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Review article
Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment Tom Mala, M.D., Ph.D.* Department of Morbid Obesity and Bariatric Surgery/Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway Received October 18, 2013; accepted January 14, 2014
Abstract
An association between post-Roux-en-Y gastric bypass (RYGB) hypoglycemia and nesidioblastosis was reported in 2005 and may cause serious neuroglycopenic symptoms. Most patients with postprandial hypoglycemia after RYGB respond to nutritional and medical treatment. A subset of patients, however, may not respond adequately and surgery may be considered. This review describes the current experience with surgical intervention for severe post-RYGB hypoglycemia. PubMed and MEDLINE searches were made for reports describing clinical outcome after such surgery. Fourteen papers including 75 patients were identified. Different surgical interventions were applied including gastric tube placement, reversal of the bypass with and without concomitant sleeve resection, gastric pouch restriction, and pancreatic resection and reresection. Pancreatic resection was performed in 51 (68%) patients, 17 (23%) had RYGB reversal and eleven (15%) had gastric pouch restriction alone. Eight (11%) patients received 2 or more consecutive procedures for hypoglycemia and combined interventions were made in several patients. Resolution of the symptoms occurred in 34/51 (67%) patients after pancreatic resection, 13/17 (76%) after reversal, and 9/11 (82%) after pouch restriction. Mean follow up, however, was short for most series and the methods applied for evaluation of hypoglycemia varied. Weight regain, diabetes and recurrent symptoms were late complications. The optimal therapy for hypoglycemia after RYGB is not defined. Long-term evaluations and knowledge about the physiology of post-RYGB hypoglycemia, may enable therapy with improved control of the glucose excursions. (Surg Obes Relat Dis 2014;]:00–00.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Hypoglycemia; Gastric bypass; Nesidioblastosis; Surgery; Review; Reversal
An association between Roux-en-Y gastric bypass (RYGB) and postprandial hypoglycemia with nesidioblastosis was reported in 2005 and has been recognized a potential complication of gastric bypass surgery [1,2]. Neuroglycopenic symptoms due to hypoglycemia may cause seizures, loss of consciousness, and accidents [3]. In a Swedish nationwide cohort study, the incidence of * Correspondence: Tom Mala, Oslo University Hospital, Department of Morbid Obesity and Bariatric Surgery, Pb 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]
hospitalization for hypoglycemia was .2% after RYGB and .04% in a reference population [4]. Although uncommon, the prevalence of such hypoglycemia may be underestimated. The extensive use of RYGB thus makes this complication clinically relevant [1,5,6]. Most patients with post-RYGB hypoglycemia benefit from dietary restrictions or more complex nutritional and medical management strategies, including continuous glucose monitoring, acarbose, calcium channel blockade, diazoxide, and octreotide, etc. [5,6]. Some, however, do not respond adequately to these measures and surgery may be considered to alleviate symptoms. Different surgical
http://dx.doi.org/10.1016/j.soard.2014.01.010 1550-7289/r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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T. Mala / Surgery for Obesity and Related Diseases ] (2014) 00–00
approaches have been applied but the physiology of the hypoglycemia is not adequately elucidated [5]. This review describes the current experience with surgery as treatment for postprandial hypoglycemia after RYGB. Methods A review was made based on screening of PubMed and MEDLINE titles and abstracts from September 2013. Papers in the English language describing surgical procedures with clinical outcome for post-RYGB hypoglycemia were included. The terms “gastric bypass and hypoglycemia, gastric bypass and reversal, gastric bypass and revision, gastric bypass and pancreatic resection/pancreatectomy, gastric bypass and hyperinsulinism, banding and hypoglycemia, bariatric surgery and nesidioblastosis, and gastric bypass and nesidioblastosis” were applied for the search. Reference lists from included reports and selected reviews were screened for additional references. If several publications were identified from the same series, the report with the largest number of patients and the most adequately documented outcome was used for estimation of the final procedure number. Symptoms of hypoglycemia after RYGB may vary from minor discomfort to severe and recurrent neuroglycopenic symptoms as in the noninsulinoma pancreatogenous hypoglycemia syndrome and nesidioblastosis. As the preoperative work up varied across the studies included and not all patients had specimens available for evaluation, the general term post-RYGB hypoglycemia is mostly applied. Results T1
Fourteen papers presenting outcome after surgery for post-RYGB hypoglycemia were included (Table 1 and Table 2). Three series including patients previously reported on were not included (Table 2). In total, 75 patients were included. The mean duration from RYGB to the recognition of the symptoms of hypoglycemia was 28 (range 1–102) months (based on data from 28 patients). The mean duration from RYGB to surgery for hypoglycemia was 63 (12–107) months (based on data from eleven patients). Different surgical techniques were applied including the placement of a gastric tube, reversal of the RYGB with and without concomitant sleeve gastrectomy, gastric pouch restriction, and pancreatic resection. In some series, several concomitant techniques were applied. Eight (11%) patients had 2 or more consecutive surgical procedures for hypoglycemia. Open and laparoscopic approaches were used. Reversal of RYGB Placement of a gastrostomy tube was used in all patients before reversal in the 2 largest series of RYGB reversal for hypoglycemia [10,11]. After nutritional delivery through the gastrostomy tube in these studies, no hypoglycemic
