eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Persistent Hyperinsulinemic Hypoglycemia of Infancy: Differential Diagnoses & Workup

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

Differential Diagnoses

Adrenal Insufficiency
Multiple Endocrine Neoplasia
Beckwith-Wiedemann Syndrome
Patau Syndrome
Growth Hormone Deficiency
Hypopituitarism
Infant of Diabetic Mother

Other Problems to Be Considered

Transient hypoglycemia of the newborn
Erythroblastosis fetalis
Drug effect (eg, tocolytics, quinine)
Withdrawal of parenteral nutrition or dextrose-containing IV fluid
Exogenous insulin administration (eg, Münchhausen syndrome, Münchhausen syndrome by proxy)
Ingestion of oral hypoglycemic agents
Hyperinsulinism with hyperammonemia
Hyperinsulinism-hyperammonemic syndrome
Insulin-secreting adenoma
Ketotic hypoglycemia

Workup

Laboratory Studies

The following laboratory studies may be indicated in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI).

  • Serum glucose, ketone, and insulin levels should be obtained while the patient is hypoglycemic (serum glucose level <60 mg/dL). The definition of hypoglycemia in neonates is dependent upon gestational age, and the threshold may be lower than described here.
    • The finding of nonketotic hypoglycemia in association with elevated insulin levels (>10 µU/mL) and normal levels of free fatty acid (FFA) supports the diagnosis of hyperinsulinism.
    • The insulin-to-glucose ratio may range from 0.4-2.7 (normal <0.3).
    • Sustained glucose use rates in excess of 10 mg/kg/min are consistent with exaggerated insulin activity.
  • Cortisol and growth hormone levels are usually elevated in specimens taken during an episode of hypoglycemia (appropriate and normal response to hypoglycemia) and are usually within the reference range during periods of normoglycemia.
  • Serum metabolic screens, pH, lactate, and ammonia studies may be obtained to exclude other metabolic diseases. The results are expected to be within the reference range in cases of PHHI.
  • Urinary ketones, amino acids, and reducing-substances studies may be obtained to exclude other metabolic diseases. The results are expected to be within the reference range in cases of PHHI.
  • Hyperinsulinism with hyperammonemia and elevated levels of FFA suggests a fatty acid oxidation disorder. Hyperinsulinism with hyperammonemia and normal levels of FFA suggest the diagnosis of hyperinsulinism with hyperammonemia, a clinically and genetically distinct variant of persistent hyperinsulinemic hypoglycemia of infancy. Patients with this disorder usually respond very well to medical therapy alone and are much less likely to require surgical intervention. The hyperammonemia is mild and not symptomatic.

Imaging Studies

  • Ultrasonography, CT scanning, and MRI have been used to search for a focal mass in the pancreas; however, in many cases, the lesion is too small to be visible by such techniques. These forms of imaging cannot identify the diffuse form of PHHI.
  • In 2003 researchers in Finland reported a new imaging technique using [18-F]-L-DOPA positron emission tomography (PET) scanning to distinguish between focal and diffuse disease and, in the case of focal disease, localize the lesions. The technique uses PET scanning with coregistered abdominal CT scanning.5  The PET scan uses a novel isotope, [18-F]-L-DOPA, for which neuroendocrine cells have a high affinity. See Multimedia.
    • A study at Children's Hospital of Philadelphia found the technique was 96% accurate for diagnosing focal or diffuse disease and 100% accurate in localizing the focal lesion.6
    • The [18-F]-L-DOPA isotope remains investigational and is technically complex to prepare. It is currently available at only a few centers worldwide. However, because of the remarkable results seen in preliminary published trials, physicians treating patients with PHHI should strongly consider consultation with an expert at one of these centers.  

Other Tests

  • The need for intravenous (IV) glucose at a rate greater than 10 mg/kg/min to maintain normoglycemia suggests the diagnosis of PHHI.

Procedures

  • Catheterization of the portal and pancreatic veins with venous sampling may help distinguish between focal and diffuse PHHI. This procedure is well described in the pediatric population.
    • In this procedure, a catheter is placed in the pancreatic venous system via a femoral vein or by direct hepatic puncture to enter the portal vein. With the use of fluoroscopic guidance and IV contrast agents, the catheter is advanced into various pancreatic veins, and blood samples are taken to measure glucose, insulin, and C-peptide levels.
    • If a focal lesion is present, elevated insulin levels are expected in veins draining the area near the lesion, and insulin levels are expected to be within the reference range for PHHI in other areas.
    • If a diffuse lesion is present, insulin levels are expected to be high throughout the pancreatic venous bed.
    • In some cases, the results of this study are difficult to interpret, and correlation of results with pathologic findings remains imperfect.
    • Pathologic examination remains the criterion standard for identification of focal disease. However, pancreatic venous sampling is one of few preoperative techniques available to identify focal lesions in patients in whom findings on conventional imaging are inconclusive.
    • Pancreatic venous sampling and intraoperative histologic studies should be strongly considered, because the identification of a focal lesion has profound implications for treatment and prognosis.
  • A test using intra-arterial calcium stimulation has been described in adults and to a lesser extent in children.
    • In this test, a rapid bolus of calcium gluconate is administered via a catheter in the celiac axis and the splenic, superior mesenteric, and gastroduodenal arteries. Blood samples are obtained through a catheter in the right hepatic vein before injection and at several intervals after injection. These blood samples are then tested for glucose, calcium, and insulin levels.
    • An excessive insulin response from calcium stimulation in a single artery suggests a focal lesion, and excessive poststimulation insulin secretion associated with all arteries suggests a diffuse form of hyperinsulinism.
    • Pancreatic venous sampling has been studied more widely to date, especially in neonates, but experience with intra-arterial calcium stimulation in children is increasing. Children's Hospital of Philadelphia has reported on a large number of cases.

Histologic Findings

The histology of PHHI has been divided into focal and diffuse categories. In the focal form (comprising one fourth to one half of cases), the focal lesion contains isletlike cell clusters with ductoinsular complexes, hypertrophic cells, and giant nuclei. A well-developed endoplasmic reticulum and prominent Golgi complex are present, suggesting a high level of protein synthetic activity. Immunohistochemical staining shows an increased proportion of insulin-containing cells. The focal lesion may occur in any part of the pancreas, although the tail and body are the most common locations. The focal lesion is commonly too small to be identified on imaging studies or palpated during surgery. Outside of the area of the focal lesion, the pancreas appears normal. Most patients with the focal form of PHHI have a solitary lesion; however, approximately one fourth of cases are multifocal (ie, contain 2 or more focal lesions).

In the diffuse form of PHHI, findings throughout the pancreas are similar to those found within a focal lesion. Again, isletlike cell clusters with ductoinsular complexes, hypertrophic cells, and enlarged, hyperchromatic nuclei are observed; endocrine cells also occur individually. (See specimens in Multimedia.) The endoplasmic reticulum is well developed, and Golgi complexes are prominent. Results of macroscopic examination are normal.

These histologic findings have also been observed in infants and older children with no known abnormalities of glucose homeostasis. Some authors suggest that this microscopic appearance may be part of a normal developmental process and that other functional abnormalities may exist in the patient with PHHI. Persistent hyperinsulinism, then, may represent a derangement of the developmental process or the extreme end of a spectrum of endocrine cell function. Other authors suggest that these histologic findings may be associated with infants of diabetic mothers or stressed, growth-retarded premature infants.

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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