Distribution Of Fibrosis Stages Research Articles

A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts.

Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.

Genotype Distribution and Characteristics of Chronic Hepatitis C Infection in Estonia, Latvia, Lithuania, and Ukraine: The RESPOND-C Study.

Background and objectives: Since 2013, highly effective direct-acting antiviral (DAA) treatment for chronic hepatitis C (CHC) has become available, with cure rates exceeding 95%. For the choice of optimal CHC treatment, an assessment of the hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage is necessary. Information about the distribution of these parameters among CHC patients in Estonia, Latvia, and Lithuania (the Baltic states) and especially in Ukraine is scarce. This study was performed to obtain epidemiologic data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (the Baltic states) and lower-middle-income (Ukraine) countries. Materials and methods: The retrospective RESPOND-C study included 1451 CHC patients. Demographic and disease information was collected from medical charts for each patient. Results: The most common suspected mode of viral transmission was blood transfusions (17.8%), followed by intravenous substance use (15.7%); however, in 50.9% of patients, the exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%), transmission by intravenous substance use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1-66.4%; GT3-28.1; and GT2-4.1%. The prevalence of GT1 was the highest in Latvia (84%) and the lowest in Ukraine (63%, p < 0.001). Liver fibrosis stages were distributed as follows: F0-12.2%, F1-26.3%, F2-23.5%, F3-17.1%, and F4-20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p < 0.001). Conclusions: This study contributes to the knowledge of epidemiologic characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.

The experience of the Moscow City Center for AIDS Prevention and Treatment of using glecaprevir/pibrentasvir in patients with HIV/HCV coinfection

The aim of the study is to analyze the experience of the Moscow Center for HIV/AIDS Prevention and Treatment on antiviral therapy of chronic hepatitis C in patients with HIV/ HCV coinfection in real-world evidence (RWE).Methods. The data from the outpatient cards of 12 adults and 53 children with HIV/HCV in the Moscow Center for HIV/AIDS Prevention and Treatment were analyzed for the period from 2020 to October 2021. In addition to standard laboratory tests, the viral load of HIV RNA, HCV RNA was examined in all patients, the HCV genotype was determined, the degree of liver fibrosis was assessed by liver fibroelastometry.Results: Among adult patients 10 (83,4%) were infected with HCV Gt 3, while 2 patients (16,6%) had Gt 1a/3. 5 (41,7%) patients were treatment-naïve and 7 (58,3%) had previously received sofosbuvir and daclatasvir. All 12 adult patients received glecaprevir/pibrentasvir for 8-16 weeks, depending on the treatment experience. 3 (25%) patients with HCV Gt 3 previously treated with DAAs received triple combination of glecaprevir/pibrentasvir, sofosbuvir and ribavirin for 12 weeks. As a result, 100% (12/12) of patients treated with glecaprevir/pibrentasvir achieved SVR12, no adverse events or cases of intolerance were identified.In the general group of adolescents with HCV/HIV coinfection (n = 53), the distribution by HCV genotypes was as follows: Gt 1 – 26 (49%), Gt 3 – 27 (51%). 15 (28,3%) adolescents received interferon-2a (SVR – 40% (6/15)), 9 adolescents received Peg-interferon-2a (SVR – 33% (3/9)) and 16 adolescents received glecaprevir/pibrentasvir. The mean duration of HIV/HCV coinfection in 16 adolescents receiving glecaprevir/pibrentasvir was 12,5 (1-17) years. Of these, 11 (68,3%) were infected with HCV Gt 1 and 5 (31,7%) with HCV Gt 3. 11 patients (68,3%) had prior treatment history with interferon and peginterferon regimens. The distribution of fibrosis stages was as follows: F0 – 56,3% (9/16), F1 – 31,3% (5/16), F2 – 12,4% (2/16). All 16 adolescents received 8 weeks of glecaprevir/pibrentasvir. 100% of patients were aviremic after 4 weeks from the start of therapy. All patients achieved SVR12. No adverse events and/or intolerance of glecaprevir/ pibrentasvir were identified.Conclusion. This observation demonstrates the high efficacy and safety of treatment with direct-acting antiviral drugs in both adults and children with HIV/HCV coinfection. Diagnosis and treatment of chronic hepatitis C in patients of reproductive age with HIV/HCV coinfection before pregnancy will help to completely eliminate the risk of mother-to-child transmission of HCV. Timely, effective, and modern antiviral therapy of already infected adolescents with HCV will make it possible to take a step towards eliminating hepatitis C through microelimination in the described socially significant groups of patients

