Effect of zinc supplementation in patients with type C liver cirrhosis


Zinc is often deficient in patients with liver cirrhosis, and treatment with zinc provides short-term improvement in protein metabolism. However, the long-term effects of zinc have not been fully clarified. The present study aimed to analyze the effect of zinc on the long-term clinical course, especially hepatocarcinogenesis, in type C liver cirrhosis. Am- ong patients with type C liver cirrhosis visiting our hospital between June 1998 and January 2009, th- ose with a serum albumin level ≤3.5 g/dL and a serum zinc level ≤70 μg (1.07 μmol)/dL were selected. Thirty-seven patients were randomly divided into 2 groups: group B (12 g/day branched-chain amino acid granules) and group BZ (same as group B plus 100 mg/day - 600 mg/day zinc sulfate or 150 mg/day - 225 mg/day polaprezinc). Multivariate analysis revealed that the administration of zinc was not a significant determinant, but pretreatment serum zinc levels (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.853–0.994) and serum zinc levels less than 80 μg (1.22 μmol)/dL 12 months after beginning this study (HR, 6.866; 95% CI, 1.399 - 33.707) were significant determinants of carcinogenesis and death. Serum albumin levels in patients whose serum zinc levels had not increased up to 80 μg/dL by the third year of this study were significantly lower (p = 0.023) than those of patients that had increased up to 80 μg/dL. Conclusions: In type C liver cirrhosis with zinc deficiency, administration of zinc does not improve cancer-free survival. However, serum zinc levels can predict outcomes in patients with type C liver cirrhosis. However, although zinc may play a role in hepatocarcinogenesis, the precise implications remain to be clarified.

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Katayama, K. , Sakakibara, M. , Imanaka, K. , Ohkawa, K. , Matsunaga, T. , Naito, M. and Ito, T. (2011) Effect of zinc supplementation in patients with type C liver cirrhosis. Open Journal of Gastroenterology, 1, 28-34. doi: 10.4236/ojgas.2011.12005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Parkin, D.M. (2001) Global cancer statistics in the year 2000. Lancet Oncology, 2, 533-543. doi:10.1016/S1470-2045(01)00486-7
[2] El-Serag, H.B., Rudolph, K.L. (2007) Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology, 132, 2557-2576. doi:10.1053/j.gastro.2007.04.061
[3] Tanaka, H., Imai, Y., Hiramatsu, N., Ito, Y., Imanaka, K., Oshita, M., Hijioka, T., Katayama, K., Yabuuchi, I., Yo-shihara, H., Inoue, A., Kato, M., Takehara, T., Tamura, S., Kasahara, A., Hayashi, N. and Tsukuma, H. (2008) De-clining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003. Annals of Internet Medicine, 148, 820-826.
[4] McGlynn, K.A., Tsao, L., Hsing, A.W., Devesa, S.S. and Fraumeni, J.F. Jr. (2001) International trends and patterns of primary liver cancer. International Journal of Cancer, 94, 290-296. doi:10.1002/ijc.1456
[5] Kasahara, A., Hayashi, N., Mochizuki, K., Takayanagi, M., Yoshioka, K., Kakumu, S., Iijima, A., Urushihara, A., Kiyosawa, K., Okuda, M., Hino, K. and Okita, K. (1998) Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Hepatology, 27, 1394-1402. doi:10.1002/hep.510270529
[6] Lok, A.S.F. (2004) Prevention of hepatitis B virus-related hapatocellular carcinoma. Gastroenterology, 127, S303- 309. doi:10.1053/j.gastro.2004.09.045
[7] El-Serag, H.B., Tran, T. and Everhart, J.E. (2004) Di-abetes increases the risk of chronic liver disease and he-patocellular carcinoma. Gastroenterology, 126, 460-468. doi:10.1053/j.gastro.2003.10.065
[8] Calle, E.E., Rodriguez, C., Walker-Thurmond, K. and Thun, M. (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. New England Journal of Medicine, 348, 1625-1638. doi:10.1056/NEJMoa021423
[9] Muto, Y., Sato, S., Watanabe, A., Moriwaki, H., Suzuki, K., Kato, A., Kato, M., Nakamura, T., Higuchi, K., Ni-shiguchi, S. and Kumada, H. (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clinical Gastroenterology and Hepatology, 3, 705-713. doi:10.1016/S1542-3565(05)00017-0
[10] Muto, Y., Sato, S., Watanabe, A., Moriwaki, H., Suzuki, K., Kato, A., Kato, M., Nakamura, T., Higuchi, K., Ni-shiguchi, S., Kumada, H. and Ohashi, Y. (2006) Over-wight and obesity increase the risk for liver cancer in pa-tients liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatology Research, 35, 204-214.
