Journal of Hepatology 1999; 31: 47–52 Copyright C European Association for the Study of the Liver 1999 Printed in Denmark ¡ All rights reserved Munksgaard ¡ Copenhagen Journal of Hepatology ISSN 0168-8278 Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis D. Keith George, Grant A. Ramm, Neal I. Walker 1 , Lawrie W. Powell and Darrell H. G. Crawford Hepatic Fibrosis Group, Joint Clinical Sciences Program, University of Queensland Department of Medicine and Queensland Institute of Medical Research, and the 1 Department of Pathology, Royal Brisbane Hospital, Brisbane, QLD, Australia Background/Aim: Hereditary haemochromatosis can now be diagnosed by genetic testing, although deter- mining the presence or absence of cirrhosis remains crucial to patient management. While many studies have investigated the utility of various serum markers of cirrhosis in chronic liver diseases, few have exam- ined specifically patients with hereditary haemo- chromatosis. The aim of this study was to assess the utility of serum type IV collagen and serum laminin in diagnosing hepatic fibrosis and cirrhosis in patients with hereditary haemochromatosis. Methods: The study group consisted of 42 patients with hereditary haemochromatosis and 19 Caucasian controls. Serum type IV collagen, laminin, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) concentrations were measured by enzyme-linked immunosorbant assay in serum from patients with haemochromatosis and con- trol subjects. Liver biopsies from patients with haemo- chromatosis were graded for fibrosis and correlated with serum markers of hepatic fibrosis. I  iron absorption in haemochromatosis re- sults in progressive hepatic iron deposition which, if untreated, leads to fibrosis, cirrhosis and consequent increased morbidity and mortality, including a 200- fold increased risk of developing hepatocellular carci- noma (1). It is critical, therefore, that cirrhosis be iden- tified in haemochromatosis patients and that such pa- tients should enter a surveillance programme for the Received 10 August; revised 21 December 1998; accepted 18 January 1999 Correspondence: Grant A. Ramm, The Hepatic Fibrosis Group, Clinical Sciences Unit, The Queensland Institute of Medical Research, The Bancroft Centre, 300 Herston Road, Brisbane, QLD, 4029, Australia. Tel: 61 7 3362 0177. Fax: 61 7 3362 0191. e-mail: grantR/qimr.edu.au 47 Results: Serum type IV collagen concentration was significantly increased in haemochromatosis patients compared to controls (130∫79 ng/ml vs 81∫17 ng/ml, p∞0.05) and was significantly correlated with both the grade of histological fibrosis (rΩ0.67, p∞0.0001) and serum MMP-2 levels (rΩ0.42, p∞0.05). A serum type IV collagen concentration ±115 ng/ml (meanπ2 SD of controls) was 100% sensitive and 69% specific in detecting severe (grade 3) fibrosis and cirrhosis. The sensitivity results of serum laminin and TIMP-1 were 11% and 56 %, respectively. Conclusions: Elevated serum type IV collagen is a sensitive indicator of the presence of severe fibrosis and cirrhosis in patients with haemochromatosis. Use- ful markers of hepatic fibrosis in other chronic liver diseases may not be applicable to haemochromatosis. Key words: Cirrhosis; Collagen type IV; Haemo- chromatosis; Laminin; Markers of hepatic fibrosis; Tissue inhibitor of metalloproteinase-1. early detection of hepatocellular carcinoma (2). Liver biopsy with a histological and biochemical assessment of the liver tissue has to date been the gold standard for the diagnosis of haemochromatosis and determin- ing the presence or absence of cirrhosis (2). Most cases of iron overload and virtually all HLA- linked haemochromatosis are now known to be caused by a single point mutation in the haemochromatosis gene (HFE) on chromosome 6p which codes for a pro- tein with a cysteine to tyrosine substitution at amino acid position 282 (C282Y) (3–7). This mutation can be easily detected in blood and the patients’ HFE geno- type can be accurately assigned. Identification of homozygosity for the C282Y mutation in cases of sus- pected haemochromatosis may lead to a reluctance to proceed to liver biopsy. However, HFE gene testing