A rare complication of gastric bypass (weight loss) surgery: nesidioblastosis.

Here, we present the case of a 31-year-old woman patient who underwent distal pancreatectomy with the history of gastric bypass surgery for obesity. The final histopathological diagnosis of the lesion was nesidioblastosis. Nesidioblastosis is the most common cause of organic persistent hyperinsulinemic hypoglycemia in newborns; however, it is rare in adults. In adults, it is difficult to diagnose nesidioblastosis with only clinical findings. The definitive diagnosis of the disease depends on the histopathological examination of pancreatic tissue and the exclusion of insulinoma.

Nesidioblastosis in adults.

The persistent hyperinsulinemic hypoglycemia may be caused either by a solitary tumor of the pancreas secreting excessive amount of insulin, known as insulinoma or, rarely, by nesidioblastosis. Nesidioblastosis is a rare cause of persistent hyperinsulinemic hypoglycemia in adults. The incidence of nesidioblastosis in adults is unknown, but it is generally thought to be very low. The ß cell changes in adult nesidioblastosis suggest a dysregulation of the function of the cell. The cause of the functional dysregulation in adults is unknown. The pathogenesis of adult nesidioblastosis may be different from infantile congenital hyperinsulinism caused by a genetic effect. Histologically nesidioblastosis is almost always characterized by a proliferation of abnormal ß cells throughout the entire pancreas. Clinically and biochemically , it is not possible to distinguish between diffuse nesidioblastosis and insulinoma. If all highly selective noninvasive imaging techiques fail to identify a tumor, selective arterial calcium stimulation testing should be performed. The final diagnosis relies on the histopathologic evaluation. The treatment of adult nesidioblastosis is surgical resection of the pancreas.

Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity.

CONTEXT: Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass (RYGB) has been increasingly reported. It is induced by ß-cell hyperplasia often referred to as nesidioblastosis. Positron emission tomography (PET) with [11C]-5-hydroxytryptophan ((11)C-HTP) and 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine ((18)F-DOPA) has been successfully applied to image neuroendocrine tumors. No data are available of the usefulness of these functional imaging techniques in post-RYGB in this new endocrine disorder, neither for diagnostic purposes nor for follow-up. OBJECTIVE: We present a patient with post-RYGB hypoglycemia who underwent (11)C-HTP and (18)F-DOPA PET scintigraphy for diagnostic purposes and to evaluate the effect of additional laparoscopic adjustable banding of the pouch as a surgical therapy for this disorder. PATIENT: We describe a woman with biochemically confirmed post-RYGB hypoglycemia who showed diffuse uptake of the (11)C-HTP and (18)F-DOPA tracers in the entire pancreas. After failure of dietary and medical treatment options, she underwent a laparoscopic adjustable banding for pouch dilatation. Subjective improvement was noted, which coincided with decreased uptake of (18)F-DOPA and (11)C-HTP in the head of the pancreas. CONCLUSIONS: Functional imaging by (18)F-DOPA- and (11)C-HTP-PET can accurately visualize diffuse endocrine pancreatic activity in post-gastric bypass hyperinsulinemic hypoglycemia. Both (11)C-HTP- and (18)F-DOPA-PET imaging appear to have a similar diagnostic performance in the presented case, and uptake of both tracers potentially relates to disease activity after surgical intervention.

Prolonged successful therapy for hyperinsulinaemic hypoglycaemia after gastric bypass: the pathophysiological role of GLP1 and its response to a somatostatin analogue.

