Nesidiodysplasia and Nesidioblastosis of Infancy: Structural and Functional Correlations with the Syndrome of Hyperinsulinemic Hypoglycemia

Subtotal pancreatectomy specimens of seven infants with persistent hyperinsulinemic hypoglycemia were studied; all showed the characteristic light microscopic picture of nesidioblastosis. Specimens were studied by electron and conventional light microscopy and by light microscopic immunohistochemistry for insulin, glucagon, somatostatin, and HPP (human pancreatic polypeptide); double staining and quantitative methods were also used. Findings were compared with those in age-matched controls.

In the hyperinsulinemic hypoglycemic infants, an increase in total endocrine cell volume was found; however, the typical features of nesidioblastosis were also found in the controls. In both groups, immunohistochemistry and electron microscopy suggested that some endocrine cells are capable of producing synchronously more than one hormone. Amphicrine (”composite” or “intermediate”) cells with exocrine and endocrine differentiation were found in three hypoglycemic infants.

Observations are discussed in relation to current concepts of embryo genesis of the gastroenteropancreative endocrine system. We conclude that nesidioblastosis, as defined anatomically cannot be considered as the morphologic basis of hyperinsulinemic hypoglycemia. The term “nesidiodysplasia” is suggested and includes increased, maldistributed, and malregulated or malprogrammed endocrine and amphicrine cells when associated with endocrine abnormality.     

Beta cell nesidioblastosis

Two patients with severe hypoglycemia since birth are described. In both hyperinsulinism was demonstrated during spontaneous hypoglycemic attacks or could be provoked by various tolerance tests. In case I considerable obesity and psychomotor retardation was present at the age of one year whereas in case II weight gain was normal and development unaffected.Immunofluorescence microscopic and electron microscopic examination of the pancreas after subtotal pancreatectomy revealed diffuse islet cell hyperplasia with nesidioblastosis in case I and -cell nesidioblastosis in case II. The hyperplastic and nesidioblastotic areas consisted mainly of -cells. In addition, an accumulation of somatostatin producing cells was observed in case I, and some cells were found with ultrastructural signs of both endocrine and exocrine function.In both cases, pancreatic insulin release was inhibited by a prolonged somatostatin infusion. The results of tolerance tests did not allow a diagnosis of the underlying pancreatic lesion. In case II, leucine-sensitive hypoglycemia detected soon after birth, was present even after subtotal pancreatic resection.Therapeutic trials with diazoxide in case I and a leucine-restricted diet in case II were only of temporary benefit. After subtotal pancreatectomy there was clinical improvement in both cases, but case II still needs a leucine-restricted diet. The familial occurrence of persistent hypoglycemia in both cases suggests that -cell nesidioblastosis may be a hereditary disorder.With support of the Landesamt für Forschung des Landes Nordrhein-Westfalen     

The Relationship between Decreased Iron Stores, Serum Iron and Neonatal Hypoglycemia in Large-for-Date Newborn Infants

ABSTRACT. We assessed the relationship between neonatal hypoglycemia and newborn iron status in 15 hypoglycemic, large-for-date newborn infants, 12 of whom were infants of diabetic mothers. These infants had significantly lower mean serum iron concentrations, ferritin concentrations, percent iron-binding saturation and calculated iron stores, and significantly higher mean transferrin concentrations, total iron-binding capacity concentrations and mid-arm circumference: head circumference ratios when compared with either 15 euglycemic large-for-date or 15 euglycemic appropriate-for-date control infants ( p < 0.001 for all comparisons). All hypoglycemic infants had ferritin concentrations below the 5th percentile as compared to 3 % of controls ( p < 0.001), and 67 % had transferrin concentrations above the 95th percentile (controls: 0 %; p < 0.001). Only the hypoglycemic infants demonstrated a significant negative linear correlation between ferritin and transferrin concentrations ( r =−0.83; p < 0.001). Decreased serum iron concentrations were associated with size at birth ( r =−0.60; p = 0.01) and with increased red cell iron ( r =−0.60; p = 0.01), implying a redistribution of iron dependent on the degree of fetal hyperglycemia and hyperinsulinemia. Infants with increased red cell iron had more profound neonatal hypoglycemia. These results show a significant association between decreased iron stores and neonatal hypoglycemia in macrosomic newborn infants associated with a significant shift of iron into red blood cells.     

The relationship between decreased iron stores, serum iron and neonatal hypoglycemia in large-for-date newborn infants

We assessed the relationship between neonatal hypoglycemia and newborn iron status in 15 hypoglycemic, large-for-date newborn infants, 12 of whom were infants of diabetic mothers. These infants had significantly lower mean serum iron concentrations, ferritin concentrations, percent iron-binding saturation and calculated iron stores, and significantly higher mean transferrin concentrations, total iron-binding capacity concentrations and mid-arm circumference:head circumference ratios when compared with either 15 euglycemic large-for-date or 15 euglycemic appropriate-for-date control infants (p less than 0.001 for all comparisons). All hypoglycemic infants had ferritin concentrations below the 5th percentile as compared to 3% of controls (p less than 0.001), and 67% had transferrin concentrations above the 95th percentile (controls: 0%; p less than 0.001). Only the hypoglycemic infants demonstrated a significant negative linear correlation between ferritin and transferrin concentrations (r = -0.83; p less than 0.001). Decreased serum iron concentrations were associated with size at birth (r = -0.60; p = 0.01) and with increased red cell iron (r = -0.60; p = 0.01), implying a redistribution of iron dependent on the degree of fetal hyperglycemia and hyperinsulinemia. Infants with increased red cell iron had more profound neonatal hypoglycemia. These results show a significant association between decreased iron stores and neonatal hypoglycemia in macrosomic newborn infants associated with a significant shift of iron into red blood cells.     

Prospective study of nesidioblastosis in newborns and infants: Hypoglycemic seizures,epileptogenesis and the significance of the C-peptide suppression test in pancreatectomy

The long-term follow-up of chronic hyperinsulinemic seizures, epileptogenesis and other neurological complications in five patients who were treated with conservative therapy followed by pancreatectomy during the neonatal period and infancy, who were confirmed to have diffuse nesidioblastosis are described. The reaction pattern of the C-peptide (CPR) suppression test and its relation to the final extent of pancreatectomy was examined in four patients. The chronological change in electro-encephalography (EEG) and its epileptogenesis was also examined in each patient during hyperinsulinemic hypoglycemia, and during normoglycemia in a long-term post-pancreatectomy follow-up. All patients demonstrated several types of hypoglycemic seizures, ranging from apnea, erratic seizures, partial seizures evolving to generalized/unilateral tonic-clonic or tonic seizures, myoclonic seizures and EEG abnormalities. Four of five patients still suffered from epilepsy at the age of 4–22 years. The reaction pattern of the CPR suppression test showed dichotomy, with a hyper-reactive pattern in two patients who required total pancreatectomy to control hypoglycemia, and a suppression pattern in two other patients treated with 90–95% pancreatectomy. Neonatal onset and subsequent myoclonic seizures were ominous signs of epileptogenesis to various types of intractable epilepsy and other neurological sequelae. A prompt diagnosis and pancreatectomy of a sufficient extent at the first operation are essential. The CPR suppression test may be useful for a prompt diagnosis and selection of the extent of pancreatectomy.     

糖尿病母亲婴儿低血糖发生情况及其与脑损伤的关系

目的探讨糖尿病母亲婴儿（IDMS）低血糖的发生情况及其与脑损伤的关系。方法分析86例IDMS低血糖的发生情况、母亲孕期血糖控制与低血糖持续时间的关系。分析其脑损伤发生及严重程度与低血糖持续时间、并其他疾病和症状性低血糖的关系。结果短暂性低血糖75例（87.2%）,反复发作性低血糖11例（12.8%）。母亲孕期血糖反复发作性低血糖发生率控制不满意组为19.4%,满意组为8%。反复发作性低血糖组脑损伤总发生率及重度脑损伤发生率高于短暂性低血糖组,并其他疾病组48.5%和无临床症状组57.4%,均有显著性差异（Pa〈0.05）。结论低血糖的持续时间与母亲妊娠期血糖控制情况及脑损伤发生、严重程度有关;低血糖并其他疾病会加重脑损伤,症状性低血糖时常存在严重脑损伤。     

婴儿持续性高胰岛素血症性低血糖症12例临床分析

目的：探讨婴儿持续性高胰岛素血症性低血糖症（PHHI）的早期诊断和治疗问题。方法：回顾性分析12例PHHI患儿的临床资料。结果：12例患儿临床表现除抽搐外,尚有发绀、嗜睡、拒奶、易激惹、出冷汗等,实验室检查有持续性低血糖和高胰岛素血症,胰高血糖素试验阳性,尿酮阴性。7例给予二氮嗪治疗(每天5~15 mg/kg),4例治疗有效。1例行胰腺次全切除术,术后血糖正常。6例随访有精神运动发育迟缓等后遗症,3例失访,3例正在随访中。结论：PHHI可通过血糖监测、血胰岛素和尿酮检查做出早期诊断,部分患儿二氮嗪治疗有效。［中国当代儿科杂志,2009,11（10）：809-812］     

