Quantitative Evaluation of D-Lactate Pathophysiology: New Insights into the Mechanisms Involved and the Many Areas in Need of Further Investigation

Abstract

In contrast to L-lactate, D-lactate is produced in minimal quantities by human cells, and the plasma D-lactate concentration normally is maintained at a concentration of only about 0.01 mM. However, in short bowel syndrome, colonic bacterial production of D-lactate may lead to plasma concentrations >3mM with accompanying acidosis and neurological symptoms - a syndrome known as D-lactic acidosis. Minor increases in plasma D-lactate have been observed in various gastrointestinal conditions such as ischemia, appendicitis and Crohn's disease, a finding touted to have diagnostic utility. The novel aspect of this review paper is the application of numerical values to the processes involved in D-lactate homeostasis that previously have been described only in qualitative terms. This approach provides a number of new insights into normal and disordered production, catabolism and excretion of D-lactate, and identifies multiple gaps in our understanding of D-lactate physiology that should be amenable to relatively simple investigative study.

Keywords: acidosis; delirium; short bowel syndrome.

Figure 1

Schematic representations of human and anaerobic bacterial metabolism of L- and D-lactate. Notes: 1, bacterial D-LDH catalyzes a reversible reaction between pyruvate and D-lactate (allowing for D-lactate production from pyruvate) while in humans this reaction irreversibly converts D-lactate to pyruvate; 2, the anaerobic bacteria cannot dispose of pyruvate via oxidative reactions, hence all pyruvate produced from glycolysis is converted to lactate or other organic acids such as acetate and butyrate.

Figure 2

Comparison of the plasma D-lactate experimental data (solid circles) of Connor et al following a 20 minute, 105 millimolar constant IV infusion versus the PBPK model prediction (line) assuming a whole body clearance of 607 mL/min and Km of 5 mM.

Figure 3

Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 500 millimoles of D-lactate with the time course described by eq. 3, each separated by 5 hours. It is assumed that the whole body clearance has the normal value of 607 mL/min. Top panel: input (see eq. 3): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.

Figure 4

Left panel: De Vrese and Barth experimental plasma D-lactate concentration following ingestion of 74 mmole of D-lactate as yoghurt (solid circles) versus the PBPK model prediction (solid line) for the normal whole body clearance of 607 mL/min. Right panel: The intestinal absorption rate used to generate the PBPK model plasma concentration (total absorption of 38.2 millimoles D-lactate, with absorption rate described by eq. 3: T_T= 21.6 and T_A = 116 minutes).

Figure 5

Schematic representation of the various processes that could influence the plasma D-lactate concentration. The direction of the solid arrows indicates whether an increase in the process potentially increases (up arrow) or decreases (down arrow) plasma D-lactate. For example, an increase in carbohydrate (CHO) ingestion would provide an increased substrate for intestinal bacteria and increase D-lactate production; while an increased CHO intestinal absorption rate would decrease the substrate for the intestinal bacteria and therefore, potentially, decrease plasma D-lactate.

Figure 6

Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 1000 millimoles of D-lactate with the time course described by eq. 3, each separated by 5 hours. It is assumed that the whole body clearance has the normal value of 607 mL/min. Top panel: input (see eq. 3): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.

Figure 7

Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 500 millimoles of D-lactate with the time course shown in Figure 3, each separated by 5 hours. It is assumed that the whole body clearance is 309 mL/min, half the normal value. Top panel: input (see eq. 3): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.