11):4189–97.
48. Spanakis E, Gragnoli C.Successful medical management of status post-Roux-en-Y-gastric- -
bypass hyperinsulinemic hypoglycemia. Obes Surg. 2009;19(9):1333–4.
49. Øhrstrøm CC, Worm D, Hansen DL.Postprandial hyperinsulinemic hypoglycemia after Roux-
en- Y gastric bypass: an update. Surg Obes Relat Dis. 2017;13(2):345–51.
50. Thom AK, Norton JA, Doppman JL, Miller DL, Chang R, Jensen RT.Prospective study of the
use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery. 1992;112(6):1002–8; discussion 8–9.
51. Jackson JE.Angiography and arterial stimulation venous sampling in the localization of pan-
creatic neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2005;19(2):229–39.
C. T. Burke
Part III
Medical Treatment of Endocrine Disorders
Chapter 11
Medical Treatment ofHypersecretory
Endocrine Disorders
DianaSoliman, AliQamar, andJorgeD.Oldan
Hyperaldosteronism
The goals of therapy in hyperaldosteronism are to normalize blood pressure, normalize serum potassium without potassium supplementation and unsuppressed
renin, and reverse the adverse cardiovascular and renal effects associated with aldosterone excess.
Surgical/Pharmacological Therapy
For patients with unilateral aldosterone-producing adenoma or unilateral hyperplasia, laparoscopic adrenalectomy is recommended. Pharmacological therapy is recommended for patients who cannot undergo surgery or those with bilateral
hyperaldosteronism [1]. In evaluating patients with hyperaldosteronism, CT imaging is used in conjunction with adrenal vein sampling (AVS) to guide clinical decisions. Although adrenal CT helps detect larger lesions, it may miss microadenomas.
Furthermore, nonfunctioning adenomas are common, and CT cannot distinguish
these from aldosterone-producing adenomas. Thus, guidelines currently
recommend that patients who seek a surgical cure undergo AVS to conrm
D. Soliman (*) · A. Qamar
Division of Endocrinology, Diabetes and Metabolism, Duke University School of Medicine,
Durham, NC, USA
e-mail: diana.botros@duke.edu; ali.qamar@duke.edu
J. D. Oldan
Division of Molecular Imaging and Therapeutics, Department of Radiology, University of
North Carolina School of Medicine, Chapel Hill, NC, USA
e-mail: jorge_oldan@med.unc.edu
Switzerland AG 2022
H. Yu et al. (eds.), Diagnosis and Management of Endocrine Disorders in
Interventional Radiology, https://doi.org/10.1007/978-3-030-87189-5_11
161© The Author(s), under exclusive license to Springer Nature
162
unilateral disease. AVS is expensive and invasive, so it should only be performed in
patients with primary hyperaldosteronism.
For those who need pharmacological therapy, mineralocorticoid receptor antagonists (MRAs) are the preferred pharmacological agents. Spironolactone is the agent
of choice, but eplerenone is an alternative. Both have been shown to reduce blood
pressure and increase serum potassium. Spironolactone can cause breast tenderness
and menstrual irregularities in women and decreased libido and gynecomastia in
men. The starting dose of spironolactone is 12.5–25mg daily and should be titrated
upward gradually to use the lowest effective dose. If side effects of spironolactone
limit its use in treating hyperaldosteronism, eplerenone can be trialed. Eplerenone
has fewer side effects but is more expensive than spironolactone. Patients with
hyperaldosteronism require high doses of MRAs, sometimes exceeding the recommended maximum doses. Serum potassium should be closely monitored when initiating therapy or increasing dosage, especially in patients with chronic kidney
disease, due to the risk of hyperkalemia. For patients who can’t tolerate MRAs,
amiloride or triamterene are second-line therapies. These are potassium-sparing
diuretics that block the aldosterone-sensitive sodium channel in the renal collecting
tubules. Patients with persistent hypertension, despite upward titration of these
medications, should have another antihypertensive medication added to their regimen to normalize their blood pressure.
D. Soliman et al.
Nuclear Medicine
At present, there are no commonly used nuclear medicine tests for hyperaldosteronism. A tracer known as NP-59 was used for a short time but is now rarely used due
to its poor sensitivity and lack of FDA approval.
Hyperparathyroidism
Management of hyperparathyroidism depends on whether it is primary, secondary,
or tertiary hyperparathyroidism and the patient’s underlying comorbidities.
Primary Hyperparathyroidism: Surgical/Pharmacological Therapy
Patients with symptomatic primary hyperparathyroidism (i.e., symptomatic hypercalcemia, nephrolithiasis, fractures) should have parathyroidectomy. Parathyroid
surgery is the only curative treatment for primary hyperparathyroidism. Indications
for parathyroidectomy in asymptomatic primary hyperparathyroidism are as follows: (1) serum calcium >1 mg/dL higher than the upper limit of normal, (2)
11 Medical Treatment ofHypersecretory Endocrine Disorders
osteoporosis as dened by bone mineral density (BMD) on dual-energy X-ray
(DXA) or presence of a vertebral fracture on imaging, (3) creatinine clearance of
<60 ml/min or nephrolithiasis on imaging, or (4) age less than 50 years [2].
Complications of surgery include hungry bone syndrome, persistent hypoparathyroidism, and recurrent laryngeal nerve injury. Patients who do not undergo surgery
require periodic monitoring for worsening hypercalcemia, renal impairment, and
bone loss.
For those who meet surgical criteria but have contraindications to surgery or do
not want to undergo surgery, medical therapy is recommended [3]. Cinacalcet is a
calcimimetic that activates the calcium-sensing receptor and decreases calcium and
parathyroid hormone (PTH) levels. Side effects include nausea, diarrhea, arthralgia,
myalgia, and paresthesia. Cinacalcet’s effects on BMD are unclear. Alendronate is
a bisphosphonate that has shown improvement in BMD at the lumbar spine and
femoral neck. Bisphosphonates have little to no effect on serum calcium and no
signicant effect on serum PTH levels. Patients with low BMD and elevated serum
calcium may need combination therapy with cinacalcet and bisphosphonate therapy.
163
Secondary Hyperparathyroidism: Surgical/Pharmacological Therapy
In secondary hyperparathyroidism, treatment is aimed at correcting the causes of
hyperparathyroidism. In patients with chronic kidney disease (CKD), serial monitoring of phosphate, calcium, vitamin D, and PTH levels is used to direct treatment
[4]. Vitamin D deciency and insufciency should be treated. Hyperphosphatemia
is managed with dietary phosphate restriction and noncalcium phosphate binders.
Phosphate should be lowered toward the normal range while avoiding hypercalcemia. Hypocalcemia can be managed with calcium supplementation. For patients
with CKD who are not on dialysis, the optimal PTH level is not known. For those
who have severe and progressive secondary hyperparathyroidism, calcitriol and
vitamin D analogs may be considered. In patients on dialysis, PTH levels should be
maintained at two to nine times the upper limit of normal. In these patients, elevated
PTH can be managed with calcimimetics, calcitriol, and/or vitamin D analogs. In
patients with CKD stages 3–5 who have severe hyperparathyroidism unresponsive
to medical therapy, parathyroidectomy should be considered.
Tertiary Hyperparathyroidism: Surgical/Pharmacological Therapy
In tertiary hyperparathyroidism, the mainstay of treatment is surgery. The most
common surgeries are subtotal parathyroidectomy or total parathyroidectomy with
autotransplantation. Although calcimimetics are not approved for tertiary hyperparathyroidism, they are sometimes used to reduce serum calcium.