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Tumor necrosis factor-[alpha]-related intraperitoneal release of CA 125 in cirrhotic patients with sterile ascites.

To the Editor:

Cancer antigen 125 (CA 125) (1-3) is commonly increased in liver cirrhosis and increased even more in ascitic fluid (4-6). Peritoneal mesothelial cells can synthesize CA 125 (7), and proliferative mesothelial cells stain for it (8). It is not clear whether mechanical stress related to ascites can stimulate mesothelium to produce CA 125 (4,6) or whether clearance of CA 125 by the diseased liver is impaired (4,5). Mesothelial cells may regulate intraperitoneal anti-bacterial defense mechanisms (9-11). Cultured mesothelial cells produce cytokines, including interleukin-6 (IL-6) and IL-8, on stimulation with tumor necrosis factor-[alpha] (TNF-[alpha]) or IL-1[beta] (9). Human peritoneal macrophages produce TNF-[alpha] and IL-1[beta] after incubation with bacteria, which in turn can trigger mesothelial cells to produce IL-8 (10) and IL-6 (12). High serum concentrations of TNF-[alpha] and IL-6, possibly of intraabdominal origin, have been observed in cirrhotic patients with sterile ascites (13). We investigated whether the intraperitoneal release of CA 125 in cirrhotic patients with sterile ascites could be influenced by the stimulation of mesothelial cells with proinflammatory cytokines, such as TNF-[alpha].

We studied 72 consecutive cirrhotic patients [28 female; mean (SD) age, 54 (13) years]. We excluded patients with liver carcinoma or other neoplasms, gastrointestinal hemorrhage, systemic infections, spontaneous bacterial peritonitis (SBP), or recent antibacterial therapy (previous 2 weeks) and those receiving prophylactic norfloxacin, corticosteroid treatment, or pentoxifylline. The etiologies of cirrhosis were chronic hepatitis B (18 cases), chronic hepatitis C (9), alcohol abuse (38), and primary biliary (3) or cryptogenic (4) cirrhosis. Ascites was evaluated by ultrasonography and graded as small (<0.5 L; 20 patients; group 2), moderate (0.5-2 L; 17 patients; group 3), or large (>2 L; 15 patients; group 4) (14). No ascites was present in 20 other patients (group 1). Ascitic fluid was aspirated from all patients with [greater than or equal to] 0.5 L of ascites. Prothrombin activity and serum concentrations of albumin, total bilirubin, and alanine aminotransferase were measured, and ascitic fluid polymorphonuclear (PMN) cells were counted. Immunoreactive CA 125 was simultaneously measured in serum and ascitic fluid (Abbott IMx; cutoff, 35 kilounits/L). We also measured TNF-[alpha] and IL-6 in serum and ascitic fluid (Bender MedSystems). Serum and ascitic fluid were centrifuged immediately after collection. For statistical analysis, we used Mann-Whitney U- and Spearman correlation tests; P <0.05 was considered significant.

We found no correlations between serum or ascitic CA 125 concentrations and prothrombin activity, albumin, total bilirubin, or alanine aminotransferase. Larger ascites volumes were associated with higher mean (SD) CA 125 concentrations: For patients with no, small, moderate, or large volumes, CA 125 was, respectively, 16.9 (12.2), 117 (62), 420 (245), and 808 (494) kilounits/L. Similarly, TNF-[alpha] concentrations were, respectively, 9.9 (4), 12.8 (4), 15.4 (4.6), and 21.4 (7.2) ng/L, and IL-6 concentrations were 9.5 (3.3), 26.2 (3.9), 47.3 (6.9), and 53 (8) ng/L. Differences were significant except for differences in TNF-[alpha] between groups 3 and 2 and in IL-6 values between groups 4 and 3. Patients with large ascites had significantly higher ascitic concentrations of CA 125 than patients with moderate ascites [1181 (648) vs 682 (404) kilounits/L], whereas differences in the ascitic concentrations of TNF-a and IL-6 and PMN cell count were not significant. The ascitic concentrations of CA 125, TNF-[alpha], and IL-6 were always higher than the corresponding serum concentrations and correlated significantly with the serum concentrations. The mean ascitic concentrations of CA 125, TNF-[alpha], and IL-6 were significantly higher than the mean serum values in groups 3 and 4. Serum CA 125 was statistically significantly correlated with the ascitic PMN cell count and serum TNF-[alpha] and IL-6 concentrations (Fig. 1). In addition, correlations between ascitic concentrations of CA 125 and PMN cell count, between ascitic concentrations of TNF-[alpha] and IL-6, and between serum and ascitic concentrations of TNF-[alpha] and IL-6 and ascitic PMN cell count were statistically significant.

Subclinical activation of ascitic fluid defense mechanisms from previous silent colonization by bacteria has been suggested in cirrhotic patients (13,15). Indeed, higher baseline serum concentrations of TNF-[alpha] and IL-6 have been observed in cirrhotic patients with sterile ascites than in patients without ascites (16). In addition, cirrhotic patients who subsequently develop SBP appear to have higher serum TNF-[alpha] concentrations and PMN cell counts in the sterile ascitic fluid than patients who do not (13). An intraabdominal origin of TNF-[alpha] and IL-6 is most likely because the concentrations of these cytokines are markedly higher in the ascitic fluid than in blood (13,14,17). Of interest, SBP has been associated with extreme increases in circulating TNF-[alpha] and IL-6 (14,16), as well as with the highest concentrations of CA 125 (4).

CA 125 is commonly increased in decompensated cirrhotic patients in proportion to the degree of ascites, and has been proposed as a sensitive marker for the detection of ascites in these patients (5). The results of the present study do not exclude the contribution of ascites-related mechanical stress of the mesothelium to the increased release of CA 125 in cirrhosis. On the other hand, our observations suggest an association between the subclinical activation of peritoneal defense mechanisms in cirrhotic patients with ascites and the production of CA 125 by the mesothelial cells. Further studies are needed to investigate the mechanisms underlying the stimulation of CA 125 synthesis by TNF-[alpha], and possibly by other cytokines, as well as whether repeated measurements of serum CA 125 could be of value as a reflection of ascitic fluid bacterial activity in cirrhotic patients with sterile ascites.



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Georgios Kalambokis Ageliki Kostoula Michalis Economou Epameinondas V. Tsianos *

Departments of [1] Internal Medicine [2] Microbiology and [3] Gastroenterology Medical School of Ioannina Ioannina, Greece

* Address correspondence to this author at: Department of Internal Medicine, Medical School of Ioannina, 45110 Ioannina, Greece. Fax 30-26510-97016; e-mail

DOI: 10.1373/clinchem.2005.053058
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Title Annotation:Letters
Author:Kalambokis, Georgios; Kostoula, Ageliki; Economou, Michalis; Tsianos, Epameinondas V.
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Nov 1, 2005
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