[11] Prasad, A.S. (1995) Zinc: An overview. Nutrition, 11, 93-95.
[12] Vallee, B.L. and Fulchuk, K.H. (1993) The biochemical basis of zinc physiology. Physiological Reviews, 73, 79-118.
[13] Pabo, C.O., Peisach, E. and Grant, R.A. (2001) Design and selection of novel Cys2His2 zinc finger proteins. Annual Review of Biochemistry, 70, 313-340. doi:10.1146/annurev.biochem.70.1.313
[14] Joazeiro, C.A. and Weissman, A.M. (2000) Ring finger proteins: Mediators of ubiquitin ligase activity. Cell, 102, 549-542. doi:10.1016/S0092-8674(00)00077-5
[15] Kadrmas, J.L. and Beckerle, M.C. (2004) The Lim do-main: From the cytoskeleton to the nucleus. Nature Re-views Molecular Cell Biology, 5, 920-931. doi:10.1038/nrm1499
[16] Vallee, B.L. (1995) The function of methallothionein. Neurochemistry International, 27, 23-33. doi:10.1016/0197-0186(94)00165-Q
[17] Eide, D.J. (2004) The SLC39 family of metal ion trans-porter. Pflugers Archiv European Journal of Physiology, 447, 796-800. doi:10.1007/s00424-003-1074-3
[18] Palmiter, R.D. and Huang, L. (2004) Efflux and com-partmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Archiv European Journal of Physiology, 447, 744-751. doi:10.1007/s00424-003-1070-7
[19] Colvin, R.A., Fontaine, C.P., Laskowski, M. and Thomas, D. (2003) Zn2+ transporters and Zn2+ homeostasis in neurons. European Journal of Pharmacology, 479, 298-302. doi:10.1016/j.ejphar.2003.08.067
[20] Kambe, T., Yamaguchi-Iwai, Y., Sasaki, R. and Nagao, M. (2004) Overview of mammalian zinc transpoters. Cellular and Molecular Life Sciences, 61, 298-302. doi:10.1007/s00018-003-3148-y
[21] Ganss, B. and Jheon, A. (2004) Zinc finger transcription factors in skeletal development. Critical Reviews in Oral Biology and Medicine, 15, 282-297. doi:10.1177/154411130401500504
[22] Licastro, F., Mariani, R.A., Faldella, G., Carpene, E., Guidicini, G., Rangoni, A., Grilli, T. and Bazzocchi, G. (2001) Immune-endocrine status and celiac disease in children with Down’s syndrome: Relationships with zinc and cognitive efficiency. Brain Research Bulletin, 55, 313-317. doi:10.1016/S0361-9230(01)00476-2
[23] Prasad, A.S. (1998) Zinc and immunity. Molecular and Cellular Biochemistry, 188, 63-69. doi:10.1023/A:1006868305749
[24] Kitamura, H., Morikawa, H., Kamon, H., Iguchi, M., Hojyo, S., Fukuda, T., Yamashita, S., Kaisho, T., Akira, S., Murakami, M. and Hirano, T. (2006) Toll-like recep-tor-mediated regulation of zinc homeostasis influences dendritic cell function. Nature Immunology, 7, 971-977. doi:10.1038/ni1373
[25] Stamoulis, I., Kouraklis, G. and Theocharis, S. (2007) Zinc and the liver: An active interaction. Digestive Dis-eases and Sciences, 52, 1595-1612. doi:10.1007/s10620-006-9462-0
