Associations between perfluoroalkyl substances and the severity of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide and the determinants driving its severity remain to be elucidated. Perfluoroalkyl substances (PFAS) are synthetic chemical compounds. They are used in commonplace products and persistent in water, soil and the human body. In vitro and animal studies suggest a pathogenic role for PFAS in metabolic diseases such as NAFLD. OBJECTIVES: We aimed to evaluate the association between NAFLD severity and serum PFAS concentrations in humans. METHODS: One hundred biopsy-proven NAFLD patients were included with a well-balanced distribution between the different stages of severity: 25 patients with simple steatosis, 25 with early non-alcoholic steatohepatitis (NASH and F0-F1 fibrosis), 33 with fibrotic NASH (NASH and F2-F3 fibrosis), and 17 with cirrhotic NASH (NASH and F4 fibrosis). Liver histological features were evaluated according to the NASH Clinical Research Network classification. Seventeen PFAS were measured by high-performance liquid chromatography coupled with tandem mass spectrometry on serum samples stored at -80 °C. RESULTS: The median age was 60 years, 61 % of patients were male, 46 % had diabetes and the median body mass index (BMI) was 32 kg/m2. Long-chain PFAS were associated with steatosis grade (p = 0.03). Among the nine PFAS detected in > 50 % of the patients, Perfluoro-n-heptanoic acid (PFHpA) showed significantly higher concentrations in grade 3 steatosis versus grade 1 (p = 0.02). Perfluoro-n-dodecanoic acid (PFDoA) concentrations were higher in patients with significant fibrosis (p = 0.04) and PFHpA in patients with advanced fibrosis (p = 0.02). The association between PFHpA and steatosis grade remained significant in multivariate analysis adjusted for age, gender, BMI, diabetes presence and dyslipidemia (p = 0.004). DISCUSSION: Our study showed a significant association between PFHpA and liver steatosis in NAFLD. According to data available in the literature, PFHpA could be implicated in liver steatosis through ß-oxidation and biosynthesis of fatty acids.

Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.

BACKGROUND AND AIMS: The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD). APPROACH AND RESULTS: One thousand fifty-one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis-4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value. CONCLUSIONS: Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.

Impact of Type 2 Diabetes on the Accuracy of Noninvasive Tests of Liver Fibrosis With Resulting Clinical Implications.

BACKGROUND & AIMS: Noninvasive tests (NITs) of liver fibrosis have been suggested to be less accurate in type 2 diabetes mellitus (T2DM). We aimed to compare the accuracy of 6 NITs between patients with or without T2DM, explain any differences, and adapt diagnostic algorithms for clinical practice accordingly. METHODS: We included 1051 patients with nonalcoholic fatty liver disease with liver biopsy, blood fibrosis tests (Nonalcoholic Fatty Liver Disease Fibrosis Score, FIB4, Fibrotest, FibroMeter), vibration-controlled transient elastography (VCTE), and the combinatory elasto-blood test FibroMeterVCTE. The study endpoint was advanced fibrosis on liver biopsy. RESULTS: NIT areas under the receiver operating characteristic curve were significantly lower in patients with T2DM, mostly because of a decrease in specificity. For FIB4, this decrease in specificity was only related to the higher age of patients with T2DM enrolled. For Fibrotest, FibroMeter, and FibroMeterVCTE, the decrease in specificity was related to age but also to higher alpha2-macroglobulin level, which is known to increase in T2DM. Sensitivity was unaffected by T2DM, but it masked a doubled raw number of false negatives because of the 2-fold higher prevalence of advanced fibrosis in that setting. The sequential algorithm FIB4-vibration-controlled transient elastography had 90.3% accuracy in patients without T2DM vs 79.0% in those with (P < .001). Algorithms using first-line specialized tests maintained a low rate of false negatives and false positives in T2DM. CONCLUSIONS: The decrease in NIT accuracy observed in T2DM is partly biased by the different characteristics of the groups studied, but also linked to T2DM itself through modification of the levels of some NIT biomarkers. Specialized tests should be used first-line to diagnose advanced liver fibrosis in T2DM.

Liver fibrosis staging by computed tomography: Prospective randomized multicentric evaluation of image analyses.

