I. Hubert

Comparison of blood tests for liver fibrosis specific or not to NAFLD

BACKGROUND/AIMS To compare blood tests of liver fibrosis specific for NAFLD: the FibroMeter NAFLD and the NAFLD fibrosis score (NFSA) with a non-specific test, APRI. METHODS Two hundred and thirty-five NAFLD patients with liver Metavir staging and blood markers from two independent centres were randomly assigned to a test (n=121) or a validation population (n=114). RESULTS The highest accuracy--91%--for significant fibrosis was obtained with the FibroMeter whose (i) AUROC (0.943) was significantly higher than those of NFSA (0.884, p=0.008) and APRI (0.866, p<10(-3); p=0.309 vs NFSA) in the whole population, and (ii) misclassification rate (9%) was significantly lower than those of NFSA (14%, p=0.04) and APRI (16%, p=0.002) and did not vary according to centre (14 vs 7%, p=0.07), unlike those of NFSA (25 vs 9%, p=0.001) and APRI (29 vs 11%, p<10(-3)). By using thresholds of 90% predictive values, liver biopsy could have been avoided in most patients: FibroMeter: 97.4% vs NFSA: 86.8% (p<10(-3)) and APRI: 80.0% (p<10(-3)). A new classification provided three reliable diagnosis intervals: F0/1, F0/1/2, F2/3/4 with 91.4% accuracy for FibroMeter, avoiding biopsy in all patients. CONCLUSIONS FibroMeter NAFLD had high performance and provided reliable diagnosis for significant fibrosis, significantly outperforming NFSA and APRI.

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.

BACKGROUND & AIMS Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowskis method. RESULTS Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowskis measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROCs ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C

The impact of ribavirin exposure on sustained virological response (SVR) in patients with chronic hepatitis C is unknown. Preliminary studies showed marked inter‐individual variability of ribavirin concentrations despite dose adjustment for body weight (BW) and suggested there was a correlation between single time point concentrations and SVR. None of them evaluated the global exposure to ribavirin. This study was conducted to determine whether early ribavirin global exposure is related with SVR. An exploratory pharmacokinetic‐pharmacodynamic (PK‐PD) study was conducted in genotype 1 hepatitis C patients treated with peginterferon alfa‐2a and ribavirin (dose‐adjusted for BW) for 12 weeks, to which amantadine was added for the following 36 weeks. Full and abbreviated ribavirin area under the concentration time curves (AUC0–12h, AUC0–4h) were derived from plasma concentration profiles at day 0 (D0), week 12 (W12), W12 + 1 day, and W24. Virological follow‐up was performed at D0 (0, 12, and 24 hours), W2, W4, W6, and monthly until W72 (TaqMan polymerase chain reaction, cut‐off 15 international units/mL). Twenty‐eight patients were enrolled in the study and 24 completed it. Patients with a SVR had a significantly higher D0 AUC0–12h (3695 [1571–6916] versus 2937 [1266–4913] μg/hour/L, P = 0.03) and D0 AUC0–4h (2010 [615–3175] versus 1340 [622–2246] μg/hour/L, P = 0.03). Patients with D0 AUCs above the cut‐off values defined by receiver operating characteristic curves (3014 μg/hour/L and 1755 μg/hour/L for AUC0–12h and AUC0–4h, respectively) had a significantly better chance of achieving an SVR than patients with AUCs under the thresholds (odds ratio = 16.0, 95% confidence interval 1.54–166.6, P = 0.02 and odds ratio = 8.9, 95% confidence interval, 1.4–56.6; P = 0.02). Conclusion: Ribavirin exposure at D0 is significantly related to SVR. To our knowledge, this is the first study to give an early pharmacokinetic predictor of SVR. We propose a minimum AUC0–4h threshold of 1755 μg/hour/L at D0 as a target for ribavirin dose adjustment. (HEPATOLOGY 2008;47:1453–1461.)

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)

FibroMeters: a family of blood tests for liver fibrosis

FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

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).

Improved fibrosis staging by elastometry and blood test in chronic hepatitis C

Our main objective was to improve non‐invasive fibrosis staging accuracy by resolving the limits of previous methods via new test combinations. Our secondary objectives were to improve staging precision, by developing a detailed fibrosis classification, and reliability (personalized accuracy) determination.

Treatment of Chronic Hepatitis C With Amantadine

TO THE EDITOR: In your November 1998 issue under “What’s New in GI,” R. L. Young reviewed a paper on anti-Saccharomyces cerevisiae mannan antibodies (ASCA) marker in Crohn’s disease (1). There has been a surge of papers in the past 6 months (1–3) confirming that ASCA should be considered as a significant diagnostic tool. In his review, the author notes that “we all need help in differentiating tough cases of ulcerative colitis from Crohn’s disease,” which was shown to be possible by combining ASCA and pANCA tests, but also states that “this test is not available for clinical use.” Although the group from France authored the paper he reviewed, one of the coauthors was Stephan Targan, Director of Gastroenterology and the IBD Center, Cedar Sinai Medical Center, Los Angeles. Through the IBD Center we were introduced to Prometheus Labs, where ASCA testing is commercially available. Prometheus accepts clinical specimens from around the world for evaluation using their proprietary testing systems. Located in San Diego, California, Prometheus is interested in professional collaborations with GI disease and IBD researchers worldwide, and will serve as a technological development center to bring exciting new diagnostic reagents and assay systems to the medical community. For additional information on Prometheus visit the Internet site: http://www. prometheus-labs.com/ , call 1-888-423-5227 or (619) 8240895, Fax: (619) 824-0896 or E-mail: email@prometheuslabs.com

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.

Liver fibrosis diagnosis by blood test and elastography in chronic hepatitis C: agreement or combination?

In chronic hepatitis C, the European Association for the Study of the Liver and the Asociacion Latinoamericana para el Estudio del Higado recommend performing transient elastography plus a blood test to diagnose significant fibrosis; test concordance confirms the diagnosis.