Diagnosis Of Congenital Hyperinsulinism Research Articles

A Sensitive Plasma Insulin Immunoassay to Establish the Diagnosis of Congenital Hyperinsulinism.

BackgroundThe diagnosis of congenital hyperinsulinism (CHI) may be hampered by a plasma (p-) insulin detection limit of 12–18 pmol/L (2–3 mU/L).ObjectiveTo evaluate the diagnostic performance of a sensitive insulin immunoassay and to find the optimal p-insulin cut-off for the diagnosis of CHI.MethodsDiagnostic fasting tests, performed without medication or i.v.-glucose, were investigated in children with a clinical diagnosis of CHI, or idiopathic ketotic hypoglycemia (IKH). The CHI diagnosis was either clinical or by the alternative, p-insulin-free criteria; hypoglycemia plus disease-causing genetic mutations and/or CHI-compatible pancreatic histopathology. We included diagnostic p-insulin samples with simultaneous p-glucose <3.2 mmol/L and used a sensitive insulin assay (Cobas e411 immunoassay analyzer; lower detection limit 1.2 pmol/L; normal range 15.1–147.1 pmol/L). Receiver operating characteristics area under the curve (ROC AUC) values and optimal cut-offs were analyzed for the performance of p-insulin to diagnose CHI.ResultsIn 61 CHI patients, the median (range) p-insulin was 76.5 (17–644) pmol/L compared to 1.5 (1.5–7.7) pmol/L in IKH patients (n=15). The ROC AUC was 1.0 for the diagnosis of CHI defined both by the clinical diagnosis (n=61) and by alternative criteria (n=57). The optimal p-insulin cut-offs were 12.3 pmol/L, and 10.6 pmol/L, at p-glucose <3.2 mmol/L (n=61), and <3.0 mmol/L (n=49), respectively.ConclusionsThe sensitive insulin assay performed excellent in diagnosing CHI with optimal p-insulin cut-offs at 12.3 pmol/L (2.0 mU/L), and 10.6 pmol/L (1.8 mU/L), at p-glucose <3.2 mmol/L, and <3.0 mmol/L, respectively. A sensitive insulin assay may serve to simplify the diagnosis of CHI.

Clinical and morphological differential diagnosis of congenital hyperinsulinism before the stage of immunohistochemical study of paraffin-embedded specimens of pancreas in children

Introduction.Differential diagnosis of various forms of congenital hyperinsulinism (CH) is required at the stage of urgent histological examination, but the difference between the exo- and endocrine parts of the pancreas in frozen sections is visualized very poorly.The objective was to search for differential diagnostic criteria of focal and diffuse forms of CH, suitable for urgent histological examination.Methods and materials. Pancreatic surgery material from 25 children with CH, of which 15 cases of focal form (FCH) and 10 cases of diffuse (DСH), and autopsy material from 10 children without CH (K). Frozen and paraffin sections stained with hematoxylin-eosin and histochemical stains were made from the tissue of the pancreas. The number of endocrinocytes with large nuclei was estimated in 10 fields of view for each case.Results. The average proportion of endocrinocytes with large nuclei was significantly (p &lt;0.01) higher compared to the control both with FCH (in the affected area) and DCH (FCH – (1.82±0.50) %, DCH – (4.68±1.66) %, K – (0.34±0.21) %). We found a tendency to detect a higher absolute number of cells with large nuclei in DCH ((4.95±1.24) DCH and (3.71±1.56) FCH). Staining with azure-eosin, picro Mallory and the PAS reaction gave unstable result, and staining with toluidine blue and May-Grunwald did not allow differentiating exo- and endocrine parts of the pancreas.Conclusion. An increase in the size of the endocrinocyte nuclei was the unsuitable criterion for the differential diagnosis of CH forms, and histochemical stains did not give a stable qualitative result. For urgent biopsy examination, new immunohistochemical methods are needed.

