Non-invasive Fibrosis Markers Research Articles

P6472Novel cardiac imaging prognostic markers of clinical outcome in patients with bicuspid aortic valve and chronic aortic regurgitation

Abstract Background Patients with chronic aortic regurgitation (AR) can have a substantial myocardial damage despite being asymptomatic. Early surgical strategy might be beneficial. Bicuspid aortic valve (BAV) is a congenital heart disease present in almost 30% of these patients. Purpose Identify novel imaging predictors of early disease progression. Methods Prospective three-centre study of patients with chronic AR of at least moderate to severe (3+) grade and BAV morphology. Patients without currently recognised indication for surgical treatment were enrolled. Baseline examination included echocardiography (ECHO) with 3-dimensional (3D) vena contracta area and magnetic resonance (MR) with regurgitant fraction measured from flow sequence. All imaging studies were analysed in CoreLab. The primary endpoint was defined as a combination of cardiovascular death, surgical treatment or hospitalization for heart failure. Results A total of 83 patients with BAV and at least 3+ AR were enrolled during 2015–2018. Median follow-up was 759±455 days, primary composite endpoint occurred in 13 patients who met criteria for surgical treatment, no patient died or was hospitalized for heart failure. Baseline parameters were compared between two groups: patients with and without endpoint. Clinical and laboratory data did not differ between the two groups. Left ventricular (LV) ejection fraction was normal in all patients. LV diameters and volumes were significantly larger in patients with primary endpoint. This was most pronounced in MR measured indexed volumes in end-diastole and end-systole, P=0.003 and P=0.003. Non-invasive markers of diffuse myocardial fibrosis (native T1 relaxation time and global longitudinal strain, P=0.614 and P=0.137 respectively) were not different. Novel markers of AR severity were significantly increased in surgically treated patients: 3D vena contracta 0.26±0.10 cm2 versus 0.38±0.11 cm2 (P<0.001), MR regurgitant fraction 33.9±15.4 versus 50.2±12.2% (P=0.001). Both 3D vena contracta with cutoff value ≥0.4 cm2 (sensitivity=85%, specificity=84%, area under the curve=0.85) and MR regurgitant fraction with cutoff value ≥34% (sensitivity=94%, specificity=58%, area under the curve=0.76) showed high accuracy to identify patients who require early surgical intervention. Adding 3D vena contracta and MR regurgitant fraction to indexed LV end-systolic volumetric parameters significantly increases the predictive value for early disease progression with p=0.001 and p=0.006 (Likelihood-ratio test). 3D vena contracta predictive value Conclusions Novel imaging parameters of AR severity such as 3D vena contracta and MR derived regurgitant fraction predict early disease progression in patients with BAV and at least 3+ chronic AR. These values significantly increase the predictive value of traditional parameters based on LV size measures.

Detecting Liver Fibrosis by Recent Reliable Biomarkers in Viral Hepatitis Patients

Abstract Objectives By far, chronic viral hepatitis and its complications have been considered a fatal health public issue. Liver biopsy has a pivotal role to distinguish patients who need proper care and regular screening. The correlation between alternative biomarkers and liver fibrosis has been studied by current research to avoid histopathology techniques. Methods Several biomarkers such as COLL-IV, COMP, and hyaluronic acid besides scoring systems (FIB-4, APRI, NAFLD, and SHASTA) were measured and calculated in 143 infected cases with HCV and HBV. Also, the same parameters were determined in 75 healthy persons as controls. The Metavir system was used to classify infected cases from F0 to F4. Alternative marker levels were determined by using the ELISA technique. HBV DNA and HCV RNA were quantified by implementing the RT-PCR assay. Noninvasive markers were approved by comparison with the mentioned scoring indexes. Results Our research has indicated that hyaluronic acid, COMP, Coll-IV, and scoring indexes of fibrosis discriminate fibrosis cases from the nonfibrosis group. The studied biomarkers have high sensitivity from 77.05% to 96.72% and accuracy from 89.71% to 97.79% as well as their cutoff, which approved the aim of this study. Thereafter, the studied markers’ reports assisted in differentiating primary stages F1+F2 from late levels F3+F4 of fibrosis. Conclusions According to reports of the current study, serum markers including HA and CO-IV have performed better than biopsy in excluding advanced fibrosis from mild fibrosis patients comfortably as well as differentiating fibrosis patients from healthy individuals, while the COMP test has low accuracy and needs further research. Scoring systems alone are likely not sufficiently sensitive to rule out significant disease. Hence, gathering serological markers and scoring indexes are being perfected to determine all stages of fibrosis definitely. However, further research is needed to prove reliable noninvasive markers of liver fibrosis.