AIM: Liver fibrosis staging is essential. We prospectively evaluated the liver fibrosis staging performance of computed tomography (CT). METHODS: 70 hepato-gastroenterology clinicians were randomized into three stratified groups with different image analyses of radiological semiology, i.e., on raw images (group 1) and on expert-annotated (group 2) and computerized-morphometry-enriched (group 3) images. Radiological fibrosis staging based on seven simple descriptors into four stages equivalent to Metavir stages (F0/1, F2, F3, F4=cirrhosis) was determined at baseline and after image analyses in 10 patients with chronic liver diseases (two per F) concordant for four independent fibrosis stagings including Metavir. 23,800 CT images were analysed, providing 1400 fibrosis stagings. RESULTS: Fibrosis staging: overall (3 groups) accuracy (correct classification rate) was, baseline: 43%, post-analysis: 60% (p < 0.001) without significant progression in group 1 (6%, p = 0.207) contrary to groups 2 (34%, p < 0.001) and 3 (13%, p = 0.007). Cirrhosis diagnosis: overall accuracy was, baseline: 84%, post-analysis: 89% (p < 0.001) without significant progression in group 1 (0%, p = 1) contrary to groups 2 (8%, p = 0.009) and 3 (7%, p = 0.015). Baseline AUROCs were good (≥0.83) for marked fibrosis (F≥3 or cirrhosis) in all groups. Post-analysis AUROCs became excellent (≥0.89) in group 2 for all diagnostic targets (≥0.98 for F≥3 and cirrhosis) and in group 3 for cirrhosis. In post-analysis group 2, discrimination between all F was excellent (especially, F1 from F0) with an Obuchowski index at 0.87. Negative and positive predictive values for marked fibrosis were 98% and 95%, respectively. CONCLUSION: Simple CT descriptors accurately discriminate all Metavir liver fibrosis stages.

Cross-linkage between bacterial taxonomy and gene functions: a study of metagenome-assembled genomes of gut microbiota in adult non-alcoholic fatty liver disease.

BACKGROUND: The reconstruction of metagenome-assembled genomes (MAGs) has emerged as a powerful approach for combining the taxonomic and functional content of microbial populations. AIM: To use this new approach to highlight mechanisms linking gut microbiota to NAFLD severity METHODS: Stool samples were collected from 96 NAFLD patients on the day of liver biopsy. Shotgun DNA sequencing of the gut microbiota was performed on an Illumina HiSeq3000 system. Contigs were binned into MAGs according to their co-abundances and tetranucleotide frequencies using Metabat v.0.32.4. Predicted protein-coding genes were clustered in orthologous groups (OGs) with DIAMOND against the EggNOG v4.5 database. Liver biopsies were read in accordance with the NASH CRN classification. RESULTS: Fifty-four patients had NASH and 44 had significant fibrosis (F ≥ 2). Sequencing of DNA extracted from stools resulted in 13.8 + 3.2 million paired-end reads per sample. Of the 4,000 reconstructed MAGs, 220 in NASH patients, 192 in non-NASH patients, 203 in F ≥ 2 patients and 230 in F0-1 patients had > 70% completeness and < 5% contamination. Within these MAGs, 28 OGs were associated with NASH, 33 with significant fibrosis, and seven with both NASH and significant fibrosis. The study of MAGs showed associations between NAFLD severity and some gut bacteria with microbiota functions related to hydrogen sulfide production, citrate transport, hemicellulose degradation, aldehyde production and vitamin B12 synthesis. CONCLUSION: Using new metagenomics methods, our study unveils potential mechanisms by which certain bacteria from the gut microbiota could protect or contribute to the development of NASH and liver fibrosis in NAFLD.

Non-selective beta-blockers increase overall and liver mortality in alcoholic cirrhosis with MELD ≥ 12 over 5 years of follow-up.

