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Congenital Hyperinsulinism Workup

  • Author: Robert S Gillespie, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 16, 2015
 

Laboratory Studies

A number of laboratory studies may be indicated in patients with congenital hyperinsulinism (CHI), also known as 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 on 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 (evidenced by the need to administer intravenous [IV] glucose at a rate higher than 10 mg/kg/min to maintain normoglycemia) are consistent with exaggerated insulin activity and suggestive of CHI.

Cortisol and growth hormone levels are usually elevated in specimens taken during an episode of hypoglycemia (as an 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 CHI. Urinary ketone, amino acid, and reducing-substance studies may be obtained to exclude other metabolic diseases. The results of these are also expected to be within the reference range in cases of CHI.

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 CHI. 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.

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Ultrasonography, CT, MRI, and PET

Ultrasonography, computed tomography (CT), and magnetic resonance imaging (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 CHI.

A newer imaging technique has been developed that uses positron emission tomography (PET) in conjunction with coregistered abdominal CT (see the image below) to distinguish between focal and diffuse disease and, in the case of focal disease, localize the lesions.[9, 10] This technique uses a novel isotope, fluorine-18 L-3,4-dihydroxyphenylalanine (18 F-L-DOPA), for which neuroendocrine cells have a high affinity.

Combined positron emission tomography (PET)/comput Combined positron emission tomography (PET)/computed tomography (CT) scan of focal lesion in head of pancreas of infant with congenital hyperinsulinism. Uptake of 18F-L-DOPA glows brightly in head of pancreas (center), pinpointing abnormal cells in focal hyperinsulinism. Large glowing areas lower in image are kidneys, where 18F-L-DOPA is excreted. Image courtesy of Charles Stanley, MD, Children's Hospital of Philadelphia.

A large series at Children’s Hospital of Philadelphia found that the technique had a specificity of 96%, sensitivity of 85%, and positive predictive value of 96% for diagnosing a focal lesion. When a focal lesion was identified by PET scan, the concordance between imaging and anatomic findings was 100%.[11]

The18 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 CHI should strongly consider consultation with an expert at one of these centers.

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Portal and Pancreatic Venous Sampling

Catheterization of the portal and pancreatic veins with venous sampling may help distinguish between focal and diffuse CHI. This procedure is well described in the pediatric population.

For venous sampling, a catheter is placed in the pancreatic venous system via a femoral vein or inserted 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 CHI 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.

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Intra-arterial Calcium Stimulation

A test using intra-arterial calcium stimulation has been employed in adults and, to a lesser extent, in children. In this test, a bolus of calcium gluconate is rapidly 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.

Although pancreatic venous sampling has been studied more widely to date, especially in neonates, experience with intra-arterial calcium stimulation in children is increasing. Children’s Hospital of Philadelphia has reported on a large number of cases.

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Histologic Findings

The histology of CHI has been divided into focal and diffuse categories. In the focal form (accounting for 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 CHI, 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 the images below). The endoplasmic reticulum is well developed, and Golgi complexes are prominent. Results of macroscopic examination are normal.

Normal pancreas. There are fewer paler-staining ne Normal pancreas. There are fewer paler-staining neuroendocrine (islet) cells, and they are arranged in more discrete islands. Image courtesy of Tom Milligan, MD, Driscoll Children's Hospital, Corpus Christi, Tex.
Pancreatic specimen showing congenital hyperinsuli Pancreatic specimen showing congenital hyperinsulinism (CHI) viewed at low power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyp Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at medium power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyp Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at high power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.

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 CHI. 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.

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Contributor Information and Disclosures
Author

Robert S Gillespie, MD, MPH Physician, Department of Pediatrics, Cook Children's Medical Center

Disclosure: Received consulting fee from Alexion Pharmaceuticals for consulting.

Coauthor(s)

Stephen Ponder, MD, CDE Director, Division of Pediatric Endocrinology, Department of Pediatrics, Driscoll Children's Hospital; Professor of Pediatrics, Texas A&M Health Science Center College of Medicine

Stephen Ponder, MD, CDE is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, Pediatric Endocrine Society, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

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; UNESCO Chair on Adolescent Health Care, University of Athens, 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, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. Laidlaw GF. Nesidioblastoma, the islet tumor of the pancreas. Am J Path. 1938. 14:125-34.

  2. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013 Apr. 168(4):557-64. [Medline]. [Full Text].

  3. Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb. 98(2):E355-63. [Medline]. [Full Text].

  4. Glaser B, Thornton P, Otonkoski T, Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed. 2000 Mar. 82(2):F79-86. [Medline]. [Full Text].

