The Journal of Pediatrics
Volume 150, Issue 2 , Pages 122-124, February 2007

PET Scanning for Infants with HHI: A Small Step for Affected Infants, A Giant Leap for the Field

  • Mark A. Sperling, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Mark A. Sperling, MD, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA.

Professor and Chair Emeritus, Department of Pediatrics, University of Pittsburgh School of Medicine, Division of Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, PA

Article Outline

Abbreviations: 18F-L-DOPA, 18F-fluoro-l-dopamine, HHI, Hyperinsulinemic hypoglycemia of infancy, KATP, Adenosine triphosphate–regulated potassium channel

 

Attempting to explain the pathophysiology of macrosomic infants with hypoglycemia has engaged physician/scientists for some 50 years. First came the era of careful observation and description suggesting a familial or genetic basis and similarities in the symptoms to an overdose of insulin.1, 2 Next came the era of biochemistry, radioimmunoassay, and glucose kinetics by means of stable isotopes that defined hyperinsulinemic hypoglycemia of infancy (HHI) as the most common and potential neurologically devastating form of neonatal hypoglycemia.3, 4 The exponential leap forward with remarkable progress occurred in the past decade, since the elucidation of the molecular mechanisms responsible for insulin secretion and its modulation through the adenosine triphosphate–regulated potassium channel (KATP).5 This channel converts the chemical energy of glucose or amino acid metabolism to electrical signals that trigger voltage-gated calcium channels leading to insulin secretion. Inactivating mutations in the actual channel pore (Kir 6.2), or its regulatory subunit (SUR1), prevent channel opening, resulting in prolonged membrane depolarization, with ongoing and unregulated insulin secretion causing hypoglycemia.5, 6 Some of these mutations are familial, mostly inherited in an autosomal recessive manner. In the general population, most cases of HHI are sporadic.

See related article, p 140

In these sporadic cases, two types of histopathologic lesions have been described: a focal form in about 40% to 50% of cases and a diffuse form in about 50% to 60% of cases.7 The focal type is characterized by focal adenomatous hyperplasia of islet-like cells with compacted small β-cell nuclei; “nodules” occur in an otherwise normal pancreatic lobular background and hence local excision is curative. By contrast, the diffuse form is characterized by irregularly sized islets with hypertrophied β-cells containing large nuclei throughout the pancreas. In such diffuse cases, even 95% pancreatectomy may not cure hypoglycemia, but it does result in a high prevalence of diabetes mellitus or abnormal glucose tolerance in the second decade of life.7 The diffuse form suggests a germline mutation causing diffuse changes throughout the pancreas.5, 6 The genetic pathology of the focal forms is due to a double-hit mechanism. The first “hit” includes loss of a maternal allele in the p15 region of chromosome 11, close to the region regulating unrestrained growth, which is also involved in the Beckwith-Wiedemann syndrome.8 It is not known why this sporadic event occurs. The second “hit” consists of a paternal mutation in the SUR1 gene (ABCC8) or Kir 6.2 (KCNJ11), which, in the fetus, is now no longer balanced by a normal maternal copy.8, 9 Effectively, this combination represents somatic reduction to hemizygosity or homozygosity for a paternal KATP channel mutation within the affected pancreatic β-cells.8, 9 However, such mutations are not always found in the focal form.

Distinguishing focal from diffuse forms is of importance in guiding the extent of surgical resection, which may result in a cure and prevent unnecessary hyperglycemia or frank diabetes mellitus in later life. The initial approach for distinguishing the diffuse from the focal form was intraoperative and based largely on β-cell morphology from serial intraoperative specimens. In one reported series, of the 52 infants with similar clinical features before surgery, 30 had diffuse hyperplasia requiring near-total pancreatectomy.7 Nevertheless, 13 of these patients had persistent hypoglycemia, 7 had hyperglycemia, and 8 had insulin-dependent diabetes mellitus, with only 3 patients of the original 30 maintaining entirely normal glucose metabolism. By contrast, of the 22 patients who had focal disease with specific excision of the lesion, all maintained normal glucose hemostasis after surgery.7 Hence, preoperative distinction of focal from diffuse forms is of supreme importance.

Early efforts at preoperative localization of a lesion focused on the ability of calcium, tolbutamide (a sulfonylurea), and sometimes, glucose, infused into a vein to elicit an insulin response sampled from a separate vein.10, 11 The expectation was that patients with either focal or diffuse lesions would show an exaggerated insulin response to calcium, but only patients with the focal form would respond to tolbutamide, since they had large areas of presumably normal pancreatic islets. By contrast, those with diffuse disease would not demonstrate a response to the sulfonylurea, as a majority of such patients were initially thought to have a mutation in the sulfonylurea receptor SUR1. This approach had low predictability and precision because some patients had mutations in Kir6.2, leaving SUR1 unaffected or minor deletions in SUR1, which could be overcome by the pharmacologic doses of tolbutamide used.10, 11 A second approach used selective infusion of calcium into the arterial branches of the celiac axis supplying discrete areas of the pancreas. Venous sampling was performed in the hepatic vein near the entry of the portal vein through retrograde femoral catheters.11 These invasive and difficult procedures also failed to distinguish reliably focal from diffuse forms; they lacked sensitivity and specificity.11 Similarly, focal lesions could not be identified by standard imaging techniques such as CT, MRI, intraoperative ultrasound, or radiolabeled octreotide scans. Most recently, PET scanning, using 18F-fluoro-l-dopamine (18F-L-DOPA), has been used with highly promising results in small series of infants to document lesions in focal hyperinsulinism.12, 13, 14 It has been known that neuroendocrine tissues such as pheochromocytomas take up l-dihydroxyphenylalanine (L-DOPA) and have aromatic amino acid decarboxylase (AADC). Decarboxylation of the l-DOPA to dopamine in a particular tissue allows meaningful localization by means of PET scanning, using the radioactive isomer 18F-L-DOPA. However, promising results in islets was surprising, since β-cells are not derived from ectodermal neuroendocrine lineage. Nevertheless, pancreatic endocrine β-cells appear to have AADC and are therefore amenable to PET scanning with the use of 18F-L-DOPA.12, 13, 14

In this issue of The Journal, Hardy et al,15 from Children’s Hospital of Philadelphia and University of Pennsylvania, describe results of the first North American study to test prospectively the accuracy, sensitivity, and specificity of [18F]–L-DOPA PET scanning in the initial 24 patients of some projected 50 cases of congenital HI to be evaluated. Each of the patients had a diagnosis of hyperinsulinism confirmed by standard criteria, and the preoperative diagnosis of focal or diffuse was confirmed at the time of surgical resection of the identified lesion with subsequent histologic examination by two independent pathologists masked as to the results of preoperative PET scan reports. Mutational analysis of the genes encoding the KATP channel were performed, but results were not used to guide surgery. Loss of heterozygosity in focal lesions was identified by absence of p57KIP2, a maternal marker of 11p15 or by other microsatellite markers. The results are dramatic, visually spectacular, and quite convincing of the value of 18F-L-DOPA for preoperative localization to distinguish focal from diffuse forms. The group of 24 patients split evenly into 12 cases each of focal and diffuse disease, affirming that about one-half of HHI in newborn infants will benefit enormously by preoperative distinction and localization of focal lesions guiding precise surgical excision. Clinically, patients with either focal or diffuse forms were large for gestational age at birth (83% each), reflecting the effects of hyperinsulinism on fetal growth in utero. Focal forms may have been somewhat milder, in that symptomatic presentation was sometimes delayed up to 90 days in the focal group but occurred within the first week of life in the diffuse cases. Loss of heterozygosity was confirmed in each patient of the focal disease group and in none of the patients in the diffuse disease group. A mutation in the father was identified in each of the focal cases in whom this test was performed.15 A mutation in the KATP channel was identified in both parents in 7 of the 11 sets in whom the test was performed in the diffuse group; a mutation was not identified in two fathers and four mothers, a reminder that we do not yet fully understand the molecular basis of some 20% to 30% of diffuse cases.16 The 18F-L-DOPA PET scans were 96% accurate in diagnosing focal or diffuse disease and 100% accurate in localizing the focal lesions.

Will these remarkable results hold up in the remaining 26 patients of this cohort or in some other series of patients to be studied by this or other groups? If these results are replicated in a cohort of 100 or so patients in independent centers, they herald a new era in managing HHI in newborn infants combining clinical acumen, standard chemical and hormonal assays, molecular diagnostics, and sophisticated imaging to localize preoperatively focal lesions guiding precise operative surgery in about one half of all affected infants. These combined approaches culminate 50 years of research. Each independent small step, when now combined, represents a giant leap for mankind and certainly for those infants affected by HHI.

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References 

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PII: S0022-3476(06)01127-9

doi:10.1016/j.jpeds.2006.11.058

Refers to article:

  • Diagnosis and Localization of Focal Congenital Hyperinsulinism by 18F-Fluorodopa PET Scan

    Olga T. Hardy, Miguel Hernandez-Pampaloni, Janet R. Saffer, Mariko Suchi, Eduardo Ruchelli, Hongming Zhuang, Arupa Ganguly, Richard Freifelder, N. Scott Adzick, Abass Alavi, Charles A. Stanley
    The Journal of Pediatrics February 2007 (Vol. 150, Issue 2, Pages 140-145)

The Journal of Pediatrics
Volume 150, Issue 2 , Pages 122-124, February 2007

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