Evidence for altered hepatic matrix degradation in genetic haemochromatosis

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.

Figure 1

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

Figure 2

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

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