Pathological features in non-neoplastic congenital and adult hyperinsulinism: from nesidioblastosis to current terminology and understanding

in Endocrine-Related Cancer
Authors:
Christine Sempoux Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

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Günter Klöppel Department of Pathology, Technical University Munich, Munich, Germany

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Correspondence should be addressed to C Sempoux: christine.sempoux@chuv.ch
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Nesidioblastoma and nesidioblastosis were terms given to neoplastic and non-neoplastic lesions of the pancreas associated with pancreatogenous hyperinsulinaemic hypoglycaemia. While nesidioblastoma was rapidly replaced by islet cell tumour, nesidioblastosis, defined as the proliferation of islet cells budding off from pancreatic ducts, was the diagnostic term associated with congenital hyperinsulinism of infancy (CHI) and adult non-neoplastic hyperinsulinaemic hypoglycaemia (ANHH). When it was shown that nesidioblastosis was not specific for CHI or ANHH, it was no longer applied to CHI but kept for the morphological diagnosis of ANHH. In severe CHI cases, a diffuse form with hypertrophic ß-cells in all islets can be distinguished from a focal form with hyperactive ß-cells changes in a limited adenomatoid hyperplastic area. Genetically, mutations were identified in several ß-cell genes involved in insulin secretion. Most common are mutations in the ABCC8 or KCNJ11 genes, solely affected in the diffuse form and associated with a focal maternal allelic loss on 11p15.5 in the focal form. Focal CHI can be localized by 18F-DOPA-PET and is thus curable by targeted resection. Diffuse CHI that fails medical treatment requires subtotal pancreatectomy. In ANHH, an idiopathic form can be distinguished from a form associated with gastric bypass, in whom GLP1-induced stimulation of the ß-cells is discussed. While the ß-cells in idiopathic ANHH are diffusely affected and are either hypertrophic or show only little changes, it is controversial whether there is a ß-cell increase or ß-cell hyperactivity in patients with gastric bypass. Recognizing morphological signs of ß-cell hyperactivity needs a good knowledge of the non-neoplastic endocrine pancreas across all ages.

Abstract

Nesidioblastoma and nesidioblastosis were terms given to neoplastic and non-neoplastic lesions of the pancreas associated with pancreatogenous hyperinsulinaemic hypoglycaemia. While nesidioblastoma was rapidly replaced by islet cell tumour, nesidioblastosis, defined as the proliferation of islet cells budding off from pancreatic ducts, was the diagnostic term associated with congenital hyperinsulinism of infancy (CHI) and adult non-neoplastic hyperinsulinaemic hypoglycaemia (ANHH). When it was shown that nesidioblastosis was not specific for CHI or ANHH, it was no longer applied to CHI but kept for the morphological diagnosis of ANHH. In severe CHI cases, a diffuse form with hypertrophic ß-cells in all islets can be distinguished from a focal form with hyperactive ß-cells changes in a limited adenomatoid hyperplastic area. Genetically, mutations were identified in several ß-cell genes involved in insulin secretion. Most common are mutations in the ABCC8 or KCNJ11 genes, solely affected in the diffuse form and associated with a focal maternal allelic loss on 11p15.5 in the focal form. Focal CHI can be localized by 18F-DOPA-PET and is thus curable by targeted resection. Diffuse CHI that fails medical treatment requires subtotal pancreatectomy. In ANHH, an idiopathic form can be distinguished from a form associated with gastric bypass, in whom GLP1-induced stimulation of the ß-cells is discussed. While the ß-cells in idiopathic ANHH are diffusely affected and are either hypertrophic or show only little changes, it is controversial whether there is a ß-cell increase or ß-cell hyperactivity in patients with gastric bypass. Recognizing morphological signs of ß-cell hyperactivity needs a good knowledge of the non-neoplastic endocrine pancreas across all ages.

Introduction

In 1935, Virginia Frantz classified the islet tumours which Allen Whipple had removed from hypoglycaemic patients as islet cell adenomas (Whipple & Frantz 1935). In 1938, George Laidlaw performed a microscopic study in these tumours and investigated their origin. He suggested that the tumour cells, like those of normal islets of Langerhans, differentiate out of the duct epithelium, and therefore called these cells as nesidioblasts, referring to the Greek words ‘nesidion’ for islet and ‘blastos‘ for builder. Consequently, he then gave the tumours that emerged from nesidioblasts the name nesidioblastoma and suggested the name nesidioblastosis for the extrainsular diffuse or disseminated proliferation of islet cells within the pancreas (Laidlaw 1938). While nesidioblastoma could not prevail against the term ‘islet cell tumours’, the term ‘nesidioblastosis’ is still used as a descriptive term for the various non-neoplastic, duct-associated islet changes found in the pancreas of patients with no clinical pancreatic diseases or as diagnostic term in adults with non-neoplastic hyperinsulinaemic hypoglycaemia (ANHH). In neonates and infants with persistent hyperinsulinaemic hypoglycaemia, nesidioblastosis is no longer in use since it was not considered correct (Palladino & Stanley 2011), and it has been replaced by the collective term ‘congenital hyperinsulinism of infancy’ (CHI).

This review focuses on CHI and ANHH, which are the two non-neoplastic conditions among the diseases that can be summarized under the heading of ‘Persistent Pancreatogenous Hyperinsulinaemic Hypoglycaemia’ (PPHH). Related to the number of resection samples, CHI and ANHH are much less common than the neoplastic diseases that include solitary and multifocal insulinoma (Table 1). While the non-neoplastic PPHH conditions occur in both early childhood and adulthood, the neoplastic PPHH diseases are largely restricted to adulthood. Before CHI and ANHH are discussed in detail regarding their histopathological features, we present the anatomical structures and changes of the endocrine pancreas whose knowledge is essential for the morpho-functional interpretation and diagnosis of the β-cell alterations characterizing CHI and ANHH. Thus, our first objective is to describe the islet types and endocrine cell clusters of the pancreas and their age-related quantitative changes. The second objective is to define islet hyperplasia and islet aggregation and the diseases in which they play a role. The third objective is then to relate the different β-cell changes in infants with CHI to the genetic alterations. Finally, the spectrum of β-cell changes that is associated with idiopathic or gastric bypass ANHH will be discussed.

Table 1

Clinico-pathological features of pancreatogenous lesions in hyperinsulinaemic hypoglycaemia.

Disease type Congenital hypoglycaemia of infancy (CHI) Adult hyperinsulinaemic hypoglycaemia (ANHH) Insulinoma
 Subtypes  Diffuse form  Idiopathic  Solitary
 Focal formb  Gastric bypass associated  Multifocal
 Atypical form   MEN1-associated
 Syndromic form, i.e., BWS   MAFA-relatedc
  Idiopathic
Pathogenesis Non-neoplastic Non-neoplastic Neoplastic
Frequencya Rare Very rare Rare
Age Infancy (childhood rare) Adulthood Adulthood (childhood rare)
Cause Gene alteration Gene alteration/acquired Somatic or germline mutations
Histopathology β-cell hypertrophy/focal hyperplasiab β-cell hypertrophy Tumour cells
Functional defect Glucoreceptor defect Glucoreceptor defect Dedifferentiation
Treatment Medical/surgical Medical/surgical Surgical

aRelated to number of resections performed; bsurgical treatment required; cMAFA (MAF BZIP Transcription Factor A)-related insulinomatosis (Iacovazzo et al. 2018).

BWS, Beckwith-Wiedemann syndrome; MEN1, multiple endocrine neoplasia type 1.

Islet types, small endocrine clusters, and their quantification in the normal pancreas

Prerequisite for any discussion of islet changes in the pancreas head is the knowledge of the presence of two types of islet. The first type was described by Langerhans and accounts for 80% to 90% of all islets. The islets of this type are round to oval and can therefore be called ‘compact islets’ (Fig. 1A and B). Compact islets are found everywhere in the pancreas except for the inferior-dorsal part of the pancreatic head, which accounts only for about 10–20% of the pancreatic volume. This inferior-dorsal part of the pancreatic head harbours the second islet type, which is characterized by an irregularly shaped outline and a distinct trabecular pattern and can be described as ‘meandering islet type’ (Fig. 1C and D). Both the compact and the meandering islets contain the four endocrine cell types of the pancreas, but the compact islet is mainly (60–80%) composed of insulin cells, followed by glucagon (15–20%), somatostatin (5–10%), and pancreatic polypeptide (PP) cells (<2%) (Stefan et al. 1982, Solcia et al. 1997, Hruban et al. 2007, Klimstra et al. 2007), while in the meandering islets the PP cells dominate (up to 80%) (Albers et al. 2014). Because of the many PP cells, the islets in the inferior-dorsal portion of the pancreatic head are called ‘PP-islets’ and the area, where they occur, ‘PP-lobe’. Embryologically, this lobe represents the ventral pancreas, while the remaining part of the pancreas with its compact islets corresponds to the dorsal pancreas. In elderly people, in whom the PP-lobe often shows a slight atrophy of the acinar cells, the PP-islets seem to increase in size and assume a tumour-like arrangement (Albers et al. 2014, Klöppel et al. 2014). Morphologically, these changes in the PP-lobe can be mistaken as islet hyperplasia or infiltrating neuroendocrine tumour. The latter misdiagnosis can be avoided by immunostaining the structure not only for PP but also for other islet hormones (Klöppel et al. 2014). Radiologically, the density of the PP-islets in the PP-lobe can be misinterpreted in somatostatin receptor imaging as neuroendocrine tumour in the uncinate process (Albers et al. 2014).

