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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1455-1461
Copyright © 1998 by The Endocrine Society

Original Studies

Neonatal Hyperinsulinemic Hypoglycemia: Heterogeneity of the Syndrome and Keys for Differential Diagnosis1

C. Sempoux, Y. Guiot, A. Lefevre, C. Nihoul-Fékété, F. Jaubert, J-M. Saudubray and J. Rahier

Department of Pathology, University Hospital St. Luc (C.S., Y.G., A.L., J.R.), 1200 Brussels, Belgium; Departments of Infantile Surgery (C.N-F.), Pathology (F.J.), and Medical Genetics (J-M.S.), Hôpital Necker Enfants Malades, 75743 Paris, France

Address all correspondence and requests for reprints to: Jacques Rahier, M.D., Ph.D, Department of Pathology ANPS 1712, University of Louvain Medical School, Cliniques St. Luc, 10 avenue Hippocrate, 1200 Brussels, Belgium.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The two major forms of infantile persistent hyperinsulinemic hypoglycemia require different treatments, but are difficult to differentiate during surgery. Indeed, one is characterized by focal adenomatous hyperplasia often macroscopically invisible, whereas the other consists of a diffuse, but discreet, ß-cell abnormality. We evaluated, in a large series of persistent hyperinsulinemic hypoglycemia, the reliability of two criteria in differentiating these two forms: the mean ß-cell nuclear radius (MNR) and the ß-cell nuclear crowding, i.e. the number of nuclei per 1000 µm2 ß-cell (BCNC). The values of the largest MNR and of BCNC in cases bearing a focal lesion (respectively, 3.27 µm ± 0.25 and 14.62 ± 1.78) were significantly different from those in the diffuse pathology (4.25 µm ± 0.43 and 10.00 ± 1.55). Setting the threshold value of MNR at 3.70 µm and that of BCNC at 12.00 enabled correct classification of 90.9% of the diffuse and 100% of the focal forms.

ß-Cell nuclear analysis can thus contribute to a subclassification of the syndrome, not allowed by clinical or biological data. If performed during surgery it could help in determining the extent of pancreatectomy necessary to cure the patient, as the diffuse form, with abnormal nuclei in the whole pancreas, requires subtotal to near-total pancreatectomy, whereas the focal form, devoid of abnormal insular ß-cell nuclei, can be cured by partial pancreatectomy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ALTHOUGH numerous studies have been devoted to the syndrome of persistent hyperinsulinemic hypoglycemia of neonates and infants (PHHI), its pathogenesis is not completely elucidated (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Linkage analysis has mapped hyperinsulinism in familial cases to chromosome 11 (17), and other genetic molecular analysis has revealed sulfonylurea receptor gene abnormalities that might explain insulin hypersecretion in such familial cases (18). The absence of functional K+ATP channels has recently been shown to induce insulin hypersecretion in sporadic PHHI (19). However, morphological diagnosis of the disease remains difficult, especially when the clinical history of recurrent hypoglycemic events is not known by the pathologist, as in certain cases of sudden infant death. Nesidioblastosis, defined as a persistent endocrine cell proliferation budding from pancreatic ducts (20), can be observed in the pancreas of normoglycemic neonates (3, 4, 6, 10, 13) and, therefore, is not pathognomonic of this syndrome. Furthermore, reliable morphological criteria for the evaluation of nesidioblastosis have yet to be defined.

There is no consensus about the optimal clinical management of the disease (21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33). Diazoxide is usually the first drug to be tried, but it is often not effective, especially in severe hyperinsulinemic hypoglycemia of neonatal onset. Somatostatin has also been recommended and, with the arrival of long acting analogs, pancreatectomy or further resections have been avoided in certain patients (24, 26, 28, 33). When medical treatment fails, surgery is unavoidable to prevent permanent brain damage. The extent of the pancreatectomy is, however, a matter of debate, as some researchers recommend an initial 95% pancreatectomy in all patients (22), which may increase the long term risk of diabetes.