Comparative diagnostic performance of ultrasound shear wave elastography and magnetic resonance elastography for classifying fibrosis stage in adults with biopsy-proven nonalcoholic fatty liver disease

ObjectivesTo compare the diagnostic accuracy of US shear wave elastography (SWE) and magnetic resonance elastography (MRE) for classifying fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD).MethodsPatients from a prospective single-center cohort with clinical liver biopsy for known or suspected NAFLD underwent contemporaneous SWE and MRE. AUCs for classifying biopsy-determined liver fibrosis stages ≥ 1, ≥ 2, ≥ 3, and = 4, and their respective performance parameters at cutoffs providing ≥ 90% sensitivity or specificity were compared between SWE and MRE.ResultsIn total, 100 patients (mean age, 51.8 ± 12.9 years; 46% males; mean BMI 31.6 ± 4.7 kg/m2) with fibrosis stage distribution (stage 0/1/2/3/4) of 43, 36, 5, 10, and 6%, respectively, were included. AUCs (and 95% CIs) for SWE and MRE were 0.65 (0.54–0.76) and 0.81 (0.72–0.89), 0.81 (0.71–0.91) and 0.94 (0.89–1.00), 0.85 (0.74–0.96) and 0.95 (0.89–1.00), and 0.91 (0.79–1.00) and 0.92 (0.83–1.00), for detecting fibrosis stage ≥ 1, ≥ 2, ≥ 3, and = 4, respectively. The differences were significant for detecting fibrosis stage ≥ 1 and ≥ 2 (p < 0.01) but not otherwise. At ≥ 90% sensitivity cutoff, MRE yielded higher specificity than SWE at diagnosing fibrosis stage ≥ 1, ≥ 2, and ≥ 3. At ≥ 90% specificity cutoff, MRE yielded higher sensitivity than SWE at diagnosing fibrosis stage ≥ 1 and ≥ 2.ConclusionsIn adults with NAFLD, MRE was more accurate than SWE in diagnosing stage ≥ 1 and ≥ 2 fibrosis, but not stage ≥ 3 or 4 fibrosis.Key Points• For detecting any fibrosis or mild fibrosis, MR elastography was significantly more accurate than shear wave elastography.• For detecting advanced fibrosis and cirrhosis, MRE and SWE did not differ significantly in accuracy.• For excluding advanced fibrosis and potentially ruling out the need for biopsy, SWE and MRE did not differ significantly in negative predictive value.• Neither SWE nor MRE had sufficiently high positive predictive value to rule in advanced fibrosis.

Economic Consequences of Anti-HCV Treatment of Patients Diagnosed Through Screening in Italy: A Prospective Modelling Analysis.

AimTo evaluate the cost-consequences of the investment for anti-hepatitis C virus (HCV) treatment by the Italian National Health System (NHS) for patients who will be newly diagnosed through active HCV screening, implemented in Italy from 2020.MethodsA previously published Markov model was used to estimate the disease complications avoided and the associated savings over 20 years to treat a standardised population of 10,000 HCV-infected patients diagnosed as a result of screening. Disease progression probabilities and fibrosis stage distribution were based on previously reported data in the literature. Real-life treatment effectiveness and medical expenses for disease management were estimated starting from a representative cohort of HCV-treated patients in Italy (Italian Platform for the Study of Viral Hepatitis Therapies). The breakeven point in time (BPT) was defined as the years required for the initial investment in treatment to be recovered in terms of cumulative costs saved.ResultsOver a 20-year time horizon, the treatment of 10,000 standardized patients diagnosed through active HCV screening results in 7769 avoided events of progression, which are associated with €838.73 million net savings accrued by the Italian NHS. The initial investment in treatment is recouped in 4.3 years in the form of savings from disease complications avoided.ConclusionInvestment in treatment of newly diagnosed patients will bring a significant reduction in disease complications, which is associated with great economic benefits. This type of action can reduce the infection rate as well as the clinical and economic disease burden of HCV in Italy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40258-021-00677-x.

