F3-F4 Fibrosis Research Articles

Association Between MR Elastography Liver Stiffness and Histologic Liver Fibrosis in Children and Young Adults With Autoimmune Liver Disease.

BACKGROUND. Liver fibrosis is an important clinical endpoint of the progression of autoimmune liver disease (AILD); its monitoring would benefit from noninvasive imaging tools. OBJECTIVE. The purpose of this study was to assess the relationship between MR elastography (MRE) liver stiffness measurements and histologic liver fibrosis, as well as to evaluate the performance of MRE and biochemical-based clinical markers for stratifying histologic liver fibrosis severity, in children and young adults with AILD. METHODS. This retrospective study used an existing institutional registry of children and young adults diagnosed with AILD (primary sclerosing cholangitis [PSC], autoimmune sclerosing cholangitis [ASC], or autoimmune hepatitis [AIH]). The registry was searched to identify patients who underwent both a research abdominal 1.5-T MRI examination that included liver MRE (performed for registry enrollment) and a clinically indicated liver biopsy within 6 months of that examination. MRE used a 2D gradient-recalled echo sequence. One analyst measured mean liver shear stiffness (in kilopascals) for each examination. Laboratory markers of liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] score) were recorded. For investigational purposes, one pathologist, blinded to clinical and MRI data, determined histologic Metavir liver fibrosis stage. The Spearman rank order correlation coefficient was calculated between MRE liver stiffness and Metavir liver fibrosis stage. ROC analysis was used to evaluate diagnostic performance for identifying advanced fibrosis (i.e., differentiating Metavir F0-F1 from F2-F4 fibrosis), and sensitivity and specificity were calculated using the Youden index. RESULTS. The study included 46 patients (median age, 16.6 years [IQR, 13.7-17.8 years]; 20 female patients, 26 male patients); 12 had PSC, 10 had ASC, and 24 had AIH. Median MRE liver stiffness was 2.9 kPa (IQR, 2.2-4.0 kPa). MRE liver stiffness and Metavir fibrosis stage showed strong positive correlation (ρ = 0.68). For identifying advanced liver fibrosis, MRE liver stiffness had an AUC of 0.81, with sensitivity of 65.4% and specificity of 90.0%; APRI had an AUC of 0.72, with sensitivity of 64.0% and specificity of 80.0%; and FIB-4 score had an AUC of 0.71, with sensitivity of 60.0% and specificity of 85.0%. CONCLUSION. MRE liver stiffness measurements were associated with histologic liver fibrosis severity. CLINICAL IMPACT. The findings support a role for MRE in noninvasive monitoring of liver stiffness, a surrogate for fibrosis, in children and young adults with AILD. TRIAL REGISTRATION. ClinicalTrials.gov NCT03175471.

Role of Alanine Transaminase and Transient Elastography in Categorising Nonalcoholic Fatty Liver Disease Subgroups.

To investigate the association of alanine transaminase (ALT) with transient elastography grades to define various nonalcoholic fatty liver disease (NAFLD) groups for disease status. Cross-sectional, descriptive study. Place and Duration of the Study: Gastroenterology Outpatient Clinic, Ziauddin Hospital, from January to December 2022. This study included 194 NAFLD patients. Demographic data, body mass index, enzymes, and transient elastography (TE) findings were recorded. NAFLD patients were categorised as nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), steatofibrosis (significant fibrosis F2-F3 with normal ALT), and cirrhosis using TE grades. The median age of the patients was 44 [IQR 18.25] years; 146 (75.3%) were males. Out of 194 NAFLD patients, 21 (10.8%) were NAFL, 116 (59.8%) were NASH, 14 (7.2%) showed steatofibrosis, and 43 (22.2%) were cirrhotic. On transient elastography, the majority were with S3 steatosis (n=107, 55.2%) and 59 (30.2%) had F0-F1 fibrosis. There was a statistically significant difference in the mean rank of age, ALT, AST, and GGT levels within 4 groups of NAFLD (p <0.001). Most of the patients with all the stages of fibrosis had increased ALT levels (p=0.034). This study concluded that a combination of ALT levels and transient elastography findings could be considered for differentiating uncomplicated steatosis from NASH, steatofibrosis, and cirrhosis, hence limiting the use of liver biopsy. This may prove a reliable way to measure the severity of the disease. Nonalcoholic fatty liver disease, Cirrhosis, Transient elastography.

