INTRODUCTION — The noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) identifies a group of hyperinsulinemic hypoglycemic patients with unique clinical, diagnostic, surgical, and pathologic features [1,2]. These patients experience predominantly postprandial hypoglycemia and have abnormal islet morphology (predominantly islet cell hypertrophy), with no evidence of a functioning islet cell tumor.
The clinical manifestations, pathological findings, diagnosis, and treatment of NIPHS will be reviewed here. Other causes of hypoglycemia and how to differentiate among these causes are reviewed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)
DEFINITION — Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a rare syndrome characterized by endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma. Pancreatic specimens from such patients show beta cell hypertrophy, islets with enlarged and hyperchromatic nuclei, and increased islets budding from periductular epithelium [1-3]. Previously, these histologic findings have been considered characteristic of nesidioblastosis, a term that refers to neoformation of islets of Langerhans from pancreatic duct epithelium [4]. However, it is clear that these appearances can be seen in asymptomatic individuals, and the term "nesidioblastosis" should be utilized to describe the histologic appearance and not necessarily imply islet dysfunction [5].
Formal epidemiologic studies have not been conducted for NIPHS; however, the condition appears to be rarer than insulinoma. For example, during the period from 1996 to 2004, 20 patients with NIPHS (16 male, 4 female) and 118 patients with insulinoma (51 male, 67 female) were surgically confirmed at the Mayo Clinic [1,2,6].
Although the underlying pathologic features of NIPHS and post-gastric bypass hypoglycemia can be similar, post-gastric bypass hypoglycemia is considered a separate clinical entity occurring after Roux-en-Y gastric bypass or similar procedures that disrupt the regulation of gastric emptying [7]. (See 'Islet abnormalities after Roux-en-Y gastric bypass surgery' below.)
CLINICAL FEATURES
Symptoms — The predominant clinical feature of noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is postprandial hypoglycemia. In a series of 18 patients from the Mayo Clinic, age range 16 to 78 years old, mean body mass index (BMI) 25.7 kg/m2, with a male predominance (70 percent), symptoms occurred postprandially, two to four hours after meals, and only rarely while fasting [1,2,8]. All patients had neuroglycopenic symptoms, and several lost consciousness or had generalized seizures. Forty percent of the patients had a history of upper gastrointestinal surgery (not gastric bypass) [6]. In smaller series and case reports, a similar preponderance of postprandial hypoglycemia, neuroglycopenic symptoms, and male predominance was noted [9-16]. However, fasting hypoglycemia has also been reported [15,17,18].
In contrast, most patients with insulinomas have fasting hypoglycemia. Though they may occasionally also have postprandial symptoms, the occurrence of symptoms solely postprandially is rare (approximately 5 percent of patients). (See "Insulinoma", section on 'Clinical features'.)
Biochemical findings — During episodes of hypoglycemia, patients with NIPHS have biochemical findings similar to those of insulinoma, including elevated plasma insulin, C-peptide, and proinsulin concentrations; low plasma beta-hydroxybutyrate; and a negative sulfonylurea/meglitinide screen (table 1).
Histopathology — Histopathology descriptions of excised pancreatic tissue include islet cell hypertrophy with enlarged and hyperchromatic nuclei, sometimes islet cell hyperplasia, and increased periductular islets [1,3,10]. Islet-like cells budding off exocrine ducts have been noted and were most evident on immunohistochemical staining for chromogranin A (picture 1) [1]. The hypertrophic islet cells also stained positively for insulin, glucagon, somatostatin, and pancreatic polypeptide [1,11]. The distribution of the hormones within the islets was normal, with between 60 to 80 percent of the islet cells staining for insulin. Many of the cells budding off ducts also contained insulin.
This constellation of pathology changes, including primary islet cell hypertrophy and neodifferentiation of islet of Langerhans cells from pancreatic duct epithelium, is similar to that observed in infants with persistent hyperinsulinemic hypoglycemia [4,19,20] and less often in adults [3,21-27]. These pathology findings have also been described in nontumor pancreatic tissue of patients with insulinomas [28,29]; in patients previously treated with insulin [24,30] or a sulfonylurea [31]; and in patients with other islet cell tumors, such as gastrinomas [32] or multiple endocrine neoplasia type 1 [33]. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Determining the cause of hypoglycemia'.)
These pathology findings probably correlate with the clinical features of the syndrome of hyperinsulinemic hypoglycemia. The presence of these findings in an individual with a hypoglycemic syndrome does not necessarily exclude an islet cell tumor [34]. In addition, subtle histologic changes referred to as nesidioblastosis have been observed in 36 percent of patients in an autopsy series of 207 patients with no history of hypoglycemia [5]. It is important to ensure that functional abnormalities are present before embarking on surgery (see 'Diagnostic evaluation' below). Surgery and histopathology are important for ensuring that abnormalities, if present, are focal and not diffuse.
