Histological Degree Of Fibrosis Research Articles

T regulatory cells and TGF-β1: Predictors of the host response in mesh complications

Polypropylene mesh is frequently used in urogynecology procedures; however, pain and mesh exposure into the vagina occur in ~10% of cases. Mesh-induced pain, which occurs with or without exposure, persists after removal in 50% of cases. Chronic pain history predicts poor response to mesh removal but only a fraction have this diagnosis. We hypothesize that mesh induced pain is correlated with fibrosis and failure to improve with a heightened inflammatory and fibrotic host response. Women undergoing mesh removal were offered participation in a mesh biorepository. Standardized questionnaires including visual analog scale (VAS) pelvic pain scores were completed at enrollment and 6 months after removal. Responders were considered those with ≥13 mm VAS improvement. 30 mesh-tissue explants were randomly selected for analysis. Samples were labeled for CD8, CD4 (Th) and FoxP3 (Tregs). Peri-fiber collagen deposition (fibrosis) was measured using a customized semi-quantitative assay. Concentrations of TGF-b1, bFGF, MCP-1, PDGF-BB, and IGFBP-1 in tissue were determined by immunoassay and compared to vaginal control biopsies with pathway analysis. VAS pain scores were correlated with degree of histologic fibrosis. Responders had more Tregs (7.8 vs 0.3 per mm2, p = 0.036) and patients were 1.6 times as likely to be a responder for every additional Treg/mm2 (p = 0.05). Pro-fibrotic TGF-β1 was doubled in nonresponders (p = 0.032). On pathway analysis, decreased bFGF and increased PDGF-BB provide a possible mechanism for upregulation of TGF-β1. In conclusion, fibrosis is a plausible mechanism of pain complications and the adaptive immune response likely contributes to mitigation/prevention of complications and recovery in affected patients. Statement of SignificancePolypropylene mesh improves anatomical outcomes in urogynecologic procedures, but is associated with complications, including pain and exposure through the vaginal epithelium. Mesh-induced pain is difficult to treat, and it is unclear why only half of women experience pain improvement after mesh removal. In this study, patient pain correlated with the presence of fibrosis and women with more T regulatory cells and lower TGF-β1 were more likely to have pain improvement following mesh removal. These findings implicate fibrosis as a mechanism of pain complications and suggest that the adaptive immune response may be responsible for prevention of complication and recovery. This improved understanding of how mesh can lead to pain moves us closer to the ultimate goal of preventing mesh complications.

Expression of Collagen (Types I, III, and V), HSP47, MMP-2, and TIMP-1 in Retrobulbar Adipose Tissue of Patients with Thyroid-Associated Orbitopathy.

Objective This study aimed to investigate the expression of collagen (types I, III, and V), heat shock protein 47 (HSP47), matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase-1 (TIMP-1) in the retrobulbar adipose tissues of patients with thyroid-associated orbitopathy (TAO). Materials and Methods The retrobulbar adipose tissues were collected from 4 TAO patients undergoing orbital decompression and 4 ocular enucleation patients with atrophic eyeball caused by ocular trauma between May 2019 and September 2019. Masson staining was performed to analyze the differences in collagen expression and degree of histologic fibrosis in each sample. The protein expressions of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 were determined by western blotting. The data of western blotting were analyzed using SPSS version 17.0, with independent t-tests. Results The results of Masson staining showed that the expression of collagen fibers in the TAO group was significantly higher than that in the control group, and the fibers were diffuse and irregular in distribution. The expression level of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 in the TAO group were significantly higher than that in the control group (P < 0.05). Conclusion The proliferation and fibrosis of retrobulbar adipose tissue in TAO patients might be related to the increased expression of collagen (types I, III, and V) and HSP47 and decreased degradation of extracellular matrix.

