Hyperinsulinemic Hypoglycemia after Bariatric Surgery JMBS

REVIEW ARTICLE

*Equal contribution

Received: April 20, 2020, Revised: May 8, 2020, Accepted: May 19, 2020

Corresponding author: Wah Yang, 613 Huangpu Avenue, Guangzhou 510630, China

Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University Tel: +86-20-38688735, E-mail: yangwah@qq.com; yangwah@connect.hku.hk

Corresponding author: Xiaomei Chen, 613 Huangpu Avenue, Guangzhou 510630, China

Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University Tel: +86-20-38688735, E-mail: 749818530@qq.com

CC

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hyperinsulinemic Hypoglycemia after Bariatric Surgery

1

Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou,

State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of Medicine, The University of Hong Kong,

Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Songhao Hu ^1, *, Hanlin Tang ^1, *, Huaxi Wang ¹ , Zhiyong Dong ¹ , Shuwen Jiang ¹ , Cunchuan Wang ¹ , Xiaomei Chen ¹ , Wah Yang ^1,2,3

Postprandial hyperinsulinemic hypoglycemia (PHH) is one of the serious complications after bariatric surgery, it can lead life-threatening neuroglycopenic symptoms, such as seizures, disorientation, impairment of version and loss of consciousness without any premonitory. The presentation, prevalence, diagnosis, pathology and treatment are reviewed in this summary.

Key Words: Postprandial hyperinsulinemic hypoglycemia (PHH), Roux-en-Y gastric bypass (RYGB), Sleeve gastrectomy (SG), Bariatric surgery

BACKGROUND

Obesity has become a worldwide epidemic especially in recent decades with the development of agriculture and food industry. Bariatric surgery has also proved to be the most effective and durable treatment of severe obesity and obesity-related disease such as hyperlipidemia, type 2 diabetes (T2D), and cardiovascular disease [1,2].

Bariatric surgery has been taken all over the world, there are approximately 833,687 operation records in IFSO (International Federation for the Surgery of Obesity) annual report 2019 [3]. But with the increments of the operation, many complications have also manifested after alterations of anatomy and function of gastrointestinal system.

Postprandial hyperinsulinemic hypoglycemia (PHH) after bariatric surgery is an uncommon and rarely reported metabolic complication of weight loss surgery, especially in post-RYGB patients. As Roux-en-Y gastric bypass (RYGB) has become the golden standard for bariatric surgery [4], the reports about PHH generally increased as from different bariatric centers.

The diagnosis and treatment of PHH is complex, so an increasing number of surgeons and physicians are investigating it.

WHAT IS PHH?

Postprandial hyperinsulinemic hypoglycemia (PHH) is

one of the serious complications after bariatric surgery, it

can lead life-threatening neuroglycopenic symptoms, such as seizures, disorientation, impairment of version and loss of consciousness without any premonitory [5]. PHH generally develops several months after RYGB and even after the first year in most cases, it happens usually 1 hour after a meal and typically associated with low blood glucose level and inappropriate hyperinsulinemia [6]. The symptom of PHH is similar with the late dumping syndrome, as the PHH usually occur from several minutes to 1 hour after feeding.

The definition of the ASMBS (American Society for Metabolic and Bariatric Surgery) [7] we based on, states (1) symptoms occurring ＞1 year after surgery, (2) normal fasting glucose and insulin levels, (3) correlation of symptoms with hypoglycemia, followed by (4) spontaneous resolution of hypoglycemia and a positive provocative test. The limitation of these definitions, however, is presence of the symptoms, which may be weak or even totally absent either primarily or by acquisition through hypoglycemia tolerance.

PREVALENCE OF PHH

Hyperinsulinemic hypoglycemia post-prandial hypogly- cemia appears to be observed after procedures that divert nutrients into the mid-small bowel, such as RYGB, and not purely restrictive procedures such as adjustable gastric banding and sleeve gastrectomy. Marsk et al. [8] have reported the prevalence of hypoglycemia is around 0.2%

by a nationwide population-based Swedish study and more than 5000 patients were enrolled for over 2 decades.

