ENDOCRINECONSULT

Noninsulinoma Pancreatogenous Hypoglycemia Syndrome Following Gastric Bypass Surgery Kristen A. Scheckel, PA-C

28-year-old white wom- dL range approximately one to ties are seen on imaging stud- an, KR, presents to pri- two hours after meals containing ies, the possibility of insulinoma A mary care with episodic > 45 g of carbohydrate. Her fasting is excluded from the differential diaphoresis and weakness that serum glucose readings are in the diagnosis. Adrenal insufficiency occur one to two hours after 80 to 95 mg/dL range. is excluded based on the nor- meals. There is no history of syn- The patient is presumptively mal ACTH and cortisol levels. cope or seizures. The hypoglyce- diagnosed with dumping syn- The possibility of noninsulinoma mic symptoms abate with intake drome and receives nutritional pancreatogenous hypoglycemia of oral glucose and do not occur counseling; she is instructed to syndrome is considered. when the patient fasts. reduce intake of simple carbohy- The patient is prescribed vera- KR underwent Roux-en-Y gas- drates and increase the protein pamil ER 100 mg/d and notes sig- tric bypass surgery 12 months content of meals. Despite these nificant reduction in the frequen- ago. At the time, her body weight dietary modifications, the epi- cy of hypoglycemic episodes and was 250 lbs and her height, 62 in sodes of hypoglycemia persist. symptoms. She is scheduled for (BMI, 46). She has lost 60 lbs since The patient is then referred to follow-up in four weeks to assess surgery (current BMI, 35). KR has . Fasting labwork for any changes in the frequency no comorbid medical conditions. reveals a serum glucose level of or severity of her hypoglycemic She denies use of insulin injection 85 mg/dL; normal adrenocortico- episodes. or oral hypoglycemic medication, tropic hormone (ACTH) and cor- as well as alcohol consumption. tisol levels; C-peptide level, 2.46 BACKGROUND There is no history of diarrhea or ng/mL (reference range, 0.80– Postprandial hypoglycemia is a abdominal pain. Her only medi- 4.00 ng/mL); and insulin level, 6.4 rare but potentially serious com- cation is a daily multivitamin. mIU/mL (reference range 2.6–24.9 plication of bariatric surgery pro- Physical exam reveals a blood mIU/mL). A 75-g two-hour oral cedures that divert nutrients into pressure of 126/80 mm Hg; pulse, glucose tolerance test (OGTT) re- the small bowel.1,2 The Bariatric 82 beats/min; respiratory rate, 16 veals peak serum glucose of 180 Outcomes Longitudinal Database

breaths/min; and O2 saturation, mg/dL at 30 minutes followed by revealed a 0.1% incidence of hy- 98%. Heart rate is regular with no a nadir serum glucose of 48 mg/ poglycemia in patients who un- murmur. Lungs are clear to aus- dL at 110 minutes, accompanied derwent Roux-en-Y gastric bypass cultation. Abdominal and neu- by hypoglycemic symptoms. The surgery.3 rologic exams are unremarkable; insulin and C-peptide levels are The most common cause of musculoskeletal strength and or- elevated during the entire two- hypoglycemia following gastric thostatic vital signs are normal. hour test. The serum cortisol level bypass surgery is dumping syn- The patient is instructed to test is 22 mg/dL when the glucose level drome, which involves rapid her blood sugar with a glucom- is 48 mg/dL. CT of the abdomen, emptying of gastric contents with eter and return to the clinic in previously ordered by the pa- reactive hypoglycemia due to in- two weeks. Fingerstick monitor- tient’s primary care provider, was creased postprandial insulin re- ing reveals that her serum glucose unremarkable. lease. In dumping syndrome, hy- level drops into the 40 to 50 mg/ Since there is no laboratory poglycemic symptoms—flushing, Kristen A. Scheckel practices at Endocri- evidence of fasting hypoglycemia diaphoresis, weakness, and dizzi- nology Associates in Denver. and no pancreatic abnormali- ness—typically occur within two

