Noninsulinoma Pancreatogenous Hyperinsulinemic Hypoglycemia in Roux-en-Y Gastric Bypass Patients

| February 1, 2015

This column is written by medical students and is dedicated to reviewing the science behind obesity and bariatric surgery.

This month: Noninsulinoma Pancreatogenous Hyperinsulinemic Hypoglycemia in Roux-en-Y Gastric Bypass Patients

by Shawn Tsuda, MD, FACS
Dr. Tsuda is from University of Nevada School of Medicine, Las Vegas, Nevada.

Bariatric Times. 2015;12(2):10–13.


Abstract
Several cases of severe hypoglycemia, requiring surgical intervention, have been reported after gastric bypass surgery. Although originally believed to be a late manifestation of the dumping syndrome, post-gastric bypass hypoglycemia is likely a separate condition with a distinct pathophysiology. Post-gastric bypass hypoglycemia is more appropriately defined as non-insulinoma pancreatogenous hyperinsulinemic hypoglycemia. This article describes possible mechanisms, as well as diagnostic and treatment considerations based on established literature and clinical experience.

Introduction
Roux-en-Y gastric bypass (RYGB) is associated with improvement of glucose homeostasis and insulin sensitivity in patients with obesity; however, in some cases, this procedure may cause hypoglycemia. Hypoglycemia is characterized by blood sugar less than 70mg/dL.[1] Hypoglycemia is associated with neuroglycopenic symptoms, such as impaired mentation, irritability, fatigue, visual changes, slurred speech, and motor deficits.[2]

Post-gastric bypass hypoglycemia is defined as non-insulinoma pancreatogenous hyperinsulinemic hypoglycemia. The phenomenon of post-gastric bypass hypoglycemia is named specfically for gastric bypass as it is uncommon to other bariatric procedures; however, some cases have been reported after adjustable gastric banding.[3] Approximately 0.2 percent of the hospitalizations related to hypoglycemia are in pateints post-gastric bypass.[4]

Mechanism
Post-gastric bypass hypoglycemia is considered to be a late manifestation of “dumping syndrome,” a condition where food reaches the small intestine too rapidly.[5] Dumping syndrome and hypoglycemia are usually managed conservatively; however in rare cases, patients present with severe, unresponsive symptoms and may require surgery.[6]

Hyperinsulinism occurs from insulinoma, a tumor in the pancreas that produces too much insulin, or nesidioblastosis, diffuse proliferation of pancreatic islet cells budding from ductal epithelium.[7]
Most reported cases of post-gastric bypass hypoglycemia are of non-insulinoma etiology. Although insulinoma causes weight gain, its prevalence is greater in patients who have overweight or mild obesity than in individuals with morbid obesity who qualify for bariatric surgery. Conversely, some patients with non-insulinoma hypoglycemia who have not undergone gastric bypass do not have severe obesity. As such, post-gastric bypass hypoglycemia is purported to occur separately from insulinoma and is a result of surgery, rather than a cause of obesity.[5,8]

Non-insulinoma beta-cell hyperfunction may be mediated by enhanced glucagon-like peptide-1 (GLP-1) secretion. Bypass of the proximal intestine results in rapid delivery of nutrients to the distal intestine facilitating GLP-1 secretion. GLP-1 is a beta-cell trophic hormone secreted by the L-cells in the ileum. Over time, excessive GLP-1 stimulates growth and/or hyperfunction of the islets and consequently increased insulin secretion.[9] Increased GLP-1 levels are exhibited in post-gastric bypass patients with severe hypoglycemia (~300 pmol/L).[5]

Familial hyperinsulinism, hypoglycemia caused by mutations in genes, may also be a root cause of post-gastric bypass hypoglycemia. Function mutations in encoding of sulfonylurea receptor (SUR1), the potassium channel (Kir6.2), or in gene encoding for glucokinase and glutamate dehydrogenase may create the disorder. Non-SUR1 mutations present as a mild form of the condition. Patients are usually not diagnosed until adulthood when an offspring presents with persistent hyperinsulinemic hypoglycemia during infancy. It is possible that an underlying congenital condition is unmasked after gastric bypass due to improved insulin sensitivity.[5]

Diagnosis
Mild hypoglycemia should be differentiated from the more severe post-gastric bypass hypoglycemia. In patients exhibiting mild hypoglycemia, symptoms should resolve with dietary modifications. In post-gastric bypass hypoglycemia, symptoms may be unresponsive to dietary modification.[6]
Diagnosis of post-gastric bypass hypoglycemia entails a thorough assessment of medical and family history, frequency and triggers of symptoms, and fasting or postprandial laboratory values. Symptoms of isolated postprandial hypoglycemia were reported as early as one month postoperative but typically at or after one year postoperative.[10]