BACKGROUND & AIMS: Non-cardioselective beta-blocker (NSBB) effects on mortality in cirrhosis are controversial. We evaluated the impact of NSBBs on mortality according to liver severity and mortality cause. METHODS: Two hundred and fifty-eight patients with alcoholic cirrhosis were included in a retroprospective cohort: 129 NSBB-treated and 129 controls. The NSBB group had the following significant baseline differences: higher MELD, more frequent previous gastrointestinal bleeding, large oesophageal varices (OV) and lower heart rate. Propranolol dose was 160 mg/d in 81% of NSBB patients. RESULTS: (i) Liver function: during 5.3 ± 2.6 years of follow-up, MELD progression was higher in NSBB patients: 1 (-1-4) than in controls: 0 (-1-1) (P = .017). (ii) Overall survival: no significant differences were observed between NSBBs and controls (Kaplan-Meier curves: P = .291). In multivariate Cox analysis, baseline MELD interacted with NSBB (P = .011). Thus, the NSBB hazard ratio (HR) was 0.99 (0.50-1.98) in MELD < 12 vs 3.17 (1.19-8.42) in MELD ≥ 12. (iii) Liver survival: NSBB decreased liver survival (Kaplan-Meier: P = .031). In multivariate Cox analysis, baseline MELD interacted with NSBB (P < .001). The NSBB HR was 0.81 (0.30-2.19) in MELD < 12 vs 6.23 (1.94-20.0) in MELD ≥ 12. In competing risk multivariate analysis for liver mortality, the MELD-NSBB interaction was significant (P < .001): the NSBB HR was 1.02 (0.36-2.91) in MELD < 12 vs 9.24 (3.18-26.9) in MELD ≥ 12. 4) Non-liver survival: contrastingly, non-liver survival was increased by NSBBs, especially in MELD ≥ 12 (competing Kaplan-Meier: P = .044). These results were confirmed in propensity risk score (PRS)-matched patients. CONCLUSION: In alcoholic cirrhosis with rather high propranolol doses, overall and liver survival are significantly aggravated when MELD is ≥12.

Simple blood fibrosis tests reduce unnecessary referrals for specialized evaluations of liver fibrosis in NAFLD and ALD patients.

BACKGROUND: Liver fibrosis evaluation is mandatory in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) to decide the patient management. Patients with these diseases are usually under the care of non-liver specialists who refer them to specialized centers where the most accurate fibrosis tests are available. We aimed to evaluate whether simple blood fibrosis tests available to all physicians help to reduce the rate of unnecessary referral of NAFLD and ALD patients without advanced fibrosis. METHODS: NAFLD and/or ALD patients newly referred to our center for a non-invasive evaluation of liver fibrosis were retrospectively included. The FibroMeterVCTE (FMVCTE, combination of blood markers and Fibroscan results) was defined as the reference test for specialized evaluation of liver fibrosis. A FMVCTE result <0.384 indicated the absence of advanced fibrosis and thus an "unnecessary referral". RESULTS: 558 patients were included (NAFLD: 283, ALD: 156, mixed NAFLD+ALD: 119). FMVCTE was <0.384 (unnecessary referral) in 58.8% of patients. FIB4 was <1.30 in 45.2% and eLIFT <8 in 47.7% of the patients. 84.9% of patients with FIB4 <1.30 and 85.3% of patients with eLIFT <8 had also FMVCTE <0.384. Therefore, using FIB4 or eLIFT as first-line evaluation of liver fibrosis decreased by three-fold the rate of unnecessary referral. The negative predictive value of FIB4 and eLIFT was >80% whatever the underlying cause of chronic liver disease. CONCLUSION: The use of eLIFT by non-liver specialists for NAFLD and ALD patients can improve the relevance of referrals for specialized evaluation of liver fibrosis.

New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD.

BACKGROUND & AIMS: Advanced liver fibrosis is an important diagnostic target in non-alcoholic fatty liver disease (NAFLD) as it defines the subgroup of patients with impaired prognosis. The non-invasive diagnosis of advanced fibrosis is currently limited by the suboptimal positive predictive value and the grey zone (representing indeterminate diagnosis) of fibrosis tests. Here, we aimed to determine the best combination of non-invasive tests for the diagnosis of advanced fibrosis in NAFLD. METHODS: A total of 938 patients with biopsy-proven NAFLD were randomized 2:1 into derivation and validation sets. All patients underwent liver stiffness measurement with vibration controlled transient elastography (VCTE) and blood fibrosis tests (NAFLD fibrosis score, Fibrosis-4 [FIB4], Fibrotest, Hepascore, FibroMeter). FibroMeterVCTE, which combines VCTE results and FibroMeter markers in a single test, was also calculated in all patients. RESULTS: For the diagnosis of advanced fibrosis, VCTE was significantly more accurate than the blood tests (area under the receiver operating characteristic curve [AUROC]: 0.840 ±â€¯0.013, p ≤0.005). FibroMeter was the most accurate blood test (AUROC: 0.793 ±â€¯0.015, p ≤0.017). The combinatory test FibroMeterVCTE outperformed VCTE and blood tests (AUROC: 0.866 ±â€¯0.012, p ≤0.005). The sequential combination of FIB4 then FibroMeterVCTE (FIB4-FMVCTE algorithm) or VCTE then FibroMeterVCTE (VCTE-FMVCTE algorithm) provided an excellent diagnostic accuracy of 90% for advanced fibrosis, with liver biopsy only required to confirm the diagnosis in 20% of cases. The FIB4-FMVCTE and VCTE-FMVCTE algorithms were significantly more accurate than the pragmatic algorithms currently proposed. CONCLUSION: The sequential combination of fibrosis tests in the FIB4-FMVCTE and VCTE-FMVCTE algorithms provides a highly accurate solution for the diagnosis of advanced fibrosis in NAFLD. These algorithms should now be validated for the diagnosis of advanced liver fibrosis in diabetology or primary care settings. LAY SUMMARY: The evaluation of liver fibrosis is mandatory in non-alcoholic fatty liver disease (NAFLD), as advanced fibrosis identifies the subgroup of patients with impaired prognosis. FibroMeterVCTE is a new fibrosis test combining blood markers and the result of vibration controlled transient elastography (VCTE) into a single diagnostic test. Our results show that FibroMeterVCTE outperforms other blood fibrosis tests and VCTE alone for the diagnosis of advanced fibrosis in a large multi-centric cohort of 938 patients with biopsy-proven NAFLD. Sequential algorithms using a simple blood test or VCTE as a first-line procedure, then FibroMeterVCTE as a second-line test accurately classified 90% of patients.