Diagnosis of congenital Hyperinsulinism can occur not only in infancy but also in later age: a new flow chart from a single center experience

BackgroundCongenital Hyperinsulinism typically occurs with a neonatal hypoglycemia but can appear even in childhood or in adolescence with different types of glucose metabolism derangements. Current diagnostic algorithms don’t take into account cases with a late presentation.Patients and methodsClinical and laboratory data of twenty-two subjects diagnosed at Federico II University of Naples have been described: patients have been divided according to the molecular defect into channel defects, metabolic defects and unidentified molecular defects. A particular focus has been made on three cases with a late presentation.Results and conclusionsLate presentation cases may not be identified by previous diagnostic algorithms. Consequently, it seems appropriate to design a new flow-chart starting from the age of presentation, also considering that late presentation cases can show glucose metabolism derangements other than hypoglycaemic crises such as diabetes, glucose intolerance, postprandial hypoglycaemia and gestational diabetes.

P07 Prescribing practices in neonatal hypoglycaemia

AimsNeonatal hypoglycaemia is a leading cause of admission of term babies to the neonatal unit (NNU).1 Intravenous glucose solutions are used as a treatment strategy for patients with severe hypoglycaemia or patients that do not respond to enteral treatment. Varying concentrations of glucose including 10%, 12.5%, 15% and 20% are used for this treatment with ≥15% only used via a central line. 10% and 20% glucose solutions are commercially available as pre-made bags, though 12.5% and 15% solutions are prepared at the bedside. We aimed to review prescribing practice for neonatal hypoglycaemia in infants requiring ≥12.5% glucose and its impact on the patient’s NNU course.MethodsPatients admitted to our tertiary NNU with hypoglycaemia between January 2018 and December 2018 inclusive were identified using an admission database. Patient information was retrospectively collected using Digital Health Records. Glucose requirements were reviewed, and patients requiring &gt;10% glucose for hypoglycaemia treatment were identified. Subsequently, patients who died, received part of their care outside the Trust, were fluid restricted, received parenteral nutrition or had an alternative underlying diagnosis for hypoglycaemia such as a genetic or mitochondrial disorder were excluded. For included patients, a designated set of parameters including demographics, medical diagnoses, risk factors for hypoglycaemia, glucose load and fluid volumes were collected.ResultsIn total, 210 patient hypoglycaemic episodes were identified, of which 26 patients required treatment with ≥12.5% glucose. Further exclusion against the defined criteria left 15 patients for review. The median number of risk factors for hypoglycaemia were 3, the most common being maternal labetalol use in pregnancy. Of the 15 included patients; 8 required 12.5% glucose (Group A), and 7 required escalation to 15% or 20% concentrations (Group B). 9/15 required a 2.5 ml/kg glucose bolus with the average length of time spent below &lt;2.6 mmol/L of 7 hours. Glucose load was highest in Group B (15.39 mg/kg/minute) vs Group A (9.90 mg/kg/minute), p=0.0013, and a higher glucose load was associated with an increased length of time on intravenous fluids. Of the patients requiring &gt;12.5% glucose, the median time to escalate from 12.5% to a higher concentration was 14.4 hours. Escalation of glucose enabled a reduction in intravenous glucose volumes. Patients who had escalation of treatment from 12.5% to 15% (n=3) had a median duration of intravenous fluid therapy of 14 days, compared to 5 days when escalating from 12.5% to 20% (n=4). 2 patients required re-escalation of treatment back to a higher glucose concentration; both had an underlying diagnosis of congenital hyperinsulinism. 8/15 patients had central access sited, consisting of 13 line insertions, with a complication rate (i.e. incorrect position or not working) of 31% (n=4).ConclusionA small proportion of neonates with hypoglycaemia require escalation of intravenous fluids to ≥12.5% glucose to achieve normoglycemia. When this escalation is required, prompt central line insertion should be considered to avoid delay and allow for administration of ≥15% glucose. Ongoing work with the Neonatal Pharmacy Team aims to reduce the length of hypoglycaemic episodes and shorten treatment duration for babies.ReferenceDeshpande SU, M; Hawdon, J.M. Admissions of term newborn infants for hypoglycaemia: their characteristics and preventability. The Neonatal Society; 2016

Challenging diagnosis of congenital hyperinsulinism in two infants of diabetic mothers with rare pathogenic KCNJ11 and HNF4A gene variants

