S. Bertrais

Determination of reliability criteria for liver stiffness evaluation by transient elastography

Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% versus 81.5% well‐classified patients for the diagnosis of cirrhosis (P = 0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of ≥10 valid measurements or LSE success rate. These two reliability criteria determined three LSE groups: “very reliable” (IQR/M ≤0.10), “reliable” (0.10< IQR/M ≤0.30, or IQR/M >0.30 with LSE median <7.1 kPa), and “poorly reliable” (IQR/M >0.30 with LSE median ≥7.1 kPa). The rates of well‐classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (P < 10−3). According to these new reliability criteria, 9.1% of LSE were poorly reliable (versus 24.3% unreliable LSE with the usual definition, P < 10−3), 74.3% were reliable, and 16.6% were very reliable. Conclusion: The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: very reliable, reliable, and poorly reliable LSE. (HEPATOLOGY 2013)

Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis.

Background/aims As a module of a standard ultrasound imaging device, acoustic radiation force impulse (ARFI) is a new technology for liver stiffness evaluation (LSE). We aimed to evaluate accuracy, feasibility, reproducibility, and training effect of ARFI for liver fibrosis evaluation. Methods One hundred and one patients with chronic liver disease had LSE by Fibroscan and ARFI. LSE by ARFI was performed in the two liver lobes by two operators: an expert and a novice. Correlation and agreement were evaluated by the Pearson (Rp) and intraclass (Ric) correlation coefficients. The independent reference for liver fibrosis was fibrosis blood tests. Results ARFI results, ranging from 0.7 to 4.6 m/s, were well correlated with Fibroscan results (Rp=0.76). Fibroscan had a significantly higher area under the receiver operating characteristic curve (AUROC) than ARFI for the perprotocol diagnosis of significant fibrosis: 0.890±0.034 versus 0.795±0.047 (P=0.04). However, LSE failure occurred in zero patients using ARFI versus six patients using Fibroscan (P=0.03). Thus, on an intention-to-diagnose basis, Fibroscan and ARFI AUROCs for the diagnosis of significant fibrosis were not different: 0.791±0.049 versus 0.793±0.046 (P=0.98). Interobserver agreement was very good (Ric=0.84) and excellent for ARFI interquartile range (IQR)≤0.30 (Ric=0.91). Indeed, agreement was independently predicted only by ARFI IQR, but not by LSE result as earlier observed for Fibroscan. ARFI AUROC was 0.876±0.057 in patients with ARFI IQR ratio≤0.30, and Fibroscan AUROC was 0.912±0.034 in patients with Fibroscan IQR ratio less than 0.21 (P=0.59). Intersite ARFI agreement between the two liver lobes was fair (Ric=0.60). There was no training effect for LSE by ARFI. Conclusion ARFI is highly feasible and reproducible, and provides diagnostic accuracy similar to Fibroscan. This new device seems noteworthy for the widespread noninvasive diagnosis of liver fibrosis.

A new combination of blood test and fibroscan for accurate non-invasive diagnosis of liver fibrosis stages in chronic hepatitis C.

