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Preoperative Evaluation of Infants with Focal or Diffuse Congenital Hyperinsulinism by Intravenous Acute Insulin Response Tests and Selective Pancreatic Arterial Calcium Stimulation

Division of Endocrinology (C.A.S., P.S.T., C.M., P.U., P.B., L.S., L.W.) and Departments of Radiology (R.K.), Pathology (E.R., M.S.), and Surgery (N.S.A.), The Children’s Hospital of Philadelphia; and Department of Genetics (A.G.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Charles A. Stanley, M.D., Division of Endocrinology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: stanleyc{at}email.chop.edu.

Infants with congenital hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (K_ATP) genes, SUR1 and K_ir6.2, cause diffuse hyperinsulinism. K_ATP channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); K_ATP channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. These results indicate that preoperative AIR tests do not distinguish focal vs. diffuse disease because some K_ATP channel mutations retain responsiveness to tolbutamide. The ASVS test can be used to localize focal lesions in infants. The combination of ASVS, careful intraoperative histologic analysis, and surgical expertise succeeded in correcting hypoglycemia in 86% of the infants with focal hyperinsulinism.

This work was supported in part by NIH Grants RR 00240, RO1 DK 56268, and RO1 DK 53012.

Abbreviations: AIR, Acute insulin response; ASVS, arterial calcium stimulation/venous sampling; GCK, glucokinase; GDH, glutamate dehydrogenase; K_ATP, ATP-dependent plasma membrane potassium channel; THPVS, transhepatic portal venous insulin sampling.

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