Hyperinsulinism/Hypoglycemia
Hyperinsulinism/Hypoglycemia: Excerpt from The 5-Minute Pediatric Consult
Vaneeta Bamba, MDDiva D. De León-Crutchlow, MD
Hyperinsulinism/Hypoglycemia - BASICS
Hyperinsulinism/Hypoglycemia - description
Hyperinsulinism (HI) is a disorder of dysregulated insulin secretion characterized by excessive and/or inappropriate insulin secretion resulting in severe hypoglycemia. Congenital HI refers to a permanent inborn condition.
Hyperinsulinism/Hypoglycemia - epidemiology
Most common cause of persistent or recurrent hypoglycemia in children beyond the immediate neonatal period.
Hyperinsulinism/Hypoglycemia - incidence
- Annual incidence estimated at ~1:40,000–50,000 live births
- May be as high as 1:2,500 in select populations (Saudi Arabians, Ashkenazi Jews)
Hyperinsulinism/Hypoglycemia - genetics
- Autosomal recessive mutations of KATP channel genesat chromosomal locus 11p14-15.1 resulting in diffuse involvement throughout the pancreas (diffuse HI)
- Autosomal dominant mutations of KATP channel
- A nonmendelian mode of inheritance with reduction to homozygosity (or hemizygosity) of paternally inherited mutation of KATP channel gene, and a specific loss of maternal alleles of the imprinted chromosome region 11p15 (focal HI).
- Autosomal dominant mutations of glucokinase (GCK): Activating mutations in the glucokinase gene
- Autosomal dominant mutations of glutamate dehydrogenase (GLUD-1): Known as hyperinsulinism/hyperammonemia syndrome owing to activating mutations of glutamate dehydrogenase (GDH) enzyme
- Autosomal recessive mutations of the mitochondrial enzyme short-chain-3-dydroxyacyl-CoA dehydrogenase (SCHAD; encoded by HADHSC)
Hyperinsulinism/Hypoglycemia - pathophysiology
- These mutations result in uncoupling of insulin secretion from the glucose-sensing machinery of the pancreatic beta cell, and inappropriate insulin secretion even in the face of low blood glucose.
- The most common and severe forms of HI arise from mutations in the KATP channel, which can manifest in focal or diffuse disease
- In hyperinsulinism/hyperammonemia syndrome, protein inappropriately stimulates insulin secretion and causes persistently elevated ammonia level. This is due to mutations in glutamate dehydrogenase.
Hyperinsulinism/Hypoglycemia - etiology
- Mutations in 5 genes have been associated with congenital HI: Genes coding for either of the 2 subunits of the beta cell KATP channel [SUR1, sulfonylurea receptor (ABCC8); Kir6.2, inwardly rectifying potassium channel (KCNJ11)], glucokinase (GCK), glutamate dehydrogenase (GLUD-1), and SCHAD (HADHSC).
- A transient form of HI has been associated with perinatal stress (small for gestational age [SGA] birth weight, maternal hypertension, precipitous delivery, or hypoxia), but the mechanism has not been elucidated.
Hyperinsulinism/Hypoglycemia - associated conditions
Hyperinsulinism can be associated with Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The underlying mechanism of hyperinsulinism in these disorders is not clear.
Hyperinsulinism/Hypoglycemia - DIAGNOSIS
Hyperinsulinism/Hypoglycemia - signs & symptoms
Hyperinsulinism/Hypoglycemia - history
Symptoms of hypoglycemia in the infant:
- Poor feeding
- Hypotonia
- Lethargy
- Cyanosis
- Tachypnea
- Tremors
- Seizures
- Early-morning irritability that responds to feeding
Hyperinsulinism/Hypoglycemia - physical exam
- Macrosomia:
- Suggests congenital HI due to mutations in the KATP channel
- Small for gestational age:
- Macroglossia, umbilical hernia, visceromegaly:
- Suggest Beckwith Wiedeman syndrome
- No midline defects, including normal palate and genitalia
- Midline defects suggest hypopituitarism.
Hyperinsulinism/Hypoglycemia - tests
Hyperinsulinism/Hypoglycemia - lab
- Plasma insulin levels are rarely dramatically elevated in HI; rather there is inadequate suppression of insulin (>2 μU/mL) at time of hypoglycemia.
- Suppressed levels of plasma free fatty acids (<1.5 mmol/L) and ketones (β-hydroxybutyrate level <2.0 mmol/L) at time of hypoglycemia:
- Indirect signs of excessive insulin action
- Glycemic response to glucagon (blood sugar rise >30 mg/dL) at time of hypoglycemia:
- Indicates inappropriately stored glycogen at time of hypoglycemia (sign of excessive insulin action)
- Suppressed insulinlike growth factor binding protein-1 (IGFBP-1) level:
- IGFBP-1 production is inhibited by insulin (sign of excessive insulin action).
- Elevated plasma ammonia levels:
- Suggest hyperinsulinism/hyperammonemia syndrome
- Elevated plasma 3-hydroxybutyryl-carnitine and urinary 3-hydroxyglutarate suggests SCHAD
- Normal growth hormone, cortisol, and thyroxine levels:
Hyperinsulinism/Hypoglycemia - imaging
At specialized hyperinsulinism centers, PET scans may be performed using uniquely mixed 18-fluoro-DOPA to identify focal or diffuse lesions, which may be helpful in deciding to pursue medical or surgical therapy in patients with congenital HI.
Hyperinsulinism/Hypoglycemia - pathological findings
- Pancreatic histology in children with HI due to KATP channel mutations can be subdivided into 2 major forms:
- Diffuse HI: Abnormally enlarged islet cell nuclei found diffusely throughout the pancreas
- Focal HI (40–60% of cases): Discrete region of adenomatous hyperplasia surrounded by normal-appearing pancreas
- Normal histology can also be seen in HI.
Hyperinsulinism/Hypoglycemia - differencial diagnosis
- Sepsis
- Congenital heart disease
- Infant of diabetic mother (IDM)
- Beckwith-Wiedemann syndrome (BWS)
- Panhypopituitarism
- Congenital disorders of glycosylation
- Respiratory distress syndrome
- Erythroblastosis fetalis
- Other inborn errors of metabolism
Hyperinsulinism/Hypoglycemia - TREATMENT
Hyperinsulinism/Hypoglycemia - general measures
The major goal is prevention of brain damage by controlling blood glucose:
- Parenteral dextrose infusions to stabilize blood sugar acutely: For an acute hypoglycemic event, give a bolus of 2–3 mL/Kg of 10% dextrose (0.2–0.3g/kg). For maintenance, use glucose infusion rates of 8–10 mg/kg/min to maintain BG >70 (some HI patients may need up to 25 mg/kg/min).
- Supplemental oral or nasogastric/G tube feeds
Hyperinsulinism/Hypoglycemia - diet
- Frequent feedings and avoidance of long fasts
- Avoidance of protein loads in those with hyperinsulinism/hyperammonemia, as high-protein diets may stimulate insulin secretion
Hyperinsulinism/Hypoglycemia - medication
- Diazoxide, a suppressant of insulin secretion, at 5–15 mg/kg/d divided q12h (most patients with KATP HI do not respond to diazoxide)
- Octreotide, a long-acting somatostatin analog, at 5–20 mcg/kg/d divided q6h or given by continuous SC infusion
- Glucagon, at 1 mg/d by continuous IV infusion, may stabilize blood glucose levels in preparation for surgery.
Hyperinsulinism/Hypoglycemia - surgery
- Subtotal pancreatectomy in children refractory to medical therapy or in those with focal lesions
- For focal HI, surgical resection of lesion can be curative.