Case-control analysis of venous thromboembolism risk in non-alcoholic steatohepatitis diagnosed by transient elastography.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Studies have shown a strong association between non-alcoholic steatohepatitis (NASH) cirrhosis and portal vein thrombosis. Specifically, there is paucity of data on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE compared to other liver diseases in hospitalized patients. The mechanism is believed to be a hepatocellular injury, which causes a chronic inflammatory state leading to the unregulated activation of procoagulant factors. There has been no prior analysis of the degree of steatosis and fibrosis (measured using transient elastography, commonly known as FibroScan) in NASH and its association with VTE. To examine the association between the degree of hepatic steatosis and fibrosis, quantified by transient elastography, and the incidence of VTE in patients with NASH. In our case-control study, we included patients with a documented diagnosis of NASH. We excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. The collected data included age, demographics, tobacco use, recreational drug use, medical history, and vibration controlled transient elastography scores. VTE-specific data included the location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter score. Fibrosis was classified based on the kilopascal score and graded as F0-F1 (Metavir stage), F2, F3, and F4 (cirrhosis). χ2 and Mann-Whitney U tests were used for the qualitative and quantitative variable analyses, respectively. Furthermore, we performed a logistic regression using VTE as the dependent variable. A total of 415 patients were analyzed, and 386 met the inclusion criteria. 51 and 335 patients were included in the VTE and non-VTE groups, respectively. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (P < 0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs 13.1%). The history of NASH was significantly higher in the VTE group (45.1% vs 30.4%, P < 0.037). Furthermore, moderate-to-severe steatosis was significantly higher in the VTE group (66.7% vs 47.2%, P < 0.009). Similarly, the F2-F4 fibrosis grade had a prevalence of 58.8% in the VTE group compared to 38.5% in the non-VTE group (P < 0.006). On logistic regression, using VTE as a dependent variable, diabetes mellitus had an odds ratio (OR) =1.702 (P < 0.015), and F2-F4 fibrosis grade had an OR = 1.5 (P < 0.033). Our analysis shows that NASH is an independent risk factor for VTE, especially deep vein thrombosis. There was a statistically significant association between the incidence of VTE, moderate-to-severe steatosis, and fibrosis. All hospitalized patients should be considered for medical thromboprophylaxis, particularly those with NASH.

Country-Wide HCV Elimination Strategies Need to Reach Older Patients in the General Population: The Italian Experience.

HCV infection is still a major burden worldwide, and most countries are not on track to meet the WHO 2030 elimination goal. The current challenge is to identify individuals to be treated. In this study, we will describe the trend of new DAA prescriptions and the changes over time in terms of the characteristics of patients starting antiviral therapy in our unit. Data of 1646 hepatitis C patients who started therapy during the period of 2015-2022 regarding annual number of prescriptions, age, gender, nationality, HCV genotype, provenance, and liver disease severity were analyzed. We observed a peak in the number of new prescriptions in 2018 and a downward trend starting in 2019. Patients from the general population, centers for addictions, and prison differed significantly. The mean age in the general population remained above 60 years, the percentage of patients from centers for addictions and prison increased and, after 2016, there was no significant change in the percentage of patients with F3-F4 fibrosis. As HCV screening and linkage-to-care pathways seem to be already well implemented and successful in centers for addictions and in prisons, efforts need to be focused on those of older age in the general population. To carry this out, the more structured involvement of different health professionals must be figured out.

SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease

Sirtuin 5, encoded by the SIRT5 gene, is a NAD+-dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD). The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics invitro were investigated by high-performance liquid chromatography. In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels. The SIRT5 rs12216101T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD. In this study we discovered that the SIRT5 rs12216101T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.