According to the Bariatric Outcomes Longitudinal Database [9], the incidence of hypoglycemia was found to be 0.1% among all patients, and all the incidence was calculated as the total number of self-reported cases of hypoglycemia post-operatively after each particular bariatric procedure (i.e. RYGB, (AGB) adjustable gastric banding and (SG) sleeve gastrectomy). Martins et al. [10]

reported that far more patients almost one third may develop some level of hypoglycemia after mix meal, but most of them may not seek medical attention. Because of the difference in estimation, we still have no consensus.

PRESENTATION

Hyperinsulinemic hypoglycemia is characterized by neuroglycopenia that occurs in the post-prandial state.

Symptoms can be nonspecific and include abroad spectrum of presentations related to Whipple’s triad for hypogly- cemia [7]: (1) symptomatic hypoglycemia, (2) documented low plasma glucose level, and (3) resolution of symptoms after glucose administration.

Specific symptoms of hypoglycemia can also divide into autonomic symptoms and neuroglycopenic symptoms.

Autonomic symptoms include anxiety, sweating, tremors and palpitations. Neuroglycopenic symptoms include confusion, weakness, lightheadedness, dizziness, blurred vision, disorientation, and eventually loss of consciousness [5,10].

DIAGNOSIS OF PHH

There is no single agreed-upon criterion for the diagnosis of postprandial hyperinsulinemic hypoglycemia after bariatric surgery. The diagnosis should be a complex patient diary, with particular attention to dietary, specific hypoglycemic symptoms and their temporal relationship, is imperative in arriving at the diagnosis. To diagnose the PPH, we also need to identify the disease with similar symptoms, including early phase dumping syndrome, nesidioblastosis and insulinoma [11].

Plasma glucose, insulin and C peptide levels should be measured. Proinsulin levels which is extremely higher in insulinomas compared to nesidioblastosis [12,13]. The 72-h diagnostic fasting test can be performed, which would be negative in cases of nesidioblastosis and dumping syndrome (normal fasting plasma glucose and insulin levels) [5,14], and positive in insulinoma [15]. Thus, negative 72 h fast is the best test to exclude insulinoma in post-RYGB patients.

Diagnostic imaging such as CT, MRI and trans- abdominal ultrasonography can locate the exocrine and endocrine tumor. In patients with endogenous hyper- insulinemic hypoglycemia and negative non-invasive radiologic localization studies.

Glycemic pattern and continuous glucose monitoring

(CGM) are useful in the diagnosis. In patients with hyperinsulinemia and 30 mins after a high carbohydrate, the insulin levels will become a rapid decline followed by spontaneous correction of their glucose levels by the CGM. CGM also correlated clinical signs with low interstitial glucose concentrations, eliminating a dumping syndrome [16,17]. CGM is also a valuable diagnostic test not only for symptomatic hypoglycemic patients, but also for identifying those who remain asymptomatic at low glucose values [18,19]. The reason for these phenomena is that adaptive mechanisms to hypoglycemia or susceptibility to neuroglycopenia may vary between individuals after RYGB [20].

For nesidioblastosis, we usually confirm and diagnose by histopathology about the pancreatic specimens. The way to accept the specimen is really complicate by a minimal invasive method. We use the criteria as below [21]: (1) exclusion of an insulinoma by macroscopic, microscopic and immunohistochemical examination; (2) multiple β cells with an enlarged and hyperchromatic nucleus and abundant clear cytoplasm; (3) islets with normal spatial distribution of the various cell types; and (4) no pro- liferative activity of endocrine cells [22].

For the dumping syndrome, the diagnosis should focus on food intake [23] and evaluate by several scoring systems, including Sigstad’s Diagnostic Index, the Visick classification and Arts scoring system [24,25].

PATHOPHYSIOLOGY

We have no specific evidence about the patho- physiology of the PPH. Firstly, as the gastric bypass changed the anatomy of gastrointestinal system, the nutrient content transit to jejunum and ileum which has abundant L cells. The L cells can also produce GLP-1 to magnify the function of β cells [26]. Rabiee et al. [27]

studied four post-RYGB patients and reported 3-4 fold increase in GLP-1 levels one year after RYGB.