Increased Risk of Low Bone Mineral Density in Patients with Non-Alcoholic Fatty Liver Disease: A Cohort Study

Background: Non-alcoholic fatty liver disease (NAFLD) has been suggested to be a risk factor associated with low BMD (bone mineral density) in several cross-sectional studies. The present study aims to explore the effect of NAFLD and its severity on low BMD in a longitudinal cohort study. Methods: Between January 2013 and August 2018, individuals who participated in annual comprehensive health examinations were included. BMD was presented using dual-energy X-ray absorptiometry (DXA). These subjects were defined as fatty liver by ultrasound detection. Findings: A total of 1,720 subjects were included (1,064 subjects with normal BMD and 656 subjects with low BMD) at baseline. Among 1064 participants with normal BMD at baseline, 399 participants developed low BMD. The multivariable-adjusted hazard ratio for incident low BMD comparing the NAFLD group vs. the non-NAFLD group was 2.24(1.178, 2.81). Increased non-invasive fibrosis markers of NAFLD were positively associated with an increased incidence of low BMD in a graded manner. In addition, obesity and women with NAFLD at baseline, are more likely to develop low BMD. Interpretation: NAFLD and its severity were independently associated with an increased incidence of low BMD. Obesity and female gender are risk factors associated with low BMD. Our findings indicated NAFLD can be a significant contributor to low BMD pathogenesis, requiring further studies to elucidate the potential mechanisms. Funding Statement: Supported by National Natural Science Foundation of China (No.81770586). Declaration of Interests: Zhe Shen, Li Cen, Xufeng Chen, Jiaqi Pan, Youming Li, Weixing Chen and Chaohui Yu declare that they have no confict of interest. Ethics Approval Statement: The present study was approved by the Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (IRB No.2018-980).

Effectiveness of Noninvasive Fibrosis Markers for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B and Chronic Hepatitis B+D Induced Cirrhosis

PurposeDespite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, the incidence and mortality of hepatocellular carcinoma (HCC) continue to rise. To obtain the best treatment result for HCC, early diagnosis is the key. In this study, we investigated the accuracy of noninvasive fibrosis markers, which have been typically used to predict liver fibrosis in recent years, in the prediction of HCC development in patients with chronic hepatitis B and chronic hepatitis B + D–induced cirrhosis. MethodsBetween 2004 and 2018, 1216 patients with chronic liver disease were retrospectively reviewed, and 331 patients (27%) with hepatitis B and hepatitis B+D virus–related cirrhosis were enrolled in our study. Patients were divided into 2 groups based on HCC diagnosis (HCC and non-HCC group). Eleven noninvasive fibrosis markers were evaluated in the groups. These markers included 3 alpha-fetoprotein (AFP)-based models (PAPAS index, Fibro-alpha, and BRC score) and 8 non-AFP based models (Lok index, FIB–4, Fibro-O index, APRI, King’s score, Forns index, Bonacini score, and HUI model) for each Child-Pugh score in the prediction of HCC. ResultsAFP-based models were higher in HCC group patients, and statistically significant outcomes were detected with these methods in each Child-Pugh score group for HCC prediction (P < .05). Non-AFP based–methods showed different and inconsistent results in each Child-Pugh score group. ConclusionThese easily applied fibrosis markers, particularly AFP-based models, may provide an effective, simple, and low-cost way to predict HCC development in patients with hepatitis B and hepatitis B + D cirrhosis.

Association of Non-Invasive Markers of Liver Fibrosis with HCV Coinfection and Antiretroviral Therapy in Patients with HIV

Abstract The aim of this study was to assess the main effects and interaction between viral hepatitis C (HCV) coinfection and antiretroviral therapy (ART) by using a nonparametric ANOVA on direct and indirect markers of liver fibrosis in HIV-infected patients. The sample included 178 HIV patients aged from 23 to 65 (36% females). The following parameters were determined in blood of patients: hyaluronic acid, pro-matrix metalloproteinase-1, alanine aminotransferase, aspartate aminotransferase, and platelet count. The FIB-4 index was also calculated. The nonparametric ANOVA revealed no significant interaction between HCV coinfection and ART. This provides evidence for an independent contribution of each factor on promotion of the pathology. The results also demonstrated that the direct and indirect indicators of liver fibrosis are associated differently with the studied factors. Therefore, a combination of markers should be used for monitoring of liver fibrosis in HIV-infected patients.

