Hyperinsulinaemic hypoglycaemia (HH) is a term used to describe a heterogeneous group of disorders characterised by unregulated insulin secretion from pancreatic beta cells. It is the most common cause of severe and persistent hypoglycaemia in the newborn period. The incidence is approximately 1 in 50,000 live births in outbred populations, but can be as high as 1 in 2500 live births in countries with high rates of consanguinuity. HH is a major risk factor for brain injury and subsequent neurodevelopmental delay, and rapid diagnosis and intervention are required to avoid this. Advances in molecular genetics, radiological imaging techniques and laparoscopic surgery have completely changed the clinical approach to infants with the severe congenital forms of HH. This page provides an outline of the clinical presentation, the underlying molecular mechanisms and the management of congenital HH.
Hyperinsulinaemic hypoglycaemia (HH) is a term used to refer to a heterogeneous cluster of conditions that can produce hypersecretion of insulin and hypoglycaemia in the new born period, and sometimes in later life. The condition was previously referred to as nesioblastosis or congenital hyperinsulinism.
HH may be transient or permanent. Transient oversecretion of insulin occurs in babies of diabetic mothers who have been exposed to maternal hyperglycaemia before birth. Babies who have sustained perinatal asphyxia and those with intrauterine growth restriction are also at increased risk of transient HH.
Permanent HH is associated with macrosomia, due to intrauterine exposure to high levels of insulin. Most severe cases are due to mutations of a single gene, and seven genes have to date been implicated. The genetic basis of HH is undetermined in about 40% of cases. HH may also occur as a feature of the Beckwith–Wiedemann or other genetic syndromes, or very rarely as a consequence of neonatal insulinoma.
The brain is developmentally normal at delivery, since a fetus derives its glucose supply from the mother before birth, but is thereafter highly vulnerable to oversecretion of insulin. Prompt diagnosis of HH and early intervention are therefore needed to avoid lasting neurological damage.
HH most commonly presents in the newborn period, but can also present during infancy and childhood. Hypoglycaemic symptoms vary from non-specific symptoms such as poor feeding, lethargy and irritability to apnoea, seizures or coma in the most severe cases.
Two main histological subtypes have been described in patients
A) Haematoxylin and eosin staining demonstrating diffuse pancreatic disease (original magnification, 400x). An islet is shown containing large and hyperchromatic nuclei. B) Insulin labelling demonstrating a focal lesion. Increased proliferation of islet cells leaves exocrine elements to the periphery of lobules (original magnification, 40x). with HH. Focal pancreatic lesions appear as small regions of islet adenomatosis measuring 2–10 mm, which are characterised by beta cells with enlarged nuclei surrounded by normal tissue. In contrast, diffuse pancreatic disease affects all the beta cells within the islets of Langerhans. A few patients have been reported to have ‘atypical histology’. In one patient this was shown to result from somatic mosaicism for segmental UPD 11 that unmasked a recessively acting ABCC8 mutation. In the remaining patients the genetic aetiology remains unknown.
Early recognition and prompt, appropriate management are essential to avoid hypoglycaemic brain injury. An intravenous glucose infusion rate of >8 mg/kg per min (normal range 4–6 mg/kg per min) is virtually diagnostic of hyperinsulinism. Biochemically, HH is diagnosed by the demonstration of an inappropriate concentration of serum insulin (and/or C-peptide) for the level of blood glucose. The metabolic effect of this inappropriate insulin secretion is reflected by the low levels of serum ketone bodies and fatty acids during the hypoglycaemic episode. In some infants the counter-regulatory hormonal response to hypoglycaemia is blunted as demonstrated by inappropriately low serum cortisol and glucagon levels.
Once normoglycaemia (3.5–6 mmol/l) has been achieved by glucose infusion, further treatments can be introduced. The mainstay of medical therapy is diazoxide, a drug that binds to the intact SUR1 component of the ATP–sensitive potassium (KATP) channels. It acts by keeping the KATP channels open, thereby preventing depolarisation of the beta cell membrane and insulin secretion. In newborns it is used in conjunction with chlorothiazide, a diuretic with hyperglycaemic properties.
Patients who fail to respond to diazoxide may be managed with subcutaneous octreotide injections in combination with frequent feeding. Nifedipine is a calcium-channel antagonist and has been used in some patients with HH although the vast majority of patients fail to show any response.
For patients that are unresponsive to medical management it is essential to differentiate focal from diffuse disease (see histology section), as the surgical approaches are radically different. The precise preoperative localisation and limited surgical removal of the focal lesion cures the patient. In contrast, patients with diffuse disease may require a near total pancreatectomy, which is associated with a high risk of diabetes mellitus and pancreatic exocrine insufficiency. For these patients insulin and/or enzyme replacement therapy may be required.