Then hypoglycemia in post-RYGB patients has also been attribute to several other possible mechanisms. (a) lack of reduction of β cell mass which was constitutively increased during the preoperative obese state; (b) increased insulin sensitivity following weight loss; (c) inappropriate

β cell secretion following early entry of ingested nutrients into the small intestine (late dumping syndrome); and (d) abnormal counter regulatory hormonal (glucagon) responses [28]. Alterations in other gastrointestinal hormones, including ghrelin, peptide YY (PYY) and leptin, have also been implicated in glycemic patterns following RYGB.

TREATMENT

1. Conservative measures 1) Diet modified treatment

The first step to treat PHH is diet modification.

According to the experience in dumping syndrome, adding the times of meal and decreasing the volume of each one is a useful treatment. On the other hand, food with low carbohydrate can present the formation high concentration chyme. Gasser et al. [29] found that mix meal with low carbohydrate can relieve the circumstance compared with normal one. Patients with the similar symptoms are recommend to intake a low carbohydrate diet. Then the pace of eating should also be controlled, by eating slowly, patients also anticipate the feeling of fullness while they are eating.

2) Pharmacotherapy

For patients without the manifest reaction to the diet adjustment, medical treatment can initiate by diazoxide, octreotide, alpha glucosidase inhibitors, or calcium channel blockers [16,30]. The previous report showed that a long-term therapy and maintain the glucose levels within a safe range [7].

Although glucagon has failed to report any significant

effect in treating hyperinsulinemic hypoglycemia [31],

GLP-1 receptor antagonists have shown efficacy and

promise for long-term treatment. Taking into consideration

the presumed pathophysiology of RYGB procedures and

their effecton GLP-1 expression with subsequent elevated

insulin levels, blocking the action of GLP-1 can suppress

postprandial insulin secretion. Infusions of GLP-1 receptor

blockers [32]—currently available only as investigative

drugs in the research setting—corrected hypoglycemia and

increased glucagon levels in individuals with recurrent

hypoglycemia after RYGB [7,33].

Table 1. Dignosis and management of PHH

Dignosis of PHH No single agreed-upon criterion Referable basis Patient diary

Dietary record

Hypoglycemic symptoms Management of PHH

Methods 1. Diet modified 2. Pharmacotherapy 3. Surgical treatment: distal

pancreatectomy (don’t recommend), gastrostomy tube place, RYGB reversal, Conversion to SG, Gastric restriction

2. Surgical treatment

Surgical treatment is an enhanced method to solve the problem without medical effect.

1) Distal Pancreatectomy

This is a kind of surgery with high risk and surgeon need to evaluate that how much of the pancreas should remove during the operation. The operation targets the presume endocrine end organ of the clinical disease,but for the complexity of different cells in pancreas, it hard to have a precise estimation before operation [34]. Some investigators have reported the benefit of this surgery is really limited [35]. Some patients with 80% pancreatectomy founded 22% of them had frequent symptoms with medical treatment [36]. In addition to its variable clinical efficacy, partial pancreatectomy is associated with significant potential morbidity, including new onset diabetes [37].

Thus, this treatment should not be recommended for treatment of postprandial hyperinsulinemic hypoglycemia after bariatric surgery [7].

2) Gastrostomy tube placement

A tube is put to connect the gastric pouch and gastric remnant. Nutrient content flow into the stomach and proximal duodenum. Small case series suggest that this can serve both an efficient therapy for postprandial hypoglycemia and per oral calorie intolerance [38].

3) RYGB reversal

Reversal of RYGB can be technically challenging and also represent a therapy of last resort. Viallonga et al. [39]

and Campos et al. [40] found symptomatic resolution in their follow up, although the cases were limited.

Long-term multicenter investigation should be taken to prove the efficiency of RYGB reversal.

4) Conversion to SG

Reversal of RYGB with the addition of primary or staged SG specifically for treatment of refractory PHH also reported in cases. Most found the resolution of hypoglycemia without weight regain in short term [41].

However, there are still much concerns about the com- plications for this surgery, including a greater incidence of gastroesophageal reflux [39-41].

5) Gastric restriction

Gastrojejunostomy restriction to slow the passage of food into the small intestine has used to treat PPH.

Z’graggen et al. [42] use a silastic ring to place under the anastomotic stoma. Of totally 12 cases, 11 patients reported improve mentor resolution of postprandial hypoglycemia symptoms within 3–12 months.