Metabolically healthy versus unhealthy obesity and risk of fibrosis progression in non-alcoholic fatty liver disease.

Little is known about the impact of metabolically healthy obesity on fibrosis progression in non-alcoholic fatty liver disease (NAFLD). We investigated the association of body mass index (BMI) category, body fat percentage and waist circumference with worsening of noninvasive fibrosis markers in metabolically healthy and unhealthy individuals with NAFLD. A cohort study was performed on 59957 Korean adults with NAFLD (13285 metabolically healthy and 46672 metabolically unhealthy individuals) who were followed for a median of 7.7years. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homoeostasis model assessment of insulin resistance <2.5. Progression from low to intermediate or high probability of advanced fibrosis was assessed using the NAFLD fibrosis score (NFS). During 339253.1 person-years of follow-up, 9857 subjects with low NFS at baseline progressed to intermediate or high NFS. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CI) for NFS worsening comparing BMIs 23-24.9, 25-29.9 and ≥30 with a BMI of 18.5-22.9kg/m2 were 1.19 (1.00-1.42), 1.79 (1.52-2.10) and 3.52 (2.64-4.69), respectively, whereas the corresponding HRs (95% CI) in metabolically unhealthy individuals were 1.37 (1.24-1.52), 2.18 (1.99-2.39) and 4.26 (3.83-4.75). A similar trend was observed in the analyses using body fat and waist circumference. In the large-scale cohort of young and middle-aged individuals with NAFLD, BMI was positively associated with worsening of noninvasive fibrosis marker regardless of metabolic health status. Excess adiposity per se, even without accompanying metabolic health status, may contribute to fibrosis progression in NAFLD.

Noninvasive Serum Fibrosis Markers are Associated with Coronary Artery Calcification in Patients with Nonalcoholic Fatty Liver Disease.

Background/AimsAdvanced hepatic fibrosis is associated with cardiovascular disease (CVD) in patients with nonalcoholic fatty liver disease (NAFLD). We investigated the association between noninvasive serum fibrosis markers and the coronary artery calcium score (CACS) in subjects with NAFLD.MethodsWe analyzed 665 NAFLD subjects without chronic liver disease or heart disease between 2011 and 2015. The noninvasive fibrosis markers that were used to evaluate the severity of hepatic fibrosis included the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4) score, Forn’s index, and the aspartate aminotransferase to platelet ratio index (APRI).ResultsThe areas under the receiver operating characteristics curves for the NFS, FIB-4 score, Forn’s index and APRI for predicting CACS >100 were 0.689, 0.683, 0.659, and 0.595, respectively. According to the multivariate analysis, older age, increased body mass index (BMI), and decreased estimated glomerular filtration rate (eGFR) were significant factors associated with CACS >100. The NFS, FIB-4 score and APRI were significantly associated with CACS >100 after adjusting for age and gender (p=0.006, p=0.012, and p=0.012, respectively) and after adjusting for age, gender, BMI and eGFR (p=0.013, p=0.022, and p=0.027, respectively). Scores integrating noninvasive fibrosis markers and other risk factors improved the predictive accuracy.ConclusionsThe NFS and FIB-4 score were associated with coronary atherosclerosis in subjects with NAFLD. Furthermore, scores integrating these noninvasive scores and risk factors for CVD showed good discriminatory power in predicting CACS >100. Therefore, noninvasive serum fibrosis markers may be useful tools for identifying NAFLD subjects at a high risk for CVD.

Practical Use of Transient Elastography in Screening for Nonalcoholic Steatohepatitis in a Japanese Population.

Background and Aims: Fatty infiltration of liver may induce insulin resistance (IR), and a proportion of patients with nonalcoholic fatty liver disease (NAFLD) is diagnosed with nonalcoholic steatohepatitis. Transient elastography is gaining popularity as a means of non-invasively determining both liver stiffness (fibrosis level) and degree of fatty infiltration, expressed as controlled attenuation parameter (CAP) value.Methods: The aims of this study were to investigate the association between IR and level of fatty liver, and to identify the group at a greater risk of nonalcoholic steatohepatitis using transient elastography and other noninvasive fibrosis markers. A total of 169 patients without chronic hepatitis B and C were analyzed.Results: The CAP value was significantly associated with IR (HOMA-IR ≥2.5; AUROC = 0.81), and the optimal cut-off to discriminate IR was 264 dB/m. The liver stiffness measurement and aspartate aminotransferase-to-platelet ratio index values were significantly higher for CAP ≥264 than in CAP <264. The 9 patients among the overall 169 patients (5.3%) and among the 102 NAFLD patients (8.8%) who showed ≥264 dB and ≥7.0 kPa in transient elastography could represent good candidates for liver biopsy.Conclusions: Evaluation of NAFLD based on CAP values was useful in diagnosing IR. About 9% of NAFLD patients in a Japanese outpatient clinic with a few metabolic complications might be considered good candidates for liver biopsy to confirm nonalcoholic steatohepatitis.

1902-P: Definition of Nonalcoholic Fatty Liver Disease (NAFLD) Stage by Independent Noninvasive Fibrosis Markers and Elastography

Aim: We sought to define the degree of NAFLD with B-mode ultrasound sono-elastography using the discriminant Bonacini scale in type 2 diabetes (T2D) patients. Materials and Methods: Forty-three patients with T2D and clinically diagnosed NAFLD (26F, 17M) were examined with liver ultrasound in B-mode elastography. The presence and degree of fibrosis was assessed using the Bonacini Classification (Discriminant) Scale. The compliance of the stage of the fibrosis was compared with results of the histological evaluation of METAVIR and Ishak. Results: An enlarged liver was found in all, often combined with the hyperechogenic, coarse-grained structure. In rare cases, a decrease in the liver echogenicity indicated development of fibrosis. The liver density index was significantly higher in men (2.63 ± 0.05) than in women (2.49 ± 0.06, p = 0.05). In a series of correlation analyses, it was found that sono-elastography strongly correlated with the results of the classification (discriminant) Bonacini score scale (r= 0.68 ± 0.13, p &amp;lt;0.001). The results of the Ishak and METAVIR scales at minimum values have a moderate correlation with sono-elastography data (r= 0.36 ± 0.17, p &amp;lt; 0.05 and r= 0.37±0.16, p&amp;lt;0.05respectively). These scales determine the degree of fibrosis as a range from the less to the greater degree, but the stronger correlation (r= 0.50 ± 0.16, p&amp;lt;0.01and r= 0.47 ± 0.15, p&amp;lt;0.01respectively) with results of sono-elastography was found in patients with severe fibrosis of the liver. Conclusion: In majority of type 2 DM patients with clinical NAFLD a slight degree fibrosis (F0-F2) was diagnosed. To better assess the degree of liver fibrosis in these patients it is advisable to use sono-elastography and the discriminant Bonacini scale. These have similar significance, can complement each other and allow identification of early manifestations of liver fibrosis in patients with type 2 DM. Disclosure O. Lavrynenko: None. O. Zemlianitsyna: None. N. Kravchun: None. I. Dunaeva: None. I. Karachentsev: None. V. Sinaiko: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.

Longitudinal effects of Nucleos(t)ide analogue therapy in chronic hepatitis B patients and the utility of non-invasive fibrosis markers during treatment: A single-center experience for up to 17 years

BackgroundFibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated. AimsTo characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients. MethodsHistology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally. Results80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4–6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03). ConclusionEarly dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment.

Peritransplant kinetics of Mac-2-binding protein glycosylation isomer levels in living donor liver transplantation: its implication of posttransplant small-for-size syndrome.