symptoms were reported and a marked normalization of the glucose tolerance test was defined. A total of 17 (23%) patients from 5 reports had reversal of RYGB (Table 1). Five patients received a concomitant sleeve resection. One had previously undergone a distal pancreatectomy for hypoglycemia. Weight regain occurred in 4 of 11 patients that had documented evaluation of postoperative weight development. At least 1 had near total weight regain. The outcome in regard to hypoglycemia is described in Table 1. Two patients had pancreatic resections after reversal both with nesidioblastosis identified in the specimens. In the largest series (9 patients), 1 patient had gastroesophageal reflux after reversal [11]. Two patients developed diarrhea and 1 developed an anastomotic stricture that was dilated endoscopically. Histologically nesidioblastosis could not be evaluated, as resections were not made. Gastric pouch restriction Adding band or ring restriction to the gastric pouch for post-RYGB hypoglycemia was used in 11 (15%) patients (Table 1). In 1 study, 10 patients received a silastic ring or adjustable band around the pouch after reduction of pouches larger than 30 mL by stapling technique [13]. Nine of the 10 patients experienced resolution of symptoms, but the mean follow-up was short. One patient developed recurrence of hypoglycemia. A distal pancreatectomy was performed, and the band was removed because of band-related problems (Table 1). Nesidioblastosis was found in the specimens of the patient having pancreatic resection, but was undefined in the remaining 10 patients. Biopsies were performed in 2 patients. Pancreatic resection Distal, subtotal, and total pancreatectomies have been made for hypoglycemia after RYGB (Table 2). Distal pancreatectomy with or without splenectomy was most common. Among the 51 (68%) patients identified, 6 (12%) were reoperated with extended resections due to recurrent or persistent hypoglycemia. Three (6%) patients ended up with total pancreatectomy. Two had RYGB reversal and 1 pouch restriction before pancreatic resection [7,8,13]. Two had concomitant banding of the gastric pouch [13]. In total, 34 of 51 (67%) patients had resolution of hypoglycemic symptoms after 1 or more pancreatic resections. Among 17 patients with persistent symptoms, 8 were classified as “having recurrent or ongoing symptoms”, 5 as “occasional symptoms”, 2 as “frequent symptoms”, 1 as “responded well to octreotide treatment”, and 1 later underwent bypass reversal with “minimal improvement” in symptoms [9]. The duration of follow-up was short in several of the series (Table 2).
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Table 1 Outcome of bypass reversal or pouch restriction for post-RYGB hypoglycemia Authors
No Pts.
Reversal Clancy et al., 1 2006 [7] Patti et al., 2005 1 [8] Lee et al.,2013 2 [9] Campos et al., 2013* [10]
4
Vilallonga et al., 9 2013 [11]
Total
17
Restriction De Heide et al., 1 2012 [12] Z’graggen et al., 10 2008†[13]
Total
Procedure
Follow-up, mo Symptom Outcome/comments resolution, number
Reversal
na
0
Reversal
na
0
Reversal
8, 18
0
3–22, mean 12 4 Reversal; 2 also had a modified sleeve gastrectomy. All had a gastrostomy tube to document improved symptoms before reversal. o1–46, 9 Reversal; limited to patients with mean 13 “marked” normalization of the gastrostomy tube glucose tolerance test 13
Adjustable band cranially to na 0 gastrojejunal anastomosis Downsizing of gastric pouch. 6 4–18, mean 11 9 patients received a silastic (Fobi) ring around the pouch, 4 received an adjustable band.
11
Still symptomatic hypoglycemia after reversal, pancreaticoduodenectomy performed (Table 2) Unsuccessful; regain of near all weight lost. A distal and subsequent total pancreatectomy performed. One had distal pancreatectomy before reversal. Reversal did not alleviate hypoglycemia as evaluated by a mixed meal examination. No postoperative episodes of neuroglycopenia, and no or minimal” symptoms from very few hypoglycemic events, classified as ”resolution”
None had new episodes of severe hypoglycemia. Three patients received a concomitant sleeve gastrectomy. Partial weight regain in 2 patients.
Marked improvement in subjective complaints None had new hypoglycemic episodes. All had improvements in the Sigstad score. One patient had later distal pancreatectomy due to recurrent symptoms, and the band was removed due to oesophageal dilation and solid food intolerance.
9
na ¼ not applicable; Pts ¼ patients. 1 patient also had hypocalcemia and hypoparathyroidism. † 2 additional patients with concomitant pancreatic resection excluded from Table 1 (included in Table 2). *
In the present review, 6 patients developed diabetes after total (3), subtotal (2), and distal (80%) (1) pancreatic resection, respectively. Diabetic status, however, was unknown in most of the patients. Nesidioblastosis was confirmed from specimens in 47 patients, 2 were classified as having pancreatic islet hyperplasia and expanded cell mass, and in 2 patients nesidioblastosis was not confirmed. Discussion Adult nesidioblastosis is rare and was first reported in 1975 [3,5,24–26]. In a paper from 2008, o 100 individuals were claimed to be identified with adult nesidioblastosis in the literature [25]. The association between nesidioblastosis and RYGB was initially described in 2005, and in a 2011 review, 80–90 patients were identified with severe postbypass hypoglycemia [3]. In 1 report a patient developed symptoms 10 years after RYGB, and in another series the mean duration from RYGB to pancreatic resection for hypoclycemia was 54 (17–264) months [6,20]. The extensive use of RYGB and the possibility of late manifestations indicate that severe post-RYGB
hypoglycemia may be more commonly encountered. Although not all published cases may have been identified in the present review, a minimum of 75 patients are documented as being operated on for post-RYGB hypoglycemia in recent years. The evidence, however, for the use of surgery for postRYGB hypoglycemia is limited [3,5]. Follow-up may be short, different surgical techniques were used across reports, and several patients received 41 type of procedure challenging the interpretation of treatment outcome. Standardized definitions of severe post-RYGB hypoglycemia including lengths and degree of symptoms and serum glucose levels, could facilitate differentiation from the more common symptoms of dumping and would be beneficial for comparative analyses between reports. Improved knowledge about the physiology, which could differ from other cases of nesidioblastosis and hypoglycemia, may facilitate maturation of a rational treatment algorithm [2,20,22]. Hypotheses for the hypoglycemia include obesity-induced β-cell hypertrophy not reversed after RYGB, inappropriate growth factor release, persistent altered gut hormonal signalling, and a genetic susceptibility [2,5,26,27]. Others,
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Table 2 Outcome of pancreatic resection for post-RYGB hypoclycemia Authors
No Pts.