Diagnostic performance of three non-invasive fibrosis scores (Hepamet, FIB-4, NAFLD fibrosis score) in NAFLD patients from a mixed Latin American population

Introduction and aimsSeveral non-invasive scoring systems have been developed and validated worldwide to predict the risk of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). However, information about the performance of these systems in Latin American populations is scarce. Our aim was to evaluate the performance of the Hepamet Fibrosis Score, Fibrosis-4 (FIB-4) and the NAFLD Fibrosis Score (NFS) in a mixed Latin American group of NAFLD patients. MethodsClinical, laboratory and liver biopsy data collected from 379 biopsy-proven NAFLD patients from Latin American tertiary health centers were reviewed. Histological fibrosis stages were classified using the Kleiner score. Accuracy was determined, and new fibrosis score thresholds were calculated to better compare the performances of non-invasive tests and to explore their usefulness in excluding fibrosis. ResultsThe distribution of fibrosis stages among the sample population was as follows: F0 (45%), F1 (27%), F2 (8%), F3 (16%) and F4 (4%). Using modified thresholds, the areas under the ROC curves (AUROC) for Hepamet and FIB-4 (0.73 and 0.74, respectively) to detect significant fibrosis were higher than that of NFS (0.58). However, the AUROCs of the three scores were not significantly different in advanced fibrosis and cirrhosis. To exclude fibrosis, we calculated lower cutoffs than standard thresholds for Hepamet, FIB-4 and NFS with similar performances. ConclusionThresholds of non-invasive fibrosis scores (Hepamet, FIB-4 and NFS) can be modified to maximize diagnostic accuracy in Latin American patients with NAFLD.

Comparison of FIB-4 and transient elastography in evaluating liver fibrosis of chronic hepatitis C subjects in community.

Background and aimThe role of non-invasive methods to evaluate fibrosis severity of chronic hepatitis C (CHC) subjects in community needs to be explored. This study investigated FIB-4 and transient elastography (TE) in staging liver fibrosis of CHC subjects in community.MethodsA total of 905 subjects who were positive for anti-HCV antibody from five districts of Tainan City of Taiwan were invited to participate in surveillance activities for CHC. FIB-4 and TE were measured for each participant.ResultsA total of 502 subjects with detectable HCV RNA and valid TE were enrolled. The distribution of FIB-4 and TE values differed markedly. Both methods exhibited a strongest correlation in subjects with at age 50~60 years (r = 0.655, p <0.001). FIB-4 score increased proportionally with age (p <0.001), but TE did not (p = 0.142). The intraclass correlation efficient of both methods was 0.255 (p <0.001). Subjects with TE defined advanced fibrosis exhibited younger age, higher BMI, higher platelet count, lower FIB-4 score, higher incidence of fatty liver and splenomegaly, and higher controlled attenuation parameter value than those defined by FIB-4. By multivariate logistic regression analysis, higher ALT levels, higher incidence of fatty liver, and presence of splenomegaly were the independent factors associated with advanced fibrosis defined by TE rather than defined by FIB-4.ConclusionsFIB-4 and TE defined different distribution of fibrosis stages in same HCV population. FIB-4 was deeply influenced by age whereas TE was not. TE had the advantages over than FIB-4 in strong association with splenomegaly and in detecting the role of non-alcoholic fatty liver disease in advanced fibrosis.

Optimal Information Collection Policies in a Markov Decision Process Framework.

The cost-effectiveness and value of additional information about a health technology or program may change over time because of trends affecting patient cohorts and/or the intervention. Delaying information collection even for parameters that do not change over time may be optimal. We present a stochastic dynamic programming approach to simultaneously identify the optimal intervention and information collection policies. We use our framework to evaluate birth cohort hepatitis C virus (HCV) screening. We focus on how the presence of a time-varying parameter (HCV prevalence) affects the optimal information collection policy for a parameter assumed constant across birth cohorts: liver fibrosis stage distribution for screen-detected diagnosis at age 50. We prove that it may be optimal to delay information collection until a time when the information more immediately affects decision making. For the example of HCV screening, given initial beliefs, the optimal policy (at 2010) was to continue screening and collect information about the distribution of liver fibrosis at screen-detected diagnosis in 12 years, increasing the expected incremental net monetary benefit (INMB) by $169.5 million compared to current guidelines. The option to delay information collection until the information is sufficiently likely to influence decisions can increase efficiency. A dynamic programming framework enables an assessment of the marginal value of information and determines the optimal policy, including when and how much information to collect.

Optimizing Implementation of Hepatitis C Birth-Cohort Screening and Treatment Strategies: Model-Based Projections.

Background: Chronic hepatitis C (HCV) is a significant public health problem affecting more than three million Americans. The US health care systems are ramping up costly HCV screening and treatment efforts with limited budget. We determine the optimal implementation of HCV birth-cohort screening and treatment strategies under budget constraints and health care payer’s perspective. Methods: Markov model and scenario-based simulation optimization. The target population is birth cohort born between 1945 and 1975. The interventions are allocating annual budget to screen a proportion of the target population and treat a proportion of the identified chronic HCV-positive patients over 10 years. Outcomes measure is to maximize lifetime discounted quality-adjusted life-years. Results: Allocate a percentage of the annual budget to screening, then treat patients with the remaining budget and prioritize the sickest patients. When the budget is $1 billion/year, the best strategy is to allocate the entire budget to treatment. When the budget is $5 billion/year, it is optimal to allocate 60% of the budget to screening in the first 2 years and 0% thereafter for age cohort 40 to 49; and allocate 20% of the budget to screening starting in year 3 for age cohorts 50 to 59 and 60 to 69. Health benefits are sensitive to budget in the first 2 years. Results are not sensitive to distribution of fibrosis stages by awareness of HCV. Conclusion: When budget is limited, all efforts should be focused on early treatment. With higher budget, better population health outcomes are achieved by reserving some budget for HCV screening while implementing a priority-based treatment strategy. This work has broad applicability to diverse health care systems and helps determine how much effort should be devoted to screening versus treatment under resource limitations.

Diagnostic accuracy of magnetic resonance elastography in liver transplant recipients: A pooled analysis

Background and aims. We conducted an individual participant data (IPD) pooled analysis on the diagnostic accuracy of magnetic resonance elastography (MRE) to detect fibrosis stage in liver transplant recipients.Material and methods. Through a systematic literature search, we identified studies on diagnostic performance of MRE for staging liver fibrosis, using liver biopsy as gold standard. We contacted study authors for published and unpublished IPD on age, sex, body mass index, liver stiffness, fibrosis stage, degree of inflammation and interval between MRE and biopsy; from these we limited analysis to patients who had undergone liver transplantation. Through pooled analysis using nonparametric two-stage receiver-operating curve (ROC) regression models, we calculated the cluster-adjusted AUROC, sensitivity and specificity of MRE for any (≥ stage 1), significant (≥ stage 2) and advanced fibrosis (≥ stage 3) and cirrhosis (stage 4).Results. We included 6 cohorts (4 published and 2 unpublished series) reporting on 141 liver transplant recipients (mean age, 57 years; 75.2% male; mean BMI, 27.1 kg/m2). Fibrosis stage distribution stage 0, 1, 2, 3, or 4, was 37.6%, 23.4%, 24.8%, 12% and 2.2%, respectively. Mean AUROC values (and 95% confidence intervals) for diagnosis of any (≥ stage 1), significant (≥ stage 2), or advanced fibrosis (≥ stage 3) and cirrhosis were 0.73 (0.66-0.81), 0.69 (0.62-0.74), 0.83 (0.61-0.88) and 0.96 (0.93-0.98), respectively. Similar diagnostic performance was observed in stratified analysis based on sex, obesity and inflammation grade.Conclusions. In conclusion, MRE has high diagnostic accuracy for detection of advanced fibrosis and cirrhosis in liver transplant recipients, independent of BMI and degree of inflammation.

The ability of Hepascore to predict liver fibrosis in chronic liver disease: a meta-analysis.