Figure 1
Figure 1

The normal pancreas. (A–B) Compact islet type, haematoxylin–eosin (A) and insulin immunohistochemistry (B). (C–D) Meandering islet type, haematoxylin–eosin (C) and pancreatic polypeptide immunohistochemistry (D). (E) Pancreas, lower power (haematoxylin–eosin) compact islet type between exocrine acini. (F) Pancreas, lower power (chromogranin immunohistochemistry): illustration of nesidioblastosis: isolated endocrine cells and small endocrine aggregates sometimes close to ducts, scattered in the exocrine pancreas, outside of islets.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0034

Apart from the clearly visible islets of Langerhans (Fig. 1E), the pancreatic tissue harbours small clusters of endocrine cells and even isolated cells between the acinar cells or as ductuloinsular complexes associated with the ducts. These nesidioblastotic features can be seen in the adult pancreas and are even more pronounced in the neonate pancreas. They usually need immunostaining for pancreatic hormones or neuroendocrine markers to be clearly identified (Fig. 1F). Studying the frequency of immunostained clusters, Rahier found that in pancreases of neonates, the number of small extrainsular clusters of β-cell between acini and associated with ductular epithelium is higher than in children and adults. These latter findings which confirmed previous and further results by other groups (Jaffe et al. 1980, Falkmer et al. 1981) demonstrated that increased numbers of nesidioblastotic foci which were regarded as the leading abnormality in CHI was a normal finding in the neonatal pancreas.

In adults, the islets account for approximately 1–2% of the total pancreatic cell mass and vary in size, from 50 to 280 μm. When islets of newborns and infants are quantitatively examined, the age must be considered. An islet volume that may represent hyperplasia in an adult could be normal in an infant. Indeed, Rahier et al. studied by morphometry and immunohistochemistry the amount and distribution of the different cell types of the endocrine pancreas in normoglycaemic neonates (<15 days) and compared the data with those in infants (6 months) and in adults to have a solid reference for the morphological studies in CHI. He showed that the volume density of the endocrine tissue is 15% in neonates, dropping to 6–7% in infants and to 2–3% in adults, combined with a decrease in somatostatin cells (from 30% to 10%), an increase in insulin cells (from 50% to 70%), and a stable proportion of glucagon cells (Rahier et al. 1980, 1981).

Islet hyperplasia and islet aggregation: definition and current use

Islet hyperplasia

Islet hyperplasia is commonly used in pancreatic pathology to describe a focal or diffuse increase in islets based on a subjective estimate. Strictly speaking, however, islet hyperplasia is a morphometric term which denotes a quantifiable increase in islet tissue resulting from an increase in islet cell size, called islet cell hypertrophy, and/or islet cell number, called islet cell hyperplasia. Usually, islet cell hyperplasia and islet cell hypertrophy go hand in hand.

Islet hyperplasia and islet cell hypertrophy, morphometrically verified, is found in newborns of mothers with badly or uncontrolled diabetes. The entire pancreas of these babies shows islet hyperplasia with an increase in hypertrophic β-cells and lacks any significant nesidioblastosis. The stimulus for these changes is the mother’s elevated glucose level, which is transferred via placenta to the fetus and the islets changes represent a hyperactive state resulting from this hyperglycaemia.

Another example of extreme islet hyperplasia and hypertrophy is found in patients with a genetically defective glucagon receptor (see article by Sipos in this volume). In this condition, the small islets look normal, but the bigger islets display an increase in glucagon cells that correlates in its extent with the islet diameter (Henopp et al. 2009). The largest islets then imperceptibly transform into glucagon cell neoplasms. The disease is therefore called glucagon cell hyperplasia and neoplasia (Sipos et al. 2015).

Extreme islet hyperplasia, probably due to stimulation by insulin-like growth factor 2 (IGF2), can occur in the Beckwith–Wiedemann syndrome (BWS) and may be associated with hyperinsulinism. BWS is caused by genetic and epigenetic defects on 11p15.5. The pancreas is typically increased in size and shows massive diffuse islet hyperplasia with abnormally large and sometimes confluent islets (Fig. 2). They are often clustered in the centre of the pancreatic lobules and surrounded by a rim of acinar cells (Stefan et al. 1985). They may also be associated with cystic duct changes.

Figure 2
Figure 2

Beckwith–Wiedemann syndrome. Islet and insulin-cell hyperplasia.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0034

Islet aggregation

Islet aggregation may occur in all conditions of the pancreas in which acinar tissue is replaced by fibrosis as in chronic pancreatitis or cystic fibrosis. This change should not be called islet hyperplasia since it is a localized and not a generalized change in the fibrotic pancreas. Islet aggregation is a clustering of differently sized islets in areas of severe fibrosis and exocrine atrophy (Klöppel et al. 1978) due to the loss of acinar cells and their replacement by fibrosis during the evolution of chronic pancreatitis (Fig. 3A). Pathogenetically, the loss of acinar cells is usually the result of duct obstruction caused by expanding interstitial fibrosis or tumour tissue. The aggregation of islets can lead to islet clusters mimicking microtumours, but in islet aggregates, contrary to microtumours, the morphology of the individual islets is generally preserved and reveals no dysplastic changes. Also, the cellular composition of the islets in the aggregates remains basically unaltered. Immunolabelling for insulin and glucagon identifies insulin and glucagon cells, distributed in a pattern like that seen in normal islets. Sometimes the aggregated islets may cluster with small pancreatic ducts forming ductuloinsular complexes (Fig. 3B) or extend into the peripancreatic fat or are found around nerves imitating ‘perineural invasion’. Plasticity of the endocrine pancreas has also been demonstrated in mice models where an exogenous insulin treatment induces significant modifications in the morphology of the islets, indirectly indicating a functional dynamic adaptation of the β-cell to its environment (Nollevaux et al. 2013, Jensen et al. 2022).

Figure 3
Figure 3

Chronic pancreatitis. (A) Islet aggregation. (B) Ductuloinsular complex largely composed of insulin-expressing cells.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0034

Beta cell changes in congenital hyperinsulinism of infancy

CHI affects approximately 1/40,000–1/50,000 live births, but these figures increase to 1/2500–1/3000 in populations with high consanguinity (Glaser et al. 2000, Arnoux et al. 2011, Banerjee et al. 2019). CHI was described for the first time in detail by McQuarrie in 1954 as a disorder that he called ‘idiopathic hypoglycaemia of infancy’, characterized clinically by severe hypoglycaemia occurring in young infants and leading potentially, if not recognized and corrected, to irreversible brain damage (McQuarrie 1954). At that time, near-total pancreatectomy was the only treatment in patients who were unresponsive to medical therapy by diazoxide which was introduced in 1964 as an inhibitor of insulin secretion. Since the resected tissues allowed detailed histological examinations, the first reports on the morphological features of the endocrine pancreas in hypoglycaemic neonates appeared in the literature. In 1971, Yakovac et al. used the term ‘nesidioblastosis’ to describe their findings in 12 patients (Yakovac et al. 1971). They hypothesized that nesidioblastosis, defined as the continuous differentiation of β-cells arising from ducts, is a specific pathologic finding representing the persistence of an embryological process that, for unknown reasons, does not come to rest after birth and leads to endogeneous insulin hypersecretion and hypoglycaemia. Heitz in 1977 found endocrine cells budding off from ducts as a prominent feature in his study of seven patients with CHI and therefore used the same terminology (Heitz et al. 1977). However, subsequent studies of pancreases from neonates, infants, and adults, performed by Rahier and others demonstrated that nesidioblastosis was, as already mentioned, a normal feature of the pancreas in early infancy (Jaffe et al. 1980, Falkmer et al. 1981, Rahier et al. 1981, Witte et al. 1984). Other studies in pancreases of CHI patients as well as in normoglycaemic controls, also using double immunostaining for Ki67 and insulin, did reveal neither an increase in β-cell volume density nor proliferating insulin cells in nesidioblastotic foci, findings that should be expected if a continuous proliferation of pancreatic β-cells had taken place (Rahier et al. 1984, Sempoux et al. 1998). The term ‘nesidioblastosis’ is not only pathogenetically incorrect but gives also the false impression that CHI is a single entity (Heitz et al. 1977, Aynsley-Green et al. 1981). Today, however, it is established that CHI is a heterogeneous condition, clinically, histologically, and genetically (Bellanné-Chantelot et al. 2010, Thornton et al. 2015, Stanley 2016, De Leon-Crutchlow & Stanley 2019, Thornton et al. 2022, Rosenfeld & De Leon 2023).

