| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Because of the possibility that surgery can cure infants with focal congenital hyperinsulinism, it would be advantageous to discriminate between the focal and diffuse forms of genetic hyperinsulinism preoperatively. Brunelle and colleagues (13) in Paris have reported success with transhepatic portal venous insulin sampling (THPVS) for preoperative diagnosis and localization of focal lesions in young infants. However, the THPVS procedure is technically difficult and requires exposing infants to hypoglycemia for prolonged periods of time. Therefore, alternative methods to distinguish focal from diffuse hyperinsulinism before surgery would be desirable.
In considering whether focal and diffuse congenital hyperinsulinism could be diagnosed preoperatively, we noted that surgery is only necessary for infants who fail to respond to medical therapy with diazoxide. Because diazoxide suppresses insulin release through its action as a KATP channel agonist, we postulated that all cases that were unresponsive to diazoxide would be associated with defects of the KATP channel genes, SUR1 or Kir6.2, either as a focal lesion expressing a mutation on the paternal allele or as a diffuse case expressing mutations on both maternal and paternal alleles. We had previously found that children with diffuse hyperinsulinism associated with the two most common mutations of SUR1 display abnormal regulation of insulin responses to pharmacological tests. These include abnormal positive acute insulin responses (AIR) to calcium, abnormal negative AIR to the KATP channel antagonist, tolbutamide, as well as impaired insulin responses to glucose (14, 15). Based on these observations, we hypothesized that infants with diffuse and focal diazoxide-unresponsive hyperinsulinism would be distinguishable by their AIRs to calcium and tolbutamide stimulation. That is, both groups of infants would be hyperresponsive to calcium; however, only the focal cases would be able to respond to tolbutamide because their pancreases contain normal, as well as defective, islet cells. In addition, we postulated that the hypersensitivity to calcium stimulation in both groups of infants would make it possible to use the procedure of selective pancreatic arterial calcium stimulation with hepatic venous insulin sampling (ASVS) to differentiate focal from diffuse disease and to localize focal lesions (14). The purpose of the present study was to examine the accuracy of the AIR and ASVS tests in the preoperative investigation of children with congenital hyperinsulinism.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Between October 1998 and October 2002, a total of 57 children underwent surgery for treatment of congenital hyperinsulinism at The Children’s Hospital of Philadelphia. Seven were excluded from analysis because their first surgery was performed elsewhere, they were diazoxide responsive and had surgery electively, or they did not undergo preoperative testing at the Children’s Hospital. The remaining 50 all required surgery because of failure to respond to medical management with diazoxide and octreotide and underwent preoperative AIR and/or ASVS testing. Clinical details of the 50 study infants are shown in Table 1
.
|
Preoperative investigations were carried out after withdrawal of diazoxide for at least 5 d or of octreotide for at least 36 h. AIR tests were carried out as previously described (14, 15). Briefly, tests were done at least 3 h postprandial. Plasma glucose levels were maintained in the normal range of 60–90 mg/dl with continuous iv infusion of dextrose, if necessary. Insulin secretagogues were administered by rapid iv infusion in the following sequence at intervals of 60 min: calcium (2 mg/kg), glucose (0.5 gm/kg), and tolbutamide (25 mg/kg). AIRs were defined as the mean increment in plasma insulin above baseline at 1 and 3 min post infusion. Results were compared with normal and disease control data previously reported in patients with diffuse, recessive hyperinsulinism due to the common Ashkenazi Jewish SUR1 mutations, g3992,-9a, or delF1388, and to children with the hyperinsulinism/hyperammonemia syndrome due to dominant mutations of GDH (14, 15, 16). Normal controls for calcium, glucose, and tolbutamide AIRs were healthy adults. Based on these previous data, the threshold AIRs for recessive, diffuse congenital hyperinsulinism associated with KATP channel mutations were defined as greater than 5 µU/ml for calcium and less than 5 µU/ml for tolbutamide.
Localization of focal lesions was determined by selective pancreatic arterial calcium stimulation with ASVS (14). The procedure was carried out under general anesthesia. Plasma glucose levels were maintained between 60 and 90 mg/dl. When necessary, lispro insulin was used to adjust glucose levels. This insulin analog did not cross-react with the assay for plasma insulin. The least detectable value for the insulin assay was 3 µU/ml. A positive response to the ASVS test was defined as a 2-fold or greater rise in plasma insulin after calcium infusion. A positive response from a single region of the pancreas was taken as evidence of focal disease (either a single artery, the superior mesenteric artery that supplies the body plus the gastroduodenal supplying the head, or the superior mesenteric plus the splenic artery supplying the tail).
