Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough (original) (raw)
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The Focal Form of Persistent Hyperinsulinemic Hypoglycemia of Infancy
Diabetes, 2003
Paternal mutation of ATP-sensitive K+ (KATP) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters of β-cells surrounded by non–β-cells. Compared with adjacent islets, proinsulin mRNA is similar and proinsulin production higher (P ≤ 0.02), indicating regulation at a translational level, with slightly lower insulin stock and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of β-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P ≤ 0.02), and higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast ...
Hyperinsulinemic Hypoglycemia in Infancy: Current Concepts in Diagnosis and Management
Indian pediatrics, 2015
Molecular basis of various forms of hyperinsulinemic hypoglycemia, involving defects in key genes regulating insulin secretion, are being increasingly reported. However, the management of medically unresponsive hyperinsulinism still remains a challenge as current facilities for genetic diagnosis and appropriate imaging are limited only to very few centers in the world. We aim to provide an overview of spectrum of clinical presentation, diagnosis and management of hyperinsulinism. We searched the Cochrane library, MEDLINE and EMBASE databases, and reference lists of identified studies. Analysis of blood samples, collected at the time of hypoglycemic episodes, for intermediary metabolites and hormones is critical for diagnosis and treatment. Increased awareness among clinicians about infants at-risk of hypoglycemia, and recent advances in genetic diagnosis have made remarkable contribution to the diagnosis and management of hyperinsulinism. Newer drugs like lanreotide a long acting so...
Reviews in Endocrine and Metabolic Disorders, 2020
Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-1...
Effects of Hypoglycemia on Developmental Outcome in Children With Congenital Hyperinsulinism
Journal of Pediatric Nursing, 2005
Children with congenital hyperinsulinism are at risk for recurring, severe episodes of hypoglycemia that can cause seizures, brain damage, and developmental delay. To assess the frequency of permanent brain damage in this disorder, we carried out a telephone survey of 68 children who presented to The Children's Hospital of Philadelphia between 1980 and 2000. One third of the group had some degree of developmental delay. Those presenting in the first week of life and those with medically unresponsive hyperinsulinism were more likely to have delays. Early recognition and control of hypoglycemia are essential for preventing developmental delay in these children.
Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy
Hormone Research in Paediatrics, 2007
Hyperinsulinaemic hypoglycaemia is a cause of persistent hypoglycaemia in the neonatal and infancy periods. Prompt recognition and management of patients with hyperinsulinaemic hypoglycaemia are essential, if brain damage and long-term neurological sequelae are to be avoided. Hyperinsulinaemic hypoglycaemia can be transient, prolonged, or persistent (congenital). Advances in the fields of molecular biology, genetics, and pancreatic β-cell physiology are beginning to provide novel insights into the mechanisms causing congenital forms of hyperinsulinism. So far mutations in six different genes have been described that lead to unregulated insulin secretion. The histological differentiation of focal and diffuse congenital hyperinsulinism has radically changed the surgical approach to this disease. Until recently, highly invasive investigations were performed to localize the focal lesion, but recent experience with 18F-L-dopa positron emission tomography scanning suggests that this techn...
Frontiers in endocrinology, 2017
Congenital hyperinsulinism (CHI) is a heterogeneous disease most frequently caused by KATP-channel (ABCC8 and KCNJ11) mutations, with neonatal or later onset, variable severity, and with focal or diffuse pancreatic involvement as the two major histological types. CHI confers a high risk of neurological impairment; however, sparsely studied in larger patient series. We assessed the neurodevelopmental outcome in children with CHI at follow-up in a mixed international cohort. In two hyperinsulinism expert centers, 75 CHI patients were included (Russian, n = 33, referred non-Scandinavian, treated in Denmark n = 27, Scandinavian, n = 15). Hospital files were reviewed. At follow-up, neurodevelopmental impairment and neurodevelopmental, cognitive and motor function scores were assessed. Median (range) age at follow-up was 3.7 years (3.3 months-18.2 years). Neurodevelopmental impairment was seen in 35 (47%). Impairment was associated with abnormal brain magnetic resonance imaging (MRI); odd...
Clinical Endocrinology, 2012
Objective Hypoglycaemia-associated autonomic failure (HAAF) with impaired neurogenic and neuroglycopaenic responses occurs in adults following recent, repeated hypoglycaemia. We aimed to evaluate whether HAAF also occurs in patients with infant-onset congenital hyperinsulinism (CHI). Design, patients A controlled fast was performed in (i) seven CHI infants with initial symptomatic hypoglycaemia and three recent episodes of spontaneous recurrent hypoglycaemia each lasting <5 min and in (ii) seven infants with idiopathic ketotic hypoglycaemia for control. Measurements At the time of hypoglycaemia (blood glucose <3 mmol/l or clinical signs), blood was drawn for serum insulin, cortisol, glucagon, adrenalin and nor-adrenalin. Signs of hypoglycaemia were documented. In CHI patients, the ABCC8 and KCNJ11 genes were analysed by denaturing high performance liquid chromatography (DHPLC) and/or direct bidirectional sequencing. Results Two CHI patients had a paternal ABCC8 mutation, five had no mutations. When repeated hypoglycaemia was provoked, all CHI patients exhibited a complete loss of clinical signs of hypoglycaemia, along with a global blunting of the counter-regulatory hormones cortisol, glucagon, growth hormone, adrenalin and noradrenalin responses (median values 256 nmol/l, 23 pmol/l, 5AE6 mU/l, 390 pmol/l and 2AE9 nmol/l, respectively), irrespective of mutational status. In the controls, hypoglycaemia was always clinically overt with normal counter-regulatory cortisol, glucagon, adrenalin and nor-adrenalin responses (530 nmol/l, 60, 920 pmol/l and 4AE0 nmol/l, respectively). Conclusion Recurrent hyperinsulinaemic hypoglycaemia even of short duration blunts the autonomic, neuroglycopaenic and
Congenital hyperinsulinism: current trends in diagnosis and therapy
Orphanet Journal of Rare Diseases, 2011
Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18 F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.