eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Persistent Hyperinsulinemic Hypoglycemia of Infancy

Author: Robert S Gillespie, MD, MPH, Consulting Staff, Department of Nephrology, Cook Children's Medical Center
Coauthor(s): Stephen Ponder, MD, CDE, Director, Division of Pediatric Endocrinology, Department of Pediatrics, Driscoll Children's Hospital; Professor, Texas A&M College of Medicine
Contributor Information and Disclosures

Updated: Nov 7, 2008

Introduction

Background

In 1938, Laidlaw coined the term nesidioblastosis to describe the neodifferentiation of islets of Langerhans from pancreatic ductal epithelium.1 Severe recurrent hypoglycemia associated with an inappropriate elevation of serum insulin, C-peptide, and proinsulin defines this disorder. The disorder later was called persistent hyperinsulinemic hypoglycemia of infancy (PHHI); currently, many authors prefer the term congenital hyperinsulinism (CHI). PHHI represents the most common cause of hyperinsulinism in neonates. If left untreated, PHHI can lead to brain damage or death secondary to severe hypoglycemia. Although PHHI was initially thought to affect only infants and children, numerous cases have been reported in adults of all ages but at a much lower incidence. PHHI is often poorly responsive or unresponsive to medical management, necessitating 95% or near-total pancreatectomy.

Pathophysiology

In PHHI, the histologic abnormalities in pancreatic structure are heterogeneous but can be grouped into 2 broad categories: (1) focal adenomatous hyperplasia (found in one fourth to one third of cases) and (2) a diffuse abnormality of the islets. In the focal form, the histologically abnormal beta cells are limited to 1 or more focal areas, whereas in the diffuse form, the beta-cell abnormality is distributed throughout the pancreas.

Recent advances in elucidating the molecular basis of PHHI have led to the discovery of mutations in the sulfonylurea receptor and an inwardly rectifying potassium channel. However, approximately 50% of cases do not involve any currently known mutation.

Presumed structural or functional molecular abnormalities in the insulin secretory mechanism or glucose-sensing mechanism result in a failure to reduce pancreatic insulin secretion in the presence of hypoglycemia (serum glucose level <60 mg/dL). Inappropriately high circulating insulin levels act to promote hepatic and skeletal muscle glycogenesis, causing a decrease in the amount of free glucose available in the bloodstream and suppression of the formation of free fatty acid (FFA), an alternative energy substrate for the brain. The net effect is hypoglycemia, which results in physiologically appropriate adrenergic and neuroglycopenic symptoms, with severe neurologic dysfunction and frank seizure activity when CNS glucose levels fall below 20-30 mg/dL.

Prolonged hypoglycemia causes death. Repeated episodes of severe, prolonged, sublethal hypoglycemia can result in permanent neurologic damage, including developmental delay, mental retardation, and focal CNS deficits. Therapy should be aimed at prevention of hypoglycemia to prevent morbidity and mortality.

Frequency

United States

Few data are available regarding PHHI. An estimated incidence of 1 in 50,000 live births in a random-mating population has been reported.

International

Again, few data are available on PHHI. The incidence may be as high as 1 in 2500 live births in populations with high rates of consanguineous unions.

Mortality/Morbidity

Permanent neurologic dysfunction (eg, seizures, developmental delay, focal neurologic deficits) or death secondary to severe, prolonged hypoglycemia may occur if PHHI goes untreated or is inadequately treated.

Sex

The diffuse form of PHHI has a male-to-female ratio of 1.2:1. Focal lesions are found in a 1.8:1 male-to-female ratio. The overall male-to-female ratio is 1.3:1.

Age

Patients with PHHI usually present from birth to age 18 months, with most cases diagnosed shortly after birth. Cases of adult-onset forms of PHHI are rare but well documented.

Clinical

History

The following may be observed in the history of patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI).

  • Most patients with PHHI present shortly after birth with symptoms of hypoglycemia (eg, hunger, jitteriness, lethargy, apnea, seizures). Older children, in addition to the above symptoms, may also show diaphoresis, confusion, or unusual mood or behavior changes.
  • Hypoglycemia is persistent, requiring frequent or continuous glucose infusions or feedings to maintain adequate blood glucose levels.
  • Presenting symptoms of PHHI reported in adults include confusion, headaches, dizziness, syncope, and loss of consciousness. The symptoms may be exacerbated by fasting and may improve after eating.

Physical

A thorough physical examination is essential. The physical examination findings are usually normal when the patient is euglycemic. No characteristic visual, auscultatory, or tactile findings are associated with PHHI.