Preoperative exposure to anti-tumor necrosis factor therapy in ulcerative colitis patients undergoing ileal pouch-anal anastomosis (IPAA) is not associated with histological fibrosis: A case control study

BackgroundWe sought to determine whether preoperative exposure to anti-TNF therapy affects objective histological measures of fibrosis in the colorectum. MethodsUlcerative colitis (UC) patients who received infliximab as maintenance therapy pre IPAA surgery were identified and compared to anti-TNF-naïve matched controls by age, sex, BMI, disease duration, albumin levels, and post-operative leak outcome. Hematoxylin and eosin- (H&E) and trichrome-stained slides from the most distal, well-oriented, full-thickness section of colorectum from each patient's total colectomy specimen were evaluated. Blinded histopathological assessment of the degree of fibrosis was performed using a semi-quantitative pictorial scale. ResultsHistological fibrosis in 65 patients from the therapy group was compared to 65 patients from the matched control group. There were no statistically significant differences in the degree of fibrosis observed in any of the bowel layers. In the lamina propria, 29% of the control group and 28% of the treatment group had fibrosis scores ≥3. Fibrosis scores were higher in the submucosa, with both groups having 66% of patients showing scores ≥3. Similarly, in the region above the muscularis propria, 77% of the control group and 80% of the treatment group had fibrosis scores ≥3. In the subserosa, fibrosis scores were lower, with 25% of the control group and 32% of the treatment group having fibrosis scores ≥3. ConclusionResection specimens from UC patients treated with maintenance anti-TNF therapy who underwent IPAA surgery showed no significant differences in the degree of histologic fibrosis in any of the bowel layers compared to a matched control group.

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AimsAction potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo.Methods and resultsWe developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans.ConclusionCombined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Liver and systemic hemodynamics in children with cirrhosis: Impact on the surgical management in pediatric living donor liver transplantation.

Cirrhosis in adults is associated with modifications of systemic and liver hemodynamics, whereas little is known about the pediatric population. The aim of this work was to investigate whether alterations of hepatic and systemic hemodynamics were correlated with cirrhosis severity in children. The impact of hemodynamic findings on surgical management in pediatric living donor liver transplantation (LT) was evaluated. Liver and systemic hemodynamics were studied prospectively in 52 children (median age, 1 year; 33 with biliary atresia [BA]). The hemodynamics of native liver were studied preoperatively by Doppler ultrasound and intraoperatively using invasive flowmetry. Portosystemic gradient was invasively measured. Systemic hemodynamics were studied preoperatively by Doppler transthoracic echocardiography and intraoperatively by using transpulmonary thermodilution. Hemodynamic parameters were correlated with Pediatric End-Stage Liver Disease (PELD) score and the histological degree of fibrosis (collagen proportionate area [CPA]). Cirrhosis was associated with a 60% reduction of pretransplant total liver flow (n = 46; median, 36 mL/minute/100 g of liver) compared with noncirrhotic livers (n = 6; median, 86 mL/minute/100 g; P = 0.002). Total blood flow into the native liver was negatively correlated with PELD (P < 0.001) and liver CPA (P = 0.005). Median portosystemic gradient was 14.5 mm Hg in children with cirrhosis and positively correlated with PELD (P < 0.001). Portal vein (PV) hypoplasia was observed mainly in children with BA (P = 0.02). Systemic hemodynamics were not altered in our children with cirrhosis. Twenty-one children met the intraoperative criteria for PV reconstruction using a portoplasty technique during the LT procedure and had a smaller PV diameter at pretransplant Doppler ultrasound (median = 3.4 mm; P < 0.001). Cirrhosis in children appears also as a hemodynamic disease of the liver, correlated with cirrhosis severity. Surgical technique for PV reconstruction during LT was adapted accordingly. Liver Transplantation 23 1440-1450 2017 AASLD.

Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients

BackgroundAdverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx.MethodsEmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach.ResultsTwenty patients (9.9 ± 6.2 years of age; 9 girls) after HTx were prospectively enrolled, at a median of 1.3 years (0.02–12.6 years) post HTx, and compared to 24 controls (13.9 ± 2.6 years of age; 12 girls). The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls (1008 ± 32 ms vs 979 ± 24 ms, p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1 (r = 0.53, p < 0.05) as well as ECV (r = 0.46, p < 0.05). Native T1 time, but not ECV and CVF, correlated with ischemia time (r = 0.46, p < 0.05).ConclusionsCMR-derived fibrosis markers correlate with histological degree of fibrosis on EmBx in children after HTx. Further, native T1 times are associated with longer ischemia times.

Analysis of effect of antiviral therapy on regression of liver fibrosis in patient with HCV infection.