BACKGROUND: Spontaneous hyperinsulinaemic hypoglycaemia following gastric bypass surgery (GBS) is increasingly recognised. However, its pathophysiology remains unclear. Some patients require pancreatectomy. Medical therapy with calcium channel blockers, acarbose and diazoxide has been reported to be beneficial but has variable adherence and response. METHOD: We demonstrate the role of GLP1, counter-regulatory hormones and the subsequent response of GLP1 to somatostatin analogue therapy in a 42-year-old woman with persistent neuroglycopaenia 6 years after GBS. Plasma GLP1, insulin and glucose were measured for 5  h on three settings: i) a 75  g oral glucose tolerance test (OGTT); ii) a standard liquid test meal (LTM); and iii) an OGTT 30  min after a s.c. injection of 100  µg octreotide. RESULTS: In comparison with obese non-diabetic controls, the patient had an elevated fasting and a markedly enhanced GLP1 response during the OGTT, followed by an exaggerated insulin response and a subsequent low glucose level. The GLP1 response to a LTM was similar but greater. Octreotide given prior to the OGTT attenuated both the GLP1 and insulin responses and abolished hypoglycaemia. Octreotide therapy significantly improved the patient's neuroglycopaenic symptoms. The hormone profile was reassessed after 6 months following the LTM preceded by octreotide injection. Peak GLP1 and insulin responses were less pronounced than pretreatment responses and without hypoglycaemia. The patient was treated with lanreotide and had remained symptom-free and euglycaemic for 4 years. CONCLUSION: An exaggerated incretin response following altered gastrointestinal anatomy was the likely cause of hypoglycaemia in our GBS patient. Somatostatin successfully suppressed this response acutely and in the long term, thereby avoiding pancreatectomy and its sequelae.

Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia.

INTRODUCTION: Postgastric bypass noninsulinoma hyperinsulinemic pancreatogenous hypoglycemia defines a group of patients with postprandial neuroglycopenic symptoms similar to insulinoma but in many cases more severe. There are few reports of patients with this condition. We describe our surgical experience for the management of this rare condition. METHODS: A retrospective study was performed at St. Vincent Hospital, Indianapolis. Fifteen patients were identified with symptomatic postgastric bypass hypoglycemia for the period 2004-2008. All patients were initially treated with medical therapy for hypoglycemia. Nine patients eventually underwent surgical treatment. The preoperative workup included triple-phase contrast CT scan of the abdomen, endoscopic ultrasound of the pancreas, a 72-h fast followed by a mixed meal test, and calcium-stimulated selective arteriography. Intraoperative pancreatic ultrasound also was performed in all patients. Patients then underwent thorough abdominal exploration, exploration of the entire pancreas, and extended distal pancreatectomy. RESULTS: Nine patients underwent surgery. The mean duration of symptoms was 14 months. The 72-h fast was negative in eight patients (as expected). Triple-phase contrast CT scan of the abdomen was negative in eight patients and showed a cyst in the head of pancreas in one patient. Extended distal (80%) pancreatectomy was performed in all nine patients. The procedure was attempted laparoscopically in eight patients but was converted to open in three. One patient had an open procedure from start to finish. Pathology showed changes compatible with nesidioblastosis with varying degrees of hyperplasia of islets and islet cells. Follow-up ranged from 8-54 (median, 22) months. All patients initially reported marked relief of symptoms. Over time, two patients had complete resolution of symptoms; three patients developed occasional symptoms (once or twice per month), which did not require any medication; two patients developed more frequent symptoms (more than twice per month), which were controlled with medications; and two patients had severe symptoms refractory to medical therapy (calcium channel blockers, diazoxide, octreotide). DISCUSSION: Postprandial hypoglycemia after gastric bypass surgery with endogenous hyperinsulinemia is being increasingly recognized and reported in the literature. Our experience with nine patients is one of the largest. The etiology of this condition is not entirely understood. There may be yet unknown factors involved but increased secretion of glucagon-like peptide 1 and decreased grehlin are being implicated in islet cell hypertrophy. There is no "gold standard" treatment-medical or surgical-but distal pancreatectomy to debulk the hypertrophic islets and islet cells is the main surgical modality in patients with severe symptoms refractory to medical management.

Bariatric surgery: unstressing or boosting the beta-cell?