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme.

BACKGROUND & AIMS: Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real-world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization. METHODS: Patients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post-liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6-92.5%), 98% (43/44) without cirrhosis (95% CI 88.2-99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5-90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5-89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died. CONCLUSIONS: Daclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells.

OBJECTIVE: Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. DESIGN: IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. RESULTS: The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16- CD56(bright) NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-ß and IFN-γ, and of the proinflammatory cytokines IL-1ß and TNF-α by NK cells. CONCLUSIONS: This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.

IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells.

UNLABELLED: Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mφ) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-34 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mφ generated with M-CSF (M-CSF-Mφ) or IL-34 (IL-34-Mφ). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL)2, CCL4, C-C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mφ accumulation in liver lesions. M-CSF-Mφ and IL-34-Mφ also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mφ and M-CSF-Mφ induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mφ and M-CSF-Mφ, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-γ) by activated natural killer cells, IL-34-Mφ and M-CSF-Mφ prevent the IFN-γ-induced killing of HSCs. CONCLUSION: These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.

Reproducibility of liver stiffness measurement by ultrasonographic elastometry.

BACKGROUND & AIMS: Fibroscan is a noninvasive device that assesses liver fibrosis by liver stiffness evaluation (LSE) with ultrasonographic elastometry. We evaluated LSE reproducibility and its influencing factors. METHODS: LSE was performed by 4 experienced physicians (>100 LSEs) in 46 patients with chronic liver disease at 4 different anatomic sites. Additional LSEs were performed for ancillary aims, so that 534 LSEs were available. RESULTS: Overall interobserver agreement for LSE results was considered as excellent, with intraclass coefficient correlation (Ric) of 0.93. Low LSE level, nonrecommended sites, LSE interquartile range >25%, and body mass index > or =25 independently decreased agreement. Thus, agreement was fair (Ric = 0.53) for LSE <9 kilopascals and excellent (Ric = 0.90) beyond. The best measurement site for LSE reproducibility was the median axillary line on the first intercostal space under the liver dullness upper limit, with the patient lying in dorsal decubitus. When LSE results were categorized into fibrosis Metavir stages, interobserver discordance was noticed in about 25% of the cases and was the highest for F2 and F3 stages and the lowest for F4. Intraobserver (Ric = 0.94), intersite (Ric = 0.92-0.98), and interequipment (Ric = 0.92) agreements for LSE results were excellent. Preliminary standard ultrasonography or probe pressure changes did not improve interobserver agreement. CONCLUSIONS: The best measurement site for LSE is the one generally used for liver biopsy. Reproducibility of LSE is globally excellent but is fair in patient with low liver stiffness. The fibrosis diagnosis by ultrasonographic elastometry in low stages or categorized into fibrosis Metavir stages must be interpreted with caution.

Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography.