Wisteria floribunda agglutinin positive human Mac-2 binding protein glycosylation isomer (M2BPGi) has recently developed as a noninvasive serum marker of liver fibrosis. Liver transplant candidates usually have high serum levels of M2BPGi due to advanced cirrhosis. The aim of the present study was to elucidate the kinetics of serum M2BPGi after liver transplantation and the relationships between the level of M2BPGi and graft function. Fifteen recipients who underwent living donor liver transplantation (LDLT) between June 2015 and January 2016 and whose pretransplant, postoperative day (POD) 1, POD 3, and POD 7 sera were available for measuring M2BPGi were enrolled in this study. Small-for-size syndrome (SFSS) was defined as the presence of cholestasis (total bilirubin >10 mg/dL) on POD 7 and intractable ascites (>1 L/day on POD 14 or >500 ml/day on POD 28) without other specific causes. The median of pretransplant M2BPGi was 9.75 cutoff index (C.O.I.) (range, 3.04-24.49). There was neither any correlation between pretransplant M2BPGi and Model for End-Stage Liver Disease scores (r=0.416, P=0.123) nor Child-Turcotte-Pugh scores (r=-0.221, P=0.428). The levels of M2BPGi dramatically decreased after LDLT (median; 1.48 on POD 1, 1.47 on POD 3, 1.49 on POD 7). However, serum levels of M2BPGi rose again on POD 7 in some recipients and all 4 recipients with serum levels of M2BPGi exceeding 3.00 C.O.I. succumbed to SFSS later. When the cutoff of M2BPGi on POD 7 for predicting SFSS was determined to be 3.06 according to its receiver operating characteristic curve, both the sensitivity and the specificity for predicting later SFSS were 100%. The levels of M2BPGi dramatically decreased after LDLT. A re-rise of M2BPGi predicted later development of SFSS.

Diagnostic Value of Anti-gp210 Combined with Indirect Serum Markers for Predicting Histological Staging in Patients with Primary Biliary Cholangitis

Background: Diagnosis of the histological stage in primary biliary cholangitis (PBC) is essential for prognosis and further therapy. Noninvasive markers of liver fibrosis in PBC remain compelling. This study aimed to validate the diagnostic value of AST to ALT ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis index based on 4 factors (FIB-4) in predicting histological severity among PBC patients combined with anti-gp210. Methods: A total of 208 PBC patients receiving liver biopsy with complete serological tests were enrolled. Clinical data including AAR, APRI and FIB-4 were compared with histological stage. Receiver operating characteristic analyses (ROCs) were used to assess the sensitivity and specificity of these markers with or without anti-gp210 in estimating liver fibrosis. Findings: The scores of AAR, APRI, and FIB-4 increased significantly according to the Ludwig's stage. Anti-gp210 was independently associated with liver fibrosis. The areas under the ROCs (AUCs) of AAR, APRI and FIB-4 combined with anti-gp210 for predicting advanced stage were 0.798, 0.816 and 0.834, respectively, which were superior to the AUCs of these markers predicting alone. The AUCs of AAR, APRI and FIB-4 for predicting advanced stage in the anti-gp210 positive patients were 0.748, 0.812 and 0.874, respectively. Using the best cutoff values of AAR, APRI, and FIB-4, 36.5%, 34.3% and 51.3% of patients could avoid liver biopsy, respectively. Interpretation: Indirect serum markers AAR, APRI, and FIB-4 represented a simple and reliable noninvasive surrogate marker of liver fibrosis especially in anti-gp210 positive PBC patients. Funding Statement: National Key Technology R&D Programme (2015BAI13B07). Declaration of Interests: All the authors declare no competing interests. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Fourth Military Medical University. Informed consent was obtained in writing from each patient, and the study protocol was approved by the ethical committee of the Fourth Military Medical University

Elevated non-invasive liver fibrosis markers and risk of liver carcinoma in adult patients after repair of tetralogy of Fallot

BackgroundCongestive hepatopathy and hepatocellular carcinoma is a serious complication after Fontan procedure. Liver fibrosis due to hepatic congestion could occur also in adult patients after repair of tetralogy of Fallot (rTOF). However, the incidence and severity remain unclear. MethodsA total of 111 patients with adult congenital heart disease between 2009 and 2016 were enrolled. Liver fibrosis markers and hemodynamic parameters assessed by cardiac magnetic resonance imaging and catheterization were analyzed in 50 rTOF patients having significant pulmonary regurgitation and/or stenosis, 50 Fontan patients and 11 controls. ResultsLiver fibrosis markers in patients with rTOF were significantly higher than controls, and tended to be lower than Fontan patients (median, hyaluronic acid: 25.8 vs. 15.9 vs. 40.8, type IV collagen: 129 vs. 113 vs. 166, ng/mL, p < 0.05, respectively). Patients with rTOF showed abnormal hyaluronic acid levels more frequently than controls, and less frequently than Fontan patients (22% vs. 0% vs. 38%, respectively, p < 0.05). Multivariate analyses indicated a positive association of right atrial pressure with type IV-collagen or hyaluronic acid levels (each, p < 0.001, p = 0.003). Abdominal ultrasonography revealed hepatic congestion in 50% of rTOF patients tested. Liver biopsy of the two rTOF patients with highest hyaluronic acid levels showed pathological evidence of moderate and severe (F2 and F3) liver fibrosis and one had combined hepatocellular and cholangiocarcinoma. ConclusionsWe first demonstrated elevated liver fibrosis markers in adult patients with rTOF. These levels may help to predict the progressive liver disease as well as consider the timing of pulmonary valve replacement.

