Hepatic pyruvate dehydrogenase activity in humans: effect of cirrhosis, transplantation, and dichloroacetate
Shangraw, R.E.; Rabkin, J.M.; Lopaschuk, G.D.
American Journal of Physiology 274(3): G569-G577
1998
ISSN/ISBN: 0002-9513 PMID: 9530159 Document Number: 486749
The liver is the major site for lactate clearance, and liver disease exacerbates lactic acidosis during orthotopic liver transplantation (OLT). This study assessed pyruvate dehydrogenase (PDH) activity in control, cirrhotic, and graft liver to test the hypotheses that 1) liver disease decreases hepatic PDH activity, 2) graft PDH activity is inhibited due to protracted ischemia, and 3) dichloroacetate (DCA) reverses functional PDH inhibition in cirrhotic and graft liver. After having given their informed consent, 43 patients received either DCA (80 mg/kg) or aqueous 5% glucose during OLT. Six patients without apparent liver dysfunction that were undergoing subtotal hepatic resection served as controls. Liver biopsy PDH activity was assayed by measuring (14C)citrate synthesis from (14C)oxaloacetate and PDH-derived acetyl-CoA. PDH in the active form (PDHa) in cirrhotic and control liver was 5.6 +- 1.3 (SE) and 57 +- 10 nmol cntdot g wet wt-1 cntdot min-1, respectively (P < 0.001). Total PDH activity (PDHt) was 21.5 +- 3.6 and 264 +- 27 nmol cntdot g wet wt-1 cntdot min-1, respectively (P < 0.001). DCA increased PDHa in cirrhotic liver to 22.3 +- 4.1 nmol cntdot g wet wt-1 cntdot min-1 (P < 0.05 vs. no DCA) without altering PDHt. Graft liver PDHa was 166 +- 19 nmol cntdot g wet wt-1 cntdot min-1, which was not altered by DCA. We conclude that decreased hepatic PDH activity secondary to decreased content may underlie lactic acidosis during OLT, which can be partially compensated by DCA administration. There is no apparent inhibition of graft liver PDH activity after reperfusion.