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Association of serum zinc levels with liver function and survival in patients awaiting liver transplantation

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Abstract

Purpose

Zinc is an important trace element with catalytic and defensive functions. We assessed the impact of zinc deficiency in patients with end-stage liver disease awaiting liver transplantation.

Methods

Serum zinc levels were measured at the time of evaluation for liver transplantation (n = 368). Patients were dichotomized in two groups based on low and normal zinc serum levels.

Results

Serum zinc levels are tightly associated with liver function as patients with low zinc levels (n = 226) had a higher Model for End-Stage Liver Disease (MELD) score (15.0 [5.0–40.0]) than patients with normal zinc (n = 142) levels (9.0 [6.0–34.0]; p < 0.00). Multivariate analysis demonstrated that serum zinc levels function as an independent predictor of hepatic decompensation (hydropic decompensation: odds ratio [OR] 0.82; 95 % confidence interval [CI] 0.70–0.96; p = 0.015; hepatic encephalopathy: OR 0.80; 95 % CI 0.71–0.90; p = 0.000; spontaneous bacterial peritonitis: OR 0.85; 95 % CI 0.72–1.00; p = 0.047; hepatorenal syndrome: OR 0.83; 95 % CI 0.72–0.95; p = 0.011). Actuarial survival free of liver transplantation was reduced for low-zinc patients (26.7 ± 4.0 months; 95 % CI 18.8–34.6) compared to patients with normal zinc levels (30.9 ± 3.0 months; 95 % CI 24.9–36.9; p = 0.008). Reduction of zinc levels for patients on the transplantation list resulted in a 28.3-fold increased risk of death/liver transplantation (95 % CI 3.2–244.8, p < 0.001).

Conclusions

Serum zinc levels are associated with reduced survival in end-stage liver disease patients. Whether or not zinc supplementation might be beneficial for patients on a liver transplantation list requires further study.

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References

  1. Tubek S, Grzanka P, Tubek I (2008) Role of zinc in hemostasis: a review. Biol Trace Elem Res 121:1–8

    Article  CAS  PubMed  Google Scholar 

  2. Liu J, Zhou ZX, Zhang W, Bell MW, Waalkes MP (2009) Changes in hepatic gene expression in response to hepatoprotective levels of zinc. Liver Int 29:1222–1229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Zhou Z (2010) Zinc and alcoholic liver disease. Dig Dis 28:745–750

    Article  PubMed  Google Scholar 

  4. Stamoulis I, Kouraklis G, Theocharis S (2007) Zinc and the liver: an active interaction. Dig Dis Sci 52:1595–1612

    Article  CAS  PubMed  Google Scholar 

  5. Prasad AS (1998) Zinc and immunity. Mol Cell Biochem 188:63–69

    Article  CAS  PubMed  Google Scholar 

  6. Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S, Fukada T, Yamashita S et al (2006) Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7:971–977

    Article  CAS  PubMed  Google Scholar 

  7. Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ (2012) Zinc and liver disease. Nutr Clin Pract 27:8–20

    Article  PubMed  Google Scholar 

  8. Rahelic D, Kujundzic M, Romic Z, Brkic K, Petrovecki M (2006) Serum concentration of zinc, copper, manganese and magnesium in patients with liver cirrhosis. Coll Antropol 30:523–528

    CAS  PubMed  Google Scholar 

  9. Reichert B, Kaltenborn A, Goldis A, Schrem H (2013) Prognostic limitations of the Eurotransplant-donor risk index in liver transplantation. J Negat Results Biomed 12:18

    Article  PubMed Central  PubMed  Google Scholar 

  10. Gotthardt D, Weiss KH, Baumgartner M, Zahn A, Stremmel W, Schmidt J, Bruckner T et al (2009) Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation. BMC Gastroenterol 9:72

    Article  PubMed Central  PubMed  Google Scholar 

  11. Hoffmann K, Hinz U, Hillebrand N, Ganten T, Gotthardt D, Longerich T, Schirmacher P et al (2014) The MELD score predicts the short-term and overall survival after liver transplantation in patients with primary sclerosing cholangitis or autoimmune liver diseases. Langenbecks Arch Surg 399:1001–1009

    Article  PubMed  Google Scholar 

  12. Bahra M, Neuhaus P (2011) Liver transplantation in the high MELD era: a fair chance for everyone? Langenbecks Arch Surg 396:461–465

    Article  PubMed  Google Scholar 

  13. EASL (2010) Clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 53:397–417

    Article  Google Scholar 

  14. Rochon J, Gondan M, Kieser M (2012) To test or not to test: preliminary assessment of normality when comparing two independent samples. BMC Med Res Methodol 12:81

    Article  PubMed Central  PubMed  Google Scholar 

  15. Murray KF, Carithers RL Jr (2005) AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 41:1407–1432

    Article  PubMed  Google Scholar 

  16. Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, Tsuji T (2001) Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 55:349–355

    CAS  PubMed  Google Scholar 

  17. Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H (2010) Clinical trial: oral zinc in hepatic encephalopathy. Aliment Pharmacol Ther 32:1080–1090

    Article  CAS  PubMed  Google Scholar 

  18. Grzegorzewska AE, Mariak I (2001) Zinc as a marker of nutrition in continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 17:223–229

    CAS  PubMed  Google Scholar 

  19. Henderson RA, Talusan K, Hutton N, Yolken RH, Caballero B (1997) Serum and plasma markers of nutritional status in children infected with the human immunodeficiency virus. J Am Diet Assoc 97:1377–1381

    Article  CAS  PubMed  Google Scholar 

  20. Xiao M, Liu CB, Sun W, Dong MW, Hu GX, Li JW (2012) Zinc supplementation effects on alcoholic liver disease and the molecular mechanism. Zhongguo Ying Yong Sheng Li Xue Za Zhi 28:84–88

    CAS  PubMed  Google Scholar 

  21. Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ (2005) Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress. Am J Pathol 166:1681–1690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Szuster-Ciesielska A, Daniluk J, Bojarska-Junak A (2005) Apoptosis of blood mononuclear cells in alcoholic liver cirrhosis. The influence of in vitro ethanol treatment and zinc supplementation. Toxicology 212:124–134

    Article  CAS  PubMed  Google Scholar 

  23. Kang YJ, Zhou Z (2005) Zinc prevention and treatment of alcoholic liver disease. Mol Asp Med 26:391–404

    Article  CAS  Google Scholar 

  24. Zhong W, Zhao Y, McClain CJ, Kang YJ, Zhou Z (2010) Inactivation of hepatocyte nuclear factor-4{alpha} mediates alcohol-induced downregulation of intestinal tight junction proteins. Am J Physiol Gastrointest Liver Physiol 299:G643–G651

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kang X, Zhong W, Liu J, Song Z, McClain CJ, Kang YJ, Zhou Z (2009) Zinc supplementation reverses alcohol-induced steatosis in mice through reactivating hepatocyte nuclear factor-4 alpha and peroxisome proliferator-activated receptor-alpha. Hepatology 50:1241–1250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Zhou Z, Kang X, Jiang Y, Song Z, Feng W, McClain CJ, Kang YJ (2007) Preservation of hepatocyte nuclear factor-4alpha is associated with zinc protection against TNF-alpha hepatotoxicity in mice. Exp Biol Med (Maywood) 232:622–628

    CAS  Google Scholar 

  27. Imam MH, Talwalkar JA, Lindor KD (2013) An update on primary sclerosing cholangitis: from pathogenesis to treatment. Minerva Gastroenterol Dietol 59:49–58

    CAS  PubMed  Google Scholar 

  28. O'Mahony CA, Vierling JM (2006) Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis 26:3–21

    Article  PubMed  Google Scholar 

  29. Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH (2002) Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 359:150–157

    Article  PubMed  Google Scholar 

  30. Pollheimer MJ, Halilbasic E, Fickert P, Trauner M (2011) Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 25:727–739

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Beker Aydemir T, Chang SM, Guthrie GJ, Maki AB, Ryu MS, Karabiyik A, Cousins RJ (2012) Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 7, e48679

    Article  PubMed Central  PubMed  Google Scholar 

  32. Xu R, Zhang Z, Wang FS (2012) Liver fibrosis: mechanisms of immune-mediated liver injury. Cell Mol Immunol 9:296–301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Matsuoka S, Matsumura H, Nakamura H, Oshiro S, Arakawa Y, Hayashi J, Sekine N et al (2009) Zinc supplementation improves the outcome of chronic hepatitis C and liver cirrhosis. J Clin Biochem Nutr 45:292–303

    Article  PubMed Central  PubMed  Google Scholar 

  34. Marchesini G, Bianchi G, Rossi B, Brizi M, Melchionda N (2000) Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. J Gastroenterol 35(Suppl 12):7–12

    CAS  PubMed  Google Scholar 

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Acknowledgments

DNG was funded by a grant of the Deutsche Forschungsgemeinschaft.

Conflicts of interest

None.

Authors’ contributions

Study concept and design: KF, WS, DNG

Acquisition of data: KF, CB, AW, CA, CR, CNH, MD

Analysis and interpretation of data: KF, DNG, KHW, PS, PS

Critical revision of the manuscript: PS, PS, KHW, CA, CNH, MD, SGS

Statistical analysis: KF, DNG

Technical or material support: KF, CB, DNG

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Correspondence to Daniel Nils Gotthardt.

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Friedrich, K., Baumann, C., Brune, M. et al. Association of serum zinc levels with liver function and survival in patients awaiting liver transplantation. Langenbecks Arch Surg 400, 805–811 (2015). https://doi.org/10.1007/s00423-015-1334-7

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  • DOI: https://doi.org/10.1007/s00423-015-1334-7

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