[26] Marchesini, G., Fabbri, A., Bianchi, G., Brizi, M. and Zoli, M. (1996) Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepa-tology, 23, 1084-1092. doi:10.1002/hep.510230523
[27] Hayashi, M., Ikezawa, K., Ono, A., Okabayashi, S., Hayashi, Y., Shimizu, S., Mizuno, T., Maeda, K., Akasaka, T., Naito, M., Michida, T., Ueshima, D., Nada, T., Kawaguchi, K., Nakamura, T. and Katayama, K. (2007) Evaluation of the effects of combination therapy with branched-chain amino acid and zinc supplements on ni-trogen metabolism in liver cirrhosis. Hepatology Research, 37, 615-619. doi:10.1111/j.1872-034X.2007.00095.x
[28] Marchesini, G., Bugianesi, E., Ronchi, M., Flamia, R., Thomaseth, K. and Pianchi, G. (1998) Zinc supplemanta-tion improves glucose disposal in patients with cirrhosis. Metabolism, 47, 792-798. doi:10.1016/S0026-0495(98)90114-7
[29] Matsuoka, S., Matsumura, H., Nakamura, H., Oshiro, S., Arakawa, Y., Hayashi, J., Sekine, N., Nirei, K., Yamagu-chi, H., Ogawa, M., Nakajima, N., Amaki, S., Tanaka, N. and Moriyama, M. (2009) Zinc supplementation improves the outcome of chronic hepatitis C and liver cirrhosis. Journal of Clinical Biochemistry and Nutrition, 45, 292-303. doi:10.3164/jcbn.jcbn08-246
[30] Yun, E.H., Lim, M.K., Oh, J.-K., Park, J.H., Shin, A., Sung, J. and Park, E.-C. (2010) Combined effect of so-cioeconomic status, viral hepatitis, and lifestyles on he-patocellular carcinoma risk in Korea. British Journal of Cancer, 103, 741-746. doi:10.1038/sj.bjc.6605803
[31] Heathcote, E.J. (2004) Prevention of hepatitis C vi-rus-related hepatocellular carcinoma. Gastroenterology, 127, S294-S302. doi:10.1053/j.gastro.2004.09.044
[32] McHutchison, J.G., Dusheiko, G., Shiffman, M.L., Ro-driguez-Torres, M., Sigal, S., Bourliere, M., Berg, T., Gordon, S.C., Campbell, F.M., Therdore, D., Blackman, N., Jenkins, J. and Afdhal, N.H. (2007) TPL102357 Study group, Eltrombopag for thrombocytopenia in pa-tients with cirrhosis associated with hepatitis C. New England Journal of Medicine, 357, 2227-2236. doi:10.1056/NEJMoa073255
[33] Ikezawa, K., Naito, M., Yumiba, T., Iwahashi, K., Onishi, Y., Kita, H., Nishio, A., Kanno, T., Matsuura, T., Ono, A., Chiba, M., Mizuno, T., Aketa, H., Maeda, K., Michida, T. and Katayama, K. (2010) Splenectomy and antiviral treatment for thrombocytopenic patients with chronic hepatitis C virus infection. Journal of Viral Hepatitis, 17, 488-492.
[34] Katayama, K. (2004) Ammonia and hepatic encephalo-pathy. Hepatology Research, 30S, S71-S78.
[35] Tajika, M., Kato, M., Mohri, H., Miwa, Y., Kato, T., Onishi, H. and Moriwaki, H. (2002) Prognostic value of energy metabolism in patients with liver cirrhosis. Nutri-tion, 18, 229-234. doi:10.1016/S0899-9007(01)00754-7

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