Hyperinsulinemic Hypoglycemia In Adults Research Articles

Clinical Presentation, Diagnosis, and Management of Hyperinsulinemic Hypoglycemia in Adults: A Single-center Experience.

Hyperinsulinemic Hypoglycemia (HH) is a rare condition characterized by inappropriately elevated insulin levels in the presence of low glucose levels. A proper diagnostic framework is fundamental to avoid patients undergoing unnecessary diagnostic and therapeutic invasive procedures. The study aimed to assess the clinical presentation, diagnostic work-up, and treatment of a single-center cohort of patients affected by HH. We conducted a retrospective analysis of data collected from January 2000-2023. Our study included 104 patients: 81 (58% F) affected by insulinoma, 11 (91% F) by autoimmune hypoglycemia, 7 (71% M) by post-gastric surgery hypoglycemia, and 5 (80% F) by factitious hypoglycemia. HH was more frequent in females (63 F vs. 41 M, p-value 0.039). The median age at diagnosis was lower in insulinoma than in the autoimmune group (52.7 vs. 63.7 y, p < 0.001). During the hypoglycemic event, insulin and C-peptide levels were significantly higher in autoimmune hypoglycemia than in insulinoma (insulin 324.6 vs. 36.4 μU/ml, p-value 0.033; C-peptide 14.25 vs. 3.99 ng/ml, p-value 0.003). Specifically, C-peptide levels <9.6 ng/ml and insulin levels <75 μU/ml exhibited 97.3% vs. 93.4% sensitivity and 80% vs. 90% specificity for insulinoma diagnosis, respectively. Regarding insulinoma, the sensitivity of localizing imaging was 88% for Endoscopic Ultrasound (EUS), 86% for Magnetic Resonance Imaging (MRI), 82% for Computed Tomography (CT) scan, 52% for nuclear imaging, and 100% for angiography with the Doppman test. Among insulinoma patients, 79% received surgical treatment while 4% radiofrequency ablation. Symptomatic remission occurred in 100% of cases. We have confirmed insulinoma as the primary cause of HH. The autoimmune form should be suspected when insulin and C-peptide levels are markedly elevated.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens

BackgroundAdult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology.MethodsWe measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists.ResultsThere was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted.ConclusionsLow circularity, which indicates an irregular islet shape, referred to as “irregular shape and occasional enlargement of islets” and “lobulated islet structure” in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to “macronucleoli in β-cells,“ has potential diagnostic value.

Successful Medical Treatment of Hyperinsulinemic Hypoglycemia in the Adult: A Case Report and Brief Literature Review

Hyperinsulinemic hypoglycemia is characterized by inappropriate insulin secretion from the pancreatic beta cells causing low blood glucose levels. Nesidioblastosis is a very rare cause of hyperinsulinemic hypoglycemia in adults. Medical therapy can effectively improve disease symptoms. In 2014, a 45-year-old man presented with recurrent severe fasting and postprandial symptomatic hypoglycemia. The symptoms resolved after glucose ingestion. Fasting test was positive after only 4 h but imaging methods (abdominal computerized tomography, magnetic resonance imaging, endoscopic ultrasonography and octreotide scintigraphy) failed to identify pancreatic lesions. Hypoglycemia in face of endogenous hyperinsulinemia and lack of focal lesions in the pancreas in multiple imaging exams suggested the diagnosis of adult nesidioblastosis. The patient preferred conservative medical treatment in association with dietary recommendations. Nifedipine (30 mg/day) did not improve the glycemic profile and was poorly tolerated by the patient. Diazoxide 150 mg/day was started, with progressive increase to 400 mg/day over 6 weeks. Patient has been successfully treated with medical treatment for 5 years, with no events of severe hypoglycemia, no significant side effects and with marked improvement in quality of life. This clinical case demonstrates that adult hyperinsulinemic hypoglycemia can be effectively controlled with medical treatment, which is a viable alternative to pancreatic surgery. J Endocrinol Metab. 2019;9(6):199-202 doi: https://doi.org/10.14740/jem617