SUMMARY

Until today, we are still lack of clinical date about postprandial hyperinsulinemic hypoglycemia. Many researches and clinical review have provided abundant information about the PHH. Not only in clinical medicine, many scientists are also investigated on the pathology of PHH and to fully understand this disease, we still have also a long way to go. Firstly, we should clarify that diagnosis by a systematic review and exclude other diseases. Then, diet modification is the first step to treat PHH. Dietitian and endocrinologist consulted in cases not responding to initial treatment. Furthermore, Pharmacotherapy produces variable results, but should be attempted before surgical intervention. The type of surgical need more research but Partial pancreatectomy is not recommended (Table 1).

CONFLICT OF INTEREST

All authors declare that they have no conflicts of interest.

STATEMENT OF HUMAN AND ANIMAL RIGHTS

Not applicable.

STATEMENT OF INFORMED CONSENT

Not applicable.

REFERENCES

1. Gloy VL, Briel M, Bhatt DL, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ 2013;347:

f5934.

2. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-37.

3. Welbourn R, Hollyman M, Kinsman R, et al. Bariatric surgery worldwide: baseline demographic description and one-year outcomes from the fourth IFSO Global Registry report 2018.

Obes Surg 2019;29:782-95.

4. Roslin MS, Dudiy Y, Brownlee A, Weiskopf J, Shah P. Response to glucose tolerance testing and solid high carbohydrate chal- lenge: comparison between Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and duodenal switch. Surg Endosc 2014;

28:91-9.

5. Kellogg TA, Bantle JP, Leslie DB, et al. Postgastric bypass hyper- insulinemic hypoglycemia syndrome: characterization and re- sponse to a modified diet. Surg Obes Relat Dis 2008;4:492-9.

6. Ritz P, Hanaire H. Post-bypass hypoglycaemia: a review of current findings. Diabetes Metab 2011;37:274-81.

7. Eisenberg D, Azagury DE, Ghiassi S, Grover BT, Kim JJ. ASMBS position statement on postprandial hyperinsulinemic hypo- glycemia after bariatric surgery. Surg Obes Relat Dis 2017;13:

371-8.

8. Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 pa- tients undergoing surgery for obesity in 1986-2006 in Sweden.

Diabetologia 2010;53:2307-11.

9. Sarwar H, Chapman WH 3rd, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg 2014;24:1120-4.

10. Martins D, Cardoso L, Baptista C, et al. Continuous glucose monitoring for evaluation of glycemic variability after bariatric surgery. Paper presented at: 18th European Congress of Endo- crinology; 2016 May 28-31; Munich, Germany.

11. Malik S, Mitchell JE, Steffen K, et al. Recognition and manage- ment of hyperinsulinemic hypoglycemia after bariatric surgery.

Obes Res Clin Pract 2016;10:1-14.

12. Ceppa EP, Ceppa DP, Omotosho PA, Dickerson JA 2nd, Park CW, Portenier DD. Algorithm to diagnose etiology of hypo- glycemia after Roux-en-Y gastric bypass for morbid obesity:

case series and review of the literature. Surg Obes Relat Dis 2012;8:641-7.

13. Vezzosi D, Bennet A, Fauvel J, Caron P. Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia re- lated to endogenous hyperinsulinism. Eur J Endocrinol 2007;

157:75-83.

14. Bernard B, Kline GA, Service FJ. Hypoglycaemia following up- per gastrointestinal surgery: case report and review of the literature.

BMC Gastroenterol 2010;10:77.

15. Zagury L, Moreira RO, Guedes EP, Coutinho WF, Appolinario JC. Insulinoma misdiagnosed as dumping syndrome after bari- atric surgery. Obes Surg 2004;14:120-3.

16. Hanaire H, Dubet A, Chauveau ME, et al. Usefulness of con- tinuous glucose monitoring for the diagnosis of hypoglycemia after a gastric bypass in a patient previously treated for type 2 diabetes. Obes Surg 2010;20:126-9.

17. Hanaire H, Bertrand M, Guerci B, Anduze Y, Guillaume E, Ritz P. High glycemic variability assessed by continuous glucose monitoring after surgical treatment of obesity by gastric bypass.

