Congenital hyperinsulinism: current trends in diagnosis and therapy

Abstract

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.

Figure 1

Histology of the focal form of HI. Histological features of focal form (A1-A4) on frozen sections stained by toluidine blue (A1, A3, A4) and on immunostaining with proinsuline antibody (A2). At low magnification (A1, x25; A2, x16) a modified architecture of pancreatic tissue is observed within the focal form. The focal form is not encapsulated and is poorly delimited. It contains focal adenomatous hyperplasia of islets (pale areas) intermingled and/or surrounded by exocrine acini (darkest area underlined by white stars) (A1 and A3). This pattern is underlined by proinsuline showing an evident contrast between the focal lesion and normal pancreas (doted line circles). At high magnification (A3 and A4, × 200), the focal lesion (A3) is composed of islets containing a heterogeneous population of endocrine cells of various sizes. Some of these cells have large nuclei (arrows, A3) and large cytoplasms. By contrast, normal islets (doted line circles) observed outside the lesion have endocrine cells of usual size without enlarged nuclei (A4).

Figure 2

Histology of the diffuse form of HI. Histological features of diffuse form (B1- B4) on frozen sections stained by toluidine blue (B1, B3) or on formalin fixed paraffin embedded section stained with HES (B4) or with proinsuline antibody (B2). At low magnification (B1, x25; B2, x16), the architecture is preserved with a normal distribution between exocrine (dark) and endocrine area (pale). At higher magnification (B3 and B4 x200), abnormal endocrine islets contain cells with voluminous nuclei (arrows, B3) and enlarged cytoplasm. The entire pancreas is interspersed with abnormal islets intermingled with morphologically normal islets in a variable proportion (B4). To confirm a diffuse form on extemporaneous frozen sections, abnormal islets must be observed on biopsies sampled from at least 2 or 3 distinct areas of the pancreas.

Figure 3

Diagnostic tree for HI. AD: Autosomal Dominant; AR: Autosomal Recessive; MODY: Maturity Onset Diabetes of the Youth; HI: Hyperinsulinism; OAC: Organic Acid Chromatography; EIHI: Exercise-Induced HyperInsulinism; SGA: Small for gestational age. T2D: Type 2 diabetes.

Figure 4

Management tree for HI patients. DZX: Diazoxide; HI: Hyperinsulinism; Med treatt: Medical treatment. * Failure of the surgery for a focal form of HI is rare, but happens when the focal form is very large or when two focal forms coexist within the same pancreas.

Figure 5

Abdominal ¹⁸F-fluoro-L-DOPA PET-scan imaging in HI. Focal form (A, B, C): PET-scan localizes accurately the focal lesion. A: Anterior view of a 3 dimensions CT-scan reconstruction fused with PET imaging. B: Transversal view (Fusion PET&CT) of the same patient with a focal form. The pancreatic uptake of the radiotracer is almost exclusively located at the head of the pancreas with a near-complete silencing of the rest of the pancreatic tissue (C: Transversal PET imaging). In a suspected diffuse form, the uptake of the radiotracer appears in the whole pancreas (D: PET, transversal view; E: Pet and 3D CT fusion). Fluoro-DOPA is excreted in the kidneys and the bile, so that liver (C, D, E), kidneys (D, E), ureteras, bladder and diaper (E) appear on the PET imaging.

Figure 6

Cerebral RMI: Brain damage after severe hypoglycemia in HI. A, B, C: Brain RMI of a patient with severe necrotic lesions of the occipital lobes, but also cysts of parietal lobes. D (Flair sequence): Another patient presenting with a characteristic unilateral occipital lesion.