Advances in the diagnosis and management of hyperinsulinemic hypoglycemia

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1 Advances in the diagnosis and management of hyperinsulinemic hypoglycemia Ritika R Kapoor, Chela James and Khalid Hussain* SUMMARY Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic β-cells and is a major cause of hypoglycemic brain injury and mental retardation. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion, seven of which have been identified (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A). Severe forms of congenital HH are caused by mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic β-cell ATP-sensitive potassium channel. Mutations in HNF4A, GLUD1, CGK, and HADH lead to transient or persistent HH, whereas mutations in SLC16A1 cause exercise-induced HH. Rapid genetic analysis combined with an understanding of the histological features (focal or diffuse disease) of congenital HH and the introduction of 18 F-l-3,4-dihydroxyphenylalanine PET-CT to guide laparoscopic surgery have totally transformed the clinical approach to this complex disease. Adult-onset HH is mostly caused by an insulinoma; however, it has also been reported to present as postprandial HH in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric-bypass surgery for morbid obesity, and in those with mutations in the insulin-receptor gene. Keywords glucose, hyperinsulinism, hypoglycemia, insulin, pancreatic β-cell Review criteria A search for original and articles published between 1975 and 2008 that focused on hyperinsulinemic hypoglycemia was performed in PubMed. The search terms used were hyperinsulinism, hypoglycemia, CHI, insulinoma and postprandial hypoglycemia. We also searched the reference lists of identified articles for further papers. RR Kapoor is a Clinical Research Fellow and Honorary Specialist Registrar, C James is a Postdoctoral Researcher, and K Hussain is a Consultant Pediatric Endocrinologist and Honorary Senior Lecturer, all at the Institute of Child Health, University College London and Great Ormond Street Hospital for Children National Health Services Trust, London, UK. Correspondence *Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK k.hussain@ich.ucl.ac.uk Received 2 September 2008 Accepted 12 November doi: /ncpendmet1046 INTRODUCTION Hyperinsulinemic hypoglycemia (HH) occurs as a consequence of inappropriate and unregulated secretion of insulin by pancreatic β-cells. This hypersecretion leads to the uptake of glucose by insulin-sensitive tissues (especially skeletal muscle, adipose tissue and the liver) and simultaneously inhibits glycogenolysis (glycogen breakdown), gluconeogenesis (glucose production from noncarbohydrate sources), lipolysis and ketogenesis. Together, these processes cause profound hypoglycemia, 1 which might occur during fasting, after exercise or postprandially, being precipitated by ingestion of a protein-rich meal. Congenital HH typically presents in newborn babies and infants as severe and persistent hypoglycemia, 2 in whom it is a major cause of hypoglycemic brain injury and mental retardation. 3 Mutations in seven different genes have been identified to date that lead to dysregulated insulin secretion. The histological differentiation of congenital HH into focal and diffuse forms marked an important turning point in the surgical approach to this disease. 4 6 If the focal lesion can be accurately located by preoperative imaging and completely resected, those with this form of the disease can now be cured. Advances in the development of 18 F-l-3,4- dihydroxyphenylalanine PET ( 18 F-l-DOPA-PET) scanning allow precise localization of the focal lesion and, in combination with laparoscopic surgery, have now completely transformed the management of these patients. 7,8 In adults, an insulinoma causes most cases of HH. Nevertheless, several conditions in which the clinical presentation is characterized mainly by postprandial HH have now been described in adults. This presentation occurs in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, 9 in those who have undergone gastric bypass surgery for morbid obesity 10 and in those with mutations in the insulin-receptor gene. 11 This Review provides an overview of the known causes of HH and describes some of the latest findings on the molecular genetics of congenital february 2009 vol 5 no 2 nature clinical practice ENDOCRINOLOGY & METABOLISM 101

2 Box 1 Differential diagnoses of hyperinsulinemic hypoglycemia. Congenital hyperinsulinemic hypoglycemia a Autosomal recessive mutations: ABCC8, KCNJ11, 17 HADH Autosomal dominant mutations: ABCC8, 23,24 KCNJ11, 24 CGK, 34 GLUD1, 33 HNF4A, 35,36 SLC16A1 b,50 Developmental syndromes 62 Postprandial hyperinsulinemic hypoglycemia Dumping syndrome 52 Following gastric bypass surgery in adults for obesity 7 Noninsulinoma pancreatogenous hypoglycemia 6 Insulin-receptor gene mutations 8 Insulin autoimmune syndrome 53 Insulinoma Sporadic insulinoma 65,66 Type 1 multiple endocrine neoplasia 65,66 Metabolic conditions Type 1a, 1b and 1d congenital disorders of glycosylation Type 1 tyrosinemia 109 Factitious hyperinsulinemic hypoglycemia 110 Other (usually transient) causes Maternal diabetes mellitus (gestational and insulin-dependent) Intrauterine growth restriction Perinatal asphyxia Rhesus isoimmunisation a Hereditary factors account for 50% of cases of hyperinsulinemic hyperglycemia. b Mutations in SLC16A1 cause exercise-induced hyperinsulinemic hyperglycemia. HH. We also outline how advances in radiology and laparoscopic surgery have transformed the clinical approach to patients with congenital HH. The known causes of HH are summarized in Box 1. CONGENITAL HYPERINSULINEMIC HYPOGLYCEMIA Congenital HH is an extremely complex and heterogeneous disorder in terms of clinical presentation, histology, molecular biology, and genetics. 12 Both sporadic and familial forms of congenital HH are known, with sporadic forms being relatively uncommon (incidence 1 case per 40,000 50,000 live births) and familial forms being relatively common (about 1 case per 2,500 in communities with high rates of consanguinity. 