Lactic acidosis in a patient with cancer

Abstract

Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.

Case presentation

A man in his forties with a history of mantle cell lymphoma who had undergone a haploidentical stem cell transplantation 2 years prior, whose disease had relapsed a year prior, presented to the emergency department (ED) with fatigue and dyspnoea. Upon presentation he was hemodynamically stable with a temperature of 98.2F, heart rate 108 bpm, blood pressure 118/86 mmHg, respiratory rate of 21 breaths per minute and normal oxygen saturation. Examination was unremarkable.

He was found to have severe metabolic acidosis. Labs on admission revealed a chemistry significant for a sodium of 133 mmol/L, potassium of 3.0 mmol/L, chloride of 99 mmol/L, serum bicarbonate of 7 mmol/L, BUN of 22 mg/dL, and a creatinine of 1.0 mg/dL. Serum glucose was 80 mg/dL. Venous blood gas with a PH of 7.1 and PCO2 of 22 mmHg. Lactate was 15.2 mmol/L with positive urine ketones. Complete blood count was significant for a white blood count of 5.52 K/uL, haemoglobin of 9.3 g/dL, and platelet count of 18 K/uL. Differential was concerning for 10% relative lymphoma cells and an absolute lymphocyte count of 3.75 K/uL. Lactate dehydrogenase was 662 U/L.

Diagnosis

There are three categories of lactic acidosis generation: type A, B and D.1, 2, 3 Type A lactic acidosis is the result of inadequate oxygenation and hypoperfusion. Type B lactic acidosis can occur in the setting of adequate tissue perfusion and oxygenation resulting from an alternative cause such as liver disease or cancer. Certain drugs can also lead to lactic acidosis, such as alcohols, metformin, reverse transcriptase inhibitors and salicylates.1, 2 Type D lactic acidosis results from the overproduction of D-lactic acid from intestinal bacterial overgrowth, short bowel syndrome, ischemic bowel disease or bowel obstruction.

Elevated lactate levels can persist if there is impaired clearance and metabolism. Lactate removal mostly occurs in the liver, with a further ∼20–30% removal carried out by the kidneys. Lactate is freely filtered in the glomerulus, but it is almost completely reabsorbed in the proximal tubule and metabolised into glucose (renal gluconeogenesis).⁴ Patients with impaired lactate metabolism due to liver dysfunction, kidney disease or low skeletal muscle mass may be at higher risk for type B lactic acidosis. However, lactic acidosis can been seen in oncology patients without liver or kidney impairment.¹

Our patient did not have underlying organ dysfunction or cachexia. He was not hypoxaemic, and initial infectious work up was unremarkable, so type A lactic acidosis was ruled out. He had no evidence of intestinal concerns, and there was low suspicion for type D lactic acidosis. Given known progression of his malignancy, he was determined to have type B lactic acidosis secondary to his malignancy.

Initial management

For his symptomatic metabolic acidosis, he was started on intravenous (IV) sodium bicarbonate therapy, which improved his serum bicarbonate to 14 mmol/L. He required both IV and oral bicarbonate supplementation initially; but was later wean off to only oral supplementation once chemotherapy was initiated with some initial tumour response. With further chemotherapy, he was able to be weaned off all bicarbonate supplementation with a sustained serum bicarbonate level over 20 mmol/L and lactate of 4.5 mmol/L.

Case progression and outcome

A few months later, he was found to have recurrent fatigue and dyspnoea with recurrent severe metabolic acidosis due to lactic acidosis. Evaluation showed continued high burden of disease, and he was transferred to hospice care.

Discussion

Type B lactic acidosis in the setting of malignancy is critical to recognise as it is associated with a high mortality rate within months of diagnosis.¹ Type B lactic acidosis occurs due to preferential glycolytic metabolism in the setting of normal oxygenation, termed the Warburg effect.1, 3 In normal cells, glucose metabolism leads to the generation of pyruvate (Fig 1), which enters the Krebs cycle via PDH to generate 36 ATP. In anaerobic metabolism, pyruvate is converted to lactate to generate only 4 ATPs, but this process is 10–100 times faster than oxidative metabolism through the Krebs cycle.³

Fig 1.

Glycolysis and the tricarboxylic acid (TCA) cycle.

Why malignant cells undergo the Warburg or reverse Warburg effect is unclear. Lactate may be important for angiogenesis, cell migration, metastasis, escape from host immunity and allowance for ‘self-sufficiency’, which allows tumour cells to continue to grow.⁵ In some studies, extracellular acidosis and lactate increases the absorption of free fatty acids, folate and glutamine, which creates energy for continued cell growth.⁵ Some tumour cells overexpress hexokinase and insulin like growth factors, which accelerated glycolysis.1, 2 Inflammatory cytokines produced by malignant cells are believe to inhibit PDH, diverting pyruvate to lactate production.² Lactate generation may also occur due to upregulation of monocarboxylate transporters (MCT) 1 and 4, which are transmembrane lactate transporters.⁵ In more recent studies, neoplastic cells have shown to induce neighboring stromal cells to undergo a high glycolytic activity, and malignant cells then utilise lactate as a fuel source. This is known as the ‘reverse Warburg effect’.⁵

Evaluation and management of severe acidemia is important. Severe acidemia may lead to cardiovascular compromise and reduced cardiac contractility. Compensation results in tachypnea and a Kussmal breathing pattern, which may lead to respiratory distress or fatigue. Treatment of lactic acidosis independent of anti-neoplastic therapy is challenging. Currently, bicarbonate infusion, thiamine administration, renal replacement therapy (RRT) and supportive care are the only options.³ Thiamine is an important cofactor of PDH, and may help to shuttle pyruvate through the tricarboxylic acid (TCA) cycle. Early initiation of chemotherapy being the most beneficial.⁶ The use of sodium bicarbonate infusion is controversial, since it can increase the production of lactate and worsen intracellular acidosis.⁷ Renal replacement therapy with bicarbonate-based replacement fluid at times is used to help increase pH and bicarbonate levels.⁴ Other therapeutic options include thiamine supplementation in the hopes to slow the production of lactate. Newer therapies to increase PDH activity or MCT 1 and MCT4 inhibitors may not only help with the lactic acidosis but may have an antineoplastic benefit as well.8, 9

Learning points

• •In the otherwise stable cancer patient, type B lactic acidosis should be considered.
• •Type B lactic acidosis is a medical emergency due to the association with high mortality.
• •Lactic acidosis can persist in cases of renal or liver impairment or skeletal muscle loss.
• •Management of type B lactic acidosis is treatment of the underlying cancer, although bicarbonate therapy can be utilised as a temporising measure especially if the patient is symptomatic.
• •The Warburg effect is the phenomonom of lactatogenesis of cancer cells.