Bariatric surgery is the most effective therapy for severe obesity in terms of reduction of morbidity and mortality and quality of life improvement. Different bariatric procedures distinctly differ with regard to their effectiveness to reduce body weight and to improve morbidities, such as type 2 diabetes. In this regard, the most effective procedures are bilio-pancreatic diversion (BPD) and duodenal switch procedure curing 98.9% of the diabetes patients, followed by Roux-en-Y gastric bypass (RYGB) with 83.7% success rate, by gastroplasty with 71.6% and by gastric banding with 47.9%. Interestingly, a net improvement up to resolution of type 2 diabetes has been consistently reported few days after RYGB and BPD. RYGB promotes incretin secretion which, in turn, stimulates insulin secretion while insulin sensitivity is slightly improved. Rarely, the long-term effect of incretin hypersecretion might result in hypertrophy and hyperplasia of the islets of Langerhans, otherwise known as nesidioblastosis, associated with hyperinsulinaemia and severe postprandial hypoglycaemia. In contrast, BDP improves insulin resistance to a greater extent and results, in the long run, in supra-normal values of insulin sensitivity with subsequent reduction of insulin secretion. The mechanism allowing diabetes resolution after surgical intestinal manipulation is extremely interesting but only partially understood.

Congenital disorder of glycosylation type Ia: heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency.

We describe three patients with congenital disorder of glycosylation (CDG) type Ia, all of whom had persistent hyperinsulinaemic hypoglycaemia responding to diazoxide therapy as a common feature. The first patient, an infant girl, presented with recurrent vomiting, failure to thrive, liver impairment, hypothyroidism and a pericardial effusion. The second patient, also female, had a milder disease with single organ involvement, presenting as isolated hyperinsulinaemic hypoglycaemia, not associated with any cognitive impairment. The third patient, a boy presented with multi-organ manifestations including congenital hypothyroidism, persistent hyperinsulinaemic hypoglycaemia, coagulopathy, olivopontocerebellar hypoplasia and recurrent pancreatitis. All three patients had a type 1 serum transferrin isoform pattern, and were subsequently found to have low phosphomannomutase activity, confirming the diagnosis of CDG type Ia. Our findings emphasize that CDG should be considered as a differential diagnosis in patients with persistent hyperinsulinaemic hypoglycaemia and that it may even occasionally be the leading symptom in CDG Ia.

Nesidioblastosis del adulto coexistente con insulinoma / Adult Nesidioblastosis Concurrent with Insulinoma

La nesidioblastosis es poco común, pero ampliamente reconocida como causa de la hipoglucemia hiperinsulinémica persistente de la infancia. En adultos, el insulinoma es la principal causa de hipoglucemia hiperinsulinémica, pero también se han identificado casos de nesidioblastosis, los cuales se denominan ‘síndrome de hipoglucemia pancreatógena no insulinoma’. Los primeros casos de nesidioblastosis del adulto que fueron descritos se asociaron con otras condiciones, como insulinoma y tumores neuroendocrinos pancreáticos y MEN-1. En este artículo se describe un caso de nesidioblastosis coexistente con insulinoma en una paciente de 20 años; se hace una revisión de la literatura; se plantea la discusión sobre su posible etiología, presentación clínica, diagnóstico, tratamiento y, finalmente, se presenta un algoritmo para su estudio.

Nesidioblastosis is infrequent; however, it is widely recognized as the cause of persistent infant hyperinsulinemic hypoglycemia. Among adults, insulinoma is the major cause of hyperinsulinemia hypoglycemia, but identification has also been made of cases of nesidioblastosis which are designated as ´non insulinoma pancreatogena hypoglycemic syndrome´. The first case descriptions of adult nesidioblastosis were associated with other conditions such as insulinoma and neuroenodocrinal pancreatic tumors, and MEN-1. This article describes a case of nesidioblastosis concurrent with insulinoma in a 20-year old patient; the literature is reviewed; discussion is provided on possible etiology, clinical manifestation, diagnosis, treatment, and a concluding algorithm.

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression.

Hypoglycemia secondary to nesidioblastosis is rare in adults, and the pathogenesis of this condition is unknown. To determine factors leading to nesidioblastosis in adults, we analyzed 36 cases of nesidioblastosis including 27 cases of postgastric bypass nesidioblastosis and 9 cases of idiopathic nesidioblastosis in adults by immunohistochemistry using antibodies to insulin-like growth factor 1, insulin-like growth factor 2 (IGF2), insulin-like growth factor one receptor-alpha epidermal growth factor receptor, transforming growth factor-beta1 and 2, and transforming growth factor-beta receptor type 3. Fifty-two surgically excised pancreatic specimens from patients with benign exocrine tumors and no evidence of hypoglycemia were used as controls. There was increased IGF2, insulin-like growth factor receptor 1 receptor-alpha and transforming growth factor-beta receptor 3 expression in islets from nesidioblastosis patients compared to controls. Peliosis-type vascular ectasia was more common in nesidioblastosis patients compared to controls. These findings suggest that increased production of growth factors and growth factor receptors may contribute to the development of nesidioblastosis in adults.

