Discussion:
Insulinomas are well differentiated NEN that most commonly present with hypoglycemia. Other presenting features include seizures, altered sensorium, unexplained weight gain or abdominal pain. The median duration between symptoms onset and diagnosis range may range between 18 to 35 months(7). Although the majority of patients have fasting hypoglycemia, upto 21% patients report both fasting and post prandial hypoglycemia and 6% patients report exclusively post-prandial hypoglycemia(8). Nevertheless, the first step in evaluating hypoglycemia is to confirm the diagnosis by establishing Whipple’s triad, which includes symptoms of hypoglycemia, plasma glucose concentration less than 55 mg/dl, and resolution of symptoms after correction of hypoglycemia(9). If the etiology of hypoglycemia is not evident based on initial history and physical examination, the further diagnostic workup includes measurement of plasma glucose, plasma insulin level, pro-insulin, C-peptide, beta-hydroxybutyrate (BHB) and screening for sulfonylureas during an episode of spontaneous hypoglycemia to assess for insulin-mediated versus non-insulin mediated hypoglycemia. In the absence of a spontaneous episode of hypoglycemia, a supervised 72-hour fast can be carried out to recreate a spontaneous hypoglycemia episode during which the above-mentioned laboratory evaluation can be performed. The hypoglycemia episode is then corrected with the administration of 1 mcg glucagon injection, and the response of glucose to glucagon injection is measured by checking serum plasma glucose level. These laboratory investigations will differentiate insulin (exogenous or endogenous) mediated hypoglycemia from hypoglycemia caused by other mechanisms (e.g., noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)). Anti-insulin antibodies can be tested to evaluate for autoimmune insulin hypoglycemia. A plasma glucose level of less than 55 mg/dl, insulin level more than 3 uU/ml, C-peptide more than 0.2 nmol/L, pro-insulin more than 5 pmol/L, beta-hydroxybutyrate less than 2.7 mmol/L with an increase in plasma glucose by more than 25 mg/dl, negative urine screen for sulfonylureas, serum insulin antibodies and negative history of previous bariatric surgery points towards insulinoma as the most probable etiology of endogenous hyperinsulinemic hypoglycemia (EHH)(10). A proposed approach to adult hypoglycemia evaluation based on endocrine society guidelines has been shown in algorithm 1(10). Hypoglycemia evaluation in our patient indicated insulinoma as the cause of hypoglycemia.
A number of non-invasive imaging modalities can be used to localize an insulinoma after the biochemical workup. These US abdomen, CT scan and MRI of the abdomen. The sensitivity of the US abdomen in localization of an insulinoma is reported to be 9-64%, CT scan 33-64% and MRI 40-90%(11). Up to 35% of patients with evidence of EHH have negative US, CT and MRI during the evaluation of insulinoma(2). Neuroendocrine tumors are rich in somatostatin receptors (SSR), especially SSR subtype 2. Hence, somatostatin receptor scintigraphy using octreotide is a vital imaging modality in localizing gastric neuroendocrine tumors. SSR, however, has low expression in insulinomas compared to other gastric neuroendocrine tumors and hence, octreotide scans have a high false-negative rate in cases of insulinoma(2). 68Ga-DOTATATE positron emission tomography/computed tomography (68Ga-DOTATATE PET) has shown a sensitivity of 95.1 % in the detection of gastric neuroendocrine tumors(3). 18F-DOPA PET is another imaging modality with a higher sensitivity rate of 90% in localizing the lesions in case of insulin-mediated hypoglycemia(4).
EUS and ASVS are invasive techniques to localize insulinoma when the non-invasive techniques fail, and the suspicion remains high. EUS has a sensitivity of up to 89%, whereas the sensitivity of ASVS has been reported to be up to 93% (5, 6). Patel et al. reported 2 cases of insulinomas with negative imaging (including negative octreotide scan in one case). Both patients were diagnosed with FNA via EUS(12). Siddharth et al. also reported a case of insulinoma diagnosed with EUS who initially had a negative CT abdomen, MRI abdomen and octreotide scan(13). Our patient also had a negative US abdomen, CT abdomen, and MRI abdomen/MRCP. Given the high suspicion of a neuroendocrine tumor as the etiology of hypoglycemia, 18F-DOPA PET/CT and 68Ga-DOTATATE PET/CT were performed, which, despite being highly sensitive modalities, were negative making it extremely challenging to localize the tumor. Hence, the diagnosis was established with EUS followed by FNA of the lesion.