Persistent Hyperinsulinemic Hypoglycemia Research Articles

A Case of 2-Month-Old Infant with Persistent Hyperinsulinemic Hypoglycemia Presenting as Atonic Seizure

Congenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. It is caused by an inappropriate insulin secretion from the pancreatic β-cells secondary to various genetic disorders. Recognition of this entity becomes important due to the fact that hypoglycemia is very severe and frequent and that it may lead to severe neurological damage in the infant manifesting as mental or psychomotor retardation or even a life-threatening events if not recognized and treated effectively in time. Hypoglycemias can be detected by seizures, fainting, or any other neurological symptoms in the neonatal period or later, usually within the first two years of life. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damages. Next, a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. We report a case of congenital hyperinsulinemia in a 2 months old infant presenting as atonic seizure which has been treated with diazoxide.

Persistent hyperinsulinaemic hypoglycaemia in infancy

Persistent hyperinsulinaemic hypoglycaemia in infancy (PHHI) is a heterogeneous condition characterised by unregulated insulin secretion in response to a low blood glucose level. It is the most common cause of severe and persistent hypoglycaemia in neonates. It is extremely important to recognise this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, PHHI is divided mainly into three types—diffuse, focal and atypical disease. Fluorine-18-l-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET/CT) scan allows differentiation between diffuse and focal diseases. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The molecular basis of PHHI involves defects in key genes (ABCC8, KCNJ11, GCK, SLC16A1, HADH, UCP2, HNF4A and GLUD1) that regulate insulin secretion. Focal lesions are cured by lesionectomy whereas diffuse disease (unresponsive to medical therapy) will require a near-total pancreatectomy with a risk of developing diabetes mellitus and pancreatic exocrine insufficiency. Open surgery is the traditional approach to pancreatic resection. However, recent advances in laparoscopic surgery have led to laparoscopic near-total pancreatectomy for diffuse lesions and laparoscopic distal pancreatectomy for focal lesions distal to the head of the pancreas.

In need of glucose – case report of a rare cause of symptomatic hypoglycaemia

Among the hypoglycemia-induced diseases we find insulinoma, insulinomatosis and also the non-insulinoma pancreatogenic hypoglycemia-syndrome (NIPHS). NIPHS is frequently caused by nesidioblastosis, which is characterized by functionally hyperactive beta cells within normal pancreatic islets. While the persistent hyperinsulinemic hypoglycemia is frequent in children, adult-onset nesidioblastosis is rare. Here we present a case of a 67-year-old female patient, who suffered from recurrent hypoglycemic episodes accompanied by cold sweats, muscle cramps, loss of consciousness, improvement of symptoms with dietary intake and weight gain. A prolonged oral glucose tolerance test with subsequent fasting revealed low- and below-normal blood glucose levels, but no disease defining hypoglycemia. Endoscopic ultrasound showed no pancreatic lesion. Ga-DOTATOC-PET/CT found 2 somatostatin receptor-positive areas in the pancreatic body and tail. By arterial calcium stimulation and venous sampling these regions showed an inappropriate insulin secretion. The clinical course until surgery was complicated by severe symptoms occurring several times a day. A therapeutic approach with acarbose and the intake of slowly absorbable carbohydrate was insufficient. Oral therapy with diazoxide was highly effective controlling the symptoms but had to be discontinued due to hypertrichosis, hypotension and edema. Thus pasireotide, a non-selective somatostatin analogue, was applied off-label achieving effective control of symptoms and blood glucose levels until surgical exploration. Finally, distal pancreatectomy was performed and pathological examination revealed adult nesidioblastosis. Postoperatively, the patient was asymptomatic without any medication or dietary interventions and lost 9 kg. The present case illustrates a rare case of adult nesidioblastosis as well as a possible targeted and pathophysiologically specific therapeutic approach with the nonselective somatostatin analogue pasireotide.

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.

Clinical Profile and Outcome of Persistent Hyperinsulinemic Hypoglycemia of Infancy

Clinical Profile and Outcome of Persistent Hyperinsulinemic Hypoglycemia of Infancy

Hormonal Response to a Mixed-Meal Challenge After Reversal of Gastric Bypass for Hypoglycemia

