HH remains a clinical challenge to be diagnosed, as well as a difficult pathology to distinguish from insulinoma or another insulin-producing tumor. Both diseases develop symptomatic hypoglycemia and endogenous hyperinsulinism, and both might have lesions found in imaging studies.
Although symptoms generally resolve upon glucose intake, hypoglycemia can be life-threatening for all ages. In addition, it is well known that severe hypoglycemia increases cardiovascular risk and worsens cognitive impairment. Our patient presented evident symptomatic hypoglycemia at night, which resolved after any form of glucose intake (33).
For the differential diagnosis of persistent HH, imaging studies can guide physicians to the focal or diffuse type of disease. Abdominal CT or MRI, remain the first-line option to visualize an insulinoma (34); although other techniques like octreotide scintigraphy, glucagon-like peptide type 1 scintigraphy (GLP-1) can be performed, they have low sensitivity (35,36,37). If diffuse disease is part of the working diagnosis, imaging with the ¹⁸F-DOPA-PET-CT scan should be performed; and it has become the preferred study for most patients, including those with a medically unresponsive disease, who are thought to have a focal lesion, in order to identify its precise location before surgery (38). Genetic mutation testing has become standard of care for prognosis, family counselling and as a diagnostic tool when a focal pancreatic lesion is present (39).
In our case, he underwent an 18-F-DOPA PET scan, which showed findings consistent with diffuse hyperfunctioning of the pancreatic tissue in body and tail.
Diazoxide is the mainstay of medical management, it acts by inhibiting glucose stimulated insulin secretion; and although it is used to try to control symptoms, in most cases relief cannot be observed, as mentioned in our case. Octreotide, a long-acting analog of somatostatin, inhibits insulin release and may control hypoglycemia in patients in whom diazoxide has failed (18).
It is important to rule out Munchausen syndrome or factitious disorder before surgical decision making. During the assessment of pediatric patients, psychological evaluation of the patient and its family should be part of the pre-surgical workup, in our setting it was not possible to correlate studies determining the use of sulfonylureas in urine and blood, nor the use of insulin.
In the real life we could not rule out Munchausen syndrome, and neither it there was evidence of elevated c- peptide; therefore, the surgical decision was made based on the patient's clinical course and the lack of non-response to pharmacotherapy; in addition to the hyperfunction of the pancreas observed in the Pet scan, and assessing the increase life threating risk.
The post-surgical outcome validates the decision made, since hypoglycemic episodes resolved and the patient is currently metabolically stable, with a significant improvement in his quality of life.
In our systematic review, 34/41 patients received medical therapy, but only 9 (26,4%) were able to maintain long term control without requiring surgery, and 1 was reported as becoming diabetic. The other 32 received surgery, the one most commonly performed is SDP in 72% of the surgical patients. This procedure requires to remove between 60 to 80% of the pancreas, less than what has been recommended in newborns or children (up to 95%) (18). In children early and aggressive surgery has been recommended to decrease neurological sequelae; but the longer follow up of these patients has shown that diabetes mellitus and linear growth impairment were frequent complications of this extensive surgery. In adolescents, the biggest surgical challenge is to perform a surgical resection able to guarantee long term symptomatic control without evolving into diabetes. This is one of the reasons why, although minor (1/23 pts), there is always a risk of requiring a second operation to extend the pancreatectomy if symptoms are not controlled with the first one; patients and parents should be notified about this alternative before surgery, and it should be part of the surgical consent (27) as well. Although the adolescent form of the disease resembles the adult form, and since there is no optimum procedure for all adolescent or adult patients with nesidioblastosis, patients should understand that a second operation involves less risk, compared to the risk of lifetime diabetes mellitus, after functional and extensive pancreatectomy (22).
Current and evolving PET-CT radioisotopes will help to maximize the chances for differential diagnoses with insulinoma. Although the response rate is low, medical therapy remains the initial therapy; but as soon as the lack of response is identified, surgery should be indicated, as the last but only therapy able to provide long term control of the disease in the vast majority of patients. Experienced surgical teams should minimize the risk of suffering from post-surgical diabetes.
Surgery was able to assure long term control of the non-insulinoma pancreatogenesis of the hypoglycemia syndrome in the vast majority of patients. As part of the findings of the systematic review, only one patient had simultaneous nesidioblastosis and insulinoma; found in the second surgery requiring total pancreatectomy (29). Except for this particular case, no patient from the whole revision, including our case, was found to have a discrete insulinoma; however, the resected pancreas demonstrates the presence of islets hypertrophy.
A great limiting factor in the assessment of our patient was the impossibility of performing genetic tests before surgery; understanding that according to the literature they have become a new fundamental diagnostic pillar for the diagnosis and management of HH in children and adults.
The systematic review showed us that more adolescents are suffering from HH than what a simple search allows to identify. However, they have been included in reports from pediatric centers when their ages ranged from 10 to 16 years, while the older (16 to 24 years) were reported in manuscripts as adult patients because they were referred to adult surgical teams.
Therefore, we might conclude that, in the light of current knowledge and available therapeutics, when HH with nesidioblastosis is suspected, multidisciplinary management is recommended; surgeons should be part of the team, since an adequate surgical procedure will allow assure long term control.