title: Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes.
abstract: Persistent hyperinsulinemic hypoglycemia (PHH) in adults that is not caused by an insulinoma is a rare and not well-characterized disease that has been named nesidioblastosis. In this study, we defined and scrutinized criteria for its histologic diagnosis, assessed its relative incidence, and discussed its pathogenesis. In pancreatic specimens from 15 adult patients with PHH in whom no insulinoma was detected and in 18 adult control patients, the endocrine tissue was screened for islet and beta-cell changes. The diagnostic reliability of the findings was checked by an interobserver analysis. The relative frequency of the disease was assessed in a series of 232 patients with PHH. Finally, genetic analysis of the menin gene was performed. Among the various indicators of islet changes, beta-cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei was the most significant and diagnostic finding in patients with PHH. The interobserver analysis revealed 100% specificity and 87.7% sensitivity. The hyperfunctional state of the beta-cells was not associated with changes in the subcellular distribution of insulin and proinsulin, proliferative activity, or mutations of the menin gene. Our results indicate that diffuse nesidioblastosis in adult patients with PHH resembles that seen in neonates suffering from PHH. The most important criterion for the diagnosis is the beta-cell hypertrophy. As approximately 4% of adult patients with PHH are affected by diffuse nesidioblastosis, this disease is not as rare as it has been thought to be. Pathogenetically, the defective insulin secretion could be based on a molecular defect.
authors.affiliation: Department of Pathology, University of Kiel, Kiel, Germany. manlauf@path.uni-kiel.de
authors.forename: Martin
authors.initials: M
authors.lastname: Anlauf
authors.forename: Daniel
authors.initials: D
authors.lastname: Wieben
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Paul
authors.initials: P
authors.lastname: Komminoth
authors.forename: Andreas
authors.initials: A
authors.lastname: Raffel
authors.forename: Marie L
authors.initials: ML
authors.lastname: Kruse
authors.forename: Christian
authors.initials: C
authors.lastname: Fottner
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.forename: Heiner
authors.initials: H
authors.lastname: Mönig
authors.forename: Philipp U
authors.initials: PU
authors.lastname: Heitz
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000235:genetics / Q000473:pathology*; D007003:Hypoglycemia / Q000150:complications / Q000235:genetics / Q000473:pathology*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D046768:Nesidioblastosis / Q000150:complications / Q000235:genetics / Q000473:pathology*; D015588:Observer Variation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016133:Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D017931:DNA Primers; D007328:Insulin