Risk of liver-related events in metabolic dysfunction-associated steatohepatitis (MASH) patients with fibrosis: A comparative analysis of various risk stratification criteria.

International regulatory agencies recommend testing drug therapy for patients with noncirrhotic high-risk metabolic dysfunction-associated steatohepatitis (MASH) because they are at risk of liver-related events (LRE). We aimed to compare the risk of LRE in patients with MASLD stratified for F2-F4 fibrosis and MASH. Overall, 1938 consecutive patients with biopsy-proven MASLD were enrolled. High-risk MASH was defined as MASH with F2-F4 fibrosis. LSM was measured by transient elastography. LRE were recorded during follow-up. Cox multivariate models were used to assess the association between high-risk MASH or F2-F4 fibrosis without MASH, of LSM (≥8 or ≥10Kpa), and of AGILE 3+ with LRE. The diagnostic performance for the prediction of LRE was assessed using the area under the receiver operating characteristic curves. The observed 5-year actuarial rate of LRE was 0.4%, 0.2%, 5.1%, and 6.6% in patients with F0-F1 fibrosis without MASH, F0-F1 fibrosis with MASH, F2-F4 fibrosis without MASH, and high-risk MASH, respectively. At multivariate Cox regression analysis using F0-F1 fibrosis without MASH as a reference, both F2-F4 fibrosis without MASH [adjusted HR (aHR) 9.96] and high-risk MASH (aHR 10.14) were associated with LRE. In the 1074 patients with available LSM, LSM ≥ 10kPa (aHR 6.31) or AGILE 3+ > 0.67 (aHR 27.45) independently predicted the development of LRE and had similarly acceptable 5-year area under the receiver operating characteristic to high-risk MASH and F2-F4 fibrosis (0.772, 0.818, 0.739, and 0.780, respectively). The risk of LRE is similar in patients with high-risk MASH and with F2-F4 fibrosis without MASH. The use of LSM ≥ 10kPa or AGILE 3+ > 0.67 could be an accurate option to identify patients with MASLD worthy to be included in clinical trials.

DIAGNOSTIC VALUE OF NITROGEN METABOLISM DISORDERS IN NON-ALCOHOLIC FATTY LIVER DISEASE IN COMORBID PATIENTS WITH METABOLIC SYNDROME AND STRATIFICATION OF DISEASE STAGES

The aim of the study is to determine the significance of hyperammonemia for the diagnosis of non-alcoholic fatty liver disease (NAFLD) in patients with metabolically associated comorbid pathology.&#x0D; Materials and Methods. A single-stage cohort randomized study was conducted to examine NAFLD in patients with metabolically associated pathology – type 2 diabetes, obesity, hypertension, coronary artery disease, and dyslipidemia. The study included 96 patients, who were divided into 3 groups: patients with steatotic liver disease (n=33), patients with non-alcoholic steatohepatitis (n=47) and patients with newly diagnosed liver cirrhosis (n=16). For NAFLD diagnosis, non-invasive methods were also applied (APRI, FIB4, NAFLD fibrosis score). To diagnose hepatocellular insufficiency, the authors evaluated ammonia level in capillary blood. Statistical processing was carried out by parametric and nonparametric methods, correlation and cluster analysis (Statistica 10.0). We also calculated odds ratio.&#x0D; Results. Metabolic syndrome in patients aged 64.2±0.85 (64.9 % females and 35.1 % males, Charleson comorbidity index 4.57±0.12) was represented by type 2 diabetes (100 %), insulin-treated diabetes (2/3 of patients), hypertension (1/3 of patients, stage 3 of NAFLD), obesity (87.5 %), coronary heart disease (90.6 %), steatotic liver disease (34.4 %), non-alcoholic steatohepatitis (49 %) and asymptomatic liver cirrhosis (16,6 %). According to NFS results, stage F3–F4 fibrosis was diagnosed in 52.1 % of patients, F2 fibrosis in 47.9 %; hyperammonemia was found in 91.7 % (up to 111.1±4.86 (101.3–120.7) µmol/l). Hyperammonemia developed from steatosis to non-alcoholic steatohepatitis and liver cirrhosis and correlated with the stage of liver fibrosis, hepatitis activity, and metabolic syndrome key criteria. NFS calculator and hyperammonemia diagnosis made it possible to stratify the stages of non-alcoholic fatty liver disease.

