Postbariatric Surgery Hypoglycemia

Etiology

The etiology is suspected to be related to altered anatomy post-surgery, its effects on the transition time of ingested food, and hormonal and glycemic patterns. The effects are usually compounded by consuming large meals of simple sugars and refined fats.[3]

Impairment of fasting glucose regulation has also been recently recognized, although the underlying mechanisms are yet to be understood.[4]

Epidemiology

Reported risk factors for hypoglycemic complications following bariatric surgery include female sex, Roux-en-Y gastric bypass (RYGB) surgery history, longer time since surgery, and absence of preexisting diabetes.[5][6] However, it's worth noting that approximately 70% to 80% of individuals undergoing bariatric surgery are female.[7]

A randomized controlled trial found no significant difference in the occurrence of hypoglycemia after SG compared with RYGB, but RYGB may be associated with more severe episodes.[8] In a study using continuous glucose monitoring, Nocturnal and asymptomatic hypoglycemia has been reported to occur more frequently after Sleeve Gastrectomy (SG) than RYGB, whereas RYGB is associated more often with post-prandial and symptomatic hypoglycemic events.[4]

There is wide variation in the reported prevalence of hypoglycemia post-bariatric surgery. This variation is likely due to different study methodologies, variability in testing, and definitions of hypoglycemia used. However, with increasing recognition of conditions such as asymptomatic hypoglycemia, meal-independent hypoglycemia, and the use of more sensitive methods such as CGM, it has become apparent that the condition is underreported. 

Studies that have relied on patient recall of symptoms have noted a prevalence of post-prandial symptomatic hypoglycemia ranging from 0.1 to 34%.[3] A prospective study that used Oral Glucose Tolerance Test (OGTT) reported a prevalence of 25.6%.[9]  Smaller studies using more sensitive methods, such as CGM, reported hypoglycemic episodes in as many as 55 to 75% of the patients studied.[4][10] 

The actual burden of this condition and risk factors are yet to be determined and would require extensive studies.

Pathophysiology

The pathophysiology still needs to be fully elucidated. There are likely different mechanisms underlying different patterns of hypoglycemia. 

Postprandial hypoglycemia is thought to occur in two phases:

1. Induction of post-meal hyper-insulinemia
2. Maintenance of inappropriately high levels of insulin

Post-Meal Hyperinsulinemia

In individuals with post-RYGB hypoglycemia, ingested food induces faster, higher glycemic peaks and lower nadirs.[11] 

Glucagon-like peptide -1 (GLP -1) is secreted by the intestinal L cells in response to ingested food, and it contributes to insulin secretion in a dose-dependent (glucose-dependent) manner. In individuals with post-bariatric surgery hypoglycemia, it was noted that meal-induced GLP-1 levels are elevated and likely result in an exaggerated insulin response compared to those without symptoms of hypoglycemia.[3]

Ghrelin suppresses insulin secretion and opposes its action. Its secretion is decreased after gastric bypass surgery, which can contribute to hypoglycemia.[12][13] Non-hormonal gut factors may also contribute to meal-induced hyper-insulinemia.[14]

Maintenance of Inappropriately High Levels of Insulin 

Specific mechanisms perpetuate high insulin levels in individuals with post-RYGB hypoglycemia, even after developing hypoglycemia. They have lower beta cell suppression in response to low blood sugar levels. They also may have diminished insulin clearance. Increased insulin sensitivity after weight loss and disturbed counter-regulatory hormonal responses to hypoglycemia also have a role.[3]

The effects of other insulinotropic factors and changes in insulin sensitivity may be contributory, although they still need to be fully understood. Increased beta cell mass was previously implicated; however, it is currently not considered a significant cause of hypoglycemia.[3] The mechanisms for meal-independent hypoglycemia are even less known.[4]

Histopathology

No consistent histopathologic pattern has been found. Initial reports of β-cell hypertrophy and islet cell hyperplasia were seen in the pancreas tissue samples from patients who underwent partial pancreatectomy to manage postprandial hypoglycemia after bariatric surgery.[15] However, these findings have been disputed. Other studies have reported the presence of increased beta cell nuclear diameter in patients who experience post-bariatric surgery hypoglycemia.[16]

History and Physical

Patients with late dumping syndrome can present autonomic or neuroglycopenic hypoglycemia symptoms months to years after the surgery, usually 1 to 3 hours after a meal. The consumption of large meals rich in simple carbohydrates exacerbates symptoms.[3]

The autonomic symptoms can be anxiety, sweating, tremors, and palpitations. Neuroglycopenic symptoms include confusion, fatigue, light-headedness, slurred speech, blurred vision, and disorientation. Seizures or a coma may occur in severe cases.[17]

Postprandial hypoglycemia is seen more commonly after RYGB, whereas meal-independent hypoglycemia occurs more commonly after Sleeve Gastrectomy.[4] However, postprandial hypoglycemia can also be seen after SG and LAGB, and some patients can have a mixed pattern. 

