Type B Lactic Acidosis in Advanced Diffuse Large B-Cell Lymphoma
Authors: Kaddis Nancy El-Shamaa 
Published: October 2019

Unlike the more common type A lactic acidosis, in type B lactic acidosis, a rare entity seen in patients with advanced malignancies, evidence of systemic hypoperfusion is not present. The pathogenesis is not well understood, and there are several theories regarding mechanisms of this disease. Lactic acidosis, when associated with hematologic malignancies, carries an extremely poor prognosis. This type of LA often goes unrecognized as a cause of acidosis in these patients. Here, we present one case of an adult with DLBCL who developed type B LA.
Our patient was a 49 year old man with a history of DLBCL, who had received extensive treatment in 2015. He developed recurrent disease within six months of treatment and was treated with more chemotherapy in April 2016; this course was complicated by sepsis. Soon after recovering from sepsis, he developed subacute liver failure of unknown etiology. IR guided percutaneous liver biopsy revealed diffuse hepatic infiltration of diffuse large B-cell lymphoma as the etiology of the liver failure.
Due to an AG acidosis, lactate was drawn on 6/11 and was high at 3.5 mmol/L. He was hemodynamically stable, with no signs of diarrhea, renal failure, or any other findings what would explain a lactic acidosis. He was discharged to Spaulding Rehabilitation Hospital on 6/17 for further medical care and rehabilitation.
At this time, total bilirubin was 27.9 mg/dL, creatinine was 0.72 mg/dL and serum bicarb was 17 mmol/L. Several days later, when his serum bicarb had further decreased to 15 mmol/L, lactic acid level was found to be 7.5 mmol/L. Again, at this point he had no evidence of sepsis, hypoperfusion, renal failure or diarrhea. Two days later, lactate was even higher at 8.4mmol/L. He was discharged two days after this last measurement and died at home, later on the same day of discharge from SRH.
In reviewing the literature, although the exact pathophysiology of lactic acidosis of this type is unknown, several mechanisms of lactic acidosis have been proposed to explain type B LA.
First, lactate is converted to pyruvate, and subsequently into glucose by both the liver and kidneys.1 Therefore, dysfunction in the liver or kidneys may lead to accumulation of lactate. The liver contributes to 90% of lactate metabolism and is frequently involved in patients with lactic acidosis.2-4 In the case that we presented, there was extensive lymphoma involvement of the liver, which we believe contributed to the lactic acidosis. However, many patients with liver and kidney dysfunction do not develop this complication, and therefore there must be more complex processes occurring that contribute.
Second, TNF-α may also play a role in the development of type B LA in patients with malignancy4,5. TNF-α is thought to reduce the activity of pyruvate dehydrogenase, which converts pyruvate to acetyl-CoA.6 It inhibits the electron transport system and increases anaerobic glycolysis. The presence of TNF-α causes a reduction in the activity of pyruvate dehydrogenase and also inhibits the electron transport system, both of which result in increased lactate.
Finally, another mechanism in the development of type B LA that has been described is thiamine deficiency. Thiamine is an important cofactor in the pyruvate dehydrogenase complex (Figure 1)7. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead anaerobic metabolism occurs by conversion into lactate8,9. This has been reported as a complication in patients receiving TPN without vitamin supplementation8-10.
Treatment of the primary condition, such as chemotherapy in malignancy, remains the mainstay of treatment.11 In 2001, Sillos, et al.11 reported a case of lactic acidosis in a patient with ALL. Blood pH improved after venous hemofiltration, but her plasma lactate concentration continued to rise, and decreased after chemotherapy began to take effect (Figure 2)12 but unfortunately the patient died soon thereafter.
In patients with a known malignancy who have evidence of metabolic acidosis without a known cause, lactic acidosis should be considered and worked up. It is important for physicians to be aware of this condition so a rapid diagnosis can be made and therapy can be started immediately; perhaps as more cases of type B LA are reported and researched, underlying causes will be better understood and ultimately, better treated than they are at today.
Figure 1 See attached image Figure 2 See attached image

Disclosures
No relevant conflicts of interest to declare.