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

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

Production, Exacerbating Effect, and EV-Mediated Transcription of Hepatic CCN2 in NASH: Implications for Diagnosis and Therapy of NASH Fibrosis.

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, hepatocyte ballooning, and inflammation and may progress to include increasingly severe fibrosis, which portends more serious disease and is predictive of patient mortality. Diagnostic and therapeutic options for NASH fibrosis are limited, and the underlying fibrogenic pathways are under-explored. Cell communication network factor 2 (CCN2) is a well-characterized pro-fibrotic molecule, but its production in and contribution to NASH fibrosis requires further study. Hepatic CCN2 expression was significantly induced in NASH patients with F3-F4 fibrosis and was positively correlated with hepatic Col1A1, Col1A2, Col3A1, or αSMA expression. When wild-type (WT) or transgenic (TG) Swiss mice expressing enhanced green fluorescent protein (EGFP) under the control of the CCN2 promoter were fed up to 7 weeks with control or choline-deficient, amino-acid-defined diet with high (60%) fat (CDAA-HF), the resulting NASH-like hepatic pathology included a profound increase in CCN2 or EGFP immunoreactivity in activated hepatic stellate cells (HSC) and in fibroblasts and smooth muscle cells of the vasculature, with little or no induction of CCN2 in other liver cell types. In the context of CDAA-HF diet-induced NASH, Balb/c TG mice expressing human CCN2 under the control of the albumin promoter exhibited exacerbated deposition of interstitial hepatic collagen and activated HSC compared to WT mice. In vitro, palmitic acid-treated hepatocytes produced extracellular vesicles (EVs) that induced CCN2, Col1A1, and αSMA in HSC. Hepatic CCN2 may aid the assessment of NASH fibrosis severity and, together with pro-fibrogenic EVs, is a therapeutic target for reducing NASH fibrosis.

Fibrosis avanzada asociada a esteatohepatitis no alcohólica (NASH) en España: resultados de un estudio Delphi

ObjectiveTo describe in detail the epidemiology, diagnosis, clinical management, treatment options, impact on quality of life and unmet needs of patients with advanced liver fibrosis (F3-F4) associated with non-alcoholic steatohepatitis (NASH) in Spain. MethodologyDelphi study of two rounds of consultation rounds with 41 expert hepatologists from 16 autonomous communities to collect their experience in clinical practice. ResultsThe estimated prevalence of adult patients diagnosed with F3-F4 fibrosis associated with NASH in Spain is 0.019% (95% confidence interval [CI]: 0.019-0.020%). Approximately 7,588 adults with this condition are currently diagnosed and managed in the Digestive System Services of Spanish hospitals, and around 1,881 new patients are diagnosed each year. Management is multidisciplinary and includes the specialties of Digestive System, Endocrinology and Internal Medicine, considering the frequently associated metabolic comorbidities (obesity, type 2 diabetes mellitus or dysmetabolic iron overload). Despite a clear impact on quality of life, this it is not routinely evaluated in clinical practice. The most widely used non-invasive diagnostic techniques are transitional elastography and liver fibrosis index 4 (FIB-4). The absence of effective and safe treatments appears as the main unmet need for the management of these patients. ConclusionsThis study provides a representation of the current situation of patients diagnosed with F3-F4 fibrosis associated with NASH in Spain, increasing the evidence available and contributing to informed decision-making by professionals and the health system.

