The direct association between elevated liver enzymes and serum C-reactive protein (CRP) was recently reported in subjects with metabolic syndrome [1]. This indicates that even mild liver disease contributes to generalized low-grade inflammation and, in consequence, may enhance cardiovascular risk. Chronic inflammation is common in patients undergoing maintenance haemodialysis (HD) therapy, and deleteriously underlies the progression of malnutrition and atherosclerosis [2]. Renal failure is also an instructive model of the metabolic syndrome, with its harmful effects on both the cardiovascular system and liver [2]. In addition, chronic viral hepatitis may affect up to 70% of HD patients [3]. The hypothesis that liver disease also contributes to generalized inflammation in the HD population has not been tested so far.
We retrospectively studied 237 patients (42% females) with a median age of 61 years (full range: 1683 years) who had been treated in our unit between 1996 and 2002. At data collection, all subjects were clinically stable, dialyzed for at least 4 weeks, without HIV infection, had not suffered from any acute infectious and inflammatory diseases or cardiovascular events in the preceding month, were not treated with statins or regularly with NSAIDs, were not suffering from alcohol abuse, and did not have liver cirrhosis. Ninety-one (38%) patients were seropositive for either hepatitis B virus surface antigen (HBV), antibodies against hepatitis C virus or hepatitis C virus RNA (HCV); none were on antiviral therapy. One hundred and five (44%) patients had cardiovascular disease. In all subjects, pre-dialysis serum alanine aminotransferase (ALT) activity and concentrations of five acute-phase reactants (APR) such as CRP, 1 acid-glycoprotein (AGP),
1-antitrypsin (AT), fibrinogen (FBG) and endothelial marker von Willebrand factor (vWF) were simultaneously measured. Definitions, methods and assays were as described previously [4,5]. Data were expressed as means±1 SD or medians (full range) depending on their distribution; all CRP values <6 mg/l were treated as 5 mg/l. For statistical analysis, several complementary approaches were used. First, the associations between ALT and the APRs were tested, by non-linear Spearman regression, in five groups: (i) the whole cohort; (ii) patients positive for HCV or HBV markers; (iii) patients negative for both hepatitis markers; (iv) seropositive subjects with increased serum ALT; and in (v) seronegative patients with normal ALT activity. Next, the comparisons were performed, by non-parametric MannWhitney U test, in three sub-groups: (i) patients with ALT activity in the top vs the lowest quartile; (ii) subjects with hepatitis markers vs those without; and (iii) in seropositive patients with elevated ALT vs seronegative subjects with normal ALT activity. The cut-off value for serum ALT activity was set at 29 IU/l, which was the upper limit of its 95% confidence interval in the seronegative patients. This ALT value was very close to 27 IU/l, which was determined in a similar manner by Espinosa et al. [6] and found to reliably indicate liver damage in maintenance HD patients.
In our whole group, the variables were as follows: ALT, 19 (5256) IU/l; CRP, 8 (5280) mg/l; AGP, 1.08 (0.483.90) g/l (reference value 0.301.30 g/l); AT, 1.49±0.39 g/l (reference 1.102.30 g/l); FBG, 314 (164568) mg/dl (reference 150350 mg/dl); and vWF, 130±27.4% of normal value (reference 60150%). In 160 (67%) patients at least one inflammatory marker was found to be increased. Serum ALT did not show significant correlations with any of the APRs studied in either of the above five groups (all P>0.075), including patients with active liver disease (seropositive with ALT 29 IU/l). On the other hand, the APRs were consistently and notably associated with each other (all P<0.0003) as already reported [4,5]. None of the APRs differed between patients with ALT activity in the top quartile vs the lowest quartile (all P>0.119). Patients with the HCV or HBV marker had almost 3x higher median ALT activity than subjects without [42 (6192) IU/l vs 15 (5256) IU/l, P<0.0001]; it is noteworthy that the ALT level in the hepatitis-free patients was comparable to those of 15.6 IU/l and 16.3 IU/l reported in previous studies [6,7]. Our hepatitis marker-positive patients presented with slightly lower vWF levels than patients without the markers (124±25.1% vs 133±28.3%, P = 0.017); the other APRs did not differ between the positive and negative subjects (all P<0.093). The variation in vWF became non-significant when adjusted for cardiovascular disease prevalence. Finally (Table 1), there were no differences in inflammation markers in HD patients with serologically and biochemically evident viral hepatitis compared to subjects without obvious liver pathology.
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Finally, the link between liver disease and systemic inflammation, although not directly evident, is biologically plausible and of potential importance in maintenance HD patients. Further studies are needed before this new trait is definitely excluded.
Conflict of interest statement. None declared.
My
liwiec
Department of Nephrology and
Transplantology with Dialysis Unit
Medical University
Biaystok
Poland
Email: jborawski{at}post.pl
References
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