Severe hypoglycemia is a rare and challenging complication of Roux-en-Y gastric bypass (RYGB), which is characterized by hypersecretion of insulin and incretin hormones in the postprandial state. The objective of the study was to determine the clinical and hormonal responses to a mixed-meal challenge after the reversal of RYGB in 2 patients with post-RYGB hypoglycemia. We hypothesized that the reversal of RYGB would lead to clinical improvement in hypoglycemia through the attenuation of incretin hormone secretion. DESIGN/SETTING/SUBJECTS/OUTCOME MEASURES: Two patients with post-RYGB hypoglycemia underwent a standardized meal tolerance test prior to and 8 and 18 months after RYGB reversal, respectively, with the measurement of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, and glucose levels. Gastric bypass was reversed by reattaching the small gastric pouch to the bypassed distal stomach and resecting the Roux limb to restore the normal flow of food bolus. Both subjects showed persistent evidence of hypoglycemia with marked hyperinsulinemia after the RYGB reversal. GLP-1 levels after the RYGB reversal decreased by 76% and 70%, respectively, from their prereversal levels and to the level of nonhypoglycemic post-RYGB controls. In contrast, GIP levels after the RYGB reversal increased by 3-10 times the level before the reversal and 8-26 times that of the nonhypoglycemic post-RYGB controls. Reversal of RYGB did not alleviate hyperinsulinemic hypoglycemia upon a mixed-meal challenge in our patients, thus suggesting its limited clinical benefit as treatment of post-RYGB hypoglycemia. The marked increase in GIP levels and concurrent decrease in GLP-1 levels in our patients suggest a possible role of GIP in persistent hyperinsulinemic hypoglycemia after the reversal of RYGB.

Conformational Transition Pathway in the Activation Process of Allosteric Glucokinase

Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins.

Diffuse nesidioblastosis diagnosed on a Ga-68 DOTATATE positron emission tomography/computerized tomography

The authors describe a 50 days old pre-term infant with persistent hyperinsulinemic hypoglycemia of infancy in whom Ga-68 DOTATATE positron emission tomography/computerized tomography scan showed diffusely increased tracer uptake in the entire pancreas with no abnormal tracer uptake anywhere else in the body, suggestive of a diffuse variant of nesidioblastosis.

Octreotide-induced hepatitis in a child with persistent hyperinsulinemia hypoglycemia of infancy

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), the most common cause of persistent hypoglycemia in the neonatal period and infancy, is a genetic disorder characterized by abnormal regulation of insulin secretion. Octreotide, a somatostatin analog, is often used as a second-line treatment when diazoxide therapy fails to control hypoglycemia. We report herein a rare development of octreotide-induced hepatitis following prolonged treatment for PHHI in an infant. Octreotide-induced hepatitis may occur mostly when high doses are given, or when dosing is increased. This warrants routine examination of liver function. When hepatitis develops, prompt cessation of octreotide therapy will probably result in subsequent resolution.

Nesidioblastosis and Pancreatic Non-functioning Islet Cell Tumor in an Adult with Type 2 Diabetes Mellitus

Nesidioblastosis is a clinically, pathologically, and genetically heterogenous disease observed in neonates with persistent hyperinsulinemic hypoglycemia of infancy, but it is very rare in adults.1 Although progression from nesidioblastosis and islet hyperplasia to pancreatic tumors has been observed in an animal study using transgenic mice,2 islet cell tumors associated with nesidioblastosis in human are exceedingly rare.3,4 Herein we report a very unusual case of nesidioblastosis coexisting with a pancreatic non-functioning islet cell tumor in an adult with type 2 diabetes mellitus (type 2 DM).

Anesthetists approach in a neonate with nesidioblastoma undergoing pancreatectomy

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is rare, but an important cause of hypoglycemia in infants, associated with a number of structural abnormalities of the endocrine pancreas is collectively termed as “Islet cell dysmaturation syndrome.” We present the anesthetic management in a clinically diagnosed case of PHHI in a 22 days old full term child, undergoing Subtotal Pancreatectomy. We have discussed the challenges faced in the intra-operative period in managing this neonate for pancreatic resection surgery with focus on intra-operative management of blood glucose levels.

Neuroendokrine Tumoren des Verdauungstrakts – Daten des deutschen NET-Registers

Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.

Novel Presentations of Congenital Hyperinsulinism due to Mutations in the MODY genes:HNF1AandHNF4A

Inactivating mutations in HNF1A and HNF4A cause the maturity-onset diabetes of youth (MODY)-3 and MODY1 forms of monogenic diabetes, respectively. Children carrying HNF4A (MODY1) mutations can present in early infancy with macrosomia and diazoxide-responsive hyperinsulinism. Our objective was to describe three novel cases of hyperinsulinism associated with MODY1 and MODY3 mutations. Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA. Case 1 was diagnosed at 20 months with persistent hyperinsulinemic hypoglycemia and was found to have a novel MODY3 HNF1A mutation, carried by her father who had diabetes. Case 2 was diagnosed with diazoxide-responsive hyperinsulinism at 3 months of age and had complete resolution of hyperinsulinism by 4 yr. She was found to have a novel MODY3 HNF1A missense mutation, also carried by her father. Case 3 presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Although the latter's features suggested Fanconi-Bickel syndrome, sequencing of the SLC2A2 gene was normal. The patient was found to have a known MODY1 mutation in HNF4A. In all cases, the hyperinsulinism improved with age. The first two cases demonstrate that mutations in HNF1A (MODY3) can cause hyperinsulinism early in life and diabetes later, similar to the phenotype recently reported for HNF4A (MODY1) mutations. Case 3 indicates that the effects of HNF4A mutations in infancy may extend beyond pancreatic β-cells to produce a disorder similar to glucose transporter 2 deficiency involving both liver glycogen metabolism and renal tubular transport.