An immunohistochemical study of islet cells with macronuclei in infancy

The presence of hypertrophic islet cells in infancy as evidenced by nuclear enlargement (2 to 6 times normal size) has been mentioned as a morphological accompaniment of hyperinsulinemic hypoglycemia of infancy. We report an immunohistochemical and semiquantitative study of hypertrophic islet cells in 14 infants with neonatal hypoglycemia (10 with documented persistent neonatal hypoglycemia and 4 with probable persistent neonatal hypoglycemia) and 6 infants born to diabetic mothers (IDM), using an indirect immunoperoxidase methods for the demonstration of insulin, somatostatin, and glucagon. Quantitation of immunoreactivity was performed in each case on 20 hypertrophic cells. Polyploid cells were positive for insulin and somatostatin but negative for glucagon; insulin-positive cells outnumbered somatostatin-positive cells in both groups. As nuclear hypertrophy is considered to be a sign of hyperfunction, our findings are in accordance with the concept that IDM involves reactive beta-cell hypertrophy and similar findings in the pancreases of infants with persistent neonatal hypoglycemia (PNH) suggest a primary dysfunction of their beta cells, too.     

Mesenchymal hamartoma of the liver associated with features of Beckwith-Wiedemann syndrome and high serum alpha-fetoprotein levels.

A 5-month-old girl with clinical features of Beckwith-Wiedemann syndrome (BWS), including a repaired omphalocele, an earlobe crease, enlarged adrenal glands, renal size discrepancy, and hyperinsulinemic hyperglycemia, presented with a 1.9-cm liver nodule. Markedly increased serum alpha-fetoprotein (AFP) levels (1,060,000 mg/L), highly suspicious for hepatoblastoma, were detected, and resection of the liver mass was performed. Histologic sections showed features characteristic of a mesenchymal hamartoma of the liver (MHL). No features of embryonal or fetal hepatocellular proliferation or heterologous stromal components were noted. By immunohistochemistry, the hepatocytes expressed AFP, but no nuclear accumulation of beta-catenin was present. Electron microscopy revealed normal, mature hepatocytes. Here we address the diagnostic challenge of the uncommon association of MHL and BWS in the setting of markedly elevated serum AFP levels. In addition, we analyze the unusual pancreatic lesion (focal endocrine adenomatosis) leading to severe hyperinsulinemic hypoglycemia in a patient with possible BWS. We emphasize that MHLs may present with markedly increased serum AFP levels, mimicking hepatoblastomas, and may also be part of the expanding spectrum of findings of BWS.     

Somatostatin in the emergency treatment of persistent hypoglycemias caused by hyperinsulinism (nesidioblastosis of the pancreas)

11 infants with persisting hypoglycemia due to hyperinsulinism (nesidioblastosis of the pancreas) were treated with somatostatin. Somatostatin administration in a relatively high dosage (initially 145 micrograms/m2 body surface as bolus followed by a continuous infusion of the same dose per hour) resulted in a suppression of the circulating insulin concentration leading to a less abrupt fall of the postprandial plasma glucose level. By somatostatin infusion we were able to keep two patients with intractable neonatal hypoglycemia in a normoglycemic state until subtotal pancreatectomy. Infants suffering from nesidioblastosis require 1.0-4.5 micrograms/kg/h somatostatin and a concomitant carbohydrate supply of 0.3-0.48 g/kg/h in order to maintain normoglycemia. An initial somatostatin bolus can be omitted. Somatostatin is very reliable in the treatment of neonatal hypoglycemia due to hyperinsulinism for a limited period of time until subtotal pancreatectomy is performed. In most cases of nesidioblastosis this operative measure seems to be inevitable for the control of hyperinsulinism.     

Nesidioblastosis and Mixed Hamartoma of the Liver in Beckwith-Wiedemann Syndrome: Case Study Including Analysis of H19 Methylation and Insulin-like Growth Factor 2 Genotyping and Imprinting

An infant with persistent hyperinsulinemic hypoglycemia, diffuse nesidioblastosis, and mixed hamartoma of the liver (MHL), in addition to demonstrating clinical, pathologic, and molecular manifestations of Beckwith-Wiedemann syndrome (BWS), is the subject of this report. H19 methylation assay and allelic expression analysis for insulin-like growth factor 2 (IGF2) indicated that the patient was mosaic for paternal isodisomic cells and normal cells in lung tissue, nontumoral liver tissue, tissue from the MHL, and pancreatic tissue. We propose that abundant IGF2 expression during development due to paternal isodisomy resulted in hepatomegaly and islet cell hyperplasia, which led to nesidioblastosis. MHL, by contrast, may have resulted from a decrease in disomic cells, compared with nontumoral liver tissue, which showed an increase in disomic cells. Thus, somatic mosaicism may result in unbalanced tissue growth, which may contribute to the formation of MHL in BWS. Received February 25, 2000; accepted October 19, 2000.     

