---

Case I

A 47-year-old female with Relapsed Refractory Multiple Myeloma (RRMM) presented to the hospital with dyspnea. The patient was found to be severely anemic and received blood transfusion. Additional work up revealed fluid overload and reduced ejection fraction and was started on anti-heart failure measures. On day 3, blood cultures grew Escherichia coli and the patient was started on piperacillin-tazobactam. On days 6-9, the patients renal function started to deteriorate with increasing levels of lactic acid. pH level dropped to 6.7 and the bicarbonate level dropped to 6 mmol/L. The anion gap was 39 and a lactate level of 30 mmol/L. Common causes of lactic acidosis were excluded. Her condition deteriorated. She was not a candidate for further chemotherapy and eventually passed away.

What is the mechanism of malignancy associated lactic acidosis?

Patients with multiple myeloma are at risk of renal complications. Common renal manifestations include cast nephropathy, light chain amyloidosis, and monoclonal immune globulin deposition disease. In addition to the direct effect on the renal parenchymal tissue, the malignant cells can overcome the renal buffering mechanisms by increasing lactic acid production. The Warburg effect is a phenomenon that describes the ability of malignant cells to selectively increase the utility of the glycolytic pathway in the presence of oxygen. It is also termed aerobic glycolysis. The acidic micro-environment favors malignant cells proliferation and metastasis. It can lead to systemic hyperlactatemia, especially in patients with thiamine deficiency.

Many theories have been proposed to explain the Warburg effect in cancer cells. Some of which include rapid ATP synthesis, preferable effect in the cancer microenvironment, and effect on cell signalling. Understanding this effect better may open the frontiers to developing new therapeutic options (1). The following figure highlights some of the potential consequences of the Warburg effect (2).

In patients with hematological malignancies and persistent hyperlactatemia, the Warburg effect can be the culprit. There are many theories that try to explain the Warburg effect, but non of them is conclusive yet. Prompt treatment of the underlying malignancy may be lifesaving in such patients.

1-      Liberti, M. and Locasale, J., 2016. The Warburg Effect: How Does it Benefit Cancer Cells?. Trends in Biochemical Sciences, 41(3), pp.211-218.

2-      2-Pascale, R., Calvisi, D., Simile, M., Feo, C. and Feo, F., 2020. The Warburg Effect 97 Years after Its Discovery. Cancers, 12(10), p.2819.