Background:HCV infection is characterized by a tendency towards chronicity. Acute HCV infection progresses to chronic infection in 70% of cases. Hepatitis C virus infection can cause progressive liver injury and lead to fibrosis and eventually cirrhosis. The degree of histologic fibrosis is an important marker of the stage of the disease. One of current standard treatment for CHC infection is the combination of PEG-IFN α and ribavirin.Objectives:The aim of the study was to investigate the effect of the therapy with Peginterferon alfa-2a or alfa-2b plus Ribavirin on evolution of liver fibrosis in patients with chronic hepatitis C. Also, our aim was to examine whether there was a difference between the genders in the efficacy of these antiviral therapy. Our goal also was to determine effect of the therapy with Peginterferon alfa-2a or alfa-2b plus Ribavirin on evolution of liver steatosis in patients with chronic hepatitis C.Patients and Methods:A retrospective study was made of chronic hepatitis C patients who had been treated from 2005 to April 2014 at the Clinic of Gastroenterohepatology, Clinical Center University of Sarajevo. We reviewed 40 patient medical records to collect demographic, epidemiological and clinical information, as information on liver biopsies that was performed prior to the antiviral therapy and FibroScan® test that was performed after the antiviral therapy. For the processing of data SPSS (Statistical Package for the Social Sciences Program) for Windows, ver. 21.0 statistical software was used. Comparisons between qualitative and quantitative variables were performed using the Student t-test. Mann Whitney U test was used to compare differences in variables such as fibrosis stage and steatosis grade. A value of p<0.05 was considered as statistically significant.Results:After treatment, there was a statistically significant increase in the number of patients with no fibrosis (p<0.05). There was no statistically significant reduction in the number of patients with cirrhosis (F4) (p>0.05). There was significantly higher decrease of fibrosis progression at the patients that were in an mild-to-moderate fibrosis (F1/F2/F3), patients that were in advanced stage of fibrosis (F4) at the time of the pre-treatment did not have a statistically significant fibrosis reduction. We found significant association in evolution of fibrosis after treatment with PEG-IFN α2a (40) kD and PEG-IFNα2a (12,5) kD with ribavirin (p< 0.05). We also found significant association in evolution of steatosis after treatment with PEG-IFN α2a (40) kD and PEG-IFNα2a (12,5) kD with ribavirin (p < 0.05). There was statistically significant differences (p<0.05) between genders within fibrosis qualitative evolution.Conclusions:There were significant regression of fibrosis especially at the patients that were in an mild-to-moderate fibrosis (F1/F2/F3), patients that were in advanced stage of fibrosis (F4) at the time of the pre-treatment did not have a statistically significant fibrosis reduction after treatment with PEG-IFN α2a (40) kD and PEG-IFNα2b (12,5) kD with ribavirin. Our results showed significant improvement in steatosis in patients infected with HCV after treatment with PEG-IFN α2a (40) kD and PEG-IFNα2b (12,5) kD with ribavirin. Those results provides further evidence for direct involvement of HCV and antiviral therapy in the pathogenesis of hepatic steatosis. Female gender showed a higher degree of fibrosis reduction.

MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis

Micro (mi)RNAs are frequently dysregulated in the development of renal fibrosis. Exosomes are small membrane vesicles that could be isolated from urine secreted from all nephron segments. Here we sought to observe for the first time whether miRNA in urine exosome could serve as a potential biomarker of renal fibrosis. Urine samples were collected from 32 chronic kidney disease (CKD) patients who underwent kidney biopsy and 7 controls. Exosome was isolated and confirmed by immunogold staining of exosome marker. Members of miR-29, miR-200, and RNU6B as endogenous control were detected by RT quantitative PCR. Electronic microscopy verified a typical shape of exosome with average size of 65.1 nm and labeled it with anti-CD9 and anti-aquaporin 2 antibody. Members of miR-29 and miR-200 are readily measured with reduced levels compared with controls (P < 0.05) and can robustly distinguish CKD from controls [area under the curve (AUC) varied from 0.902 to 1 by receiver operating characteristics analysis]. miR-29c correlated with both estimated glomerular filtration rate (r = 0.362; P < 0.05) and degree of tubulointerstitial fibrosis (r = -0.359; P < 0.05) for CKD patients. Moreover, miRNA in exosome was decreased in mild fibrosis group compared with moderated to severe group. miR-29a and miR-29c could predict degree of tubulointerstitial fibrosis with AUC of 0.883 and 0.738 (P < 0.05). The sensitivity and specificity for distinguishing mild from moderate to severe fibrosis were 93.8 and 81.3% with the use of miR-29a and 68.8 and 81.3% for miR-29c. Overall, miR-29c in urinary exosome correlates with both renal function and degree of histological fibrosis, suggesting it as a novel, noninvasive marker for renal fibrosis.

