Hypoglycemia & Lactic Acidosis Due to Warburg Effect

Introduction:
Warburg effect (Aerobic Glycolysis) is a form of cellular adaptation by cancer cells to support its biosynthetic requirement, when in the presence of abundant oxygen and mitochondria, cell utilizes anaerobic pathway to convert glucose to lactate producing only 2 ATP’s. This phenomenon has been studied extensively and clinically can results in high glucose uptake by the tumor cells causing hypoglycemia and type B lactic acidosis.

Case Description:
41 Yr male with no PMHx admitted with weakness, instability, vision changes & unintentional 30 lbs weight loss x 3 months. In the ER he was found to be have BP 90/60, HR 113 and afebrile with Glucose of 20, lab showed AKI with lactic acidosis (Cr. 2.17 and lactic acid >10) and CT Abd/Plv showed multiple liver metastatic disease and entrocolitis. Started on IV fluids with dextrose, Pressor support, Antibiotics and admitted to ICU for care. Workup showed HIV positive and antibiotics coverage was broadened. Kidney function continued to worsen and started on CRRT. Patient’s hypoglycemia persisted despite dextrose infusion and endocrine team was consulted. Work up showed appropriately low insulin and c-peptide with negative sulfonylurea screen. Biopsy of liver confirmed Large B-Cell Lymphoma, but not a candidate for therapy due to acute illness. Patient lactic acidosis persisted >10 despite therapy suggestive of Type B lactic acidosis. Family changed goals of care and patient passed away within 48 hours of comfort care measures.

Discussion:
Presence of hypoglycemia and lactic acidosis is a medical emergency suggesting hyper metabolic state with poor tissue oxygenation, mostly caused by severe inflammatory resulting in Type A Lactic Acidosis. Rarely this is seen in normoxic condition called Type B Lactic acidosis and one of the potential cause is Warburg effects, in patients with solid and hematological malignancy. This is triggered by oncogenic lesions such as expression of hypoxia-inducible factor-1α (HIF1α) causing up regulation of major glycolytic enzymes like hexokinase and Tumor M2 Pyruvate Kinase. This provides cancer cell with metabolic intermediates required for synthesis of cellular components for cell proliferation and also produces less amount of free radicals. Proliferating cancer cells also outpace the vascular supply and warburg effect ensures survival in the hypoxic environment. Patients with type B lactic acidosis and hypoglycemia poses grim prognosis with mortality around 75% (7 out of 29 patient survivals, in chart review of cases). Therapeutic measure includes: tumor directed therapies, IV Bicarb Infusion, IV Dextrose, Renal Replacement Therapy and Thiamine replacement. Purpose of this case presentation is to further enhance clinical evidence of Warburg effect.