26B
Hyperinsulinism of Infancy:
Localization of Focal Forms
Olga T. Hardy and Charles A. Stanley
Congenital Hyperinsulinism
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Infants with severe forms of the disorder (formerly termed nesidioblastosis) present with hypo- glycemia in the newborn period and are at high risk of seizures, per- manent brain damage, and retardation. Infants with congenital hyperinsulinism may have either focal or diffuse abnormalities of the pancreatic b cells. In cases with diffuse disease, an underlying defect in the b-cell adenosoine triphosphate (ATP)-dependent potassium channel may be present, caused by recessive loss of function mutations of the two genes encoding the KATP channel, SUR1 or Kir6.2 (1,2).
These mutations may also cause focal hyperinsulinism in which there is an area of b-cell adenomatosis due to loss of heterozygosity for the maternal 11p region and expression of a paternally derived KATP channel mutation (3). Most of the cases with severe hyperinsulinism do not respond to medical therapy with diazoxide, octreotide (Fig.
26B.1), or continuous feedings and require near-total pancreatectomy to control hypoglycemia. However, cases of focal hyperinsulinism can be treated effectively with partial pancreatectomy. The surgical approach and therapeutic outcome for the infants depends on preop- eratively distinguishing between focal and diffuse forms of hyperin- sulinism. This chapter describes the focal lesions of hyperinsulinism, the pancreatectomy procedure, previous methods of determining the site of focal lesions, and the rationale for using positron emission tomo- graphy (PET) scans with 18F-fluoro-L-DOPA.
Focal Hyperinsulinism
Histologically, focal hyperinsulinism has the appearance of b-cell ade- nomatosis (Fig. 26B.2) but does not affect pancreatic architecture and is invisible to the naked eye. Focal hyperinsulinism is clonal in origin
479
Diazoxide
Membrane depolarization KATP
channel
Octreotide
Glucose
Glucokinase
Glucose-6 phosphate
TCA cycle [ATP]
[ADP]
Increased intracellular Ca+
Insulin Voltage-dependent
Ca+ channel
SUR SUR
Ca2+
[K+] [K+]
GLUT2
Figure 26B.1. Pathways of insulin secretion in the b cell. Glucose is metabo- lized through GLUT2 and glucokinase to increase adenosine triphosphate (ATP) formation. The elevation of the ATP/adenosine diphosphate (ADP) ratio leads to closure of KATP channels, depolarization of the membrane, opening of voltage-gated Ca2+channels, and an increase in intracellular Ca2+, which trig- gers the exocytosis of insulin granules. Because diazoxide suppresses insulin secretion by opening KATP channels, infants with diffuse or focal HI due to KATP mutations can not respond to treatment with diazoxide.
Figure 26B.2. Gross and histopathologic section of focal hyperinsulinism. This is an area of focal adenomatosis characterized by a pattern of crowded islets and limited exocrine tissue present in the surrounding periphery. Normal neighboring tissue to the right has an appropriate amount of islets present.
and the result of a specific loss of maternal alleles (loss of heterozy- gosity, LOH) in the p15 region of chromosome 11 (4) where the two KATP channel genes, SUR1 and Kir6.2, are located. The maternal LOH results in loss of one or more maternally expressed tumor suppressor genes p57KIP2 and H19 as well as isodisomy for the paternally expressed insulin-like growth factor 2 gene (4). The loss of the mater- nal 11p thus leads to expansion of a clone of b cells that expresses a paternally derived KATP channel defect. These focal lesions are treat- able with focal resection of the affected pancreatic area.
Pancreatectomy
Infants with congenital hyperinsulinism that fail medical management require partial or near-total pancreatectomy. During this operation, biopsies from the pancreatic head, body, and tail are examined for b cells with large nuclei and abundant cytoplasm suggestive of diffuse disease. When frozen sections demonstrate the absence of nuclear enlargement in biopsies from the head, body, and tail of the pancreas, further search for a focal lesion is conducted using additional biopsies until the focal lesion is found. Infants in whom frozen sections demon- strate diffuse disease, as evidenced by islet nuclear enlargement in all areas of the pancreas, undergo near-total pancreatectomy, removing approximately 98% of the organ. Many of these children subsequently develop iatrogenic diabetes. Preoperative differentiation between diffuse and focal disease and localization of a potential focal lesion is important to guide the surgical approach and improve surgical outcome.
Localization of Focal Pancreatic Lesions
Previous efforts to image focal congenital hyperinsulinism have been unsuccessful, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (preoperative and intra- operative), and radiolabeled octreotide scans (5). As discussed below, pharmacologic tests and techniques using interventional radiology have had limited success.