  5. Fournet JC, Verkarre V, De Lonlay P, et al. Loss of imprinted genes and paternal SUR1 mutations lead to hyperinsulinism in focal adenomatous hyperplasia. Ann Endocrinol (Paris). 1998. 59(6):485-91. [Medline].

  6. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005 Jul 21. 353(3):249-54. [Medline].

  7. Lovvorn HN 3rd, Nance ML, Ferry RJ Jr, et al. Congenital hyperinsulinism and the surgeon: lessons learned over 35 years. J Pediatr Surg. 1999 May. 34(5):786-92; discussion 792-3. [Medline].

  8. Gussinyer M, Clemente M, Cebrián R, Yeste D, Albisu M, Carrascosa A. Glucose intolerance and diabetes are observed in the long-term follow-up of nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene. Diabetes Care. 2008 Jun. 31(6):1257-9. [Medline].

  9. Otonkoski T, Näntö-Salonen K, Seppänen M, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes. 2006 Jan. 55(1):13-8. [Medline].

  10. Hashimoto Y, Sakakibara A, Kawakita R, Hosokawa Y, Fujimaru R, Nakamura T, et al. Focal form of congenital hyperinsulinism clearly detectable by contrast-enhanced computed tomography imaging. Int J Pediatr Endocrinol. 2015. 2015 (1):20. [Medline].

  11. Laje P, States LJ, Zhuang H, Becker SA, Palladino AA, Stanley CA, et al. Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism. J Pediatr Surg. 2013 Feb. 48(2):388-93. [Medline]. [Full Text].

  12. Thornton PS, Alter CA, Katz LE, Baker L, Stanley CA. Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr. 1993 Oct. 123(4):637-43. [Medline].

  13. Lord K, Radcliffe J, Gallagher PR, Adzick NS, Stanley CA, De León DD. High risk of diabetes and neurobehavioral deficits in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 2015 Sep 1. jc20152539. [Medline].

  14. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed. 2000 Mar. 82(2):F98-F107. [Medline]. [Full Text].

  15. Bas F, Darendeliler F, Demirkol D, Bundak R, Saka N, Günöz H. Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab. 1999 Nov-Dec. 12(6):873-8. [Medline].

  16. Mazor-Aronovitch K, Gillis D, Lobel D, et al. Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007 Oct. 157(4):491-7. [Medline].

  17. Chinnakotla S, Bellin MD, Schwarzenberg SJ, Radosevich DM, Cook M, Dunn TB, et al. Total Pancreatectomy and Islet Autotransplantation in Children for Chronic Pancreatitis: Indication, Surgical Techniques, Postoperative Management, and Long-term Outcomes. Ann Surg. 2014 Feb 6. [Medline].

  18. Wilson GC, Sutton JM, Salehi M, Schmulewitz N, Smith MT, Kucera S, et al. Surgical outcomes after total pancreatectomy and islet cell autotransplantation in pediatric patients. Surgery. 2013 Oct. 154(4):777-83; discussion 783-4. [Medline].

  19. Robertson RP, Lanz KJ, Sutherland DE, Kendall DM. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes. 2001 Jan. 50(1):47-50. [Medline].

  20. Boulanger C, Vezzosi D, Bennet A, Lorenzini F, Fauvel J, Caron P. Normal pregnancy in a woman with nesidioblastosis treated with somatostatin analog octreotide. J Endocrinol Invest. 2004 May. 27(5):465-70. [Medline].

  21. Maiorana A, Manganozzi L, Barbetti F, Bernabei S, Gallo G, Cusmai R, et al. Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage. Orphanet J Rare Dis. 2015 Sep 24. 10 (1):120. [Medline].

  22. Shah P, Rahman SA, McElroy S, Gilbert C, Morgan K, Hinchey L, et al. Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact. Horm Res Paediatr. 2015 Sep 17. [Medline].

 
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Pancreatic specimen showing congenital hyperinsulinism (CHI) viewed at low power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at medium power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at high power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Normal pancreas. There are fewer paler-staining neuroendocrine (islet) cells, and they are arranged in more discrete islands. Image courtesy of Tom Milligan, MD, Driscoll Children's Hospital, Corpus Christi, Tex.
Combined positron emission tomography (PET)/computed tomography (CT) scan of focal lesion in head of pancreas of infant with congenital hyperinsulinism. Uptake of 18F-L-DOPA glows brightly in head of pancreas (center), pinpointing abnormal cells in focal hyperinsulinism. Large glowing areas lower in image are kidneys, where 18F-L-DOPA is excreted. Image courtesy of Charles Stanley, MD, Children's Hospital of Philadelphia.
 
 
 
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