Hepascore is a serum model that was developed to assess the severity of liver fibrosis. It has been well validated in common causes of chronic liver disease. This study performed a meta-analysis to evaluate the pooled diagnostic performance of Hepascore and to compare it for different aetiologies of chronic liver disease. Two reviewers searched electronic databases from October 2005 to September 2015 for studies that evaluated the diagnostic performance of Hepascore for liver fibrosis in chronic liver disease. 21 studies were included. The AUROC was adjusted according to the distribution of fibrosis stages. The mean adjusted AUROC was 0.83 (95% CI, 0.81-0.85) for significant fibrosis, 0.89 (95% CI, 0.85-0.92) for advance fibrosis and 0.93 (95% CI, 0.91-0.95) for cirrhosis. A cut point of 0.50-0.55 achieved a summary sensitivity of 70% and a summary specificity of 79% to predict significant fibrosis. A cut point of 0.50-0.61 had a summary sensitivity of 81% and a summary specificity of 74% to predict advanced fibrosis. A cut point of 0.80-0.84 had a summary sensitivity of 72% and a summary specificity of 0.88% to predict cirrhosis. The accuracy of Hepascore was similar among all disease aetiologies for the prediction of cirrhosis. However, Hepascore had better diagnostic ability for significant and advanced fibrosis in chronic hepatitis C, chronic hepatitis B and alcoholic liver disease than for non-alcoholic fatty liver disease and HIV co-infected viral hepatitis. Hepascore is a clinically useful measure of liver fibrosis in patients with common causes of chronic liver disease.

Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis.

We conducted an individual participant data (IPD) pooled analysis on diagnostic accuracy of MRE to detect fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). Through a systematic literature search, we identified studies of MRE (at 60-62.5 Hz) for staging fibrosis in patients with NAFLD, using liver biopsy as gold standard, and contacted study authors for IPD. Through pooled analysis, we calculated the cluster-adjusted AUROC, sensitivity and specificity of MRE for any (≥stage 1), significant (≥stage 2) and advanced (≥stage 3) fibrosis and cirrhosis (stage 4). We included nine studies with 232 patients with NAFLD (mean age, 51 ± 13 years; 37.5% males; mean BMI, 33.5 ± 6.7 kg/m(2); interval between MRE and biopsy <1 year, 98.3%). Fibrosis stage distribution (stage 0/1/2/3/4) was 33.6, 32.3, 10.8, 12.9 and 10.4%, respectively. Mean AUROC (and 95% CIs) for diagnosis of any, significant or advanced fibrosis and cirrhosis was 0.86 (0.82-0.90), 0.87 (0.82-0.93), 0.90 (0.84-0.94) and 0.91 (0.76-0.95), respectively. Similar diagnostic performance was observed in stratified analysis based on sex, obesity and degree of inflammation. MRE has high diagnostic accuracy for detection of fibrosis in NAFLD, independent of BMI and degree of inflammation. • MRE has high diagnostic accuracy for detection of fibrosis in NAFLD. • BMI does not significantly affect accuracy of MRE in NAFLD. • Inflammation had no significant influence on MRE performance in NAFLD for fibrosis.

Disease burden of chronic hepatitis C among immigrants in Canada.

Immigrants with chronic hepatitis C (CHC) in Canada have doubled risk of hepatocellular carcinoma. To measure the burden of CHC among immigrants in Canada. A decision analytic model was developed to compare immigrants with CHC and age-matched immigrants without CHC for survival years, quality-adjusted life-years (QALYs) and medical costs per life year. Hepatitis C epidemiology among immigrants was based on hepatitis C prevalence in their home countries. A cohort of immigrant patients was retrospectively followed up to estimate fibrosis stage distribution, treatment patterns and prognosis of compensated cirrhosis. Other model variables were based on published sources. Base case analysis, one-way sensitivity analysis and probabilistic sensitivity analysis were performed to measure the burden of CHC and assess the impact of uncertainty associated with model variables on the burden of CHC. CHC could reduce survival by 9.6years [95% credible interval (CI): 8.0-10.9years], reduce QALYs by 9.5years (95% CI: 6.0-13.8years) and increase medical costs per life year by $1950 (95% CI: $1518 to $2486, 2006 Canadian dollars). Because nearly half of immigrants with CHC were not diagnosed until the development of cirrhosis, the burden of CHC was highly sensitive to the risks of liver-related complications and mortality but insensitive to pegylated interferon plus ribavirin. The burden of CHC among immigrants in Canada is substantial mainly due to liver-related complications and mortality. The delay in diagnosis was another important contributor to the burden of CHC among immigrants.

