Digestive Diseases and Sciences

, Volume 51, Issue 11, pp 1967–1977 | Cite as

Clinical Significance of Evaluation of Serum Zinc Concentrations in C-Viral Chronic Liver Disease

  • Mitsuhiko MoriyamaEmail author
  • Hiroshi Matsumura
  • Akiko Fukushima
  • Kenji Ohkido
  • Yasuo Arakawa
  • Kazushige Nirei
  • Hiroaki Yamagami
  • Miki Kaneko
  • Naohide Tanaka
  • Yasuyuki Arakawa
Original Paper


We evaluated zinc concentrations in patients with hepatitis C virus (HCV)-positive chronic liver disease and correlated them with the clinical profiles of the patients. A total of 100 patients with chronic hepatitis (CH), 29 with liver cirrhosis (LC), and 6 who were asymptomatic HCV carriers (ASC) were examined. All of the patients were positive for serum HCV RNA. One hundred eighteen HCV antibody-positive hepatocellear carcinoma (HCC) patients and 11 healthy subjects also were included in this study. Serum zinc concentrations were evaluated using conventional atomic absorption spectrometry. The median concentration of zinc in patients with CH was statistically lower than that in healthy control subjects. The median zinc concentrations of the LC and HCC groups were significantly lower than that of the CH group. A significant correlation was observed between the zinc concentrations and the platelet counts and albumin concentrations. The zinc concentrations did not correlate with tumor size and number and decreased with the development of Child-Pugh stage. The cumulative survival rate after therapy for HCC nodules in the low zinc concentration group was significantly lower than in the high group. We conclude that the serum concentration of zinc influences the clinical profiles in patients with C-viral chronic liver disease.


Zinc Hepatocellular carcinoma (HCC) Cumulative incidence of HCC development Multivariate analysis Chronic hepatitis C Liver cirrhosis 