Clinical and epidemiological characteristic of chronic hepatitis C in the republic of Tyva

Aim: To assess the current epidemiological situation and establish the dominant clinical profile of patients with chronic hepatitis C, taking into account the stage of the disease and the molecular genetic characteristics of the virus in the Republic of Tyva. Materials and methods: Based on the annual reports of the dispensary observation office of the Infectious Hospital of the Republic of Tyva, an electronic database was developed using the licensed Office Excel 2016 program, which included results on the health status of patients, clinical, laboratory and instrumental data, including molecular biological data with the determination of HCV genotypes. The analysis of the data of the state statistical reporting of infectious morbidity in the Russian Federation (form №2 “Information on infectious and parasitic diseases”) was carried out. Analytical tables developed by specialists of the Scientific and Methodological Center of the Saint-Petersburg Pasteur Institute for the period 2012-2022. The data of the Reference Center for Monitoring Viral Hepatitis of the Federal State Budgetary Institution “Central Research Institute of Epidemiology” of Rospotrebnadzor were used. Results. Over the past two years, the decrease in incidence in the Republic of Tyva is likely due to a decrease in the number of examinations, a decrease in patients seeking outpatient care, and insufficient screening in the context of the COVID-19 pandemic. Clinical, laboratory and instrumental examination of patients with HCV revealed the predominance of HCV-infected genotype 1 (49.4%), with F0-F2 fibrosis in 79% of cases. The clinical profile of typical patients with chronic hepatitis C was established; whose share in the total structure of the examined was 38.4%. Conclusion: There is a tendency to reduce the incidence of chronic hepatitis C in the Republic of Tyva. Based on the clinical information base, the most typical characteristics of chronic hepatitis C patients living in the Republic of Tyva have been established.

Noninvasive assessment of liver disease severity in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes.

We evaluated the diagnostic accuracy of simple, noninvasive tests (NITs) in NAFLD patients with type 2 diabetes (T2D). This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score (NFS), aspartate aminotransferase-to-platelet ratio index, liver stiffness measurement (LSM) by vibration-controlled transient elastography, and AGILE 3+. The target conditions were advanced fibrosis, NASH, and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of noninvasive tests. individually or in sequential combination, was assessed by area under the receiver operating characteristic curve and by decision curve analysis. Comparison with 2278 NAFLD patients without T2D was also made. In NAFLD with T2D LSM and AGILE 3+ outperformed, both NFS and FIB-4 for advanced fibrosis (area under the receiver operating characteristic curve:LSM 0.82, AGILE 3+ 0.82, NFS 0.72, FIB-4 0.75, aspartate aminotransferase-to-platelet ratio index 0.68; p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%. The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40%-60% in necessary LSM tests. Decision curve analysis showed that all scores had a modest net benefit for ruling out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH (area under the receiver operating characteristic curve:LSM 0.79, AGILE 3+ 0.77, NFS 0.71, FIB-4 0.71; p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were suboptimal for diagnosing NASH. LSM and AGILE 3+ individually or in low availability settings in sequential combination after FIB-4 or NFS have a similar good diagnostic accuracy for advanced fibrosis and an acceptable diagnostic accuracy for fibrotic NASH in NAFLD patients with T2D.

ПОЛИМОРФИЗМЫ ГЕНОВ ФЕРМЕНТОВ АНТИОКСИДАНТНОЙ СИСТЕМЫ SOD2 (C47T, rS4880) И CAT (G262A, rS1001179) В ПАТОГЕНЕЗЕ ХРОНИЧЕСКОГО ГЕПАТИТА С