Procedure
Follow- up, mo
Symptom Outcome/comments resolution, number
Lee et al., 2013 [9]
1
Distal pancreatectomy
424
0
Ceppa et al., 2012 [14] Qintar et al., 2012 [15]
1 1
Distal pancreatectomy 24 Distal (80%) pancreatectomy 4 6
1 0
Rabiee et al, 2011 [16] Alvarez et al., 2007 [17] Clancy et al., 2006 [7]
1 1 2
Distal (85%) pancreatectomy 2 Distal pancreatectomy 10 Distal (80%) pancreatectomy na in 1, and 1 with 95% pancreatectomy
1 1 2
Barbour et al., 2008 [18]
2
12, 91 Duodenum preserving pancreatic head resection in 1, distal pancreatectomy in 1 2 had distal pancreatectomy 4, 4, 15 and Fobi ring around gastric pouch, 1 had distal pancreatectomy (50–60%) and removal of pouch band 2 had distal (80%) na pancreatectomy, 1 subtotal (85%)
2
Mathavan et al., 2010 [19] 9
Distal (80%) pancreatectomy 8–84, mean 30‡
3
Rumilla et al., 2009† [20]
27
Partial pancreatectomy
Total
51
Z’graggen et al., 2008 [13] 3
Patti et al., 2005* [8]
3
Persistent hypoglycemia, later bypass reversal (Table 1) Still hypolycemia. Subsequent total pancreatectomy Hypoglycemia recurred 6 mo after pancreatic resection—responded well to octreotide injections Symptom resolution Symptom resolution The patient with 80% pancreatectomy had previously reversed the bypass for hypoglycemia, which persisted after pancreatic resection. Pancreaticoduodenectomy performed. The other patient successfully treated. The patient with pancreatic head resection had persistent symptoms and underwent distal pancreatectomy
3
No patients with new hypoglycemic episodes
2
1 patient had previous take down of gastric bypass (Table 1) and after distal pancreatic resection total pancreatectomy was performed for recurrent symptoms, 1 patient with improvements but still episodes of hypoglycemia, 1 was without hypoglycemic episodes 2 patients had complete symptom resolution, 3 had occasional symptoms, 2 frequent symptoms. 2 patients with severe symptoms had extended (95%) pancreatic resection. 1 of these had resolution of symptoms, the other had still symptoms 8 patients with recurrent/ongoing mild symptoms
1–55, mean 11 19 34
na ¼ not applicable; Pts ¼ patients. The definition of distal pancreatic resection varied and if presented the extent of resection (%) is given. * A later report of 6 patients from the group is not included (lack of clinical outcome data) [21]. † Includes the 6 patients in the original series by Service GJ et al. [1]. Additional publications from the same group not included in Table 2 [22,23]. ‡ Follow-up counted from first procedure in patients with reresections.
however, claim that the hypoglycemia is not accompanied by islet hyperplasia or increased β-cell turnover [28]. The preoperative evaluation including the level of plasma glucose used to define hypoglycemia varied across the reports identified. The postoperative evaluation was not standardized. In some reports, a mixed meal or oral glucose examination was performed, and in others, hypoglycemia was less clearly defined [9]. The Whipple triad is recommended in the evaluation of these patients and includes symptoms of hypoglycemia, which in the case of postRYGB occurs after meals, documented low plasma glucose levels at the time of symptoms (o2.8 mmol/L), and the relief of symptoms after correction of the low glucose levels [3]. A diagnostic algorithm should also include a negative preoperative 72-hour fast test, continuous glucose
monitoring, and negative imaging studies for insulinoma [14]. Although uncommon, insulinomas have been identified in patients with post-RYGB hypoglycemia [22,29]. Cpeptide and insulin should be evaluated and are typically inappropriately high after meals. Oral glucose tolerance tests may be of value in regard to preoperative and outcome analyses. Interestingly, in a report of 10 non-RYGB adults with neuroglycopenia, 5 had previous partial gastrectomy [30]. Severe hypoglycemia has also been reported after duodenal switch [31]. In a Swedish study, an increased risk for hospitalization due to hypoglycemia was documented after RYGB, but not after vertical banded gastroplasty or gastric banding [4]. The exclusion of the proximal gut and the increased nutrient transit to the distal intestines may thus be
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important in the development of hypoglycemia [32]. The worldwide extensive use of RYGB and the focus on the metabolic effects of this surgery, may promote awareness of this problem after other upper gastrointestinal surgical procedures. Dietary modifications and medication are the first-line treatment for post-RYGB hypoglycemia [3,5,6]. Even in a subset of individuals with life-threatening neuroglycopenia, complex nutritional and medical management strategies are valid options to reduce postprandial insulin secretion and stabilise glucose excursions [32]. Surgery should be evaluated in the context of the perioperative risk, long-term outcome, potential weight regain, and its effects on obesity related co-morbidity—and late complications such as diabetes, reflux, and diarrhea. Reversal of RYGB to “normal anatomy” was first described in 2006, and subsequently in larger series [11,33]. Adding sleeve gastrectomy may reduce weight regain after reversal but increase the risk of complications [11]. Improvements in symptoms of hypoglycemia after the placement of a gastrostomy tube for feeding in the gastric remnant may normalize abnormal metabolic responses to ingested nutrients after RYGB in patients with hypoglycemia refractory to diet and medications [34]. This procedure may be of use in the selection of patients that could benefit from RYGB reversal as described in 2 of the papers included. The findings may contribute to the understanding of the physiology of post-RYGB hypoglycemia [10,11]. Hypoglycemia may be controlled in the short term by adding or restoring restriction [13]. Adding a (non)adjustable band is not major surgery compared to pancreatic resection and RYGB reversal and may ensure sustained weight loss. However, band-related