Remethylation and transsulfuration of methionine in cirrhosis: Studies with L ‐[ 2 H 3 ‐methyl‐1‐ 13 C]methionine

Disturbances of the methionine cycle may result in liver injury. Patients with alcohol‐induced liver disease often exhibit hypermethioninemia and a delayed clearance (CL) of methionine, but the extent to which transsulfuration and remethylation pathways of the cyclic methionine metabolism are affected is unknown. Methionine turnover was determined in 7 healthy volunteers and 6 patients with alcohol‐induced cirrhosis after oral administration of 2 mg/kg [ 2 H 3 ‐methyl‐1‐ 13 C]methionine, which permitted us to follow transsulfuration by its decarboxylation to 13 CO 2 and remethylation by replacement of the labeled methyl group by an unlabeled one. Basal plasma concentrations of endogenous methionine (50 ± 5 vs. 25 ± 2 μmol/L, mean ± SEM, P < .001) were significantly higher in patients with cirrhosis and its CL was significantly decreased (774 ± 103 vs. 2,050 ± 141 mL/min, P < .001). Methionine turnover amounted to 42 ± 4 vs. 27 ± 3 μmol/kg/h ( P < .05) in controls and patients with cirrhosis, respectively. The fraction of administered methionine undergoing remethylation was lower in patients with cirrhosis (7.6 ± 1.5 vs. 14.1 ± 1.1%, P < .005). However, because of the larger pool of circulating methionine, the total flux of methionine through the remethylation pathway was similar in both groups. A significantly lower fraction of the administered dose appeared in the form of 13 CO 2 in breath in patients with cirrhosis (2.2 ± 0.4 vs. 11.0 ± 0.8%, P < .001). In conclusion, the data indicate that the liver with cirrhosis compensates for a decreased activity of remethylating enzymes by operating at higher concentrations of methionine. In contrast, transsulfuration is impaired in patients with alcohol‐induced cirrhosis such that an assessment of transsulfuration by a simple breath test may provide a clinically useful estimate of hepatic function.