Introduction. An important component in the pathogenesis of chronic hepatitis C is the imbalance in oxidant and antioxidant systems. It is known that mutations in genes of antioxidant enzymes can lead to changes in antioxidant potential. Aim. To determine correlations of polymorphic variants of SOD2 (C47T, rs4880), CAT (G262A, rs1001179) superoxide dismutase and catalase genes with antioxidant system activity and features of clinical course of chronic hepatitis C. Material and Methods. The study of single nucleotide variants of genes of antioxidant enzymes of superoxide dismutase SOD2 (C47T) and catalase CAT (G262A) was undertaken in 90 patients with chronic hepatitis C and 64 healthy controls. Genomic deoxyribonucleic acid from the epithelium of the inner surface of the cheek using ‘SNP-screen ‘ diagnostic reagents was analysed. The levels of superoxide dismutase, catalase, alanine aminotransferase enzymes and degree of liver fibrosis were determined in the group of chronic hepatitis C patients. Correlations between investigated indexes were studied. Results and discussion. The distribution of alleles and genotypes of single nucleotide variants of catalase CAT (G262A) and superoxide dismutase SOD2 (C47T) genes among healthy subjects and chronic hepatitis C patients (p&gt;0,05) had no significant difference (p&gt;0,05), which testified to absence of influence of the studied gene variants on the risk of hepatitis C virus infection. We revealed statistically significant correlation of single-nucleotide variants of SOD2 (C47T) and CAT (G262A) genes with the development of chronic hepatitis C. Patients having G allele (genotypes GG and GA) of CAT (G262A) single nucleotide variants had low level of catalase enzyme, high level of alanine aminotransferase and high degree of F3-F4 fibrosis (correlation coefficient = -0,88*, p˂0,01). In patients with CC genotype SOD2 (C47T) a strong correlation with serum superoxide dismutase activity, severity of cytolysis syndrome (increased alanine aminotransferase) and degree of liver fibrosis (correlation coefficient = +0,70; p˂0,01) was established. Conclusion. In infection with hepatitis C virus polymorphic variants of SOD2 (C47T) and CAT (G262A) antioxidant system enzyme genes are the risk factors of hepatitis C progression, influencing catalase and superoxide dismutase enzyme activity, cytolysis syndrome development, determining liver fibrosis formation.

An observational, prospective, multicenter study on the utilization and effectiveness of elbasvir-grazoprevir treatment association for chronic hepatitis C in France (ZEPHYR study).

The efficacy and safety profiles of elbasvir-grazoprevir (EBR/GZR) has been established in more than 10 clinical trials. However, the characteristics of patients treated in routine clinical practice may differ. The present study was therefore designed to assess the real-life effectiveness of EBR/GZR therapy in the general population and among subgroups with a high hepatitis C virus(HCV) prevalence in France. The Zephyr study was designed as a French, multicentre, prospective, observational study on EBR/GZR use and effectiveness in current practice in chronic hepatitis Cpatients. These results are based on data regardingthe adult patients who received at least one dose of EBR/GZR between December 2017 and June 2019 in 67 French hospitals and clinics. Overall, 478 patients were included. The Full Analysis Setcorresponded to the 467 patients who met all the inclusion criteria and none of the exclusion criteria. Gender was balanced and the mean age was 55.7 ± 13.3 years. The patients were mainly treatment-naive (89.5%) and infected with Genotype 1b (70.4%). Among the 75 patients with HCV Gt1a genotype, 56% had HCV RNA ≥ 800,000 IU/ml. F3-F4 fibrosis stage involved 24.2% of our population. Our subgroups were distributed among 110 migrants (23.6%), 58 (15.3%) using opioid agonist treatment, including people who inject drugs, 30 (6.8%) with chronic kidney disease Stages 3-5, 9 (1.9%) with aninherited blood disorder, and 4 (0.9%) coinfected with HIV. The remaining 269 (58.7%) were included in the general population subgroup. Overall, sustained virologic response 12 weeks after the end of treatment reached 98.0% and remained consistent among genotype, HCV RNA values, fibrosis stage, and the subgroup of interest. The rate of Alcohol Use Disorders Identification Test-Consumption​​​and Life Habit questionnaire completion was high at each visit, with data suggesting alcohol consumption decrease and an improvement in quality of life. Using real-world evidence data on a French population representative of HCV patients, we confirmed the results obtained during EBR/GZR development program.

Does Non-Alcoholic Steatohepatitis Independently Increase the Risk of Venous Thromboembolism?

