Hypoglycemia after gastric bypass: An emerging complication

DIAGNOSIS AND TREATMENT

We recommend a stepwise approach to evaluating and treating PGBH (Figures 1 and 2).

Step 1: Evaluate blood glucose and Whipple triad

Figure 1. Assessment and treatment of postprandial post-gastric bypass hypoglycemia (PGBH). See Figure 2 for assessment and treatment of fasting PGBH.

The first step is a thorough history, including food consumption and timing of hypoglycemic symptoms. Give the patient a glucometer to take home, with instructions to check blood glucose levels when hypoglycemic symptoms occur. The patient should keep a log documenting time tested, food consumed, symptoms, and blood glucose data.

Hypoglycemic symptoms are categorized as autonomic and neuroglycopenic. Autonomic symptoms include anxiety, palpitations, tremulousness, and diaphoresis. Neuroglycopenic symptoms include confusion, falls, seizures, and loss of consciousness.¹²

There are degrees of hypoglycemia and hypoglycemic symptoms. Clinical hypoglycemia—a blood glucose level low enough to cause signs or symptoms—can be confirmed by the Whipple triad:

• Measured low blood glucose
• Symptoms of low blood glucose
• Relief of symptoms when low blood glucose is corrected.

Hypoglycemic symptoms can occur when the blood glucose level falls to less than 55 mg/dL in healthy people, but this cutoff can shift lower in someone who has recurrent hypoglycemia.

When the Whipple triad is documented, rule out nonhyperinsulinemic causes of hypoglycemia such as hypothyroidism, adrenal insufficiency, underlying organ dysfunction (ie, liver disease), and medications that cause hypoglycemia.

Step 2: Modify the diet

Figure 2. Assessment and treatment of fasting post-gastric bypass hypoglycemia (PGBH). See Figure 1 for assessment and treatment of postprandial PGBH.

If postprandial hypoglycemia is occurring, the next step is dietary modification. Two studies showed that a low-carbohydrate diet prevented hypoglycemia; however, these diets contained nearly no carbohydrates (with meals consisting of eggs, sausage, cheese, and black coffee or tea).^15,22

Instruct patients to never eat pure carbohydrates without fat or protein, as this can result in a more severe hypoglycemic response.²² In addition, foods with a high glycemic index (a measure of how a carbohydrate-containing food raises blood sugar) should be avoided, and a low glycemic index diet is recommended.²³ High glycemic index foods include white bread, bagels, pretzels, and pineapple. Low glycemic index foods include 100% stone-ground whole wheat or pumpernickel bread, lima beans, butter beans, peas, legumes, lentils, and nonstarchy vegetables.

Our bariatric surgeons provide all postbariatric surgery patients with the dietary guidelines shown in Table 3.²⁴ We also ask our patients with PGBH to limit carbohydrates to 15 to 30 g per meal and to limit added sugars to less than 4 g per meal, including regular and sugar alcohols (polyols). Snacks should contain only protein and fat. In severe cases, we further limit the diet to 15 g of carbohydrate per meal, with no added sugars.

The hypoglycemia occurring with PGBH is treated differently than the hypoglycemia that occurs in diabetic patients. Advise patients with PGBH to treat their hypoglycemic episodes with a simple sugar combined with a protein or fat (eg, a small handful of candy with a spoonful of peanut butter), as they will often have recurrent hypoglycemia if a simple sugar is used alone. If patients regain weight, ask them about frequent eating, which would be related to self-treatment of hypoglycemia.

Step 3: Start an alpha-glucosidase inhibitor

If postprandial hypoglycemia persists despite dietary modification, then start an alpha-glucosidase inhibitor such as acarbose. Acarbose inhibits carbohydrate absorption, resulting in a decreased insulin response; thus, it blunts the decline in postprandial blood glucose.

Unfortunately, gastrointestinal side effects such as flatulence, diarrhea, and abdominal pain occur in up to 20% of patients who take acarbose, often leading to its discontinuation.²⁵ To minimize gastrointestinal side effects, we usually start with 25 mg of acarbose with 1 meal daily for 1 week, then increase the dosage weekly to 25 mg with the other 2 meals. If tolerated, acarbose can be increased to 50 to 100 mg with 3 meals daily.

Step 4: Obtain a mixed meal tolerance test or a provocation meal test

If dietary changes and an alpha-glucosidase inhibitor do not prevent postprandial hypoglycemia from recurring, then confirmation of PGBH is needed, using a mixed meal tolerance test or a provocation meal test.

