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Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy

Agneta Sunehag, MD, PhD
Morey W Haymond, MD
Section Editor
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Alison G Hoppin, MD


Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also referred to as congenital hyperinsulinism, familial hyperinsulinemic hypoglycemia, and primary islet cell hypertrophy (nesidioblastosis), is the most common cause of persistent hypoglycemia in neonates and infants. PHHI is a genetic disorder with both familial and sporadic forms, characterized by dysregulation of insulin secretion. Early recognition, diagnosis, and treatment are necessary to prevent or minimize neurologic damage from recurrent or prolonged episodes of hypoglycemia.

PHHI is a clinically and genetically heterogeneous disorder [1-4]. The clinical manifestations range from life-threatening hypoglycemia presenting on the first day of life to only mildly symptomatic hypoglycemia in a child or adolescent that may be difficult to identify. The response to medical and surgical therapy also varies [1-3].

An overview of the pathology, genetics, clinical features, and diagnosis of PHHI will be presented here. The treatment and complications of PHHI and a review on islet cell tumors (insulinomas), which have similar clinical and biochemical features to PHHI, are discussed in more detail separately. (See "Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy" and "Insulinoma".)


The incidence of PHHI in individuals of northern European extraction is approximately 1:30,000 live births [1,3]. The incidence is increased in genetically isolated populations with a high prevalence of consanguinity or a founder effect (eg, 1:2675 in Saudi Arabia and 1:3200 in central Finland) [5,6].


When the plasma glucose concentration decreases to below 60 mg/dL (3.3 mmol/L) in children who do not have PHHI, only small amounts of insulin are secreted. In children who have PHHI, the normal relationship between plasma glucose concentration and insulin secretion is disturbed, so that insulin is released even during periods of hypoglycemia. This disturbance of the normal feedback relationship between the plasma glucose concentration and insulin secretion can be caused by a variety of genetic mutations, as discussed below, most commonly by mutations causing abnormal function or regulation of the ATP-dependent potassium (KATP) channel of the pancreatic beta cells (figure 1) [7-9]. Other mutations interfere with the function or regulation of glutamate dehydrogenase, which is necessary for normal control of insulin secretion.


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Literature review current through: Sep 2016. | This topic last updated: Jul 11, 2016.
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