In an analysis of pancreatic tissue from 36 cases (27 post-gastric bypass) of nesidioblastosis, increased insulin-like growth factor-2, insulin-like growth factor-1 receptor alpha, and transforming growth factor receptor beta 3 expression were noted in the islets of patients compared with controls who had benign exocrine pancreatic tumors [8]. These findings suggest a role for growth factors in the pathogenesis of these abnormalities in adults.
DIFFERENTIAL DIAGNOSIS — In adults, hypoglycemia due to endogenous hyperinsulinism, with negative screens for sulfonylurea/meglitinide and insulin antibodies, can be caused by:
●A beta cell tumor (eg, insulinoma)
●A functional beta cell disorder (eg, due to noninsulinoma pancreatogenous hypoglycemia syndrome [NIPHS] or islet abnormalities after Rous-en-Y gastric bypass surgery)
Insulinoma — It is usually not difficult to distinguish insulinoma from NIPHS, considering the timing of symptoms (typically fasting for insulinoma and postprandial for NIPHS), sex preference (male predominance), and, ultimately, the results of localization studies. Overall, with appropriate preoperative localization studies plus intraoperative ultrasonography and palpation, a tumor (or tumors) can be identified in 98 percent of patients with insulinomas. (See "Insulinoma".)
A 72-hour fast should not be performed to differentiate insulinoma from NIPHS, because of potential overlap in responses; rare cases of insulinoma may have negative fasts [35] and rare cases of NIPHS may have positive fasts [10,17,21,36]. Thus, the hypoglycemic response to a 72-hour fast cannot definitively distinguish NIPHS from insulinoma. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on '72-hour fast'.)
Islet abnormalities after Roux-en-Y gastric bypass surgery — Although endogenous hyperinsulinemic hypoglycemia is rare, there have been several reports of it occurring after Roux-en-Y gastric bypass (RYGB) surgery [37-40]. In the initial series, six patients were described with symptomatic postprandial hypoglycemia (symptoms of confusion, tunnel vision, and loss of consciousness occurring one to three hours after eating) six months to eight years following RYGB [37]. Five of these patients had evidence of islet cell hyperplasia, and one had both islet cell hyperplasia and evidence of a multifocal insulinoma. In a subsequent report, 36 patients who underwent partial pancreatectomy for nesidioblastosis at Mayo Clinic between 1994 and 2007 were evaluated [8]. Twenty-seven of the patients had previously undergone RYGB. The time from RYGB to pancreatic resection was on average 54 months. In contrast to patients with NIPHS, there was a female predominance (92 percent). Patients with severe postprandial hypoglycemia and pancreatic islet hyperplasia after RYGB have also been reported from other institutions [38-40]. However, in other reports of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass surgery, there was no evidence of islet cell hyperplasia [41].
Although islet cell hyperplasia following RYGB and NIPHS have some features in common (eg, postprandial hyperinsulinemic hypoglycemia, negative radiologic localization but positive calcium stimulation test, and histologic findings of nesidioblastosis), they appear to be distinct diseases [7]:
●NIPHS is much less common than post-gastric bypass hypoglycemia.
●Patients with NIPHS have never undergone gastric bypass and they are predominantly male, as opposed to the female predominance for post-gastric bypass hypoglycemia.
●Patients with NIPHS never have insulinoma and virtually never have fasting hypoglycemia, both of which may be observed rarely in post-gastric bypass hypoglycemia [42].
Several hypotheses have been proposed for the etiology of islet cell hyperplasia following RYGB surgery: hormonal changes (possibly involving insulin-stimulating glucagon-like peptide-1 [GLP-1], glucose-dependent insulinotropic polypeptide [GIP], or ghrelin), unidentified factors from the proximal intestine, or disruption in the presurgery homeostasis of insulin resistance and hyperinsulinemia with rapid weight loss [37,38,43-46]. After reversal of gastric bypass, hypoglycemia persisted in some case reports [38,47] but improved in others [48-50].
Dumping syndrome — Dumping syndrome, which can occur after gastric bypass surgery, particularly when high levels of simple carbohydrates are ingested, is characterized by postprandial diaphoresis, weakness, dizziness, and palpitations due to intravascular volume contraction and not hypoglycemia. In patients with dumping syndrome, symptoms can occur within 15 to 30 minutes of a meal and the plasma glucose can be normal when symptoms are present. (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes".)
