Decreased production of glutathione in patients with cirrhosis


2 Department of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland


Abstract. Studies in animals have demonstrated the central role of the liver in regulating the circulating pool of glutathione (GSH). Most of the hepatic GSH production is released into blood and most of the circulating GSH originates in the liver. We have estimated the production of GSH in eight healthy volunteers and eight patients with cirrhosis by an analysis of the kinetics of plasma GSH. The basal plasma concentrations of free GSH were 9·3 ± 2·4 μM in healthy volunteers and 3·6 ± 1·1 μM in cirrhotics (P<0·001), and the concentrations of total GSH 16·6 ± 6·2 μM in control subjects and 7·1 ± 2·6 μM in cirrhotics (P<0·002). The concentration of GSH in the circulating pool depends on the input of GSH into this compartment and is inversely proportional to the volume of distribution of GSH (Vd) and to the fractional rate of elimination of GSH from plasma (kel). Assuming that the kinetics of endogenously produced and exogenously administered GSH are identical, Vd and kel can be calculated from the plasma concentration-time curve of a single i.v. injection of GSH. Both Vd (0·100 ± 0·044 1 kg-1 in controls and 0·131 ± 0·043 1 kg-1 in cirrhotics) and kel (0·2718 ± 0·0555 min-1 in controls and 0·2912 ± 0·0781 min-1 in cirrhotics) were identical in the two groups. The estimated input of GSH into the circulation calculated as the product of the basal concentration of GSH, kel and Vd amounted to 392 ± 100 nmol min-1 kg-1 in control subjects and 242 ± 68 nmol min-1 kg-1 in cirrhotics (P<0·01). We conclude that the lower plasma concentrations of GSH in patients with cirrhosis are due to a decreased input of GSH into the circulation rather than an increased peripheral consumption of GSH. Most likely the defect reflects a decreased hepatic production of GSH and may increase the susceptibility of patients with cirrhosis to toxic insults.