The postprandial laboratory values of pancreatogenous hyperinsulinemic hypoglycemia include the following: serum insulin levels > 3 µU/mL, c-peptide > 0.6ng/mL, and glucose < 55mg/dL.[6] The presence of sulfonylurea indicates factitious hypoglycemia, such as exogenous insulin administration, and thus should not be detected. Alternatively, a negative 72-hour fast is indicative of endogenous hyperinsulinemia.[8] Healthcare providers may use an algorithm for diagnosing and managing hypoglycemia in RYGB patients ( “href=”http://bariatrictimes.com/wp-content/uploads/tsuda-feb15-figure1.jpg”>Figure 1)

Insulinoma is excluded by more definitive tests, such as pancreatic imaging or DNA tests. Positive multiple endocrine neoplasia, type 1 (MEN1) or pancreatic lesions on a spiral computed tomography (CT) or transgenic ultrasonography (US) suggest insulinoma. When non-insulinoma is suspected, selective arterial calcium-stimulation is tested to determine and identify region(s) of beta-cell hyperfunction. Hyperfunction is present when vascular distribution of basal insulin doubles with calcium (0.025 meq per kg of bodyweight) injection to the splenic, superior mesenteric, and gastroduodenal arteries.[8] The gradient in the vascular distribution indicates location of hyperfunction in the pancreas (e.g., tail, head, body). This is also a helpful guide for pancreatectomy if later performed. Additionally, hypertrophic beta-cells inspected by pancreas histology confirm nesidioblastosis. However, histopathology is not known until after pancreatic resection.[8]

Treatment
Mild hypoglycemia after gastric bypass can be managed with dietary modification and careful glucose monitoring. When hypoglycemia occurs, immediate consumption of 15 to 20g of carbohydrate should improve symptoms.[11] Later, patients may supplement with carbohydrates with low glycemic index to prevent reactive hypoglycemia. Patients should eat small, frequent meals low in carbohydrate and high in protein and fiber.

Medications are prescribed if diet alone does not improve hypoglycemic episodes. Among common drugs are the following: acarbose (alpha-glucosidase inhibitor) and diazoxide (potassium channel activator). These medications should be prescribed with caution for fluid retention, hypotension, and bone marrow suppression in bariatric patients. The use of ocreotide and glucocorticoids has been successful in some patients, but has not been validated in larger trials.[5]

Patients with refractory symptoms may require surgical intervention.[5,8] Reversal of gastric bypass may be considered; however, its effectiveness for this condition remains unknown. Conversely, partial or subtotal pancreatectomy has been successful.[5,8] However, distal pancreatectomy is associated with a 14 or 39 percent incidence of diabetes.[12] In a series by Service et al, three of five patients had complete resolution of symptoms after distal pancreatectomy, whereas two patients had an overall improvement with occasional mild symptoms but no hypoglycemia. One patient did experience recurrence of symptoms, which was attributed to insufficient resection of the pancreas.. In another series, recurrence after pancreatectomy occurred in one patient, albeit in decreased frequency and severity.[5]

Conclusion
Post-gastric bypass hypoglycemia may be a distinct disorder with possible etiology from nesidioblastosis, genetic mutations, or a combination of both. This rare condition should be recognized for severe symptoms after ruling out the dumping syndrome, factitious hypoglycemia, and insulinoma. Reported cases have demonstrated resolution or significant improvement of post-gastric bypass hypoglycemia with pharmacologic or surgical treatment; however, further investigation is necessary prior to any recommendations.

References
1.    American Diabetes Association. Hypoglycemia? Low Blood Glucose? Low Blood Sugar? Clinical Diabetes. 2012;30(1):38
2.    Cryer PE. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am. 1999;28(3):495–500, v–vi.
3.    Scavini M, Pontiroli AE, Folli F. Asymptomatic hyperinsulinemic hypoglycemia after gastric banding. N Engl J Med. 2005;353:2822–2823.
4.    Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986-2006 in Sweden. Diabetologia. 2010;53(11):2307–2311.
5.    Patti ME, Mcmahon G, Mun EC, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005;48(11):2236–2240.
6.    Foster-Schubert KE. Hypoglycemia complicating bariatric surgery: incidence and mechanisms. Curr Opin Endocrinol Diabetes Obes. 2011;18(2):129–133.
7.    Singh D, Singh R. Adult onset nesidioblastosis: A diagnostic dilemma. Practical Gastroenterology. 2010; 34(9): 57–60.
8.    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):249–254.
9.    Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145(6):2653–2659.
10.    Mathavan VK, Arregui M, Davis C, Singh K, Patel A, Meacham J. Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia. Surg Endosc. 2010;24(10):2547–2555.
11.    Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25(1):148–198.
12.    De bruijn KM, Van eijck CH. New-onset diabetes after distal pancreatectomy: A systematic review. Ann Surg. 2014 Jun 30. [Epub ahead of print]

FUNDING: No funding was provided.

DISCLOSURES: The author reports no conflicts relevant to the content of this article.

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Category: Nutritional Considerations in the Bariatric Patient, Past Articles

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