BackgroundCongenital hyperinsulinism (CHI) is the leading cause of persistent hypoglycemia in infants. The infants of diabetic mothers (IDMs) very frequently present with neonatal hypoglycemia associated to transient hyperinsulinism however the incidence of CHI in IDMs is unknown.Case presentationHere we report 2 cases of CHI where the diagnoses were challenged and delayed because both patients were infants of diabetic mothers (IDMs) and had concomitant complicated medical conditions. Case 1 was heterozygous for a likely pathogenic variant in KCNJ11(p.Arg206Cys), and Case 2 was heterozygous for a pathogenic HNF4A variant, (p.Arg267Cys). HNF4A-associated CHI is very rare, and this particular case had a clinical phenotype quite different from that of previously described HNF4A-CHI cases.ConclusionsThis case series is one of few reports in the medical literature describing two IDMs with persistent recurrent hypoglycemia secondary to CHI, and a different clinical phenotype for HNF4A-associated CHI. IDMs typically present with transient hyperinsulinism lasting no more than 2–3 days. Since being an IDM does not exclude CHI, this diagnosis should always be considered as the mostly likely etiology if neonatal hypoglycemia persists longer than the described time frame and genetic testing for CHI confirmation is highly suggested.

Congenital hyperinsulinism and Poland syndrome in association with 10p13-14 duplication.

SummaryPoland syndrome (PS) is a rare congenital condition, affecting 1 in 30 000 live births worldwide, characterised by a unilateral absence of the sternal head of the pectoralis major and ipsilateral symbrachydactyly occasionally associated with abnormalities of musculoskeletal structures. A baby girl, born at 40 weeks’ gestation with birth weight of 3.33 kg (−0.55 SDS) had typical phenotypical features of PS. She had recurrent hypoglycaemic episodes early in life requiring high concentration of glucose and glucagon infusion. The diagnosis of congenital hyperinsulinism (CHI) was biochemically confirmed by inappropriately high plasma concentrations of insulin and C-peptide and low plasma free fatty acids and β-hydroxyl butyrate concentrations during hypoglycaemia. Sequencing of ABCC8, KCNJ11 and HNF4A did not show any pathogenic mutation. Microarray analysis revealed a novel duplication in the short arm of chromosome 10 at 10p13–14 region. This is the first reported case of CHI in association with PS and 10p duplication. We hypothesise that the HK1 located on the chromosome 10 encoding hexokinase-1 is possibly linked to the pathophysiology of CHI.Learning points:Congenital hyperinsulinism (CHI) is known to be associated with various syndromes.This is the first reported association of CHI and Poland syndrome (PS) with duplication in 10p13–14.A potential underlying genetic link between 10p13–14 duplication, PS and CHI is a possibility.

Limited Value of 18F-F-DOPA PET to Localize Pancreatic Insulin-Secreting Tumors in Adults with Hyperinsulinemic Hypoglycemia

Fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-FDOPA PET) imaging is increasingly used in the workup of neuroendocrine tumors. It has been shown to be an accurate tool in the diagnosis of congenital hyperinsulinism, but limited information is available on its value in adult disease. OBJECTIVE, PATIENTS, AND DESIGN: The objective of this study was to review our experience with 18F-FDOPA PET imaging in six consecutive patients with hyperinsulinemic hypoglycemia (HH) (four solitary insulinomas, one diffuse beta-cell hyperplasia, one malignant insulinoma). 18F-FDOPA uptake was also evaluated in 37 patients (43 procedures) without HH or other pancreatic neuroendocrine tumors, which acted as a control group. Using visual analysis, 18F-FDOPA-PET proved positive in only one case (a multiple endocrine neoplasia type 1 related insulinoma). In diffuse beta-cell hyperplasia, the pancreatic uptake was similar to controls. In the patient with liver metastases, the extent of disease was underestimated. The pancreatic uptake was not statistically different between controls and hyperinsulinemic patients. The main limitation for identifying insulinomas or beta-cell hyperplasia in adults appears to be to the 18F-FDOPA uptake and retention in the whole pancreas. This drawback is potentially circumvented in focal hyperplasia in newborns due to a lower aromatic amino acid decarboxylase expression in the extralesional pancreatic parenchyma. 18F-FDOPA PET is of limited value in localizing pancreatic insulin secreting tumors in adult HH. Our results contrast with the referential study and require further analysis.

A36 PET/CT scan with 18F-FDOPA in the diagnosis of congenital hyperinsulinism in children

Zonoozi, A.a; Beaumont, P.A.b; Plant, G.c; Hussain, K.d; Hall, J.R.W.e Author Information