Clinically, CHI is heterogeneous in responses to diazoxide treatment and the patients are classically described under two different categories: diazoxide unresponsive and diazoxide responsive (Table 2). Histologically, CHI shows different patterns of β-cell changes. Detailed microscopic analyses of the pancreas in large series of severely affected infants unresponsive to diazoxide revealed that there are at least two different morphological manifestations of CHI, a focal and a diffuse form of islet and β-cell changes (Table 2), which affect approximately 40% and 60% of the CHI patients, respectively (Klöppel et al. 1975, Rahier et al. 1984, Goossens et al. 1989). Clinically, the most important group is the focal form, since this form of CHI can be cured by targeted resection and makes large pancreatectomies with their consequences of diabetes and exocrine insufficiency unnecessary. Jacques Rahier and his collaborators from Brussels, working closely with the paediatric and surgical teams of Hôpital Necker-Enfants malades in Paris, established in the 90s the morphological criteria to distinguish the focal from the diffuse form on haematoxylin–eosin-stained slides and frozen sections during surgery (Rahier et al. 1998, Sempoux et al. 1998). In the focal form (Fig. 4A, B, and C), there is a small insulinoma-like nodule, usually no more than 5 mm in diameter. It is composed of densely arranged large islets with hypertrophic β-cells showing enlarged nuclei (Sempoux et al. 2003). This lesion differs from insulinoma in the absence of a fibrous delineation from the acinar cells that have retained their lobular distribution and may be seen as small cords in between the islets. On immunohistochemistry, the islets of the lesion are composed of an increased number of β-cells surrounded by an irregular and incomplete rim of non-β-cells (Sempoux et al. 2003). The islets outside of the lesion are normally distributed, with rather small endocrine cells, corresponding to functionally inactive β-cells (Fig. 4C). In the diffuse form of CHI, in contrast to the focal form, hypertrophic β-cells showing abundant cytoplasm and enlarged nuclei reflecting an hyperfunctional state are found in all islets throughout the entire gland (Fig. 4D). These features are so distinct that they are not only evident in haematoxylin–eosin (H&E) stained slides or on slides immunostained for insulin and proinsulin but also already recognizable on frozen sections during surgery. Indeed, if all islets are small and shrunken in frozen sections, it indicates that there is a focal lesion elsewhere in the gland. The focal form can be localized prior to surgery and the first technique that was developed for this purpose and stayed for years was the selective pancreatic venous sampling (Brunelle et al. 1989). Both this technique and the pathologist’s experience in frozen sections examination advanced the surgical procedure as shown in 1999 by de Lonlay who published the first European series (de Lonlay et al. 1999), followed in 2004 by another large series of CHI cases from Philadelphia (Suchi et al. 2004). Although pancreatic venous sampling combined with selective pancreatic arterial calcium stimulation further improved the localization of focal lesions (Stanley et al. 2004), the most significant step forward was made when Otonkoski and colleagues demonstrated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) (18F-DOPA) positron emission tomography (PET) to detect the focal lesion and to guide the surgical approach in 14 CHI patients (Otonkoski et al. 2006). Soon other groups confirmed this approach (Ribeiro et al. 2007, Laje et al. 2013). False negative results making frozen section examination still necessary during surgery are nowadays only rarely reported (Yau et al. 2020). Precise resection of the focal lesion with sparing of the normal pancreas is the treatment of choice for this form of CHI, with a cure rate of 97% (Adzick et al. 2019). Near-total pancreatectomy is only performed in the most severe diffuse forms of CHI, resistant to the best medical treatment, in which imaging techniques and frozen sections do not identify an abnormal area in the pancreas (Adzick et al. 2019).

Figure 4
Figure 4

Congenital hyperinsulinism. (A) Focal form of CHI: adenomatoid islet hyperplasia with some preserved exocrine acini at the periphery of the lobule. (B) Focal form of CHI: several hypertrophic β-cells and entrapped ductal structures within the hyperplastic area. (C) Focal form of CHI: shrunken hypoactive islets are found outside of the lesion. (D) Diffuse form of CHI: large islets with hyperactive β-cells showing enlarged nuclei. (E–G) Atypical form of CHI: presence of both hyperfunctional (arrow) and hypofunctional (arrowhead) islets close to each other (E), with higher proinsulin production in the hyperfunctional islet (F) than in the hypofunctional one (G).

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0034

Table 2

Stratification of congenital hyperinsulinism of infancy (CHI) according to clinical, genetic, and histopathological criteria.

Clinico-genetic presentationa Histopathological featuresb
Unresponsive to diazoxide
KATP channels 85–90%
  Inactivating ABCC8 or KCNJ11 mutations
   Recessive (majority of the cases)
    Biallelic 60% Diffuse form of CHI
    Monoallelic (paternal) + maternal 11p somatic loss 40% Focal form of CHI
   Dominant (minority of the cases) Diffuse form of CHI
Glucokinase2%
  Activating GCK mutations Discrete signs of β-cell hyperfunction, islets increased in size
Atypical CHI, single cases
Hexokinase (% unknown)
  Non-coding variants Atypical CHI, single cases
No mutation found 10% Atypical CHI, single cases
Responsive to diazoxide
KATP channels 14–18%
  Dominant inactivating ABCC8 or KCNJ11 mutations Unknown
Glutamate dehydrogenase 12–19%
  Activating mutations of GLUD1 Discrete signs of β-cell hyperfunction
Other genes 7–9%
  HNF1A, HNF4A, HADH, UCP2, SLC16A1, GCK, HK1… Unknown
No mutation found 55–65 % Atypical CHI, single cases

A careful review of a series of pancreatectomy specimens from CHI infants revealed that not all cases could be assigned either to the typical focal or diffuse form of CHI (Sempoux et al. 2011). These cases were called atypical and mostly identified in older children with milder forms of CHI, some of them partly responsive to diazoxide. The morphological change in atypical CHI is a mosaic pattern with the presence of both hyperfunctional islets with some hypertrophic β-cells showing nuclear enlargement and shrunken hypofunctional islets with small β-cells storing insulin without proinsulin production (Rahier et al. 2011, Sempoux et al. 2011, Han et al. 2017) (Fig. 4E, F, and G). Because the hyperactive islets, even if dispersed among the exocrine lobules in contrast with the focal form of CHI, were mostly confined to a limited area of the pancreas, also the atypical form of CHI can be cured by partial resection. It was therefore called ‘localized islet cell nuclear enlargement’ (LINE) by some groups (Boodhansingh et al. 2022).

Genetically, CHI is very diverse (Table 2). All identified genes are involved in the pathways regulating insulin secretion (Dunne et al. 2004, Nessa et al. 2016, Stanley 2016, Rosenfeld & De Leon 2023). The most frequent genetic cause of severe CHI unresponsive to diazoxide are inactivating mutations in the ABCC8 and KCNJ11 genes which encode for the two subunits of the β-cell ATP-sensitive K+ channel (KATP), the sulphonylurea receptor 1 (SUR1), and the inwardly rectifying potassium channel 6.2 (KIR6.2), respectively (Aguilar-Bryan et al. 1995, Thomas et al. 1995, 1996). In the normal β-cell, closure of this channel, following the increase of ATP/ADP ratio resulting from the phosphorylation of glucose by the glucokinase enzyme, leads to depolarization of the membrane with activation of the voltage-gated calcium channels and a rise in free intracellular Ca2+ concentration, which in turn triggers insulin secretion (Ashcroft & Ashcroft 1990, Henquin 2004). In severe cases of CHI, inactivating mutations lead to trafficking defects of the channel that is therefore non-functional (meaning permanently ‘closed’), resulting in a persistent stimulation of insulin release, independent from the glucose levels. As diazoxide is acting as an ‘opener’ of this channel, it is also clear why these CHI patients have a severe clinical form of the disease, not responsive to diazoxide treatment (Table 2). In rare cases, in vitro recovery of functional KATP channels can occur by modifying β-cells in culture conditions (Powell et al. 2011).

Genotype–phenotype correlations (Table 2) showed that KATP defects linked to recessive ABCC8 or KCNJ11 mutations were responsible for most of the diazoxide unresponsive severe diffuse forms of CHI, which affect neonates and, nowadays, may still require near-total pancreatectomy in some cases (Bellanné-Chantelot 2010, Snider et al. 2013). In the focal form, patients were found to have both a single paternally inherited recessive ABCC8 or KCNJ11 mutation and a somatic allelic loss of the corresponding maternal allele located in 11p15.5 in cells of the hyperplastic area. This loss of heterozygosity results in a focal imbalance between genes controlling cell proliferation, high expression of IGF2, and hyperplasia, while inappropriate insulin secretion is the consequence of the complete loss of either ABCC8 or KCNJ11 (de Lonlay et al. 1997, Verkarre et al. 1998, Fournet et al. 2001).

In vitro insulin secretion studies of the islets have been performed in CHI cases unresponsive to diazoxide, both focal and diffuse, and showed results in line with the KATP channel dysfunction (Henquin et al. 2011). When the same studies were performed in atypical forms of CHI, it was found that there were no KATP channel defects (Henquin et al. 2013). A large stimulation of insulin secretion in response to 1 mmol/L glucose was observed, suggestive of a glucose metabolism abnormality and pointing to a possible role for hexokinase and glucokinase. An aberrant immunohistochemical expression of hexokinase-1 was indeed found in the β-cells of the hyperfunctional islets in the majority of the cases, while the case that was not showing this peculiar feature was found to harbour a somatic activating mutation in the glucokinase (GCK) gene restricted to the abnormal area (Henquin et al. 2013). GCK mutations were confirmed in some patients from a further series of atypical CHI cases that also showed mosaic somatic mutations of ABCC8 in other cases (Boodhansingh et al. 2022). Non-coding variants found in the HK1 gene and leading, as in the study by Henquin, to loss of repression of hexokinase-1 in the hyperactive islets confirmed the role of HK1 gene in the pathogenesis of some cases of atypical CHI (Wakeling et al. 2022).

