Phenomenon of hypoglycemia unawareness in patients with insulinoma - single center experience.

Introduction: Insulinomas are rare neuroendocrine tumors of pancreas. Clinical manifestations include various symptoms of hypoglycemia, which is the result of insulin overproduction. Symptoms of hypoglycemia are heterogenous what most probably contributes to diagnostic delay. In this study we retrospectively evaluated clinical features of hypoglycemia. We discovered that a substantial number of patients suffered from hypoglycemia unawareness.

Materials and methods: We performed retrospective analysis of prospectively collected patients with histologically confirmed insulinoma. We evaluated clinical features and signs of hypoglycemia and the duration of symptoms and performed thorough review of the patients' files in order to identify whether patients had been falsely diagnosed previously. Each patient underwent 72 hour fasting test during which levels of immunoreactive insulin (IRI), C-peptide and nadir blood glucose level were obtained. Based on the clinical findings and results of 72 hour fasting test we identified a subgroup of patients with hypoglycemia unawareness. These had an episode of clinically silent hypoglycemia. We compared IRI and C-peptide levels obtained at the time of the fasting test termination in the unawareness group and the group without hypoglycemia unawareness.

Results: Twenty two patients with insulinoma that had been hospitalized in our tertiary center were included in the analysis. Mean age was 51±16.7 years. The most common symptom reported by 63.6% of patients was fatigue, followed by increased appetite with consequent weight gain and the loss of consciousness, both reported by 40.9% of patients. Based on the review of clinical features and the results of the fasting test we identified a group of patients with hypoglycemia unawareness. We labeled the patient accordingly in case of the loss of consciousness in personal history as well as asymptomatic hypoglycemia or severe neuroglycopenic symptoms during the fasting test without any accompanying or preceding clinical signs. There were 7 patients with hypoglycemia unawareness in our cohort (31.8%). Patients with this phenomenon had significantly lower levels of both IRI (2.35±1.25 vs. 5.88±3.92ng/ml, p=0.01) and C-peptide (9.14±7.36 vs. 50±42.8 µU/ml, p=0.01) than the rest of the patients. Nadir blood glucose level during the fasting test showed no significant difference (9.4±8.2 vs. 12.2±8.2 months, p=0.28) in the unawareness group and the rest of the patients, respectively.

Conclusion: We described the phenomenon of unawareness to hypoglycemia in the patients with insulinoma. This has not been recognized in insulinoma patients yet since available evidence mostly relates to type I diabetic patients. It might lead to higher morbidity and diagnostic delay. Further studies with prospective evaluation should be performed to further confirm relatively high prevalence in patients with insulinoma.