Some individuals with repeated episodes of hypoglycemia may develop hypoglycemia unawareness defined as the development of symptoms of neuroglycopenia before the onset of autonomic warning symptoms.[18]

There are no physical exam findings specific to this condition.

Evaluation

A consensus on the criteria for diagnosing postprandial hyperinsulinemic hypoglycemia after bariatric surgery is yet to be developed. Making a diagnosis can be challenging due to the variation in symptoms and the definitions of hypoglycemia.

The International Hypoglycemia Study Group considers a glucose level of <3.0 mmol/L (<54 mg/dL) to indicate clinically significant hypoglycemia.[19]

The ASMBS recommends the following criteria for diagnosis of postprandial hyperinsulinemic hypoglycemia or late dumping syndrome:[3]

1. Symptoms occurring more than one year after surgery
2. Normal fasting glucose and insulin levels
3. Correlation of symptoms with hypoglycemia, followed by spontaneous resolution of hypoglycemia
4. Positive provocative test.

Others have recommended additional criteria and specific cut-off values - the presence of hyperinsulinemia (serum insulin >50 µU/L or 300 pmol/L) concurrently with hypoglycemia (plasma glucose <50 mg/dL or 2.8 mmol/L) after a mixed meal.[20]

Provocative tests such as the oral glucose tolerance test (OGTT) and mixed meal tolerance test (MMTT) aid in the diagnosis. OGTT involves the administration of 75 to 100 grams of glucose followed by serial serum glucose measurements at intervals up to 120 to 240 minutes after administration. In MMTT, a standardized meal of carbohydrates, protein, and fat is administered. Glucose and insulin levels are determined during fasting and 30-minute intervals after the mixed meal.[3] 

In patients with bariatric surgery, an oral glucose tolerance test (OGTT) for evaluation of meal-induced hypoglycemia may not be well tolerated since hyperosmolar glucose liquid loads may provoke severe hypoglycemia and should be avoided. A mixed meal test with carbohydrates, protein, and fat may be better, but this approach remains controversial. Any provoked tests should be performed in a supervised setting with trained medical personnel equipped to deal with the situation due to the risk of a severe hypoglycemic event.[11]

Continuous glucose monitoring (CGM) is more sensitive and specific than provocative tests.[21] CGM provides more details regarding glucose excursions while allowing subjects to follow their usual feeding patterns. CGM has the added benefit of capturing asymptomatic hypoglycemia and fasting hypoglycemia episodes.

In individuals with fasting hypoglycemia, the possibility of insulinoma should be considered. Workup for insulinoma entails a 72-hour fasting test and computerized tomography (CT)/magnetic resonance imaging (MRI). Invasive studies such as endoscopic ultrasound or selective arterial calcium stimulation testing may be considered if the imaging is unrevealing.[3]

As the name implies, a 72-hour fasting test entails fasting for 72 hours (calorie-free beverages are allowed). Capillary blood samples for glucose are collected every 2 hours, and venous blood sugar samples are collected every 6 hours. Once blood sugar levels are less than 60 mg/dL, insulin, C-peptide, pro-insulin, and beta-hydroxybutyrate should also be collected.[22] Concurrently with hypoglycemia, a high insulin level, high C-peptide levels, and absence of sulfonylurea suggest insulinoma.[23]

Some clinicians consider the presence of Whipple’s triad (Measured low blood glucose with corresponding symptoms of hypoglycemia and low blood glucose and the relief of symptoms when low blood glucose is corrected) essential for diagnosis. However, since some people can have atypical symptoms of hypoglycemia or asymptomatic hypoglycemia, reliance on Whipple’s triad may miss the diagnosis in these individuals. Hence, a clinician needs to be aware of the various patterns of hypoglycemia, as this may inform the choice of diagnostic tests ordered. 

It is also crucial to consider other conditions, such as insulinoma, adrenal insufficiency, liver dysfunction, and medication-induced hypoglycemia, and rule them out when indicated based on history and physical examination.

Diagnostic evaluation for differentiating etiologies of hypoglycemia is summarized in Table 1. 

Table 1.

Treatment / Management

Medical Nutrition Therapy

Medical nutritional therapy is the first line of treatment. A strategy of consuming small portions of low glycemic index carbohydrates (30 grams of carbohydrates per meal, 15 grams per snack), adequate protein consumption (30 grams per meal and total of 60 to 80 grams/day), adequate fat consumption (15 grams/meal, 5 grams/snack), spacing meals 3 to 4 hours apart, avoidance of alcohol, caffeine, and fluids with meals is recommended. 