Over the years, mutations in other genes have been found in CHI (Nessa et al. 2016, Stanley 2016, Rosenfeld & De Leon 2023) (Table 2). Patients are mostly responsive to diazoxide treatment and do not require surgery. Since pancreatic tissue is not or only rarely available in these cases, the morphology of the pancreas has not been studied in detail (Table 2). When described, it is reported to be either completely unremarkable or to show discreet morphological features of β-cell hyperfunction (β-cell with larger cytoplasm and nucleus) but less pronounced than in case of KATP channels defects. Genetically, the most frequently found mutations involve GLUD1, the gene coding for the glutamate dehydrogenase enzyme, and responsible for the leucine-sensitive form of CHI called ‘hyperinsulinism–hyperammonaemia syndrome’ (Stanley et al. 1998) or the GCK gene coding for the glucokinase enzyme (Glaser et al. 1998). The clinical phenotype of patients with germinal GCK mutations is highly variable and surgery is sometimes required in the more severe forms unresponsive to diazoxide in which morphological analyses revealed a peculiar feature of islets increased in size in addition to the slightly enlarged β-cell nuclei (Table 2) (Cuesta-Munoz et al. 2004). Other genes have been identified in cases of milder form of CHI responsive to diazoxide (Table 2). These include inactivating mutations in HNF4A and HNF1A that causes Maturity Onset Diabetes of the Young (MODY), with some patients showing a biphasic phenotype and exhibiting first CHI at birth, then evolving to diabetes later on (De Leon-Crutchlow & Stanley 2019). Among the other reported genes, SCL16A1 is worth to mention as it has been described only in older children and found in ANHH (see later). Interestingly, in case of diazoxide unresponsive forms of CHI, only 10% of the cases do not show, so far, a specific identified underlying mutation. By contrast, no mutation is found in more than 50% of the diazoxide responsive cases (Table 2). Finally, there are also syndromic causes of CHI that may be suggested by physical examination. The most frequent one is the already mentioned BWS responsible for 5–10% of CHI. Other syndromes include Kabuki syndrome in which up to 10% of the patients have hyperinsulinaemic hypoglycaemia and Turner syndrome mostly prone to diabetes but with rare cases showing hypoglycaemia, responsive to diazoxide (De Leon-Crutchlow & Stanley 2019).

Challenges remain in the clinical management of CHI when patients have neurological damage due to late diagnosis and inadequate treatment (Lord & De Leon 2018, 2020, Banerjee et al. 2019, Rosenfeld & De Leon 2023). In CHI patients who are unresponsive to diazoxide, the current practice is to perform a rapid mutational analysis as first step, followed by a preoperative imaging by 18F-DOPA-PET in case of paternally recessive monoallelic ABCC8 or KCNJ11 mutation that suggests a focal form of CHI curable by targetable and limited resection.

Beta cell changes in adult hyperinsulinism

Adult nesidioblastosis is the term, although pathogenetically incorrect, that is most frequently used for idiopathic ANHH (Klöppel et al. 2008) and acquired conditions such as persistent hyperinsulinaemic hypoglycaemia associated with gastric bypass surgery (Rumilla et al. 2009). The term ‘non-insulinoma pancreatogenous hypoglycaemia syndrome’ that was also proposed (Service et al. 1999) emphasizes the non-neoplastic and functional nature of this β-cell disease.

Idiopathic ANHH is a rare disease. By the year 2000 there were only approximately 20 case reports (Stefanini et al. 1974, Albers et al. 1989, van der Wal et al. 2000) and two small cohorts (Harness et al. 1981, Service et al. 1999). In 2005, histological criteria of idiopathic ANHH were established in a series of 15 patients (Anlauf et al. 2005). The proportional frequency of idiopathic ANHH was 3% among 128 adult hyperinsulinaemic hypoglycaemia patients (Raffel et al. 2007). In a recent nationwide study in Japan this frequency was approximately 10% (Yamada et al. 2020). This study also revealed that patients with hyperinsulinaemic hypoglycaemia associated with gastric bypass or with postprandial hypoglycaemia were ten times more frequent than patients with idiopathic ANHH.

Most patients with idiopathic ANHH are in the fifth decade with a wide range from 18 to 76 years and a slight female predilection (Raffel et al. 2007). The diagnosis should be made with caution since the secure exclusion of an insulinoma can be difficult. A clinical indication of an idiopathic ANHH is the absence of a typical Whipple triad while fasting, but the occurrence of postprandial hypoglycaemia. Intraarterial calcium stimulation and selective pancreatic venous sampling may show an abnormal insulin response that cannot be localized to a certain region of the pancreas. Recently, glucagon-like-peptide-1 receptor imaging was successfully used in the distinction between idiopathic ANHH and insulinoma (Demartin et al. 2022). If the hypoglycaemia cannot be controlled by medical treatment, the patients need pancreas resection, usually a distal pancreatectomy which often at least improves the symptoms (Raffel et al. 2007).

The histologic spectrum of idiopathic ANHH ranges from a pancreas with only discrete to a pancreas with distinct islet changes (Albers et al. 1989, van der Wal et al. 2000, Anlauf et al. 2005, Klöppel et al. 2008). In the pancreas with distinct islet alterations, the most important histologic finding is single enlarged β-cells with pronounced nuclear hypertrophy (Fig. 5A). However, this finding is often not obvious at first glance since there are only few enlarged β-cells per islet and some islets may look completely normal. Moreover, the hypertrophic β-cell nuclei do not show as much enlargement as in the diffuse form of CHI. Immunostaining for MAFA, a transcription factor which regulates the β-cell glucose-stimulated insulin secretion, is often of help to highlight the enlarged β-cell nuclei (Fig. 5B). Another β-cell change, however, rarely observed, is a faint eosinophilia which brightens up the cytoplasm. Immunohistochemically, the cytoplasm shows a uniform staining for insulin (Fig. 5C) and the other islet hormones with a non-random normal distribution. The Ki67 index is low and does not exceed that in the normal pancreas (Anlauf et al. 2005, Raffel et al. 2007, Klöppel et al. 2008). There is no diffuse islet hyperplasia, but in a few cases, the islets appear to be irregularly distributed with a focal increase in some areas. Also, they can have a distinctly variable size and shape and single islets may be enlarged (Fig. 5D). If the islets of the pancreas show only discrete alterations or look even normal, the resected pancreatic tissue requires systematic examination, with serial sections to safely rule out a small insulinoma. If there is no insulinoma, it must be assumed that the hypersecretory function of the β-cells is not reflected by morphologically recognizable β-cell hyperactivity. Ductuloinsular complexes may be observed, but their presence does not belong to the diagnostic criteria of idiopathic ANHH. A focal type of ANHH, if it exists at all, seems to be very rare. The examples that have been reported are not comparable to what is found in CHI, because the described and illustrated lesions do not show the focal adenomatoid hyperplasia of large islets with β-cell hypertrophy, typical for the focal form of CHI (McElroy et al. 2010, Qin et al. 2015). The same is true for cases of idiopathic ANHH reported to occur concurrently with an insulinoma (Orujov et al. 2019, Dardano et al. 2020). Whether idiopathic ANHH can only partially affect the pancreas, as has recently been suggested, needs to be confirmed (Hercus et al. 2022).

Figure 5
Figure 5

Adult non-neoplastic hyperinsulinaemic hypoglycaemia. (A) Islet with scattered hypertrophic cells showing enlarged nuclei and a partially lightened cytoplasm. (B) Islets with scattered hypertrophic nuclei highlighted by immunostaining for MAFA, an insulin cell-specific transcription factor. (C) Islets with cells positive for insulin, some of which have hypertrophic nuclei. (D) Insulin positive islets with distinctly variable size and shape.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0034

The aetiology of idiopathic ANHH is not known. Mutational analysis performed in five patients with idiopathic adult nesidioblastosis revealed no mutations in either ABBC8 or KCNJ11 genes (Service et al. 1999). However, another study in families with a dominantly inherited hypoglycaemic disorder in adults that only manifests after exercise and has therefore been called exercise-induced hyperinsulinism (EIHI) found genetic alterations of the promoter of the SLC16A1 gene (Otonkoski et al. 2007), indicating that mutations in genes that are not known to be involved in CHI could be associated with idiopathic ANHH. There are also individual reports on adults with activating GCK mutations confirming the highly variable clinical phenotype of this group of patients (Ping et al. 2019, Gilis-Januszewska et al. 2021).

The postprandial form of hyperinsulinaemic hypoglycaemia observed in some individuals after partial gastrectomy for the treatment of morbid obesity (Service et al. 2005) is an acquired disease whose etiology is probably linked to the special hormonal situation caused by weight loss after gastric bypass operation. The hormone that is the focus of discussion is glucagon-like peptide 1 (GLP-1). However, after several studies, it is still an open question whether GLP-1 has a role as β-cell-trophic gut hormone that stimulates β-cell growth and function after gastric bypass surgery (Meier et al. 2006, Craig et al. 2017). Another problem concerns the β-cell changes after bypass surgery. On the one hand, no β-cell changes that are comparable to those in idiopathic ANHH have so far been described; on the other hand, it has also remained controversial whether there is an increase in the β-cell mass after bypass surgery (Meier et al. 2006, Rumilla et al. 2009, Dadheech et al. 2018).

Conclusions

Morphological studies have clarified that neither nesidioblastosis, defined as budding of islet cells from duct epithelium with subsequent β-cell proliferation, nor an increase in the number of β-cells are the lesions that characterize CHI or idiopathic ANHH. Instead, it has been shown that β-cell hypertrophy with nuclear enlargement reflecting the hyperactive state of the β-cell is the basic change in CHI and idiopathic ANHH. Apart from this fundamental morphological alteration, CHI and idiopathic ANHH show considerable clinico-pathological heterogeneity, not only among each other but also among the cases classified as either CHI or ANHH. CHI mainly occurs as a severe hypoglycaemic disease in early infancy, while idiopathic ANHH usually manifests in adulthood and is less severe than CHI. Assuming that in both groups, genetic changes are the major disease causes, the differences in age of manifestation and severity of the disease could mean that the pathogenetic mechanisms leading to hypoglycaemia are driven by probably very different genetic abnormalities, even if there are some overlap illustrated by the wide clinical phenotype seen for GCK mutations. In CHI, the severely defective insulin secretion was found to be mainly due to mutations in genes that code for proteins regulating the KATP channel, SUR1 and KIR6.2. In idiopathic ANHH, the possible gene defects seem to have less serious consequences so that the disease only becomes apparent later in life and possibly only under special circumstances. In line with this assumption may be the cases in which EIHI or activating GCK mutations have been identified. The most profound heterogeneity is found in CHI. Morphogenetic studies in CHI have demonstrated that this disease is not a single entity, but a group of genetically driven disorders based on different gene abnormalities and manifesting with different morphologies. This means that in every case of CHI at the beginning of the diagnosis, an accurate genetic status must be ascertained, which combined with the morphological findings then guides the treatment of the CHI patient.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Acknowledgements

Christine Sempoux is grateful to Jacques Rahier who paved her way into scientific research and clinical pathology with wisdom and generosity and to Jean-Claude Henquin for his invaluable collaboration in understanding insulin secretion in congenital hyperinsulinism. Working with them both was a great privilege and an honour.