Pharmacologic Tests
Children with diffuse hyperinsulinism associated with the two most common mutations of SUR1 display abnormal positive acute insulin responses (AIRs) to calcium and abnormal negative AIR to the KATP channel antagonist tolbutamide as well as an impaired insulin response to glucose (6). It was hypothesized that infants with diffuse and focal diazoxide-unresponsive hyperinsulinism could be distinguished by their AIRs to calcium and tolbutamide stimulation. That is, both types would respond to calcium, but only focal lesions would respond to tolbutamide. This hypothesis was tested in a group of 30 focal and 13 diffuse cases. Only two thirds of these cases responded to calcium;
although most focal cases responded to tolbutamide, half of the diffuse cases responded as well (7). This probably reflects the fact that some of the disease-causing mutations retain some partial function of the KATP channel (8). As a consequence, preoperative AIR tests cannot be used to distinguish focal vs. diffuse disease.
Interventional Radiology
Over the past 5 years, we have used the procedure of selective pan- creatic arterial calcium stimulation with hepatic vein sampling (ASVS) for localization of focal hyperinsulinism lesions. It relies on the hypo- thesis that hypersensitivity to calcium stimulation in children with both diffuse and focal hyperinsulinism would make it possible to use selective pancreatic arterial stimulation with hepatic venous insulin sampling to differentiate focal from diffuse disease and to localize focal lesions. The ASVS procedure is carried out under general anes- thesia, and plasma glucose levels must be maintained between 60 and 90 mg/dL. A positive response to the ASVS test is defined as a twofold or greater rise in plasma insulin after calcium infusion. A positive response from a single region of the pancreas is taken as evidence of focal disease. Results from a study looking at ASVS in 50 children revealed that ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. The ASVS test has about the same accuracy as transhepatic portal venous insu- lin sampling (THPVS), which correctly identified the region of focal lesions in only 76% of 45 cases (3). Both of these tests are technically difficult to perform and are associated with significant risks of general anesthesia and intubation, hypoglycemia, femoral artery catheteriza- tion and thrombosis, radiation exposure, and need for transfusion due to blood sampling.
PET Using 18F-fluoro-L-DOPA for Focal Hyperinsulinism
Fluorine-18 (18F)-labeled L-fluoro-DOPA has been used successfully to detect neuroendocrine tumors, such as carcinoids and endocrine pan- creatic tumors in adults (9). Neuroendocrine tumors belong to the amine precursor uptake and decarboxylation (APUD) cell system and have the capacity to take up and to decarboxylate amine precursors, transform them into biogenic amines, and store them in vesicles. Thus, these cells can take up radioactively labeled 18F-fluoro-L-DOPA to store as dopamine, which can be detected by PET imaging. 18F-fluoro-L- DOPA-PET was not successful in localizing insulinomas but was accu- rate in localizing focal lesions of hyperinsulinism (10).
Researchers in France recently published their experience with 18F- fluoro-L-DOPA PET scan on infants with congenital hyperinsulinism (11). They studied 15 patients with hyperinsulinism based on clinical diagnosis. Under conscious sedation, they injected a mean dose of 4 MBq/kg 18F-labeled L-fluoro-DOPA intravenously 30 to 50 minutes before transmission acquisition. They observed an abnormal focal pan- creatic uptake of 18F-fluoro-L-DOPA in five patients and a diffuse uptake in the other 10 patients. All five of the patients with focal uptake
and four of the patients with diffuse uptake underwent surgery. The histopathologic results were consistent with the PET findings in these nine cases.
The results from France, as well as preliminary data from a research group in Finland, suggest that 18F-labeled L-fluoro-DOPA is an accu- rate noninvasive technique to distinguish between focal and diffuse forms of hyperinsulinism and to localize areas of focal lesions. As described in abstracts presented at the Endocrine Society meeting and the International Pediatric Endocrinology conference, our group at the Children’s Hospital of Philadelphia has accumulated preliminary data using 18F-fluoro-L-DOPA-PET in children with congenital hyperin- sulinism (Fig. 26B.3). The very encouraging results suggest that this test is 100% accurate in distinguishing diffuse from focal disease and in localizing the site of the focal lesion.
Conclusion
Focal hyperinsulinism is an important cause of hypoglycemia in young infants and is potentially curable by surgery. Preliminary informa- tion about the success of 18F-fluoro-L-DOPA PET suggests that this may be a method of choice for preoperative identification of focal lesions.
An advantage to this technique is that it may be used to select out patients with diffuse disease who may be candidates for nonsurgical treatment. More important, the information acquired using 18F-fluoro- L-DOPA-PET should make it possible for the surgeon to cure focal hyperinsulinism by local excision.
Acknowledgment
This work was supported in part by National Institutes of Health (NIH) grants RO1 DK 56268 (to C.A.S.) and MO1 RR 00240. O.T.H. was sup- ported by NIH training grant T32 DK63688 (C.A.S.).
Figure 26B.3. Focal uptake of 18F-labeled L-fluoro-DOPA believed to be behind the superior mesenteric artery (SMA).
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