Diagnostic Accuracy of Noninvasive Markers of Steatosis, NASH, and Liver Fibrosis in HIV-Monoinfected Individuals at Risk of Nonalcoholic Fatty Liver Disease (NAFLD): Results From the ECHAM Study.

HIV-monoinfected individuals are at high risk of nonalcoholic fatty liver disease. Noninvasive tests of steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis have been poorly assessed in this population. Using liver biopsy (LB) as a reference, we assessed the accuracy of noninvasive methods for their respective diagnosis: magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), FibroScan/controlled attenuation parameter (CAP), and biochemical tests. We enrolled antiretroviral therapy-controlled participants with persistently elevated transaminases and/or metabolic syndrome, and/or lipodystrophy. All had hepatic MRI-PDFF, FibroScan/CAP, FibroTest/NashTest/SteatoTest, APRI, FIB-4, and nonalcoholic fatty liver disease-fibrosis score. A LB was indicated if suspected significant fibrosis (FibroScan ≥7.1 kPa and/or FibroTest ≥0.49). Performance was considered as good if area under a receiver operating characteristic curves (AUROCs) was >0.80. Among the 140 patients with suspected significant fibrosis out of the 402 eligible patients, 49 had had a LB: median age of 54 years (53-65), body mass index: 26 kg/m (24-30), steatosis in 37 (76%), NASH in 23 (47%), and fibrosis in 31 (63%) patients [F2: 7 (14%); F3: 6 (12%); and F4: 2 (4%)]. Regarding steatosis, MRI-PDFF had excellent and CAP good performances with AUROCs at 0.98 (95% confidence interval: 0.96 to 1.00) and 0.88 (0.76 to 0.99), respectively, whereas the AUROCs of SteatoTest was 0.68 (0.51 to 0.85). Regarding fibrosis (≥F2), APRI and FIB-4 had good performance with AUROCs at 0.86 (0.74 to 0.98) and 0.81 (0.67 to 0.95). By contrast, FibroScan and FibroTest had poor AUROCs [0.61 (0.43 to 0.79) and 0.61 (0.44 to 0.78)], with very low specificity. Regarding NASH, alanine aminotransferase ≥36 IU/L had good performance with AUROCs of 0.83 (0.71 to 0.94), whereas the NashTest had an AUROC of 0.60 (0.44 to 0.76). In HIV-monoinfected patients, MRI-PDFF and FibroScan/CAP are highly accurate for the diagnosis of steatosis. The alanine aminotransferase level and APRI should be considered for the detection of NASH and fibrosis.

Relationship between three commonly used non‐invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non‐alcoholic steatohepatitis

Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25mg OCA or placebo once daily for 72weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72weeks. In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P=0.015) and FIB-4 (P=0.036), but not NFS (P=0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P<0.0001); NFS (P<0.05)]. Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.

Non-invasive markers of fibrosis at 3 years of follow-up in liver transplant recipients with moderate/severe hepatitis C recurrence, successfully treated with DAAs

Non-invasive markers of fibrosis at 3 years of follow-up in liver transplant recipients with moderate/severe hepatitis C recurrence, successfully treated with DAAs

Association Between Noninvasive Fibrosis Markers and Postoperative Mortality After Hepatectomy for Hepatocellular Carcinoma