30 Clinician Reviews • DECEMBER 2014 clinicianreviews.com ENDOCRINECONSULT

to three hours after meals; pa- Nesidioblastosis is the lead- likelihood of hypoglycemia. Oth- tients do not experience the more ing cause of in er hormones that may contribute severe symptoms of neuroglyco- newborns and infants (annual to the metabolic effects of bariat- penia (eg, cognitive impairment, incidence, 1 in 50,000 births) but ric surgery include peptide YY, seizures, and loss of conscious- is quite rare in adults, occurring oxyntomodulin, and others as yet ness).4 The symptoms of dumping in 0.5% to 7.0% of all those with unidentified.5,6 syndrome typically improve with hyperinsulinism.7,8 Islet cell hy- reduced intake of simple carbo- pertrophy—characteristic of ne- CLINICAL MANIFESTATIONS hydrates and increased protein sidioblastosis—is seen in both NIPHS is characterized by mod- consumption.1 adults and children, whereas ge- erate to severe postprandial hy- Other causes of postprandial netic mutations are present only poglycemia. Symptoms include hypoglycemia include insuli- in infants.7 confusion, diaphoresis, tremu- noma and noninsulinoma pan- Although rare in adults, nesid- lousness, anxiety, weakness, creatogenous hypoglycemia syn- ioblastosis is more common in blurred vision, and disorienta- drome (NIPHS). Although both the setting of gastric bypass than tion, as well as more severe neu- diagnoses are rare, they should be in the general population.7 As of roglycopenic symptoms, such as considered if no improvement in 2011, there have been 40 cases cognitive impairment, seizures, hypoglycemic symptoms occurs of nesidioblastosis in adults who and loss of consciousness.5 after dietary modification.1 received gastric bypass.2 With the These symptoms do not Insulinoma is the most com- rapid increase in the number of typically manifest until several mon cause of persistent hyper- these surgeries performed each months after gastric bypass sur- insulinemic hypoglycemia. It year, nesidioblastosis should be gery. (By contrast, symptoms is defined by Whipple’s triad: considered in the differential di- experienced with dumping syn- symptomatic hypoglycemia dur- agnosis for patients who experi- drome typically manifest shortly ing fasting, a serum glucose level ence hypoglycemia following the after the procedure.) Of note, hy- > 50 mg/dL at the time of symp- procedure.2,7 poglycemic symptoms of NIPHS tom onset, and relief of symptoms do not typically improve after di- after administration of glucose.5 HORMONAL MECHANISMS etary modifications aimed at re- NIPHS is less common than There are multiple theories re- ducing carbohydrate intake.2 insulinoma. It is characterized by garding the etiology of b-cell postprandial hypoglycemia due hyperplasia following bariatric DIAGNOSIS to increased insulin secretion surgery. The specific causes for Diagnosis of NIPHS is based on resulting from pancreatic b-cell NIPHS after gastric bypass re- hypoglycemic/neuroglycopenic hyperplasia. Hypoglycemia does main under investigation.2 signs and symptoms without fast- not typically occur during a 72- The most common theory is ing hypoglycemia; endogenous hour fast. In addition, pancreatic that b-cell hyperplasia may occur hyperinsulinemia in the presence imaging studies yield normal re- as a result of the surgical proce- of hypoglycemia; negative local- sults in cases of NIPHS. The selec- dure itself and not due to obesity. ization studies for insulinoma tive arterial calcium stimulation The rapid delivery of food to the (using triple-phase spiral CT); test is positive in NIPHS.5 NIPHS distal ileum after gastric bypass and positive selective arterial cal- is definitively diagnosed by his- surgery may result in elevated cium stimulation test.4,6 topathologic examination of the production of incretin hormones If fasting hypoglycemia is re- , which reveals nesidio- (eg, GLP-1 and GIP), which in- ported or suspected, the patient blastosis.6 crease b-cell proliferation, insulin should be evaluated for insulino- Nesidioblastosis involves secretion, and insulin sensitivity.7 ma using a 72-hour fast. During it, pathologic b-cell overgrowth in Roux-en-Y gastric bypass also glucose, insulin, C-peptide, and the pancreas that results in excess impairs ghrelin secretion. Ghrelin pro-insulin levels should be test- insulin secretion.4 Nesidioblasto- normally acts to suppress insulin ed every six hours; results will be sis is characterized by pancreatic secretion and directly opposes normal in patients with NIPHS.5 b-cell hypertrophy, islet hyper- the action of insulin. Reduced The use of OGTT is controver- plasia, and increased b-cell mass.2 levels of ghrelin may increase the sial, as patients can experience

