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.