Recent advances in hyperinsulinemic hypoglycemia of infancy

Hyperinsulinemia-induced hypoglycemia is the most common cause of persistent hypoglycemia in adults, children, and infants. Our understanding of the disorders responsible for this type of hypoglycemia has been increasing due to the recent discoveries in the molecular and biochemical regulation of insulin secretion. In this article, we review the current knowledge of the pathophysiology, clinical presentation, and diagnosis of disorders that cause hyperinsulinemic hypoglycemia of infancy. We highlight the distinction between the diffuse and focal forms of the disease, especially the promising results with ¹⁸F-L-dopa positive emission tomography (PET) scanning for preoperative localization and distinction to guide the extent of surgical removal of pancreatic tissue that may result in cure rather than persistence of disturbed carbohydrate metabolism.

Conclusion: Despite all these discoveries, much remains to be learned, as currently about one third of infants with hyperinsulinemic hypoglycemia have no identifiable cause.     

Double pancreatic tumors in an adolescent: Imaging features

Insulinoma is generally identified as a single tumor and seldom occurs in children or adolescents. A 14‐year‐old girl with difficulty in waking was found to have hyperinsulinemic hypoglycemia. On abdominal ultrasonography two hypoechoic masses (8 and 12 mm in diameter) were seen in the pancreatic body: the larger mass was hypervascular, whereas the smaller one was hypovascular. Contrast‐enhanced computed tomography showed enhancement of the larger mass, but did not delineate the smaller mass. On fat‐suppressed T1‐weighted magnetic resonance imaging, the larger mass was hypointense, but the smaller mass was hyperintense. Pathologically, the larger tumor was normal density, insulin positive, and rich in vascularity, whereas the smaller tumor was high density, insulin negative, and poor in vascularity. The present case suggests that difficulty waking should be considered as a potential etiology in insulinoma, and multiple suspected pancreatic insulinomas should be evaluated using a combination of imaging modalities to characterize each tumor.     

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15‐yr‐old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti‐emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.     

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.     

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.     

Severe fasting hypoglycemia in a child after total pancreatectomy with islet autotransplantation

TPIAT is an increasingly utilized treatment option for select children with CP. Post‐TPIAT fasting hypoglycemia, unrelated to exogenous insulin, is a complication recently reported in adults. This phenomenon has not been described in children. We review a case of severe fasting hypoglycemia in an adolescent female occurring 10 months post‐TPIAT. A 12‐year‐old girl underwent TPIAT for CP. Ten months postoperatively she developed recurrent hypoglycemia on a total daily insulin dose of 0.03 units/kg. Consequently, insulin therapy was discontinued. Approximately 20 hours after her last rapid‐acting insulin exposure, she had an episode of fasting hypoglycemia (33 mg/dL on glucometer). Her CGM documented two separate, precipitous drops in glucose overnight. The family was instructed to revise her diet, and there were no subsequent episodes of severe, fasting hypoglycemia. This is the first report of fasting hypoglycemia occurring post‐TPIAT in a pediatric patient. Use of a CGM allowed for documentation of glucose trends and alarm notification of hypoglycemic events. Dietary changes appeared to help mitigate hypoglycemia recurrence. This report demonstrates that fasting hypoglycemia is a potential complication that should be recognized and safeguarded against in post‐TPIAT pediatric patients.     

Neonatal case of novel KMT2D mutation in Kabuki syndrome with severe hypoglycemia

A newborn Japanese girl with Kabuki syndrome had neonatal persistent hyperinsulinemic hypoglycemia, which seemed to be a rare complication of Kabuki syndrome. On sequence analysis she was found to have a novel heterozygous KMT2D mutation. Diazoxide therapy was effective for the hypoglycemia. Hypoglycemia should be considered when Kabuki syndrome patients have convulsion or other non‐specific symptoms. Diazoxide may help to improve hypoglycemia in patients with Kabuki syndrome complicated with hyperinsulinemic hypoglycemia.     

婴幼儿持续性高胰岛素血症的术中冰冻诊断意义及病理分析

目的探讨婴幼儿持续性高胰岛素血症(persistent hyperinsulinemic hypoglycemia in infancy,PHHI)的病理分型以及术中冰冻病理对外科手术治疗方法选择的指导意义。方法2011年4月至2016年10月,复旦大学附属儿科医院共25例PHHI患儿经外科手术治疗,回顾性分析其相关临床资料、手术治疗经过及术后病理特征。结果25例患儿中男17例,女8例,年龄16 d至12个月,术前经内分泌科明确诊断患有PHHI,空腹血糖0.6~5.5 mmol/L,禁食实验胰岛素水平为3.1~50.1 mU/L。结合术前检查及术中冰冻结果,5例患儿诊断为局灶性病变,行胰腺病灶切除术,20例诊断为弥漫性病变,行胰腺次全切术。术后随访2~38个月,空腹血糖3.0~12.6 mmol/L,15例术后血糖恢复较好,1例仍有低血糖症状,需加用激素治疗,3例空腹时血糖偏低,进食后可恢复,另6例有术后高血糖症状,需药物治疗。1例术前疑诊为局灶性病变,行50%胰腺切除术后2周复发。术后病理检查有5例诊断为局灶型,1例为不典型型,余19例为弥漫型。结论对于内科治疗无效的PHHI以手术治疗为主,术前明确病理分型对手术方式的选择极为重要,术中快速冰冻切片结合术前辅助检查可以较为准确的指导手术方式。婴幼儿PHHI主要以弥漫型为主,但从术后病理区分弥漫型及局灶性仍存在困难,其中不典型型尚无明确的定义或分类,还有待在病理学方面进一步详细研究。     

Near-Total Pancreatectomy for Hyperinsulinism: Spontaneous Remission of Resultant Diabetes

ABSTRACT. Persistent hyperinsulinism in the newborn may warrant surgical intervention to prevent neurologic sequelae. Subtotal pancreatectomy may not be adequate, necessitating near-total pancreatectomy with subsequent development of diabetes mellitus. We report an infant with hyperinsulinemic hypoglycemia who underwent near-total pancreatectomy. The postoperative period was characterized by insulin-dependency and extreme insulin sensitivity. Clinical follow-up and C-peptide determinations showed a return of insulin secretory capacity permitting the discontinuation of insulin therapy after five months. This experience reaffirms the potential for a favorable outcome after near-total pancreatectomy in the newborn period for severe hyperinsulinism.     

Focal or Diffuse Lesions in Persistent Hyperinsulinemic Hypoglycemia of Infancy: Concerns about Interpretation of Intraoperative Frozen Sections

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) results from defects of regulated insulin release from pancreatic β cells and is often refractory to medical treatment. Histological changes in the pancreas associated with PHHI may be focal or diffuse, and the intraoperative confirmation and siting of focal lesions would require frozen section diagnosis. The recognition of focal involvement and its distinction from diffuse disease by frozen section depends on the identification and distribution pattern of islet cells with large hyperchromatic nuclei. This study was designed to test the feasibility of using this parameter in PHHI to delineate focal from diffuse diseases prior to the introduction of frozen sections to guide intraoperative management in our institution. A total of 66 coded and randomized paraffin sections (from 18 PHHI and 4 postmortem pancreases) were scored by three independent observers into the following categories: a focal lesion (A), no large endocrine nuclei (B), few large endocrine nuclei (C), and frequent large endocrine nuclei (D). Interobserver concordance was complete in 88%, but there were minor discrepancies in the remaining 12%. When a focal lesion was present in one section no large endocrine nuclei were seen in sections from the rest of the pancreas. In four patients with diffuse PHHI, no or only very scanty large endocrine nuclei were seen. From this finding, and the observation that in other examples of diffuse disease, large endocrine nuclei were sparse even in large paraffin sections, we have reservations about using small frozen sections for reliable diagnosis. Received January 31, 2000; accepted May 2, 2000.     