32 Clinician Reviews • DECEMBER 2014 clinicianreviews.com variable degrees of postprandial TREATMENT operatively. Occasionally, a sec- hyperinsulinism and symptom- There is no consensus on treat- ond surgery with 95% to complete atic hypoglycemia during the ment of NIPHS in postbariatric pancreatectomy is employed if test. There are no guidelines on surgery patients, and no “gold recurrent hypoglycemia develops whether to perform OGTT in the standard” exists. Pharmacologic that is refractory to medical man- work-up for NIPHS. In research treatment is recommended prior agement.5 protocols, it is common to per- to surgical intervention in pa- Reversal of Roux-en-Y bypass form a five-hour OGTT; subjects tients who present with symp- surgery has been described as an consume a mixed meal contain- tomatic hypoglycemia without attempted treatment method in ing 50 g of carbohydrates, then loss of consciousness or seizures.1 several case reports of patients their glucose, insulin, and C-pep- Pharmacologic treatments in- with NIPHS. In at least one pa- tide levels are tested every 30 to clude calcium channel blockers tient, hyperinsulinemic hypogly- 60 minutes (or sooner if hypogly- (eg, verapamil or nifedipine), the cemia persisted after Roux-en-Y cemic symptoms occur). b-cell inhibitor diazoxide, the se- gastric bypass reversal.2 Adjust- Elevated insulin and C-peptide cretory inhibitor octreotide, and able gastric band placement was levels in the setting of hypogly­ a-glucosidase inhibitors.1 In one recently reported to reverse hy- cemia are characteristic findings hospital group, patients were poglycemic symptoms and main- in patients with NIPHS.5,9 In the initially treated with verapamil tain weight loss, due to restricted setting of hypoglycemia, a cortisol ER 100 mg/d.5 If patients did not gastric emptying.2 Conversion of level > 20 mg/dL is considered an respond to this therapy or devel- Roux-en-Y gastric banding to gas- appropriate adrenal response and oped adverse effects, diazoxide tric sleeve may also be employed excludes adrenal insufficiency. was added (starting dose, 25 mg to restore normal gastrointestinal Triple-phase CT of the abdomen tid, titrated to 75 mg tid).5 If this continuity and resolve hypoglyce- should be performed to rule out combination did not produce mia, though limited data is avail- insulinoma if strongly suspect- results, octreotide (dose ranging able regarding the efficacy of this ed and if work-up for NIPHS is from 25 mg/d to 50 mg tid, subcu- procedure.2 negative.­ 5 taneously) was added. Acarbose Close monitoring is necessary The selective arterial calcium can also be added, with the typi- in patients treated with pharma- stimulation test is employed to cal starting dose of 50 mg tid.1 cologic therapy to ensure that confirm the diagnosis of NIPHS Distal or subtotal pancreatec- symptoms are well controlled and and to guide the extent of pancre- tomy to debulk the hypertrophic that surgery is not necessary.1 atic resection, in an effort to mini- islets is the most common surgical mize postoperative complications method used in patients with se- SUMMARY AND CONCLUSION of insulin-dependent vere hypoglycemia that is refrac- Symptomatic hypoglycemia is a and exocrine insufficiency. In this tory to medical management.2,5 potential complication associ- procedure, the splenic, gastrodu- The extent of pancreatic resection ated with gastric bypass surgery odenal, superior mesenteric, and is guided by calcium angiography and is most commonly caused by hepatic arteries that supply the and typically ranges from 80% to dumping syndrome. It is impor- pancreas are selectively injected 95%.7 Smaller pancreatic resec- tant to consider other causes of with calcium gluconate. After tion is associated with higher risk postprandial hypoglycemia, such injection of calcium, the insulin for persistent postoperative hy- as insulinoma and NIPHS, in pa- level is measured within each ar- poglycemia.5 Complications as- tients who continue to experience tery.4,5,7 The selective arterial cal- sociated with pancreatectomy in- hypoglycemia despite making di- cium stimulation test can also be clude insulin-dependent diabetes etary modifications.1,4 used to localize an insulinoma. and exocrine insufficiency.5 NIPHS is a rare and poorly un- NIPHS is distinguished from in- It is not uncommon for pa- derstood complication of gastric sulinoma by a diffuse increase tients to experience recurrent bypass surgery involving patho- in insulin secreted from multiple symptoms after subtotal pancre- logic b-cell overgrowth, leading to segments of the arteries that sup- atectomy, but the symptoms are hyperinsulinemia and potentially ply the pancreas, following cal- typically easier to manage phar- severe hypoglycemia.6 Some pa- cium stimulation.4,5,7 macologically than they were pre- tients may present with complete

