Evidence for impairment of transsulfuration pathway in cirrhosis

Abstract

Cirrhotic patients display fasting hypermethioninemia and delayed plasma clearance of methionine. These findings could be explained by an impairment in the main hepatic (“transsulfuration”) pathway for methionine degradation: methionine → S-adenosylmethionine → homocystine → cystathionine → cyst(e)ine → sulfate and taurine. In this study we quantified by pharmacokinetic methods the degree of methionine intolerance after an oral methionine load. The site of metabolic impairment was investigated by measuring the aforementioned amino acids in the venous blood plasma and urine, plus urinary sulfate excretion. In normal subjects, fasting plasma methionine concentration was 26.1 ± 2.5 μmol/L (mean ± SEM). After an oral load the methionine elimination half-life (t1/2) was 146 ± 10 min. Urine SO42− excretion averaged 632 ± 92 μmol/h before oral load; this rate increased to 1528 ± 248 μmol/h at 0–6 h and 1881 ± 214 μmol/h at 7–12 h after the load. Intermediates (i.e., homocystine, cystathionine, homoserine, or cystine) did not accumulate in the blood or urine after methionine administration. In cirrhotic patients basal plasma methionine concentration at 65.0 ± 19.4 μmole/L, and t1/2 at 458 ± 81 min were significantly elevated (p < 0.01) above normal. Urine SO42− excretion, initially 664 ± 84 μmol/h, increased after the load to 809 ± 64 μmol/h at 0–6 h and to 1201 ± 107 μmol/h at 7–12 h, but was significantly less than in normals in both periods (p < 0.05). Intermediary metabolites did not accumulate in blood or urine before or after the oral methionine load. Although the normals excreted 71% of the load of methionine sulfur as urinary SO42− within 24 h, cirrhotic patients excreted only 38%. The clearance of methionine after an oral load is retarded in cirrhosis. The simultaneous delay in SO42− excretion implies a block in the transsulfuration pathway. Because intermediates do not accumulate in plasma or urine during the prolonged hypermethioninemia after oral loading, the block appears to be above the level of homocystine synthesis.