In a mixed meal tolerance test, the meal consists of 55% carbohydrate, 30% fat, and 15% protein. Patients with hyperinsulinemic hypoglycemia have a rapid rise in blood glucose (> 200 mg/dL) with a robust insulin response that is often followed by hypoglycemia after ingesting a meal containing carbohydrates in this test. Insulin levels that remain elevated after the plasma glucose level falls to less than 55 mg/dL indicate hyperinsulinism.¹¹

Nevertheless, a mixed meal tolerance test will not always induce hypoglycemia. In a study of 51 patients with PGBH, all wore a continuous glucose monitor, were instructed to follow their normal diet for 5 days, and then underwent a mixed meal tolerance test on day 6. The glucose monitor revealed hypoglycemia in 75% of patients, while the mixed meal tolerance test was positive in only 29%.⁵

Moreover, to date, there is no standardized mixed meal.^5,15 This might also explain the difference in prevalence of hypoglycemia detected by this test.

Based on these conflicting findings, we recommend a provocation meal test—ie, the patient is given foods that have induced hypoglycemia earlier.

Of note, the Endocrine Society guidelines on hypoglycemia state that an oral glucose tolerance test should never be used to document postprandial hypoglycemia.²⁶ Lev-Ran and Anderson²⁷ found that an oral glucose tolerance test could be positive in at least 10% of normal people.

Step 5: Consider other pharmacotherapy

For moderate to severe PGBH in which dietary modification and acarbose have failed, additional medical therapy is the next step. Medical therapies include calcium channel blockers, somatostatin analogues (eg, octreotide), and diazoxide.

Calcium channel blockers inhibit insulin release from beta cells²⁸ but at the risk of hypotension. Mordes and Alonso²⁹ treated 6 PGBH patients with nifedipine or verapamil with or without acarbose, and symptoms resolved in 5 of the 6 patients.

When we treat PGBH, we often add a calcium channel blocker as the next step in therapy if the patient has hypertension or if the blood pressure can tolerate this. If the patient’s blood pressure is low, then avoiding calcium channel blocker therapy may be necessary. The next step would be octreotide and then diazoxide.

Somatostatin analogues such as octreotide inhibit GLP-1 and insulin release.³⁰ The most common side effects of octreotide are diarrhea and abdominal pain. Bile stone formation can also occur, but this is not common.

Diazoxide opens adenosine triphosphate-sensitive potassium channels and reduces the opening of calcium channels, inhibiting insulin release and raising blood glucose. In a study of 6 Japanese patients with inoperable insulinoma, diazoxide was used to treat hypoglycemia.³¹ Unfortunately, the doses required to control the low blood sugars also led to adverse reactions, most of which involved edema secondary to volume overload and other heart failure symptoms. Diazoxide also commonly causes hypotension and hirsutism.

Step 6: 72-hour fast

A 72-hour fast is recommended in severe cases of PGBH in patients for whom dietary modification and the additional pharmacotherapy outlined in step 5 have failed. A 72-hour fast is always indicated in evaluating confirmed fasting hypoglycemia. People with insulinoma usually have fasting hypoglycemia, while patients with dumping syndrome do not. Patients with PGBH usually do not have fasting hypoglycemia, but they can in severe cases.¹¹

For safety, this test should be done in the hospital. Baseline plasma levels of insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose should be obtained. The patient then fasts, consuming only noncaloric and noncaffeinated beverages for 72 hours. During this time, capillary glucose checks are performed every 6 hours. If the capillary glucose level falls below 55 mg/dL,^11,26 then the baseline tests are redrawn along with a sulfonylurea screen. To reduce costs and unnecessary testing, the tests are not sent for laboratory processing unless the plasma glucose is less than 55 mg/dL.

When the plasma glucose is less than 55 mg/dL, insulin production should cease. Elevated insulin levels and insulin byproducts raise concern for hyperinsulinism. These values confirm hyperinsulinemic hypoglycemia²⁶:

• Glucose < 55 mg/dL
• Insulin ≥ 3 µU/mL
• C-peptide ≥ 0.2 nmol/L
• Proinsulin ≥ 5.0 pmol/L.

After hypoglycemia is confirmed, 1 mg of glucagon is given intravenously, and plasma glucose levels are obtained at 10, 20, and 30 minutes.^11,26 A rise in plasma glucose of at least 25 mg/dL after intravenous glucagon injection indicates hypoglycemia due to hyperinsulinemia. Two-thirds of patients with insulinoma experience hypoglycemia within the first 24 hours, and nearly all experience hypoglycemia within 48 hours.²⁶