Comparison of Fibrotest and PGAA for the diagnosis of fibrosis stage in patients with alcoholic liver disease

The PGAA index was one of the first composite liver fibrosis markers. This study aims, prospectively, to confirm the diagnostic value of PGAA and Fibrotest in patients with alcoholic liver disease and to compare their diagnostic performances. We prospectively included 200 consecutive patients (159 men and 41 women; mean age: 51±0.7 years).The PGAA index was calculated by combining the results of four laboratory tests (prothrombin time, γ-glutamyl transpeptidase, apolipoprotein A1, and α-2-macroglobulin) scored on a 0-4 scale. The Fibrotest score was computed using the Biopredictive website. The overall diagnostic performances of scores were evaluated in terms of the area under the receiver operating characteristic (AUROC) curve. The Obuchowski measure was assessed taking into account the distribution of fibrosis stages observed in the cohort. For predicting F≥2 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.83±0.03 and 0.80±0.03, respectively. For predicting F4 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.87±0.03 and 0.86±0.03. There was no difference between the AUROC curves of PGAA and Fibrotest. The Obuchowski measure was 0.92±0.01 for PGAA and Fibrotest. For a value of 10, PGAA had 98% specificity and 97% positive predictive value for the detection of F≥2 fibrosis stage and 80% sensitivity and 92% negative predictive value for F4 stage fibrosis. We confirm the comparable diagnostic values of Fibrotest and PGAA. When Fibrotest use is constrained by an increase in unconjugated bilirubin or is not financially viable, PGAA may be an alternative.

PWE-286 Direct serum markers are more accurate than simple marker panels for the detection of fibrosis in non-alcoholic fatty liver disease (NAFLD)

IntroductionThe identification of fibrosis in patients with NAFLD is important for ascertaining prognosis and stratifying patients for emerging therapeutic interventions. Use of both direct marker panels (liver matrix components) and...

1076 DIRECT SERUM MARKERS ARE MORE ACCURATE THAN SIMPLE MARKER PANELS FOR THE DETECTION OF FIBROSIS IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Introduction The identification of fibrosis in patients with NAFLD is important for ascertaining prognosis and stratifying patients for emerging therapeutic interventions. Use of both direct marker panels (liver matrix components) and indirect marker panels (simple biochemical tests) have been described for the detection of fibrosis in NAFLD. The aim of this study was to compare the performance of direct and indirect serum marker panels in the detection of fibrosis in NAFLD as compared with liver biopsy. Methods From two centres, 177 patients were recruited and underwent percutaneous liver biopsy. Fibrosis staging was assessed using Kleiner criteria by two senior liver-histopathologists. Serum at the time of biopsy was used to calculate six indirect marker panels of fibrosis (APRI, BAAT, BARD, Cirrhosis discriminate score, NAFLD fibrosis index and Fib4). These panels were compared with the ELF Test (HA, TIMP1, PIIINP) and HA alone. Diagnostic accuracy was assessed using receiver operating characteristic curves which were compared using the method of DeLong. Results The distribution of fibrosis stages in the cohort were as follows: F0 39.5% (n=70), F1 19.2% (n=34), F2 17.5% (n=31), F3 13.6% (n=24), F4 10.2% (n=18). While ELF and HA alone had the best performance overall, the ELF test was better than HA in its ability to discriminate minimal fibrosis (p=0.02) and cirrhosis (p=0.06). All indirect serum markers tested had significantly worse performance than ELF in the detection of cirrhosis (p Conclusion In patients with NAFLD, direct serum marker panels have superior performance compared to indirect marker panels allowing superior stratification and prognostication. The performance of HA alone is enhanced by the addition of PIIINP and TIMP1. Competing interests None declared.

Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection

We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population. Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10(-3) between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (< or =F1, F1+/-1, > or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis. Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients.

