Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

Plasma MMP2/TIMP4 Ratio at Follow-up Assessment Predicts Disease Progression of Idiopathic Pulmonary Arterial Hypertension.

PURPOSE: Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are of particular interest in the remodeling processes of pulmonary hypertension. The aim of this study was to investigate MMP/TIMP ratios of selected biomarkers (MMP2, MMP9, TIMP1, TIMP4) at follow-up examination (V2) and their prognostic value in patients with idiopathic pulmonary arterial hypertension (iPAH). METHODS: Blood samples were taken from iPAH patients during right heart catheterization at diagnosis (V1, from 2003 to 2012) and first follow-up examination (V2). MMP2, MMP9, TIMP1, and TIMP4 plasma levels at V2 were determined by ELISA. Coincident with sample collection hemodynamic, laboratory, and clinical parameters were acquired. Additionally, death and clinical worsening (CW) events were listed until July 2015. RESULTS: MMP2/TIMP1 and MMP9/TIMP1 did not correlate with hemodynamic and clinical parameters. MMP2/TIMP4 showed a good correlation with mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance, estimated glomerular filtration rate (eGFR), and tricuspid annular plain systolic excursion (TAPSE). MMP9/TIMP4 shows good correlation with mPAP and eGFR. MMP2/TIMP4 showed significant results in the receiver operating characteristics analysis predicting death (AUC = 0.922; p = 0.005) and CW event (AUC = 0.818; p = 0.026). Patients above the cut-off values had a significantly higher probability to die or experience CW, respectively, estimated by log-rank test (p = 0.010 for death; p = 0.032 for CW). CONCLUSIONS: MMP2/TIMP4 ratio was detected as a marker of disease severity and right ventricular function as well as a predictor for survival and time to clinical worsening and therefore might help for guidance of disease progression in iPAH patients at V2.

Dynamic assessment of myocardial involvement in patients with end-stage renal disease by ultrasonic tissue characterization and serum markers of collagen metabolism.

BACKGROUND: Congestive heart failure is the most common cause of mortality in patients with end-stage renal disease (ESRD). However, noninvasive assessment for cardiac involvement in ESRD has not been established. HYPOTHESIS: Assessment of ultrasonic tissue characterization and serum markers of collagen degradation is useful for defining myocardial involvement in ESRD. METHODS: Cyclic variation of ultrasonic integrated backscatter of the ventricular septum (CV-IBS) and the serum levels of free matrix metalloproteinase-I (MMP-I) and tissue inhibitor of metalloproteinase-I (TIMP-I) were measured in 30 patients with ESRD undergoing routine hemodialysis (HD) and in 40 patients with essential hypertension (HTN). RESULTS: Compared with the group with HTN, ESRD (before HD) showed larger left ventricular (LV) mass index (217 +/- 56 vs. 146 +/- 45 g/m2, p < 0.01), worse LV diastolic function (E/A, 0.6 +/- 0.2 vs. 0.9 +/- 0.3, p < 0.05), smaller CV-IBS (9.0 +/- 1.3 vs. 12.4 +/- 0.9 dB, p < 0.01), and larger TIMP-I/MMP-I (46 +/- 10 vs. 34 +/- 10, p < 0.05), in spite of the comparable ventricular wall thickness. Thus, these indices may possibly reflect myocardial interstitial fibrosis. After HD (after the improvement of myocardial interstitial edema), a negative linear relationship between CV-IBS and TIMP-I/MMP-I was observed (r= -0.52, p < 0.05). CONCLUSIONS: Noninvasive assessment of ultrasonic tissue characterization and serum markers of collagen type I degradation may be a new diagnostic tool for defining myocardial interstitial fibrosis in patients with ESRD and LV hypertrophy.