Confirmed Hypoglycemia Without Whipple Triad: A Rare Case of Hyper-Warburgism

Spontaneous hypoglycemia in nondiabetic patients poses a diagnostic challenge. Hypoglycemia in malignancy has several etiologies; an extremely rare mechanism is the Warburg effect causing excess lactate production and avid glucose consumption. We describe the clinical course of a 52-year-old man admitted for chest wall mass and severe but asymptomatic hypoglycemia. Laboratory workup was obtained for insulin vs noninsulin-mediated hypoglycemia, and biopsy of the chest wall mass and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) scan were performed. D10 infusion and intravenous/oral steroids started for severe hypoglycemia. Chemotherapy was initiated after biopsy, and blood glucose (BG) and lactate levels followed with clinical response in tumor size and changes in PET/CT. Investigations were significant for venous BG in the 40s (Ademolus Classification of Hypoglycemia grade 2 hypoglycemia), plasma insulin of less than 2 µU/mL (2-20 µU/mL), C-peptide of 0.2 ng/mL (0.8-6.0 ng/mL), insulin-like growth factor 2 (IGF-2) of 113 ng/mL (333-967 ng/mL), serum lactate of 16 mmol/L (0.5-2 mmol/L), and albumin of 2.3 g/dL (3.4-5.4 g/dL). Biopsy showed diffuse large B-cell lymphoma, and PET revealed highly FDG-avid disease in the chest, abdomen, and pelvis, but no FDG uptake was seen in the brain. Hypoglycemia and lactic acidosis improved remarkably after chemotherapy. PET/CT at 4 weeks showed complete metabolic response with reappearance of physiological FDG uptake in the brain. Noninsulin-mediated hypoglycemia was likely due to the combination of profound malnutrition and rapid glucose use by cancer cells. The patient presented with exaggerated Warburg effect (hyper-Warburgism), evident by extreme glucose consumption, severe lactic acidosis, and large tumor burden on PET/CT. Absence of cognitive symptoms was probably due to use of lactate by the brain. Chemotherapy corrected these abnormalities rapidly, and must be instituted in a timely manner.