Prenatal diagnosis of familial neonatal hyperinsulinemia

A kindred with familial neonatal hyperinsulinemia is described. Infant A was macrosomatic and stillborn. Infant B was macrosomatic at birth following a pregnancy uncomplicated by maternal diabetes. Following diagnosis of hyperinsulinemic hypoglycemia, this patient was treated with oral diazoxide. Therapy continued until hyperinsulinemia resolved by two years of age. Based on this history, the pregnancy with infant C was intensively monitored using ultrasonography and amniocentesis. Insulin and C-peptide concentrations in amniotic fluid were markedly increased compared to control pregnancies. Based on these results, infant C was delivered immediately upon obtaining evidence of lung maturation. Neonatal hyperinsulinemia was confirmed by a markedly increased cord plasma insulin concentration. Based on our experience, we recommend that insulin concentrations in amniotic fluid be used as an indicator of fetal hyperinsulinemia in kindreds with prior newborn hyperinsulincmic hypoglycemia. This information may be used to direct timing of delivery and therapy in the immediate postnatal period.     

Ketotic hypoglycemia in patients with allergic diseases

BACKGROUND: Ketotic hypoglycemia is the most common cause of recurrent hypoglycemia in early childhood but its etiology is poorly understood. Elimination diets have been used for the prevention or treatment of some allergic diseases; however, these diets entail a risk to the normal nutrition and growth of children. The present study investigated whether elimination diets are related to the occurrence of ketotic hypoglycemia. METHODS: The prevalence of allergy treated with elimination diet therapy was retrospectively investigated in 18 patients with ketotic hypoglycemia seen in Yamaguchi University Hospital between January 1995 and September 1999. Data were gathered by reviewing the patients' medical charts. RESULTS: Ten (55.6%) of 18 patients with ketotic hypoglycemia had allergic diseases. Six (60%) of the patients had been treated with strict elimination diets and the others were on incomplete elimination diets for the prevention of allergy. The ketotic hypoglycemia patients with allergic diseases had experienced fewer pre-existing infectious diseases than those without allergic diseases. CONCLUSIONS: Patients with allergic diseases treated with elimination diets have a relatively high tendency towards developing ketotic hypoglycemia. They might have a lower capacity to tolerate fasting due to their excessive avoidance of many foods, even during periods when they are not undergoing strict elimination diets.     

Severe hypoglycemia secondary to methimazole‐induced insulin autoimmune syndrome in a 16 year old African‐American male

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African‐American adolescent. A 16‐yr‐old healthy African‐American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio‐ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.     

Use of a real‐time continuous glucose monitoring system in children and young adults on insulin pump therapy: patients' and caregivers' perception of benefit

Cemeroglu AP, Stone R, Kleis L, Racine MS, Postellon DC, Wood MA. Use of a real‐time continuous glucose monitoring system in children and young adults on insulin pump therapy: patients' and caregivers' perception of benefit. Background: Real‐time continuous glucose monitoring systems (RT‐CGMS) are a recently introduced technology for type 1 diabetes and experience in children is limited. Objective: To assess patient and caregiver's perception of benefits and disadvantages of RT‐CGMS in children or young adults with type 1 diabetes mellitus (DM) on insulin pump therapy. Subjects and Methods: Forty‐three subjects (3–25 yr) on insulin pump therapy were included in the study. Thirty‐four used RT‐CGMS for a short‐term trial (4 wk, ST group) and nine as a long‐term tool (2–18 months, LT group). Forty subjects or their caregivers completed a questionnaire. Results: On the basis of the questionnaire responses, hypoglycemia prevention was the most common perceived benefit (88%), followed by elimination of hypoglycemia‐related anxiety (83%), ease of pattern management (85%), improvement of diabetes control (80%), improvement of quality of life (78%), and ease of diabetes care (78%). Negative effects included irritation/annoyance from the sensor alarm (48%) and insertion site bruising, pain, or irritation (43%). A small percentage of patients who were interested in purchasing the device (12%) decided against using it LT after a 4‐wk trial on RT‐CGMS. Conclusions: The most common perceived benefits of RT‐CGMS are prevention of hypoglycemia and decrease in hypoglycemia‐related anxiety. Negative effects are uncommon and seem to be unlikely to affect the decision to use RT‐CGMS for a LT. A ST trial seems to be a valuable tool for the patient/caregiver in determining whether to purchase the device and in setting realistic expectations of its potential benefits.     

