Basics
Description
Hyperinsulinism (HI) is a disorder of dysregulated insulin secretion resulting in hypoglycemia. Congenital HI refers to a permanent inborn condition, other forms can be transient. é á
Epidemiology
Most common cause of persistent or recurrent hypoglycemia in children é á
Incidence
- Annual incidence estimated at ó ł ╝1:40,000 " ô50,000 live births in United States.
- May be as high as 1:2,500 in select populations (Saudi Arabians, Ashkenazi Jews)
Genetics
- KATPHI: inactivating mutations in KATP channel genes ABCC8 and KCNJ11 (on 11p15)
- Mutations inherited in an autosomal recessive manner result in diffuse involvement throughout the pancreas (diffuse HI).
- Autosomal dominantly inherited mutations can also rarely cause diffuse HI.
- Non-Mendelian inheritance: A paternally inherited recessive mutation of KATP channel gene and a loss of maternal alleles on the imprinted chromosome region 11p15, leads to paternal uniparental disomy; results in focal adenomatous lesion (focal HI)
- Glucokinase-HI: autosomal dominant " ôactivating mutations of glucokinase (GCK)
- GDH-HI: autosomal dominant " ôactivating mutations of glutamate dehydrogenase (GDH), encoded by GLUD1; known as hyperinsulinism/hyperammonemia (HI/HA) syndrome
- SCHAD-HI: autosomal recessive mutations of mitochondrial enzyme short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD), encoded by HADH
- UCP2-HI: autosomal dominant mutations of mitochondrial carrier uncoupling protein 2 (UCP2), encoded by UCP2
- HNF4A and HNF1A-HI: autosomal dominant mutations in transcription factors, HNF4A and HNF1A. Mutations in HNF4A and HNF1A also are known to cause familial monogenic diabetes.
- MCT1-HI: autosomal dominant mutations in the regulatory region of SLC16A1 " ôencoding monocarboxylate transporter 1 (MCT1)
- Causes exercise-induced HI
Pathophysiology
- These mutations result in uncoupling of insulin secretion from the glucose-sensing machinery of the pancreatic Ä ▓ cell.
- Leads to inappropriate insulin secretion even in the face of low plasma glucose concentrations
- In the absence of functional KATP channels, plasma membrane is depolarized leading to opening of voltage-dependent calcium channels and constant insulin secretion.
- In the focal form of the disease ( ó ł ╝60% of cases), a cluster of pancreatic Ä ▓ cells are affected, whereas in diffuse HI, all Ä ▓ cells are abnormal.
- In HI/HA syndrome, activating mutations of GDH (an enzyme that regulates amino acid " ôstimulated insulin secretion) cause dysregulated insulin secretion (particularly after ingestion of protein) and persistently elevated ammonia levels.
- Glucokinase acts as "glucose sensor " Ł of the Ä ▓ cell. Activating mutations result in lower glucose threshold for insulin secretion.
- SCHAD is an inhibitory regulator of GDH. Inactivating mutations of HADH result in insulin dysregulation due to loss of GDH inhibition.
- UCP2 is a negative regulator of insulin secretion. Loss-of-function mutations lead to HI.
- In exercise-induced HI, ectopic expression of MCT1 allows transport of pyruvate, elevated during anaerobic exercise, into the Ä ▓ cell; leads to an increased ATP-to-ADP ratio, thus stimulating insulin secretion
Etiology
- Mutations in 9 genes have been associated with congenital HI: Genes coding for the two subunits of the Ä ▓ cell KATP channel [SUR1, sulfonylurea receptor (ABCC8); Kir6.2, inwardly rectifying potassium channel (KCNJ11)]; glucokinase (GCK), glutamate dehydrogenase (GLUD1), SCHAD (HADH), UCP2 (UCP2), HNF4A, HNF1A and monocarboxylate transporter-1 (SLC16A1).
- 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.
Commonly Associated Conditions
HI can be associated with Beckwith-Wiedemann syndrome and congenital disorders of glycosylation (CDG). The underlying mechanism of HI in these disorders is not clear. é á
Diagnosis
History
- Symptoms of hypoglycemia in the infant:
- Poor feeding
- Hypotonia
- Lethargy
- Cyanosis
- Tachypnea
- Tremors
- Seizures
- May have high IV glucose infusion requirements (>10 mg/kg/min)
Alert
Infants with severe hypoglycemia may be asymptomatic. é á
Physical Exam
- Large for gestational age
- Small for gestational age
- Suggests transient HI or CGD
- Macroglossia, umbilical hernia, hemihypertrophy
- Suggest Beckwith-Wiedemann syndrome
- No midline defects, including normal palate and genitalia
- Midline defects suggest hypopituitarism as cause of hypoglycemia.
Diagnostic Tests & Interpretation
Lab
- Obtain critical sample at time of hypoglycemia (plasma glucose <50 mg/dL).
- Evidence of excess insulin action at time of hypoglycemia:
- May have detectable insulin
- Suppressed levels of Ä ▓-hydroxybutyrate (<0.6 mm) and free fatty acids (< 0.5 mm)
- Glycemic response to 1 mg glucagon (blood glucose rise >30 mg/dL in 40 minutes)
- Elevated plasma ammonia levels
- Elevated plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate
- Low cortisol and growth hormone at time of hypoglycemia is not diagnostic of adrenal insufficiency/growth hormone deficiency.
- Perform appropriate stimulation tests to confirm.
