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 methionine catabolic pathway in cirrhotics exists at the level of the enzyme S-adenosylmethionine synthetase because in previous studies using conventional amino-acid analyzers, no intermediates of transmethylation/transsulfuration were found to accumulate in plasma downstream of S-adenosylmethionine synthesis. We therefore measured serum concentration intermediates of methionine transmethylation/transsulfuration using an improved gas chromatography/mass spectrometry technique.


METHODS
Serum concentrations of methionine, homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, 2-methylcitric acid and alpha-aminobutyric acid were determined by gas chromatography/mass spectrometry in 108 consecutive patients with liver cirrhosis at Child stages A (mild cirrhosis, n = 27) and B/C (severe cirrhosis, n = 81), 18 outpatients with non-cirrhotic liver disease, and 55 healthy individuals.


RESULTS
Serum levels of methionine, N,N-dimethylglycine, N-methylglycine, cystathionine, and homocysteine were significantly higher 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, respectively). They also correlated with the Child-Pugh score (P < 0.01). Homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, and 2-methylcitric acid correlated with serum creatinine. The mean cystathionine concentration was significantly higher in patients with creatinine > or = 1.4 mg/dl than in patients with normal creatinine values (P < 0.01). However, the differences between cirrhotics and healthy controls were still significant after correcting for creatinine.


CONCLUSIONS
Our data provides indirect evidence for two hitherto unrecognized alterations of methionine metabolism in cirrhotics, i.e. impairment of the transsulfuration of homocysteine at the level of cystathionine degradation and a shift in remethylation of homocysteine towards the betaine-homocysteine-methyltransferase reaction.
Look
M P
MP
Dept. of Internal Medicine I, University of Bonn, Germany.
Riezler
R
R
Reichel
C
C
Brensing
K A
KA
Rockstroh
J K
JK
Stabler
S P
SP
Spengler
U
U
Berthold
H K
HK
Sauerbruch
T
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002849:Chromatography, Gas; D003540:Cystathionine / Q000032:analysis / Q000097:blood*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011336:Probability; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
D015415:Biomarkers; D006710:Homocysteine; D003540:Cystathionine; D003542:Cystathionine gamma-Lyase