Mutations of SUR1 and Kir6.2 were identified in genomic DNA by screening of PCR amplified exons using conformation-sensitive gel electrophoresis as previously described (17). Products displaying aberrant band shifts were sequenced or digested by restriction endonucleases to confirm the presence or absence of the mutations (18). SUR1 cDNA nucleotides and amino acids were numbered according to the sequence reported by Nestorowicz et al. (5), which includes the alternatively spliced exon 17 sequence (L78224). All novel mutations were confirmed by screening a panel of 100 normal alleles to exclude rare polymorphisms and through amino acid conservation analysis.
All operations were performed by the same surgeon using careful palpation and inspection of the pancreas to identify focal lesions. Biopsies from the pancreatic head, body, and tail were examined for evidence of diffuse islet nuclear enlargement or focal adenomatosis, as described by Rahier et al. (19). When frozen sections demonstrated normal pancreatic histology, further search for a focal lesion was conducted using additional biopsies until the focal lesion was found. Patients in whom frozen sections demonstrated diffuse disease underwent near-total pancreatectomy, removing approximately 98% of the organ.
After full recovery from surgery, all patients underwent fasting tests to evaluate persistence of hyperinsulinism. Fasts were extended up to 18 h or a plasma ß-hydroxybutyrate greater than 2.5 mmol/liter or a plasma glucose less than 50 mg/dl. Bedside meters were used to monitor plasma glucose and ß-hydroxybutyrate (SureStep; Precision Xtra, Lifescan, Inc., Milpitas, CA). Adequate control of hypoglycemia was defined as fasting for 10 or more hours with plasma glucose maintained above 70 mg/dl. Cure of hypoglycemia was defined by demonstration of normal fasting adaptation: either being able to fast for 18 or more hours while maintaining plasma glucose above 70 mg/dl or having an appropriate increase in plasma ß-hydroxybutyrate (>2.5 mmol/liter) and a glycemic response to glucagon of less than 30 mg/dl at a plasma glucose level of 50 mg/dl.
Written informed consent was obtained from the parents of patients for these studies. Studies were reviewed and approved by the Children’s Hospital institutional review board.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
, 35 of the children (70%) were diagnosed with focal disease and 15 (30%) with diffuse disease. In both groups, the number of females and males was similar; average birth weights were larger than normal; hypoglycemia frequently began on the first day of life; and surgery was commonly required within the first 2 months after birth. The plasma insulin values taken at the time of initial diagnosis were usually not markedly elevated. Although there was considerable overlap in clinical features of the two groups, there was a tendency toward less severe disease in the focal compared with the dif-fuse cases. Thus, the proportion of children presenting after 1 wk of age was greater in the focal compared with the diffuse cases (33% vs. 0%, P = 0.02). In addition, the mean of the log transformed plasma insulin concentrations was lower in the focal compared with the diffuse group (P = 0.002). Insulin response tests
Table 2 shows the results of the preoperative AIR tests in 30 focal and 13 diffuse hyperinsulinism cases. Slightly more than half of the focal cases (17 of the 30 who were tested) had a positive AIR (> 5 µU/ml) to both tolbutamide and calcium stimulation (group 1). A second large group of focal cases showed a positive response to tolbutamide, but failed to respond to calcium stimulation (group 2). With the exception of one case in each group that failed to respond to glucose, the AIR glucose was similar to normal controls. Only three of the 30 focal cases failed to respond to tolbutamide (group 3). Two of the latter children also had minimal responses to glucose and calcium stimulation, suggesting a generalized suppression of insulin release. The third child who failed to respond to tolbutamide had brisk responses to both calcium and glucose. He was subsequently shown to have a paternal g3392-9a SUR1 mutation, consistent with the loss of heterozygosity model for focal hyperinsulinism. The negative response in this boy may reflect an error in administration of tolbutamide because two other focal cases with the same mutation responded positively to tolbutamide. Including one case not shown in Table 2, who was only tested with tolbutamide (AIR 8.4 µU/ml), 28 of 31 focal cases (90%) had a positive AIR to tolbutamide.
|
, of the 13 children with diffuse disease tested, five had the expected negative AIR tolbutamide and positive AIR calcium (group 1). However, six other diffuse cases had a positive AIR tolbutamide (>5 µU/ml), ranging from 7–98 µU/ml (group 2). Two other diffuse cases (group 3) had AIRs that were uninterpretable because of very elevated basal plasma insulin concentrations. Among the diffuse cases in groups 1 and 2, the AIR glucose varied over a wide range and did not consistently follow the pattern of blunted response seen previously in older children with recessive g3992-9a and delF1388 SUR1 mutations (15). For focal disease, the AIR tolbutamide test had a positive predictive value of 82% and a negative predictive value of 67% where n = 42 (30 focal and 12 diffuse cases).