Several studies have clearly established the existence of two forms of PHHI, one characterized by focal pancreatic adenomatous hyperplasia (focal PHHI) and the other characterized by a diffuse ß-cell abnormality (diffuse PHHI) (5, 10, 13, 16, 34).

The distinction between these two forms should be of paramount importance, because infants suffering from the focal form may be cured by a partial pancreatectomy (35). However, for several reasons, few clinicians take this distinction into account when determining the extent of pancreatectomy. Firstly, the experience of most clinicians is generally limited because of the rarity of the disease. Secondly, contrary to adult insular adenomas, focal lesions in infants are often difficult and sometimes impossible to identify macroscopically, as they are lobulated like the normal pancreatic parenchyma. Thirdly, the selective catheterization recommended by our group guides the surgeon in locating a focal lesion, but is, as yet, not readily available in all hospitals. Fourthly, this technique is not infallible in differentiating the focal from the diffuse form of PHHI (36, 37).

In a previous study of 16 cases (13), we have drawn attention to the fact that morphology could help to differentiate the two forms of the syndrome. Indeed, we showed that the diffuse form of PHHI could be characterized by the presence of numerous abnormal large ß-cell nuclei, whereas such nuclei were not observed in the insular ß-cells of cases bearing a focal lesion.

In the present study, we have evaluated ß-cell nuclear analysis and other morphological criteria from a large retrospective series to differentiate the two forms of the syndrome, with the hope that these criteria might be used to determine the extent of pancreatectomy during surgery.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Partial or near-total pancreatectomy specimens were obtained from 50 infants suffering from diazoxide-resistant hyperinsulinemic hypoglycemia of neonatal onset. Infants with late-onset hypoglycemia (>3 months of age) and hypoglycemic children were excluded from this study.

Each resected pancreas was cut into thin (1- to 2-mm) slices. After fixation and embedding, 5-µm sections were cut from each slice, stained with hematoxylin-eosin, and processed by immunoperoxidase technique to reveal insulin and ensure recognition of even very small focal lesions of adenomatous hyperplasia. For insulin immunodetection, the sections were incubated overnight with a monoclonal antiinsulin antibody (HUI-018, Novo-Biolabs, Bagvaerd, Denmark) at a dilution of 1:2000. After rinsing, the sections were successively treated by antimouse IgG-biotin conjugate (1089-285, Boehringer Mannheim, Mannheim, Germany) at a dilution of 1:500 and a streptavidin peroxidase conjugate (1089-153, Boehringer Mannheim) at a dilution of 1:1000. Before counterstaining in Mayer’s hematoxylin, peroxidase activity was revealed by immersion in a solution of 3,3'-diaminobenzidine hydrochloride (50 mg/mL Tris-HCl, pH 7.4; Amersham, Aylesbury, UK) containing 0.02% H2O2.

After verification that the morphological features were identical in each section, two sections were selected at random for ß-cell nuclear measurements. The measurements were made by one observer who was not aware of the final diagnosis (diffuse or focal). The two whole sections were screened to analyze the ß-cell nuclei. In a first series of 20 cases (6 focal and 14 diffuse lesions), we initially measured the mean nuclear radius (MNR) of 500 randomly selected insular ß-cell nuclei at a x1200 magnification with a camera lucida connected to an Orthoplan Leitz microscope (Leitz, Wetzler, Germany) and a semiautomatic image analyzer (Videoplan Kontron, Munich, Germany). Thereafter, we measured only the largest insular ß-cell nuclei, calculating the mean nuclear radius of the 50 largest nuclei (50-MNR). On the same slides and with the same device at a x300 magnification, we measured ß-cell nuclear crowding (BCNC), which is the number of ß-cell nuclei per 1000 µm2 of ß-cell cytoplasm. This parameter was chosen rather than the nuclear/cytoplasmic ratio because the cytoplasmic limits of individual ß-cells were difficult to define accurately on these specimens. This has the advantage of being independent of the nuclear size variation of the ß-cells. The BCNC was systematically measured in all islets present in the sections from the two randomly selected paraffin blocks.