  1. 1.
    Dibley MJ (2002) Present knowledge in nutrition, 18th ed. Kenpakusha, Tokyo, pp 344–345Google Scholar
  2. 2.
    Krebs NF (2000) Overview of zinc absorption and excretion in the human gastrointestinal tract. J Nutr 130(Suppl 5):1374S–137SPubMedGoogle Scholar
  3. 3.
    Yoshikawa T, Naito Y, Tanigawa T, Yoneta T, Yasuda M, Ueda S, Oyamada H, Kondo M (1991) Effect of zinc-carnosine chelate compound (Z-103), a novel antioxidant, on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Free Radic Res Commun 14(4):289–296PubMedGoogle Scholar
  4. 4.
    Handa O, Yoshida N, Tanaka Y, Ueda M, Ishikawa T, Takagi T, Matsumoto N, Naito Y, Yoshikawa T (2002) Inhibitory effect of polaprezinc on the inflammatory response to Helicobacter pylori. Can J Gastroenterol 16(11):785–789PubMedGoogle Scholar
  5. 5.
    Yoshikawa T, Yamaguchi T, Yoshida N, Yamamoto H, Kitazumi S, Takahashi S, Naito Y, Kondo M (1997) Effect of Z-103 on TNB-induced colitis in rats. Digestion 58(5):464–468PubMedCrossRefGoogle Scholar
  6. 6.
    Ferahman M, Unal E, Sakoglu N, Ersoy YE, As A, Ozdemir S (2003) Zinc and copper status in acute pancreatitis: an experimental study. Biol Trace Elem Res 91(1):89–94PubMedCrossRefGoogle Scholar
  7. 7.
    Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, Kakizaki S, Hashimoto Y, Matsumoto T, Kojima A, Takezawa J, Suzuki K, Sato S, Mori M (2001) Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat 8(5):367–371PubMedCrossRefGoogle Scholar
  8. 8.
    Ebara M, Fukuda H, Hatano R, Yoshikawa M, Sugiura N, Saisho H, Kondo F, Yukawa M (2003) Metal contents in the liver of patients with chronic liver disease caused by hepatitis C virus. Reference to hepatocellular carcinoma. Oncology 65(4):323–330PubMedCrossRefGoogle Scholar
  9. 9.
    Riggio O, Merli M, Capocaccia L (1992) Zinc supplementation reduce blood ammonia and increases liver ornithin transcarbamirase activity in experimental cirrhosis. Hepatology 16:785–789PubMedGoogle Scholar
  10. 10.
    Muranaka H, Kato N (1969) Detection of serum zinc by atomic absorption spectrometry. Rinsho Byori 17:559–562 (in Japanese)PubMedGoogle Scholar
  11. 11.
    Oka S, Ogino K, Matsuura S, Yoshimura S, Yamamoto K, Okazaki Y, Takemoto T, Kato N, Uda T (1989) Human serum immuno-reactive copper, zinc-superoxide dismutase assayed with an enzyme monoclonal immunosorbent in patients with digestive cancer. Clin Chim Acta 182(2):209–219PubMedCrossRefGoogle Scholar
  12. 12.
    Matsumura H, Moriyama M, Goto I, Tanaka N, Okubo H, Arakawa Y (2000) Natural course of progression of liver fibrosis in patients with chronic liver disease type C in Japan—A study of 527 patients at one establishment in Japan. J Viral Hepat 7:375–381CrossRefGoogle Scholar
  13. 13.
    Ono E, Shiratori Y, Okudaira T, Imamura M, Teratani T, Kanai F, Kato N, Yoshida H, Shiina S, Omata M (1999) Platelet count reflects stage of chronic hepatitis C. Hepatol Res 15:192–200CrossRefGoogle Scholar
  14. 14.
    Moriyama M, Matsumura H, Aoki H, Shimizu T, Nakai K, Saito T, Yamagami H, Shioda A, Kaneko M, Goto I, Tanaka N, Arakawa Y (2003) Long-term outcome, with monitoring of platelet counts, in patients with chronic hepatitis C and liver cirrhosis after interferon therapy. Intervirology 46:296–307PubMedCrossRefGoogle Scholar
  15. 15.
    Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y, Tanaka T, Tanaka T, Sato K, Tsuda F, Miyakawa Y, Mayumi M (1992) Typing of hepatitis C virus by PCR with type–specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol 73:673–679PubMedCrossRefGoogle Scholar
  16. 16.
    Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, Brouwer JT, Chan SW, Chayama K, Chen DS, Choo QL, Colombo M, Cuypers HTM, Date T, Dusheiko GM, Esteban JI, Fay O, Hadziyannis SJ, Han J, Hatzakis A, Holmes EC, Hotta H, Houghton M, Irvine B, Kohara M, Kolberg JA, Kuo G, Lau JYN, Lelie PN, Maertens G, McOmish F, Miyamura T, Mizokami M, Nomoto A, Prince AM, Reesink HW, Rice C, Roggendorf M, Schalm SW, Shikata T, Shimotohno K, Stuyver L, Trepo C, Weiner A, Yap PL, Urdea MS (1994) A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 19:1321–1324PubMedCrossRefGoogle Scholar
  17. 17.
    Levy I, Sherman M, the Liver Cancer Study Group of the University of Toronto (2002) Staging of hepatocellular carcinoma: assessment of the CLIP, Okuda, and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut 50:881–885PubMedCrossRefGoogle Scholar
  18. 18.
    Boyett JD, Sullivan JF (1970) Distribution of protein-bound zinc in normal and cirrhotic serum. Metabolism 19(2):148–157PubMedCrossRefGoogle Scholar
  19. 19.
    Boyett JD, Sullivan JF (1970) Zinc and collagen content of cirrhotic liver. Am J Dig Dis 15(9):797–802PubMedCrossRefGoogle Scholar
  20. 20.
    Scholmerich J, Becher MS, Kottgen E, Rauch N, Haussinger D, Lohle E, Vuilleumier JP, Gerok W (1983) The influence of portosystemic shunting on zinc and vitamin A metabolism in liver cirrhosis. Hepatogastroenterology 30(4):143–147PubMedGoogle Scholar
  21. 21.
    Wakiyama K, Arakawa Y, Suzuki T, Miyamoto M, Matsuo Y, Honda T, Tomioka E, Mano M, Kigoshi K, Sasaki A, Takeuchi S (1986) A pathophysiological significance of trace metals in rats with experimental cirrhosis. Acta Pathol Hepatica 140:1182–1183 (In Japanese)Google Scholar
  22. 22.
    Evans GW, Winter TW (1975) Zinc transport by transferrin in rat portal blood plasma. Biochem Biophys Res Commun 66(4):1218–1224PubMedCrossRefGoogle Scholar
  23. 23.
    Evans GW (1976) Transferrin function in zinc absorption and transport. Proc Soc Exp Biol Med 151(4):775–778PubMedGoogle Scholar
  24. 24.
    Fisher GL (1975) Function and homeostasis of copper and zinc in mammals. Sci Total Environ 4(4):373–412PubMedCrossRefGoogle Scholar
  25. 25.
    Vargaftig BB, Tranier Y, Chignard M (1975) Blockade by metal complexing agents and by catalase of the effects of arachidonic acid on platelets: relevance to the study of anti-inflammatory mechanisms. Eur J Pharmacol 33:19–29PubMedCrossRefGoogle Scholar
  26. 26.
    Nagasue N, Kolno H, Chang YC, Nakamura T (1989) Iron, copper and zinc levels in serum and cirrhotic liver of patients with and without hepatocellular carcinoma. Oncology 46:293–296PubMedCrossRefGoogle Scholar
  27. 27.
    Ebara M, Fukuda H, Hatano R, Saisho H, Nagato Y, Suzuki K, Nakajima K, Yukawa M, Kondo F, Nakayama A, Sakurai H (2000) Relationship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma. J Hepatol 33(3):415–422PubMedCrossRefGoogle Scholar
  28. 28.
    Stempniak M, Hostomska Z, Nodes BR, Hostomsky Z (1997) The NS3 proteinase domain of hepatitis C virus is a zinc-containing enzyme. J Virol 71(4):2881–2886PubMedGoogle Scholar
  29. 29.
    Love RA, Parge HE, Wickersham JA, Hostomsky Z, Habuka N, Moomaw EW, Adachi T, Hostomska Z (1996) The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 87(2):331–342PubMedCrossRefGoogle Scholar
  30. 30.
    Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM (2004) The NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem 279(47):48576–48587PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang Y, Kang YJ (2004) Metallothionein gene therapy for chemical-induced liver fibrosis in mice. Mol Ther 10:1130–1139PubMedCrossRefGoogle Scholar
  32. 32.
    Camps J, Bargallo T, Gimenez A, Alie S, Caballeria J, Pares A, Joven J, Masana L, Rodes J (1992) Relationship between hepatic lipid peroxidation and fibrogenesis in carbon tetrachloride-treated rats: effect of zinc administration. Clin Sci (Lond) 83:695–700Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Mitsuhiko Moriyama
    • 1
    Email author
  • Hiroshi Matsumura
    • 1
  • Akiko Fukushima
    • 1
  • Kenji Ohkido
    • 1
  • Yasuo Arakawa
    • 1
  • Kazushige Nirei
    • 1
  • Hiroaki Yamagami
    • 1
  • Miki Kaneko
    • 1
  • Naohide Tanaka
    • 1
  • Yasuyuki Arakawa
    • 1
  1. 1.Division of Gastroenterology and Hepatology, Department of MedicineNihon University School of MedicineTokyoJapan

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