A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease.
OBJECTIVE
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 22000 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).


CONCLUSIONS
Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.
Utsunomiya
Tohru
T
Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Tsurumihara 4546, Beppu 874-0838, Japan.
Okamoto
Masahiro
M
Wakiyama
Shigeki
S
Hashimoto
Masaji
M
Fukuzawa
Kengo
K
Ezaki
Takahiro
T
Aishima
Shinichi
S
Yoshikawa
Yasuji
Y
Hanai
Taizo
T
Inoue
Hiroshi
H
Barnard
Graham-F
GF
Mori
Masaki
M
D015415:Biomarkers; D018450:Disease Progression; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D008111:Liver Function Tests; D012720:Severity of Illness Index
D015415:Biomarkers