13 The genetic basis of congenital HH has begun to be unraveled: mutations in seven different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A) that lead to dysregulated insulin secretion have so far been identified. Mutations in ABCC8 and KCNJ11, which encode components of the pancreatic β-cell s ATP-sensitive potassium (K ATP ) channel, cause severe forms of congenital HH. Mutations in HNF4A, GLUD1, CGK and HADH lead to transient (HNF4A) or persistent HH, whereas mutations in SLC16A1 are related to exercise-induced HH. Mutations in all these genes combined, however, account for only 50% of the known cases of congenital HH. Molecular basis of congenital hyperinsulinemic hypoglycemia The severe forms of congenital HH are caused by mutations in genes that regulate key components of insulin secretion in pancreatic β-cells. Glucose-induced insulin secretion is regulated in part by K ATP channels of pancreatic β-cells. 14 In the pancreatic β-cell, the K ATP channel is composed of the inwardly rectifying potassium subunit (Kir6.2) and the sulfonylurea receptor 1 (SUR1), which couple changes in plasma glucose concentration to electrical excitability and insulin release. 15 Glucose metabolism in the pancreatic β-cell results in an increase in the intracellular ATP:ADP ratio, which in turn leads to cellmembrane depolarization, increased intracellular Ca 2+ entry via voltage-gated calcium channels, and insulin exocytosis. Figure 1 outlines the molecular mechanisms that regulate insulin secretion in pancreatic β-cells; Figure 2 summarizes the known genetic mutations that underlie these molecular mechanisms. Mutations that affect K ATP channels in pancreatic β-cells The SUR1 and Kir6.2 proteins are encoded by adjacent genes (ABCC8 and KCNJ11, respectively) located on chromosome 11p15.1. Recessive inactivating mutations in ABCC8 and KCNJ11 cause the most common and most severe forms of congenital HH Patients with mutations in these genes are usually unresponsive to medical therapy and may require pancreatectomy. The underlying molecular basis of congenital HH due to mutations in these genes includes defects in K ATP channel turnover, channel trafficking and alterations of channel sensitivity to nucleotides Autosomal-dominant mutations in ABCC8 and KCNJ11 cause mild, medically responsive HH. 23,24 In general, mutations in ABCC8 and KCNJ11 account for approximately 50% of the cases of congenital HH, but in some populations (e.g. in 102 nature clinical practice ENDOCRINOLOGY & METABOLISM KAPOOR ET AL. february 2009 vol 5 no 2

3 some Japanese patients) mutations of these two genes account for only 20% of cases. 25 Recessive inactivating mutations in ABCC8 and KCNJ11 are typically associated with the diffuse type of congenital HH. Typical diffuse disease is characterized by enlarged nuclei of pancreatic β-cells, although the degree of nuclear enlargement might show variation from one islet to another. 11 Other changes in the β-cells include an increase in quantity of proinsulin in the Golgi area and an increased amount of cytoplasm. 6 By contrast, the focal form of the disease is characterized by the presence of adenomatous hyperplasia confined to a single region of the pancreas. In the majority of cases this hyperplasia is macroscopically invisible; loci can be 2 10 mm in diameter. 4 6 The genetic basis of focal disease involves the paternal inheritance of a recessive ABCC8 or KCNJ11 mutation and the somatic loss of heterozygosity in the distal portion of the short arm of the maternal chromosome ,27 Somatic loss of heterozygosity represents the loss of normal function of one allele of a gene, the other allele of which was already inactivated in a cell (in this case, a pancreatic β-cell). Patients with focal, congenital HH might have more than one focal pancreatic lesion, which can be caused by a separate somatic maternal deletion of the 11p15.1 region. 28 Focal lesions are different from insulinomas (which are also called adenomas) in terms of their histology and molecular mechanisms of insulin secretion. 29 Some forms of congenital HH cannot be classified as focal or diffuse, 30,31 as pancreatic β-cells with nuclear enlargement are confined to discrete regions of the pancreas; this feature raises the possibility of mosaicism. Somatic mosaicism as a result of uniparental isodisomy in patients with ABCC8 (or KCNJ11) mutations leads to atypical diffuse disease. 32 Mutations that affect leucine and glucose metabolism in pancreatic β-cells Mutations in GLUD1 (encoding the glutamate dehydrogenase enzyme) and GCK (encoding the glucokinase enzyme) genes have been previously described and well characterized. 33,34 Activating mutations in GLUD1 lead to hyperinsulinism and hyperammonemia syndrome, which is the second most common forms of congenital HH. GLUD1 mutations diminish the inhibitory effect of GTP on glutamate dehydrogenase and facilitate its activation by leucine. The activation of glutamate dehydrogenase leads to increased oxidation of Glycolysis Glucose TCA cycle Secretory vesicles ATP: ADP ATP closes K ATP channel Ca 2+ initiates exocytosis Ca 2+ Insulin glutamate, and thereby increases the ATP:ADP ratio in the pancreatic β-cell. 33 GCK mutations affect the activity of glucokinase, which catalyzes the rate-limiting step in the metabolism of glucose and acts as the cellular sensor of glucose concentrations. Activating mutations in GCK lower the threshold for glucose-stimulated insulin secretion, which causes HH. 34 Mutations in the HNF4A gene Mutations in HNF4A (encoding the hepatocyte nuclear factor-4 α protein) have been identified to cause transient and persistent HH. 35,36 HNF4A has a key role in regulation of the multiple transcription-factor networks in pancreatic islets and, in combination with other hepatocyte nuclear factors (such as HNF1A), this protein has been suggested to form a functional regulatory loop in β-cells. 37 Mutations in the human ATP-gated K + channel Depolarization opens Ca 2+ channels Ca 2+ Figure 1 Outline of the molecular mechanisms that regulate insulin secretion in pancreatic β-cells. K ATP channels of β-cells have a key role in transduction of the metabolic signals generated from glucose metabolism into changes in plasma-membrane electrical activity and insulin secretion. Glucose metabolism in the pancreatic β-cell results in an increase in the intracellular ATP:ADP ratio, which leads to the closure of K ATP channels and subsequent cell-membrane depolarization. Depolarization results in increased Ca 2+ influx via voltage-gated calcium channels, which leads to the exocytosis of insulin. Abbreviation: TCA, tricarboxylic acid. february 2009 vol 5 no 2 KAPOOR ET AL. nature clinical practice ENDOCRINOLOGY & METABOLISM 103