References

  • Adzick NS, De Leon DD, States LJ, Lord K, Bhatti TR, Becker SA & & Stanley CA 2019 Surgical treatment of congenital hyperinsulinism: results from 500 pancreatectomies in neonates and children. Journal of Pediatric Surgery 54 2732. (https://doi.org/10.1016/j.jpedsurg.2018.10.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP 4th, Boyd AE 3rd, González G, Herrera-Sosa H, Nguy K, Bryan J & & Nelson DA 1995 Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268 423426. (https://doi.org/10.1126/science.7716547)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Albers MB, Maurer E, Klöppel G & & Bartsch DK 2014 Pancreatic polypeptide-rich islets in the posterior portion of the pancreatic head--a tumor mimic in somatostatin receptor scintigraphy. Pancreas 43 648650. (https://doi.org/10.1097/MPA.0000000000000070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Albers N, Löhr M, Bogner U, Loy V & & Klöppel G 1989 Nesidioblastosis of the pancreas in an adult with persistent hyperinsulinemic hypoglycemia. American Journal of Clinical Pathology 91 336340. (https://doi.org/10.1093/ajcp/91.3.336)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A, Kruse ML, Fottner C, Knoefel WT, Mönig H, et al.2005 Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes. American Journal of Surgical Pathology 29 524533. (https://doi.org/10.1097/01.pas.0000151617.14598.ae)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet JC, Robert JJ, Aigrain Y, et al.2011 Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases 6 63. (https://doi.org/10.1136/jmg.2009.075416)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ashcroft SJ & & Ashcroft FM 1990 Properties and functions of ATP-sensitive K-channels. Cellular Signalling 2 197214. (https://doi.org/10.1016/0898-6568(9090048-f)

  • Aynsley-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJ, Turner RC & & Baum JD 1981 Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycemia. Archives of Disease in Childhood 56 496508. (https://doi.org/10.1136/adc.56.7.496)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banerjee I, Salomon-Estebanez M, Shah P, Nicholson J, Cosgrove KE & & Dunne MJ 2019 Therapies and outcomes of congenital hyperinsulinism-induced hypoglycemia. Diabetic Medicine 36 921. (https://doi.org/10.1111/dme.13823)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bellanné-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, et al.2010 ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. Journal of Medical Genetetics 47 752759. (https://doi.org/10.1136/jmg.2009.075416)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boodhansingh KE, Yang Z, Li C, Chen P, Lord K, Becker SA, States LJ, Adzick NS, Bhatti T, Shyng SL, et al.2022 Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations. European Journal of Endocrinology 187 301313. (https://doi.org/10.1530/EJE-21-1095)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brunelle F, Negre V, Barth MO, Fekete CN, Czernichow P, Saudubray JM, Kuntz F, Tach T & & Lallemand D 1989 Pancreatic venous samplings in infants and children with primary hyperinsulinism. Pediatric Radiology 19 100103. (https://doi.org/10.1007/BF02387895)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Craig CM, Liu LF, Deacon CF, Holst JJ & & McLaughlin TL 2017 Critical role for GLP-1 in symptomatic post-bariatric hypoglycemia. Diabetologia 60 531540. (https://doi.org/10.1007/s00125-016-4179-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cuesta-Muñoz AL, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, López-Enriquez S, García-Gimeno MA, Sanz P, Soriguer FC, et al.2004 Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53 21642168. (https://doi.org/10.2337/diabetes.53.8.2164)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dadheech N, Garrel D & & Buteau J 2018 Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery. Islets 10 213220. (https://doi.org/10.1080/19382014.2018.1513748)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dardano A, Daniele G, Lupi R, Napoli N, Campani D, Boggi U, Del Prato S & & Miccoli R 2020 Nesidioblastosis and insulinoma: A rare coexistence and a therapeutic challenge. Frontiers in Endocrinology (Lausanne) 11 10. (https://doi.org/10.3389/fendo.2020.00010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • De Leon-Crutchlow DD & & Stanley CA 2019 Congenital Hyperinsulinism: A Practical Guide to Diagnosis and Management. Cham: Humana Press.

  • de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, 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. Journal of Clinical Investigation 100 802807. (https://doi.org/10.1172/JCI119594)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, Sempoux C, Dionisi Vici C, Brunelle F, Touati G, Rahier J, Junien C, Nihoul-Fékété C, et al.1999 Clinical features of 52 neonates with hyperinsulinism. New England Journal of Medicine 340 11691175. (https://doi.org/10.1056/NEJM199904153401505)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Demartin S, Goffette P, Christ E, Freitag MT, Maiter D & & Maria Furnica R 2022 Adult-onset nesidioblastosis: a challenging diagnosis revealed by glucagon-like-peptide-1 receptor imaging. Endocrinology, Diabetes and Metabolism Case Reports 2022 220325. (https://doi.org/10.1530/EDM-22-0325)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A & & Lindley KJ 2004 Hyperinsulinism in infancy: from basic science to clinical disease. Physiological Reviews 84 239275. (https://doi.org/10.1152/physrev.00022.2003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Falkmer S, Søvik O & & Vidnes J 1981 Immunohistochemical, morphometric, and clinical studies of the pancreatic islets in infants with persistent neonatal hypoglycemia of familial type with hyperinsulinism and nesidioblastosis. Acta Biologica et Medica Germanica 40 3954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fournet JC, Mayaud C, de Lonlay P, Gross-Morand MS, Verkarre V, Castanet M, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, et al.2001 Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. The American Journal of Pathology 158 21772184. (https://doi.org/10.1016/s0002-9440(1064689-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gilis-Januszewska A, Bogusławska A, Kowalik A, Rzepka E, Soczówka K, Przybylik-Mazurek E, Głowa B & & Hubalewska-Dydejczyk A 2021 Hyperinsulinemic hypoglycemia in three generations of a family with glucokinase activating mutation, c.295T>C (p.Trp99Arg). Genes (Basel) 12 1566. (https://doi.org/10.3390/genes12101566)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, et al.1998 Familial hyperinsulinism caused by an activating glucokinase mutation. New England Journal of Medicine 338 226230. (https://doi.org/10.1056/NEJM199801223380404)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Glaser B, Thornton P, Otonkoski T & & Junien C 2000 Genetics of neonatal hyperinsulinism. Archives of Disease in Childhood. Fetal and Neonatal Edition 82 F79F86. (https://doi.org/10.1136/fn.82.2.f79)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goossens A, Gepts W, Saudubray JM, Bonnefont JP, Nihoul-Fekete HeitzPU, Heitz PU & & Klöppel G 1989 Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. American Journal of Surgical Pathology 13 766775. (https://doi.org/10.1097/00000478-198909000-00006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han B, Mohamed Z, Estebanez MS, Craigie RJ, Newbould M, Cheesman E, Padidela R, Skae M, Johnson M, Flanagan S, et al.2017 Atypical forms of congenital hyperinsulinism in infancy are associated with mosaic patterns of immature islet cells. Journal of Clinical Endocrinology and Metabolism 102 32613267. (https://doi.org/10.1210/jc.2017-00158)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harness JK, Geelhoed GW, Thompson NW, Nishiyama RH, Fajans SS, Kraft RO, Howard DR & & Clark KA 1981 Nesidioblastosis in adults. A surgical dilemma. Archives of Surgery 116 575580. (https://doi.org/10.1001/archsurg.1981.01380170055010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Heitz PU, Klöppel G, Häcki WH, Polak JM & & Pearse AG 1977 Nesidioblastosis: the pathologic basis of persistent hyperinsulinemic hypoglycemia in infants. Morphologic and quantitative analysis of seven cases based on specific immunostaining and electron microscopy. Diabetes 26 632642. (https://doi.org/10.2337/diab.26.7.632)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henopp T, Anlauf M, Schmitt A, Schlenger R, Zalatnai A, Couvelard A, Ruszniewski P, Schaps KP, Jonkers YM, Speel EJ, et al.2009 Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. Journal of Clinical Endocrinology and Metabolism 94 213217. (https://doi.org/10.1210/jc.2008-1300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC 2004 Pathways in beta-cell stimulus-secretion coupling as targets for therapeutic insulin secretagogues. Diabetes 53(Supplement 3) S48S58. (https://doi.org/10.2337/diabetes.53.suppl_3.s48)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC, Nenquin M, Sempoux C, Guiot Y, Bellanné-Chantelot C, Otonkoski T, de Lonlay P, Nihoul-Fékété C & & Rahier J 2011 In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions. Journal of Clinical Investigation 121 39323942. (https://doi.org/10.1172/JCI58400)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC, Sempoux C, Marchandise J, Godecharles S, Guiot Y, Nenquin M & & Rahier J 2013 Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of β-cells. Diabetes 62 16891696. (https://doi.org/10.2337/db12-1414)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hercus JC, Pasha P, Al Lawati S, Kim P, Mattman A, Webber D & & Thompson DM 2022 Functional localization of adult-onset idiopathic nesidioblastosis. Case Reports in Endocrinology 2022 2802975. (https://doi.org/10.1155/2022/2802975)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hruban RH, Pitman MB & & Klimstra DS 2007 Tumors of the pancreas. In Atlas of Tumor Pathology. Eds. Silverberg SG, & Sobin LH. Washington, DC: Armed Forces Institute of Pathology, pp. 1316, 364377.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iacovazzo D, Flanagan SE, Walker E, Quezado R, de Sousa Barros FA, Caswell R, Johnson MB, Wakeling M, Brändle M, Guo M, et al.2018 MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 115 10271032. (https://doi.org/10.1073/pnas.1712262115)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jaffe R, Hashida Y & & Yunis EJ 1980 Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Laboratory Investigation; a Journal of Technical Methods and Pathology 42 356365.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jensen VFH, Mølck AM, Nowak J, Fels JJ, Lykkesfeldt J & & Bøgh IB 2022 Prolonged insulin-induced hypoglycemia reduces β-cell activity rather than number in pancreatic islets in non-diabetic rats. Scientific Reports 12 14113. (https://doi.org/10.1038/s41598-022-18398-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klimstra DS, Hruban RH & & Pitman MB 2007 Pancreas. In Histology for Pathologists 3 rd ed. Ed. Mills SA. Philadelphia: Lippincott Williams & Wilkins, pp. 723760.