Diabetes Technol Ther 2011;13:625-30.

18. Vidal J, Nicolau J, Romero F, et al. Long-term effects of Roux-en-Y gastric bypass surgery on plasma glucagon-like peptide-1 and islet function in morbidly obese subjects. J Clin Endocrinol Metab 2009;94:884-91.

19. Scavini M, Pontiroli AE, Folli F. Asymptomatic hyper- insulinemic hypoglycemia after gastric banding. N Engl J Med 2005;353:2822-3.

20. Halperin F, Patti ME, Skow M, Bajwa M, Goldfine AB. Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass. J Obes 2011;2011:869536.

21. Cummings DE. Gastric bypass and nesidioblastosis--too much of a good thing for islets? N Engl J Med 2005;353:300-2.

22. Mathavan VK, Arregui M, Davis C, Singh K, Patel A, Meacham J. Management of postgastric bypass noninsulinoma pan- creatogenous hypoglycemia. Surg Endosc 2010;24:2547-55.

23. Frantzides CT, Carlson MA, Shostrom VK, et al. A survey of dumping symptomatology after gastric bypass with or without lesser omental transection. Obes Surg 2011;21:186-93.

24. Hammer HF. Medical complications of bariatric surgery: focus on malabsorption and dumping syndrome. Dig Dis 2012;30:

182-6.

25. Tzovaras G, Papamargaritis D, Sioka E, et al. Symptoms sugges- tive of dumping syndrome after provocation in patients after laparoscopic sleeve gastrectomy. Obes Surg 2012;22:23-8.

26. Vella A. Enteroendocrine secretion after Roux-en-Y gastric by- pass: is it important? Neurogastroenterol Motil 2013;25:1-3.

27. Rabiee A, Magruder JT, Salas-Carrillo R, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction. J Surg Res 2011;167:199-205.

28. Cummings DE. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery. Int J Obes (Lond) 2009;33 Suppl 1:S33-40.

29. Gasser M, Meier C, Herren S, Aubry E, Steffen R, Stanga Z. Is testing for postprandial hyperinsulinemic hypoglycemia after gastric bypass necessary? Clin Nutr 2019;38:444-9.

30. Spanakis E, Gragnoli C. Successful medical management of sta- tus post-Roux-en-Y-gastric-bypass hyperinsulinemic hypoglycemia.

Obes Surg 2009;19:1333-4.

31. Halperin F, Patti ME, Goldfine AB. Glucagon treatment for post-gastric bypass hypoglycemia. Obesity (Silver Spring) 2010;

18:1858-60.

32. Salehi M, Gastaldelli A, D'Alessio DA. Blockade of gluca-

gon-like peptide 1 receptor corrects postprandial hypoglycemia

after gastric bypass. Gastroenterology 2014;146:669-80.e2.

33. Abrahamsson N, Engström BE, Sundbom M, Karlsson FA. GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication? Eur J Endocrinol 2013;169:885-9.

34. Lash RW, Giordano TJ, Moraitis AG, Hodish I. Histological in- sights into the pathogenesis of post-Roux-en-Y hyper- insulinaemic hypoglycaemia. Diabet Med 2014;31:e29-32.

35. Bose M, Oliván B, Teixeira J, Pi-Sunyer FX, Laferrère B. Do in- cretins play a role in the remission of type 2 diabetes after gastric bypass surgery: what are the evidence? Obes Surg 2009;19:

217-29.

36. Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 1973;37:826-8.

37. Slezak LA, Andersen DK. Pancreatic resection: effects on glu- cose metabolism. World J Surg 2001;25:452-60.

38. McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyper-

insulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab 2010;95:

1851-5.

39. 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 2013;27:4640-8.

40. 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 2014;10:36-43.

41. Carter CO, Fernandez AZ, McNatt SS, Powell MS. Conversion from gastric bypass to sleeve gastrectomy for complications of gastric bypass. Surg Obes Relat Dis 2016;12:572-6.

42. Z’graggen K, Guweidhi A, Steffen R, et al. Severe recurrent hy- poglycemia after gastric bypass surgery. Obes Surg 2008;18:

981-8.