4 Mutations in SLC16A1 Pyruvate Glucose Glucose-6-P TCA cycle β-oxidation Activating mutations in GCK α-ketoglutarate Glutamate Mutations in HADH Mutations in HNF4a Mutations in the ATP-gated K + channel genes (ABCC8 and KCNJ11) HNF4A gene are known to cause maturity-onset diabetes of youth (MODY), which is characterized by autosomal-dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic β-cells. 38 Heterozygous mutations in HNF4A were reported to cause transient or persistent HH associated with macrosomia, 35,36 but the underlying mechanism is still unclear. In mice, conditional inactivation and deletion of the Hnf4a gene in pancreatic β-cells leads to HH, but paradoxically also to impaired glucose tolerance. 39 These mice show a 60% reduction in the protein expression of Kir6.2, and cotransfection assays demonstrated that the Kir6.2 gene is a transcriptional target of Hnf4a. Two studies, however, reported? Activating mutations in GLUD1 Figure 2 Summary of the molecular mechanisms that lead to congenital hyperinsulinemic hypoglycemia. Recessive inactivating mutations in ABCC8 or KCNJ11 cause continuous β-cell membrane depolarization and subsequent calcium influx, which result in unregulated insulin secretion. Activating mutations in GLUD1 diminish the inhibitory effect of GTP on glutamate dehydrogenase and facilitate its activation by leucine. The activation of glutamate dehydrogenase causes increased oxidation of glutamate, thereby raising the ATP:ADP ratio in pancreatic β-cells, which leads to increased insulin secretion. Activating mutations in GCK lower the threshold for glucose-stimulated insulin secretion. The exact roles that HADH and HNF4A have in congenital HH is currently unclear, but HADH seems to be a negative regulator of insulin secretion. Dominant mutations in SLC16A1 increase the expression of MCT1R transporter, which allows pyruvate to act as an insulin secretagogue. Abbreviations: GCK, glucokinase (hexokinase 4); Glucose-6-P, glucose-6-phosphate; GTP, guanosine triphosphate. no change in expression of KCNJ11 in Hnf4adeficient mice, which suggests that the reduction in the expression of Kir6.2 might not be the only mechanism responsible for the HH in these mice. 35, 40 Haploinsufficiency of HNF4A probably results in a variety of phenotypes, ranging from macrosomia without HH to macrosomia with transient or persistent HH. Mutations that cause defective fatty-acid metabolism in pancreatic β-cells HADH, (previously known as short-chain l-3 hydroxyacyl-coenzyme A dehydrogenase, SCHAD), is a mitochondrial enzyme that catalyzes the penultimate step in β-oxidation of fatty acids the NAD+-dependent dehydrogenation of l-3 hydroxyacyl coenzyme A to the corresponding 3-ketoacyl-coenzyme A. Mutations that cause loss of function in the HADH gene are associated with congenital HH The molecular basis of how these mutations lead to dysregulated insulin secretion is currently unknown. However, several studies have shown that HADH has a pivotal role in regulation of insulin secretion 44,45 and that it interacts with other genes, which are known to be important for β-cell development and function. 46,47 In one study, suppression of HADH activity using small, interfering RNAs (sirna; small RNA molecules that interfere with transcriptional-specific RNAs within a cell) caused an increase in basal insulin secretion compared with that of untreated cells. 45 This study was the first to demonstrate that HADH is directly involved in the regulation of basal insulin release in β-cells. The addition of diazoxide, which blocks the ATP-sensitive potassium channel in the β-cell, did not alter the enhanced basal insulin secretion caused by suppression of HADH, which indicates that HADH regulates insulin secretion via pathways independent of the K ATP channel. In another study that used rat β-cells and the β-cell line INS , silencing of HADH expression resulted in increased insulin release at low and high glucose concentrations. These changes did not seem to be caused by increased rates of glucose metabolism or inhibition of fattyacid oxidation, 44 and indicated that the normal β-cell phenotype is characterized by a high expression of HADH and a low expression of other β-oxidation enzymes. Downregulation of HADH causes elevated insulin-secretory activity, which suggests that this enzyme protects individuals against inappropriately high insulin levels and hypoglycemia nature clinical practice ENDOCRINOLOGY & METABOLISM KAPOOR ET AL. february 2009 vol 5 no 2