Figure 1 compares the AIRs to calcium and tolbutamide between the focal and diffuse cases. The proportion with an AIR calcium less than 5 µU/ml was significantly greater among the focal compared with the diffuse cases (12 of 29 vs. three of 13, P < 0.04 by Fisher’s exact test). The proportion of cases with AIR tolbutamide > 5 µU/ml was significantly greater in the focal cases (27 of 30 vs. six of 12, P < 0.01). However, there was considerable overlap between the two groups. As shown in Fig. 1, the subgroup of patients with identified mutations of SUR1 and Kir6.2 (see Mutation analysis) also showed overlap of AIR responses between the focal and diffuse groups. Some mutation positive cases in both groups failed to respond to calcium. Four of the nine diffuse cases with KATP channel mutations had positive responses to tolbutamide.
|
Table 3a shows the results of ASVS tests done preoperatively in 33 of the 35 children who had focal congenital hyperinsulinism. In two other children with focal disease, the test could not be done, because of inability to cannulate the arteries supplying the pancreas. As shown, the plasma glucose levels were usually maintained within the normal range during the procedure. Baseline hepatic vein plasma insulin concentrations were infrequently elevated above the range for fasting insulin in normal children. In 24 of the 33 focal hyperinsulinism cases (73%), the ASVS result was a greater than 2-fold step-up in insulin release in one or two arteries which agreed with the location of lesion in the pancreas. In 19 of these 24 children (group 1, Table 3a), the ASVS revealed a step-up in a single artery. In five others, there was a step-up in the superior mesenteric plus one other artery, which was felt to correctly identify the region of the lesion as being toward the head (superior mesenteric plus gastroduodenal arteries) or the tail of the pancreas (superior mesenteric plus splenic arteries). The increment in insulin in the dominant artery after calcium stimulation was variable, but was frequently only two to three times the baseline insulin. In nine of the 33 focal cases, ASVS was not helpful (group 2, Table 3a). One case had a step-up in both the gastroduodenal and splenic arteries which could not regionalize the lesion to either the head or the tail of the pancreas. In a second child, the ASVS data were unhelpful, because the gastroduodenal artery supplied 90% of the pancreas. In seven other focal cases, calcium stimulation failed to provoke release of insulin from any artery; in five of these seven, the peripheral AIR calcium was also negative.
|
shows the results of the ASVS tests done preoperatively in 13 of the 15 diffuse hyperinsulinism cases. The test results were interpreted as being correctly consistent with diffuse disease in four of the 13 cases (group 1). The results wrongly suggested a focal location of disease in four cases (group 2). The remaining five cases were uninformative because they failed to show a 2-fold step up in any artery (group 3). One exceptional case in group 3, 1D, had extreme elevations of baseline plasma insulin throughout both ASVS and AIR testing. In group 1, the key indicator of diffuse disease was the step-up in both the gastroduodenal and splenic arteries, which, as noted above, was a result that failed to locate a lesion in the region of the head vs. tail of the pancreas. The ASVS test was able to correctly diagnose diffuse disease in 50% of cases that responded to calcium and in 31% of diffuse cases overall. For detecting focal disease, the ASVS test had a positive predictive value of 86% and a negative predictive value of 50% in those patients that responded to calcium where n = 34 (28 focal and six diffuse cases). Among cases having both positive AIR tolbutamide and localized ASVS equaling a positive result for detecting focal disease, the positive predictive value was 90% and the negative predictive value was 75% where n = 24 (20 focal and four diffuse cases).