Food aversion among patients with persistent hyperinsulinemic hypoglycemia of infancy

IntroductionPersistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most common cause of neonatal hypoglycemia. Feeding plays a major role in its management. We evaluated the magnitude of food aversion among our patients with PHHI. MethodsA retrospective medical record review was conducted for patients with PHHI managed during the last 15 years. Demographic and clinical data were retrieved, and descriptive data were generated. ResultsForty-two patients (18 were male and 24 were female) were managed for PHHI over the study period. Thirty-three patients had subtotal pancreatectomy, and 9 were managed medically, with a mean follow-up of 5 years. Nineteen patients (45%) had aversion to food, and 9 of them were developmentally delayed. Of 14 patients assessed by a speech pathologist, 5 had aversive sensory behavior, 4 had dysfunctional pharyngeal swallowing, and 5 had a normal assessment. Ten were managed with oral feeding, 4 had gastrostomy feedings, and 5 were managed with oral and nasogastric tube feeds for various periods. ConclusionsFood aversion is significantly prevalent among patients with PHHI. The presence of food aversion appears to be independent of developmental delay. Aggressive measures to manage food aversion could help in the management of patients with PHHI.

Near-total pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis)

Background/purpose Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most common cause of persistent hypoglycemia in infancy with consequences such as seizures and brain damage. Treatment that prevents the occurrence of these sequele is essential. When medical therapy fails or complications are anticipated, early pancreatectomy is recommended to maintain euglycemia. The aim of this study was short-term evaluation of near-total pancreatectomy for PHHI after failure of medical treatment in patients in Mansoura, Egypt. Patients and methods During May 2002 to May 2010, 33 patients suffering from persistent hyperinsulinemic hypoglycemia were admitted to Mansoura university child hospital. Twenty patients responded to medical treatment and 13 patients (eight girls and five boys) were treated by near-total (90–95%) pancreatectomy after failure of medical treatment. Their ages at the time of surgery ranged from 20 days to 27 months. Only patients who were surgically managed were included in this study. All of them suffered from symptoms of PHHI: thermoregulatory problems in five cases, tremors in five cases, seizures in three, irritability in five, respiratory distress in eight, apnea in four, hypotonia in four, lethargy in five, and feeding difficulty in four cases. All cases were diagnosed following strict criteria that included bouts of hypoglycemia without acidosis coinciding with increased insulin level. Follow-up ranged from 3 months to 8 years. Results Primary success occurred in two cases (15%); four more cases (31%) developed temporary diabetes mellitus, and one case (8%) had a temporary pancreatic fistula. Eventually, total cure occurred in seven cases (54%); six cases (46%) developed a variety of complications; and persistent hypoglycemia was seen in two. Persistent diabetes mellitus was observed in three patients, developmental delay in one, and persistent neurological deficit in two patients; there was one case of mortality. Conclusion Near-total (90–95%) pancreatectomy is a suitable procedure for treatment of nesidioblastosis not responding to medical treatment and should be performed as early as possible. Keywords : Mansoura, near-total pancreatectomy, persistent hyperinsulinemic hypoglycemia

Anesthetic management of a 6 month-old infant for near total pancreatectomy with persistent hyperinsulinemic hypoglycemia

Anesthetic management of a 6 month-old infant for near total pancreatectomy with persistent hyperinsulinemic hypoglycemia

Persistent hyperinsulinemic hypoglycemia of infancy: An overview of current concepts

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is relatively rare but one of the most important causes of severe neonatal hypoglycemia. Recognition of this entity becomes important due to the fact that the hypoglycemia is so severe and frequent that it may lead to severe neurological damage in the infant manifesting as mental or psychomotor retardation or even a life-threatening event if not recognized and treated effectively in time. Near-total pancreatectomy may be required for patients with intractable hypoglycemia despite medical treatment; however, that may result in diabetes mellitus or recurrent postoperative hypoglycemia. This review aims to consolidate the traditional concepts and current information related to the pathogenesis and management of PHHI.

Susceptibility of glucokinase-MODY mutants to inactivation by oxidative stress in pancreatic β-cells.

OBJECTIVEThe posttranslational regulation of glucokinase (GK) differs in hepatocytes and pancreatic β-cells. We tested the hypothesis that GK mutants that cause maturity-onset diabetes of the young (GK-MODY) show compromised activity and posttranslational regulation in β-cells.RESEARCH DESIGN AND METHODSActivity and protein expression of GK-MODY and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) mutants were studied in β-cell (MIN6) and non–β-cell (H4IIE) models. Binding of GK to phosphofructo-2-kinase, fructose-2,6-bisphosphatase (PFK2/FBPase2) was studied by bimolecular fluorescence complementation in cell-based models.RESULTSNine of 11 GK-MODY mutants that have minimal effect on enzyme kinetics in vitro showed decreased specific activity relative to wild type when expressed in β-cells. A subset of these were stable in non–β-cells but showed increased inactivation in conditions of oxidative stress and partial reversal of inactivation by dithiothreitol. Unlike the GK-MODY mutants, four of five GK-PHHI mutants had similar specific activity to wild type and Y214C had higher activity than wild type. The GK-binding protein PFK2/FBPase2 protected wild-type GK from oxidative inactivation and the decreased stability of GK-MODY mutants correlated with decreased interaction with PFK2/FBPase2.CONCLUSIONSSeveral GK-MODY mutants show posttranslational defects in β-cells characterized by increased susceptibility to oxidative stress and/or protein instability. Regulation of GK activity through modulation of thiol status may be a physiological regulatory mechanism for the control of GK activity in β-cells.

Persistent hyperinsulinemic hypoglycemia of infancy

Aim The aim of this study was to investigate the long-term outcome of six children with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) after pancreatectomy who have been followed since 1990 at the Riyadh Military Hospital, Riyadh, Kingdom of Saudi Arabia. Patients and methods Data from six patients were retrospectively analyzed from chart review. PHHI was diagnosed on the basis of having high-insulin levels and low-glucose levels and a high insulin-to-glucose ratio. Lactate, pyruvate, ammonia, and urinary organic acid levels were recorded and tandem mass spectrometry screening was performed. The patients were assessed radiologically by MRI of the brain and by ultrasound examination of the abdomen. Patients who failed medical therapy underwent near-total pancreatectomy. Results Hypoglycemic convulsion was the most common presenting complaint. None of the patients responded to medical treatment and thus underwent surgery. Two patients still had hypoglycemic episodes after surgery, requiring medical treatment. However, they underwent subsequent surgery because of unresponsiveness to medical therapy. Three patients developed diabetes. None of them had malabsorption, and two patients later developed epilepsy. Conclusion The earlier the age at diagnosis, the better the neurological outcome. Delayed surgery might be associated with higher risk of development of diabetes. Near-total (90–95%) pancreatectomy is the treatment of choice for PHHI not responsive to medical treatment. Keywords: Near-total pancreatectomy, outcome, persistent hyperinsulinemic hypoglycemia of infancy

Morphological Mosaicism of the Pancreatic Islets: A Novel Anatomopathological Form of Persistent Hyperinsulinemic Hypoglycemia of Infancy

Morphological studies of the pancreas in persistent hyperinsulinemic hypoglycemia of infancy (PHHI) have focused on the diagnosis of focal vs. diffuse forms, a distinction that determines the optimal surgical management. ABCC8 or KCNJ11 genomic mutations are present in most of them. Our aim was to report a new form of PHHI with peculiar morphological and clinical characteristics. Histopathological review of 217 pancreatic PHHI specimens revealed 16 cases morphologically different from diffuse and focal forms. They were analyzed by conventional microscopy, quantitative morphometry, immunohistochemistry, and in situ hybridization. Their morphological peculiarity was the coexistence of two types of islet: large islets with cytoplasm-rich β-cells and occasional enlarged nuclei and shrunken islets with β-cells exhibiting little cytoplasm and small nuclei. In small islets, β-cells had abundant insulin content but limited amount of Golgi proinsulin. Large islets had low insulin storage and high proinsulin production and were mostly confined to a few lobules. No evidence for K(ATP) channels involvement or 11p15 deletion was found. Genomic mutations for ABCC8, KCNJ11, and GCK were absent. Patients had normal birth weight and late hypoglycemia onset and improved with diazoxide. Ten were cured by limited pancreatectomy. Six recurred after surgery and were medically controlled. This new form of PHHI is characterized by a morphological mosaicism. Pathologists should recognize this mosaicism on intraoperative frozen sections because it is often curable by partial pancreatectomy. The currently unknown genetic background does not involve the classical genomic mutations responsible for diffuse and focal PHHI.