‘” Hyper-Warburg“ Phenomenon - A Rare Complication

Background: Malignant cells rewire metabolism to promote growth and survival through fermentation of glucose to lactate known as Warburg phenomenon; this process occurs even in aerobic conditions. To produce enough ATP the cells must increase the rate of glucose uptake. We report a fatal case of severe hypoglycemia and progressive lactic acidosis in a patient with lymphoma thought to be from Hyper-Warburgism. Case: 57-year-old male with no past medical history presented with diarrhea, abdominal cramping, nausea, vomiting of 1-week duration. At presentation he was hemodynamically stable except for mild tachycardia. Biochemical evaluation showed normal renal function, glucose of 115 mg/dl, sodium of 126 mmol/dL, mild leukocytosis and anemia. CT scan of the abdomen and pelvis showed large retroperitoneal mesenteric portacaval and periportal nodes, biopsy of which revealed CD 30 + T- cell lymphoma. He was discharged with outpatient oncology follow up but re-presented within 1 week with weakness. He was noted to be hypoglycemic with a serum glucose of 55 mg/dl, which was corrected with D50. Laboratory work up showed anemia, mild leukocytosis. Lactic acid was elevated at 5 mmol/dl (0.5–2.2). Chest X ray showed increased peri-hilar markings and he was admitted for presumed sepsis secondary to community acquired pneumonia. Throughout the hospitalization he had persistent hypoglycemia with a serum glucose as low as 33 mg/dl but with only mild neurocognitive symptoms. He was started on a continuous glucose infusion up to 20 g/hr with no significant improvement of the hypoglycemia. He was started on stress dose steroids again without much improvement. Lab evaluation to rule out insulin mediated hypoglycemia was limited an IGF level 1.3 mcg/ml (3.4–6.9), insulin level 2.4 uIU/ml (2.5- 25) with a corresponding serum glucose of 119 mg/dl. He had negative urine and blood cultures. Lactate level continued to increase throughout the hospitalization to as high as 11.3 mmol/dl with the continuous glucose infusion. He unfortunately suffered a cardiac arrest and passed away. Discussion: Warburg phenomenon is an adaptive form of metabolism where malignant cells utilize glucose via the glycolytic pathway irrespective of the oxygen content. This process requires increased glucose uptake to sustain energy production and, in some cases, can result in clinically asymptomatic hypoglycemia and concurrent lactic acidosis. Infusions of dextrose are thought to ‘feed’ the cycle. This severe complication is very rare and associated more commonly with lymphoproliferative disorders as demonstrated in this case. Hypoglycemia and lactic acidosis has been shown to improve only after institution of chemotherapy for treatment of the underlying malignancy. It is important to maintain a high index of suspicion as this cause of hypoglycemia has important therapeutic implications.