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Factors Influencing the Concentration of Cytokines During Liver Transplantation
Factors Influencing the Concentration of Cytokines During Liver Transplantation H.-J. Koh, K.-H. Ryu, M.-L. Cho, Y.-J. Heo, and J. Lee ABSTRACT Not only does the underlying disease that requires surgery constitute a significant stress to the human body, but also the surgery itself serves as a stressor. Cytokine secretion is activated in response to the surgical stress during liver transplantation. We examined 44 patients to compare cytokine levels, according to the underlying diseases causing liver failure (viral hepatitis vs alcoholic hepatitis), examining whether the values differed according to the model for end-stage liver disease (MELD) score [high (ⱖ20) vs low (⬍20)]. Pro-inflammatory cytokines tumor necrosis factor (TNF)-␣, interleukin (IL)1, and IL-6 and anti-inflammatory cytokines IL-4 and IL-10 were quantified using sandwich enzyme- linked immunoassays at three times: (1) after inducing anesthesia, (2) 60 minutes after the start of the anhepatic period, and (3) 60 minutes after reperfusion. No difference in the level of any cytokine measured in our study was detected at any time point between the viral and the alcoholic hepatitis groups. Among the high MELD group, IL-1 and IL-4 contents were higher than in the low MELD group at all time points (P ⬍ .05). IL-10 concentrations at time 1 and TNF-␣ at time 2 were higher among the high MELD group (P ⬍ .05). In conclusion, the severity of the inflammatory and stress reactions expressed as cytokine concentrations did not differ according to the underlying liver disease, but did associate with the MELD score. HE PROCESS of liver transplantation, together with liver failure itself, serves as a stressor threatening the homeostasis of the body. Cytokine secretion is activated during liver transplantation.1 Few studies, however, have investigated the many factors associated with liver transplantation surgery. This study examined differences in plasma cytokine concentrations among patients undergoing transplantation for liver failure due to viral hepatitis versus alcoholic hepatitis. Among the presurgical variables, the model for end-stage liver disease (MELD) score has been associated with the severity of disease and prognosis of liver transplant patients.2 Therefore, we divided the patients into a high (ⱖ20) versus a low (⬍20) MELD group to examine differences in cytokine concentrations.
T
PATIENTS AND METHODS The study enrolled 44 patients who underwent living donor liver transplantation between 1 September 2007 and 28 February 2009. To measure cytokines, blood samples were collected from the radial artery 3 times: after inducing anesthesia (time 1), 60 minutes after the start of the anhepatic period (time 2), and 60 minutes after reperfusion (time 3). The pro-inflammatory cyto-
kines tumor necrosis factor (TNF)␣, interleukin (IL)1, and IL-6 and anti-inflammatory cytokines IL-4 and IL-10 were quantified using commercial sandwich enzyme-linked immunoassay (ELISA) kits (Quantikine; R&D Systems, Minneapolis, Minn, USA). According to the underlying diseases that induced liver failure, the patients were divided into viral (n ⫽ 33) versus alcoholic (n ⫽ 11) hepatitis groups. The cytokine concentrations in each group were assessed at each time to compare the level of induced inflammatory or stress reaction according to the underlying disease causing the liver failure.
From the Departments of Anesthesiology and Pain Medicine (H.J.K., K.H.R., J.L.), Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea, and the Rheumatism Research Center (M.L.C., Y.J.H.), Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea. Address reprint requests to Dr. Jaemin Lee, Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040, Korea. E-mail: jmlee@ catholic.ac.kr
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.06.034
Transplantation Proceedings, 42, 3617–3619 (2010)
3617
3618 MELD scores were calculated as a presurgical variable based on the most recent biochemical laboratory data, and the patients were divided into high (ⱖ20) (n ⫽ 25) and low (⬍20) (n ⫽ 19) MELD groups. The concentration of cytokines was compared between the groups at each time. The data are presented as median values and interquartile ranges. Wilcoxon rank sum test was performed for statistical analysis. A P value ⬍.05 was considered significant.