problems can occur. The physiologic mechanisms for the improvements in symptoms after adding restriction may include enforced dietary changes and slower nutrient delivery to the jejunal limb. Long-term outcome, however, is not established. The adequate extent of pancreatic resection for postRYGB hypoglycemia is not defined. Extended resections may be beneficial, but the risk of diabetes and pancreatic exocrine dysfunction are increased [3]. The use of selective arterial calcium stimulation to identify areas of the pancreas responsible for hyperinsulinism may help to reduce the extent of resection [13,19]. Laparoscopy and spleen preserving techniques make the surgery less invasive but significant morbidity rates have been reported [17,19,35,36]. Several studies describe beneficial long-term outcome after pancreatic resection for nesidioblastosis in non-RYGB patients [24,37,38]. Similarly, in an editorial, 37 patients with post-RYGB hypoglycemia were reported on of which 23 underwent resection of about 60% of the pancreas. Symptom relief was found in 21 of 23 patients [22]. However, in a later report from the group, half of the 48 patients receiving pancreatic resection for hypoglycemia, of which 33 were after bariatric surgery, were classified as
5
“minimally successful” or “surgical failures”. Although 75% had improvements in quality of life and fewer symptoms, 25% experienced no benefit from partial pancreatectomy. Nearly 90% reported recurrent symptoms after a mean follow-up of 53 months, and 37% had complications. Nine (18%) patients developed diabetes, and 4 (8%) underwent additional operations for hypoglycemia [23]. In the present review symptom resolution seemed to occur in 34 of 51 (67%) patients after pancreatic resection, but the follow-up was short. Subtotal pancreatic resection may not be the optimal treatment for hypoglycemia after RYGB in all patients, as the underlying cause for hyperinsulinemia may persist [3]. In summary, pancreatic resection is the most common surgical procedure applied for post-RYGB hypoglycemia. The adequate extent of resection is not defined, and symptoms may persist or recur. Reversal of the RYGB or added restriction have been used as alternatives with undefined effects in the long term. The patients should be informed about the incomplete knowledge of post-RYGB hypoglycemia and the variability in treatment options and outcomes reported to date. Improved knowledge about the physiology and long-term therapeutic outcome, may allow therapy with improved control of the glucose excursions.
457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 Q7482 Disclosures 483 The authors hae no commercial associations that might 484 be a conflict of interest in relation to this article. 485 486 References 487 488 [1] Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblasto- 489 490 sis after gastric-bypass surgery. N Engl J Med 2005;353:249–54. [2] Foster-Schubert KE. Hypoglycemia complicating bariatric surgery: 491 incidence and mechanisms. Curr Opin Endocrinol Diabetes Obes 492 2011;18:129–33. 493 [3] Ritz P, Hanaire H. Post-bypass hypoglycemia: a review of current 494 findings. Diabetes Metab 2011;37:274–81. [4] Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study 495 of post-gastric bypass hypoglycemia including 5,040 patients under- 496 going surgery for obesity in 1986–2006 in Sweden. Diabetologia 497 2010;53:2307–11. 498 [5] Cui Y, Elahi D, Andersen DK. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y 499 500 gastric bypass. J Gastrointest Surg 2011;15:1879–88. [6] Kellogg TA, Bantle JP, Leslie DB, et al. Postgastric bypass hyper- 501 insulinemic hypoglycemia syndrome: characterisation and response to 502 a modified diet. Surg Obes Relat Dis 2008;4:492–9. 503 [7] Clancy TE, Moore FD Jr, Zinner MJ. Post-gastric bypass hyperinsulinism with nesidioblastosis: subtotal or total pancreatectomy may 504 be needed to prevent recurrent hypoglycemia. J Gastrointest Surg 505 2006;10:1116–9. 506 [8] Patti ME, McMahon G, Mun EC, et al. Severe hypoglycemia post- 507 gastric bypass requiring partial pancreatectomy: evidence for inap508 propriate insulin secretion and pancreatic islet hyperplasia. Diabeto509 logia 2005;48:2236–40. [9] Lee CJ, Brown T, Magnuson TH, Egan JM, Carlson O, Elahi D. 510 Hormonal response to a mixed-meal challenge after reversal of gastric 511
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T. Mala / Surgery for Obesity and Related Diseases ] (2014) 00–00 bypass for hypoglycemia. J Clin Endocrinol Metab 2013;98: E1208–12. Campos GM, Ziemelis M, Paparodis R, Ahmed M, Davis DB. Laparoscopic reversal of Roux-en-Y gastric bypass: technique and utility for treatment of endocrine complications. Surg Obes Relat Dis. In press 2013. Vilallonga R, van de Vrande S, Himpens J. Laparoscopic reversal of Roux-en-Y gastric bypass into normal anatomy with or without sleeve gastrectomy. Surg Endosc. Epub 2013 Jul 17. de Heide LJ, Glaudemans AW, Oomen PH, Apers JA, Totté ER, van Beek AP. Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity. J Clin Endocrinol Metab 2012;97:E963–7. Z'graggen K, Guweidhi A, Steffen R, et al. Severe recurrent hypoglycemia after gastric bypass surgery. Obes Surg 2008;18:981–8. Ceppa EP, Ceppa DP, Omotosho PA, Dickerson JA 2 nd, Park CW, Portenier DD. Algoritm to diagnose etiology of hypoglycemia after Roux-en-Y gastric bypass for morbid obesity: case series and review of the litterature. Surg Obes Relat Dis 2012;8:641–7. Qintar M, Sibai F, Taha M. Hypoglycemia due to an adult-onset nesidioblastosis, a diagnostic and management dilemma. Avicenna J Med 2012;2:45–7. Rabiee A, Magruder JT, Salas-Carrillo R, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of the gut hormonal and pancreatic endocrine function. J Surg Res 2011;167:199–205. Alvarez GC, Faria EN, Beck M, Girardon DT, Machado AC. Laparoscopic spleen-reserving distal pancreatectomy as treatment for nesidioblastosis after gastric bypass surgery. Obes Surg 2007;17:550–2. Barbour JR, Thomas BN, Morgan KA, Byrne TK, Adams DB. The practice of pancreatic resection after Roux-en-Y gastric bypass. Am Surg 2008;74:729–34. Mathavan VK, Arregui M, Davis C, Singh K, Patel A, Meacham J. Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia. Surg Endosc 2010;24:2547–55. Rumilla KM, Erickson LA, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis: histological features and growth factor expression. Mod Pathol 2009;22:239–45. Reubi JC, Perren A, Rehmann R, et al. Glucagon –like petide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinemic hypoglycemia following gastric bypass. Diabetologia 2010;53:2641–5. Vella A, Service FJ. Incretin hypersecretion in post-gastric bypass hypoglycemia — primary problem or red herring? J Clin Endocrinol Metab 2007;92:4563–5. Vanderveen KA, Grant CS, Thompson GB, et al. Outcome and quality of life after partial pancreatectomy for noninsulinoma pancreatogenous hypoglycemia from diffuse islet cell disease. Surgery
2010;148:1237–45. [24] Witteles RM, Straus FH II, Sugg SL, Koka MR, Costa EA, Kaplan EL. Adult-onset nesidioblastosis causing hypoglycemia: an important clinical entity and continuing treatment dilemma. Arch Surg 2001;136:656–63. [25] Klöppel G, Anlauf M, Raffel A, Perren A, Knoefel WT. Adult diffuse nesidioblastosis: genetically or environmentally induced? Hum Pathol 2008;39:3–8. [26] Ashrafian H, Athanasiou T, Li JV, et al. Diabetes resolution and hyperinsulinaemia after metabolic Roux-en-Y gastric bypass. Obes Rev 2011;12:e257–72. [27] Thaler JP, Cummings DE. Minireview: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology 2009;150:2518–25. [28] Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet cell hyperplasia or increased beta-cell turnover. Diabetes Care 2006;29:1554–9. [29] Abellan P, Camara R, Merino-Torres JF, et al. Severe hypoglycemia after gastric bypass surgery for morbid obesity. Diab Res Clin Pract 2008;79:e7–9. [30] Won JG, Tseng HS, Yang AH, et al. Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Clin Endocrinol (Oxf) 2006;65:566–78. [31] Aasheim ET, Frigstad SO, Søvik TT, Birkeland KI, Haukeland JW. Hyperinsulinemic hypoglycemia and liver cirrhosis presenting after duodenal switch; a case report. Surg Obes Rel Dis 2010;6:441–3. [32] Patti ME, Goldfine AB. Hypoglycemia following gastric bypass surgery – diabetes remission in the extreme? Diabetologia 2010;53:2276–9. [33] Himpens J, Dapri G, Cadière GB. Laparoscopic conversion of the gastric bypass into a normal anatomy. Obes Surg 2006;16:908–12. [34] McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab 2010;95:1851–5. [35] Edwin B, Mala T, Mathisen Ø, et al. Laparoscopic resection of the pancreas: a feasibility study of the short-term outcome. Surg Endosc 2004;18:407–11. [36] Briggs CD, Mann CD, Irving GR, et al. Systematic review of minimally invasive pancreatic resection. J Gastrointest Surg 2009;13: 1129–37. [37] Anlauf M, Wieben D, Perren A, et al. Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes. Am J Surg Pathol 2005;29:524–33. [38] Thompson GB, Service FJ, Andrews JC, et al. Noninsulinoma pancreatogenous hypoglycemia syndrome: an update in 10 surgically treated patients. Surgery 2000;128:937–44.
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Review article
Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment Tom Mala, M.D., Ph.D.* Department of Morbid Obesity and Bariatric Surgery/Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway Received October 18, 2013; accepted January 14, 2014
Abstract
An association between post-Roux-en-Y gastric bypass (RYGB) hypoglycemia and nesidioblastosis was reported in 2005 and may cause serious neuroglycopenic symptoms. Most patients with postprandial hypoglycemia after RYGB respond to nutritional and medical treatment. A subset of patients, however, may not respond adequately and surgery may be considered. This review describes the current experience with surgical intervention for severe post-RYGB hypoglycemia. PubMed and MEDLINE searches were made for reports describing clinical outcome after such surgery. Fourteen papers including 75 patients were identified. Different surgical interventions were applied including gastric tube placement, reversal of the bypass with and without concomitant sleeve resection, gastric pouch restriction, and pancreatic resection and reresection. Pancreatic resection was performed in 51 (68%) patients, 17 (23%) had RYGB reversal and eleven (15%) had gastric pouch restriction alone. Eight (11%) patients received 2 or more consecutive procedures for hypoglycemia and combined interventions were made in several patients. Resolution of the symptoms occurred in 34/51 (67%) patients after pancreatic resection, 13/17 (76%) after reversal, and 9/11 (82%) after pouch restriction. Mean follow up, however, was short for most series and the methods applied for evaluation of hypoglycemia varied. Weight regain, diabetes and recurrent symptoms were late complications. The optimal therapy for hypoglycemia after RYGB is not defined. Long-term evaluations and knowledge about the physiology of post-RYGB hypoglycemia, may enable therapy with improved control of the glucose excursions. (Surg Obes Relat Dis 2014;]:00–00.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Hypoglycemia; Gastric bypass; Nesidioblastosis; Surgery; Review; Reversal
An association between Roux-en-Y gastric bypass (RYGB) and postprandial hypoglycemia with nesidioblastosis was reported in 2005 and has been recognized a potential complication of gastric bypass surgery [1,2]. Neuroglycopenic symptoms due to hypoglycemia may cause seizures, loss of consciousness, and accidents [3]. In a Swedish nationwide cohort study, the incidence of * Correspondence: Tom Mala, Oslo University Hospital, Department of Morbid Obesity and Bariatric Surgery, Pb 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]