Results are expressed as the mean ± SD. The statistical significance of the results was assessed by the Wilcoxon rank-sum test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Seventeen of the 50 specimens studied showed focal adenomatous hyperplasia at microscopic examination (Table 1Go, patients 34–50). This lesion is very different from adenomas occurring in children and adults, as in neonates it consists of an agglomerate of apparently normal islets with a peripheral ring of non-ß-cells (Fig. 1Go, A and B). In every case but one, the lesion was unifocal. The size of the lesions varied from 2.5–13.0 mm in diameter. Their limits were often irregular. Within the lesions, the nuclear polymorphism of the ß-cell nuclei was evident (Fig. 2AGo), but outside the lesions, ß-cell nuclei were regular and small, the ß-cell cytoplasm was scanty, and these cells often appeared squeezed together (Fig. 2BGo). The MNR measured in 500 randomly selected insular ß-cells was 2.95 ± 0.09 µm (Fig. 3AGo), and the MNR of the 50 selected largest radii of insular ß-cell nuclei (50-MNR) was 3.27 ± 0.25 µm (Fig. 3BGo). The BCNC was 14.62 ± 1.78 ß-cell nuclei/1000 µm2 (Fig. 3CGo). Fifteen of these 17 patients were cured as a result of the first operation, including the 13 patients treated by partial pancreatectomy, whereas hypoglycemia recurred in only two infants: in one case a second focal lesion was found during the second operation (no, 34), and in another case the lesion had not been completely resected (no. 44).


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  		Table 1. Descriptions of the patients

 


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  		Figure 1. A, Focal adenomatous hyperplasia corresponds to an agglomerate of apparently normal islets (arrowheads; hematoxylin-eosin staining; magnification, x2.5). B, Indeed, as in normal islets, non-ß-cells are located at the periphery (immunostaining of somatostatin; magnification, x10).

 


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  		Figure 2. A, A mild nuclear polymorphism is observed within focal adenomatous hyperplasia (arrowheads; hematoxylin-eosin staining; magnification, x40). B, The ß-cell nuclei are small and regular outside the focal lesion (hematoxylin-eosin staining; magnification, x40). C, In the diffuse form of the disease, the islets are characterized by the presence of abnormal large ß-cell nuclei (arrowheads; hematoxylin-eosin staining; magnification, x40).

 


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  		Figure 3. A, Mean radius of 500 nonselected ß-cell nuclei (microns) measured outside the focal lesions ({diamond}) and in cases without focal lesion ({diamondsuit}). B, Mean radius of 50 selected ß-cell nuclei (microns) measured outside the focal lesions ({diamond}) and in cases without focal lesion ({diamondsuit}). · · ·, Threshold value. C, BCNC (number per 1000 µm2) measured outside the focal lesions ({diamond}) and in cases without focal lesion ({diamondsuit}). · · ·, Threshold value. Numbers refer to Table 1Go.

 
In the other 33 infants (Table 1Go, patients 1–33), no focal lesion could be found after systematic and detailed macroscopic and microscopic analyses of the whole resected specimens. Nine of these infants, despite their 80–90% pancreatectomy, suffered from severe recurrent hypoglycemic attacks requiring near-total pancreatectomy. All of these pancreatic specimens (including second operation specimens) displayed similar morphological features; the islets were not evidently more abundant than in the pancreas of infants with a focal lesion. ß-Cells with very large nuclei were observed in all but 3 cases (no. 6, 7, and 9). These ß-cells with an extremely large nucleus also showed a large and clear cytoplasm and were easily recognizable even at low magnification (Fig. 2CGo). Their frequency varied from case to case. In certain infants, they were present in almost every islet, whereas in others, only a few islets had such abnormal ß-cell nuclei. These abnormal nuclei were evenly distributed throughout the pancreas and were found in each section of these 33 specimens of neonatal-onset PHHI. The ß-cell MNR was 3.15 ± 0.02 µm. This value was statistically higher than that measured in the insular ß-cells of cases with a focal lesion (P < 0.05), but the overlap would not allow a reliable discrimination between the two groups (Fig. 3AGo). The mean nuclear radius of the 50 largest ß-cell nuclei was 4.25 ± 0.43 (Fig. 3BGo), a value significantly higher than that of insular ß-cells of infants with a focal lesion (P < 0.001), with only 3 patients nuclei having radii smaller than 3.70 µm (no. 6, 7, and 9). The nuclear crowding of the ß-cells was 10.00 ± 1.55 ß-cell nuclei/1000 µm2 (P < 0.001 vs. cases with a focal lesion), with only 3 patients having densities above 12.00 ß-cell nuclei/1000 µm2 (no. 7, 9, and 25; Fig. 3CGo), two of whom corresponded to the smaller 50-MNR (no. 7 and 9; Fig. 3BGo).