DIAGNOSTIC EVALUATION — The diagnostic approach to hypoglycemia is reviewed briefly below and in more detail separately. Findings on pathology should ultimately confirm the presence of abnormal islet structure in patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and is only rarely described as a concomitant finding in patients with insulinoma [28,29]. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Approach to testing'.)
Laboratory evaluation
●The initial evaluation of hypoglycemia includes measurement of glucose, insulin, proinsulin, C-peptide, beta-hydroxybutyrate, and sulfonylurea/meglitinide screening during an episode of hypoglycemia (table 1).
●In patients with endogenous hyperinsulinism, insulin antibodies should be measured to distinguish insulin autoimmune hypoglycemia from other causes of hyperinsulinism. Insulin antibodies do not need to be drawn during hypoglycemia.
Localization studies
●Transabdominal ultrasound – In patients with endogenous hyperinsulinemic hypoglycemia (and negative screens for sulfonylurea/meglitinide and insulin antibodies), localization studies are necessary to distinguish between the presence of an insulinoma versus a diffuse process (islet cell hyperplasia). The choice of localization procedure depends upon which tests are available and local radiologic skill. Transabdominal ultrasonography is our preferred initial test for the identification of an insulinoma. (See "Insulinoma", section on 'Tumor localization'.)
Several noninvasive procedures are available, including computed tomography (CT), magnetic resonance imaging (MRI), transabdominal ultrasonography, 111-In-pentetreotide imaging, and fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET). Radiological localization studies are negative for insulinoma in patients with NIPHS. In the Mayo series, as an example, all radiologic studies (transabdominal ultrasonography, triple phase CT, celiac axis angiography, and intraoperative ultrasonography) were negative for insulinoma [1]. The sensitivity of each of these preoperative studies is only approximately 50 to 60 percent, but their combined sensitivity is significantly higher.
●When imaging is negative: SACST – In patients with complex cases of endogenous hyperinsulinemic hypoglycemia and negative radiologic localization studies, a selective arterial calcium stimulation test (SACST) with hepatic venous sampling should be performed to establish that the hyperinsulinemia has a pancreatic origin and, in addition, its regionality within the pancreas. This procedure is important to perform in cases where pancreatic exploration is considered, and it should be conducted by an interventional radiologist skilled in cannulating intraabdominal vessels. The patient may have to be referred to a tertiary center.
A SACST involves injections of calcium gluconate, an insulin secretagogue, into arteries supplying the pancreas with subsequent sampling of the right hepatic venous effluent for insulin [51,52]. A positive result is defined as a doubling or tripling of the basal hepatic venous serum insulin concentration. The increase in insulin occurs in samples from the artery supplying the region with hyperfunctioning islets, either an insulinoma or islet hypertrophy, which facilitates operative localization.
In patients with NIPHS, positive responses are usually observed after injection of multiple arteries, in contrast to insulinoma where the response is positive in one artery alone, unless the tumor resides in an area fed by two arteries or the patient has multiple insulinomas scattered throughout the pancreas [1]. Thus, focal versus diffuse positivity does not provide incontrovertible evidence for or against insulinoma/NIPHS, since insulinoma may be multiple and NIPHS may be caused by focal pathology. The magnitude of the response, however, may differ from that observed in insulinoma [53]. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Selective arterial calcium stimulation' and "Insulinoma", section on 'Tumor localization' and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
TREATMENT
Mild to moderate symptoms — For patients with mild to moderate symptoms, nutritional modification is a reasonable initial intervention. Nutritional modification, particularly reduction of free carbohydrate intake and spacing carbohydrate intake evenly throughout the day, has been reported to reduce postprandial glycemic excursions and mild symptoms of hypoglycemia in some patients with post-bypass postprandial hypoglycemia [39,54].
For patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), similar nutritional modification may be helpful. If mild to moderate symptoms persist, we prescribe the alpha-glucosidase inhibitor acarbose (initial dose 25 mg three times daily, with each main meal).
In case reports, octreotide, verapamil, diazoxide, and acarbose have reportedly improved hypoglycemic symptoms in patients with post-gastric bypass hypoglycemia or, in fewer reports, NIPHS [39,55-58]. The evaluation of the post-gastric bypass patients did not always include careful documentation of postprandial hyperinsulinemic hypoglycemia, and therefore, the diagnosis of hypoglycemia due to nesidioblastosis is uncertain in some of these cases. Nevertheless, in patients with NIPHS and mild to moderate symptoms refractory to a low carbohydrate diet, we believe it is worthwhile to try a course of acarbose, starting at a low dose and advancing to the point of balance between tolerance and benefit, not to exceed 100 mg three times/day. Success with this approach avoids surgery.
