Diagnostic value of platelet derived growth factor-BB, transforming growth factor-beta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis.
OBJECTIVE
Noninvasive diagnosis of hepatic fibrosis has become the focus because of the limited biopsy, especially in the surveillance of treatment and in screening hepatic fibrosis. Recently, regulatory elements involved in liver fibrosis, such as platelet derived growth factor-BB (PDGF-BB), transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), have been studied extensively. To determine whether these factors or enzymes could be used as the indices for the diagnosis of hepatic fibrosis, we investigated them by means of receiver operating characteristic (ROC) curve.


METHODS
Serum samples from sixty patients with chronic viral hepatitis B and twenty healthy blood donors were assayed to determine the level of PDGF-BB, TGF-beta1, MMP-1, and TIMP-1 with ELISA, and HA, PCIII, C-IV, and LN level with RIA. The message RNA (mRNA) expression of TIMP-1 and MMP-1 in peripheral blood mononuclear cells (PBMCs) was detected by RT-PCR and Northern blot hybridization. Liver biopsy was performed in all patients. The biopsy samples were histopathologically examined. The trial was double-blind controlled.


RESULTS
The serum level of PDGF-BB, TIMP-1, the ratio of TIMP-1 and MMP-1 (TIMP-1/MMP-1), mRNA expression of TIMP-1 (TIMP-1mRNA), and the ratio of TIMP-1mRNA and MMP-1mRNA (TIMP-1mRNA/MMP-1mRNA) in patients was significantly higher than those in the healthy blood donors (t=2.514-11.435, P=0.000-0.016). The serum level of PDGF-BB, TIMP-1, TIMP-1/MMP-1, and TIMP-1mRNA was positively correlated with fibrosis stage and inflammation grade (r=0.239-0.565, P=0.000-0.033), while the serum level of MMP-1 was negatively correlated with fibrosis stage and inflammation grade, and TIMP-1mRNA/MMP-1mRNA was positively correlated with inflammation grade. Through the analysis by ROC curve, serum PDGF-BB was the most valuable marker, and its sensitivity was the highest among the nine indices. The markers with the highest specificity were TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA in PBMCs. The area under the curve (AUC) of PDGF-BB, TIMP-1mRNA, TIMP-1mRNA/MMP-1mRNA, TIMP-1/MMP-1, HA, PCIII, TIMP-1, C-IV, and LN was 0.985, 0.876, 0.792, 0.748, 0.728, 0.727, 0.726, 0.583, and 0.463, respectively. The sensitivity and the specificity in the parallel test was 99.0% and 95.0% when serum PDGF-BB, TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA was detected simultaneously.


CONCLUSIONS
Serum level of PDGF-BB, TIMP-1mRNA, TIMP-1mRNA/MMP-1mRNA in PBMCs, and serum level of TIMP-1 and TIMP-1/MMP-1 can be used as the indices for the diagnosis of hepatic fibrosis, but the former three are more useful. The combination of serum PDGF-BB, TIMP-1mRNA and TIMP-1mRNA/MMP-1mRNA in PBMCs is even more efficient in screening liver fibrosis.
Zhang
Bin-Bin
BB
Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China. zbb-2051@163.com
Cai
Wei-Min
WM
Weng
Hong-Lei
HL
Hu
Zhong-Rong
ZR
Lu
Jun
J
Zheng
Min
M
Liu
Rong-Hua
RH
D000077214:Becaplermin; D015415:Biomarkers; D019694:Hepatitis B, Chronic / Q000097:blood / Q000175:diagnosis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008103:Liver Cirrhosis / Q000097:blood* / Q000175:diagnosis* / Q000821:virology; D020781:Matrix Metalloproteinase 1 / Q000097:blood* / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000097:blood* / Q000235:genetics; D053773:Transforming Growth Factor beta1
D015415:Biomarkers; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077214:Becaplermin; D020781:Matrix Metalloproteinase 1