  • Klöppel G, Altenähr E & & Menke B 1975 The ultrastructure of focal islet cell adenomatosis in the newborn with hypoglycemia and hyperinsulinism. Virchows Archiv. A, Pathological Anatomy and Histology 366 223236. (https://doi.org/10.1007/BF00427411)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Anlauf M, Perren A & & Sipos B 2014 Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. Endocrine Pathology 25 181185. (https://doi.org/10.1007/s12022-014-9317-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Anlauf M, Raffel A, Perren A & & Knoefel WT 2008 Adult diffuse nesidioblastosis: genetically or environmentally induced? Human Patholology 39 38. (https://doi.org/10.1016/j.humpath.2007.09.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Bommer G, Commandeur G & & Heitz P 1978 The endocrine pancreas in chronic pancreatitis. Immunocytochemical and ultrastructural studies. Virchows Archiv. A, Pathological Anatomy and Histology 377 157174. (https://doi.org/10.1007/BF00427003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Laidlaw GF 1938 Nesidioblastoma, the islet tumor of the pancreas. American Journal of Pathology 14 125134.5.

  • Laje P, States LJ, Zhuang H, Becker SA, Palladino AA, Stanley CA & & Adzick NS 2013 Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism. Journal of Pediatric Surgery 48 388393. (https://doi.org/10.1016/j.jpedsurg.2012.11.025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lord K & & De León DD 2018 Hyperinsulinism in the neonate. Clinics in Perinatology 45 6174. (https://doi.org/10.1016/j.clp.2017.10.007)

  • Lord K & & De León DD 2020 Meeting Report: Updates in diagnosis and management of hyperinsulinism and neonatal hypoglycemia: highlights from the fourth international hyperinsulinism symposium. Pediatric Endocrinology Reviews 17 268277. (https://doi.org/10.17458/per.vol17.2020.mr.ll.hyperinsulinismneonatalhypoglycemia)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McElroy MK, Lowy AM & & Weidner N 2010 Case report: focal nesidioblastosis ("nesidioblastoma") in an adult. Human Patholology 41 447451. (https://doi.org/10.1016/j.humpath.2009.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McQuarrie I 1954 Idiopathic spontaneously occurring hypoglycemia in infants; clinical significance of problem and treatment. AMA American Journal of Diseases of Children 87 399428.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meier JJ, Butler AE, Galasso R & & Butler PC 2006 Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care 29 15541559. (https://doi.org/10.2337/dc06-0392)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nessa A, Rahman SA & & Hussain K 2016 Hyperinsulinemic hypoglycemia - the molecular mechanisms. Frontiers in Endocrinology 7 29. (https://doi.org/10.3389/fendo.2016.00029)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nollevaux MC, Rahier J, Marchandise J, Thurion P, Godecharles S, Van den Steen G, Jamart J, Sempoux C, Jacquemin P & & Guiot Y 2013 Characterization of β-cell plasticity mechanisms induced in mice by a transient source of exogenous insulin. American Journal of Physiology. Endocrinology and Metabolism 304 E711E723. (https://doi.org/10.1152/ajpendo.00304.2012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Orujov M, Lai KK & & Forse CL 2019 Concurrent adult-onset diffuse β-cell nesidioblastosis and pancreatic neuroendocrine tumor: A case report and review of the literature. International Journal of Surgical Pathology 27 912918. (https://doi.org/10.1177/1066896919858129)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipilä I, Mayatepek E, et al.2007 Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. American Journal of Human Genetics 81 467474. (https://doi.org/10.1086/520960)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekström K, et al.2006 Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 55 1318. (https://doi.org/10.2337/diabetes.55.01.06.db05-1128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Palladino AA & & Stanley CA 2011 Nesidioblastosis no longer! It's all about genetics. Journal of Clinical Endocrinology and Metabolism 96 617619. (https://doi.org/10.1210/jc.2011-0164)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ping F, Wang Z & & Xiao X 2019 Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase-activating mutations: A report of two cases and a brief overview of the literature. Journal of Diabetes Investigation 10 14541462. (https://doi.org/10.1111/jdi.13072)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Powell PD, Bellanné-Chantelot C, Flanagan SE, Ellard S, Rooman R, Hussain K, Skae M, Clayton P, de Lonlay P, Dunne MJ, et al.2011 In vitro recovery of ATP-sensitive potassium channels in β-cells from patients with congenital hyperinsulinism of infancy. Diabetes 60 12231228. (https://doi.org/10.2337/db10-1443)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Qin H, Li Z, Qu L, Liu Y, Gao Y, Li F & & Wang G 2015 A rare case of focal nesidioblastosis causing adult-onset hypoglycemia. Experimental and Therapeutic Medicine 10 723726. (https://doi.org/10.3892/etm.2015.2541)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raffel A, Krausch MM, Anlauf M, Wieben D, Braunstein S, Klöppel G, Röher HD & & Knoefel WT 2007 Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge. Surgery 141 179186. (https://doi.org/10.1016/j.surg.2006.04.015)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rahier J, Fält K, Müntefering H, Becker K, Gepts W & & Falkmer S 1984 The basic structural lesion of persistent neonatal hypoglycemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of B cells? Diabetologia 26 282289. (https://doi.org/10.1007/BF00283651)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rahier J, Guiot Y & & Sempoux C 2011 Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism. Seminars in Pediatric Surgery 20 312. (https://doi.org/10.1053/j.sempedsurg.2010.10.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rahier J, Sempoux C, Fournet JC, Poggi F, Brunelle F, Nihoul-Fekete C, Saudubray JM & & Jaubert F 1998 Partial or near-total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycemia: the pathologist's role. Histopathology 32 1519. (https://doi.org/10.1046/j.1365-2559.1998.00326.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rahier J, Wallon J & & Henquin JC 1980 Abundance of somatostatin cells in the human neonatal pancreas. Diabetologia 18 251254. (https://doi.org/10.1007/BF00251925)