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relief of symptoms with pharma- could lead to novel drug develop- J Med. 2005;353(3):249-254. cologic treatment, while others ment to treat diabetes.6 CR 5. Mathavan VK, Arregui M, Davis C, et al. Man- agement of postgastric bypass noninsulino- will need surgical treatment with ma pancreatogenous hypoglycemia. Surg subtotal pancreatectomy.1 REFERENCES Endosc. 2010;24:2547-2555. The findings of increased lev- 1. Moreira RO, Moreira RBM, Machado NAM, 6. Cummings D. Gastric bypass and nesidioblas- els of GLP-1 hormone in patients et al. Post-prandial hypoglycemia after bar- tosis—too much of a good thing for islets? iatric surgery: pharmacological treatment N Engl J Med. 2005;353(3):300-302. who have received gastric bypass with verapamil and acarbose. Obes Surg. 7. Clancy TE, Moore FD, Zinner MJ. Post-gastric surgery and the fact that only a 2008;18:1618-1621. bypass hyperinsulinism with nesidioblasto- very small subset of gastric by- 2. Cui Y, Elahi D, Andersen D. Advances in the sis: subtotal or total pancreatectomy may be etiology and management of hyperinsulin- needed to prevent recurrent hypoglycemia. pass patients develop NIPHS with emic hypoglycemia after Roux-en-Y gastric J Gastrointest Surg. 2006;10(8):1116 -1119. histologic features of nesidio- bypass. J Gastrointest Surg. 2011;15:1879- 8. Kaczirek K, Niederle B. Nesidioblastosis: an blastosis are subjects for further 1888. old term and a new understanding. World J 3. Sarwar H, Chapman III WH, Pender JR, et al. Surg. 2004;28:1227-1230. research. Further understanding Hypoglycemia after Roux-en-Y gastric 9. Salehi M, Gastaldelli A, D’Alessio DA. Altered of the hormonal factors involved bypass: the BOLD experience. Obes Surg. islet function and insulin clearance cause in the pathogenesis of NIPHS 2014; 24(7):1120 -1124. hyperinsulinemia in gastric bypass patients 4. Service GJ, Thompson GB, Service FJ, et al. with symptoms of postprandial hypoglyce- and adult-onset nesidioblastosis Hyperinsulinemic hypoglycemia with nesidio- mia. J Clin Endocrinol Metab. 2014;99(6): following gastric bypass surgery blastosis after gastric-bypass surgery. N Engl 2008-2017.

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