RESULTS
No significant difference in demographic data existed between the groups. No difference in the serum concentrations of all of the cytokines measured in our study was detected at any time between the viral versus alcoholic hepatitis groups (Fig 1). Comparing cytokine concentrations according to MELD scores showed that the IL-1 and IL-4 levels were higher among the high MELD versus the low MELD group at all times (Fig 2). The IL-10 concentrations at time 1 and TNF-␣ at time 2 were higher in the high than in the low MELD group. DISCUSSION
Studies on perioperative cytokine levels have primarily addressed fluctuations in the concentrations of cytokines after liver transplantation surgery and their associations with prognosis.3– 6 Few comprehensive studies have examined the pathophysiologic abnormalities in end-stage liver disease, including the association of prognostic indices such as the MELD score to the underlying liver disease with cytokine levels. Hence, we examined these associations. We did not detect a difference in cytokine concentrations based on the underlying disease that induced liver failure, implying that the induction of inflammatory and stress reactions that occur with viral or alcoholic hepatitis do not differ. In contrast, the MELD score affected cytokine concentrations. The MELD score is a reliable index of the severity
KOH, RYU, CHO ET AL
and prognosis of liver failure in transplant candidates. Cytokine concentrations have been reported to be associated with the course and prognosis after liver transplantation.5,6 Our finding of a difference in cytokine concentrations between the high vs low MELD groups agreed with previous studies.5,6 Regardless of the time, IL-1 and IL-4 were significantly higher among the high MELD, whereas IL-10 and TNF-␣ differed between high and low MELD groups at some times. Therefore, surgical stress factors, such as bleeding and clamping major vessels, and the resultant hemodynamic and acid– base instability acted in combination with the presurgical MELD score. In this study, the cutoff value between the groups was 20, based on one report that the mean MELD score of patients who had undergone liver transplantation was 20.77 and another that indicated that cases with MELD scores higher than 20 showed an increased mortality.8 According to Saab et al,9 the fluctuation in the MELD score with time was not predicted by the underlying disease that caused the liver failure. This observation implied that the fluctuation in the MELD score and in underlying liver disease were not associated with each other. Our finding that cytokine concentrations, which were dependent on the MELD score, were not different according to the underlying liver disease concurs with their results. Although the cytokine concentrations were not different among the viral versus alcoholic hepatitis groups, this did not imply that the cytokine concentrations do not differ among all liver diseases causing hepatic failure. We compared viral hepatitis (hepatitis B or C) with alcoholic hepatitis, which is reportedly increasing in our country, because these 2 diseases are the most common ones among our transplant patients. Other diverse diseases that induce liver failure include hepatomas, biliary cirrhosis, and metabolic diseases. The clinical features of these diseases are different from those of viral or alcoholic hepatitis. While conducting this study, liver transplantation was rarely performed in patients with these
Fig 1. Comparison of cytokines concentrations between disease groups. The box plots show the median (thick line in the box), interquartile range (box), and range (whickers). All cytokines concentrations are pg/ml in value. There are no differences between disease groups. T1: after induction of anesthesia. T2: 60 min after the start of anhepatic stage, T3: 60 min after reperfusion.
INFLUENCING CYTOKINE CONCENTRATION
3619
Fig 2. Comparison of cytokines concentrations between MELD-based groups. The box plots show the median (thick line in the box), interquartile range (box), and range (whickers). All cytokines concentrations are pg/ml in value. *P ⬍ .05 vs low MELD. MELD: model for end-stage liver disease, high MELD ⱖ20, low MELD ⬍20, Time 1: after induction of anesthesia. Time 2: 60 min after the start of anhepatic stage. Time 3: 60 min after reperfusion.
