The patient was an obese 8.5-year-old white/Mexican boy who initially presented with seizures after initiation of dietary changes for obesity. The paramedics were called, and his blood glucose concentration measured upon the paramedics’ arrival was 30 mg/dL. Low blood glucose levels persisted despite dextrose administration in the emergency department. The patient's medical history was notable for only obesity. The parents were nonconsanguineous. There was no family history of hypoglycemia, diabetes, or neuroendocrine disease. His father had epilepsy. Physical examination findings were normal. The patient was prescribed diazoxide, 5 mg/kg daily (typical dosage range for newborns and infants is 8-15 mg/kg daily; for children and adults 3-8 mg/kg daily); instructed on home glucose monitoring; and discharged home.
The patient was hospitalized 2 months later because of formal laboratory test results that were obtained while the patient was fasting and not taking diazoxide. Laboratory tests performed during fasting hypoglycemia revealed the following results (reference ranges in parentheses): glucose, 40 mg/dL (70-105 mg/dL); cortisol, 12 μg/dL (6.2-19.4 μg/dL); normal fatty acid profile; glucagon, 79 pg/mL (40-130 pg/mL); insulinlike growth factor–binding protein 1, 3.2 ng/mL (30-1000 ng/mL); C-peptide, 1.1 ng/mL (0.9-4.3 ng/mL); growth hormone, 0.4 ng/mL (<1.5 ng/mL); and insulin, 52 μIU/mL (2.0-17.8 μIU/mL). His body mass index (BMI) was 33 kg/m2 (weight 65.7 kg). Abdominal computed tomography imaging was normal. The patient was discharged home on diazoxide, 4.5 mg/kg daily.
At 10 years of age, the patient was evaluated further after transferring care to our medical center. His BMI was 44 kg/m2 (weight 103.5 kg), and he had acanthosis nigri-cans. Before taking morning medications, the following laboratory results were documented (reference ranges in parentheses): serum glucose, 55 mg/dL (70-99 mg/dL); proinsulin, 5.9 ng/mL (≤0.20 ng/mL); C-peptide, 3.8 ng/ mL (0.8-4.0 ng/mL); and insulin, 9.9 μIU/mL (1.9-23.0 μIU/mL). When he was formally fasting, his serum glucose concentration was 38 mg/dL (70-99 mg/dL) at 18.5 hours, with an insulin concentration of 8 μIU/mL (1.9-23.0 μIU/mL) and a C-peptide concentration of 4.2 ng/mL (0.8-4.0 ng/mL). After simultaneous infusions of insulin (0.05 units/kg per hour) and dextrose for 180 minutes, the patient's C-peptide level failed to suppress (2.0 ng/mL [0.8-4.0 ng/mL]) when his glucose concentration was 37 mg/dL (65-160 mg/dL). The patient did not have urinary ketones or elevated ammonia levels during hypoglycemia, and he exhibited glucagon responsiveness. A serum hypoglycemia screen for common diabetes medications was negative. Genetic testing did not identify mutations in the ABCC8, KCNJ11, GLUD1, or GCK genes (Athena Diagnostics). Endoscopic ultrasonography of the pancreas showed no lesions suggestive of insulinoma. Chromogranin A level was normal.
The patient underwent selective arterial calcium stimulation and hepatic venous sampling (4
), and his insulin levels did not demonstrate a regional response to the calcium injections. While the patient was not taking diazoxide, positron emission tomography was performed with 5.3 mCi (196 MBq) of 18-fluoro-L-3,4-dihydroxyphenylalanine (18
F-DOPA). The human subjects committee at the Los Angeles Biomedical Research Institute at Harbor-UCLA approved compassionate use of 18
F-DOPA. The patient and his guardian signed written informed consent. The images demonstrated diffuse uptake throughout the pancreas and no focal lesion was identified ().
Anterior view of 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography 3-dimensional reconstruction showing increased uptake throughout the pancreas.