Prolonged hyperinsulinemic hypoglycemia in a small for date preterm

Hyperinsulinism is an important cause of hypoglycemia in early infancy. Many forms of hyperinsulinemic hypoglycemia are described: transient, prolonged, persistent. Transient forms are well recognized in infants of diabetic mother; prolonged forms are responsible for the hypoglycemia in small-for-date (SGA) infants and asphyxiated newborns. Persistent hyperinsulinemic hypoglycemia occurs in a group of congenital disorders associated with an abnormality of beta-cell regulation throughout the pancreas. Accurate diagnosis and treatment are essential in all various forms of hyperinsulinism also because newborns are at high risk of permanent brain damage. We report a case of prolonged hyperinsulinemic hypoglycemia in a SGA preterm, immediately treated with a high dose of glucose and glucocorticoid and then with diazoxide. Hypoglycemia was continued until 2 months of age when it resolved spontaneously and completely.     

Ultrastructure of carotid bodies in sudden infant death syndrome

Recent studies have implicated an abnormality in carotid body structure and function in the pathogenesis of sudden infant death syndrome (SIDS). In the present investigation, the light and electron microscopic findings in carotid bodies from ten victims of SIDS were compared with those in six control infants and five infants dying of congenital heart disease. The cross-sectional area of carotid body chemoreceptor cells and the frequency, distribution, and size of neurosecretory granules were assessed morphometrically. The area of carotid body occupied by chemoreceptor cells (the functional area) was comparable in SIDS victims, control infants, and infants with congenital heart disease. By electron microscopy, the carotid body chief cells from all groups contained numerous electron-dense neurosecretory granules. Distribution, frequency, and size of neurosecretory granules in SIDS victims and control infants did not differ significantly. Morphology of carotid bodies from SIDS victims was found to be normal. The presence of neurosecretory granules in chemoreceptor cells of SIDS victims suggests that the cellular mechanism of neurotransmitter synthesis and storage is not altered.     

Neonatal hypoglycemia in a growth hormone registry: incidence and pathogenesis

OBJECTIVE: To examine the characteristics of infants with neonatal hypoglycemia treated with growth hormone (GH) in order to gain insights into factors aiding in the identification of and timely treatment of hypopituitary neonates. STUDY DESIGN: The National Cooperative Growth Study (NCGS) database was examined to identify infants with neonatal hypoglycemia started on GH by 6 months of age. 169 infants (100 males, 69 females) were found and their data analyzed for physical characteristics, the presence of other hormone deficits, and the diagnostic methods used. RESULTS: Mean +/- SD baseline length standard deviation score (SDS) was -1.5 +/- 1.8. 148/169 infants had hypopituitarism. Twelve had isolated GH deficiency (GHD). Nine had hypoglycemia without hypothalamic or pituitary pathology. Structural central nervous system (CNS) lesions and/or midline facial defects were present in 66/169. 55/100 males had micropenis. Although 158 infants had GHD, only 90 infants had it documented by stimulation testing (80) or a critical sample when hypoglycemic (10). Multiple hormone replacement therapy was necessary in 89% of the hypoglycemic infants. CONCLUSIONS: The great majority of these hypoglycemic infants had GHD, usually secondary to hypopituitarism. Over 1/3 had structural lesions of the hypothalamic-pituitary area or midline facial defects. Although lengths may be normal in these infants, physical features such as micropenis or cleft lip and/or palate should suggest pituitary dysfunction as the etiology of their hypoglycemia. A critical blood sample for GH taken during hypoglycemia is a quick and definitive diagnostic tool.     

Ketonuria does not exclude hyperinsulinemic hypoglycemia

We examined the relationship between serum beta-hydroxybutyrate (BOHB) and plasma glucose concentrations and between serum free fatty acid (FFA) and glucose concentrations in 34 normal children who fasted for up to 24 hours. The BOHB concentration correlated inversely with the glucose concentration, as did the FFA concentration. We compared these results with those in six patients with hypoglycemia due to hyperinsulinism. In the hyperinsulinemic children, hypoglycemia was invariably associated with relative hypoketonemia (glucose concentration, less than 40 mg/dL; BOHB concentration, less than 2mM; greater than 2 SDs below the mean). The FFA concentrations were also unduly low (greater than 2 SDs). However, despite being significantly hypoketonemic when hypoglycemic, four of the six hyperinsulinemic patients had ketonuria. Since it does not exclude hyperinsulinism, ketonuria may be a potentially misleading finding in a hypoglycemic child.     