Severe or refractory symptoms — For patients with NIPHS and severe postprandial hypoglycemia (eg, neuroglycopenia with loss of consciousness) or with symptoms refractory to medical management, surgery is the mainstay of therapy. In case series and reports, partial or subtotal pancreatectomy successfully relieved hypoglycemic symptoms in the majority of patients with NIPHS and post-gastric bypass nesidioblastosis [1,2,15,26,27,37,38,40,59].
The degree of surgery is determined by the results of the selective arterial calcium stimulation test (SACST). The pancreas to the left of the superior mesenteric vein is resected when the SACST is positive only after splenic artery injection, and the resection is extended to the right of the superior mesenteric vein when the test is positive after injection of an additional artery. The pancreas can be debulked in a gradient-guided fashion, even in patients whose disease appears to involve the whole pancreas.
For post-gastric bypass patients with severe hypoglycemia, reversal of gastric bypass has been suggested as an alternative to pancreatectomy. After reversal, hypoglycemia persisted in some case reports [38,47] but improved in others [48-50]. Conversion of the Roux-en-Y gastric bypass (RYGB) to sleeve gastrectomy may be the procedure of choice. For the patient with post-gastric bypass hypoglycemia from insulinoma, surgery is the preferred treatment. (See "Insulinoma", section on 'Treatment'.)
Recurrent symptoms — Recurrent hypoglycemia after partial pancreatectomy has been observed in both NIPHS and post-gastric bypass hypoglycemia [6,8,40,59]. In a series of 75 patients, 48 of whom responded to a questionnaire, 87 percent reported recurrence of symptoms but to a lesser degree than preoperatively [6]. Despite symptom recurrence, 75 percent reported overall improvement in symptoms and quality of life. There was no difference between patients with NIPHS and post-gastric bypass hypoglycemia. Since the symptoms are usually mild when they recur, lifestyle modification or medical management may suffice. Only rarely has completion pancreatectomy been conducted [8].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults" and "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Definition – Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a syndrome characterized by endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma. Pancreatic specimens from such patients show abnormal islet architecture. (See 'Definition' above.)
●Clinical features – The predominant clinical feature of NIPHS is postprandial hypoglycemia and the presence of neuroglycopenic symptoms. During episodes of hypoglycemia, patients with NIPHS have biochemical findings similar to those of insulinoma, including elevated plasma insulin, C-peptide, and proinsulin concentrations; low plasma beta-hydroxybutyrate; and a negative sulfonylurea/meglitinide screen (table 1). (See 'Clinical features' above.)
●Differential diagnosis – In adults, hypoglycemia due to endogenous hyperinsulinism, with negative screens for sulfonylurea/meglitinide and insulin antibodies, can be caused by a beta cell tumor (eg, insulinoma) or a functional beta cell disorder (eg, NIPHS, post-gastric bypass hypoglycemia). Although hypoglycemia following Roux-en-Y gastric bypass (RYGB) and NIPHS have some features in common (eg, postprandial hyperinsulinemic hypoglycemia, negative radiologic localization but positive calcium stimulation test, and, perhaps, histologic findings), they appear to be distinct diseases. (See 'Differential diagnosis' above and 'Islet abnormalities after Roux-en-Y gastric bypass surgery' above.)
●Localization studies – In patients with endogenous hyperinsulinemic hypoglycemia (and negative screens for sulfonylurea/meglitinide and insulin antibodies), localization studies (eg, transabdominal ultrasound) are necessary to distinguish between the presence of an insulinoma versus a diffuse process (islet cell hyperplasia). Radiological localization studies are negative in patients with NIPHS and typically positive in patients with insulinoma. When radiologic localization studies are negative, a selective arterial calcium stimulation test (SACST) with hepatic venous sampling should be performed to establish that the hyperinsulinemia has a pancreatic origin and, in addition, its regionality within the pancreas. (See 'Diagnostic evaluation' above.)
The diagnosis of NIPHS may then be confirmed when pancreatic specimens from such patients show beta cell hypertrophy, islets with enlarged and hyperchromatic nuclei, and increased periductular islets. (See 'Diagnostic evaluation' above and 'Histopathology' above.)
●Treatment – For patients with mild to moderate symptoms, dietary modification (low carbohydrate diet) is a reasonable initial intervention. Those patients that are refractory to a low carbohydrate diet may respond to an alpha-glucosidase inhibitor (eg, acarbose).
For patients with persistent symptoms despite medical therapy, or for patients with severe hypoglycemia (neuroglycopenia with loss of consciousness), graded pancreatectomy is required to control symptoms. For patients with post-RYGB hypoglycemia, conversion of the RYGB to sleeve gastrectomy is an alternative option. (See 'Treatment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.