5 Mutations that cause exercise-induced hyperinsulinemic hypoglycemia In exercise-induced HH, patients typically present with symptoms of hypoglycemia (syncope or disturbance of consciousness) within the 30 min after a short period of anaerobic exercise. Patients demonstrate a massive increase in insulin secretion after anaerobic exercise and demonstrate exaggerated insulin secretion in response to a pyruvate load. 48,49 The molecular basis of exercise-induced HH is increased expression of the plasma membrane monocarboxylate transporter 1 (MCT1) caused by mutations in the promoter region of the SLC16A1 gene. 50 The SLC16A1 promoter seems to be silenced by an unknown mechanism (possibly involving inhibitory transcription factors), which accounts for this increased basal transcriptional activity. These mutations lead to an increase in MCT1activity in the β-cells. Under normal conditions, expression of MCT1in pancreatic β-cells is very low, which minimizes the effects of pyruvate and lactate on insulin secretion. 51 Increased levels of MCT1protein in the β-cells will allow pyruvate (or lactate) to stimulate the β-cell s mitochondrial metabolism. 51 POSTPRANDIAL HYPERINSULINEMIC HYPOGLYCEMIA Postprandial HH refers to the development of hypoglycemia within a few hours of meal ingestion. This syndrome is associated with inappropriate insulin secretion in response to a meal, the most common presentation of which is the dumping syndrome in infants who have undergone gastroesophageal surgery. 52 Most other presentations of postprandial HH have been reported in adults. Postprandial HH also occurs in patients with insulin autoimmune syndrome, which is characterized by the presence of insulinbinding autoantibodies in individuals who have not been previously exposed to exogenous insulin. 53 Furthermore, postprandial HH has been described in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric bypass surgery for morbid obesity and in carriers of mutations in the insulin-receptor gene Noninsulinoma pancreatogenous hypoglycemia syndrome Noninsulinoma pancreatogenous hypoglycemia syndrome is characterized by postprandial HH in conjunction with pancreatic β-cell hyperfunction detected by selective arterial calcium stimulation tests, but without any evidence of an insulinoma in prolonged fasting tests or in perioperative investigations. 9 Histological features of noninsulinoma pancreatogenous hypoglycemia syndrome include β-cell hypertrophy characterized by enlarged and hyperchromatic β-cell nuclei (similar to the changes observed in diffuse congenital HH). 54,55 Patients with this syndrome do not carry mutations in ABCC8 and KCNJ11 and the molecular basis of this disease remains unknown. PPHH after gastric bypass surgery Gastric bypass surgery is an increasingly common therapy for patients with morbid obesity. 56 Several studies reported postprandial neuroglycopenic symptoms owing to endogenous HH in patients who underwent Roux-en-Y gastric bypass surgery. 10 Some investigators reported an increase in pancreatic islet size and pancreatic β-cell proliferation, whereas others observed no increase in either β-cell area or β-cell turnover. 57,58 The increased secretion of gastrointestinal hormones, such as glucagon-like peptide 1 (GLP-1), after gastric bypass surgery has been hypothesized to lead to increased β-cell proliferation, and to result in an enlarged β-cell mass. 57,59 PPHH in patients with insulin-receptor gene mutations Autosomal-dominant, postprandial HH that begins in adolescence or early adulthood has been observed in patients who carried a mutation (Arg1174Gln) in the insulin-receptor kinase gene. 60 A prolonged (5 h) oral glucosetolerance test demonstrates marked postprandial HH in these individuals, but hyperinsulinemic euglycemic clamp studies showed that affected patients had reduced insulin sensitivity and decreased clearance of serum insulin compared with control individuals. CLINICAL OVERVIEW Patients with HH present with symptoms of hypoglycemia due to unregulated insulin secretion. Age at presentation of HH is variable, and the severe forms typically present in the neonatal period. Newborn babies might present with nonspecific symptoms of hypoglycemia, such as poor feeding, lethargy and irritability, or specific symptoms, such as apnea, seizures or coma. Macrosomia, which is a common feature of congenital HH in newborn babies, results from fetal hyperinsulinemia. Nevertheless, february 2009 vol 5 no 2 KAPOOR ET AL. nature clinical practice ENDOCRINOLOGY & METABOLISM 105

6 not all babies with congenital HH have macrosomia. Those who carry mutations in HNF4A present with HH and macrosomia and have a family history of MODY. 35 Macrosomia is also a feature of Beckwith Weidemann syndrome (a developmental disorder characterized by excessive prenatal and postnatal growth, in addition to and various developmental anomalies) and several other developmental syndromes. 61 Mild forms of HH might present in late infancy or childhood along with recurrent symptoms of hypoglycemia. Perinatal asphyxia can lead to either transient or prolonged HH, and might require diazoxide treatment. 62 Symptoms of hypoglycemia generally develop after a relatively short period of fasting. Some patients with HH, however, demonstrate marked sensitivity to dietary protein (and leucine), and symptoms of hypoglycemia become manifest or aggravated following a protein-rich meal, rather than a fast. 33 Patients with exercise-induced HH typically present with symptoms of hypoglycemia within the 30 min period after a short period of anaerobic exercise. 50 In adults, symptoms of HH can be divided into those caused by hypoglycemiarelated, autonomic-nervous-system discharge, (which leads to hunger, sweating, paresthesia, anxiety, tremor and palpitations), and neuroglycopenic symptoms, such as behavioral changes, confusion, lethargy, blurred vision, change in personality, seizures and loss of consciousness, that result from glucose-deprivation of the central nervous system neurons. 63, 64 Adult-onset HH is usually caused by an insulinoma. The mean age at presentation is around 45 years; however, patients with insulinoma associated with type 1 multiple endocrine neoplasia usually present earlier, at around the age of 25 years. 65, 66 HH symptoms are typically evident the morning after an overnight fast. Patients generally learn to cope with these symptoms by frequent feeding, which results in weight gain. In rare cases, an insulinoma can cause postprandial HH, which is characterized by hypoglycemia after meal ingestion. 