  • Rahier J, Wallon J & & Henquin JC 1981 Cell populations in the endocrine pancreas of human neonates and infants. Diabetologia 20 540546. (https://doi.org/10.1007/BF00252762)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ribeiro MJ, Boddaert N, Bellanné-Chantelot C, Bourgeois S, Valayannopoulos V, Delzescaux T, Jaubert F, Nihoul-Fékété C, Brunelle F & & De Lonlay P 2007 The added value of [18F]fluoro-L-dopa PET in the diagnosis of hyperinsulinism of infancy: a retrospective study involving 49 children. European Journal of Nuclear Medicine and Molecular Imaging 34 21202128. (https://doi.org/10.1007/s00259-007-0498-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rosenfeld E & & De León DD 2023 Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism. Current Opinion in Pediatrics. (https://doi.org/10.1097/MOP.0000000000001243)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rumilla KM, Erickson LA, Service FJ, Vella A, Thompson GB, Grant CS & & Lloyd RV 2009 Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression. Modern Pathology 22 239245. (https://doi.org/10.1038/modpathol.2008.169)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sempoux C, Capito C, Bellanné-Chantelot C, Verkarre V, de Lonlay P, Aigrain Y, Fekete C, Guiot Y & & Rahier J 2011 Morphological mosaicism of the pancreatic islets: a novel anatomopathological form of persistent hyperinsulinemic hypoglycemia of infancy. Journal of Clinical Endocrinology and Metabolism 96 37853793. (https://doi.org/10.1210/jc.2010-3032)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sempoux C, Guiot Y, Dahan K, Moulin P, Stevens M, Lambot V, de Lonlay P, Fournet JC, Junien C, Jaubert F, 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 784794. (https://doi.org/10.2337/diabetes.52.3.784)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sempoux C, Guiot Y, Dubois D, Nollevaux MC, Saudubray JM, Nihoul-Fekete C & & Rahier J 1998 Pancreatic B-cell proliferation in persistent hyperinsulinemic hypoglycemia of infancy: an immunohistochemical study of 18 cases. Modern Pathology 11 444449.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sempoux C, Guiot Y, Lefevre A, Nihoul-Fékété C, Jaubert F, Saudubray JM & & Rahier J 1998 Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. Journal of Clinical Endocrinology and Metabolism 83 14551461. (https://doi.org/10.1210/jcem.83.5.4768)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Service FJ, Natt N, Thompson GB, Grant CS, van Heerden JA, Andrews JC, Lorenz E, Terzic A & & Lloyd RV 1999 Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. Journal of Clinical Endocrinology and Metabolism 84 15821589. (https://doi.org/10.1210/jcem.84.5.5645)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML & & Lloyd RV 2005 Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. New England Journal of Medicine 353 249254. (https://doi.org/10.1056/NEJMoa043690)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sipos B, Sperveslage J, Anlauf M, Hoffmeister M, Henopp T, Buch S, Hampe J, Weber A, Hammel P, Couvelard A, et al.2015 Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. Journal of Clinical Endocrinology and Metabolism 100 E783E788. (https://doi.org/10.1210/jc.2014-4405)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA & & Ganguly A 2013 Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. Journal of Clinical Endocrinology and Metabolism 98 E355E363. (https://doi.org/10.1210/jc.2012-2169)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Solcia E, Capella C & & Kloppel G 1997 Tumors of the pancreas. In Atlas of Tumor Pathology Eds. Rosai J, & Sobin LH. Washington, DC: Armed Forces Institute of Pathology, pp. 323, 237246.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stanley CA 2016 Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders. Journal of Clinical Endocrinology and Metabolism 101 815826. (https://doi.org/10.1210/jc.2015-3651)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E & & Poncz M 1998 Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. New England Journal of Medicine 338 13521357. (https://doi.org/10.1056/NEJM199805073381904)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, Steinkrauss L, Wanner L, Kaye R, Ruchelli E, et al.2004 Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. Journal of Clinical Endocrinology and Metabolism 89 288296. (https://doi.org/10.1210/jc.2003-030965)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stefan Y, Bordi C, Grasso S & & Orci L 1985 Beckwith-Wiedemann syndrome: a quantitative, immunohistochemical study of pancreatic islet cell populations. Diabetologia 28 914919. (https://doi.org/10.1007/BF00703136)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y & & Unger RH 1982 Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 31 694700. (https://doi.org/10.2337/diab.31.8.694)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stefanini P, Carboni M, Patrassi N & & Basoli A 1974 Hypoglycemia and insular hyperplasia: review of 148 cases. Annals of Surgery 180 130135. (https://doi.org/10.1097/00000658-197407000-00020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suchi M, Thornton PS, Adzick NS, MacMullen C, Ganguly A, Stanley CA & & Ruchelli ED 2004 Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. American Journal of Surgical Pathology 28 13261335. (https://doi.org/10.1097/01.pas.0000138000.61897.32)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thomas P, Ye Y & & Lightner E 1996 Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Human Molecular Genetics 5 18091812. (https://doi.org/10.1093/hmg/5.11.1809)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF & & Bryan J 1995 Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268 426429. (https://doi.org/10.1126/science.7716548)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thornton PS, Stanley CA & & De Leon DD 2022 Congenital hyperinsulinism: an historical perspective. Hormone Research in Paediatrics 95 631637. (https://doi.org/10.1159/000526442)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, et al.2015 Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. Journal of Pediatrics 167 238245. (https://doi.org/10.1016/j.jpeds.2015.03.057)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van der Wal BC, de Krijger RR, de Herder WW, Kwekkeboom DJ, van der Ham F, Bonjer HJ & & van Eijck CH 2000 Adult hyperinsulinemic hypoglycemia not caused by an insulinoma: a report of two cases. Virchows Archiv 436 481486. (https://doi.org/10.1007/s004280050476)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, 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. Journal of Clinical Investigation 102 12861291. (https://doi.org/10.1172/JCI4495)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wakeling MN, Owens NDL, Hopkinson JR, Johnson MB, Houghton JAL, Dastamani A, Flaxman CS, Wyatt RC, Hewat TI, Hopkins JJ, et al.2022 Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nature Genetics 54 16151620. (https://doi.org/10.1038/s41588-022-01204-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Whipple AO & & Frantz VK 1935 Adenoma of islets cells with hyperinsulinism: a review. Annals of Surgery 101 12991335. (https://doi.org/10.1097/00000658-193506000-00001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Witte DP, Greider MH, DeSchryver-Kecskemeti K, Kissane JM & & White NH 1984 The juvenile human endocrine pancreas: normal v idiopathic hyperinsulinemic hypoglycemia. Seminars in Diagnostic Pathology 1 3042.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yakovac WC, Baker L & & Hummeler K 1971 Beta cell nesidioblastosis in idiopathic hypoglycemia of infancy. Journal of Pediatrics 79 226231. (https://doi.org/10.1016/s0022-3476(7180105-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yamada Y, Kitayama K, Oyachi M, Higuchi S, Kawakita R, Kanamori Y & & Yorifuji T 2020 Nationwide survey of endogenous hyperinsulinemic hypoglycemia in Japan (2017–2018): congenital hyperinsulinism, insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease). Journal of Diabetes Investigation 11 554563. (https://doi.org/10.1111/jdi.13180)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yau D, Marwaha R, Mohnike K, Sajjan R, Empting S, Craigie RJ, Dunne MJ, Salomon-Estebanez M & & Banerjee I 2020 Case report: contradictory genetics and imaging in focal congenital hyperinsulinism reinforces the need for pancreatic biopsy. International Journal of Pediatric Endocrinology 2020 17. (https://doi.org/10.1186/s13633-020-00086-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Figure 1

    The normal pancreas. (A–B) Compact islet type, haematoxylin–eosin (A) and insulin immunohistochemistry (B). (C–D) Meandering islet type, haematoxylin–eosin (C) and pancreatic polypeptide immunohistochemistry (D). (E) Pancreas, lower power (haematoxylin–eosin) compact islet type between exocrine acini. (F) Pancreas, lower power (chromogranin immunohistochemistry): illustration of nesidioblastosis: isolated endocrine cells and small endocrine aggregates sometimes close to ducts, scattered in the exocrine pancreas, outside of islets.

  • Figure 2

    Beckwith–Wiedemann syndrome. Islet and insulin-cell hyperplasia.

  • Figure 3

    Chronic pancreatitis. (A) Islet aggregation. (B) Ductuloinsular complex largely composed of insulin-expressing cells.

  • Figure 4

    Congenital hyperinsulinism. (A) Focal form of CHI: adenomatoid islet hyperplasia with some preserved exocrine acini at the periphery of the lobule. (B) Focal form of CHI: several hypertrophic β-cells and entrapped ductal structures within the hyperplastic area. (C) Focal form of CHI: shrunken hypoactive islets are found outside of the lesion. (D) Diffuse form of CHI: large islets with hyperactive β-cells showing enlarged nuclei. (E–G) Atypical form of CHI: presence of both hyperfunctional (arrow) and hypofunctional (arrowhead) islets close to each other (E), with higher proinsulin production in the hyperfunctional islet (F) than in the hypofunctional one (G).

  • Figure 5

    Adult non-neoplastic hyperinsulinaemic hypoglycaemia. (A) Islet with scattered hypertrophic cells showing enlarged nuclei and a partially lightened cytoplasm. (B) Islets with scattered hypertrophic nuclei highlighted by immunostaining for MAFA, an insulin cell-specific transcription factor. (C) Islets with cells positive for insulin, some of which have hypertrophic nuclei. (D) Insulin positive islets with distinctly variable size and shape.

  • Adzick NS, De Leon DD, States LJ, Lord K, Bhatti TR, Becker SA & & Stanley CA 2019 Surgical treatment of congenital hyperinsulinism: results from 500 pancreatectomies in neonates and children. Journal of Pediatric Surgery 54 2732. (https://doi.org/10.1016/j.jpedsurg.2018.10.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP 4th, Boyd AE 3rd, González G, Herrera-Sosa H, Nguy K, Bryan J & & Nelson DA 1995 Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268 423426. (https://doi.org/10.1126/science.7716547)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Albers MB, Maurer E, Klöppel G & & Bartsch DK 2014 Pancreatic polypeptide-rich islets in the posterior portion of the pancreatic head--a tumor mimic in somatostatin receptor scintigraphy. Pancreas 43 648650. (https://doi.org/10.1097/MPA.0000000000000070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Albers N, Löhr M, Bogner U, Loy V & & Klöppel G 1989 Nesidioblastosis of the pancreas in an adult with persistent hyperinsulinemic hypoglycemia. American Journal of Clinical Pathology 91 336340. (https://doi.org/10.1093/ajcp/91.3.336)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A, Kruse ML, Fottner C, Knoefel WT, Mönig H, et al.2005 Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes. American Journal of Surgical Pathology 29 524533. (https://doi.org/10.1097/01.pas.0000151617.14598.ae)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet JC, Robert JJ, Aigrain Y, et al.2011 Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases 6 63. (https://doi.org/10.1136/jmg.2009.075416)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ashcroft SJ & & Ashcroft FM 1990 Properties and functions of ATP-sensitive K-channels. Cellular Signalling 2 197214. (https://doi.org/10.1016/0898-6568(9090048-f)

