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Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease.

ABSTRACT: Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/absence of fibrosis/cirrhosis and confirmed in the sub-group of patients phenotyped by elastography only. Logistic and uni- and multivariate regression analyses were used to test for association of markers with liver fibrosis stages and for independent prediction of liver histology and stiffness. Marker concentrations correlated significantly (P<0.001) with histology and stiffness. Cut-offs for liver fibrosis (?F2) were PLGF = 20.20 pg/ml, GDF15 = 1582.76 pg/ml and HGF = 2598.00 pg/ml. Logistic regression confirmed an increase of ORs from 3.6 over 33.0 to 108.4 with incremental (1-3) markers positive for increased liver stiffness (?12.8kPa; all P<0.05). Subgroup analysis revealed associations with advanced fibrosis for HCV (three markers positive: OR = 59.9, CI 23.4-153.4, P<0.001) and non-HCV patients (three markers positive: OR = 144, CI 59-3383, P<0.001). Overall, serum markers identified additional 50% of patients at risk for advanced fibrosis presenting with low elastography results. In conclusion, this novel combination of markers reflects the presence of significant liver fibrosis detected by elastography and histology and may also identify patients at risk presenting with low elastography values.

SUBMITTER: Krawczyk M

PROVIDER: S-EPMC5354278 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease.

Krawczyk Marcin M Zimmermann Simone S Hess Georg G Holz Robert R Dauer Marc M Raedle Jochen J Lammert Frank F Grünhage Frank F

PloS one 20170316 3

Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/abs ...[more]

PMID: 28301573

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Project description:BackgroundThe accurate assessment of liver fibrosis is essential for patients with chronic liver disease. A liver biopsy is an invasive procedure that has many potential defects and complications. Therefore, noninvasive assessment techniques are of considerable value for clinical diagnosis. Liver and spleen magnetic resonance elastography (MRE) and serum markers have been proposed for quantitative and noninvasive assessment of liver fibrosis. This study aims to compare the diagnostic performance of liver and spleen stiffness measured by MRE, fibrosis index based on the 4 factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and their combined models for staging hepatic fibrosis.MethodsOne hundred and twenty patients with chronic liver disease underwent MRE scans. Liver and spleen stiffness were measured by the MRE stiffness maps. Serum markers were collected to calculate FIB-4 and APRI. Liver biopsies were used to identify pathologic grading. Spearman’s rank correlation analysis evaluated the correlation between the parameters and fibrosis stages. Receiver operating characteristic (ROC) analysis evaluated the performance of the four individual parameters, a liver and spleen stiffness combined model, and an all-parameters combined model in assessing liver fibrosis.ResultsLiver stiffness, spleen stiffness, FIB-4, and APRI were all correlated with fibrosis stage (r=0.87, 0.64, 0.65, and 0.51, respectively, all P<0.001). Among the 4 individual diagnostic markers, liver stiffness showed the highest values in staging F1–4, F2–4, F3–4 and F4 (AUC =0.89, 0. 97, 0.95, and 0.95, all P<0.001). The AUCs of the liver and spleen stiffness combined model in the F1–4, F2–4, F3–4, and F4 staging groups were 0.89, 0.97, 0.95, and 0.96, respectively (all P<0.001). The corresponding AUCs of the all-parameters combined model were 0.90, 0.97, 0.95, and 0.96 (all P<0.001). The AUCs of the liver and spleen stiffness combined model were significantly higher than those of APRI, FIB-4 in the F2–4, F3–4, and F4 staging groups (all P<0.05). Both combined models were not significantly different from liver stiffness in staging liver fibrosis (all P>0.05).ConclusionsLiver stiffness measured with MRE had better diagnostic performance than spleen stiffness, APRI, and FIB-4 for fibrosis staging. The combined models did not significantly improve the diagnostic value compared with liver stiffness in staging fibrosis.

Project description:OBJECTIVES:The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC). METHODS:462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ?2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child-Turcotte-Pugh) score to ?7. RESULTS:Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663). CONCLUSION:Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Project description:The severity of fatty liver at ultrasound has been associated with QT length, a finding invoked to explain the excess cardiovascular risk of patients with fatty liver. However, the ability of ultrasound to stage accurately the severity of fatty liver is limited, with fibrosis a major confounder. Here, we aimed to verify the alleged relationship between fat liver content and QT length using a technique apt at discriminating steatosis from fibrosis noninvasively, i.e., transient elastography (TE) with measure of liver stiffness (LS) and controlled attenuation parameter (CAP). A prospectively collected derivation cohort of 349 patients with chronic liver disease (CLD) of any etiology (N = 105 with nonalcoholic fatty liver) was studied to identify clinical, laboratory, and instrumental predictors of the corrected QT interval (QTc) and QTc prolongation, including LS and CAP. The results were validated on a subgroup of patients belonging to the derivation cohort (out of sample validation), as well as on a completely different group of N = 149 subjects with CLD (out of time validation). QTc values were directly related to liver stiffness (LS; ρ = 0.137; p = 0.011), heart rate (HR; ρ = 0.307; p < 0.001), and age (ρ = 0.265; p < 0.001) and were significantly longer in females (p < 0.001). In contrast, QTc was not associated with the value of controlled attenuation parameter (ρ = 0.019; p = 0.718); moreover, no discernible differences in QTc length were noted based on CLD etiology. QTc was prolonged in 24/349 patients (6.9%); age, HR, and LS were independent predictors of QTc prolongation (χ 2 = 23.7, p < 0.001). Furthermore, QTc values (after logarithmic transformation) were predicted by a model including age, gender, HR, and LS (F = 14.1, R 2 = 0.198, p < 0.001). These latter results were validated by both out-of-sample and out-of-time methods. In conclusion, TE findings strongly suggest that among patients with CLD, fibrosis, not steatosis, is a major determinant of QTc length.

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Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease.

Publications

Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease.

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