Insulinoma or non-insulinoma pancreatogenous hypoglycemia? A diagnostic dilemma

Insulinoma is the most common cause of endogenous hyperinsulinemic hypoglycemia in adults. An alternate etiology, non-insulinoma pancreatogenous hypoglycemia (NIPH), is rare. Clinically, NIPH is characterized by postprandial hyperinsulinemic hypoglycemia, negative 72-h fasts, negative preoperative localization studies for insulinoma and positive selective arterial calcium infusion tests. Histologically, diffuse islet hyperplasia with increased number and size of islet cells is present and confirms the diagnosis. Differentiating NIPH from occult insulinoma preoperatively is challenging. Partial pancreatectomy is the procedure of choice; however, recurrence of symptoms, although less debilitating, occurs commonly. Medical management with diazoxide, verapamil and octreotide can be used for persistent symptoms. Ultimately, near-total or total pancreatectomy may be necessary. We report a case of a 67-year-old male with hypoglycemia in whom preoperative workup, including computerized tomography abdomen, suggested insulinoma, but whose final diagnosis on pathology was NIPH instead.

Evaluation, Medical Therapy, and Course of Adult Persistent Hyperinsulinemic Hypoglycemia After Roux-En-Y Gastric Bypass Surgery: A Case Series

To describe the evaluation and treatment of hyperinsulinemic hypoglycemia in adults who had undergone gastric bypass surgery. A small number of patients who undergo Roux-en-Y bypass surgery develop postprandial hypoglycemia in the absence of dumping. In some cases, such patients have been treated with pancreatectomy. We report the demographics, diagnostic results, response to medical therapy, and subsequent course of 6 referral patients with post-Roux-en-Y gastric bypass hypoglycemia. Characteristic clinical and metabolic parameters consistent with hyperinsulinemic hypoglycemia were identified. Parameters were similar for both spontaneous and glucose-challenge-induced hypoglycemia. In the context of exclusively postprandial symptoms, simultaneous glucose ≤55 mg/dL, insulin ≥17 μU/mL, C peptide ≥3.0 ng/mL, and insulin to glucose ratio >0.3 were associated with Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia. Five of 6 patients improved on therapy consisting of dietary modification plus either calcium channel blockade, acarbose, or both. Two patients have remained on therapy for 12 to 15 months. The nonresponder was atypical and had had hypoglycemic events for several decades. Three treated patients were subsequently observed to have undergone partial or complete remission from hypoglycemic episodes after 2 to 37 months of therapy. None of the 6 have undergone pancreatectomy, and none have evidence of insulinoma. Invasive diagnostic procedures were of limited utility. In a subset of patients with post-Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia, medical management can be efficacious and an alternative to partial pancreatectomy. In some cases, the disorder remits spontaneously.

Insulinoma Localization by Glucagon-Like Peptide-1 Receptor Imaging After 18 Years of Hypoglycemia

ABSTRACT Objective: Insulinoma is the most frequent cause of hyperinsulinemic hypoglycemia in adults, but its preoperative localization may be challenging. Methods: We report on a patient with a remarkably long history of persistent hypoglycemia due to an insulinoma, which was finally localized after 18 years using glucagon-like peptide-1 receptor (GLP-1R) imaging. Results: The patient was admitted in 1995 for hypoglycemia. A fasting test documented inadequate insulin suppression. She had given birth to a baby who was small for gestational age a few weeks earlier. The patient underwent surgery for a pancreatic tail nodule, which histologically proved to be normal tissue. Hypoglycemia recurred postoperatively. Diazoxide initially controlled symptoms, but over the years, the patient had recurrent hypoglycemic seizures and coma. The patient underwent repeated pancreatic magnetic resonance imaging (MRI), indium-111 (111In)-octreotide scintigraphy, galladium-68 (68Ga)-DOTATATE-positron emission tomography (PET) scan, 18F-DOPA-PET scan and arterial calcium stimulation with hepatic venous sampling; all were negative. Finally, a SPECT-CT with indium-111 diethylene triamine pentaacetic acid (111In-DTPA)-exendin-4, a radioligand with high affinity to the GLP-1R, showed focally increased tracer uptake in the pancreas tail. Endoscopic ultrasound (US) and fine-needle aspiration confirmed the endocrine origin of the tumor. The patient underwent laparoscopic tail pancreatectomy and was cured after 18 years of hyper-insulinemic hypoglycemia. Ex vivo studies of the insulinoma confirmed elevated insulin secretion at low glucose concentrations and abundant GLP-1R expression. Conclusion: GLP-1R imaging is a highly valuable tool in the localization of insulinoma when other conventional methods fail to identify the tumor. This new imaging tool will enable timely localization and cure for insulinoma patients. Abbreviations: ASVS selective arterial calcium stimulation and hepatic venous sampling 11C carbon 11 CT computed tomography DTPA diethylene triamine penta-acetic acid 18F-DOPA 18F-3,4-dihydroxyphenylalanine GLP-1R glucagonlike peptide-1 receptor 111In indium-111 KATP channels adenosine triphosphate-sensitive potassium channels MRI magnetic resonance imaging PET positron emission tomography SPECT single-photon-emission computed tomography SST2R somatostatin receptor type 2 SST5R somatostatin receptor type 5 US ultrasound

