Despite the severity of type B LA, little is known about its pathophysiological basis and there is no consensus on empirical treatment [
2]. Review of the case literature reveals it to be a well-recognised phenomenon, despite its rarity, highlighting the need for development of clinical practice aimed at the rapid diagnosis and treatment of this condition.
Mechanisms
Lactate is converted to and from pyruvate in the liver and kidney. In acidosis, the renal clearance of lactate predominates as hepatic uptake is significantly impaired. At pH 7.45 the kidneys clear 16% of lactate, whereas at pH 6.75 this rises to approximately 44%; compensating for half of the reduced hepatic function [
13,
14]. Hence, metabolic impairment of these organs either by ischaemic damage or neoplastic infiltration could precipitate an impediment of lactate clearance [
5]. Despite inconsistent laboratory or radiographic findings, metabolic disruption is a common occurrence among patients with haematological malignancies and those on critical care wards. However, type B LA and liver or renal failure do not always coexist (neither were apparent in our case), therefore another mechanism must also contribute to LA.
The Warburg effect is the observation that tumour cells favour glycolysis instead of oxidative metabolism, even at normal oxygen concentrations (‘aerobic glycolysis’) [
15]. This fact underlies the near 90% sensitivity and specificity of fluorodeoxyglucose positron emission tomography [
16]. Although a relatively inefficient metabolic process, it is hypothesised the glycolytic phenotype initially arises as an adaption to local hypoxia [
16]. Likewise, hypoxic pressure may also arise due to the impaired perfusion of healthy tissues either by solid tumour infiltrate or leukemic micro-emboli [
6].
Hexokinase and insulin-like growth factors (IGFs) are regularly overexpressed in malignant cells and promote glycolysis [
3]. Hexokinase catalyses the initial rate-limiting step in glycolysis and when present at high concentrations can promote glycolytic metabolism, even in the presence of oxygen. In addition, IGFs can mimic insulin, an activator of hexokinase. Similarly, the role of the hypoxia-inducible factor genes, which allow cellular adaption to hypoxia can upregulate glycolysis and are known to drive neoplastic growth in some tumour types (for example Von Hippel–Lindau disease) [
5]. Nevertheless, the promotion of aerobic glycolysis in haematological malignancies may precipitate uncontrollable lactate production.
A shift from oxidative to glycolytic metabolism may also be mediated by inflammatory cytokines released by, and in response to, haematological malignancy. For example, tumour necrosis factor alpha (TNFα) is often correlated to plasma lactate concentration and have been shown to inhibit pyruvate dehydrogenase (PDH) [
3]. However, the causal relationship between TNFα and LA has not been elucidated; for example,
in vitro hyperlacticacidemia itself has been shown to promote the transcription of TNFα [
17]. PDH is an important enzyme in the production of acetyl-CoA, which enters the Krebs cycle and ultimately drives the electron transport chain as part of oxidative respiration. Disruption of this process may drive lactate production and, ultimately, LA [
6].
Another described mechanism postulates deficiencies in thiamine may drive LA. Thiamine is required for PDH enzymatic activity [
18]. One case reported reversal of LA with thiamine supplementation to a patient receiving total parenteral nutrition [
19].
In sepsis, with rapid leukocyte production, excessive pyruvate and lactate production occurs due to an accelerated glycolytic rate, independent of anaerobic glycolysis and impairment of PDH [
20]. Lactate is produced by leukocytes, which have few mitochondria and little capacity to metabolise pyruvate aerobically [
21]. Haematological malignancies could conceivably drive LA by similar mechanisms. Likewise, a high rate of cellular apoptosis may also drive compensatory glycolysis due to a loss of mitochondrial function; for example, this occurs in tumour lysis syndrome [
6,
22].
Therapy prospects
On the premise that neoplastic cells are driving the type B LA, cytoreductive chemotherapy is the most widely used therapeutic strategy. Our report and other clinical data in the literature are supportive of this, as resolution of LA often occurs with treatment and reoccurs with a relapse of malignancy [
23‐
26]. While this occurred in this case within 7 hours of doxorubicin administration, causality cannot be definitely determined. A repeat bone marrow aspiration or blood film was not performed, with reduction of leukemic status only being inferred from the full blood count.
The benefit of empiric Pabrinex® (vitamins thiamine, riboflavin, pyridoxine, ascorbic acid and nicotinamide) therapy is unknown, although the patient was not deficient in thiamine on testing. Haemodialysis aimed at removing excess lactate has shown some efficacy as an adjunct to chemotherapy, although its efficacy remains controversial [
27]. No liver or renal dysfunction was apparent in this case. Despite haemodialysis, the lactate levels of our patient remained stubbornly high, peaking at 21mmol/L. The persistent elevation of his lactate was possibly due to a suspected concurrent gastrointestinal bleed. Therefore, the contributory effect of haemodialysis in this case, as well as treating type B LA in general, may be questioned.