Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism.
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Congenital Hyperinsulinism↗
Biomedical subjects
K Hussain
Publications and source records attributed to K Hussain.
Prolonged hyperinsulinaemic hypoglycaemia in newborns with intrauterine growth retardation.
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Chlorothiazide↗
Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.
ATP-Binding Cassette Transporters↗
Congenital hyperinsulinism.
Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a heterogeneous disease with respect to clinical presentation, molecular biology, genetic aetiology and response to medical therapy. The clinical heterogeneity may range from severe life-threatening disease to very mild clinical symptoms. Recent advances have begun to clarify the molecular pathophysiology of this disease, but despite these advances treatment options remain difficult and there are many long-term complications. So far mutations in five different genes have been identified in patients with congenital hyperinsulinism. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). Two histological subtypes of the disease - diffuse and focal - have been described. The preoperative histological differentiation of these two subtypes is now mandatory as surgical management will be radically different. The ability to distinguish diffuse from focal lesions has profound implications for therapeutic approaches, prognosis and genetic counselling.
Animals↗
Hypoketotic hypofattyacidaemic hypoinsulinaemic hypoglycaemia in a child with hemihypertrophy? A new syndrome.
BACKGROUND: Recurrent and persistent hypoketotic, hypofattyacidaemic hypoglycaemia in infancy and childhood is most frequently due to hyperinsulinism of infancy. This biochemical profile can also be due to non-islet cell tumour hypoglycaemia or circulating insulin-receptor autoantibodies. Hyperinsulinaemic hypoglycaemia is also seen in children with the Beckwith-Wiedemann syndrome, where it is usually transient. METHODS/RESULTS: We report a novel case of child with hemihypertrophy and severe persistent hypoketotic, hypofattyacidaemic hypoinsulinaemic hypoglycaemia. No 'big' pro-IGF2 forms or circulating insulin-receptor antibodies were found. Glucose and protein isotope turnover studies showed marked suppression of hepatic glucose production during fasting. There was no evidence for constitutive autophosphorylation of the insulin or IGF-1 receptor, and no evidence for up-regulation of IGF-1 receptor. CONCLUSION: The precise pathophysiology of this novel case is still unclear.
Abnormalities, Multiple↗
Reducing ventilator-associated pneumonia rates through a staff education programme.
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in patients on mechanical ventilation and results in increases in mortality, prolonged hospitalization and costs. Preventive measures for VAP are well-documented and evidence-based, yet remain poorly implemented in most intensive care units. We undertook an observational pre and post-intervention study to assess whether an educational programme focusing on preventive practices for VAP could reduce the incidence. Six hundred and seventy-seven adult patients, mechanically ventilated for >48 h were included in the study population. An evidence-based guideline for preventive practices at the bedside was developed and disseminated to the intensive care unit staff. VAP incidence rates before and after implementation of the educational programme were compared. VAP infection rates reduced by 51%, from a mean of 13.2+/-1.2 in the pre-intervention period to 6.5+/-1.5/1000 device days in the post-intervention period (mean difference 6.7; 95% CI: 2.9-10.4, P =0.02). A multidisciplinary educational programme geared towards intensive care unit staff can successfully reduce the incidence rates of VAP. Further studies will be needed to assess the impact on broader outcome measures such as costs or mortality.
Adult↗
Hyperinsulinaemic hypoglycaemia in preterm neonates.
Hyperinsulinism in infancy (HI) is an important cause of severe and recurrent hypoglycaemia in newborn infants. It usually appears in infants born at term, and only one case of its occurrence in a prematurely born infant has been reported as an incidental finding. This is a report of seven infants born at 31-36 weeks gestation who experienced severe persistent hyperinsulinism. Two infants were large for dates. All infants were difficult to manage, suggesting that the occurrence of HI with prematurity may be associated with a particularly aggressive illness. HI should be considered in the differential diagnosis of severe hypoglycaemia in preterm infants.
Birth Weight↗
Hyperinsulinaemic hypoglycaemia in infancy and childhood--resolving the enigma.