The selection criteria for hepatectomy for hepatocellular carcinoma (HCC) is not well established. The role of noninvasive fibrosis markers in this setting is unknown in the US population. To evaluate whether aspartate aminotransferase-platelet ratio index (APRI) and fibrosis 4 (Fib4) values are associated with perioperative mortality and overall survival after hepatectomy for HCC. In a multicenter cohort study, Veterans Administration Corporate Data Warehouse was used to evaluate a retrospective cohort of 475 veterans who underwent hepatectomy for HCC between January 1, 2000, and December 31, 2012, in Veterans Administration hospitals. Data analysis occurred between September 30, 2016, and December 30, 2017. Logistic regression, survival analysis, and change in concordance index analysis were performed to evaluate the association between APRI and Fib4 values and mortality. The cohort was stratified based on preoperative APRI and Fib4 values. Analysis was performed accounting for the validated and established predictors of outcome. Thirty-day mortality, 90-day mortality, and overall survival were the primary outcomes. An APRI value greater than 1.5 was considered high risk (cirrhosis), and an Fib4 value greater than 4.0 was considered high risk (advanced fibrosis). Portal hypertension (diagnosis of ascites or encephalopathy indicates presence of portal hypertension) and Child-Turcotte-Pugh (CTP) class (A indicates preserved liver function; B, mild to moderate liver dysfunction) served as 2 other measures of liver function. A total of 475 patients with HCC underwent hepatectomy. The mean (SD) age was 65.6 (9.4) years; Model for End-Stage Liver Disease score, 8.9 (3.1); and body mass index, 28.1 (4.9) (calculated as weight in kilograms divided by height in meters squared). A total of 361 patients (76.0%) were men, 294 (61.9%) were white; 308 (64.8%) were hepatitis C positive, and 346 (72.8%) were categorized as CTP class A. The most common surgical procedure was partial lobectomy, with 321 (67.6%) procedures. The APRI value greater than 1.5 vs 1.5 or lower was associated with increased 30-day mortality (odds ratio [OR], 6.45; 95% CI, 2.80-14.80) and 90-day mortality (OR, 2.65; 95% CI, 1.35-5.22), as was Fib4 greater than 4.0 vs Fib4 4.0 or lower for 30-day mortality (OR, 5.41; 95% CI, 2.35-12.50) and 90-day mortality (OR, 2.74; 95% CI, 1.41-5.35). Survival analysis showed that overall survival was significantly different for APRI greater than 1.5 vs 1.5 or lower (mean survival time, 3.6 vs 5.4 years; log-rank P < .001) and Fib4 greater than 4.0 vs 4.0 or lower (mean survival time, 4.1 vs 5.3 years; log rank P = .01). Adjusted Cox proportional hazards regression analysis revealed that elevated APRI was significantly associated with worse survival (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23) but Fib4 values were not (HR, 1.04; 95% CI, 0.99-1.09). Change in concordance index showed that APRI and Fib4 improved the ability of CTP class and portal hypertension to predict postoperative mortality. Elevated APRI and Fib4 values, which are noninvasive markers of fibrosis, were associated with higher perioperative mortality. The APRI was also associated with worse overall survival. Use of APRI and Fib4 measures improved the ability of established markers to predict postoperative mortality. These findings suggest incorporating APRI and Fib4 to the selection process for hepatectomy for HCC as predictors associated with mortality may be warranted.

Serum alkaline phosphatase levels as a simple and useful test in screening for significant fibrosis in treatment-naive patients with hepatitis B e-antigen negative chronic hepatitis B.

BackgroundStaging of liver fibrosis is critical in guiding the treatment of chronic hepatitis B (CHB) virus. Many efforts have been made toward the research of noninvasive techniques, mostly focusing on hepatitis B e-antigen (HBeAg)-positive [HBeAg(+)] CHB patients, whereas HBeAg(+) and HBeA-negative [HBeAg(−)] represent different stages of hepatitis B virus infection. Thus, in this study, we aimed to search for routinely available clinical noninvasive liver fibrosis markers and separately analysed the markers in HBeAg(+) and HBeAg(−) CHB patients.MethodsPatients with CHB who were treatment naive and who underwent a liver biopsy at our hospital from 1 January 2016 to 31 April 2017 were enrolled. Liver histology was scored using the Scheuer classification system. The area under the receiver operator curve was used to determine the diagnostic accuracy.ResultsA total of 191 patients, including 104 HBeAg(+) and 87 HBeAg(−) treatment-naive CHB patients, were enrolled in this study. Serum alkaline phosphatase (ALP) levels increased gradually in all patients and separately in HBeAg(−) CHB patients, but not in HBeAg(+) CHB patients. ALP was an independent factors predicting significant fibrosis (S≥2) in all of the patients and separately in HBeAg(−) patients, with area under the receiver operator curves of 0.651 and 0.717, respectively. Further, the optimal cut-off value of ALP (>69.5 IU/l) for distinguishing HBeAg(−) CHB patients with significant fibrosis was determined (S≥2).ConclusionSerum ALP levels can identify significant fibrosis (S≥2) in treatment-naive HBeAg(−) CHB patients and could potentially reduce the need for liver biopsies and help to guide the clinical treatment of CHB.