  • The presence of hepatomegaly suggests a metabolic disorder, such as glycogen storage disease, galactosemia, or fructosemia.
  • The presence of syndromic or dysmorphic features suggests a different diagnosis. PHHI is not usually associated with a genetic syndrome or characteristic physical features.
  • Infants may be large for their gestational age because of the influence of chronic hyperinsulinism in utero.
  • Older children and adults may have signs of residual neurologic damage from episodes of prolonged hypoglycemia. These signs may widely vary.

Causes

PHHI is a clinically, pathologically, and genetically heterogeneous disease.

  • Most cases of PHHI are sporadic. In approximately 50% of cases, no known genetic abnormality is found.
  • Familial forms of PHHI are rare but well documented. These cases of PHHI involve autosomal recessive or dominant defects in 4 genes.
    • Beta-cell high-affinity sulfonylurea receptor gene (ABCC8, also known as SUR1)
    • Inwardly rectifying potassium channel gene (KCNJ11, also known as Kir6.2)
    • Glucokinase gene (GCK, also called GK): Only 5 persons have been described with this mutation.
    • Glutamate dehydrogenase gene (GLUD1, also called GUD1): This gene is associated with hyperinsulinism with hyperammonemia. It is unclear whether this disorder (described below) is a variant of persistent hyperinsulinemic hypoglycemia of infancy or a distinct clinical entity.
  • Some data have helped elucidate the mechanism of the focal form of PHHI. In the focal form, data have shown that a specific loss of maternal alleles occurs in the imprinted chromosome region 11p15 in the cells of the hyperplastic area, but no loss occurs in the normal pancreatic cells. This loss of heterozygosity results in a reduction to hemizygosity or homozygosity of the remaining paternal alleles that carry a mutation of ABCC8 (SUR1) or KCNJ11 (Kir6.2). This abnormality occurs during embryonic development in a single pancreatic cell, resulting in a proliferative monoclonic lesion. However, other pancreatic cell lines not derived from this cell, as well as all other cells of the body, do not carry this genetic defect. The result is similar to uniparental disomy, but it occurs only in a clonal cell line and not constitutionally. This is a nonmendelian mechanism. This abnormality has not been observed in patients with the diffuse form of PHHI.
  • High rates of consanguinity have been noted in some series.
  • No known genetic abnormalities have been found in approximately half (in some series, the majority) of the patients studied, suggesting the existence of other mutations that have not yet been described.
  • See the references by Glaser2 and Fournet3 for a more detailed treatment of the genetics of hyperinsulinism.
  • Adult-onset hyperinsulinemic hypoglycemia with pancreatic beta cell hypertrophy has been reported in adults undergoing Roux-en-Y gastric bypass surgery.4  The relationship between the surgery and the pancreatic disease remains poorly understood. Service and colleagues theorize that gastric bypass may increase activity of beta-cell trophic factors.

More on Persistent Hyperinsulinemic Hypoglycemia of Infancy

Overview: Persistent Hyperinsulinemic Hypoglycemia of Infancy
Differential Diagnoses & Workup: Persistent Hyperinsulinemic Hypoglycemia of Infancy
Treatment & Medication: Persistent Hyperinsulinemic Hypoglycemia of Infancy
Follow-up: Persistent Hyperinsulinemic Hypoglycemia of Infancy
Multimedia: Persistent Hyperinsulinemic Hypoglycemia of Infancy
References
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Further Reading

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Keywords

persistent hyperinsulinemic hypoglycemia of infancy, PHHI, nesidioblastosis, congenital hyperinsulinism, CHI, islet cell dysmaturation syndrome, islet cell adenomatosis, nesidioblastoma, familial hyperinsulinism with pancreatic nesidioblastosis, focal adenomatous hyperplasia, diffuse discrete beta cell abnormality, beta cell, beta-cell, B cell, B-cell, focal adenomatous hyperplasia, seizures, developmental delay, focal neurologic deficits, hepatomegaly, glycogen-storage disorder, galactosemia, fructosemia

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Contributor Information and Disclosures

Author

Robert S Gillespie, MD, MPH, Consulting Staff, Department of Nephrology, Cook Children's Medical Center
Robert S Gillespie, MD, MPH is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology, and Texas Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Stephen Ponder, MD, CDE, Director, Division of Pediatric Endocrinology, Department of Pediatrics, Driscoll Children's Hospital; Professor, Texas A&M College of Medicine
Stephen Ponder, MD, CDE is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece
George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfiser, Inc. Honoraria Consulting

 
 
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