Hyperinsulinism/Hypoglycemia - FOLLOW UP
Hyperinsulinism/Hypoglycemia - prognosis
- Up to 30–44% of patients can have neurodevelopmental retardation due to hypoglycemia
- Diabetes may develop later in life, especially after pancreatectomy
Hyperinsulinism/Hypoglycemia - complications
- Severe refractory hypoglycemia
- Cognitive deficits, especially short-term memory, visual-motor integration, and arithmetic skills
- Seizures
- Coma
- Permanent brain damage
- Glucose intolerance or frank diabetes mellitus after treatment
Hyperinsulinism/Hypoglycemia - patient monitoring
- Home blood glucose monitoring, especially with longer fasts or intercurrent illnesses
- Hospitalizations for IV glucose infusions may be necessary during intercurrent illnesses with vomiting.
- Follow-up fasting studies may be needed to evaluate safety and/or disease regression.
- Diazoxide may cause fluid retention and hypertrichosis.
- Tachyphylaxis and hyperglycemia may occur with octreotide.
- Close observation of linear growth is necessary, because octreotide can suppress GH secretion.
Hyperinsulinism/Hypoglycemia - bibliography
- Bruining GJ. Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr. 1990;2:758–765.
- Clayton PT, Eaton S, Aynsley-Green A, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest. 2001;108:457–465.
- De León DD, Stanley CA. Mechanisms of disease: Advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Prac Endocrinol Metab. 2007;3(1):57–68.
- De Lonlay P, Fournet J-C, Rahier J, et al. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest. 1997;100:802–807.
- Dunne MJ, Cosgrove KE, Sheperd RM, et al. Hyperinsulinism in infancy: From basic science to clinical disease. Physiol Rev. 2004;84:239–275.
- Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998;338:226–230.
- Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in infants with syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006;148:207–212.
- Meissner T, Wendel, U. Burgard P, et al. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol. 2003;149:43–51.
- Nestorowicz A, Inagaki N, Gonoi T, et al. A nonsense mutation in the inward rectifier potassium channel gene, Kir 6.2, is associated with familial hyperinsulinism. Diabetes. 1997;46:1743–1748.
- Stanley CA. Hyperinsulinism in infants and children. Pediatr Clin North Am. 1997;44:363–374.
- Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338:1352–1357.
- Suchi M, MacMullen C, Thornton PS, et al. Histopathology of congenital hyperinsulinism: Retrospective study with genotype correlations. Pediatr Dev Pathol. 2003;6(Jul-Aug):322–333.
- Thornton PS, MacMullen C, Ganguly A, et al. Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor. Diabetes. 2003;52:2403–2410.
Hyperinsulinism/Hypoglycemia - CODES
Hyperinsulinism/Hypoglycemia - icd9
- 251.1 Other specified hypoglycemic hyperinsulinism: NOS, ectopic, functional, hyperplasia of pancreatic islet beta, cells (NOS)
- 251.2 Hypoglycemia unspecified hypoglycemia: NOS, reactive, spontaneous
- 775.6 Neonatal hypoglycemia
Hyperinsulinism/Hypoglycemia - FAQ
- Q: What is the chance of hyperinsulinism in the sibling of an affected child?
- A: 25% in the autosomal-recessive type; as high as 50% in the autosomal-dominant type
- Q: How low and for how long can glucose go before brain damage occurs?
- A: The definition of hypoglycemia has been the subject of controversy in pediatrics, but activation of glucose counterregulatory systems occurs when blood glucose levels reach the 65–70 mg/dL range; symptoms of hypoglycemia present at the 50–55 mg/dL level, and cognitive dysfunction occurs when blood glucose levels are in the 45–50 mg/dL range. Taking these data into account, blood glucose concentration should be maintained >70 mg/dL. The duration of hypoglycemia necessary for brain damage to occur is unknown.
- Q: What is the chance that HI will eventually resolve without surgery?
- A: Only ~40–50% of cases are controlled with medication alone. Patients with mutations in KATP channel may be more likely to require surgery, and in those patients with focal disease, surgery may be curative.
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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