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Studies have shown a strong association between NASH (non-alcoholic steatohepatitis) cirrhosis and portal vein thrombosis (PVT). Data is scarce on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE in comparison to other liver diseases in hospitalized patients. The mechanism is believed to be hepatocellular injury causing a chronic inflammatory state leading to unregulated activation of procoagulant factors. There is no prior analysis of the degree of steatosis and fibrosis (measured on transient elastography, commonly known as Fibroscan®) in NASH patients and its association with VTE. We performed an analysis to study the risk of unexplained VTE in patients with NASH. Methods: In our case-control study, we included patients with a documented diagnosis of NASH and excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. Collected data included age, tobacco use, recreational drug use, medical history, and vibration-controlled transient elastography (VCTE) scores. Venous thromboembolism specific data included location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter (CAP) score. Fibrosis was classified based on the kilopascal(KPA) score and graded as F0-F1 (metavir stage), F2, F3, and F4(cirrhosis). Chi-square and Mann-Whitney U tests were used for qualitative and quantitative variable analysis, respectively. Furthermore, we computed logistic regression using VTE as a dependent variable. Results: A total of 415 patients were analyzed, and 386 met the inclusion criteria (Figure 1). Fifty-one patients were in the VTE group and 335 in the non-VTE group. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (p=0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs. 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs. 13.1%, p=0.002). The history of NASH was significantly higher in the VTE group (45.1% vs. 30.4%, p=0.037). Further, moderate to severe steatosis was significantly higher in the VTE group (66.7% vs. 47.2%, p=0.009). Similarly, the F2-F4 fibrosis grade had a higher prevalence of 58.8 % in the VTE group compared to 38.5% in the non-VTE group (p=0.006) (Table 1). On logistic regression, using VTE as a dependent variable, diabetes mellitus type II had an OR =1.702 (p = 0.015) and F2-F4 fibrosis grade had an OR = 2.5 (p=0.033). In the VTE group, 58.8% had deep vein thrombosis (DVT), 17.6 % had superficial venous thrombosis (SVT), 13.7 % had pulmonary embolism (PE), 5.9% had portal vein thrombosis, and embolic stroke (3.9%). The most common location of VTE was the lower extremity (56.9%), followed by the upper extremity (19.6%). Right-sided VTE (66.7%) was more common and a majority of patients (74.5%) required hospital admission with 2% requiring ICU admission. Concerning anticoagulation 64.71% of patients were on direct oral anticoagulants (DOAC), 25.5% were on warfarin, and 84.3% of patients continued indefinite anticoagulation. Discussion: Our analysis shows that NASH is an independent risk factor for VTE, especially DVT. Demographics including gender, tobacco use, alcohol consumption, and ethnicity, were equally distributed between the two groups. There is a statistically significant association between the incidence of VTE and moderate to severe steatosis and fibrosis. The current management strategy for NASH includes abstinence from alcohol and intense lifestyle modification to lose weight. Newer medications like glucagon-like peptides (semaglutide) and bariatric surgery are other recommended modalities for weight loss. All hospitalized patients should be considered for medical thromboprophylaxis, particularly in those with NASH, where a high index of suspicion for VTE should be maintained even in the presence of thromboprophylaxis. Additional studies are needed to analyze the risk of bleeding in this patient population who continue indefinite anticoagulation. Another area of interest would be to determine the reversibility of VTE risk with appropriate management of NAFLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S3260 A Case of Smoldering Multiple Myeloma in a Patient With Gaucher’s Disease Diagnosed on Liver Biopsy