hospitalization for hypoglycemia was .2% after RYGB and .04% in a reference population [4]. Although uncommon, the prevalence of such hypoglycemia may be underestimated. The extensive use of RYGB thus makes this complication clinically relevant [1,5,6]. Most patients with post-RYGB hypoglycemia benefit from dietary restrictions or more complex nutritional and medical management strategies, including continuous glucose monitoring, acarbose, calcium channel blockade, diazoxide, and octreotide, etc. [5,6]. Some, however, do not respond adequately to these measures and surgery may be considered to alleviate symptoms. Different surgical
http://dx.doi.org/10.1016/j.soard.2014.01.010 1550-7289/r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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approaches have been applied but the physiology of the hypoglycemia is not adequately elucidated [5]. This review describes the current experience with surgery as treatment for postprandial hypoglycemia after RYGB. Methods A review was made based on screening of PubMed and MEDLINE titles and abstracts from September 2013. Papers in the English language describing surgical procedures with clinical outcome for post-RYGB hypoglycemia were included. The terms “gastric bypass and hypoglycemia, gastric bypass and reversal, gastric bypass and revision, gastric bypass and pancreatic resection/pancreatectomy, gastric bypass and hyperinsulinism, banding and hypoglycemia, bariatric surgery and nesidioblastosis, and gastric bypass and nesidioblastosis” were applied for the search. Reference lists from included reports and selected reviews were screened for additional references. If several publications were identified from the same series, the report with the largest number of patients and the most adequately documented outcome was used for estimation of the final procedure number. Symptoms of hypoglycemia after RYGB may vary from minor discomfort to severe and recurrent neuroglycopenic symptoms as in the noninsulinoma pancreatogenous hypoglycemia syndrome and nesidioblastosis. As the preoperative work up varied across the studies included and not all patients had specimens available for evaluation, the general term post-RYGB hypoglycemia is mostly applied. Results T1
Fourteen papers presenting outcome after surgery for post-RYGB hypoglycemia were included (Table 1 and Table 2). Three series including patients previously reported on were not included (Table 2). In total, 75 patients were included. The mean duration from RYGB to the recognition of the symptoms of hypoglycemia was 28 (range 1–102) months (based on data from 28 patients). The mean duration from RYGB to surgery for hypoglycemia was 63 (12–107) months (based on data from eleven patients). Different surgical techniques were applied including the placement of a gastric tube, reversal of the RYGB with and without concomitant sleeve gastrectomy, gastric pouch restriction, and pancreatic resection. In some series, several concomitant techniques were applied. Eight (11%) patients had 2 or more consecutive surgical procedures for hypoglycemia. Open and laparoscopic approaches were used. Reversal of RYGB Placement of a gastrostomy tube was used in all patients before reversal in the 2 largest series of RYGB reversal for hypoglycemia [10,11]. After nutritional delivery through the gastrostomy tube in these studies, no hypoglycemic
symptoms were reported and a marked normalization of the glucose tolerance test was defined. A total of 17 (23%) patients from 5 reports had reversal of RYGB (Table 1). Five patients received a concomitant sleeve resection. One had previously undergone a distal pancreatectomy for hypoglycemia. Weight regain occurred in 4 of 11 patients that had documented evaluation of postoperative weight development. At least 1 had near total weight regain. The outcome in regard to hypoglycemia is described in Table 1. Two patients had pancreatic resections after reversal both with nesidioblastosis identified in the specimens. In the largest series (9 patients), 1 patient had gastroesophageal reflux after reversal [11]. Two patients developed diarrhea and 1 developed an anastomotic stricture that was dilated endoscopically. Histologically nesidioblastosis could not be evaluated, as resections were not made. Gastric pouch restriction Adding band or ring restriction to the gastric pouch for post-RYGB hypoglycemia was used in 11 (15%) patients (Table 1). In 1 study, 10 patients received a silastic ring or adjustable band around the pouch after reduction of pouches larger than 30 mL by stapling technique [13]. Nine of the 10 patients experienced resolution of symptoms, but the mean follow-up was short. One patient developed recurrence of hypoglycemia. A distal pancreatectomy was performed, and the band was removed because of band-related problems (Table 1). Nesidioblastosis was found in the specimens of the patient having pancreatic resection, but was undefined in the remaining 10 patients. Biopsies were performed in 2 patients. Pancreatic resection Distal, subtotal, and total pancreatectomies have been made for hypoglycemia after RYGB (Table 2). Distal pancreatectomy with or without splenectomy was most common. Among the 51 (68%) patients identified, 6 (12%) were reoperated with extended resections due to recurrent or persistent hypoglycemia. Three (6%) patients ended up with total pancreatectomy. Two had RYGB reversal and 1 pouch restriction before pancreatic resection [7,8,13]. Two had concomitant banding of the gastric pouch [13]. In total, 34 of 51 (67%) patients had resolution of hypoglycemic symptoms after 1 or more pancreatic resections. Among 17 patients with persistent symptoms, 8 were classified as “having recurrent or ongoing symptoms”, 5 as “occasional symptoms”, 2 as “frequent symptoms”, 1 as “responded well to octreotide treatment”, and 1 later underwent bypass reversal with “minimal improvement” in symptoms [9]. The duration of follow-up was short in several of the series (Table 2).
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Table 1 Outcome of bypass reversal or pouch restriction for post-RYGB hypoglycemia Authors
No Pts.