  • Aynsley-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJ, Turner RC & & Baum JD 1981 Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycemia. Archives of Disease in Childhood 56 496508. (https://doi.org/10.1136/adc.56.7.496)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banerjee I, Salomon-Estebanez M, Shah P, Nicholson J, Cosgrove KE & & Dunne MJ 2019 Therapies and outcomes of congenital hyperinsulinism-induced hypoglycemia. Diabetic Medicine 36 921. (https://doi.org/10.1111/dme.13823)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bellanné-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, et al.2010 ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. Journal of Medical Genetetics 47 752759. (https://doi.org/10.1136/jmg.2009.075416)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boodhansingh KE, Yang Z, Li C, Chen P, Lord K, Becker SA, States LJ, Adzick NS, Bhatti T, Shyng SL, et al.2022 Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations. European Journal of Endocrinology 187 301313. (https://doi.org/10.1530/EJE-21-1095)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brunelle F, Negre V, Barth MO, Fekete CN, Czernichow P, Saudubray JM, Kuntz F, Tach T & & Lallemand D 1989 Pancreatic venous samplings in infants and children with primary hyperinsulinism. Pediatric Radiology 19 100103. (https://doi.org/10.1007/BF02387895)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Craig CM, Liu LF, Deacon CF, Holst JJ & & McLaughlin TL 2017 Critical role for GLP-1 in symptomatic post-bariatric hypoglycemia. Diabetologia 60 531540. (https://doi.org/10.1007/s00125-016-4179-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cuesta-Muñoz AL, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, López-Enriquez S, García-Gimeno MA, Sanz P, Soriguer FC, et al.2004 Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53 21642168. (https://doi.org/10.2337/diabetes.53.8.2164)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dadheech N, Garrel D & & Buteau J 2018 Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery. Islets 10 213220. (https://doi.org/10.1080/19382014.2018.1513748)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dardano A, Daniele G, Lupi R, Napoli N, Campani D, Boggi U, Del Prato S & & Miccoli R 2020 Nesidioblastosis and insulinoma: A rare coexistence and a therapeutic challenge. Frontiers in Endocrinology (Lausanne) 11 10. (https://doi.org/10.3389/fendo.2020.00010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • De Leon-Crutchlow DD & & Stanley CA 2019 Congenital Hyperinsulinism: A Practical Guide to Diagnosis and Management. Cham: Humana Press.

  • de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, 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. Journal of Clinical Investigation 100 802807. (https://doi.org/10.1172/JCI119594)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, Sempoux C, Dionisi Vici C, Brunelle F, Touati G, Rahier J, Junien C, Nihoul-Fékété C, et al.1999 Clinical features of 52 neonates with hyperinsulinism. New England Journal of Medicine 340 11691175. (https://doi.org/10.1056/NEJM199904153401505)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Demartin S, Goffette P, Christ E, Freitag MT, Maiter D & & Maria Furnica R 2022 Adult-onset nesidioblastosis: a challenging diagnosis revealed by glucagon-like-peptide-1 receptor imaging. Endocrinology, Diabetes and Metabolism Case Reports 2022 220325. (https://doi.org/10.1530/EDM-22-0325)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A & & Lindley KJ 2004 Hyperinsulinism in infancy: from basic science to clinical disease. Physiological Reviews 84 239275. (https://doi.org/10.1152/physrev.00022.2003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Falkmer S, Søvik O & & Vidnes J 1981 Immunohistochemical, morphometric, and clinical studies of the pancreatic islets in infants with persistent neonatal hypoglycemia of familial type with hyperinsulinism and nesidioblastosis. Acta Biologica et Medica Germanica 40 3954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fournet JC, Mayaud C, de Lonlay P, Gross-Morand MS, Verkarre V, Castanet M, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, et al.2001 Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. The American Journal of Pathology 158 21772184. (https://doi.org/10.1016/s0002-9440(1064689-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gilis-Januszewska A, Bogusławska A, Kowalik A, Rzepka E, Soczówka K, Przybylik-Mazurek E, Głowa B & & Hubalewska-Dydejczyk A 2021 Hyperinsulinemic hypoglycemia in three generations of a family with glucokinase activating mutation, c.295T>C (p.Trp99Arg). Genes (Basel) 12 1566. (https://doi.org/10.3390/genes12101566)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, et al.1998 Familial hyperinsulinism caused by an activating glucokinase mutation. New England Journal of Medicine 338 226230. (https://doi.org/10.1056/NEJM199801223380404)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Glaser B, Thornton P, Otonkoski T & & Junien C 2000 Genetics of neonatal hyperinsulinism. Archives of Disease in Childhood. Fetal and Neonatal Edition 82 F79F86. (https://doi.org/10.1136/fn.82.2.f79)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goossens A, Gepts W, Saudubray JM, Bonnefont JP, Nihoul-Fekete HeitzPU, Heitz PU & & Klöppel G 1989 Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. American Journal of Surgical Pathology 13 766775. (https://doi.org/10.1097/00000478-198909000-00006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han B, Mohamed Z, Estebanez MS, Craigie RJ, Newbould M, Cheesman E, Padidela R, Skae M, Johnson M, Flanagan S, et al.2017 Atypical forms of congenital hyperinsulinism in infancy are associated with mosaic patterns of immature islet cells. Journal of Clinical Endocrinology and Metabolism 102 32613267. (https://doi.org/10.1210/jc.2017-00158)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harness JK, Geelhoed GW, Thompson NW, Nishiyama RH, Fajans SS, Kraft RO, Howard DR & & Clark KA 1981 Nesidioblastosis in adults. A surgical dilemma. Archives of Surgery 116 575580. (https://doi.org/10.1001/archsurg.1981.01380170055010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Heitz PU, Klöppel G, Häcki WH, Polak JM & & Pearse AG 1977 Nesidioblastosis: the pathologic basis of persistent hyperinsulinemic hypoglycemia in infants. Morphologic and quantitative analysis of seven cases based on specific immunostaining and electron microscopy. Diabetes 26 632642. (https://doi.org/10.2337/diab.26.7.632)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henopp T, Anlauf M, Schmitt A, Schlenger R, Zalatnai A, Couvelard A, Ruszniewski P, Schaps KP, Jonkers YM, Speel EJ, et al.2009 Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. Journal of Clinical Endocrinology and Metabolism 94 213217. (https://doi.org/10.1210/jc.2008-1300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC 2004 Pathways in beta-cell stimulus-secretion coupling as targets for therapeutic insulin secretagogues. Diabetes 53(Supplement 3) S48S58. (https://doi.org/10.2337/diabetes.53.suppl_3.s48)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC, Nenquin M, Sempoux C, Guiot Y, Bellanné-Chantelot C, Otonkoski T, de Lonlay P, Nihoul-Fékété C & & Rahier J 2011 In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions. Journal of Clinical Investigation 121 39323942. (https://doi.org/10.1172/JCI58400)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henquin JC, Sempoux C, Marchandise J, Godecharles S, Guiot Y, Nenquin M & & Rahier J 2013 Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of β-cells. Diabetes 62 16891696. (https://doi.org/10.2337/db12-1414)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hercus JC, Pasha P, Al Lawati S, Kim P, Mattman A, Webber D & & Thompson DM 2022 Functional localization of adult-onset idiopathic nesidioblastosis. Case Reports in Endocrinology 2022 2802975. (https://doi.org/10.1155/2022/2802975)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hruban RH, Pitman MB & & Klimstra DS 2007 Tumors of the pancreas. In Atlas of Tumor Pathology. Eds. Silverberg SG, & Sobin LH. Washington, DC: Armed Forces Institute of Pathology, pp. 1316, 364377.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iacovazzo D, Flanagan SE, Walker E, Quezado R, de Sousa Barros FA, Caswell R, Johnson MB, Wakeling M, Brändle M, Guo M, et al.2018 MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 115 10271032. (https://doi.org/10.1073/pnas.1712262115)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jaffe R, Hashida Y & & Yunis EJ 1980 Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Laboratory Investigation; a Journal of Technical Methods and Pathology 42 356365.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jensen VFH, Mølck AM, Nowak J, Fels JJ, Lykkesfeldt J & & Bøgh IB 2022 Prolonged insulin-induced hypoglycemia reduces β-cell activity rather than number in pancreatic islets in non-diabetic rats. Scientific Reports 12 14113. (https://doi.org/10.1038/s41598-022-18398-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klimstra DS, Hruban RH & & Pitman MB 2007 Pancreas. In Histology for Pathologists 3 rd ed. Ed. Mills SA. Philadelphia: Lippincott Williams & Wilkins, pp. 723760.

  • Klöppel G, Altenähr E & & Menke B 1975 The ultrastructure of focal islet cell adenomatosis in the newborn with hypoglycemia and hyperinsulinism. Virchows Archiv. A, Pathological Anatomy and Histology 366 223236. (https://doi.org/10.1007/BF00427411)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Anlauf M, Perren A & & Sipos B 2014 Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. Endocrine Pathology 25 181185. (https://doi.org/10.1007/s12022-014-9317-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Anlauf M, Raffel A, Perren A & & Knoefel WT 2008 Adult diffuse nesidioblastosis: genetically or environmentally induced? Human Patholology 39 38. (https://doi.org/10.1016/j.humpath.2007.09.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G, Bommer G, Commandeur G & & Heitz P 1978 The endocrine pancreas in chronic pancreatitis. Immunocytochemical and ultrastructural studies. Virchows Archiv. A, Pathological Anatomy and Histology 377 157174. (https://doi.org/10.1007/BF00427003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Laidlaw GF 1938 Nesidioblastoma, the islet tumor of the pancreas. American Journal of Pathology 14 125134.5.

  • Laje P, States LJ, Zhuang H, Becker SA, Palladino AA, Stanley CA & & Adzick NS 2013 Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism. Journal of Pediatric Surgery 48 388393. (https://doi.org/10.1016/j.jpedsurg.2012.11.025)

    • PubMed
    • Search Google Scholar
    • Export Citation
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