Hypoglycemia after gastric bypass: An emerging complication
ABSTRACT
As the obesity epidemic worsens, more people are opting for weight-loss surgery, including gastric bypass. Of the possible complications associated with this procedure, hypoglycemia secondary to hyperinsulinemia is becoming a more common and therefore more relevant problem.
KEY POINTS
- The differential diagnosis for endogenous causes of hyperinsulinemic hypoglycemia after gastric bypass surgery includes insulinoma, late dumping syndrome, and post-gastric bypass hypoglycemia (PGBH).
- The Whipple triad consists of measured low blood glucose, symptoms of low blood glucose, and reversal of symptoms when low blood glucose is corrected. If the triad is not present, then hypoglycemia is not causing the patient’s symptoms.
- PGBH should initially be treated with a high-protein, high-fiber, low-carbohydrate diet and then, if hypoglycemia persists, by medication (initially acarbose, then a calcium channel blocker and octreotide or diazoxide or both).
- PGBH ranges from mild, in which neuroglycopenia resolves with dietary changes with or without acarbose, to severe, in which neuroglycopenia persists despite dietary changes and multiple drugs.
- Gastric bypass reversal and pancreatic surgery are a last resort for patients with debilitating neuroglycopenia when dietary modification and drug therapy fail.
Step 7: Obtain pancreatic imaging
If fasting hypoglycemia is present and hyperinsulinemic hypoglycemia is confirmed during a 72-hour fast, then pancreatic imaging should be obtained to evaluate for an insulinoma. We also recommend pancreatic imaging to rule out insulinoma when severe PGBH has not responded to dietary modification or pharmacotherapy.
Imaging is not recommended in PGBH that has been successfully treated with dietary modification with or without pharmacotherapy.
Endoscopic ultrasonography alone has 80% to 92% sensitivity for localizing a pancreatic mass as small as 5 mm. However, when coupled with computed tomography or magnetic resonance imaging, the sensitivity increases to nearly 100%.12
Step 8: Selective arterial calcium stimulation test
If a patient is found to have hyperinsulinemic hypoglycemia during a 72-hour fast but pancreatic imaging is negative, then selective arterial calcium stimulation testing (SACST) and hepatic vein sampling should be performed. Also, for severe PGBH, in which hypoglycemia has persisted despite dietary modification and pharmacotherapy, SACST can be performed to evaluate for possible localization of hyperinsulinism in patients considering surgery. For mild and moderate cases of PGBH, in which the hypoglycemia has been successfully treated with dietary changes with or without pharmacotherapy, SACST is not necessary.
This test can localize the area of excess insulin production in the pancreas in patients with an insulinoma. Patients with severe PGBH usually have diffuse hyperinsulinism without localization on SACST.32,33
When SACST is performed, a sampling catheter is placed in the femoral vein. Calcium gluconate is injected into the major arteries of the pancreas (superior mesenteric, gastroduodenal, and splenic arteries). Calcium stimulates release of insulin from an insulinoma or hyperplastic beta cells. Resultant insulin levels are measured in the hepatic vein. If there is a greater than twofold increase in insulin release from 2 segments, then the test is considered positive.
Thompson et al34 documented that insulin release from insulinoma is almost 4 times higher than in diffuse nesidioblastosis. SACST has a sensitivity of 96% for detecting insulinomas.35
Step 9: Other alternatives and surgery
In patients with severe PGBH for whom dietary modification and all pharmacotherapy have failed and who continue to have debilitating neuroglycopenia, there are options before proceeding with surgery, the last resort in this condition.
Continuous glucose monitoring is helpful in many patients with severe PGBH. Many of them have hypoglycemia unawareness, and the monitor alerts them when their blood sugar is low. In addition, the monitor indicates when the blood sugar is dropping, so that intervention can occur before hypoglycemia occurs.
Unfortunately, insurance coverage for continuous monitors in this patient population is limited. We argue that insurance should cover the cost for these severe cases.
Pasireotide, a somatostatin analogue that is longer-acting than octreotide, is approved for use in Cushing disease and acromegaly and actually causes hyperglycemia. In a case report of a 50-year-old woman, pasireotide resulted in less hypoglycemia and higher glucagon levels then octreotide.36 Pasireotide is available from Novartis for compassionate use in patients with severe PGBH.
Glucocorticoids are another off-label option. However, in excess, they can lead to iatrogenic Cushing syndrome, which has its own complications. Prednisone and diazoxide have been used together to help prevent hypoglycemia in a patients with inoperable insulinoma.31
Tube feeding. Some researchers have studied altering nutrition access through surgical means. McLaughlin et al37 discussed a case of gastric tube insertion into the remnant stomach of a patient with PGBH, with resolution of hypoglycemic symptoms and hypoglycemia; however, this does not always provide complete resolution of symptoms.37,38 If gastric bypass reversal is being considered, a trial of solely remnant stomach tube feeds (with no oral intake) should be pursued first. If this ameliorates the hypoglycemia, then gastric bypass reversal may be of benefit.
Surgery is the last resort if all of the above treatments have failed and severe debilitating neuroglycopenia persists. However, surgery poses risks, and the success rate in correcting hypoglycemia is not ideal. Surgical options include Roux-en-Y reversal, gastric pouch resection, and pancreatic resection.
In a review by Mala,2 75 patients with documented PGBH underwent surgical therapy. Hypoglycemic symptoms resolved in 34 of 51 pancreatic resections, 13 of 17 Roux-en-Y reversals, and 9 of 11 gastric pouch resections. However, the follow-up period was short.
As noted above, we recommend calcium stimulation testing only for severe cases of PGBH when surgery is being considered to evaluate for possible localization of hyperinsulinism for which partial pancreatectomy would be of benefit. Since there is no localization in many PGBH cases and the success rates are slightly higher in gastric bypass reversal, bypass reversal is usually preferred over partial or complete pancreatectomy.2,32,33
POTENTIAL FUTURE THERAPIES
Given the elevated GLP-1 levels and robust insulin response to glucose observed in PGBH, blocking GLP-1 may provide clinical benefit. Salehi et al16 found that a GLP-1 antagonist prevented surges in GLP-1 and reduced hypoglycemic episodes in patients with PGBH. Unfortunately, the medication they used was given as a continuous infusion and is not currently available.
Conversely, a GLP-1 agonist showed benefit in a series of 5 cases of PGBH.39 In addition, an insulin receptor antibody is undergoing phase 2 trials and has been shown to reverse insulin-induced hypoglycemia in rodents and humans; it may be a novel therapy in the future for hyperinsulinemic hypoglycemia.40
MORE STUDY NEEDED
As the prevalence of obesity continues to rise and more people opt for bariatric surgery for weight loss, we will likely continue to see an increase in PGBH, since the onset of PGBH can be delayed for many years after surgery.28
Unfortunately, the disease process involved in PGBH is not well understood. For example, we do not know why GLP-1 elevations or a robust insulin response causing hypoglycemia occurs in some but not all gastric bypass patients. Study is needed to elucidate the pathophysiology to further understand why most patients have no hypoglycemia after gastric bypass, some have mild to moderate PGBH, and a small percentage have severe PGBH with debilitating neuroglycopenia unresponsive to dietary changes and medications.