Reversal Clancy et al., 1 2006 [7] Patti et al., 2005 1 [8] Lee et al.,2013 2 [9] Campos et al., 2013* [10]
4
Vilallonga et al., 9 2013 [11]
Total
17
Restriction De Heide et al., 1 2012 [12] Z’graggen et al., 10 2008†[13]
Total
Procedure
Follow-up, mo Symptom Outcome/comments resolution, number
Reversal
na
0
Reversal
na
0
Reversal
8, 18
0
3–22, mean 12 4 Reversal; 2 also had a modified sleeve gastrectomy. All had a gastrostomy tube to document improved symptoms before reversal. o1–46, 9 Reversal; limited to patients with mean 13 “marked” normalization of the gastrostomy tube glucose tolerance test 13
Adjustable band cranially to na 0 gastrojejunal anastomosis Downsizing of gastric pouch. 6 4–18, mean 11 9 patients received a silastic (Fobi) ring around the pouch, 4 received an adjustable band.
11
Still symptomatic hypoglycemia after reversal, pancreaticoduodenectomy performed (Table 2) Unsuccessful; regain of near all weight lost. A distal and subsequent total pancreatectomy performed. One had distal pancreatectomy before reversal. Reversal did not alleviate hypoglycemia as evaluated by a mixed meal examination. No postoperative episodes of neuroglycopenia, and no or minimal” symptoms from very few hypoglycemic events, classified as ”resolution”
None had new episodes of severe hypoglycemia. Three patients received a concomitant sleeve gastrectomy. Partial weight regain in 2 patients.
Marked improvement in subjective complaints None had new hypoglycemic episodes. All had improvements in the Sigstad score. One patient had later distal pancreatectomy due to recurrent symptoms, and the band was removed due to oesophageal dilation and solid food intolerance.
9
na ¼ not applicable; Pts ¼ patients. 1 patient also had hypocalcemia and hypoparathyroidism. † 2 additional patients with concomitant pancreatic resection excluded from Table 1 (included in Table 2). *
In the present review, 6 patients developed diabetes after total (3), subtotal (2), and distal (80%) (1) pancreatic resection, respectively. Diabetic status, however, was unknown in most of the patients. Nesidioblastosis was confirmed from specimens in 47 patients, 2 were classified as having pancreatic islet hyperplasia and expanded cell mass, and in 2 patients nesidioblastosis was not confirmed. Discussion Adult nesidioblastosis is rare and was first reported in 1975 [3,5,24–26]. In a paper from 2008, o 100 individuals were claimed to be identified with adult nesidioblastosis in the literature [25]. The association between nesidioblastosis and RYGB was initially described in 2005, and in a 2011 review, 80–90 patients were identified with severe postbypass hypoglycemia [3]. In 1 report a patient developed symptoms 10 years after RYGB, and in another series the mean duration from RYGB to pancreatic resection for hypoclycemia was 54 (17–264) months [6,20]. The extensive use of RYGB and the possibility of late manifestations indicate that severe post-RYGB
hypoglycemia may be more commonly encountered. Although not all published cases may have been identified in the present review, a minimum of 75 patients are documented as being operated on for post-RYGB hypoglycemia in recent years. The evidence, however, for the use of surgery for postRYGB hypoglycemia is limited [3,5]. Follow-up may be short, different surgical techniques were used across reports, and several patients received 41 type of procedure challenging the interpretation of treatment outcome. Standardized definitions of severe post-RYGB hypoglycemia including lengths and degree of symptoms and serum glucose levels, could facilitate differentiation from the more common symptoms of dumping and would be beneficial for comparative analyses between reports. Improved knowledge about the physiology, which could differ from other cases of nesidioblastosis and hypoglycemia, may facilitate maturation of a rational treatment algorithm [2,20,22]. Hypotheses for the hypoglycemia include obesity-induced β-cell hypertrophy not reversed after RYGB, inappropriate growth factor release, persistent altered gut hormonal signalling, and a genetic susceptibility [2,5,26,27]. Others,
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Table 2 Outcome of pancreatic resection for post-RYGB hypoclycemia Authors
No Pts.
Procedure
Follow- up, mo
Symptom Outcome/comments resolution, number
Lee et al., 2013 [9]
1
Distal pancreatectomy
424
0
Ceppa et al., 2012 [14] Qintar et al., 2012 [15]
1 1
Distal pancreatectomy 24 Distal (80%) pancreatectomy 4 6
1 0
Rabiee et al, 2011 [16] Alvarez et al., 2007 [17] Clancy et al., 2006 [7]
1 1 2
Distal (85%) pancreatectomy 2 Distal pancreatectomy 10 Distal (80%) pancreatectomy na in 1, and 1 with 95% pancreatectomy
1 1 2
Barbour et al., 2008 [18]
2
12, 91 Duodenum preserving pancreatic head resection in 1, distal pancreatectomy in 1 2 had distal pancreatectomy 4, 4, 15 and Fobi ring around gastric pouch, 1 had distal pancreatectomy (50–60%) and removal of pouch band 2 had distal (80%) na pancreatectomy, 1 subtotal (85%)
2
Mathavan et al., 2010 [19] 9
Distal (80%) pancreatectomy 8–84, mean 30‡
3
Rumilla et al., 2009† [20]
27
Partial pancreatectomy
Total
51
Z’graggen et al., 2008 [13] 3
Patti et al., 2005* [8]
3
Persistent hypoglycemia, later bypass reversal (Table 1) Still hypolycemia. Subsequent total pancreatectomy Hypoglycemia recurred 6 mo after pancreatic resection—responded well to octreotide injections Symptom resolution Symptom resolution The patient with 80% pancreatectomy had previously reversed the bypass for hypoglycemia, which persisted after pancreatic resection. Pancreaticoduodenectomy performed. The other patient successfully treated. The patient with pancreatic head resection had persistent symptoms and underwent distal pancreatectomy
3
No patients with new hypoglycemic episodes
2
1 patient had previous take down of gastric bypass (Table 1) and after distal pancreatic resection total pancreatectomy was performed for recurrent symptoms, 1 patient with improvements but still episodes of hypoglycemia, 1 was without hypoglycemic episodes 2 patients had complete symptom resolution, 3 had occasional symptoms, 2 frequent symptoms. 2 patients with severe symptoms had extended (95%) pancreatic resection. 1 of these had resolution of symptoms, the other had still symptoms 8 patients with recurrent/ongoing mild symptoms
1–55, mean 11 19 34
na ¼ not applicable; Pts ¼ patients. The definition of distal pancreatic resection varied and if presented the extent of resection (%) is given. * A later report of 6 patients from the group is not included (lack of clinical outcome data) [21]. † Includes the 6 patients in the original series by Service GJ et al. [1]. Additional publications from the same group not included in Table 2 [22,23]. ‡ Follow-up counted from first procedure in patients with reresections.
