*Purpose: Liver normothermic machine perfusion (NMP) has been increasingly performed as a tool of organ preservation and to evaluate donor function. The perfusate lactate clearance (LC) is considered as one of the useful indicators of liver viability assessment during NMP. However, the applicable scope and potential mechanisms of LC remain poorly defined.

*Methods: We studied the extracellular signal-regulated kinases (pERK1/2) pathway, lactate dehydrogenase A (LDHA), ischemic time, perfusate and bile chemistry, steatosis, hepatic glycogen, inflammatory cell infiltration, necrosis, and apoptosis of the OrganOx Metra device-perfused discarded human livers with successful lactate clearance (sLC, n=5) compared with non-sLC (nLC, n=5) in the perfusate (<2.2mmol/L at 2hr NMP).

*Results: We found that the expression of LDHA was significantly higher in the livers with sLC than in the livers without at 2hr NMP (p=0.031). In contrast, the pERK1/2 level was substantially higher in the nLC livers than in the sLC livers at 2hr and 6hr NMP (Fig.A, p=0.035 and 0.006, respectively). Immunostaining showed that up-regulation of pERK1/2 was in both the hepatocytes and cholangiocytes in the nLC livers (Fig.B). We also found that sLC was associated with a marginally higher glycogen restoration than nLC at 2hr NMP (p=0.065). Furthermore, bile lactate levels in sLC livers were cleared into the normal range at 6hr NMP, but the bile lactate levels were inconsistent in the livers with nLC. H&E staining suggested that the necrosis scores were higher in the nLC than in the sLC livers at 0hr and 6hr NMP (p=0.047 and 0.053, respectively).

*Conclusions: The dual lactate clearance in the perfusate and bile can be helpful in evaluating the hypoxic injury of hepatocytes and cholangiocytes following the NMP of discarded human livers.

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