A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease

Abstract

AIM:To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease. METHODS:Using a cDNA microarray containing over 22 000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azanstained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis. RESULTS:We identified 39 genes that collectively showed a good correlation (r > 0.50) between geneexpression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis, we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r = 0.76, 2.2% vs 2.8%, P < 0.0001) and 12 independent additional test samples (r = 0.75, 9.8% vs 8.6%, P < 0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r = -0.53), type Ⅳ collagen 7s (r = 0.48), hyaluronic acid (r = 0.41), and aspartate aminotransferase to platelets ratio index (APRI) (r = 0.38). CONCLUSION:Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

A subset of metzincins and related genes constitutes a marker of human solid organ fibrosis

“…In our own analysis of the liver microarray data, we observed similar trends of gene expression changes as the Utsunomiya group and confirm the importance of inflammatory genes in that dataset (not shown). We found that most MARGS were in fact underrepresented in the fibrosis group (not shown), while proinflammatory genes were largely overrepresented and correlated with the adjusted MFI fibrosis grade, as published [9]. Recently, the group of Takahara has shown in gene expression studies of fibrosis in HCV patients that ECM modulatory genes in general positively correlate with the METAVIR F-score 1 through 4, and some genes had peak expression changes in fibrosis score 2 and 3 [28].…”

“…Gene expression datasets for heart and lung were downloaded from Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo, Heart: GSE5406 [7], Lung: GSE10667 [1]. Liver and pancreas data were provided by the authors [9,10].…”

“…Fibrotic and non-fibrotic tissue specimens from a total of 50 patients were utilized (Table 2). Great care was taken to select the cases with best match to the histological diagnosis of cases used for microarray data analyses [6][7][8][9][10]. All patients remained anonymized except for age and gender, and all studies were approved by the local ethics commission.…”

“…Samples for the liver analysis were selected from the healthy control group and from those patients with an adjusted morphologic fibrosis index (MFI) score ≥10 (average F-score for this group is 3.4). The adjusted MFI is the mean MFI determined from nine section images, adjusted by a factor of 1.13, which corrects for a mean MFI of 1.13 in samples of healthy control patients [9]. The majority of the fibrosis samples originated from patients with hepatocellular carcinoma, most of which were positive for hepatitis C virus (HCV) antibody.…”

Molecular signatures of noncancerous liver tissue can predict the risk for late recurrence of hepatocellular carcinoma

“…The molecular characteristics of hepatic fibrosis have been examined during the progression [26], and a number of differentially expressed genes, such as Tmsb10, emp1, Cd24, and Lgals3, possibly associated with hepatocarcinogenesis were identified [27,28]. Therefore, it is plausible to expect that a specific molecular signature in the noncancerous liver tissue specimens might predict a risk of multicentric occurrence of HCC or late recurrence after surgery [20].…”