Tissue insulin contents in nesidioblastosis. Report of two cases

We present two cases of nesidioblastosis, a common cause of persistent hypoglycemia in infancy that, if inadequately treated, can lead to mental retardation. Tissue insulin data obtained from both radioimmunoassay and immunohistochemistry are presented. In each case, the insulin content correlated well with the quantity of insulinpositive cells in each portion of the pancreas. However, the insulin content varied from case to case and from portion to portion of the same pancreas. Thus, discrepancies in clinical results in nesidioblastosis may be due to variability of insulin content in the resected pancreas.Presented at the 26th Annual Meeting of the Pacific Association of Pediatric Surgeons, Cairns, Australia, May 9–14, 1993     

新生儿低血糖脑损伤的临床研究

目的探讨低血糖脑损伤的临床表现与早期影像学特征,为诊断与预后判定提供依据。方法6例人院时血糖为0.48～1.70mmol/L。胎龄35周^＋5至40周,出生体重1545～3900g。均无窒息史、败血症、颅内感染、遗传代谢及内分泌性疾病。在入院24～48h完成T1WI、T2WI和DWI磁共振扫描。结果6例均有明显的临床表现,以惊厥、萎靡最为常见,其次为呼吸暂停,4例血糖正常时仍有惊厥发生。5例低血糖发生在生后6～53h,1例在生后12d。低血糖持续时间[（47.7±38.8）（4～96）]h,最低值[（1.05±0.44）（0.48～1.70）]mmol／L。首次MRI检查1例在生后15d,余在生后2～5d,受累部位为枕叶（6例）和顶叶（3例）皮层及皮层下白质：DWI上表现为高信号6例,TlwI为低信号4例,T2WI高信号1例。3例在生后第2周接受第2次检查,1例DWI转为低信号,余信号正常;3例此时TlwI和T2W1分别表现为低信号和高信号,局部水肿明显减轻。1例3个月随访发育正常,未见顶枕部萎缩,但内囊后枝和视放射髓鞘化不良。结论枕顶叶是新生儿低血糖脑损伤的主要受累部位,DWI可以早期反映脑损伤的改变。     

Diagnostic evaluation of persistent neonatal hypoglycemia using the fasting test: behavior of glucoregulatory hormones and intermediary metabolites (1)

The effect of insulin induced hypoglycemia on glucoregulatory hormones and intermediary substrates was studied in four infants (three boys and one girl, ages 12-89 days) with persistent hyperinsulinism secondary to nesidioblastosis (two) or microadenoma of the pancreas (two). During the "fasting test" the following data expressed as mean basal plasma values +/- SEM vs. mean hypoglycemic values +/- SEM were obtained: insulin (57.3 +/- 17.9 vs. 27.5 +/- 10.6 microU/ml), C-peptide (4.9 +/- 1.1 vs. 3.5 +/- 0.9 ng/ml), free fatty acids (0.30 +/- 0.01 vs. 0.32 +/- 0.02 mmol/l), beta-hydroxybutyrate (less than 0.03 vs. 0.05 +/- 0.02 mmol/l), alanine (204.0 +/- 67.5 vs. 228.3 +/- 64.9 mumol/l), lactate (5.3 +/- 0.7 vs. 5.4 +/- 1.1 mg/dl), pyruvate (41.3 +/- 4.8 vs. 19.7 +/- 4.2 mg/dl). These data suggest "inappropriate" elevation of insulin and C-peptide levels, inhibition of lipolysis and lack of gluconeogenic substrates secondary to endogenous HI. An increase of cortisol (6.5 +/- 4.1 vs. 16.3 +/- 5.7 micrograms/dl), adrenaline (0.015 +/- 0.05 vs. 0.25 +/- 0.24 ng/ml) (3 out of 4) and noradrenaline (0.28 +/- 0.06 vs. 0.64 +/- 0.14 ng/ml) was noted, whereas only minute increase was found for glucagon (134.3 +/- 51.7 vs. 177.0 +/- 76.2 pg/ml) and HGH (5.7 +/- 1.1 vs. 7.1 +/- 1.1 ng/ml). Although some stimulation of neonatal glucoregulatory hormones was evident, this was not strong enough for counteracting endogenous HI.