however, claim that the hypoglycemia is not accompanied by islet hyperplasia or increased β-cell turnover [28]. The preoperative evaluation including the level of plasma glucose used to define hypoglycemia varied across the reports identified. The postoperative evaluation was not standardized. In some reports, a mixed meal or oral glucose examination was performed, and in others, hypoglycemia was less clearly defined [9]. The Whipple triad is recommended in the evaluation of these patients and includes symptoms of hypoglycemia, which in the case of postRYGB occurs after meals, documented low plasma glucose levels at the time of symptoms (o2.8 mmol/L), and the relief of symptoms after correction of the low glucose levels [3]. A diagnostic algorithm should also include a negative preoperative 72-hour fast test, continuous glucose
monitoring, and negative imaging studies for insulinoma [14]. Although uncommon, insulinomas have been identified in patients with post-RYGB hypoglycemia [22,29]. Cpeptide and insulin should be evaluated and are typically inappropriately high after meals. Oral glucose tolerance tests may be of value in regard to preoperative and outcome analyses. Interestingly, in a report of 10 non-RYGB adults with neuroglycopenia, 5 had previous partial gastrectomy [30]. Severe hypoglycemia has also been reported after duodenal switch [31]. In a Swedish study, an increased risk for hospitalization due to hypoglycemia was documented after RYGB, but not after vertical banded gastroplasty or gastric banding [4]. The exclusion of the proximal gut and the increased nutrient transit to the distal intestines may thus be
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important in the development of hypoglycemia [32]. The worldwide extensive use of RYGB and the focus on the metabolic effects of this surgery, may promote awareness of this problem after other upper gastrointestinal surgical procedures. Dietary modifications and medication are the first-line treatment for post-RYGB hypoglycemia [3,5,6]. Even in a subset of individuals with life-threatening neuroglycopenia, complex nutritional and medical management strategies are valid options to reduce postprandial insulin secretion and stabilise glucose excursions [32]. Surgery should be evaluated in the context of the perioperative risk, long-term outcome, potential weight regain, and its effects on obesity related co-morbidity—and late complications such as diabetes, reflux, and diarrhea. Reversal of RYGB to “normal anatomy” was first described in 2006, and subsequently in larger series [11,33]. Adding sleeve gastrectomy may reduce weight regain after reversal but increase the risk of complications [11]. Improvements in symptoms of hypoglycemia after the placement of a gastrostomy tube for feeding in the gastric remnant may normalize abnormal metabolic responses to ingested nutrients after RYGB in patients with hypoglycemia refractory to diet and medications [34]. This procedure may be of use in the selection of patients that could benefit from RYGB reversal as described in 2 of the papers included. The findings may contribute to the understanding of the physiology of post-RYGB hypoglycemia [10,11]. Hypoglycemia may be controlled in the short term by adding or restoring restriction [13]. Adding a (non)adjustable band is not major surgery compared to pancreatic resection and RYGB reversal and may ensure sustained weight loss. However, band-related problems can occur. The physiologic mechanisms for the improvements in symptoms after adding restriction may include enforced dietary changes and slower nutrient delivery to the jejunal limb. Long-term outcome, however, is not established. The adequate extent of pancreatic resection for postRYGB hypoglycemia is not defined. Extended resections may be beneficial, but the risk of diabetes and pancreatic exocrine dysfunction are increased [3]. The use of selective arterial calcium stimulation to identify areas of the pancreas responsible for hyperinsulinism may help to reduce the extent of resection [13,19]. Laparoscopy and spleen preserving techniques make the surgery less invasive but significant morbidity rates have been reported [17,19,35,36]. Several studies describe beneficial long-term outcome after pancreatic resection for nesidioblastosis in non-RYGB patients [24,37,38]. Similarly, in an editorial, 37 patients with post-RYGB hypoglycemia were reported on of which 23 underwent resection of about 60% of the pancreas. Symptom relief was found in 21 of 23 patients [22]. However, in a later report from the group, half of the 48 patients receiving pancreatic resection for hypoglycemia, of which 33 were after bariatric surgery, were classified as
5
“minimally successful” or “surgical failures”. Although 75% had improvements in quality of life and fewer symptoms, 25% experienced no benefit from partial pancreatectomy. Nearly 90% reported recurrent symptoms after a mean follow-up of 53 months, and 37% had complications. Nine (18%) patients developed diabetes, and 4 (8%) underwent additional operations for hypoglycemia [23]. In the present review symptom resolution seemed to occur in 34 of 51 (67%) patients after pancreatic resection, but the follow-up was short. Subtotal pancreatic resection may not be the optimal treatment for hypoglycemia after RYGB in all patients, as the underlying cause for hyperinsulinemia may persist [3]. In summary, pancreatic resection is the most common surgical procedure applied for post-RYGB hypoglycemia. The adequate extent of resection is not defined, and symptoms may persist or recur. Reversal of the RYGB or added restriction have been used as alternatives with undefined effects in the long term. The patients should be informed about the incomplete knowledge of post-RYGB hypoglycemia and the variability in treatment options and outcomes reported to date. Improved knowledge about the physiology and long-term therapeutic outcome, may allow therapy with improved control of the glucose excursions.
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