Fig 1.
Etiology of hyperlactatemia in malaria.
Both increased lactate production and impaired lactate clearance play a role in the pathogenesis of lactic acidosis. The increased lactate production might have several origins. Intraerythrocytic parasites rely on glycolysis to meet their energy requirements and produce lactate. Parasite sequestration may lead to blood vessel obstruction and induction of hypoxia in the surrounding tissues and cells, which results in increased anaerobic glycolysis. Destruction of uninfected RBCs and iRBCs causes anemia in malaria and decreases the oxygen delivery by the blood. This causes systemic hypoxia and increased anaerobic glycolysis. Malaria infection is characterized by a strong immune response with activated immune cells, which switch to aerobic glycolysis to rapidly generate ATP and metabolic intermediates for proliferation. Under all of these circumstances, glycolysis and thus the conversion of glucose into pyruvate increases. Pyruvate is further converted to lactate by LDHA, and lactate is excreted via an MCT into the circulation, which results in elevated blood lactate levels. Lactate is cleared from the circulation by uptake by gluconeogenic cells in the liver and renal cortex via MCTs. Lactate is subsequently converted to pyruvate by LDHB, and further converted to glucose via the gluconeogenic pathway. Glucose is excreted in the circulation via GLUT transporters and can be used again in the cells and tissues with increased glycolysis. This internal recycling of lactate produced by glycolytic cells and its conversion back to glucose by gluconeogenesis in the liver and kidney is known as the Cori cycle. In malaria, lactate clearance might be decreased due to liver dysfunction, decreased hepatic blood flow, and suppressed gluconeogenesis. In addition, AKI in malaria is associated with necrosis of gluconeogenic cells in the renal cortex and decreased urine excretion, which can both contribute to impaired lactate clearance. Therefore, both liver and kidney pathology can contribute to hyperlactatemia and lactic acidosis in malaria. AKI, acute kidney injury; DC, dendritic cell; GLUT, glucose transporter; iRBC, infected red blood cell; LDH, lactate dehydrogenase; M1, M1 macrophage; MCT, monocarboxylic acid transporter; RBC, red blood cell; T, T cell.
Table 1.
Comparison of causes of lactic acidosis in malaria versus sepsis.
Fig 2.
Glycolysis and LDH net reaction and acid production.
During glycolysis, for 1 molecule of glucose, 2 ATP and 2 NADH are synthesized, and 2 protons are produced. In the conversion of pyruvate to lactate by LDH, NADH is converted back to NAD+, and an equivalent amount of protons are consumed. Upon ATP hydrolysis (e.g., for energy utilization in other reactions), protons are released, resulting in a net acidification. LDH, lactate dehydrogenase.