Histology of focal lesions
As shown in Fig. 2, 24 of the 35 focal cases had small lesions that measured less than 1 cm in diameter and had the typical appearance of endocrine adenomatosis. These lesions were distributed throughout the pancreas. One additional focal case had a presumed lesion in the head of the pancreas that was not found, because the scope of surgery was limited to inspection and several small biopsies. The remaining 10 focal cases had large lesions ranging from slightly greater than 1 cm in diameter to as much as half of the pancreas. Seven of these large lesions had the same histologic appearance of adenomatosis as the small lesions. KATP channel mutations were identified in four of these seven. Three other large focal lesions did not have the typical appearance of adenomatosis. These consisted of a confined region of the pancreas that contained normally formed islets that displayed the same nuclear enlargement seen in the islets of patients with diffuse disease. Mutations have not been identified in these three cases. A total of 18 of the 34 identified focal lesions (53%) were located in the head of the pancreas, many of which would not have been cured by the traditional approach of distal subtotal pancreatectomy. Ten of the lesions involved the region between the duodenum and common bile duct and would not have been removed by 95% pancreatectomy.
|
Tables 4 and 5 show the results of mutation analysis of the SUR1 and Kir6.2 genes in the 50 cases of focal and diffuse congenital hyperinsulinism. Screening has been completed in 46 cases and is incomplete in four. As shown in Table 4, of the 31 children with mutations, 27 had mutations in SUR1 and four had Kir6.2 mutations; three of the latter were focal cases. Four children (one diffuse, three focal) had the common Ashkenazi Jewish g3992-9a mutation of SUR1. As seen in Table 5, no other mutations occurred with significant frequency; 16 mutations had not previously been reported (5, 20, 21, 22). Two mutations were identified in eight of 15 (60%) diffuse cases. One diffuse patient possessed a single mutation, a de novo mutation of S1387F (see Discussion). In 71% of the focal cases, only single mutations of the KATP channel genes were found, affecting the nonmaternal allele or arising spontaneously in all cases.
|
|
shows the most recent information on the outcomes of the 50 cases. As expected, none of the diffuse cases were cured by surgery, although all but four had either improvement of their hypoglycemia or required insulin treatment. Two of the diffuse cases died: one due to necrotizing enterocolitis before surgery was attempted and one postoperatively due to sepsis associated with splenectomy. Surgery provided adequate control or cure of hypoglycemia in only 8% of diffuse cases vs. 86% of focal cases (P < 0.00001). Half of the latter focal cases were completely cured of their hyperinsulinism. Five of the focal cases had persistent hypoglycemia at the time of discharge after surgery, but demonstrated adequate control of hypoglycemia when reevaluated several months later. In three of these, the formal fasting tests showed no evidence of residual hyperinsulinism.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The high frequency of focal disease found in the present series is noteworthy because congenital hyperinsulinism has commonly been assumed to represent diffuse disease of the entire pancreas. Previous reviews of infants operated on at the Children’s Hospital and in Toronto and London reported focal lesions in only 20–35% of cases (23, 24, 25, 26). In contrast, in the large series of cases from Paris where special efforts were made to identify focal lesions, 46% had focal disease (27). The present series found an even higher proportion of focal cases consistent with the suggestion of the Paris group that infants requiring surgery for hyperinsulinism are very likely to have a potentially curable focal lesion. In a population with a frequent recessive SUR1 mutation, Glaser et al. (28) found that 40% of children with hyperinsulinism had paternal-only mutations. Thus, even in a population at risk for recessively inherited hyperinsulinism, a large proportion of cases appear to be focal disease. It is probable that the earlier series from the Children’s Hospital and elsewhere underestimated the prevalence of focal lesions because the usual surgical procedure of distal subtotal pancreatectomy is likely to miss many lesions (see Fig. 2). Because the outcome of surgery was markedly better in focal cases than in the diffuse cases (Table 6), efforts to identify and localize focal lesions are clearly important.
The results of the AIR to calcium tests were generally compatible with the hypothesis that recessive mutations of the KATP channel genes are responsible for both focal and diffuse disease in children with congenital hyperinsulinism who require surgery because of failure to respond to diazoxide. Nearly all of the diffuse cases, as well as the majority of the focal cases, demonstrated abnormal hypersensitivity to calcium stimulation of insulin secretion. This result is consistent with our previous observations showing abnormal positive AIR to calcium in a group of older children with recessive hyperinsulinism due to the two common g3992-9a and delF1388 SUR1 mutations (14). Huopio et al. (29, 30) have reported abnormal positive AIR to calcium in patients with additional KATP channel mutations, including both dominant and recessive SUR1 mutations and recessive Kir6.2 mutations. In five infants with focal disease that failed to respond to calcium stimulation, mutation analysis confirmed a KATP channel defect. It is possible that the small mass of abnormal ß-cells in these focal cases accounts for the failure to detect a response to calcium.