Children with severe hypoglycaemia due to persistent hyperinsulinism in infancy (HI) generate some of the most formidable problems of management in contemporary paediatric endocrinology. Until recently its pathophysiology was an enigma, although it was thought to be due to an anatomical abnormality in the islets of Langerhans (so called 'nesidioblastosis'). During the last 6 years there has been an explosion of knowledge providing fundamental insights into the pathological mechanisms underpinning the abnormal insulin secretion. This knowledge has been facilitated by ENRHI, a programme of research funded by the European Union, which brings together clinicians and basic scientists from 14 different countries. This collaboration encompasses clinical paediatric endocrinology, intracellular biochemistry, membrane physiology and molecular biology. This collaboration has resulted in numerous publications generating new insights into the pathophysiology of HI and represents a paradigm for collaboration in paediatric endocrinology. This review article is based on a plenary lecture delivered at the European Society for Paediatric Endocrinology meeting in Montreal on behalf of the European Network for Research into Hyperinsulinism of Infancy (ENRHI).
Blood Glucose↗
Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants.
Transient hyperinsulinism (HI) occurs in infants born to diabetic mothers, in infants experiencing perinatal asphyxia and in infants with intrauterine growth retardation. The precise mechanism of transient HI in these different aetiologies is not fully understood. Lactic acidosis is commonly seen in neonates as a secondary phenomenon due to hypoxia, hypovolaemia, anaemia and infection. The combination of transient HI and lactic acidosis is rare. We present the clinical and biochemical features of five infants presenting with transient HI associated with hyperlactataemia in the absence of markers of perinatal stress. This combination lasted for 3-4 weeks with complete resolution except in one patient in whom the hyperinsulinism lasted until 6 months before resolution. The precise mechanism of this association is not clear but may be related either to immaturity of the pyruvate dehydrogenase complex or to the accumulation of abnormal intramitochondrial intermediary metabolites. Infants presenting with HI should have a free flowing blood sample drawn for the measurement of plasma lactate levels.
Acidosis↗
Haemangioma of the body of the mandible: a case report.
We present a case of haemangioma of the mandible in a 46-year-old woman. The radiological appearance was of a unilocular radiolucency that looked similar to other more common lesions of the mandible. This case shows that a potentially life-threatening haemangioma can present as an apparently benign cyst-like unilocular radiolucency, and highlights the need to include haemangioma in many differential diagnoses, and the importance of taking all radiological features into account.
Diagnosis, Differential↗
Hyperinsulinism in infancy: understanding the pathophysiology.
Hyperinsulinism in infancy (HI) is the commonest cause of persistent and recurrent hypoglycaemia in the infancy and childhood period. HI is a heterogeneous disorder with respect to clinical presentation, histology, molecular biology and genetics. Recent advances have provided unique insights into the pathophysiology of this intriguing disease as well as providing an understanding of the normal physiological and biochemical mechanisms regulating insulin secretion from pancreatic beta-cells. The histological differentiation of focal and diffuse forms of HI has radically changed the surgical management to this disease. So far mutations in five different genes have been described which lead to dysregulated insulin secretion from beta-cells. Despite these advances the genetic defect is still unknown in about 60% of cases.
3-Hydroxyacyl CoA Dehydrogenases↗
Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose-fatty acid cycle?
Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic beta-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as K(ATP) channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial beta-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.
3-Hydroxyacyl CoA Dehydrogenases↗
Basal cell adenocarcinoma in minor salivary glands.
Basal cell adenocarcinoma is a rare and relatively recently characterized malignant salivary gland tumour, the malignant counterpart of basal cell adenoma. Diagnosis depends on finding features similar to adenoma but with an infiltrative growth pattern and exclusion of adenoid cystic carcinoma, sialoblastoma and basaloid squamous carcinoma. Basal cell adenocarcinoma is very rarely reported in minor salivary glands. We report three cases of basal cell adenocarcinoma affecting the labial, buccal and palatal minor salivary glands. One recurred following complete removal but with lesional disruption and further local wide excision appeared curative. A further lesion failed to recur in 5 years' follow-up despite marginal excision and a third after 3 years' follow-up. Basal cell adenocarcinoma is considered a low-grade malignancy, and in the minor glands wide excision and radiotherapy are recommended. However, the reported lesions appear to have a more indolent behaviour than previously reported lesions in minor glands.
Adenocarcinoma↗
Transient hyperinsulinism associated with macrosomia, hypertrophic obstructive cardiomyopathy, hepatomegaly, and nephromegaly.
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Cardiomyopathy, Hypertrophic↗
Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses.
Serum cortisol plays an important role in counterregulation to hypoglycemia. It antagonizes the peripheral effects of insulin and also directly influences glucose metabolism. Classically serum cortisol concentrations rise in response to hypoglycemia, but the response in neonates with hyperinsulinemic hypoglycemia is unclear. To investigate the serum cortisol responses in neonates with hyperinsulinemic hypoglycemia, 13 neonates (34-40 wk gestation; male/female ratio, 7/6) with hyperinsulinemic hypoglycemia underwent diagnostic fasts. The serum cortisol concentration was measured before the commencement of the fast and at the time of hyperinsulinemic hypoglycemia. The hypoglycemia was then treated with iv glucose (1 ml/kg bolus of 10% dextrose), and serum cortisol concentrations were measured at 10-min intervals for a total of 50 min. Six of the 13 neonates had plasma ACTH concentrations measured at the time of hypoglycemia and then received a 62.5- microg i.v. bolus injection of Synacthen. The mean (+/-SEM) serum cortisol concentration 15 min before the hypoglycemic episode was 156 +/- 24 nmol/liter, and that at the time of hypoglycemia was 182 +/- 28 nmol/liter. Mean cortisol concentrations at 10, 20, 30, 40, and 50 min for the first seven neonates who were not given Synacthen at the time of hypoglycemia were 213 +/- 44, 223 +/- 48, 209 +/- 49, 228 +/- 46, and 252 +/- 30 nmol/liter, respectively. The six neonates who received an i.v. bolus dose of Synacthen had significantly greater (P < 0.01) serum cortisol concentrations at the same time points, 208 +/- 39, 219 +/- 46, 378 +/- 139, 664 +/- 57, 905 +/- 121, 1048 +/- 247, and 1192 +/- 105 nmol/liter, respectively. Plasma ACTH levels were inappropriately low in all six neonates at the time of hypoglycemia (mean plasma ACTH concentration, 13.2 pg/ml). Neonates with hyperinsulinemic hypoglycemia fail to generate an adequate serum cortisol counterregulatory hormonal response. This appears to be related to the lack of drive from the hypothalamic-pituitary axis, with inappropriately low plasma ACTH concentrations at the time of hypoglycemia. The normal serum cortisol response to an i.v. bolus injection of Synacthen suggests that this is a centrally mediated phenomenon and does not imply that these patients have adrenal insufficiency.
Adrenocorticotropic Hormone↗
Spontaneous hypoglycemia in childhood is accompanied by paradoxically low serum growth hormone and appropriate cortisol counterregulatory hormonal responses.
Hypoglycemia is a potent stimulus for GH and cortisol secretion. The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol responses from the hypothalamic-pituitary-adrenal axis. The serum GH and cortisol responses to spontaneous hypoglycemia in 22 children were compared with those of 16 children undergoing an ITT for diagnostic purposes. The mean serum GH and cortisol concentrations 1 h before spontaneous hypoglycemia were 6.9 +/- 1.1 mU/liter and 424 +/- 51 nmol/liter, respectively, and at the time of spontaneous hypoglycemia they were 6.7 +/- 1.3 mU/liter and 601 +/- 66 nmol/liter, respectively. The mean serum GH and cortisol values at +10, +20, +30, +40, and +50 min from the time of hypoglycemia were 5.4 +/- 1.0, 4.7 +/- 0.7, 4.6 +/- 1.0, 5.4 +/- 1.4, and 5.5 +/- 1.3 mU/liter and 633 +/- 69, 645 +/- 71, 668 +/- 70, 680 +/- 72, and 662 +/- 77 nmol/liter, respectively. There was no significant difference between any of these means for GH secretion. In contrast, in the ITT the mean serum GH concentration before hypoglycemia was 5.1 +/- 1.3 mU/liter, and at the time of hypoglycemia it was 29.2 +/- 7.30 mU/liter. The difference between these means was highly significant (P < 0.01, by t test). There was no significant difference between the cortisol response to spontaneous hypoglycemia and that to the ITT. Physiological changes in the serum nonesterified fatty acid concentration had no significant effect on serum GH secretion. In conclusion, the mechanism(s) of the serum GH response to spontaneous hypoglycemia is different from that due to the ITT. A low GH level detected at the time of spontaneous hypoglycemia does not necessarily imply GH deficiency or GH as a cause of the hypoglycemia.
Blood Glucose↗
Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.
We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy.
Adenoma, Islet Cell↗
Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.
A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.
3-Hydroxyacyl CoA Dehydrogenases↗