Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase?

Background: It has been suggested that the major metabolic block in the met hionine catabolic pathway in cirrhotics exists at the level of the enzyme S -adenosylmethionine synthetase because in previous studies using convention al amino-acid analyzers, no intermediates of transmethylation/transsulfurat ion were found to accumulate in plasma downstream of S-adenosylmethionine s ynthesis. We therefore measured serum concentration intermediates of methio nine transmethylation/transsulfuration using an improved gas chromatography /mass spectrometry technique. Methods: Serum concentrations of methionine, homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylma lonic acid, 2-methylcitric acid and alpha-aminobutyric acid were determined by gas chromatography/mass spectrometry in 108 consecutive patients with l iver cirrhosis at Child stages A (mild cirrhosis, n = 27) and B/C (severe c irrhosis, n = 81), 18 outpatients with non-cirrhotic liver disease, and 55 healthy individuals. Results: Serum levels of methionine. N,N-dimethylglyci ne, N-methylglycine, cystathionine, and homocysteine were significantly hig her in patients at Child stages B/C compared with those of healthy controls (P < 0.01), and they were also significantly higher than in patients with non-cirrhotic liver disease (P < 0.01 and P < 0.05 for homocysteine, respec tively). They also correlated with the Child-Pugh score (P < 0.01). Homocys teine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic a cid, and 2-methylcitric acid correlated with serum creatinine. The mean cys tathionine concentration was significantly higher in patients with creatini ne greater than or equal to 1.4 mg/dl than in patients with normal creatini ne values (P < 0.01). However, the differences between cirrhotics and healt hy controls were still significant after correcting for creatinine. Conclus ions: Our data provides indirect evidence for two hitherto unrecognized alt erations of methionine metabolism in cirrhotics, i.e. impairment of the tra nssulfuration of homocysteine at the level of cystathionine degradation and a shift in remethylation of homocysteine towards the betaine-homocysteine- methyltransferase reaction.