An important goal of the present study was to evaluate whether the AIR to tolbutamide could reliably distinguish between focal and diffuse forms of congenital hyperinsulinism. As anticipated, nearly all of the focal cases responded to tolbutamide. However, seven of the diffuse cases also showed a positive AIR to tolbutamide. In several of these responders, recessive KATP channel mutations were confirmed. Thus, some KATP channel mutations appear to impair channel responsiveness to activation by diazoxide without completely eliminating the ability of the channels to be inhibited by tolbutamide. Huopio et al. (29) also observed a positive AIR to tolbutamide in a patient with diffuse hyperinsulinism due to a recessive Kir6.2 mutation. Cosgrove et al. (31) have noted that the electrophysiologic abnormalities of ß-cells isolated from infants with congenital hyperinsulinism can be variable, including some cases that demonstrate responses to diazoxide in vitro, but not in vivo. As a consequence of the variability in AIR tolbutamide among the different KATP channel mutations, the tolbutamide stimulation test is unable to accurately distinguish between infants with focal and diffuse disease preoperatively.
The present study evaluated the ASVS procedure both for purposes of preoperative diagnosis, as well as for localization of focal lesions in children with congenital hyperinsulinism. The ASVS test was originally developed for localizing insulinomas in adults based on a 2-fold or greater rise in hepatic vein insulin after calcium infusion into one of the three major arteries supplying the pancreas (32). The present experience indicates that it is feasible to perform the ASVS test in infants as young as 1 month old. The responses in infants with either focal or diffuse congenital hyperinsulinism were often modest compared with those reported in adults, and some infants in both the focal and diffuse groups failed to show any response. The magnitude of the insulin responses during ASVS did not correlate with AIR to calcium. Brunelle and colleagues (12) in Paris have reported that an alternative localization procedure, transhepatic portal venous insulin sampling, was able to correctly diagnose 17 of 22 infants with focal disease (78%), but gave incorrect or uninterpretable results in 25% of diffuse cases. Their results are comparable to those obtained with ASVS in the present series (correct in 73% of focal cases, incorrect in 50% of diffuse cases). We have not made a direct comparison between the ASVS and portal venous sampling procedures because the latter test has been carried out in only seven infants. Since a large proportion of the diffuse cases give misleading responses with either test, we consider that neither the ASVS nor the portal sampling test is an accurate diagnostic method for distinguishing between diffuse and focal congenital hyperinsulinism. However, both tests can be useful for localization of focal lesions.
The fact that a majority of the cases had mutations of SUR1 or Kir6.2 (Table 4) indicates that mutation identification might provide a means of diagnosing focal and diffuse hyperinsulinism preoperatively. For example, in two infants, not included in the present series, diffuse disease was diagnosed before surgery by demonstrating homozygosity for one of the two common Ashkenazi Jewish SUR1 mutations. Mutation screening, unfortunately, is not currently practical, because with few exceptions, none of the disease-causing mutations are frequent (see Table 5). Genetic screening uncovered two mutations in diffuse patients, with the exception of one case with a single, de novo mutation of S1387F. This may be a dominant mutation because one other diffuse case has been reported to have S1387F with no additional mutation (21). We have also recently demonstrated that deletion of S1387 causes dominantly expressed disease (33). In 33% of the patients in the present study, no mutation was found in the coding sequences of SUR1 or Kir6.2. These cases could reflect mutations having gone undetected elsewhere in the promoter region or the large areas of intronic sequences of the SUR1/Kir6.2 complex. However, several exceptional cases in the present series suggest the possibility of other genetic loci in some infants with diazoxide-unresponsive hyperinsulinism. For example, one diffuse case without any identified mutation had unusual elevations of plasma insulin, ranging from 80–200 µU/ml (Tables 2 and 3). The authors are aware of at least one other similar case, suggesting that these might represent a different genetic form of congenital hyperinsulinism. A second subgroup of exceptional cases included four children with focal or diffuse disease that failed to respond to any of the insulin secretagogues, including glucose. No obvious explanation for these poor responses could be found, and this group could also represent a novel form of hyperinsulinism. A third set of exceptional cases was three children with atypical focal lesions consisting of a confined area of islets with nuclear enlargement typical of diffuse disease. The nature of these atypical lesions remains to be defined.