The recent introduction of 18F-L-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET scanning) for pancreatic imaging, has revolutionised the ability to localise the focal lesion pre-operatively. The principle of the 18FDOPA-PET scan is based on the fact that pancreatic islets take up L-3,4-dihydroxyphenylalanine (L-DOPA, and convert it to dopamine by DOPA decarboxylase. The uptake of the positron emitting tracer 18F is increased in beta cells with a high rate of insulin synthesis and secretion compared with unaffected areas, which results in the visualisation of the focal lesion.
The genetics of HH
HH is a genetically heterogeneous condition with mutations in seven different genes described (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A and SLC16A1)
Schematic representation of the genetic causes of hyperinsulinaemic hypoglycaemia in the pancreatic beta cell.. Mutations in these genes are identified in just 40–50% of all cases.
KATP channel mutations Patients with inactivating KCNJ11 or ABCC8 mutations often show a poor response to diazoxide therapy. Some patients may be managed with octreotide, but many will require a partial or near total pancreatectomy. Diffuse disease results from the inheritance of a dominant or two recessively acting mutations. In contrast focal lesions result from paternal uniparental disomy (UPD) of chromosome 11p15.5–11p15.1 within a single pancreatic beta cell. The UPD unmasks the paternally inherited KATP channel mutation at 11p15.1 and causes altered expression of imprinted genes that include the maternally expressed tumor suppressor genes, H19 and CDKN1C, and the paternally expressed growth factor IGF2, at 11p15.5. This disruption in the expression of key cell cycle genes results in clonal expansion of the single cell and dysregulated insulin secretion from the resulting focal lesion. A genetic diagnosis of focal hyperinsulinism can be confirmed following surgery, by analysis of microsatellite makers on chromosome 11 to investigate loss of heterozygosity for the maternal allele within the focal lesion.
Glutamate dehydrogenase (GLUD1) Heterozygous activating mutations in the GLUD1 gene, which encodes the mitochondrial enzyme glutamate dehydrogenase (GDH), are associated with protein-sensitive HH. These patients usually present with a milder form of HH that is often diagnosed outside of the neonatal period and shows good response to diazoxide therapy. A consistent feature is the presence of hyperammonaemia with plasma ammonium levels being persistently raised to three to eight times the upper limit of normal. There is also an increased risk of epilepsy in these patients.
Hepatocyte nuclear factor 4A (HNF4A) Patients with heterozygous inactivating HNF4A mutations are often born macrosomic and may be diagnosed with hyperinsulinism within the first week of life. The clinical severity ranges from mild transient hypoglycemia that does not require pharmacological treatment to persistent HH treated with diazoxide for up to 8 years. As HNF4A mutations cause maturity onset diabetes of the young (MODY) patients will be at increased risk of developing diabetes in later life and will often have a family history of diabetes. Variable penetrance, as demonstrated by the absence of neonatal hypoglycaemia in some HNF4A mutation carriers, is often observed within families.
Glucokinase (GCK) Patients with heterozygous activating GCK mutations often have a dominant family history of hypoglycaemia, with the severity of symptoms varying markedly within and between families. The age at presentation ranges from birth to adulthood and in some cases is asymptomatic. Patients are often diazoxide responsive, however there have been a few reports of patients who have required surgery.
Hydroxyacyl-coenzyme A dehydrogenase (HADH) Recessively inherited inactivating mutations in the HADH gene cause protein-sensitive HH which responds well to diazoxide. The clinical presentation is heterogeneous with age at presentation ranging from birth to 4 months. In some patients increased plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate levels are observed.
Solute carrier family 16, member 1 (SLC16A1) Heterozygous activating mutations in the SLC16A1 gene, which encodes monocarboxylate transporter 1 (MCT-1), cause exercise-induced hyperinsulinism (EIHI). For these patients treatment is not usually necessary as hypoglycaemic episodes may be prevented by avoiding strenuous exercise.
Making a genetic diagnosis
A rapid genetic diagnosis is clinically important for patients as the mode of inheritance of a KATP channel mutation(s) can provide information regarding the histological subtype. For example the majority of patients with diffuse pancreatic disease have homozygous, compound heterozygous or dominantly acting ABCC8 or KCNJ11 mutations. In contrast patients with a paternal mutation in ABCC8 and KCNJ11 potentially have focal disease and require a 18F-DOPA-PET scan for precise pre-operative localisation of the focal lesion. Patients with genetically confirmed diffuse disease do not require further imaging studies.
A genetic diagnosis is also important for patients with diazoxide-responsive HH. For example the identification of a GLUD1 or HADH mutation will inform the clinician of the protein sensitive nature of hypoglycaemia allowing for the manipulation of diet (protein restriction) as a useful, sometimes mandatory, adjunct to diazoxide therapy.
Furthermore, the presence of a HNF4A mutation would identify patients who are at a risk of developing MODY. Unless the mutation has arisen de novo, one of the parents, and potentially other family members, will be at an increased risk of developing diabetes, if not already affected. For these patients the diabetes can be successfully managed with low dose sulphonylureas. Finally, a genetic diagnosis will also allow for an accurate recurrence risk for siblings and future offspring.
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