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Technical Briefs |
1
Centre de Recerca Biomèdica and
2
Unitat de Medicina Preventiva, Facultat de Medicina i Ciències de la Salut, Institut de Recerca en Ciències de la Salut, Hospital Universitari de Sant Joan, C/. Sant Joan s/n, 43201-Reus, Catalunya, Spain;
aauthor for correspondence: fax 34-977-312569, e-mail jcamps{at}grupsgs.com
Plasma homocysteine (tHcy) is a marker of folate or cobalamin deficiency states (1) and a risk factor for cardiovascular diseases (2), and is altered by renal insufficiency (3). Increased tHcy in liver diseases may also play a role in hepatic disorders (4)(5). Chronic treatment of experimental animals with ethanol or CCl4 is associated with hyperhomocysteinemia, and the hepatoprotective effect of S-adenosylmethionine on experimental cirrhosis is accompanied by a normalization of methionine metabolism and a decrease in tHcy concentration (4)(5). Studies in cultured hepatocytes suggest a role of the liver in metabolism of Hcy (6). However, the presence and degree of hyperhomocysteinemia in patients with liver disease and its modulation by chronic alcohol intake are, as yet, not well defined.
We studied 76 patients with liver cirrhosis (55 men and 21 women; age range, 57 ± 11 years) who were being treated in the outpatient clinic of Hospital Universitari de Sant Joan. The diagnosis of cirrhosis was based on liver biopsy or on clinical evidence, including echography to evaluate splenomegaly and portal vein dilation and fiber-optic gastroscopy to detect the presence of gastroesophageal varices. The etiology of cirrhosis was alcoholic in 48 patients (63%) and nonalcoholic in 28 (37%). Twenty-nine of the 48 alcoholic patients studied had stopped alcohol consumption at least 3 months before the study; the other 19 had continued drinking. The severity of the liver disease was measured in all patients by the Child-Pugh score (7). This classification estimates the severity of cirrhosis based on biochemical and clinical indices. The concept is to give a numeric score to certain aspects of liver function (plasma albumin and bilirubin concentrations, prothrombin time, and the degree of ascites and hepatic encephalopathy). Adding these numbers together provides a final score of liver cell function (7). The control group consisted of 83 healthy volunteers (36 men and 47 women; age range, 42 ± 14 years) participating in an epidemiologic study being conducted in our area.
In all participants, venous blood was collected, after an overnight fast, into sodium EDTA-containing tubes kept at 4 °C for tHcy, folate, and cobalamin determinations, or into tubes with no anticoagulants added for the other biochemical tests. The tubes were centrifuged at 2500g at 4 °C, and plasma or serum was stored at -80 °C. This handling minimizes preanalytical errors in tHcy measurements (8).
tHcy was measured by fluorescence polarization immunoassay (9). Folate and cobalamin concentrations were measured by ion-capture and microparticle immunoassay, respectively, in an AxSYM® analyzer (Abbott Laboratories). Serum alanine aminotransferase, alkaline phosphatase, and 
-glutamyltransferase activities and albumin and bilirubin concentrations were measured by standard techniques (ITC Diagnostics). Hemoglobin and erythrocyte mean corpuscular volume were measured in a Coulter® STKS counter (Beckman Coulter).
Means were compared by a linear multivariate model taking into account age and gender. Pearson correlation coefficients were used to evaluate the degree of association between pairs of variables. When the distribution of variables was skewed, statistical analysis was performed using log-transformed data. All calculations were performed with the SPSS 10.0 statistical package.
As expected, mean serum bilirubin concentrations and mean alanine aminotransferase activities were higher in cirrhotic patients than in the controls (Table 1
). The mean corpuscular volume of red blood cells and mean serum -glutamyltransferase activity were significantly increased, especially in nonabstaining alcoholic cirrhotics. Mean plasma folate concentrations were mildly decreased in nonalcoholic and abstaining cirrhotics and more severely decreased in nonabstaining alcoholic cirrhotics. The mean plasma cobalamin concentration was significantly increased in nonabstaining cirrhotics, presumably because of hepatic release from injured hepatocytes (10).
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Mean tHcy concentrations were similar in the controls and the nonalcoholic cirrhotics, but were significantly higher in nonabstaining alcoholic cirrhotics. An intermediate situation applied to abstaining alcoholic cirrhotics, in whom the differences from controls did not reach statistical significance (Table 1
).
There was a significant inverse correlation between tHcy and folate concentrations in controls (r = -0.35; P <0.001), but not in cirrhotic patients (r = -0.17; P, not significant). tHcy concentration (log transformed) was inversely correlated (r = -0.35; P <0.05) with the severity of the liver disease measured by the Child-Pugh score in alcoholic cirrhotics (Fig. 1
).
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The present study shows that the mean tHcy concentration in patients with liver cirrhosis is related to the etiology of their disease, alcohol intake habits at the time of the study, and the severity of their liver impairment. Chronic alcoholism may influence alterations in Hcy by promoting hepatic folate deficiency (1). However, the lack of correlation between tHcy and folate concentrations in cirrhotic patients suggests that other factors may also play a role. Studies in experimental models have shown that chronic alcohol intake may increase tHcy concentration through a direct inhibitory effect of ethanol on hepatic methionine synthase activity, which would cause a compensatory increase of betaine/homocysteine methyltransferase activity and Hcy synthesis (3)(11). The inverse correlation of tHcy with Child-Pugh score may be explained by a reduction in the functional mass of liver cells in the most severe cirrhotic patients.
Hyperhomocysteinemia and the related disturbances of methionine metabolism may inhibit cell proliferation (12) and produce hypomethylation and, consequently, destabilization of DNA (5) in patients with liver disease. The intracellular concentration of glutathione may decrease, thus increasing lipid peroxide production and collagen synthesis (13). An interesting recent study showed that Hcy directly induces the expression of procollagen type I and tissue inhibitor of metalloproteinases-1 genes in hepatocytes and stellate cells in vitro (14). This suggests that Hcy may be an effective inducer of liver fibrogenesis.
We conclude that the tHcy concentration is influenced by alcohol intake and the degree of liver impairment in cirrhosis. These results raise questions regarding the utility of tHcy as a marker of folate deficiency in patients with impaired liver function. However, tHcy measurement may be relevant in further research on the biochemistry of chronic liver impairment.
Acknowledgments
This study was supported, in part, by a grant from Fondo de Investigaciones Sanitarias (00/0954). N.F. was recipient of a fellowship from the Generalitat de Catalunya (FI/FIAP-99).
References
The following articles in journals at HighWire Press have cited this article:
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  R. Saffroy, P. Pham, F. Chiappini, M. Gross-Goupil, L. Castera, D. Azoulay, A. Barrier, D. Samuel, B. Debuire, and A. Lemoine The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis Carcinogenesis, August 1, 2004; 25(8): 1443 - 1448. [Abstract] [Full Text] [PDF]
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 B W M Spanier, J Frederiks, and H L A Janssen Aetiology of extrahepatic portal vein thrombosis Gut, November 1, 2002; 51(5): 755 - 756. [Full Text] [PDF]
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 R. P. Woitas, B. Stoffel-Wagner, U. Poege, T. Sauerbruch, N. Ferre, J. Camps, and J. Joven Increased Homocysteine in Liver Cirrhosis: A Result of Renal Impairment? * Drs. Ferre, Camps, and Joven respond: Clin. Chem., May 1, 2002; 48(5): 796 - 797. [Full Text]
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