Medical management was attempted. The patient's condition initially responded to diazoxide (4.5 mg/kg daily). He attempted to lose weight by eating small, frequent meals, and he reached a BMI of 30 kg/m2 (weight 78.7 kg). When the patient's hypoglycemia eventually worsened, diazoxide dosage escalation up to 8 mg/kg daily was attempted, but the patient progressively gained weight (highest BMI 48.5 kg/m2, weight 139.3 kg) and outgrew his dosage. His last dosage was 4 mg/kg daily (525 mg daily). Addition of octreotide, 50 mcg twice daily by sub-cutaneous injection, did not eliminate hypoglycemic episodes, although the events occurred in the 40- to 50-mg/dL range instead of the 20- to 40-mg/dL range. The patient was in a personalized education program at school because hypoglycemic episodes regularly interfered with his learning, but he did not have neurocognitive defects.
Because medical therapy failed, the patient underwent a 45% distal pancreatectomy with splenectomy at age 15 years. Preoperative glucose concentrations were as low as 48 mg/dL (65-110 mg/dL). No focal lesions were identified intraoperatively by palpation or ultrasonography. Intraoperative glucose levels were used to guide extent of pancreatectomy (). Ten minutes after an initial 25% resection of the pancreas, the dextrose infusion was stopped temporarily, and the patient's intraoperative glucose concentration rose to 115 mg/dL. To account for dextrose already received and intraoperative stress, a final 20% resection was performed, and the glucose concentration rose to 143 mg/dL. Four hours after surgery, the blood glucose was 221 mg/dL on 5% dextrose intravenous fluids. Laboratory test results from the morning after surgery (off dextrose) were as follows: glucose, 154 mg/dL (65-110 mg/dL); C-peptide, 7.4 ng/mL (0.8-3.1 ng/mL); insulin 41, μIU/mL (5-27 μIU/mL); and proinsulin, 66.5 pmol/L (2.1-26.8 pmol/L).
Fig. 2 Intraoperative and postoperative glucose concentrations by point-of-care testing. The lowest glucose concentration before pancreatic resection was 48 mg/dL. After initial 25% pancreatic resection, the glucose concentration rose to 115 mg/dL. After 20% (more ...)
Gross and microscopic examination of serial histologic sections along the 9-cm resected pancreatic body and tail revealed normal architecture. The parenchyma consisted of typical pancreatic lobules with the exocrine tissue divided normally into acini. The islets were scattered among the exocrine pancreas in the usual way. No coalescent islet focality, islet neoplasia, or adenomatous foci was present. The only abnormality was conspicuous islet anisonucleosis in the form of enlarged islet cell nuclei seen throughout the pancreatic islets. The enlarged nuclei were greater than 3 times the diameter of the surrounding more typical islet cell nuclei ().
Fig. 3 Islets from the patient, demonstrating conspicuous anisonucleosis in both the tail (Panel A) and the body (Panel B) of the pancreas (hematoxylin and eosin stain, ×600 magnification). The enlarged nuclei were found in islets throughout the resected (more ...)
Postoperatively, the patient no longer required diazoxide or octreotide. At home, his blood glucose concentration ranged from 88 to 262 mg/dL. Six months after surgery, the patient had an impaired fasting glucose concentration of 107 mg/dL (70-99 mg/dL) with an insulin concentration of 9.2 μU/mL (1.9-23.0 μIU/mL) (homeostasis model assessment of insulin resistance, 2.43; BMI, 46.6 kg/m2; weight, 131.4 kg). His 2-hour serum glucose concentration after ingestion of 75 g of glucose was 196 mg/dL (65-160 mg/dL) with an insulin level of 52.5 μIU/mL (1.9-23.0 μIU/mL), thus indicating impaired glucose tolerance. The patient continued to receive nutritional counseling with advice to lose weight to prevent overt diabetes. One year after surgery, his BMI was 42 kg/m2 (weight 123.3 kg), and his fasting blood glucose concentration was 78 mg/dL. His 2-hour blood glucose concentration after 75-g glucose ingestion was 190 mg/dL, with a hemoglobin A1c level of 5.0%.