Setting the threshold values for 50-MNR at 3.70 µm and 12.00 for the BCNC analysis enabled correct classification of 90.9% of the diffuse forms at PHHI and 100% of the focal cases.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The recognition that a focal lesion(s) could be responsible for PHHI is not new (20, 38), and some researchers have suggested that all cases of PHHI result from the presence of a focal lesion, often so small that it escapes diagnosis (6). The existence of 2 forms of PHHI suggested by our previous analysis of a series of 16 cases (13) has been confirmed (5). Although now well documented, this concept of 2 distinct forms requiring different types of treatment is not taken into account by most researchers who recommend an initial near-total pancreatectomy in all cases of PHHI resistant to medical therapy regardless of whether its pathology is focal or diffuse (22). This probably results from the difficulties of the differential diagnosis.

In the present study, we have tried to define precisely the pathognomic morphological criteria enabling this diagnosis. We have thus combined conventional microscopy, to search for the presence of abnormal ß-cell nuclei and evaluate the nucleo-cytoplasmic ratio, with morphometry, to accurately analyze the characteristic differences between islets in both focal and diffuse forms of PHHI. The morphometric analysis did not change the classification into focal or diffuse, but it clearly established the relevance of the criteria selected for the differential diagnosis. In the first series of 20 cases, where we measured 500 insular ß-cell nuclei, although the MNR of the ß-cell nuclei was significantly higher with a diffuse lesion than with a focal lesion, this parameter did not allow a clear distinction between the 2 groups, as 21% of the patients with diffuse pathology were within the range of those with a focal lesion. The frequency of the large ß-cell nuclei characteristic of the diffuse form of PHHI was probably too low in certain cases to influence the MNR. For this reason, we decided to focus our measurement specifically on the 50 largest ß-cell nuclei (50-MNR). This method of evaluation proved to be a fast measurement and increased the sensitivity of the analysis, because the results were not influenced by the frequency of these abnormal nuclei. It enabled differential diagnosis between the 2 forms of the disease. Instead of measuring the nucleo-cytoplasmic ratio, we also decided to measure BCNC. This method, giving the mean amount of cytoplasm per ß-cell, proved to be fast and easy, and again had the advantage of being independent of the nuclear size variation of the ß-cells.

Both 50-MNR and BCNC are linked to cellular function. Indeed, an increase in nuclear size has repeatedly been demonstrated in hyperfunctional endocrine cells (39, 40, 41, 42). On the other hand, although an increase in cytoplasmic size is not pathognomonic of hyperfunction, they are generally linked. Thus, it is likely that hyperinsulinism in the diffuse form of the disease is related to an increased function of the ß-cells, as their number has been demonstrated to be normal (10, 13, 16). It has recently been suggested that in this form, hyperinsulinism results from the absence of functional K+ATP channels in ß-cells (19), but we still do not know whether all cases of diffuse PHHI are the consequence of this abnormality.

In the focal form of the disease, the 50-MNR value of insular ß-cells located away from the focal lesion was never higher than 3.70 µm. This was quite the opposite in cases without focal lesion, where numerous abnormal ß-cell nuclei were observed, and where all but three cases had 50-MNR values higher than 3.70 µm. As two of these three cases also had quite distinct values for the BCNC (cases 7 and 9), it is not excluded that they actually belong to the group of focal lesions and that the lesion has not been recognized because of its small size. On the other hand, we have no explanation for case 6, whose 50-MNR value is lower than 3.70 µm and whose BCNC remains inferior to 12.00, or for case 25, who has a high 50-MNR value and BCNC. This might suggest that other forms of PHHI exist, different from those we have already reported.

Despite these exceptions, it can be claimed that the presence of obvious abnormal ß-cell nuclei in the different parts of the pancreas has never been observed in the presence of a focal lesion. It is interesting to note that in all cases devoid of abnormal nuclei, hyperinsulinemic hypoglycemia has always been radically cured by partial pancreatectomy, sometimes even limited to the focal lesion itself, as long as the focal lesion was unique and totally resected. On the other hand, when abnormal ß-cell nuclei were observed in the different parts of the pancreas, none of the infants with hypoglycemia of neonatal onset was cured by partial pancreatectomy. Preliminary results suggest that the recognition of these abnormal nuclei may be performed on frozen sections during surgery (43). This could obviously help the surgeon, as it is now clear that the two forms of PHHI require different treatments: the diffuse form, associated with abnormal ß-cell nuclei in the whole pancreas and a low BCNC requires subtotal pancreatectomy, whereas this cannot be justified in the case of a focal lesion, which can be recognized by the absence of abnormal ß-cell nuclei, and of which the patient can be cured by partial pancreatectomy restricted to the lesion.


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  		Table 1A. Continued

 

   Acknowledgments
 
We gratefully acknowledge the kind help from our colleagues (Prof. Brauner and Dr. Poggi, Hôpital Necker (Paris, France); Profs. Czernichow and Aigrain and Dr. Touati, Hôpital Debré (Paris, France); Profs. Creusy and Vittu, Hôpital St. Antoine (Lille, France); Profs. Craen and De Rom, Universitair Ziekenhuis (Ghent, Belgium); Prof. Geis, Hôpital Hautepierre (Strasbourg, France); and Profs. de Ville, Maes, Moulin, and Otte, Cliniques Universitaires St. Luc, Université Catholique de Lourain (Brussels, Belgium), who allowed us to study the pancreas of their young patients and provided us with clinical data. We thank Prof. J-C. Henquin and Dr. C. de Burbure for critical reading of the manuscript, and D. Dubois, S. Lagasse and M. April for technical, photographic, and editorial assistance.


   Footnotes
 
1 This work was supported by Grant 3–461593 from the Fonds de la Recherche Scientifique et Médicale, Brussels. Back

Received June 16, 1997.

Revised November 14, 1997.

Accepted December 15, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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C. Sempoux, Y. Guiot, K. Dahan, P. Moulin, M. Stevens, V. Lambot, P. d. Lonlay, J.-C. Fournet, C. Junien, F. Jaubert, et al.
The Focal Form of Persistent Hyperinsulinemic Hypoglycemia of Infancy: Morphological and Molecular Studies Show Structural and Functional Differences With Insulinoma
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K. E. Cosgrove, M.-H. Antoine, A. T. Lee, P. D. Barnes, P. de Tullio, P. Clayton, R. McCloy, P. De Lonlay, C. Nihoul-Fekete, J.-J. Robert, et al.
BPDZ 154 Activates Adenosine 5'-Triphosphate-Sensitive Potassium Channels: In Vitro Studies Using Rodent Insulin-Secreting Cells and Islets Isolated from Patients with Hyperinsulinism
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H. Huopio, S.-L. Shyng, T. Otonkoski, and C. G. Nichols
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B. Dekel, D. Lubin, D. Modan-Moses, J. Quint, B. Glaser, and J. Meyerovitch
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P. de Lonlay-Debeney, F. Poggi-Travert, J.-C. Fournet, C. Sempoux, C. D. Vici, F. Brunelle, G. Touati, J. Rahier, C. Junien, C. Nihoul-Fekete, et al.
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