OBJECTIVES:Precise evaluation of the level of liver fibrosis is recommended in patients with chronic hepatitis C (CHC). Blood fibrosis tests and Fibroscan are now widely used for the non-invasive diagnosis of liver fibrosis. Detailed fibrosis stage classifications have been developed to provide an estimation of the liver fibrosis stage from the results of these non-invasive tests. Our aim was to develop a new and more accurate fibrosis stage classification by using new scores combining non-invasive fibrosis tests.METHODS:In all, 729 patients with CHC (exploratory set: 349; validation set: 380) had liver biopsy for Metavir fibrosis (F) staging, and 6 fibrosis tests: Fibroscan, Fibrotest, FibroMeter, Hepascore, FIB-4, APRI.RESULTS:Exploratory set: Fibroscan and FibroMeter were the independent predictors of different diagnostic targets of liver fibrosis. New fibrosis indexes combining FibroMeter and Fibroscan were thus developed for the diagnosis of clinically significant fibrosis (CSF-index) or severe fibrosis (SF-index). The association of CSF- and SF-indexes provided a new fibrosis stage classification (CSF/SF classification): F0/1, F1/2, F2±1, F2/3, F3±1, F4. Validation set: CSF/SF classification had a high diagnostic accuracy (85.8% well-classified patients), significantly higher than the diagnostic accuracies of FibroMeter (69.7%, P<0.001), Fibroscan (63.3%, P<0.001), or Fibrotest (43.9%, P<0.001) classifications.CONCLUSIONS:The association of new fibrosis indexes combining FibroMeter and Fibroscan provides a new fibrosis stage classification. This classification is significantly more accurate than Fibrotest, FibroMeter, or Fibroscan classifications, and improves the accuracy of the non-invasive diagnosis of liver fibrosis stages to 86% without any liver biopsy.

Evolution of noninvasive tests of liver fibrosis is associated with prognosis in patients with chronic hepatitis C

No data are available about the prediction of long‐term survival using repeated noninvasive tests of liver fibrosis in chronic hepatitis C (CHC). We aimed to assess the prognostic value of 3‐year liver stiffness measurement (LSM), aspartate aminotransferase to platelet ratio index (APRI), and fibrosis 4 (FIB‐4) evolution in CHC. CHC patients with two LSM (1,000‐1,500 days interval) were prospectively included. Blood fibrosis tests APRI and FIB‐4 were calculated the day of baseline (bLSM) and follow‐up (fLSM) LSM. Evolution of fibrosis tests was expressed as delta: (follow‐up‐baseline results)/duration. Date and cause of death were recorded during follow‐up that started the day of fLSM. In all, 1,025 patients were included. Median follow‐up after fLSM was 38.0 months (interquartile range [IQR]: 27.7‐46.1) during which 35 patients died (14 liver‐related death) and seven had liver transplantation. Prognostic accuracy (Harrell C‐index) of multivariate models including baseline and delta results was not significantly different between LSM and FIB‐4 (P ≥ 0.24), whereas FIB‐4 provided more accurate prognostic models than APRI (P = 0.03). By multivariate analysis including LSM variables, overall survival was independently predicted by bLSM, delta (dLSM), and sustained virological response (SVR). Prognosis was excellent in patients having bLSM <7 kPa, SVR, or no increase (<1 kPa/year) in 7‐14 kPa bLSM. Prognosis was significantly impaired in patients with an increase (≥1 kPa/year) in 7‐14 kPa bLSM, or decrease (≤0 kPa/year) in ≥14 kPa bLSM (P = 0.949 between these two groups). Patients with an increase (>0 kPa/year) in ≥14 kPa bLSM had the worst prognosis. Baseline and delta FIB‐4 also identified patient subgroups with significantly different prognosis. Conclusion: Three‐year evolution of noninvasive tests of liver fibrosis has a strong prognostic value in CHC patients. These tests should be repeated to monitor patients and predict their outcome. (Hepatology 2014;60:65‐76)

Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease

BACKGROUND & AIMS NAFLD is highly prevalent but only a small subset of patients develop advanced liver fibrosis with impaired liver-related prognosis. We aimed to compare blood fibrosis tests and liver stiffness measurement (LSM) by FibroScan for the diagnosis of liver fibrosis and the evaluation of prognosis in NAFLD. METHODS Diagnostic accuracy was evaluated in a cross-sectional study including 452 NAFLD patients with liver biopsy (NASH-CRN fibrosis stage), LSM, and eight blood fibrosis tests (BARD, NAFLD fibrosis score, FibroMeter(NAFLD), aspartate aminotransferase to platelet ratio index (APRI), FIB4, FibroTest, Hepascore, FibroMeter(V2G)). Prognostic accuracy was evaluated in a longitudinal study including 360 NAFLD patients. RESULTS LSM and FibroMeter(V2G) were the two best-performing tests in the cross-sectional study: AUROCs for advanced fibrosis (F3/4) were, respectively, 0.831±0.019 and 0.817±0.020 (p⩽0.041 vs. other tests); rates of patients with ⩾90% negative/positive predictive values for F3/4 were 56.4% and 46.7% (p<0.001 vs. other tests); Obuchowski indexes were 0.834±0.014 and 0.798±0.016 (p⩽0.036 vs. other tests). Two fibrosis classifications were developed to precisely estimate the histological fibrosis stage from LSM or FibroMeter(V2G) results without liver biopsy (diagnostic accuracy, respectively: 80.8% vs. 77.4%, p=0.190). Kaplan-Meier curves in the longitudinal study showed that both classifications categorised NAFLD patients into subgroups with significantly different prognoses (p<0.001): the higher was the class of the fibrosis classification, the worse was the prognosis. CONCLUSIONS LSM and FibroMeter(V2G) were the most accurate of nine evaluated tests for the non-invasive diagnosis of liver fibrosis in NAFLD. LSM and FibroMeter(V2G) fibrosis classifications help physicians estimate both fibrosis stage and patient prognosis in clinical practice. LAY SUMMARY The amount of liver fibrosis is the main determinant of the liver-related prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated eight blood tests and FibroScan in a cross-sectional diagnostic study and found that FibroScan and the blood test FibroMeter(V2G) were the two most accurate tests for the non-invasive evaluation of liver fibrosis in NAFLD. A longitudinal prognostic study showed these two tests initially developed for the diagnosis are also prognostic markers as they allow for the stratification of NAFLD patients in several subgroups with significantly different prognosis.

Diagnosis of different liver fibrosis characteristics by blood tests in non-alcoholic fatty liver disease.

Aims: Our aim was to develop an accurate, non‐invasive, blood‐test‐based method for identifying the main characteristics of liver fibrosis in non‐alcoholic fatty liver disease (NAFLD).

Optimization and robustness of blood tests for liver fibrosis and cirrhosis.

OBJECTIVES To optimize the performance and feasibility of fibrosis blood tests and evaluate their robustness. DESIGN AND METHODS The derivation population included 1056 HCV patients with liver biopsy and blood markers. Validation populations included 984 patients with various viral hepatitis causes, and Fibroscan and/or liver biopsy and/or blood markers. RESULTS The bootstrap method validated the markers of the original FibroMeter(2G), but not those of Fibrotest and Hepascore, and provided a hyaluronate-free FibroMeter(3G). AUROCs for significant fibrosis were: FibroMeter(2G): 0.853 vs. FibroMeter(3G): 0.851, p=0.489. Compared to FibroMeter(2G), FibroMeter(3G) had a significantly higher patient rate with predictive values ≥90% for significant fibrosis. Accuracy for fibrosis stage classification was: Fibrotest: 37.9%, FibroMeter(2G): 74.9%, and FibroMeter(3G): 86.9% (p<10(-3)). CONCLUSION The bootstrap method validated FibroMeter(2G) and provided a cheaper and more feasible hyaluronate-free FibroMeter(3G) with comparable performance. Compared to binary diagnosis, fibrosis stage classification increased discrimination, with an increased accuracy to 87% for FibroMeter(3G).

Combination of blood tests for significant fibrosis and cirrhosis improves the assessment of liver-prognosis in chronic hepatitis C.

Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross‐sectional studies have shown their combination significantly improves diagnostic accuracy.

Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C

BackgroundNon-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-invasive tests and liver biopsy. The secondary aim was to validate these accuracies in independent populations.MethodsFour HCV populations provided 2,068 patients with liver biopsy, four different pathologist skill-levels and non-invasive tests. Results were expressed as percentages of correctly classified patients.ResultsIn population #1 including 205 patients and comparing liver biopsy (reference: consensus reading by two experts) and blood tests, Metavir fibrosis (FM) stage accuracy was 64.4% in local pathologists vs. 82.2% (p < 10-3) in single expert pathologist. Significant discrepancy (≥ 2FM vs reference histological result) rates were: Fibrotest: 17.2%, FibroMeter2G: 5.6%, local pathologists: 4.9%, FibroMeter3G: 0.5%, expert pathologist: 0% (p < 10-3). In population #2 including 1,056 patients and comparing blood tests, the discrepancy scores, taking into account the error magnitude, of detailed fibrosis classification were significantly different between FibroMeter2G (0.30 ± 0.55) and FibroMeter3G (0.14 ± 0.37, p < 10-3) or Fibrotest (0.84 ± 0.80, p < 10-3). In population #3 (and #4) including 458 (359) patients and comparing blood tests and Fibroscan, accuracies of detailed fibrosis classification were, respectively: Fibrotest: 42.5% (33.5%), Fibroscan: 64.9% (50.7%), FibroMeter2G: 68.7% (68.2%), FibroMeter3G: 77.1% (83.4%), p < 10-3 (p < 10-3). Significant discrepancy (≥ 2 FM) rates were, respectively: Fibrotest: 21.3% (22.2%), Fibroscan: 12.9% (12.3%), FibroMeter2G: 5.7% (6.0%), FibroMeter3G: 0.9% (0.9%), p < 10-3 (p < 10-3).ConclusionsThe accuracy in detailed fibrosis classification of the best-performing blood test outperforms liver biopsy read by a local pathologist, i.e., in clinical practice; however, the classification precision is apparently lesser. This detailed classification accuracy is much lower than that of significant fibrosis with Fibroscan and even Fibrotest but higher with FibroMeter3G. FibroMeter classification accuracy was significantly higher than those of other non-invasive tests. Finally, for hepatitis C evaluation in clinical practice, fibrosis degree can be evaluated using an accurate blood test.

Steatosis degree, measured by morphometry, is linked to other liver lesions and metabolic syndrome components in patients with NAFLD.

Background and aim We carried out morphometric measurements of steatosis to evaluate relationships between steatosis degree and other liver lesions or metabolic syndrome components in nonalcoholic fatty liver disease (NAFLD). Patients and methods We developed an algorithm to measure steatosis area. Two hundred and fourteen patients with NAFLD were included in derivation (10) and validation (204) groups. Controls consisted of patients who were steatosis-free (12), patients with chronic hepatitis C (188), and patients with alcoholic chronic liver disease (94). Results Accuracy of steatosis area was considered as good or very good in at least 72% of cases by three pathologists. Steatosis areas were as follows: NAFLD=10.3±9.7%, virus=2.4±3.1%, alcohol=7.8±8.2% (P<0.0001). Steatosis area was closely related to steatosis grades in NAFLD (P<0.0001 for linear trend). Steatosis area increased from the fibrosis stage F0 to the fibrosis state F2, then decreased in the stages F3 and F4 (cirrhosis) (P<0.0001 for quadratic trend). Fibrosis was present in an average steatosis area of approximately 4% (defining significant steatosis) and in nonalcoholic steatohepatitis by approximately 8% (defining severe steatosis). Steatosis and fibrosis area increased symmetrically until approximately 10%, then steatosis area decreased to null as average fibrosis area reached 32%. Average fasting glycemia (approximately 92 mg/dl) or triglycerides and BMI plateaued before a steatosis area of approximately 4%, then increased thereafter. Significant steatosis was present in 61.3% of NAFLD versus 20.2% of viral hepatitis (P<0.0001) and in 58.7% of alcoholic liver diseases (P=0.674). Conclusions The average threshold of steatosis area is 4% for the development of fibrosis or metabolic syndrome components and 8% for nonalcoholic steatohepatitis. Steatosis area may contribute to defining the normal range and clinical course of metabolic components.