After surgery, several of the focal cases in the present series had evidence of residual hyperinsulinism that subsequently disappeared. A tendency for hypoglycemia to improve over time has also been noted in children with diffuse hyperinsulinsm. Kassem et al. (34) have suggested that the latter might reflect increased rates of apoptosis in islet cells with KATP channel defects, due to their abnormally elevated intracellular calcium levels. Such a process would not lead to a cure in diffuse cases of hyperinsulinism but could explain the disappearance of residual hyperinsulinism after surgery in cases of focal disease. Alternatively, the loss of one or more maternal genes might impair the long-term survival of ß-cells in focal lesions.
The results of the present series demonstrate that focal congenital hyperinsulinism cannot be distinguished clinically from cases with diffuse disease based on presentation or by their insulin responsiveness to the secretagogues calcium, glucose, and tolbutamide. Because many cases of diffuse disease with proven KATP channel mutations retain sensitivity to the channel inhibitor, tolbutamide, we have abandoned insulin response tests for purposes of distinguishing focal from diffuse disease. The interventional radiologic procedure of ASVS was also not reliable in discriminating focal from diffuse disease. However, ASVS often provided useful information on the location of focal lesions. Our data support the concept that a large proportion of children with congenital hyperinsulinism, who cannot be controlled medically, have focal lesions. These focal cases are potentially curable by close coordination between surgeons and surgical pathologists during surgery.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: AIR, Acute insulin response; ASVS, arterial calcium stimulation/venous sampling; GCK, glucokinase; GDH, glutamate dehydrogenase; KATP, ATP-dependent plasma membrane potassium channel; THPVS, transhepatic portal venous insulin sampling.
Received June 5, 2003.
Accepted September 23, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  W. Barthlen, O. Blankenstein, H. Mau, M. Koch, C. Hohne, W. Mohnike, T. Eberhard, F. Fuechtner, B. Lorenz-Depiereux, and K. Mohnike Evaluation of [18F]Fluoro-L-DOPA Positron Emission Tomography-Computed Tomography for Surgery in Focal Congenital Hyperinsulinism J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 869 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Palladino, M. J. Bennett, and C. A. Stanley Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough Clin. Chem., February 1, 2008; 54(2): 256 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. T. Hardy, M. Hernandez-Pampaloni, J. R. Saffer, J. S. Scheuermann, L. M. Ernst, R. Freifelder, H. Zhuang, C. MacMullen, S. Becker, N. S. Adzick, et al. Accuracy of [18F]Fluorodopa Positron Emission Tomography for Diagnosing and Localizing Focal Congenital Hyperinsulinism J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4706 - 4711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shi, Z. Wu, N. Cui, W. Shi, Y. Yang, X. Zhang, A. Rojas, B. T. Ha, and C. Jiang PKA phosphorylation of SUR2B subunit underscores vascular KATP channel activation by beta-adrenergic receptors Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1205 - R1214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hussain, M. Seppanen, K. Nanto-Salonen, N. S. Adzick, C. A. Stanley, P. Thornton, and H. Minn The Diagnosis of Ectopic Focal Hyperinsulinism of Infancy with [18F]-Dopa Positron Emission Tomography J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2839 - 2842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. de Lonlay, A. Simon-Carre, M.-J. Ribeiro, N. Boddaert, I. Giurgea, K. Laborde, C. Bellanne-Chantelot, V. Verkarre, M. Polak, J. Rahier, et al. Congenital Hyperinsulinism: Pancreatic [18F]Fluoro-L-Dihydroxyphenylalanine (DOPA) Positron Emission Tomography and Immunohistochemistry Study of DOPA Decarboxylase and Insulin Secretion J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 933 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Otonkoski, K. Nanto-Salonen, M. Seppanen, R. Veijola, H. Huopio, K. Hussain, P. Tapanainen, O. Eskola, R. Parkkola, K. Ekstrom, et al. Noninvasive Diagnosis of Focal Hyperinsulinism of Infancy With [18F]-DOPA Positron Emission Tomography Diabetes, January 1, 2006; 55(1): 13 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Henwood, A. Kelly, C. MacMullen, P. Bhatia, A. Ganguly, P. S. Thornton, and C. A. Stanley Genotype-Phenotype Correlations in Children with Congenital Hyperinsulinism Due to Recessive Mutations of the Adenosine Triphosphate-Sensitive Potassium Channel Genes J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 789 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. N. Magge, S.-L. Shyng, C. MacMullen, L. Steinkrauss, A. Ganguly, L. E. L. Katz, and C. A. Stanley Familial Leucine-Sensitive Hypoglycemia of Infancy Due to a Dominant Mutation of the {beta}-Cell Sulfonylurea Receptor J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4450 - 4456. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