Prenatal diagnosis of familial neonatal hyperinsulinemia

A kindred with familial neonatal hyperinsulinemia is described. Infant A was macrosomatic and stillborn. Infant B was macrosomatic at birth following a pregnancy uncomplicated by maternal diabetes. Following diagnosis of hyperinsulinemic hypoglycemia, this patient was treated with oral diazoxide. Therapy continued until hyperinsulinemia resolved by two years of age. Based on this history, the pregnancy with infant C was intensively monitored using ultrasonography and amniocentesis. Insulin and C-peptide concentrations in amniotic fluid were markedly increased compared to control pregnancies. Based on these results, infant C was delivered immediately upon obtaining evidence of lung maturation. Neonatal hyperinsulinemia was confirmed by a markedly increased cord plasma insulin concentration. Based on our experience, we recommend that insulin concentrations in amniotic fluid be used as an indicator of fetal hyperinsulinemia in kindreds with prior newborn hyperinsulincmic hypoglycemia. This information may be used to direct timing of delivery and therapy in the immediate postnatal period.     

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 embryogenesis 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.     

Newly diagnosed T1 diabetes presenting with hypoglycemia due to simultaneous co‐existence of Addison disease

Type 1 diabetes mellitus (TIDM) classically presents with symptomatic hyperglycemia and many patients develop diabetic ketoacidosis prior to their diagnosis. However, non‐classical presentation or co‐presentation with associated diseases may delay diagnosis or lead to challenges in acute, clinical management. An 18‐yr‐old girl presented to hospital with severe, symptomatic hypoglycemia. Clinical history and serum electrolyte concentrations suggested a diagnosis of adrenal insufficiency. She remained hypoglycemic until glucocorticoid replacement was commenced, at which point she developed persistent hyperglycemia requiring insulin therapy. Subsequent follow up confirmed the diagnosis of Addison's disease (AD), the treatment of which unmasked co‐existing type 1 diabetes. Autoimmune diseases often cluster together in affected patients and first‐degree relatives. Approximately 1 in 200 patients with T1DM develop AD. However, months or more commonly years usually elapse between the presentation of different autoimmune conditions. The co‐diagnosis T1DM and AD in the acute setting is rare. Moreover, the first presentation of T1DM with severe hypoglycemia is even more exceptional. This case highlights the need for vigilance during the acute, emergency management of patients with autoimmune conditions and, in particular, to consider the possibility of concurrent antibody‐mediated diseases which may need to be addressed during resuscitation.     

Persistent hyperinsulinemic hypoglycemia presenting with a rare complication: West syndrome

BACKGROUND: Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is characterized by disproportional secretion of insulin from pancreatic beta-cells. Although one of the manifestations of hypoglycemia is West syndrome, it is rarely reported in PHHI. PATIENT REPORT: A 6 month-old girl who was followed up with the diagnosis of PHHI was admitted to hospital with the complaint of jerky movements at her extremities. EEG revealed the typical pattern of hypsarrhythmia leading to the diagnosis of West syndrome. CONCLUSION: To our knowledge, there is only one report in the literature of West syndrome as a manifestation of PHHI, and that was the hyperammoniemic form of the disease. The present report is the first of normoammoniemic PHHI leading to West syndrome. We wish to highlight the potential risks of PHHI, especially in inadequately treated patients, and to emphasize that close neurological follow-up is very important in children who suffer from PHHI.     

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.