Avoiding high glycemic index foods is essential because a sudden rise in glucose can trigger more insulin release after meals and contribute to significant post-prandial hypoglycemia. High glycemic foods are digested quickly, whereas low glycemic foods are digested relatively slowly and cause a relatively slow rise in glucose levels.[24]

Pharmacotherapy

Pharmacotherapy may be considered for individuals with moderate-severe symptoms refractory to nutritional therapy; however, large-scale studies comparing the efficacy of medications are yet to be performed. The choice in the use of medications depends on the clinician's preference/experience and patient choice. The use of nifedipine, acarbose, GLP-1 analogs, diazoxide, and somatostatin analogs for treatment has been reported in case reports and small case series.  

Acarbose, an alpha-glucosidase inhibitor, delays the digestion of carbohydrates and may help decrease post-prandial glucose level spikes. Diazoxide acts via ATP-sensitive Potassium channels to inhibit the secretion of insulin. Somatostatin analogs slow gastric and small bowel transit of ingested material, affecting the release of hormones, insulin, and vasculature tone. Calcium channel blockers work via calcium channels on Beta cells to affect insulin secretion.[25][26](B3)

The International consensus on diagnosing and managing dumping syndrome endorses using acarbose as the first-line pharmacotherapeutic agent and using somatostatin analogs in patients not responding to acarbose. Usually, acarbose at a dose of 50–100 mg three times daily, with meals recommended. The adverse effects associated with acarbose are bloating and flatulence. Somatostatin analogs require frequent injections.[25] Some clinicians have used combination therapy.(B3)

A recent randomized, placebo-controlled crossover study (PREVENT) reported promising results with Avexitide, a GLP -1 antagonist, in treating post-bariatric surgery hypoglycemia.[27] The "DEEP-EMPA" trial investigates the effects of Empagliflozin, a sodium-glucose cotransporter 2-inhibitor, on hypoglycemia post-bariatric surgery.[28](A1)

Surgical Management

Surgical management may be considered for patients with moderate-to-severe symptoms refractory to nutritional therapy and pharmacotherapy. As with pharmacotherapy, large-scale trials comparing efficacy and safety are yet to be performed; surgical modality depends on the clinician's preference/expertise, comorbidities, anatomy, and patient choice. Gastrostomy tube placement in the remnant stomach, gastric outlet restriction surgery, RYGB reversal, and conversion of RYGB to SG have been reported in small case series. A partial pancreatectomy has been performed for this indication. However, it has not been found effective, and the ASMBS does not recommend it.[3]

Differential Diagnosis

An insulinoma should be considered in the differential diagnosis and ruled out. Postprandial hypoglycemia has been seen in individuals with nonalcoholic fatty liver disease (NAFLD); obesity is a risk factor for developing NAFLD.[29]

Exogenous insulin or secretagogue use may also induce hypoglycemia; C peptide levels (low in case of exogenous insulin, normal or elevated with secretagogues) and medication screening may help investigate these causes.

In the appropriate context, the differential diagnosis may also consider hormone deficiencies, autoimmune conditions, or non-islet cell tumors.[11]

Prognosis

Patients with mild to moderate symptoms usually respond well to nutritional therapy.[3] However, only limited data are available regarding the proportion of people with post-bariatric surgery hypoglycemia requiring pharmacotherapy, with pharmacotherapy failure requiring surgery for correction and failure of surgery to correct this condition. 

A recent retrospective observational study of patients with post-bariatric surgery hypoglycemia reported on outcomes of patients who had failed nutritional therapy. It defined the efficacy of medication as “greater than fifty percent reduction of hypoglycemic symptoms and as a combination of no or almost no hypoglycemic events.” In this study, overall reported medication efficacy ranged from 45 to 80%. Approximately 20% of the patients were referred for surgical treatment due to the failure of conservative measures. About 63% of the patients who underwent surgery reported complete resolution of the symptoms, about 16% reported 50 to 100% resolution of the symptoms, and no improvement was reported in 21%. Different types of surgeries had different efficacies.[30] However, more studies are needed to draw firm conclusions. Persistent symptoms can have profound effects on quality of life.

Complications

Severe hypoglycemia can be associated with signs and symptoms such as anxiety, irritability, slurred speech, shakiness, disorientation, agitation, seizures, loss of consciousness, and even death. 

Repeated episodes of hypoglycemia can result in a condition called “hypoglycemia unawareness,” wherein despite low blood sugar levels, the counter-regulatory responses are blunted, and the symptoms of hypoglycemia diminish over time. A study in patients with post-bariatric surgery hypoglycemia demonstrated impaired driving performance associated with low glucose levels even in the absence of symptoms of hypoglycemia.[30]

In patients with diabetes mellitus, hypoglycemia can also have insidious harmful effects on various organ systems, significantly affecting the quality of life. However, the long-term effects of post-bariatric surgery hypoglycemia are unknown.[31]