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Elevated Homocysteine Concentrations in Liver Cirrhosis - A Result of Renal Impairment ?
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Rainer P Woitas 1Medizinische Klinik und Poliklinik I, 2Dept. of Clinical Biochemistry, University of Bonn, Germany, Birgit Stoffel-Wagner2, Uwe Poege1, & Tilman Sauerbruch1
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Woitas{at}uni-bonn.de Rainer P Woitas, et al.
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Rainer P Woitas1, To the Editor: In their recent publication, Ferré et al (1) investigated homocysteine concentrations in 76 patients with liver cirrhosis. The majority of these patients suffered from alcoholic liver disease (63%). The authors described significantly elevated levels of homocysteine in nonabstaining alcoholic cirrhotics. Furthermore, the homocysteine concentrations were inversely correlated to the severity of the liver disease (Child-Pugh score) and to the folate concentrations in these patients. The authors proposed that homocysteine concentration was influenced by alcohol intake and by the degree of liver impairment. Therefore, the authors discuss that apart from nutritional factors other factors also apply for hyperhomocysteinemia. Since hyperhomocysteinemia occurs also in patients with intact liver function but decreased renal function, renal insufficiency has to be taken into account for interpretation of the data. Unfortunately, the investigators did not provide any information about the renal function of these patients. This would have been an important issue as renal function in liver cirrhosis is already considerably reduced in patients with compensated cirrhosis (2). An inverse relationship between the glomerular filtration rate and plasma homocysteine levels has been noted and declining renal function is associated with higher plasma homocysteine levels (3). Therefore, this may at least in part be the reason for the increased homocysteine levels noted in the patient cohort investigated by Ferré and coworkers (1). To strengthen this hypothesis we report on 23 patients with liver cirrhosis (median age 54 years, range 20-68; 16 male, 7 female). The etiology of cirrhosis was alcoholic liver disease in 78.3% (18/23). 91.3% of the patients had ascites (21/23), the median Child-Pugh score was 9 points (range 7-14), and the bilirubin level was 35.9 µmol/L (6.8-415.6). All patients had their GFR determined by steady state inulin clearance and adjusted to a standard body surface of 1.73 m2. The median GFR was 22.3 ml/min/1.73 m2 (range 13.5-61.3). The median homocystein levels measured by a microplate enzyme immunoassay (BIO-RAD Laboratories Diagnostic Group by Axis Shield AS, Oslo, Norway) were 13.3 µmol/L (range 3.4-27.2) thus confirming the results of Ferré. Median serum creatinine was 106 µmol/L (range 44.2-168.0) and median cystatin C was 1.38 mg/L (range 0.54-2.76). Homocysteine concentrations significantly correlated with the bilirubin (r = 0.473, [ 95% confidence interval, 0.076 - 0.741]; z-statistic 2.3, p = 0.022), the serum creatinine (r = 0.514, [ 95% confidence interval, 0.129 - 0.764]; z-statistic 2.5, p = 0.01) and cystatin C concentrations (r = 0.676, [95% confidence interval, 0.366 - 0.851]; z statistic 3.7, p = 0.0002), respectively. As expected, we found an inverse correlation of homocysteine levels with the GFR measured as inulin clearance (r = - 0.512, [95% confidence interval, -0.773 - -0.102]; z-statistic -2.4, p = 0.016). No correlation was found with respect to the Child-Pugh score (r = 0.356, [95% confidence interval, -0.066 - 0.670]; z-statistic 1.7, p = 0.1). Proposed mechanisms for elevated homocysteine concentrations in plasma include reduced renal elimination of homocysteine or impaired vitamin dependent liver metabolism (4). Urinary homocysteine excretion in man is minimal. However, loss of a putative renal homocysteine extraction in chronic renal failure has been hypothesized as significant homocysteine uptake has been demonstrated in the normal rat kidney. Yet, in fasting humans with normal renal function no significant net renal uptake of homocysteine occurs (5). To date, the pathways of methionine-homocysteine metabolism are not yet fully understood and further research is needed. Nonetheless, it should be stressed that baseline data on renal function are mandatory to support a satisfactory interpretation of hyperhomocysteinemia, which correlates with both renal and liver impairment. Acknowledgments We thank Mrs. Claudia Blasius, Department of Clinical Biochemistry University of Bonn, Germany, for excellent technical assistance. References 1. Ferre N, Gomez F, Camps J, Simo JM, Murphy MM, Fernandez-Ballart J, Joven J. Plasma homocysteine concentrations in patients with liver cirrhosis. Clin Chem. 2002;48:183-5. 2. Woitas RP, Heller J, Stoffel-Wagner B, Spengler U, Sauerbruch T. Renal functional reserve and nitric oxide in compensated liver cirrhosis. Hepatology. 1997;26:858-864. 3. van Guldener C, Stam F, Stehouwer CD. Homocysteine metabolism in renal failure. Kidney Int Suppl. 2001;78:S234-7. 4. Look MP, Riezler R, Reichel C, Brensing KA, Rockstroh JK, Stabler SP, Spengler U, Berthold HK, Sauerbruch T. Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma- cystathionase? Scand J Gastroenterol 2000;35:866-872. 5. van Guldener C, Donker AJ, Jakobs C, Teerlink T, de Meer K, Stehouwer CD. No net renal extraction of homocysteine in fasting humans. Kidney Int. 1998;54:166-9. |
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