Skip to main content
NCBI home page
Gut logoLink to Gut
. 1998 May;42(5):715–720. doi: 10.1136/gut.42.5.715

Evidence for altered hepatic matrix degradation in genetic haemochromatosis

D George 1, G Ramm 1, L Powell 1, L Fletcher 1, N Walker 1, L Cowley 1, D Crawford 1
PMCID: PMC1727107  PMID: 9659170

Abstract

Background—Altered matrix degradation contributes to fibrosis in some liver diseases but the role of matrix degradation in fibrogenesis associated with genetic haemochromatosis has not previously been addressed. 
Aims—To measure serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and matrix metalloproteinases (MMP), MMP-1, MMP-2, and MMP-3 in patients with haemochromatosis and control subjects. 
Patients—Forty patients with haemochromatosis and 19 healthy control subjects. Ten of the 40 patients were studied before and after venesection therapy. 
Methods—Serum levels of TIMP-1, MMP-1, MMP-2, and MMP-3 were measured by enzyme immunoassay and correlated to hepatic iron concentration and degree of histological fibrosis. 
Results—Serum TIMP-1 was increased in patients with haemochromatosis compared with controls (163 (30) versus 123 (28) ng/ml, p<0.0002). Mean serum TIMP-1 concentration of patients with haemochromatosis without fibrosis was significantly higher than in controls (153(16) versus 123 (28) ng/ml, p=0.03). Serum TIMP-1 concentration correlated with both hepatic iron concentration and hepatic iron index (r=0.42, p<0.01; r=0.42, p<0.01). Serum MMP-2 concentrations correlated with increasing degree of fibrosis in patients with haemochromatosis (r=0.38, p=0.01). The mean MMP-1:TIMP-1, MMP-2:TIMP-1 and age/sex matched MMP-3:TIMP-1 ratios were significantly lower in patients with haemochromatosis than controls (0.11 (0.06) versus 0.2 (0.14), p=0.02; 3.32 (0.9) versus 3.91 (0.81), p=0.05; and 0.26 (0.12) versus 0.47 (0.27), p=0.007, respectively). Following venesection, MMP-2 and MMP-3 concentrations increased by 11% (p=0.03) and 19% (p=0.03), respectively. 
Conclusions—This study provides the first evidence of an alteration in matrix degradation in haemochromatosis that may be a contributing factor to hepatic fibrogenesis in this disease. 



Keywords: hepatic stellate cell; hepatic fibrosis; matrix metalloproteinase; tissue inhibitor of metalloproteinase-1; genetic haemochromatosis

Full Text

The Full Text of this article is available as a PDF (119.9 KB).

Figure 1 .

Figure 1

Open in a new tab

Serum TIMP-1 concentrations in control subjects, and in patients with haemochromatosis graded for the degree of fibrosis (Scheuer grades 0-4). 


Figure 2 .

Figure 2

Open in a new tab

Linear regression analysis of the correlation between serum TIMP-1 concentrations and HIC in all patients with haemochromatosis (all circles, continuous line). The broken line represents analysis after exclusion of the 14 patients with mild acinar and/or portal inflammation (open circles). 


Figure 3 .

Figure 3

Open in a new tab

Linear regression analysis of the correlation between serum MMP-2 concentrations and (A) the degree of fibrosis and (B) HIC, in patients with haemochromatosis. 


Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arthur M. J. Degradation of matrix proteins in liver fibrosis. Pathol Res Pract. 1994 Oct;190(9-10):825–833. doi: 10.1016/S0344-0338(11)80985-4. [DOI] [PubMed] [Google Scholar]
  2. Arthur M. J., Iredale J. P. Hepatic lipocytes, TIMP-1 and liver fibrosis. J R Coll Physicians Lond. 1994 May-Jun;28(3):200–208. [PMC free article] [PubMed] [Google Scholar]
  3. Arthur M. J., Stanley A., Iredale J. P., Rafferty J. A., Hembry R. M., Friedman S. L. Secretion of 72 kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem J. 1992 Nov 1;287(Pt 3):701–707. doi: 10.1042/bj2870701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bassett M. L., Halliday J. W., Powell L. W. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986 Jan-Feb;6(1):24–29. doi: 10.1002/hep.1840060106. [DOI] [PubMed] [Google Scholar]
  5. Benyon R. C., Iredale J. P., Goddard S., Winwood P. J., Arthur M. J. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology. 1996 Mar;110(3):821–831. doi: 10.1053/gast.1996.v110.pm8608892. [DOI] [PubMed] [Google Scholar]
  6. Cartwright G. E., Edwards C. Q., Kravitz K., Skolnick M., Amos D. B., Johnson A., Buskjaer L. Hereditary hemochromatosis. Phenotypic expression of the disease. N Engl J Med. 1979 Jul 26;301(4):175–179. doi: 10.1056/NEJM197907263010402. [DOI] [PubMed] [Google Scholar]
  7. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R., Jr, Ellis M. C., Fullan A. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar]
  8. Fujimoto N., Mouri N., Iwata K., Ohuchi E., Okada Y., Hayakawa T. A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 2 (72-kDa gelatinase/type IV collagenase) using monoclonal antibodies. Clin Chim Acta. 1993 Nov 30;221(1-2):91–103. doi: 10.1016/0009-8981(93)90024-x. [DOI] [PubMed] [Google Scholar]
  9. Hepatic stellate cell nomenclature. Hepatology. 1996 Jan;23(1):193–193. [PubMed] [Google Scholar]
  10. Iredale J. P., Murphy G., Hembry R. M., Friedman S. L., Arthur M. J. Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. J Clin Invest. 1992 Jul;90(1):282–287. doi: 10.1172/JCI115850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ishimura E., Nishizawa Y., Shoji S., Mori H. Serum type III, IV collagens and TIMP in patients with type II diabetes mellitus. Life Sci. 1996;58(16):1331–1337. doi: 10.1016/0024-3205(96)00099-9. [DOI] [PubMed] [Google Scholar]
  12. Kasahara A., Hayashi N., Mochizuki K., Oshita M., Katayama K., Kato M., Masuzawa M., Yoshihara H., Naito M., Miyamoto T. Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C. Relationship to interferon response. J Hepatol. 1997 Mar;26(3):574–583. doi: 10.1016/s0168-8278(97)80423-0. [DOI] [PubMed] [Google Scholar]
  13. Kodama S., Iwata K., Iwata H., Yamashita K., Hayakawa T. Rapid one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases. An application for rheumatoid arthritis serum and plasma. J Immunol Methods. 1990 Feb 20;127(1):103–108. doi: 10.1016/0022-1759(90)90345-v. [DOI] [PubMed] [Google Scholar]
  14. Li J., Rosman A. S., Leo M. A., Nagai Y., Lieber C. S. Tissue inhibitor of metalloproteinase is increased in the serum of precirrhotic and cirrhotic alcoholic patients and can serve as a marker of fibrosis. Hepatology. 1994 Jun;19(6):1418–1423. [PubMed] [Google Scholar]
  15. Manicourt D. H., Fujimoto N., Obata K., Thonar E. J. Serum levels of collagenase, stromelysin-1, and TIMP-1. Age- and sex-related differences in normal subjects and relationship to the extent of joint involvement and serum levels of antigenic keratan sulfate in patients with osteoarthritis. Arthritis Rheum. 1994 Dec;37(12):1774–1783. doi: 10.1002/art.1780371211. [DOI] [PubMed] [Google Scholar]
  16. Milani S., Herbst H., Schuppan D., Grappone C., Pellegrini G., Pinzani M., Casini A., Calabró A., Ciancio G., Stefanini F. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol. 1994 Mar;144(3):528–537. [PMC free article] [PubMed] [Google Scholar]
  17. Murawaki Y., Ikuta Y., Idobe Y., Kitamura Y., Kawasaki H. Tissue inhibitor of metalloproteinase-1 in the liver of patients with chronic liver disease. J Hepatol. 1997 Jun;26(6):1213–1219. doi: 10.1016/s0168-8278(97)80454-0. [DOI] [PubMed] [Google Scholar]