67 As mentioned before, postprandial hypoglycemia also occurs in patients with noninsulinoma pancreatogenous hypoglycemic syndrome, after gastric bypass surgery for severe obesity, and in those carrying mutations in the insulin-receptor gene. DIAGNOSIS The most important biochemical clue to the presence of unregulated insulin secretion is the patient s increased glucose requirement for maintenance of normoglycemia (>8 mg/kg min, normal range 4 6 mg/kg min). The biochemical diagnosis of HH is based on demonstration of an inappropriate insulin level (and/or inappropriate C-peptide level) during an episode of hypoglycemia. Corresponding levels of serum ketone bodies and fatty acids are low, which reflects the metabolic effects of insulin. 2 A normal level of insulin is abnormal if it occurs in the face of hypoglycemia, especially in the context of high glucose requirement to maintain normoglycemia. 2 In children with hyperinsulinism and hyperammonemia syndrome, plasma ammonia levels are raised. 33 In some patients with protein-sensitive congenital HH owing to GLUD1 mutations, a leucine provocation test might be required to demonstrate HH. 68 Analyses of urinary organic acids and acylcarnitine should also be performed, as results could aid in the diagnosis of HADH deficiency. 41 Serum glucagon levels are decreased in congenital HH. 69 Patients with HH demonstrate a positive glycemic response (a rise in blood glucose level of >1.5 mmol/l) to intramuscularly or intravenously administered glucagon during times of hypoglycemia. 70 Decreased serum levels of insulin-like growth-factor binding protein 1 (IGFBP-1) aid the diagnosis in some patients, because insulin suppresses transcription of the IGFBP1 gene. 71 Patients with exercise-induced HH will require an exercise provocation test and/or a pyruvate load to induce hypoglycemia. 49 In adults with symptoms of neuroglycopenia or a documented low blood glucose level, a 72 h fast can elucidate the cause of hypoglycemia. This prolonged fasting test can detect up to 99% of insulinomas. 72 The fast will end earlier than 72 h if the patient develops the above mentioned symptoms with concomitant low blood glucose level ( 2.5 mmol/l). 72 Elevated plasma insulin levels with undetectable C-peptide levels indicate exogenous insulin administration. In the case of factitious hypoglycemia due to administration of sulfonylureas, the levels of all β-cell polypeptides are raised; therefore, plasma and urine measurement of sulfonylureas is recommended for all patients in whom the cause of HH is not clear. In all adults with HH, measurement of insulin antibodies is also essential, to rule out insulin autoimmune syndrome. 73 Patients with postprandial HH do not exhibit symptoms after fasting tests, but hypoglycemia can be provoked by an oral glucose tolerance test or by a mixed-meal 106 nature clinical practice ENDOCRINOLOGY & METABOLISM KAPOOR ET AL. february 2009 vol 5 no 2

7 provocation test. 74,75 No consensus exists on the best method with which to investigate postprandial HH. The oral glucose tolerance test, in particular, is often followed by a physiological dip in blood glucose level, which might lead to misdiagnosis. Nevertheless, accompanying biochemical evidence of endogenous hyperinsulinemia and symptoms of neuroglycopenia during a hypoglycemic episode (either spontaneous or following provocation) can help clinicians to distinguish between pathological postprandial HH and reactive hypoglycemia. In patients with suspected noninsulinoma pancreatogenous hypoglycemia syndrome, a selective arterial calcium stimulation test is recommended. 9 Patients with insulin-receptor gene mutations demonstrate fasting hyperinsulinemia, an elevated serum insulin:c-peptide ratio and postprandial HH on a prolonged (5 h) oral glucose-tolerance test. 60 MEDICAL MANAGEMENT Rapid diagnosis, avoidance of recurrent episodes of hypoglycemia and prompt management of hypoglycemia are the cornerstones of management to prevent brain damage and mental retardation in patients with congenital HH. The mainstay of medical therapy is the provision of large amounts of carbohydrates to maintain normoglycemia. This treatment often requires insertion of a central venous catheter to administer concentrated solutions of dextrose and enable frequent monitoring of blood glucose levels. Specific medical therapy includes the use of diazoxide (in combination with a diuretic), nifedipine, glucagon and octreotide. 2 Diazoxide is an agonist of the K ATP channel and is usually effective in all forms of diffuse congenital HH, except for those caused by autosomal recessive mutations in the ABCC8 and KCNJ11 genes. A few patients with mutations in the CGK gene require subtotal pancreatectomy. 76 Nifedipine is a calcium-channel antagonist that has been successfully used in some patients with congenital HH; 77 however, in the vast majority of patients this drug is ineffective. Focal forms of congenital HH are generally unresponsive to diazoxide. Octreotide and glucagon are used to stabilize the patient until the clinician has planned the next stage of investigation or management. Some infants with congenital HH, however, are managed with longterm octreotide therapy. 78 Figure 3 outlines diagnostic and management algorithms for patients with congenital HH. Establish diagnosis of congenital hyperinsulinemic hypoglycemia: Glucose infusion rate >8 mg/kg min 1 Blood glucose <3 mmol/l Detectable insulin and/or C-peptide Undetectable or low ketone bodies Undetectable or low fatty acids Raised serum ammonia Positive glycemic response to glucagon Abnormal serum acylcarnitines and/or urine organic acids Hypoglycemia after a protein or leucine load Hypoglycemia after exercise test or pyruvate load Responsive Assess fasting tolerance and discharge Assess response to diazoxide therapy Paternal ABCC8 and/or KCNJ11 mutations (highly indicative of focal lesion), or no mutations in ABCC8/ KCNJ11 (focal lesion unlikely) 18 F-L-DOPA-PET CT scan Focal disease Surgical resection of focal lesion (preferably by laparoscopic surgery Follow-up: Assessment of growth and development Neurological assessment Genetic counselling After near-total pancreatectomy: Management of diabetes mellitus Monitoring pancreatic exocrine function Unresponsive Rapid screening for ABCC8 and KCNJ11 mutations Homozygosity or compound heterozygosity a for ABCC8 and/or KCNJ11 mutations (indicative of diffuse disease) Diffuse disease High calorie diet and/or frequent feeds Octreotide therapy Near-total pancreatectomy Figure 3 Outline of a diagnostic and management algorithm for patients with congenital hyperinsulinemic hypoglycemia. 18 F-l-DOPA-PET CT examination is only indicated in patients who potentially have a focal lesion (i.e. those with a paternal ABCC8 or KCNJ11 gene mutation, or those in whom the genetic basis of the disease is unknown). This imaging examination is not indicated in patients with genetically confirmed diffuse disease. a In compound heterozygosity, the patient inherits two recessive alleles (either in ABCC8 or KCNJ11) that can cause congenital hyperinsulinemic hypoglycemia in a heterozygous state. Abbreviation: 18 F-l-DOPA-PET CT, 18 F-l-3,4-dihydroxyphenylalanine PET CT. february 2009 vol 5 no 2 KAPOOR ET AL. nature clinical practice ENDOCRINOLOGY & METABOLISM 107

8 1[ Head of pancreas SUV 3,1 Body of pancreas SUV 5,3 Tail of pancreas Figure 4 An 18 F-l-DOPA-PET scan of a focal lesion in the tail of the pancreas. The standard uptake value of the 18 F-DOPA is higher in the tail region than the body and head of the pancreas. The focal lesion (indicated by a box and 1) measured approximately 5.1 mm in diameter. This patient underwent laparoscopic resection of the focal lesion with complete cure. Abbreviations: 18 F-l-DOPA-PET, 18 F-l-3,4-dihydroxyphenylalanine PET; SUV, standard uptake value. Advances in the management of congenital hyperinsulinemic hypoglycemia 18 F-l-DOPA-PET imaging The histological distinction between focal and diffuse congenital HH has important therapeutic implications, as patients with the focal form of the disease can be completely cured by partial pancreatectomy. Preoperative identification and precise anatomical localization of focal lesions are therefore fundamentally important. Advances in 18 F-l-DOPA-PET imaging have changed the diagnostic approach to these patients. 7,79 81 The use of this radiological technique is based on the fact that pancreatic islets take up l-dopa and convert it into dopamine by the aromatic amino acid decarboxylase. The uptake of the positronemitting tracer 18 F-l-DOPA is augmented in β-cells with an increased rate of insulin synthesis and secretion, compared with unaffected areas. 82 Dopamine receptors are expressed in pancreatic β-cells, which suggests that these receptors have a role in regulation of insulin secretion. 83 The detection limit of 18 F-l-DOPA-PET imaging is equivalent to cells, or a diameter of approximately 1 mm. 84 The sensitivity of this technique for detecting focal lesions varies between 88% and 94%, with a specificity of 100%. 81,85 The introduction of integrated 18 F-l-DOPA-PET CT technique has allowed for increased precision in the preoperative visualization of the focal lesion. 7 The new 18 F-l-DOPA-PET CT technique allows the splenic artery, portal vein, superior mesenteric and inferior mesenteric arteries to be seen as well as the duodenum, and enables exact anatomical and functional descriptions of the pancreatic focus. 7 Ectopic focal lesions can also be detected by 18 F-l -DOPA-PET. 86,87 Rapid genetic screening for mutations in ABCC8 and KCNJ11 allows clinicians to identify patients who might have a focal lesion (i.e. those with a paternal ABCC8 or KCNJ11 mutation). 88 If a paternal ABCC8 (or KCNJ11) mutation is identified, then a 18 F-l-DOPA-PET scan is indicated to allow precise preoperative localization of the focal lesion. Patients with genetically confirmed diffuse disease do not require routine 18 F-l-DOPA-PET imaging. Figure 4 shows an 18 F-l-DOPA-PET scan of a focal lesion in the tail of the pancreas. Laparoscopic surgery Patients with the focal form of congenital HH require partial pancreatectomy, whereas patients with diffuse congenital HH who do not respond to medical therapy require near-total pancreatectomy. 89 These operations are traditionally carried out via an open approach and are associated with perioperative and postoperative complications. 90 Laparoscopy is a new approach to the diagnosis and management of patients with congenital HH. 91 This method of pancreatectomy is preferred by many clinicians, as it is quicker and associated with less operative trauma and faster postoperative recovery than traditional open pancreatectomy. 8 Laparoscopic exploration for focal lesions in congenital HH has been used to locate and excise the focal area. 8,92 Laparoscopic surgery in combination with 18 F-l-DOPA-PET CT has proved to be a very powerful technique for removing focal lesions around the tail region of the pancreas. 81 Lesions in the head of the pancreas, however, might not be amenable to this surgical approach. Laparoscopic subtotal pancreatectomy has been described in one patient with diffuse disease. 93 Management of insulinoma and postprandial hyperinsulinemic hypoglycemia in adults In adults, insulinoma-localization studies are carried out following the biochemical diagnosis of endogenous HH. A high percentage of insulinomas can be identified intraoperatively by an experienced surgeon, often with the aid of intraoperative ultrasonography. Nevertheless, 108 nature clinical practice ENDOCRINOLOGY & METABOLISM KAPOOR ET AL. february 2009 vol 5 no 2

