Hyperinsulinemic Hypoglycemia after Bariatric Surgery

Abstract

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.

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 hypoglycemia 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 hypoglycemia [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 transabdominal ultrasonography can locate the exocrine and endocrine tumor. In patients with endogenous hyperinsulinemic 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 proliferative 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 pathophysiology 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].

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 complications for this surgery, including a greater incidence of gastroesophageal reflux [39,40,41].

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).

Table 1. Dignosis and management of PHH.

Dignosis of PHH Referable basis	No single agreed-upon criterion
	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