Adult diffuse nesidioblastosis: genetically or environmentally induced?

Persistent hyperinsulinemic hypoglycemia in adults is usually caused by solitary benign insulinomas. Nesidioblastosis, a term that has been used to designate a functional disorder of the beta cells, is a rare cause of persistent hyperinsulinemic hypoglycemia in adults, but seems to have increased in frequency. The histopathologic criteria for adult nesidioblastosis are similar to those used for the diagnosis of the diffuse form of congenital hyperinsulinism in infants and include beta-cell hypertrophy, islet hyperplasia, and an increase in the beta-cell mass. However, the degree and extent of these features vary much more from patient to patient than in newborns. The cause of adult nesidioblastosis is not known, but the recently observed association with gastric bypass surgery in obese patients suggests that a reactive process possibly unmasks or induces a defect in the beta cell, resulting in its hyperfunction.

Laparoscopic spleen-preserving distal pancreatectomy as treatment for nesidioblastosis after gastric bypass surgery.

Nesidioblastosis is characterized by hyperfunction of pancreatic islets caused by hypertrophic beta cells. Postprandial symptoms of hypoglycemia are the clinical presentation of the disease. A female patient with diabetes mellitus who underwent a Roux-en-Y gastric bypass began to present postprandial symptoms of hypoglycemia. There was no radiologic (MRI) evidence of insulinoma. Selective arterial calcium-stimulation test identified hyperfunction only in the splenic artery. Laparoscopic spleen-preserving distal pancreatectomy was performed. The patient has been entirely free of any postprandial symptoms for 10 months after the partial pancreatectomy.

Recurrent hypoglycaemia in HIV-positive narcotic addicts.

QUESTIONS UNDER STUDY: We describe two narcotic addict women with recurrent hypoglycaemic episodes. In both patients, hyperinsulinaemic hypoglycaemia occurring in the fasting state was documented and computed tomography of the pancreas was normal. METHODS AND RESULTS: In patient 1, selective arterial calcium stimulation with hepatic venous sampling (ASVS) revealed pronounced insulin hypersecretion predominantly in the tail and, to a lesser extent, in the corpus and the head of the pancreas. On laparoscopic exploration, tumours could not be detected be it grossly or by intraoperative ultrasound. Distal pancreatectomy was performed laparoscopically, and histological examination of the resected tissue revealed nesidioblastosis. ASVS was also performed in patient 2 revealing less marked increases in insulin secretion, ie up to 2.3-fold in response to calcium stimulation of the superior mesenteric artery, consistent with the presence of pathological beta-cells located predominantly in the head of the pancreas. Surgical exploration was not performed in this patient. CONCLUSION: HIV infection had been known in both women for around ten years and both patients were not on antiretroviral therapy. Because symptomatic nesidioblastosis in adult patients is a very rare disorder, we speculate that nesidioblastosis may develop in the context of HIV infection and/or abuse of narcotic drugs. Our observations illustrate that neurocognitive impairment in HIV positive patients is not always due to toxic compounds or a cerebral disorder but may be caused by an apparently rare pancreatic disorder, nesidioblastosis. Thus, the patients should be checked for the presence of hyperinsulinaemic hypoglycaemia.

Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery.

We describe six patients (five women and one man; median age, 47 years; range, 39 to 54) with postprandial symptoms of neuroglycopenia owing to endogenous hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass surgery. Except for equivocal evidence in one patient, there was no radiologic evidence of insulinoma. Selective arterial calcium-stimulation tests, positive in each patient, were used to guide partial pancreatectomy. Nesidioblastosis was identified in resected specimens from each patient, and multiple insulinomas were identified in one. Hypoglycemic symptoms diminished postoperatively. We speculate that hyperfunction of pancreatic islets did not lead to obesity but that beta-cell trophic factors may have increased as a result of gastric bypass.