  18. Murawaki Y., Ikuta Y., Koda M., Kawasaki H. Serum type III procollagen peptide, type IV collagen 7S domain, central triple-helix of type IV collagen and tissue inhibitor of metalloproteinases in patients with chronic viral liver disease: relationship to liver histology. Hepatology. 1994 Oct;20(4 Pt 1):780–787. doi: 10.1002/hep.1840200403. [DOI] [PubMed] [Google Scholar]
  19. Murawaki Y., Yamamoto H., Kawasaki H., Shima H. Serum tissue inhibitor of metalloproteinases in patients with chronic liver disease and with hepatocellular carcinoma. Clin Chim Acta. 1993 Sep 17;218(1):47–58. doi: 10.1016/0009-8981(93)90221-o. [DOI] [PubMed] [Google Scholar]
  20. Nakatsukasa H., Ashida K., Higashi T., Ohguchi S., Tsuboi S., Hino N., Nouso K., Urabe Y., Kinugasa N., Yoshida K. Cellular distribution of transcripts for tissue inhibitor of metalloproteinases 1 and 2 in human hepatocellular carcinomas. Hepatology. 1996 Jul;24(1):82–88. doi: 10.1053/jhep.1996.v24.pm0008707287. [DOI] [PubMed] [Google Scholar]
  21. Niederau C., Fischer R., Pürschel A., Stremmel W., Häussinger D., Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996 Apr;110(4):1107–1119. doi: 10.1053/gast.1996.v110.pm8613000. [DOI] [PubMed] [Google Scholar]
  22. Niederau C., Fischer R., Sonnenberg A., Stremmel W., Trampisch H. J., Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985 Nov 14;313(20):1256–1262. doi: 10.1056/NEJM198511143132004. [DOI] [PubMed] [Google Scholar]
  23. Obata K., Iwata K., Okada Y., Kohrin Y., Ohuchi E., Yoshida S., Shinmei M., Hayakawa T. A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 3 (stromelysin-1) using monoclonal antibodies. Clin Chim Acta. 1992 Oct 15;211(1-2):59–72. doi: 10.1016/0009-8981(92)90105-y. [DOI] [PubMed] [Google Scholar]
  24. Pietrangelo A., Gualdi R., Casalgrandi G., Geerts A., De Bleser P., Montosi G., Ventura E. Enhanced hepatic collagen type I mRNA expression into fat-storing cells in a rodent model of hemochromatosis. Hepatology. 1994 Mar;19(3):714–721. doi: 10.1002/hep.1840190325. [DOI] [PubMed] [Google Scholar]
  25. Powell L. W., Bassett M. L., Halliday J. W. Hemochromatosis: 1980 update. Gastroenterology. 1980 Feb;78(2):374–381. [PubMed] [Google Scholar]
  26. Ramm G. A., Crawford D. H., Powell L. W., Walker N. I., Fletcher L. M., Halliday J. W. Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron and response to phlebotomy. J Hepatol. 1997 Mar;26(3):584–592. doi: 10.1016/s0168-8278(97)80424-2. [DOI] [PubMed] [Google Scholar]
  27. Ramm G. A., Li S. C., Li L., Britton R. S., O'Neill R., Kobayashi Y., Bacon B. R. Chronic iron overload causes activation of rat lipocytes in vivo. Am J Physiol. 1995 Mar;268(3 Pt 1):G451–G458. doi: 10.1152/ajpgi.1995.268.3.G451. [DOI] [PubMed] [Google Scholar]
  28. Roeb E., Graeve L., Müllberg J., Matern S., Rose-John S. TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes. FEBS Lett. 1994 Jul 25;349(1):45–49. doi: 10.1016/0014-5793(94)00636-9. [DOI] [PubMed] [Google Scholar]
  29. Sallie R. W., Reed W. D., Shilkin K. B. Confirmation of the efficacy of hepatic tissue iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis. Gut. 1991 Feb;32(2):207–210. doi: 10.1136/gut.32.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Scheuer P. J. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991 Nov;13(3):372–374. doi: 10.1016/0168-8278(91)90084-o. [DOI] [PubMed] [Google Scholar]
  31. Terada T., Okada Y., Nakanuma Y. Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. Hepatology. 1996 Jun;23(6):1341–1344. doi: 10.1053/jhep.1996.v23.pm0008675149. [DOI] [PubMed] [Google Scholar]
  32. Ueno T., Tamaki S., Sugawara H., Inuzuka S., Torimura T., Sata M., Tanikawa K. Significance of serum tissue inhibitor of metalloproteinases-1 in various liver diseases. J Hepatol. 1996 Feb;24(2):177–184. doi: 10.1016/s0168-8278(96)80027-4. [DOI] [PubMed] [Google Scholar]
  33. Vyas S. K., Leyland H., Gentry J., Arthur M. J. Rat hepatic lipocytes synthesize and secrete transin (stromelysin) in early primary culture. Gastroenterology. 1995 Sep;109(3):889–898. doi: 10.1016/0016-5085(95)90399-2. [DOI] [PubMed] [Google Scholar]
  34. Zhang J., Fujimoto N., Iwata K., Sakai T., Okada Y., Hayakawa T. A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 1 (interstitial collagenase) using monoclonal antibodies. Clin Chim Acta. 1993 Oct 15;219(1-2):1–14. doi: 10.1016/0009-8981(93)90192-7. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES