Time Of Liver Biopsy Research Articles

Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes

Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM. A total of 330 outpatients with T2DM and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-proton density fat fraction and MRE at the time of liver biopsy were studied. The main outcome was fibrotic MASH, defined as NAS ≥4 (with at least one point for each parameter) and fibrosis stage ≥2 (centrally reviewed). All data for score comparisons were available for 245 patients (median age 59 years, 65% male, median BMI 31kg/m2; fibrotic MASH in 39%). FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p=0.41) but outperformed FNI (0.74; p=0.01) and MEFIB (0.68; p<0.0001). When using original cut-offs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom liver biopsy would be avoided (69% vs. 48%, 46%, 39%, respectively; p<0.001). When using cut-offs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p<0.001). Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. Among patients with type 2 diabetes (T2DM), identifying those with metabolic dysfunction-associated steatohepatitis and significant fibrosis, who are the most at risk of developing clinical liver-related outcomes and who may benefit from pharmacologic treatments, is an unmet need. In this prospective multicenter study, we compared four non-invasive scores, three based on imaging (MRI or ultrasound technologies) and one on laboratory blood tests, for this purpose, using original and study-specific cut-offs. Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. NCT03634098.

Abstract 16282: Incident Heart Failure With Preserved Ejection Fraction in a Cohort of Patients With Biopsy-Proven Non-Alcoholic Fatty Liver Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.

Impact of fibrosis on liver-related event incidence in nonalcoholic fatty liver disease: A multicenter observational study.

There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients. Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL)+nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models. The mean age and body mass index at the time of liver biopsy was 55.7years old and 28.04kg/m2 , respectively The cumulative incidence of liver-related events at 1080days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL+nonfibrotic NASH group, with a significant difference (p=0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL+nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death. The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL+nonfibrotic NASH group in Japanese NAFLD patients.

1348-P: Glycemic Control Is Associated with the Histological Severity of Nonalcoholic Fatty Liver Disease

Background: Diabetes mellitus (DM) is a major risk for progression of nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL). Although DM influences on the pathophysiology of NASH, the impact of glycemic control status on the histological severity of NASH is unclear. Methods: We conducted an observational study of 331 patients (140 men and 191 women) diagnosed with nonalcoholic fatty liver disease (NAFLD) by liver biopsy. Impact of glycemic control status on histological severity of NAFLD was evaluated by comparison of the four divided groups, based on the hemoglobin A1c (HbA1c) levels: HbA1c ≤5.4%; 5.5-6.4%; 6.5-7.4%; and ≥7.5%, at the time of liver biopsy. The histological severity of NAFLD was determined by fibrosis staging; stage 0-4, and NAS score; 0-8 points. The advanced liver fibrosis and the high NAS score were defined as stage 3-4 and 5-8 points, respectively. Results: Higher HbA1c groups (5.5-6.4%; 6.5-7.4%; and ≥7.5%) were associated with advanced fibrosis compared to the lowest HbA1c group. In the multivariate analysis, the HbA1c 6.5-7.4% group was significantly associated with advanced fibrosis compared to the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index, as well as uric acid, total cholesterol, and triglyceride levels, HbA1c 5.5-6.4%, 6.5-7.4%, ≥7.5% groups were significantly associated with advanced fibrosis compared to the lowest HbA1c group. These HbA1c groups (5.5-6.4%; 6.5-7.4%; and ≥7.5%) were also associated with higher NAFLD activity scores, these associations remained significant in the multivariate analysis. Conclusions: The glycemic control status is strongly associated with the histological severity of NAFLD, even with mild deterioration in glycemic control. Therefore, adequate glycemic control in NAFLD patients might be important in improving NAFLD activity and preventing progression to NASH. Disclosure T.Miyake: None. Y.Hiasa: None. S.Furukawa: Speaker's Bureau; Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Novo Nordisk, Eli Lilly Japan K.K. B.Matsuura: None. O.Yoshida: None. M.Miyazaki: None. A.Shiomi: None. S.Kanzaki: None. H.Nakaguchi: None. M.Abe: None.

Ataxia Telangiestasia Mutated (ATM) Inhibition Disrupts Nuclear And Mitochondrial Homeostasis In Pediatric Nonalcoholic Fatty Liver Disease (PNAFLD)

BACKGROUND: The pathophysiology of PNAFLD is important to understand in order to improve outcomes. Integration of critical components including metabolic stress, inflammation, organelle function, and DNA damage and repair should be particularly critical for this purpose. To emphasize the contribution of DNA damage response and cell survival mechanisms on PNAFLD outcomes during the period of active liver growth, we focused on the ATM pathway. In toxic liver injury settings, replenishment of ATM overcomes restrictions in liver homeostasis and regeneration. METHODS and RESULTS: We undertook a study of PNAFLD in a cohort of children under 12 years of age to represent the period of active liver growth (N=47). Demographic details were noted including age, gender, ethnic origin and duration of obesity as defined by BMI greater than 85th percentile. B iopsies were examined for NAFLD activity score (NAS) components steatosis, ballooning and inflammation as well as fibrosis. Mitochondrial DNA content was quantitated by qPCR for the mitochondrial gene, TL1, vs the nuclear gene, RNAseP. Ploidy class distributions was evaluated by cytofluorimetric analysis of nuclei stained with Hoechst dye. Cell growth-arrest was examined by immunostaining of p21. ATM expression was quantitated by qPCR for ATM relative to GAPDH. Mitochondrial homeostasis in mice with PNAFLD was evaluated by electron microscopy and Western Blot of fission and fusion proteins. Of the 47 children in the cohort, 74% were male, 26% female; 85% hispanic, 11% white, black or asian, and 4% unspecified. Mean BMI of the cohort was 94±7th percentile. The duration of obesity until time of liver biopsy was 4±2 years. 61% displayed simple steatosis or fatty liver (FL) with NAS less than 5, and 39% had steatohepatitis (NASH), with NAS equal to or greater than 5. Significantly, 50% of children in the cohort had fibrosis at the time of liver biopsy. Disease progression was associated with dyregulated ATM expression as evidenced by less ATM mRNA expression in FL compared to healthy controls (obtained from NIDDK supported biorepository LTPADS from the University of Minnesota) which further declined with NASH. This was associated with greater degree of mitochondrial DNA depletion in NASH vs FL, compared to healthy controls, which is dependent on ATM. Consequences of mitochondrial depletion extended to increased p21 mediated cell growth arrest and pathological polyploidy. In modelling of PNAFLD in mice, exposure of weanling mice to high fat diet plus low dose CCl4 plus ATM kinase antagonism for 4 weeks reproduced hepatic steatosis, inflammation ballooning and fibrogenesis. Moreover, there was disruption of mitochondrial homeostatis including fission and fusion. CONCLUSION: Disruption of ATM is particularly critical for PNAFLD in early liver growth stage by increasing susceptibility to nuclear and mitochondrial injury. These insights should advance translational and clinical studies in this area. 1K08DK125881-01A1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multicenter, retrospective, cohort study shows platelet counts predict hepatocellular carcinoma development in patients with nonalcoholic fatty liver disease.

Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. During a median follow-up period of 4.6years (range, 0.3-21.6years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192×109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p<0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192×109/L, patients with platelet counts of 100×109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; p<0.001), adjusting for age, sex, NASH,anddiabetes. Baseline platelet counts of 192×109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

Liver biopsy in inflammatory bowel disease patients with sustained abnormal liver function tests: a retrospective single-center study.

Inflammatory bowel disease (IBD) may be associated with a wide range of hepatobiliary manifestations. This study aimed to characterize the spectrum of hepatobiliary disorders in patients with IBD who underwent liver biopsy for sustained abnormal liver function tests (LFT). A retrospective study was performed of all patients with IBD who underwent liver biopsy between January 2010 and December 2020 for sustained abnormal LFT (at least 6-month duration). A total of 101 patients were included, mostly male (62.4%), with a mean age of 44.4±13.3 years. The most common IBD type was Crohn's disease (61.4%). Median time interval between abnormal LFT and biopsy was 14 (7-36) months. Abnormal LFT was predominantly hepatocellular in 40 patients (39.6%), cholestatic in 26 (25.7%) and mixed in 35 (34.7%). The most frequent diseases were nonalcoholic fatty liver disease (NAFLD) in 33 patients (32.7%), drug-induced liver disease (DILI) in 30 (29.7%), autoimmune hepatitis (AIH) in 13 (12.9%) and primary sclerosing cholangitis (PSC) in 13 (12.9%). Three patients had primary biliary cholangitis. Remarkably, 70 patients (69.3%) already had fibrosis by the time of liver biopsy and in 6 (5.9%) liver disease was already detected in the stage of cirrhosis. Abnormal LFT in IBD patients had a wide range of etiologies and histology was often essential for reaching a correct diagnosis. NAFLD, DILI, AIH and PSC were the most common diagnoses and patients often presented in cirrhotic stage. Therefore, liver biopsy must be considered early in IBD patients with unexplained sustained abnormal LFT.

Crohn's Disease Is Associated with Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease.

Chronic inflammation in IBD is postulated to drive NAFLD progression from steatosis to fibrosis. To study the histopathological spectrum of NAFLD in Crohn disease (CD) and Ulcerative colitis (UC). Patients with biopsy proven NAFLD at a quaternary center from 2008 to 2018 were included in this retrospective analysis. Inflammatory bowel disease (IBD) diagnosed either clinically and/or endoscopically at the time of liver biopsy. Multivariable regression and propensity score (PS) weighted analysis were conducted. Statistical analysis were performed using SAS statistical software. Among 1009 patients with NAFLD a diagnosis of IBD was identified in 50 cases (34 CD and 16 UC). On multivariable analysis; CD was independently associated with significantly higher odds of advanced fibrosis (AF) on liver biopsy (adjusted OR = 4.09, 95% CI = 1.40-11.94) compared to NAFLD patients without IBD. Similar results were obtained with both the overlap PS weighted model (OR = 3.17, 95% CI = 1.55-6.49) and the PS matched model (OR = 3.49, 95% CI = 1.50-8.13). In a large cohort of patients with histologically well characterized NAFLD, AF was more common in CD patients than NAFLD patients without IBD. These findings must be confirmed in a larger cohort, but suggest CD patients with NAFLD could be at greater risk for liver fibrosis.

An Appraisal of Immunohistochemical Stain Use in Hepatic Metastasis Highlights the Effectiveness of the Individualized, Case-Based Approach: Analysis of Data From a Tertiary Care Medical Center.

Liver biopsy plays an important role in the clinical management of metastases and often requires workup using immunohistochemical (IHC) markers, but the approach varies among institutions. To evaluate the utility of a morphologic pattern-based, individualized approach in the workup of hepatic metastases. All liver biopsies with metastasis between 2015 and 2018 were identified from our institutional database and were reviewed. The morphologic pattern of the metastasis and IHC markers used in each case were recorded. The final identification of primary site of the tumor was assessed based on all the available clinicopathologic data. The academic ranking and practice pattern of the pathologist signing out the case were also recorded. A total of 406 liver biopsies with metastasis were identified, and the cases were classified as adenocarcinoma (253 of 406; 62%), carcinoma not otherwise specified (12 of 406; 3%), neuroendocrine neoplasm (54 of 406; 13%), poorly differentiated carcinoma (43 of 406; 11%), nonepithelial tumor (24 of 406; 6%), and squamous cell carcinoma (20 of 406; 5%). The primary site was unknown in 39% (158 of 406) at the time of liver biopsy. A primary site was determined in 97% (395 of 406) of all cases, and only 3% (11 of 406) remained true carcinoma of unknown primary. The average number of IHC markers/case in patients with known primary was 2.6, compared with 5.9 with an initial unknown primary and 9.5 in cases of true carcinoma of unknown primary. An individualized, case-based approach seems to be highly cost-effective and uses fewer IHC markers compared with preset panels that often comprise 10 or more IHC markers.

Impact of Donor and Recipient Clinical Characteristics and Hepatic Histology on Steatosis/Fibrosis Following Liver Transplantation.

Deceased donor and recipient predictors of posttransplant steatosis/steatohepatitis and fibrosis are not well known. Our aim was to evaluate the prevalence and assess donor and recipient predictors of steatosis, steatohepatitis, and fibrosis in liver transplantation recipients. Using the immune tolerance network A-WISH multicenter study (NCT00135694), donor and recipient demographic and clinical features were collected. Liver biopsies were taken from the donor liver at transplant, and from recipients per protocol and for-cause (ie, abnormal transaminases and to rule out rejection) and were interpreted by a central pathologist. One hundred eighty-three paired donor/recipients liver biopsies at the time of transplant and posttransplant follow-up (median time 582 d; average time to last biopsies was 704 d [SD ± 402 d]) were analyzed. Donor steatosis did not influence recipient steatosis or fibrosis. Ten of 183 recipients had steatohepatitis on the last biopsy. Recipient body mass index at the time of liver biopsy was the most influential factor associated with posttransplant steatosis. Both donor and recipient metabolic syndrome features were not associated with graft steatosis. Untreated hepatitis C viral (HCV) infection was the most influential factor associated with the development of allograft fibrosis. In a large experience evaluating paired donor and recipient characteristics, recipient body mass index at the time of liver biopsy was most significantly associated with posttransplant steatosis. Untreated HCV etiology influenced graft fibrosis. Thus relative to untreated HCV, hepatic fibrosis in those with steatosis/steatohepatitis is less common though long-term follow-up is needed to determine the course of posttransplant fibrosis. Emphasis on recipient weight control is essential.

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects.

Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects. 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated. Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01). Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.

O-21 SOLUBLE CD163 PERFORMANCE AS A NON-INVASIVE BIOMARKER OF DIFFERENT LIVER CONDITIONS

Development of noninvasive tests to predict liver injury represents a current goal. Soluble CD163 (sCD163) is a specific plasma biomarker of macrophage activation with promising clinical relevance in estimating damage severity and predicting the outcome in different liver conditions. To evaluate sCD163 performance as a non-invasive marker of liver damage. sCD163 was quantified by enzyme-linked-immunosorbent assay in plasma from 123 patients (57 HCV, 20 HCV/HIV, 10 HBV, 36 MAFLD) obtained at time of liver biopsy. 20 healthy donors were included as controls. sCD163 values were compared among disease conditions and related to histological parameters of liver damage. Diagnostic performance was assessed by the area under the receiver operating characteristic curves (AUROC). Patients´ sCD163 levels [0.579g/L (0.034 -3.596)] were higher than controls´ [0.221g/L (0.116-0.549)] (p<0.0001, Mann-Whitney). However, in a detailed analysis according to disease etiology, only viral conditions showed significantly higher sCD163 levels [HCV+ 0.7520g/L (0.168-3.468), p<0.0001; HCV+/HIV+ 0.964g/L (0.345-3.596), p<0.0001; HBV+ 0.526g/L (0.199-0.802), p=0.0375, Dunn's-multiple-comparisons]. MAFLD patients displayed similar sCD163 levels to the control group [0.345g/L (0.0338-1.804)]. HCV mono- and HIV-coinfected patients shared the highest sCD163 levels. In relation to liver injury, HCV+ and HCV+/HIV+ patients specifically displayed a profile with higher sCD163 levels associated with more severe hepatitis. Remarkably, just in HCV+/HIV+ cases these differences were significant (p=0.0097 Mann-Whitney) and the AUROC analysis demonstrated a good performance in predicting hepatitis severity [AUROC=0.875; cutoff: 0.672g/L (91.67% sensitivity, 83.33% specificity)]. Concerning fibrosis, only HCV+ and HCV+/HIV+ patients with significant fibrosis displayed a profile with high sCD163 level; however, the AUROC analysis showed good performance just for HCV+/HIV+ patients [AUROC=0.825); cutoff: 0.9640g/L (100% sensitivity, 60% specificity)]. Plasmatic sCD163 is elevated in patients with several liver conditions but it can be particularly used as a marker of liver inflammation and fibrosis in HCV/HIV co-infected patients.

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity. Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases). Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups. Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Protein Tyrosine Phosphatase Nonreceptor Type 2 Expression Does Not Correlate with Viral Load or Response to Direct-Acting Antiviral Therapy in Hepatitis C Virus Infections-Infected Patients

Background/Aims: The hepatitis C virus nonstructural 3/4A protease has been shown to cleave protein tyrosine phosphatase nonreceptor type 2 (PTPN2, also known as T cell protein tyrosine phosphatase), thereby inducing a shift from a Th1 toward a nonantiviral Th2 immunity. Ribavirin therapy reverses these effects and supports direct-acting antiviral (DAA) therapy as an immunomodulatory compound and ultimately improves the response to DAA therapy. Here we aimed to assess whether intrahepatic levels of PTPN2 might be used as a clinical prognostic marker for the response to DAA therapy. Methods: Liver biopsies from hepatitis C virus-infected patients with and without cirrhosis were immunohistochemically stained for PTPN2 and scored for staining intensity as well as percentage of hepatocytes positive for nuclear PTPN2 localization. PTPN2 scores were correlated to sustained virologic response after DAA therapy, viral load, serum levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase (GGT), and the Model for End-Stage Liver Disease (MELD) score at the time of liver biopsy. Results: We did not detect a difference in intrahepatic PTPN2 levels between responders with cirrhosis, responders without cirrhosis, and nonresponders to DAA therapy. There was no correlation between intrahepatic PTPN2 levels and viral load or clinical markers such as liver transaminases, GGT, or the MELD score. Conclusion: Intrahepatic PTPN2 levels assessed via IHC staining do not represent a clinical prognostic marker for the response to DAA therapy.

Long-term outcomes in patients with decompensated alcohol-related liver disease, steatohepatitis and Maddrey's discriminant function

Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) <32 have a low risk of short-term mortality. However, few data exist concerning long-term outcomes. The aims of this study were to evaluate 5-year survival rates and to identify predictive factors for long-term prognosis in this patient population. We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF <32. Clinical and biological parameters were recorded at the time of liver biopsy and alcohol consumption was recorded during follow-up. We performed Cox proportional hazard survival analysis to identify factors associated with 5-year survival. One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage liver disease and mDF scores were 14 (IQR 11.7-16.1) and 19 (IQR 11.1-24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively. The mortality rate of patients with alcoholic hepatitis and an mDF <32 is around 50% at 5 years. Hepatic encephalopathy at baseline and lack of alcohol abstinence impair long-term prognosis. New treatment strategies, including measures to ensure abstinence, are required. Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.

Diagnostic performance of extrinsic apoptosis pathway in hepatitis C virus patients: apoptosis fibrosis crosstalk.

Liver fibrosis assessment and evaluation of disease severity in hepatitis C virus (HCV) patients provides useful information for therapeutic decisions. Chronic HCV infection is associated with increased levels of peripheral T cell apoptosis. The aim was to study whether peripheral blood T lymphocyte apoptosis markers may contribute to clinical progression, and develop a simple index based on combination of apoptosis and routine biomarkers for accurate evaluation of fibrosis stages in HCV patients. Peripheral blood T lymphocytes were isolated from 72 patients with hepatitis C virus and 25 healthy control individuals. Serum samples were collected at time of liver biopsy. Liver fibrosis was tested in biopsies using the Metavair score system. Stepwise linear discriminate analysis and area under receiver-operating characteristic curves were utilized to produce a predictive score comprising significant apoptosis biomarkers. A novel score named apoptosis fibrosis index (AFI) was created on the basis of a combination of CD8/Annexin, albumin and platelets. The multivariate discriminate analysis selected a score based on absolute values of the three biochemical markers; score = 5.8 + 0.008×CD8/Annexin-V (%) - 1.4×Albumin (g/dl) - 0.001×Platelet count (10/L), where 5.8 considered numerical constant. AFI produce an area under the curve of one for significant fibrosis, 0.80 for advanced fibrosis, and 0.889 for cirrhosis. Apoptosis biomarkers in HCV patients were associated with liver fibrosis. AFI score, a novel noninvasive test, can be used easily for the prediction of liver fibrosis stage and may decrease the need for liver biopsy in hepatitis C virus Egyptian patients.

P44 Liver injury in children on long-term low dose methotrexate

Abstract Background Liver injury is known in patients on methotrexate (MTX). We retrospectively reviewed records of patients who had liver biopsy for suspected MTX induced liver injury and identify risk factors if any. Methods Children (≤ 16 years) referred to us from 2002 to 2015 with suspected MTX induced liver injury were identified and data related to their underlying diagnosis, biochemical parameters, Body Mass Index (BMI), dose and duration of MTX at the time of liver biopsy, use of concomitant drugs, duration and other causes for elevated transaminases, liver histology including clinical decisions to continue or stop MTX were extracted from the data base. All the liver biopsies were re-analysed for this study and scored using the Roenigk classification by a single histopathologist blinded to patient characteristics. Results Seventeen liver biopsies were performed in 14 children (3 had repeat biopsies) who were referred for frequent/persistent transaminitis (&gt; 2 times upper limit normal). The base line bilirubin, transaminases and synthetic liver function were normal in all prior to MTX therapy. All were on MTX at the time of biopsy except two who had been off the drug for 3 and 8 months following frequent transaminitis. They had liver biopsy to guide reintroduction of MTX in their treatment regime. None of the patients had renal impairment, diabetes or underlying liver disease. Thirteen biopsies (82 %) had none (n = 6) to mild liver injury (n = 7) and were advised to continue MTX. Four biopsies (18%) showed significant liver injury (grade 3b and 4). Of these 3 patients were advised to stop MTX while one was advised to continue and repeat liver biopsy in 6 months. He however, stopped MTX soon thereafter. All biopsies of children (n = 3) with BMI ≥ 91st centile had liver damage. Two of thirteen biopsies with BMI &lt; 91 centile had moderate-severe damage. No correlation was seen between the histologic findings or their severity with dose or duration of MTX, concomitant use of other drugs, severity/highest transaminase peak, total duration of transaminase abnormality, longest single episode of transaminase abnormality or frequency/number of peaks of abnormal transaminases. Of the 3 with repeat biopsies, fibrosis had progressed in 2, necessitating discontinuation of MTX in 1. Conclusion The finding of significant liver injury in our cohort is not entirely in keeping with previous paediatric studies which report non-significant fibrosis or cirrhosis. We could not identify any risk factors though children with BMI ≥ 91st centile seemed more likely to have liver injury. This finding is similar to adult studies implicating obesity as risk factor though it is difficult to draw definitive conclusions given the small size of our cohort. Other limitations include the retrospective nature of the study, bias as MTX dose modifications and referral were at the discretion of the rheumatologist and no information on alcohol intake in the teenagers. This study emphasises the need for careful monitoring to prevent severe fibrosis and cirrhosis. Conflicts of Interest The authors declare no conflicts of interest.

New diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient on ultrasound B mode.

PurposeWe have developed a diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient (ATT) in ultrasound B mode imaging. A controlled attenuation parameter (CAP) by vibration-controlled transient elastography (VCTE) has also been used to evaluate hepatic steatosis. As that method uses ultrasound A mode, visualizing the liver in real time is difficult. We designed this clinical study to evaluate the diagnostic advantage of our technique using ATT compared to CAP.Materials and methodsThe study group included 94 patients with chronic liver disease who had undergone both ATT and CAP assessment at the time of liver biopsy. The M-probe and XL-probe were used for CAP measurement. Data for ATT and CAP were compared as a function of the steatosis grade.ResultsThe area under the receiver operating characteristic curve (AUC-ROCs) for ATT and PAC as a function of the steatosis grade were as follows: grade 1, 0.74 and 0.81; grade 2, 0.80 and 0.85; and grade 3, 0.96 and 0.98, respectively.ConclusionThe accuracy of steatosis grade diagnosis using ATT was the same as that using CAP, with no significant differences and with the added advantage of B mode ultrasound being more convenient and rapid, compared to A mode ultrasound, particularly for patients with subcutaneous fat thickness ≥2 cm.

Development and Validation of Hepamet Fibrosis Scoring System–A Simple, Noninvasive Test to Identify Patients With Nonalcoholic Fatty Liver Disease With Advanced Fibrosis

Fibrosis affects prognoses for patients with nonalcoholic fatty liver disease (NAFLD). Several non-invasive scoring systems have aimed to identify patients at risk for advanced fibrosis, but inconclusive results and variations in features of patients (diabetes, obesity and older age) reduce their diagnostic accuracy. We sought to develop a scoring system based on serum markers to identify patients with NAFLD at risk for advanced fibrosis. We collected data from 2452 patients with NAFLD at medical centers in Italy, France, Cuba, and China. We developed the Hepamet fibrosis scoring system using demographic, anthropometric, and laboratory test data, collected at time of liver biopsy, from a training cohort of patients from Spain (n = 768) and validated the system using patients from Cuba (n = 344), Italy (n=288), France (n = 830), and China (n = 232). Hepamet fibrosis score (HFS) were compared with those of previously developed fibrosis scoring systems (the NAFLD fibrosis score [NFS] and FIB-4). The diagnostic accuracy of the Hepamet fibrosis scoring system was assessed based on area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, diagnostic odds ratio, and positive and negative predictive values and likelihood ratios. Variables used to determine HFS were patient sex, age, homeostatic model assessment score, presence of diabetes, levels of aspartate aminotransferase, and albumin, and platelet counts; these were independently associated with advanced fibrosis. HFS discriminated between patients with and without advanced fibrosis with an AUROC curve value of 0.85 whereas NFS or FIB-4 did so with AUROC values of 0.80 (P = .0001). In the validation set, cut-off HFS of 0.12 and 0.47 identified patients with and without advanced fibrosis with 97.2% specificity, 74% sensitivity, a 92% negative predictive value, a 76.3% positive predictive value, a 13.22 positive likelihood ratio, and a 0.31 negative likelihood ratio. HFS were not affected by patient age, body mass index, hypertransaminasemia, or diabetes. The Hepamet fibrosis scoring system had the greatest net benefit in identifying patients who should undergo liver biopsy analysis and led to significant improvements in reclassification, reducing the number of patients with undetermined results to 20% from 30% for the FIB-4 and NFS systems (P < .05). Using clinical and laboratory data from patients with NAFLD, we developed and validated the Hepamet fibrosis scoring system, which identified patients with advanced fibrosis with greater accuracy than the FIB-4 and NFS systems. the Hepamet system provides a greater net benefit for the decision-making process to identify patients who should undergo liver biopsy analysis.