Hepatic pyruvate dehydrogenase activity in humans: effect of cirrhosis, transplantation, and dichloroacetate.
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.g wet wt-1.min-1, respectively (P < 0.001). Total PDH activity (PDHt) was 21.5 +/- 3.6 and 264 +/- 27 nmol.g wet wt-1.min-1, respectively (P < 0.001). DCA increased PDHa in cirrhotic liver to 22.3 +/- 4.1 nmol.g wet wt-1.min-1 (P < 0.05 vs. no DCA) without altering PDHt. Graft liver PDHa was 166 +/- 19 nmol.g wet wt-1.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.
Shangraw
R E
RE
Department of Anesthesiology, Oregon Health Sciences University, Portland, USA.
Rabkin
J M
JM
Lopaschuk
G D
GD
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000328:Adult; D000368:Aged; D001706:Biopsy; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007511:Ischemia / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008102:Liver Circulation; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid