Liver disease vs systemic inflammation in haemodialysis patients

Sir,

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: 16–83 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, {alpha}1 acid-glycoprotein (AGP), {alpha}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 Mann–Whitney 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 (5–256) IU/l; CRP, 8 (5–280) mg/l; AGP, 1.08 (0.48–3.90) g/l (reference value 0.30–1.30 g/l); AT, 1.49±0.39 g/l (reference 1.10–2.30 g/l); FBG, 314 (164–568) mg/dl (reference 150–350 mg/dl); and vWF, 130±27.4% of normal value (reference 60–150%). 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 (6–192) IU/l vs 15 (5–256) 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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Table 1. Characteristics and inflammatory markers in HD patients with and without evident liver disease

 
Our study shows that liver disease does not clearly contribute to systemic inflammation in HD patients. The disparity between this and previous investigation [1] may be due to methodological limitations as well as conditions that are specific for HD therapy. Namely, our cohort was apparently undersized compared to 1740 subjects with metabolic syndrome [1], and serum CRP was not quantified with the high-sensitivity method. However, the advantage of the present report could be the variety of APRs studied, including not only CRP but also the long-lived reactants and endothelial injury marker vWF. The specific condition that probably masks the association between hepatic and systemic inflammation is repeated stimulation of the inflammatory response by HD procedures themselves [2]. Another potential confounder is the unusual presentation of liver disease in HD patients, in whom serum aminotransferases are inexplicably lower [6,7], while liver damage caused by hepatitis C virus is significantly less severe than in subjects without renal failure [8].

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.

Jacek Borawski, Beata Naumnik and Michal Mysliwiec

Department of Nephrology and Transplantology with Dialysis Unit Medical University Bialystok Poland Email: jborawski{at}post.pl

References

  1. Kerner A, Avizohar O, Sella R et al. Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol 2005; 25: 193–197[Abstract/Free Full Text]
  2. Nishizawa Y, Shoji T, Emoto N et al. Roles of metabolic and endocrinological alterations in atherosclerosis and cardiovascular disease in renal failure: another form of metabolic syndrome. Semin Nephrol 2004; 24: 423–425[ISI][Medline]
  3. Fehr T, Ambhl PM. Chronic hepatitis virus infections in patients on renal replacement therapy. Nephrol Dial Transplant 2004; 19: 1049–1053[Free Full Text]
  4. Borawski J, Pawlak K, Mysliwiec M. Inflammatory markers and platelet aggregation tests as predictors of hemoglobin and endogenous erythropoietin levels in hemodialysis patients. Nephron 2002; 91: 671–681[CrossRef][ISI][Medline]
  5. Borawski J, Naumnik B, Pawlak K, Mysliwiec M. Endothelial dysfunction marker von Willebrand factor antigen in haemodialysis patients: associations with pre-dialysis blood pressure and the acute phase response. Nephrol Dial Transplant 2001; 16: 1442–1447[Abstract/Free Full Text]
  6. Espinosa M, Martin-Malo A, Alvarez de Lara MA, Soriano S, Aljama P. High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied. Clin Nephrol 2000; 54: 151–156[ISI][Medline]
  7. Fabrizi F, Lunghi G, Finazzi S et al. Decreased serum aminotransferase activity in patients with chronic renal failure: impact on the detection of viral hepatitis. Am J Kidney Dis 2001; 38: 1009–1015[ISI][Medline]
  8. Rampino T, Arbustini E, Gregorini M et al. Hemodialysis prevents liver disease caused by hepatitis C virus: role of hepatocyte growth factor. Kidney Int 1999; 56: 2286–2291[CrossRef][ISI][Medline]




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