We performed a thorough literature review and found less than one hundred pediatric insulinoma cases were reported since 1960 [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30] (Table 1), of which three children had malignant insulinoma [9, 22, 26]. Presentation varied from subtle and non- specific to catastrophic events. The spectrum of symptoms included confusion, palpitation, sweating, tremors, hunger, irritability, dizziness, drowsiness, generalized weakness, abdominal pain, psychomotor slowing, syncope and seizures. Most of the episodes occurred during the morning hours, after exercise or fasting, and resolved after food or juice intake [9, 10, 14, 15, 17,18,19, 27]. Eighteen children experienced seizure activity [13, 14, 16, 18,19,20,21, 23,24,25, 27, 29, 30], four children were found in a comatose state [29, 30], three children had mental retardation as sequelae after surgery [11, 27, 30] and two children died [22, 30]. Duration of hypoglycemia symptoms before the diagnosis of insulinoma in children ranged from 1 month to 7 years, and averaged 10–13.4 months [14, 17]. The reasons behind the delayed diagnosis likely include not seeking medical attention due to symptom ambiguity [10], as well as failure of conventional imaging methods such as CT [10] and ultrasound [11] to localize the tumor. In our case, the family did not seek medical attention for at least 2–3 months because EM’s symptoms of increased fatigue, tremors, sweating, and somnolence followed skipped meals and resolved after eating, making her symptoms mimic hunger, until EM became unresponsive. This delay in diagnosis may be dangerous, since prolonged hypoglycemia can lead to seizures, mental status changes and sometimes death [30]. Halpin et al. recently reported a 15-year-old adolescent female with symptoms of fatigue, confusion, irritability and staring lasting for 5 months before she was found to have a 1.3 cm size insulin-secreting tumor [10]. This and our case emphasize that in the adolescent population, “normal” teenage behaviors can mask hypoglycemia symptoms, making the diagnosis more difficult in this age group.
EM’s physical examination indicated noticeable weight gain over the past few months and a BMI at the 98th percentile. Weight gain in insulinoma can be attributed to overeating to treat hypoglycemia symptoms, as patients discover that they feel better after food intake. There is also increased hunger due to release of catecholamines, occurring as a result of hypoglycemia, as low blood glucose levels stimulate the autonomic nervous system [31]. One study reported that 14% of the patients with insulinoma gained weight [32]; the incidence was even higher at 72% in another study [33]. The etiology of AN noted in our patient and also previously described in an obese 14-old-year male with insulinoma who initially presented with hypoglycemia and a 37 kg weight gain [16] is unclear and may be attributed to obesity-induced insulin resistance or increased insulin levels due to the insulinoma [16]. AN is thought to be caused by proliferation of fibroblasts and keratinocytes when excess insulin binds to insulin like growth factor-1 receptors [34]. This would lead one to believe that all cases of hyperinsulinism would be associated with AN; however, not all insulinomas present with AN [9, 10]. Why AN is present in some and not in others is not clear. What we know is that severe insulin resistance associated with obesity leads to compensatory hyperinsulinemia [35] and AN severity is proportional to increased insulin resistance [36]. Our patient’s AN could be a combined result of both obesity induced insulin resistance and hyperinsulinemia due to the insulinoma.
EM’s biochemical evaluation revealed inappropriately low cortisol and growth hormone levels in her critical samples (Table 2). These abnormal counter regulatory hormone responses to hypoglycemia in a patient with insulinoma have been previously documented [10, 16, 18, 37] and found to be due to a lower glycemic threshold for hormone release [37]. After tumor resection, the reversal in this pattern of cortisol response was noted (37). Inappropriately low counter-regulatory hormones for a low serum glucose level likely reflect the physiologic blunting seen due to chronic hypoglycemic stimuli and are most notable in patients who have diabetes mellitus, congenital hyperinsulinism and insulinoma [38]. In patients with diabetes mellitus and hyperinsulinism, hypoglycemia unawareness develops as recurrent iatrogenic hypoglycemia shifts the glycemic threshold for counter regulation and development of hypoglycemic symptoms to lower plasma glucose concentrations. The mechanisms underlying the development of hypoglycemia unawareness may be related to both altered central sensing of hypoglycemia and impaired coordination of responses to hypoglycemia [39]. Our patient’s delay in seeking medical care and discovery of hypoglycemia only after EM was found to be unresponsive with POC levels at 19 mg/dl (1.05 mmol/L) may be explained by this hypoglycemia unawareness.
The literature review suggests that imaging studies confirmed the clinically suspected diagnosis of insulinoma in 35 cases including ours. The tumors were first detected by MRI in 19 cases, by CT - in 12, by 18 F-DOPA PET - in 3, and ultrasound - in one case. Insulinoma in our patient was first detected by MRI, and later confirmed by ultrasound, CT and PET scans. Surgical removal of the tumor is the best treatment and considered in all cases (31), as it has very high cure rate [10, 17, 20]. Location of the tumor was reported in 47 cases including our case: tumors were found in the head of the pancreas in 14 cases, in the neck and the body - in 16 cases, and in the tail of the pancreas - in 17 cases. The size of resected insulinomas in the pediatric population ranged from 0.7 cm to 9.6 cm (9, 10, 11, 14, 15, 17, 18, 19) (Table 1) and averaged 1.14 cm (17) and 1.26 cm (14) in the noted studies. In our patient, 1.5 cm tumor was resected from the neck of the pancreas that promptly cured hypoglycemia symptoms.
Our case highlights the importance of careful evaluation of biochemical hypoglycemia. The diagnosis of insulinoma could be delayed because the symptoms are often non-specific.. Any patient presenting to the ED with documented Whipple’s triad, should be thoroughly investigated to rule out potentially life threatening exogenous and endogenous hyperinsulinemia and surreptitious use of oral hypoglycemic agents [40]. This patient’s initial presentation to the ED should have warranted a more detailed evaluation with an ultimate goal to establish the cause of hypoglycemia. Careful history (sometimes tracing back for a few months to years) including medication use and the presence of MEN1 in the family, physical examination and biochemical evaluation (serum glucose, insulin, C-peptide and urine and serum drug levels) are the initial steps in establishing a diagnosis and differentiating between the various causes. If hyperinsulinism is suspected, supervised fasting with a glucagon challenge test is the next step [1]. Our patient was discharged after symptomatic treatment, and before the cause of the hypoglycemia was established and was advised to see a pediatric endocrinologist for further investigation. This girl had not returned to her primary care doctor for surveillance physical exams for a few years and therefore could not promptly obtain a referral from him required by state health insurance in order to be evaluated by a pediatric endocrinologist. This situation delayed her access to specialized care and made the family return to the ED instead. Evaluation of her social situation, including health insurance at the initial ED visit may have changed disposition decision and prevented a second hypoglycemia event.
