(nesidioblastosis)

The incidence is 1/30,000 to 50,000 births. Generic term for a group of genetic diseases that result in deregulation and excessive secretion of insulin. Congenital hyperinsulinism, formerly nesidioblastosis, is a cause of recurrent hypoglycemia without ketosis of the newborn and infant. There are diffuse (the whole pancreas is involved) and focal (localized lesion, 30 % of cases) forms that cannot be distinguished with certainty on the basis of clinical signs, radiological examinations or the macroscopic aspect at laparotomy. 

From a genetic point of view (HHF acronym for Hyperinsulinemic Hypoglycemia Familial), seven types have been identified:

• HHF1 [MIM 256 450]: mutation of the ABCC8 gene (11p15.1) coding for the SUR1 subunit (regulatory protein, sulfonylurea receptor) of the beta cells of the pancreas. This mutation is the most common cause of the isolated forms and is associated, at the level of the hyperplastic cells of the pancreatic islands, with a heterozygous mutation of paternal origin and the absence of the maternal allele for this gene.
• HHF2 [MIM 601 820]: mutation of the KCNJ11 gene (11p15) coding for the ATP-dependent potassium channel of the beta cells in the pancreas
• HHF3 [MIM 602 485]: mutation of the GCK gene (glucokinase) (7p13)
• HHF4 [MIM 609 975]: mutation of the HADH gene (4q25)
• HHF5 [MIM 609 968]: mutation of the INSULIN RECEPTOR (INSR) gene (19p13)
• HHF6 [MIM 606 762]: mutation of the gluD1 gene (glutamate dehydrogenase) (10q23)
• HHF7 [MIM 610 021]: mutation of the SC16A1 gene (1p13)

Diffuse forms are transmitted in an autosomal recessive or dominant manner: they result from abnormalities of the transmembrane channels (chanellopathies: HHF1 and HHF2), metabolic abnormalities in the Krebs cycle of pancreatic cells (HHF3, HHF6 and HHF7) or abnormalities in the transcription of insulin, insulin receptor or proinsulin synthesis (HHF4 and HHF5 gene).

Some cases are part of a polymalformative syndrome such as Beckwitt-Wiedemann, Sotos, Perlman, or Kabuki syndrome, or metabolic diseases such as congenital glycosylation disorders (forms Ia and Ic) see these terms).

Diffuse and syndromic forms respond to treatment with diazoxide, unlike localized forms (called diazoxide resistant).

In 60 % of cases, the onset is neonatal with severe hypoglycemia before 72 hours of life. In 35 % of cases, symptoms do not appear until one month (early infantile form) or one year (late infantile form) with convulsions or convulsive equivalents (staring spells, loss of consciousness ...).

The diagnosis is established by glucose needs greater than 10 mg/kg/min to maintain normoglycemia, a high blood insulin level, a response to the administration of glucagon (0.5 mg IM or subcutaneous) and the absence of ketosis. It is also important to measure NH4 to diagnose rare forms of abnormalities in the metabolism of amino acids or of the short chain fatty acid metabolism.

In the neonatal cases, the emergency treatment is to administer significant amounts of glucose by IV route to prevent hypoglycemia. Other medications are often needed such as the administration of glucagon (1 mg/day IV or subcutaneous injection). Some teams use somatostatin IV (0.5-3.5 µg/kg/h) or octeotride (10-50 µg/kg/day in 3 doses by subcutaneous or IV injection). Oral diazoxide (15 mg/kg/day for the newborn and 10 mg/kg/day for infants, in 3 doses) is used for long-term treatment, with/or nifedipine (0.5 to 2 mg/kg/day in 2 doses taken orally) which allows, in general, to obtain normoglycemia with a normal diet for age. 

Treatment options are:

-         focal form: surgical resection of the lesion (cephalic  , isthmic or caudal pancreatectomy)

-         diffuse form: either subtotal pancreatectomy or medical treatment. 

To make the difference between a diffuse or a focal form (i.e. typically in the absence of response to diazoxide), and locate the lesion, a PET scan with [18F] fluoro-L-dopa coupled with an MRI or a CTScan is performed. For this examination, diazoxide and  octeotride treatments can be continued but glucagon administration should be interrupted.

Preoperatively, verify the absence of gallstones or biliary sludge: preventive treatment with ursodeoxycholic acid is often needed.

Anesthetic implications: 

in case of treatment with diazoxide: check blood count (neutropenia), liver enzymes (cytolysis) and the absence of pulmonary hypertension (reversible when the treatment is stopped). Hirsutism and peripheral edema are frequent. In case of laparotomy for pancreatic exploration, stop diazoxide 5 days before and octeotride 2 days before surgery; the association of epidural block with general anesthesia is the first choice in the absence of contraindications: the reaction of intraoperative stress is blocked, allowing to see a rapid increase in blood glucose levels when the causal lesion is excised, and one can achieve good postoperative analgesia. Extemporaneous biopsy are performed to confirm the diagnosis of focal or diffuse form. 

References : 

• Arnoux J-B, de Lonlay P, Ribeiro M-J, Hussain K, Blankenstein O, Mohnike K, Valayannopoulos V, robert J-J, Rahier J, Sempoux C, Bellanné C, Verkarre V, Aigrain Y, Jaubert F, Brunelle F, Nihoul-Fékété C. 
  Congenital hyperinsulinism. 
  Early Human Develop 2010 ; 86 : 287-94.
• Mali M, Bagry H, Vas L. 
  Anaesthetic management of a case of nesidioblastosis for subtotal pancreatectomy. 
  Pediatr Anesth 2002; 12: 80-4.
• Hardy OT, Litman RS. 
  Congenital hyperinsulinismm: a review of the disorder and a discussion of the anesthesia management. 
  Pediatr Anesth 2007; 17: 616-21.

Updated: March 2019