Neonatal Hypo-Ketotic Hypoglycemia Secondary to Transient Hyperinsulinism: Diazoxide Responsiveness and Experience With Fasting Test After Treatment Withdrawal

Introduction:: Transient neonatal hyperinsulinism (TNH) is frequently reported in neonates with stress factors (intrauterine growth restriction (IUGR), large for gestational age (LGA), perinatal asphyxia, infants of diabetic mother, etc.). Early recognition and treatment are prioritary to avoid neurological morbidity. Objective: Clinical, molecular characterization and treatment response in neonates with hypoglycemia due to transient hyperinsulinism admitted to a tertiary hospital Neonatal Unit from January 2015 to August 2020. Materials and Methods: Prospective cohort study. Newborns older than 7 days of age, with diagnostic criteria of hyperinsulinism: non ketotic hypoglycemia with detectable insulin, low free fatty acids, glucose infusion rate > 10mg/kg/min, and positive response to glucagon test, were recruited. Results: Out of 5374 patients admitted, 46 (0.85%) presented hypoglycemia secondary to TNH (57% males and 43% females). 78% were delivered by Cesarean section, 59% were European, 17% Latino-Americans, 11% Asians, 9% Africans, and 4% Arabs. 78% were preterm newborns (median 33 weeks gestational age), 70% had birth weights or heights <-1.6 SDS (medians: -1.8 SDS and -2 SDS, respectively). Median age at diagnosis was 22 days (IQE 10–29 days), and feeding was exclusively enteral. Median blood glucose at diagnosis was 37mg/dl (IQE 31-44mg/dl), median insulin: 3mu/ml, median ketonemia: 0.2mmol/L, GH: 15 ng/ml, Cortisol: 16 ug/dl and AAL: 75mg/dl. 90% received diazoxide (dose ranged between 5-10mg/kg/day), presenting as most prevalent side effects hypertrichosis (80%) and edema (13%). Diazoxide median treatment duration was 83 days (IQE 41–110). Response was positive in 100%, with fasting tests response yielding a glycemia > 60mg / dl after 10 hours of fasting post treatment withdrawal. Molecular analysis was carried out with help of a custom NGS panel (MonDIAB.V3; 385 genes) in 80% of the patients. No mutations were identified in known genes implicated in the etiology of congenital hyperinsulinism (ABCC8, KCNJ11, HNF4A, GLUD1, HADH, SLC16A1, GCK, UCP2, HNF1A, AKT2, INSR, CACNA1D), however, predicted deleterious variants were found in other candidate genes such as G6PC2, TH, PMM2, and APPL1, implicated in insulin secretion or glycemic homeostasis. Conclusions: TNH is a prevalent entity to be considered in neonates with risk factors. In our series, TNH is also present in term newborns (22% of patients) and in newborns with weight and/or height appropriate for gestational age (30%). Treatment with diazoxide at low doses is effective in the resolution of these hypoglycemias. The fasting test could be useful for a safe treatment withdrawal when resolution is suspected. No monogenic cause explaining the TNH was identified. Most of the cases molecularly examined presented with 2 or more predicted deleterious variants, suggesting a multifactorial genetic component.

Comparison of the diagnostic accuracy of the current guidelines for detecting insulinoma

Objective Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test. Design Retrospective cohort study. Methods From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA). Results Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73–1.00), specificity of 0.89 (0.76–0.96) and accuracy of 0.91 (0.81–0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52–0.94), specificity of 1.00 (0.92–1.00) and accuracy of 0.94 (0.85–0.98). Conclusions These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.

Insulinoma: diagnostic features and treatment management

Background. Insulinoma is the most common functional pancreatic neuroendocrine tumor originating from β-cells, with unregulated insulin production and rarely associated with MEN-I syndrome. Diagnosis and treatment of insulinoma are a challenge in the practice of endocrinologist. Aim. To determine on the basis of retrospective analysis the optimal approaches to the management of patients with organic hyperinsulinism. Material and methods. Medical records of 72 patients admitted with suspected organic hyperinsulinism had been screened and medical histories of patients with a confirmed diagnosis of organic hyperinsulinism were included into the analysis. Anamnesis, results of objective, laboratory and instrumental examinations, methods and results of the treatment were analyzed. Results. The diagnosis of insulinoma was confirmed in thirty two cases. Hypoglycemia was achieved within the first 48 hours after the start of the 72-hour fasting test in 100% of cases. Study results showed that in 50% of cases the size of the pancreatic neoplasm was more than 1.4 cm. Inverse correlation between tumor size and plasma glucose concentration at the time of hypoglycemia was found (r=–0.45; р=0.02). Surgical treatment was carried out in thirty out of 32 patients. Surgical enucleation of insulinoma was performed in 12 (40%) cases, distal pancreatectomy — in 18 (60%). Insulinoma was confirmed in 27 cases, while in three patients diagnosis of non-insulinoma pancreatogenous hypoglycemia («nesidioblastosis») was established according to histological findings. Positive clinical result was achieved after all surgeries. In postoperative period patients were discharged within 11—30 days. Patients without post-operative complications were discharged 13.0±1.4 days after surgery. Twelve (40%) patients developed post-operative complications. The duration of hospital stay in these cases was significantly longer 20.1±1.9 (р<0,01). Conclusion. Obtained data confirmed that comprehensive approach including 72-hours fasting test, use of modern imaging techniques and application of high-tech treatment methods, is crucial for successful diagnosis and treatment of insulinoma.

Increased plasma β-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia

ObjectiveThe objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).Research design and methodsWe retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-h fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels >2700 μmol/l (group 1), EHH patients with BOHB levels <2700 μmol/l (group 2) and 59 controls (median glycaemia: 3.2 mmol/l and median BOHB: 6095 μmol/l).ResultsDuring a 72-h fasting test, nine patients (group 1) had BOHB levels >2700 μmol/l (median 6140 and range 2957–7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0–2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.ConclusionDuring a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

Pancreatic Insulinoma Presenting with Postprandial Hypoglicemias

Pancreatic Insulinoma Presenting with Postprandial HypoglicemiasWe report the case of an obese 58 years old patient evaluated for hypoglycemia. The response to a prolonged fasting test was normal, but symptomatic hypoglycemia ensued after mixed meals and with oral glucose loading. A magnetic resonance scan of the abdomen revealed a pancreatic tail tumor, histologically diagnosed as benign insulinoma after successful laparotomy. "Glucose-responsive" insulinomas, although rare, have been previously described in the literature. Therefore, the diagnosis of insulinoma should also be considered in patients that exhibit postprandial rather than fasting hypoglycemia.

Octreotide-Treated Diabetes Accompanied by Endogenous Hyperinsulinemic Hypoglycemia and Protein-Losing Gastroenteropathy

Occurrence of hypoglycemia in diabetes patients is very rare. We report here a case of frequent hypoglycemic attacks caused by inappropriate endogenous hyperinsulinemia in a female patient with poorly controlled diabetes and protein-losing gastroenteropathy. The blood glucose profiles of the patient were unstable. Results of the fasting test performed to investigate the cause of hypoglycemia suggested endogenous hyperinsulinism. Repeated selective arterial calcium injection tests suggested that hyperinsulinemia might be extrapancreatic in origin. However, efforts to detect a responsible lesion such as insulinoma were unsuccessful. Octreotide was used for the treatment of hypoglycemia and protein-losing gastroenteropathy. After treatment, although her leg edema caused by hypoalbuminemia persisted, hypoglycemia almost disappeared.