diseases; therefore, only scant data were available regarding them. In conclusion, the underlying disease inducing liver failure did not produce a difference in cytokine secretion, whereas the presurgical MELD score was related to cytokine secretion. REFERENCES 1. Pirenne J, Noizat-Pirenne F, De Groote D, et al: Intraoperative cytokines production during orthotopic liver transplantation. Transpl Int 5(suppl 1):S631, 1992 2. Yost CS, Niemann CU: Anesthesia for abdominal organ transplantation. In Miller RD: Miller’s Anesthesia, 7th Ed. Philadelphia, Elsevier; 2009, p 2169 3. Santiago F, Bueno P, Olmedo C, et al: Time course of intraoperative cytokine levels in liver transplant recipients. Transplant Proc 38:2492, 2006
4. Faybik P, Hetz H, Krenn CG, et al: Perioperative cytokines during orthotopic liver transplantation without venovenous bypass. Transplant Proc 35:3019, 2003 5. Boros P, Suehiro T, Curtiss S, et al: Differential contribution of graft and recipient to perioperative TNF-␣, IL-1, IL-6 and IL-8 levels and correlation with early graft function in clinical liver transplantation. Clin Transpl 11:588, 1997 6. Mueller AR, Platz KP, Haak M, et al: The release of cytokines, adhesion molecules, and extracellular matrix parameters during and after reperfusion in human liver transplantation. Transplantation 62:1118, 1996 7. Axelrod DA, Koffron AJ, Baker T, et al: The economic impact of MELD on liver transplant centers. Am J Transplant 5:2297, 2005 8. Edwards EB, Harper AM: The impact of MELD on OPTN liver allocation: preliminary results. Clin Transpl 21, 2002 9. Saab S, Landaverde C, Ibrahim AB, et al: The MELD score in advanced liver disease: association with clinical portal hypertension and mortality. Exp Clin Transplant 4:395, 2006
T
PATIENTS AND METHODS The study enrolled 44 patients who underwent living donor liver transplantation between 1 September 2007 and 28 February 2009. To measure cytokines, blood samples were collected from the radial artery 3 times: after inducing anesthesia (time 1), 60 minutes after the start of the anhepatic period (time 2), and 60 minutes after reperfusion (time 3). The pro-inflammatory cyto-
kines tumor necrosis factor (TNF)␣, interleukin (IL)1, and IL-6 and anti-inflammatory cytokines IL-4 and IL-10 were quantified using commercial sandwich enzyme-linked immunoassay (ELISA) kits (Quantikine; R&D Systems, Minneapolis, Minn, USA). According to the underlying diseases that induced liver failure, the patients were divided into viral (n ⫽ 33) versus alcoholic (n ⫽ 11) hepatitis groups. The cytokine concentrations in each group were assessed at each time to compare the level of induced inflammatory or stress reaction according to the underlying disease causing the liver failure.
From the Departments of Anesthesiology and Pain Medicine (H.J.K., K.H.R., J.L.), Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea, and the Rheumatism Research Center (M.L.C., Y.J.H.), Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea. Address reprint requests to Dr. Jaemin Lee, Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040, Korea. E-mail: jmlee@ catholic.ac.kr
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.06.034
Transplantation Proceedings, 42, 3617–3619 (2010)
3617
3618 MELD scores were calculated as a presurgical variable based on the most recent biochemical laboratory data, and the patients were divided into high (ⱖ20) (n ⫽ 25) and low (⬍20) (n ⫽ 19) MELD groups. The concentration of cytokines was compared between the groups at each time. The data are presented as median values and interquartile ranges. Wilcoxon rank sum test was performed for statistical analysis. A P value ⬍.05 was considered significant.
RESULTS
No significant difference in demographic data existed between the groups. No difference in the serum concentrations of all of the cytokines measured in our study was detected at any time between the viral versus alcoholic hepatitis groups (Fig 1). Comparing cytokine concentrations according to MELD scores showed that the IL-1 and IL-4 levels were higher among the high MELD versus the low MELD group at all times (Fig 2). The IL-10 concentrations at time 1 and TNF-␣ at time 2 were higher in the high than in the low MELD group. DISCUSSION
Studies on perioperative cytokine levels have primarily addressed fluctuations in the concentrations of cytokines after liver transplantation surgery and their associations with prognosis.3– 6 Few comprehensive studies have examined the pathophysiologic abnormalities in end-stage liver disease, including the association of prognostic indices such as the MELD score to the underlying liver disease with cytokine levels. Hence, we examined these associations. We did not detect a difference in cytokine concentrations based on the underlying disease that induced liver failure, implying that the induction of inflammatory and stress reactions that occur with viral or alcoholic hepatitis do not differ. In contrast, the MELD score affected cytokine concentrations. The MELD score is a reliable index of the severity