The use of transient elastography and non‐invasive serum markers of fibrosis in pediatric liver transplant recipients

The use of non-invasive markers to diagnose liver allograft fibrosis is not well established in children after LTx. TE, FT, and ELF score were performed in 117 liver-transplanted children (60M, 8.9 [0.5-18.5]yr) and 336 healthy controls. Liver biopsy was available in 36 children. Results of histology and non-invasive markers were compared using correlation coefficient or Mann-Whitney U-test as appropriate. TE correlated best with histological degree of fibrosis (r=0.85 vs. r=0.04 [FT] or r=-0.38 [ELF]). Liver stiffness values for transplanted children without fibrosis were significantly higher than those of healthy controls (7.55 [5.4-20.4]kPa vs. 4.5 [2.5-8.9]kPa). Presence of rejection was a potent confounder for the performance of TE. Both TE and FT reflected clinical changes (acute rejection, cholestasis, increasing fibrosis) in a total of 16 patients who underwent serial measurements. TE correlates better with histological degree of fibrosis in liver-transplanted children than FT or ELF, but an individual baseline value needs to be determined for each patient. Normal or cutoff values for pathological degrees of fibrosis cannot be transferred from non-transplanted children. Follow-up studies, preferably with protocol biopsies, might help to improve the diagnostic quality of TE.

Magnetic Resonance Elastography Noninvasively Detects In Vivo Renal Medullary Fibrosis Secondary to Swine Renal Artery Stenosis

Magnetic resonance elastography (MRE) can noninvasively sample tissue stiffness in vivo. Renal fibrosis secondary to renal artery stenosis (RAS), which is aggravated in atherosclerotic RAS (ARAS), may increase its stiffness. An increase in cortical stiffness in vivo can be masked by intrinsic hemodynamic determinants, whereas renal medullary stiffness is less dependent on renal hemodynamics. Therefore, this study tested the hypothesis that MRE-determined medullary stiffness would correspond to the histological degree of medullary fibrosis in stenotic kidneys in RAS and detect its exacerbation in ARAS. Seventeen pigs were studied 10 weeks after induction of unilateral RAS (n = 6), ARAS (n = 5), or sham (n = 6). Stiffness of the cortex and the medulla was determined through 3-dimensional MRE, and renal perfusion and function were determined using multidetector computed tomography. Kidney fibrosis was subsequently assessed ex vivo using the Masson trichrome staining. Renal stenotic cortex and medulla were significantly more fibrotic in RAS and ARAS compared with healthy kidney. However, MRE detected increased stiffness in RAS compared with the healthy kidney (12.7 ± 0.41 kPa vs 10.7 ± 0.18 kPa; P = 0.004) only in the medulla, which was further increased in ARAS (16.6 ± 1.3 kPa; P = 0.017 vs RAS). Magnetic resonance elastography-derived medullary, but not cortical, stiffness significantly correlated with histological degree of fibrosis, although cortical and medullary fibroses were correlated. Renal blood flow and function were similarly decreased in RAS and ARAS compared with the healthy kidney. Noninvasive 3-dimensional MRE detects increased renal medullary stiffness in RAS and ARAS in vivo, which correlates with its fibrosis ex vivo and may also reflect cortical fibrosis. Hence, MRE-derived medullary stiffness can be potentially useful in detecting renal fibrosis and track disease progression.

Endoscopic Ultrasound, Secretin Endoscopic Pancreatic Function Test, and Histology: Correlation in Chronic Pancreatitis

Endoscopic ultrasound (EUS) and hormone-stimulated pancreatic function tests are considered useful, and possibly complementary, in the diagnosis of early chronic pancreatitis (CP). Few past studies have compared either methods with a histological gold standard. The aims were to assess correlations of EUS score and endoscopic pancreatic function test (ePFT) results with the degree of histological fibrosis, as well as the sensitivity of each method for detecting fibrosis. This was a retrospective study of patients who underwent EUS, ePFT, or both within 12 months of pancreatic resection or wedge biopsy. EUS scoring was performed using 9 standard criteria, with ≥4 considered abnormal. An ePFT peak bicarbonate concentration <80 mM was considered abnormal. Surgical specimens were reviewed in a blinded manner by an expert pancreatic pathologist and assigned a fibrosis score from 0 to 12. Correlations of the EUS score and ePFT peak bicarbonate with the fibrosis score are reported using the Spearman correlation coefficient. Sensitivity and specificity was calculated for each method against the histological gold standard (fibrosis score ≥2). Twenty-five patients were included. The fibrosis score significantly correlated with the EUS score (r=0.72; 95% confidence interval (CI)=0.43, 0.87; P<0.001) and the ePFT peak bicarbonate (r=-0.57; 95% CI=-0.81, -0.10; P=0.016). EUS had a sensitivity of 84% (95% CI=69, 100) and specificity of 100% (95% CI=40, 100) compared with histology. The ePFT had a sensitivity of 86% (95% CI=67, 100) and specificity of 67% (95% CI=13, 100). When both modalities were combined, the sensitivity increased to 100% (95% CI=63, 100). Both EUS and ePFT are useful tests in the diagnosis of CP. Combining EUS with ePFT may improve the sensitivity for detection of early fibrosis.

Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus

Liver biopsy has been considered to be a gold standard for assessing hepatic fibrosis. Sample variability, interobserver variability and step-wise evaluation limit its use. Hepatic venous pressure gradient (HVPG) correlates with hepatic fibrosis in chronic liver disease (CLD) because of hepatitis C. To evaluate the utility of HVPG for assessing hepatic fibrosis in patients with hepatitis B virus (HBV)-related CLD. Sixty-one patients with HBV-related CLD who underwent both liver biopsy and hepatic haemodynamic studies were studied. Forty-nine (80.3%) patients had clinically significant portal hypertension (PHT) (HVPG>or=10 mmHg), 39 (63.9%) severe PHT (i.e. HVPG>or=12 mmHg), six (9.8%) HVPG<or=5 mmHg and another six (9.8%) had preclinical PHT (i.e. HVPG>5 but <10 mmHg). A positive correlation between HVPG and fibrosis score was found (r=0.436, P<0.001). In patients with HVPG<10 or <12 mmHg there was a significant correlation with fibrosis score (r=0.603, P=0.029 and r=0.887, P<0.001 respectively). A positive correlation also existed in patients with HVPG>or=10 mmHg and in patients with HVPG>or=12 mmHg (r=0.512, P<or=0.001 and r=0.543, P<0.001 respectively). Receiver operating characteristic curve of HVPG for the prediction of advanced fibrosis (stage>or=3) had an area under curve of 0.906. HVPG value above 13.0 mmHg had a sensitivity of 79% and a specificity of 89% for predicting advanced fibrosis on histology. HVPG correlates well with the degree of histological fibrosis in patients with HBV-related CLD.

Influence of iron on the severity of hepatic fibrosis in patients with chronic hepatitis C

To evaluate the association among hepatic fibrosis, serum iron indices, and hepatic iron stores in patients with Chronic Hepatitis C (CHC). Thirty-two CHC patients were included in our study. The histological degree of fibrosis and inflammation activity was assessed according to the Metavir system. The serum iron indices including ferritin, iron and transferrin saturation were measured. Hepatic iron deposition was graded by Perls' stain. The CHC patients with severe hepatic fibrosis (n = 16) were significantly older than CHC patients with mild fibrosis (n = 16) (P = 0.024). The serum iron indices, increased serum iron store and positive hepatic iron stain were not significantly different between the two groups. In multivariate logistic regression analysis, the age at biopsy was an independent predictor of severe hepatic fibrosis (Odds ratio = 1.312; P = 0.035). The positive hepatic iron stain was significantly associated with the values of alanine aminotransferase (ALT) (P = 0.017), ferritin (P = 0.008), serum iron (P = 0.019) and transferrin saturation (P = 0.003). The ferritin level showed significant correlation with the value of ALT (r = 0.531; P = 0.003), iron (r = 0.467; P = 0.011) and transferrin saturation (r = 0.556; P = 0.002). Our findings suggest that the severity of hepatitis C virus (HCV)-related liver injury is associated with patient age at biopsy. Both serum iron indices and hepatic iron deposition show correlation with serum indices of chronic liver disease but are not related to grade and stage of liver histology.

Evidence for altered hepatic matrix degradation in genetic haemochromatosis

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 r =0.42, p r =0.42, p 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.