Alert
Insulin levels may not be elevated or detectable at time of hypoglycemia in some patients with HI. Base diagnosis on other evidence of insulin excess. é á
Imaging
- 18F-DOPA PET scans at specialized HI centers to identify and to localize focal lesions
- Traditional imaging studies such as US, CT scan, and MRI are not helpful in identifying focal HI lesions.
Pathologic Findings
- Two major forms of pancreatic histology in children with HI due to KATP channel mutations:
- Diffuse HI: abnormally enlarged islet cell nuclei found throughout the pancreas
- Focal HI: discrete area of islet cell hyperplasia surrounded by normal pancreas
Differential Diagnosis
- Infant of diabetic mother (IDM)
- Beckwith-Wiedemann syndrome
- Neonatal (pan)hypopituitarism
- Congenital disorders of glycosylation
- Children with dumping syndrome after fundoplasty can have severe postmeal hypoglycemia due to excessive insulin secretion after a meal.
Treatment
Additional Therapies
General Measures
- The major goal is prevention of brain damage.
- IV dextrose infusions should be given to stabilize blood glucose acutely.
- For an acute hypoglycemic event, give a bolus of 2 " ô3 mL/kg of 10% dextrose (0.2 " ô0.3 g/kg).
- Use dextrose infusion to maintain blood glucose >70 mg/dL.
- May require central line to administer higher concentrations of dextrose and to avoid fluid overload
- Frequent oral feeds are not sufficient as treatment for hypoglycemia due to HI.
Medication
- Diazoxide, a KATP channel agonist, at 5 " ô15 mg/kg/24 h PO divided q12h
- Most KATPHI patients do not respond.
- Patients with HI/HA, SCHAD-HI, or transient HI typically respond well.
- Diuretic may be necessary due to fluid retention.
- Octreotide, a somatostatin analog, at 5 " ô20 mcg/kg/24 h divided q6h or given by continuous IV infusion at 0.08 " ô0.40 mcg/kg/h
- Tachyphylaxis and hyperglycemia may occur.
- May increase the risk of necrotizing enterocolitis in neonates
- Glucagon, at 1 mg/24 h by continuous IV infusion, may stabilize blood glucose levels prior to surgery.
Surgery/Other Procedures
- Pancreatectomy in children refractory to medical therapy or in those with focal lesions. Near total pancreatectomy with gastrostomy tube for those with diffuse disease. Resection of pancreatic adenomatous lesion for focal disease
- For focal HI, surgery can be curative.
Ongoing Care
Follow-up Recommendations
- Up to 30 " ô44% of patients can have neurodevelopmental abnormalities due to hypoglycemia.
- Patients who undergo near total pancreatectomy are at very high risk of developing diabetes later in life.
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 or poor oral intake.
- Follow-up fasting studies may be needed to evaluate safety and/or disease regression.
- Diazoxide may cause fluid retention and hypertrichosis.
- Neonates treated with octreotide should be closely monitored for evidence of necrotizing enterocolitis.
- Octreotide can suppress GH secretion, so close observation of linear growth is necessary. Thyroid function tests should also be monitored.
- Evaluation of pancreatic exocrine function after near-total pancreatectomy
- Periodic neurodevelopmental assessments
Diet
- Avoidance of long fasts
- Avoidance of protein loads in those with HI/HA, SCHAD, and KATPHI, as high-protein diets may stimulate insulin secretion
Complications
- Severe refractory hypoglycemia
- Cognitive deficits
- Seizures
- Coma
- Permanent brain damage
- Glucose intolerance or frank diabetes mellitus after pancreatectomy
- Pancreatic exocrine insufficiency after pancreatectomy
Additional Reading
- Beltrand é áJ, Caquard é áM, Arnoux é áJB, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care. 2012;35(2):198 " ô203. é á[View Abstract]
- De Le â │n é áDD, Stanley é áCA. Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Prac Endocrinol Metab. 2007;3(1):57 " ô68. é á[View Abstract]
- Hoe é áFM, Thornton é áPS, Wanner é áLA, et al. Clinical features and insulin regulation in infants with syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006;148(2):207 " ô212. é á[View Abstract]
- Laje é áP, States é áLJ, Zhuang é áH, et al. Accuracy of PET/CT scan in the diagnosis of the focal form of congenital hyperinsulinism. J Pediatr Surg. 2013;48(2):388 " ô393. é á[View Abstract]
- Lord é áKL, De Le â │n é áDD. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol. 2013;2013(1):3. é á[View Abstract]
- Meissner é áT, Wendel é áU, Burgard é áP, et al. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol. 2003;149(1):43 " ô51. é á[View Abstract]
- Otonkoski é áT, Jiao é áH, Kaminen-Ahola é áN, et al. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet. 2007;81(3):467 " ô474. é á[View Abstract]
- Palladino é áAA, Stanley é áCA. A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):32 " ô37. é á[View Abstract]
Codes
ICD09
- 251.1 Other specified hypoglycemia
ICD10
SNOMED
- 83469008 Hyperinsulinism (disorder)
FAQ
- Q: What is the chance of HI in the sibling of an affected child?
- A: 25% in the autosomal recessive type; 50% in the autosomal dominant type; <1% for siblings of children with focal HI
- 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 " ô70-mg/dL range; symptoms of hypoglycemia present at the 50 " ô55-mg/dL level, and cognitive dysfunction occurs when blood glucose levels are in the 45 " ô50-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 ó ł ╝40 " ô50% of cases are controlled with medication alone. Patients with KATPHI may be more likely to require surgery, and in those patients with focal disease, surgery can be curative. Perinatal stress " ôinduced HI usually resolves within the first 6 months of life.