GlycoFibroTest Is a Highly Performant Liver Fibrosis Biomarker Derived from DNA Sequencer-based Serum Protein Glycomics

Liver fibrosis is currently assessed by liver biopsy, a costly and rather cumbersome procedure that is unsuitable for frequent patient monitoring, which drives research into biomarkers for this purpose. To investigate whether the serum N-glycome contains information suitable for this goal, we developed a 96-well plate-based serum N-glycomics sample preparation protocol that only involves fluid transfer steps and incubations in a PCR thermocycler yielding 8-aminopyrene-1,3,6-trisulfonic acid-labeled N-glycans. These N-glycans are then ready for analysis on the capillary electrophoresis-based DNA sequencers that are the current standard in clinical genetics laboratories worldwide. Subsequently we performed a multicenter, blinded study of 376 consecutive chronic hepatitis C virus patients for which liver biopsies and extensive serum biochemistry data were available. Among patients, the METAVIR fibrosis stage distribution was as follows: 10.6% F0, 44.4% F1, 20.5% F2, 18.4% F3, and 6.1% F4. We found that the ratio of two N-glycans, here called GlycoFibroTest, correlates with the histological fibrosis stage equally well as FibroTest (rho = 0.4-0.5 in F1-F4), which is used in the clinic today. Finally using affinity chromatography we depleted sera of immunoglobulin G, and this resulted in a complete removal of the undergalactosylated biantennary glycans from the N-glycome, which are partially determining GlycoFibroTest.

How to Measure the Diagnostic Accuracy of Noninvasive Liver Fibrosis Indices: The Area Under the ROC Curve Revisited

The area under the ROC curve (AUC) is widely used to measure the diagnostic accuracy of noninvasive fibrosis indices. However, use of the AUC assumes a binary gold standard, whereas fibrosis staging is based on an ordinal scale and also depends on the distribution of fibrosis stages in the study sample. We explored other fibrosis staging accuracy measures designed for ordinal gold standards, the C-statistic and the Obuchowski measure. We performed a simulation study to assess the bias in estimating the accuracy measures when the distribution of fibrosis stages in the study sample do not fit the reference distribution in the population to which the indices are applied. We also estimated the type I error of the tests comparing these measures in 2 samples with different distributions of fibrosis stages. We illustrated the practical use of these measures by reanalyzing real data. Compared with the AUC or the C-statistic, the Obuchowski measure showed limited bias when the distribution of fibrosis stages in the study sample differed from the reference distribution. The type I error was strongly inflated with the AUC or the C-statistic but was preserved in the Obuchowski measure. When we compared noninvasive indices on real data, AUC analysis led to discordant results depending on how the fibrosis stages were grouped together. One single conclusion was drawn from the analysis based on the Obuchowski measure. We recommend using the Obuchowski measure for assessing the diagnostic accuracy of noninvasive indices of fibrosis.

Magnetic Resonance Elastography for the Noninvasive Staging of Liver Fibrosis

The purpose of our study was to prospectively compare the success rate and diagnostic accuracy of magnetic resonance elastography, ultrasound elastography, and aspartate aminotransferase to platelets ratio index (APRI) measurements for the noninvasive staging of fibrosis in patients with chronic liver disease. We performed a prospective blind comparison of magnetic resonance elastography, ultrasound elastography, and APRI in a consecutive series of patients who underwent liver biopsy for chronic liver disease in a university-based hospital. Histopathologic staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 141 patients were assessed. The technical success rate of magnetic resonance elastography was higher than that of ultrasound elastography (133/141 [94%] vs 118/141 [84%]; P = .016). Magnetic and ultrasound elastography, APRI measurements, and histopathologic analysis of liver biopsy specimens were technically successful in 96 patients. The areas under the receiver operating characteristic curves of magnetic resonance elasticity (0.994 for F >or= 2; 0.985 for F >or= 3; 0.998 for F = 4) were larger (P < .05) than those of ultrasound elasticity, APRI, and the combination of ultrasound elasticity and APRI (0.837, 0.709, and 0.849 for F >or= 2; 0.906, 0.816, and 0.936 for F >or= 3; 0.930, 0.820, and 0.944 for F = 4, respectively). Magnetic resonance elastography has a higher technical success rate than ultrasound elastography and a better diagnostic accuracy than ultrasound elastography and APRI for staging liver fibrosis.