KOH, RYU, CHO ET AL
and prognosis of liver failure in transplant candidates. Cytokine concentrations have been reported to be associated with the course and prognosis after liver transplantation.5,6 Our finding of a difference in cytokine concentrations between the high vs low MELD groups agreed with previous studies.5,6 Regardless of the time, IL-1 and IL-4 were significantly higher among the high MELD, whereas IL-10 and TNF-␣ differed between high and low MELD groups at some times. Therefore, surgical stress factors, such as bleeding and clamping major vessels, and the resultant hemodynamic and acid– base instability acted in combination with the presurgical MELD score. In this study, the cutoff value between the groups was 20, based on one report that the mean MELD score of patients who had undergone liver transplantation was 20.77 and another that indicated that cases with MELD scores higher than 20 showed an increased mortality.8 According to Saab et al,9 the fluctuation in the MELD score with time was not predicted by the underlying disease that caused the liver failure. This observation implied that the fluctuation in the MELD score and in underlying liver disease were not associated with each other. Our finding that cytokine concentrations, which were dependent on the MELD score, were not different according to the underlying liver disease concurs with their results. Although the cytokine concentrations were not different among the viral versus alcoholic hepatitis groups, this did not imply that the cytokine concentrations do not differ among all liver diseases causing hepatic failure. We compared viral hepatitis (hepatitis B or C) with alcoholic hepatitis, which is reportedly increasing in our country, because these 2 diseases are the most common ones among our transplant patients. Other diverse diseases that induce liver failure include hepatomas, biliary cirrhosis, and metabolic diseases. The clinical features of these diseases are different from those of viral or alcoholic hepatitis. While conducting this study, liver transplantation was rarely performed in patients with these
Fig 1. Comparison of cytokines concentrations between disease groups. The box plots show the median (thick line in the box), interquartile range (box), and range (whickers). All cytokines concentrations are pg/ml in value. There are no differences between disease groups. T1: after induction of anesthesia. T2: 60 min after the start of anhepatic stage, T3: 60 min after reperfusion.
INFLUENCING CYTOKINE CONCENTRATION
3619
Fig 2. Comparison of cytokines concentrations between MELD-based groups. The box plots show the median (thick line in the box), interquartile range (box), and range (whickers). All cytokines concentrations are pg/ml in value. *P ⬍ .05 vs low MELD. MELD: model for end-stage liver disease, high MELD ⱖ20, low MELD ⬍20, Time 1: after induction of anesthesia. Time 2: 60 min after the start of anhepatic stage. Time 3: 60 min after reperfusion.
diseases; therefore, only scant data were available regarding them. In conclusion, the underlying disease inducing liver failure did not produce a difference in cytokine secretion, whereas the presurgical MELD score was related to cytokine secretion. REFERENCES 1. Pirenne J, Noizat-Pirenne F, De Groote D, et al: Intraoperative cytokines production during orthotopic liver transplantation. Transpl Int 5(suppl 1):S631, 1992 2. Yost CS, Niemann CU: Anesthesia for abdominal organ transplantation. In Miller RD: Miller’s Anesthesia, 7th Ed. Philadelphia, Elsevier; 2009, p 2169 3. Santiago F, Bueno P, Olmedo C, et al: Time course of intraoperative cytokine levels in liver transplant recipients. Transplant Proc 38:2492, 2006
4. Faybik P, Hetz H, Krenn CG, et al: Perioperative cytokines during orthotopic liver transplantation without venovenous bypass. Transplant Proc 35:3019, 2003 5. Boros P, Suehiro T, Curtiss S, et al: Differential contribution of graft and recipient to perioperative TNF-␣, IL-1, IL-6 and IL-8 levels and correlation with early graft function in clinical liver transplantation. Clin Transpl 11:588, 1997 6. Mueller AR, Platz KP, Haak M, et al: The release of cytokines, adhesion molecules, and extracellular matrix parameters during and after reperfusion in human liver transplantation. Transplantation 62:1118, 1996 7. Axelrod DA, Koffron AJ, Baker T, et al: The economic impact of MELD on liver transplant centers. Am J Transplant 5:2297, 2005 8. Edwards EB, Harper AM: The impact of MELD on OPTN liver allocation: preliminary results. Clin Transpl 21, 2002 9. Saab S, Landaverde C, Ibrahim AB, et al: The MELD score in advanced liver disease: association with clinical portal hypertension and mortality. Exp Clin Transplant 4:395, 2006