BACKGROUND/AIMS: Fibroscan allows liver stiffness examination (LSE) that is well correlated with fibrosis stages. Our main objective was to evaluate LSE learning curve. METHODS: LSE results of five novice observers with different medical status were compared with those of five expert observers (physicians with >100 examinations) in 250 patients with chronic liver disease. Each novice-expert pair had to blindly examine 50 consecutive patients divided into five consecutive subgroups of 10 patients. RESULTS: In each observer group, novice-expert agreement [intraclass correlation coefficient (Ric)] for LSE results was excellent from the first to the last subgroup. Novice-expert agreement for LSE results varied with liver stiffness level: <9 kPa: Ric=0.49; >or=9 kPa: Ric=0.87. Relative difference (%) between novice and expert LSE results was independently associated with the number of valid LSE measurements, and stabilizes around 20-30% after the fourth valid measurement. In each observer group, novice-expert agreement (Ric) for LSE success rate progressively increased as a function of time. CONCLUSION: LSE requires no learning curve: a novice is able to obtain a reliable result after a single training session, whatever the professional status. However, success rate will progressively increase. An LSE with less than four valid measurements should not be considered as reliable.

Reproducibility of blood tests of liver fibrosis in clinical practice.

OBJECTIVES: To evaluate the inter-laboratory reproducibility of blood test for liver fibrosis: FibroMeter, Fibrotest, APRI and their composites variables. DESIGN AND METHODS: Four studies, including 147 patients, were performed: study #1 included 2 metachronous blood samples and 2 laboratories; studies #2, #3 and #4 included synchronous samples with assays delayed at day 1 in 12 laboratories, at day 0 in 10 laboratories and at day 0 or 1 in 2 laboratories, respectively. Agreement was evaluated by the intraclass correlation coefficient (r(ic)). RESULTS: In studies #1, #2 and #4, r(ic) for FibroMeter was 0.893, 0.942 and 0.991, respectively. In study #3, the r(ic) were: FibroMeter: 0.963, Fibrotest: 0.984, APRI: 0.949. Large simulated variations in composite variables had a weak impact on FibroMeter. CONCLUSIONS: When blood marker limits are controlled, inter-laboratory agreement of blood tests is excellent in clinical practice conditions. Blood tests are robust against the variability of composite blood variables.

A novel panel of blood markers to assess the degree of liver fibrosis.

The objective was to develop new blood tests to characterize different fibrosis parameters in viral and alcoholic chronic liver diseases. Measurements included 51 blood markers and Fibrotest, Fibrospect, ELFG, APRI, and Forns scores. The clinically significant fibrosis was evaluated via Metavir staging (F2-F4), and image analysis was used to determine the area of fibrosis. In an exploratory step in 383 patients with viral hepatitis, the area under the receiving operator characteristic (AUROC) curve for stages F2-F4 in a test termed the "Fibrometer" test combining platelets, prothrombin index, aspartate aminotransferase, alpha2-macroglobulin (A2M), hyaluronate, urea, and age was 0.883 compared with 0.808 for the Fibrotest (P = .01), 0.820 for the Forns test (P = .005), and 0.794 for the APRI test (P < 10(-4)). The Fibrometer AUROC curve was 0.892 in the validating step in 120 patients. The AUROC curve for stages F2-F4 in a test combining prothrombin index, A2M, hyaluronate, and age was 0.962 in 95 patients with alcoholic liver diseases. The area of fibrosis was estimated in viral hepatitis by testing for hyaluronate, gamma-glutamyltransferase, bilirubin, platelets, and apolipoprotein A1 ((a)R(2) = 0.645), and in alcoholic liver diseases by testing for hyaluronate, prothrombin index, A2M, and platelets ((a)R(2) = 0.836). In conclusion, the pathological staging and area of liver fibrosis can be estimated using different combinations of blood markers in viral and alcoholic liver diseases. Whereas the Fibrometer has a high diagnostic accuracy for clinically significant fibrosis, blood tests for the area of liver fibrosis provide a quantitative estimation of the amount of fibrosis, which is especially useful in cirrhosis.

Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients.

This article presents a prospective study of 71 patients infected with chronic viral hepatitis C and treated with interferon alpha during one year. The objective was to assess the incidence and predictive factors of anxiety and depression symptoms during and after the therapy. Each patient received psychiatric assessment before, during and after treatment, with evaluations using Hamilton-anxiety and MADRS scales. Results confirm the great incidence of depression and anxiety not only during interferon alpha therapy but also after treatment is discontinued. Sleep disorders and MADRS ratings of M4 seem to be predictive of the therapy's side effects. Thus, there seem to be easily discernable parameters allowing depression and suicidal behaviour to be anticipated. This paper emphasises their possible occurrence after the treatment and, therefore, the need for routine assessments after treatment is discontinued. Teams comprising both hepatologists and psychiatrists should complete these assessments. This shows the necessity of interdisciplinary collaboration treatment of this kind.