Lysosomal Acid Lipase: Can it be a New Non-Invasive Serum Biomarker of Cryptogenic Liver Fibrosis and Cirrhosis?

Introduction and aim. The association between lysosomal acid lipase (LAL) activity and liver steatosis or fibrosis is poorly studied. The aim of our study was to determine the predictive power of LAL for cryptogenic liver steatosis and cryptogenic significant fibrosis/cirrhosis.Material and methods. Cross-sectional observational study of 101 adult patients with unexplained elevated liver enzymes/hepatomegaly with or without dyslipidemia submitted to the determination of LAL activity and LIPA gene (E8SJM-C.894G^A) mutation. Seventy-one patients underwent liver biopsy or FibroScan®. Patients with an identifiable liver dysfunction cause and well-stablished NAFLD/NASH risk factors were excluded. Predictors for liver steatosis, significant fibrosis (> F2) or cirrhosis (F4) were evaluated.Results. Liver steatosis and fibrosis were mainly assessed by liver biopsy (74.6%; n = 53). Steatosis was present in 62.0% (n = 44), significant fibrosis in 47.9% (n = 34) and cirrhosis in 39.4% (n = 28). The median LAL was 0.36 (0.21-0.46)nmol/spot/h (vs. 0.29 (0.20-0.47); p = 0.558) for liver steatosis, 0.22 (0.11-0.29) nmol/spot/h (vs. 0.40 (0.34-0.51); p <0.001) for significant fibrosis and 0.21 (0.11-0.27) nmol/spot/h (vs. 0.40 (0.32-0.52); p < 0.001) for cirrhosis. No LIPA gene mutations were found. LAL activity was the strongest predictor of significant fibrosis (AUROC: 0.833; p < 0.001) with a cut-off of 0.265 (sensitivity: 85.9%; specificity: 75.0%) and cirrhosis (AUROC: 0.859; p < 0.001) with a cut-off of 0.235 (sensitivity: 86.2%; specificity: 75.0%), being higher than FIB4, GUCI or APRI. However, LAL activity was not associated with liver steatosis (AUROC: 0.536; p =0.558).Conclusion. LAL activity can be considered a non-invasive new marker of cryptogenic liver fibrosis with higher accuracy than other known biomarkers. LAL activity < 0.265 nmol/spot/h was strongly associated with cryptogenic significant fibrosis and <0.235 nmol/spot/h with cryptogenic cirrhosis. LAL activity was not associated with cryptogenic liver steatosis.

Recent Advances in Imaging of Hypertensive Heart Disease.

To review recent advances in the imaging of hypertensive heart disease (HHD) with an emphasis on developments in the imaging of diffuse myocardial fibrosis using cardiac magnetic resonance (CMR). HHD results from long-standing hypertension and is characterized by the development of left ventricular hypertrophy and diffuse interstitial fibrosis. Diffuse fibrosis traditionally required endomyocardial biopsy to diagnose, but recent developments using T1 mapping in CMR allow for noninvasive assessment. Studies using T1 mapping have shown an increase in extracellular volume fraction (ECV) in patients with HHD compared to normal controls, suggesting ECV can be used as a noninvasive marker for fibrosis in HHD. In addition to T1 mapping, other recent advances in HHD imaging include improvements in three-dimensional echocardiography, allowing for accurate real-time volumetric measurements, and the use of speckle tracking echocardiography to detect subclinical systolic dysfunction. Measurement of ECV using T1 mapping in CMR can be used as a noninvasive marker of diffuse myocardial fibrosis in HHD. While further studies are needed to validate this approach with larger patient cohorts, ECV can potentially be used to both monitor disease progression and assess therapeutic interventions in HHD.