Clinical Research
Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 21, 2007; 13(3): 383-390
Published online Jan 21, 2007. doi: 10.3748/wjg.v13.i3.383
A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease
Tohru Utsunomiya, Masahiro Okamoto, Shigeki Wakiyama, Masaji Hashimoto, Kengo Fukuzawa, Takahiro Ezaki, Shinichi Aishima, Yasuji Yoshikawa, Taizo Hanai, Hiroshi Inoue, Graham F Barnard, Masaki Mori
Tohru Utsunomiya, Masahiro Okamoto, Hiroshi Inoue, Masaki Mori, Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Yasuji Yoshikawa, Department of Pathology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Shigeki Wakiyama, Department of Surgery, Iizuka Hospital, Iizuka, Japan
Masaji Hashimoto, Department of Digestive Surgery, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Kengo Fukuzawa, Department of Surgery, Oita Red Cross Hospital, Oita, Japan
Takahiro Ezaki, Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
Shinichi Aishima, Department of Anatomic pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Taizo Hanai, Laboratory for Bioinformatics, Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, Japan
Graham F Barnard, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, MA, United States
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Masaki Mori, Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Tsurumihara 4546, Beppu 874-0838, Japan. mmori@tsurumi.beppu.kyushu-u.ac.jp
Telephone: +81-977-271650 Fax: +81-977-271651
Received: August 5, 2006
Revised: August 30, 2006
Accepted: September 22, 2006
Published online: January 21, 2007
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 azan-stained: 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 gene-expression 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.

Keywords: Liver fibrosis, Hepatitis virus, DNA microarray, Supervised learning analysis, Scoring system