9 even in the most experienced hands, 10 20% of insulinomas may not be identified during surgical exploration. Preoperative localization of the insulinoma is therefore desirable, because it helps surgical planning and reduces the operative time, with consequent reduction in morbidity. Various imaging techniques, including transabdominal ultrasound, CT, MRI, somatostatin receptor scanning, angiography and venous sampling, have been used to help localize insulinomas. 94,95 Although initial studies on the use of these modalities reported disappointing sensitivities, recent advances, particularly in MRI and CT, have resulted in a significant improvement in the tumor detection rate. 96,97 In addition, endoscopic ultrasonography has been reported to have a high sensitivity for detection and localization of an insulinoma and is gaining popularity as a primary diagnostic tool. 98 A novel technique that has been reported as successful in two patients with occult insulinomas is the glucagon-like peptide 1 receptor (GLP1R) scan. 99 This scan is based on the principle that nearly all insulinomas overexpress GLP1R, and in vitro studies of insulinoma in mice have demonstrated that GLP1-like radioligands target insulinomas satisfactorily. 100 These findings indicate that GLP1R scanning might offer a new diagnostic approach to localization of occult insulinomas. Partial resection of the pancreas is the most widely used approach to management of patients with noninsulinoma pancreatogenous hypoglycemia syndrome. 9 Recommendations vary on how much pancreatic resection is optimal. Although partial pancreatectomy might need to be followed by a second operation, it is preferred to near-total pancreatectomy, which results in lifelong diabetes mellitus. 101 In some patients with noninsulinoma pancreatogenous hypoglycemia syndrome, treatment with diazoxide has been reported as successful. 54 Patients who develop postprandial HH after gastric bypass surgery are managed by a low-carbohydrate diet, α-glucosidase inhibitors, calcium-channel blockers, reversal of gastric restoration and distal pancreatectomy CONCLUSIONS HH is caused by unregulated secretion of insulin. Mutations in ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A genes can lead to congenital HH. The availability of rapid genetic screening (for mutations in ABCC8 and KCNJ11), in the context of an understanding of the histological basis of focal and diffuse congenital HH and the introduction of 18 F-l-DOPA-PET CT and laparoscopic surgery have totally transformed the clinical approach to patients with congenital HH. Adult-onset HH is usually caused by an insulinoma, but can be also caused by noninsulinoma pancreatogenous hypoglycemia syndrome, gastric bypass surgery for morbid obesity, and mutations in the insulin-receptor gene. Key points Hyperinsulinemic hypoglycemia is a consequence of unregulated insulin secretion by pancreatic β-cells and is a major cause of brain injury and mental retardation in children Congenital hyperinsulinemic hypoglycemia is caused by mutations in key genes that are involved in the regulation of insulin secretion, seven of which have been so far identified: ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A Rapid genetic screening for mutations in ABCC8 and KCNJ11 combined with recent advances in 18F-l-DOPA-PET CT imaging and laparoscopic surgery have transformed the management of children with focal congenital hyperinsulinemic hypoglycemia 18F-l-DOPA-PET CT scans enable accurate preoperative localization of pancreatic focal lesions focus and hence offer the prospect of cure by partial pancreatectomy An insulinoma accounts for the majority of the cases of adult-onset hyperinsulinemic hypoglycemia and, in 99% of cases, is detectable by a prolonged fast Postprandial hyperinsulinemic hypoglycemia in adults can be cause by noninsulinoma pancreatogenous hypoglycemia syndrome, gastric bypass surgery for morbid obesity, or mutations in the insulin receptor gene References 1 Hussain K et al. (2007) Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management. Arch Dis Child 92: Aynsley-Green A et al. (2000) Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 82: F98 F107 3 Menni F et al. (2001) Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 107: Kloppel G et al. (1975) The ultrastructure of focal islet cell adenomatosis in the newborn with hypoglycemia and hyperinsulinism. Virchows Arch A Pathol Anat Histol 366: february 2009 vol 5 no 2 KAPOOR ET AL. nature clinical practice ENDOCRINOLOGY & METABOLISM 109

10 5 Goossens A et al. (1989) Diffuse and focal nesidioblastosis: a clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 13: Rahier J et al. (2000) Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 82: F108 F112 7 Otonkoski T et al. (2006) Noninvasive diagnosis of focal hyperinsulinism of infancy with 18 F-DOPA positron emission tomography. Diabetes 55: de Vroede M et al. (2004) Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 114: Service FJ (1999) Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 84: Service GJ (2005) Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 353: Højlund K et al. (2004) A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 53: de Lonlay P (2002) Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr 161: Glaser B et al. (2000) Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 82: F79 F86 14 Ashcroft FM et al. (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312: Aguilar-Bryan L et al. (1999) Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 20: Thomas PM et al. (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268: Thomas PM et al. (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5: Nestorowicz A et al. (1996) Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5: Dunne MJ et al. (1997) Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 336: Kane C et al. (1996) Loss of functional K ATP channels in pancreatic beta-cells causes persistent hyperinsulinaemic hypoglycemia of infancy. Nat Med 2: Cartier EA et al. (2001) Defective trafficking and function of K ATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci USA 98: Matsuo M et al. (2000) Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy. J Biol Chem 275: Huopio H et al. (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106: Pinney SE et al. (2008) Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant K ATP channel mutations. J Clin Invest 118: Tanizawa Y et al. (2000) Genetic analysis of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Diabetes 49: de Lonlay P et al. (1997) Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 100: Verkarre V et al. (1998) Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 102: Giurgea I et al. (2006) The Knudson s two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism. J Clin Endocrinol Metab 91: Sempoux C et al. (2003) The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Diabetes 52: Suchi M et al. (2003) Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 6: Jack MM et al. (2000) Histologic findings in persistent hyperinsulinemic hypoglycemia of infancy: Australian experience. Pediatr Dev Pathol 3: Hussain K et al. (2008) An ABCC8 gene mutation and mosaic uniparental isodisomy resulting in atypical diffuse congenital hyperinsulinism. Diabetes 57: Stanley CA (2004) Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 81 (Suppl 1): S45 S51 34 Christesen HB et al. (2008) Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Eur J Endocrinol 159: Pearson ER et al. (2007) Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4: e Kapoor R et al. (2008) Persistent hyperinsulinaemic hypoglycaemia and maturity-onset diabetes of the young (MODY) due to heterozygous HNF4A mutations. Diabetes 57: Boj SF et al. (2001) A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA 98: Yamagata K et al. (1996) Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384: Gupta RK et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115: Miura A et al. (2006) Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem 281: Clayton PT et al. (2001) Hyperinsulinism in short-chain l-3-hydroxyacyl-coa dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108: nature clinical practice ENDOCRINOLOGY & METABOLISM KAPOOR ET AL. february 2009 vol 5 no 2

11 42 Hussain K et al. (2005) Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr 146: Molven A et al. (2004) Familial hyperinsulinaemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: Martens GA et al. (2007) Specificity in beta cell expression of l-3-hydroxyacyl-coa dehydrogenase, short chain, and potential role in down-regulating insulin release. J Biol Chem 282: Hardy OT et al. (2007) Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K + currents. Mol Endocrinol 21: Lantz KA et al. (2004) Foxa2 regulates multiple pathways of insulin secretion. J Clin Invest 114: Sund NJ et al. (2001) Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev 15: Meissner T et al. (2005) Massive insulin secretion in response to anaerobic exercise in exercise-induced hyperinsulinism. Horm Metab Res 37: Otonkoski T et al. (2003) Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomaldominant trait characterized by abnormal pyruvateinduced insulin release. Diabetes 52: Otonkoski T et al. (2007) Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 81: Ishihara H et al. (1999) Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. J Clin Invest 104: Bufler P et al. (2001) Dumping syndrome: a common problem following Nissen fundoplication in young children. Pediatr Surg Int 17: Hirata Y (1973) Insulin autoimmune syndrome. Nippon Rinsho 31: Won JG et al. (2006) Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS). Clin Endocrinol (Oxf) 65: Sahloul R et al. (2007) Noninsulinoma pancreatogenous hypoglycemia syndrome: quantitative and immunohistochemical analyses of islet cells for insulin, glucagon, somatostatin, and pancreatic and duodenal homeobox protein. Endocr Pract 13: Steinbrook R (2004) Surgery for severe obesity. N Engl J Med 350: Patti ME et al. (2005) Severe hypoglycaemia postgastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia 48: Meier JJ et al. (2006) Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care 29: Cummings DE (2005) Gastric bypass and nesidioblastosis: too much of a good thing for islets? N Engl J Med 353: Højlund K et al. (2004) A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 53: Kapoor R et al. Hyperinsulinism in developmental syndromes. Endocr Dev, in press 62 Hoe FM et al. (2006) Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 148: Cryer PE (1999) Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am 28: DeRosa MA and Cryer PE (2004) Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. Am J Physiol Endocrinol Metab 287: E32 E41 65 Jani N et al. (2007) Pancreatic endocrine tumors. Gastroenterol Clin North Am 36: Oberg K and Eriksson B (2005) Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol 19: Connor H and Scarpello JH (1979) An insulinoma presenting with reactive hypoglycaemia. Postgrad Med J 55: Hsu BY et al. (2001) Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/ hyperammonemia syndrome. J Pediatr 138: Hussain K et al. (2005) Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes 54: Finegold DN et al. (1980) Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 96: Levitt Katz LE et al. (1997) Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr 131: Service FJ and Natt N (2000) The prolonged fast. J Clin Endocrinol Metab 85: Basu A et al. (2005) Insulin autoimmunity and hypoglycemia in seven white patients. Endocr Pract 11: Thompson GB et al. (2000) Noninsulinoma pancreatogenous hypoglycemia syndrome: an update in 10 surgically treated patients. Surgery 128: Tsujino M et al. (2005) Noninsulinoma pancreatogenous hypoglycemia syndrome: a rare case of adult-onset nesidioblastosis. Intern Med 44: Cuesta-Munoz et al. (2004) Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53: Bas F et al. (1999) Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab 12: Glaser B et al. (1993) Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 123: Ribeiro MJ et al. (2005) Characterization of hyperinsulinism in infancy assessed with PET and 18 F-fluoro-l-DOPA. J Nucl Med 46: Mohnike K et al. (2006) Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res 66: Mohnike K et al. (2008) [18F]-DOPA positron emission tomography for preoperative localization in congenital hyperinsulinism. Horm Res 70: de Lonlay P et al. (2006) CHH: pancreatic [18F]fluorol-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion. J Clin Endocrinol Metab 91: february 2009 vol 5 no 2 KAPOOR ET AL. nature clinical practice ENDOCRINOLOGY & METABOLISM 111