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 β 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 β 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.

An unusual cause of reversible axonal neuropathy and hypertension in a 10-year-old girl

A 10-year-old girl, who was referred with refractory epilepsy, had 1.5years of episodic abnormal behavior. On examination, she also had hypertension and peripheral neuropathy. Hypoglycemia with correspondingly high insulin levels was documented during a confusional episode. MRI of the abdomen revealed an islet cell tumor in the body of the pancreas. One year after tumor excision, both the neuropathy and hypertension showed remarkable improvement. A final diagnosis of insulinoma with hypoglycemic axonal neuropathy and hypertension (reversed with tumor excision) was made. Insulinoma is the commonest cause of hyperinsulinemic hypoglycemia in adults, but is rare in childhood. To our knowledge, distal symmetrical motor–sensory axonal neuropathy has been described in only 40 patients, and hypertension has not been reported with insulinoma.

Overtly Manifested Diabetes Mellitus after Resection of Insulinoma

Insulinoma is the most common cause of endogenous hyperinsulinemic hypoglycemia in adults. However, the coincidence of insulinoma and diabetes is extremely uncommon. We describe a rare, but very interesting case of diabetes mellitus which was masked by insulinoma and was overtly manifest after the removal of the insulinoma.

Hyperinsulinemic hypoglycemia in adults. Case reports and a short review

Persistent hyperinsulinemic hypoglycemia (nesidioblastosis) not caused by an insulinoma is rare in adults. Morphologically no insulin secreting tumor is present. Keystones of diagnosis are not only low glucose levels but to maintain normoglycemia by use of intravenous glucose and the presence of high insulin and C-peptide levels. Noninvasive and invasive diagnostic techniques are required to rule out a hormone secreting tumor. Both conservative and/or surgical therapy are suggested to prevent damaging effects of repeated hypoglycemia. Two patients with frequent and serious episodes of hypoglycemia are reported. In the 34-year-old female symptoms appeared with sweating, dizziness, trembling, nervousness and serious neuroglycopenic signs. In the 22-year-old male the main complaint was tympany, a rare and unusual sign of hypoglycemia, and intense feeling of esurience. The 24-hour fasting test was positive in both cases, i.e. it had to be stopped because of symptomatic hypoglycemia. No insulinoma could be localized, despite extensive search, therefore in both cases the diagnosis of adult-onset nesidioblastosis was set up, despite lack of histological confirmation. Diazoxide therapy resulted in symptom-free life for both patients. Several diagnostic methods and treatment options are suggested for the rare disease nesidioblastosis to balance defective insulin secretion. However, once the decision is made in favour of surgical therapy, there is a thin line between successful treatment, persistence of the disease, and pancreatic insufficiency. Therefore it is worth considering to try conservative therapy especially when surgery is of high risk. Our cases suggest that diazoxide therapy is an effective and safe alternative in the treatment of adult-onset nesidioblastosis.

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.

Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: A diagnostic and therapeutic challenge

Hyperinsulinemic hypoglycemia is caused by uncontrolled insulin release either from neoplastic pancreatic beta-cells or from functionally defective beta-cells. The latter disorder, which is usually seen in newborns, has been called nesidioblastosis and is divided histopathologically into a focal and diffuse type. In adults, nesidioblastosis is rare, and therefore its histopathologic and clinical features are not well known. In our institution, 4 of 128 adult patients (>3%) suffering from hyperinsulinemic hypoglycemia were found to have diffuse nesidioblastosis. The remaining patients had an insulinoma resected successfully in all but one patient. The diagnosis of diffuse nesidioblastosis was established histopathologically after removing a segment of the distal pancreas. Resection of up to 90% of the pancreas relieved 2 of the 4 patients of their symptoms. We conclude that diffuse nesidioblastosis is rare in adults but may account for more than 3% of patients with hyperinsulinemic hypoglycemia. The histopathologic diagnosis relies predominantly on demonstration of beta-cell hypertrophy. The cause of the disease is not known but may be related to defects in the glucose recognition system of the beta-cell. Treatment consists of operative reduction of the beta-cell mass, but the extent of pancreatic resection required is hard to judge, and there is a thin line between successful treatment, persistence of the disease, and pancreatic endocrine insufficiency.

Noninsulinoma Pancreatogenous Hypoglycemia Syndrome: A Rare Case of Adult-onset Nesidioblastosis

The most common cause of hyperinsulinemic hypoglycemia in adults is insulinoma. Nesidioblastosis is a rare, but well-recognized disorder of persistent hyperinsulinemic hypoglycemia in infancy, but adult-onset nesidioblastosis associated with hyperinsulinemic hypoglycemia, termed noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS), has been reported. Here, we describe an extremely rare case of NIPHS in an elderly man. A 78-year-old man was admitted to our hospital due to hypoglycemic coma. During the previous 3 months, he noticed excessive sweating at midafternoon. His low fasting plasma glucose level (27 mg/dl) and high immunoreactive insulin level (11.1 muU/ml) were consistent with the possible presence of insulinoma. Localizing studies including computed tomography of the abdomen and celiac arteriography were negative, but selective arterial calcium infusion (SACI) test suggested the presence of insulinoma in the body and tail of the pancreas. Surgical exploration by palpation and intraoperative ultrasonography failed to detect any mass in the pancreas, and 60% distal pancreatectomy was performed. Postoperatively, his hypoglycemic episodes completely disappeared. Histological examination of the resected pancreas revealed diffuse islet cell hyperplasia consistent with a pathological diagnosis of nesidioblastosis. Thus, our case is a very rare case of NIPHS, or adult-onset nesidioblastosis, in which SACI test was proven to be a useful diagnostic tool for localization of the pancreatic lesion.

Nesidioblastosis with Hyperinsulinemic Hypoglycemia in Adults: Report of Two Cases

Nesidioblastosis with Hyperinsulinemic Hypoglycemia in Adults: Report of Two Cases

Hyperinsulinemic hypoglycemia in adults with islet-cell hyperplasia and degranulation of exocrine cells of the pancreas.

Five adults with pancreatic islet-cell hyperplasia presenting as hyperinsulinemic hypoglycemia are reported. Additional insular lesions including nesidioblastosis, adenomatosis, and insulinoma were variably present. This apparent spectrum of islet-cell lesions has been rarely noticed in hypoglycemic adults, although it is a recognized cause of a similar clinical syndrome in children. B-cell hyperplasia was confirmed in all five cases by histochemistry, immunochemistry, and electron microscopy. In addition, nodules of eosinophilic exocrine cells, another recently recognized finding in similar cases, were present in all cases studied. Ultrastructural study revealed that these nodules were composed of degranulated acinar cells. These acinar changes may provide a diagnostic aid in cases of pancreatic endocrine hyperplasia. Consideration of the embryologic development of the pancreas suggests that this spectrum of islet-cell hyperplasia and acinar cell change is due to neoformation of islets from ducts. The etiologic factors of such proliferation are still unknown.