Introduction: We describe a rare case of Gaucher Disease (GD) diagnosed on liver biopsy in a patient with thrombocytopenia and hepatic steatosis with subsequent findings of smoldering multiple myeloma (SMM). Case Description/Methods: 59-year-old male with history of chronic thrombocytopenia presented to the clinic for mild elevation in liver enzymes. At the time of evaluation, patient was asymptomatic and denied any history or risk factors for liver disease. Labs were notable for ALT 53, AST 43, Total bilirubin 0.5, alkaline phosphatase 111, INR 1, platelet 73, and ferritin 1157. Serology for hemochromatosis, autoimmune hepatitis, and viral hepatitis were negative. A CT scan of abdomen revealed hepatic steatosis and splenomegaly. Transient elastography was consistent with stage F3-F4 fibrosis. Subsequent liver biopsy showed features of steatohepatitis and sinusoidal cells with pale-gray striated cytoplasm characteristic of Gaucher’s cells. No evidence of iron overload and cirrhosis on trichome stain. The degree of thrombocytopenia and splenomegaly were out of proportion to the liver disease, prompting further hematological evaluation. Serum protein electrophoresis showed 1300 mg/dL IgA kappa monoclonal protein spike. Bone marrow biopsy revealed hypercellular marrow (50%), Gaucher cells, and plasma cell neoplasm ( >20%) consistent with Type I GD with smoldering multiple myeloma given absence of end organ damage. He was treated conservatively with close monitoring for disease progression. (Figure) Discussion: GD is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme glucocerebrosidase that leads to accumulation of glycophospholipids in the cells of the reticuloendothelial system. It is a multisystem progressive disorder with involvement of bone marrow, liver and spleen. Type 1 GD is the most common non-neuropathic variant in adults with prevalence of 1:1000. Predominant clinical features include thrombocytopenia, hepatosplenomegaly with variable patterns of liver involvement ranging from sub-clinical to decompensated cirrhosis. GD is often associated with laboratory abnormalities including hyperferritinemia or hypergammaglobulinemia that may lead to misdiagnosis with other chronic liver conditions. Additionally, there is an increased risk of multiple myeloma and other gammopathies in type 1 GD. Lack of awareness of early clinical course and its associated conditions can lead to delay in diagnosis and treatment.Figure 1.: (A) There is mild pericellular fibrosis, but no periportal or bridging fibrosis. Mild steatosis supportive of a component of NASH accompany the Gaucher's cells is seen (Trichrome, 100X). (B) Sinusoidal cells are enlarged and show pale-gray striated cytoplasm representing Gaucher's cells whereas the hepatocytes are ballooned. Inflammatory infiltrates are absent(hematoxylin and eosin, 200X). (C) The Gaucher's cell are positive for the histiocytic marker CD68 (Immunohistochemistry, 200X).

Chronic hepatitis C in hemodialysis patients: Prevalence and liver fibrosis impact in the National Center for Renal Health in Peru

Hepatitis C (HCV) remains a serious public health problem in high-risk persons such as patients on chronic hemodialysis. We aimed to estimate the serological prevalence of HCV, the HCV viral load and genotype, and liver fibrosis stage among patients on chronic hemodialysis at the National Renal Health Center in Lima, Peru. From June 2019 to March 2021, all patients who received chronic hemodialysis were invited to participate. Subjects who provided written informed consent were enrolled. Patients with HCV-positive serology underwent determination of HCV viral load. Samples from subjects with detectable viral load, underwent determination of HCV genotype. Then, HCV infected subjects underwent determination of liver fibrosis using transitional elastography (Fibroscan 402): Metavir score: F0–F1: 2.5–7.5 kPa, F2: 7.6–9.5 Kpa, F3: 9.6–12 Kpa, F4 (Cirrhosis): 12.1–75 Kpa. Of the 303 subjects invited to participate, 174 (57.4%) subjects gave their written consent. Mean age was 52 years (range 22–91) and 116 (66.6%) were male. HCV serology was positive in 35.1% of patients (61/174); however, the prevalence of positive serology with detectable viral load was 20.11% (35/174). Genotype 1a was the most prevalent (85%). The majority (83.6%) of subjects with detectable viral load had values lower than 800.000 IU/mL. Twenty-nine of those 35 subjects underwent elastography evaluation, and 13 (44.8%) of them were found to have stage F2–F4 fibrosis. The prevalence of HCV at the largest reference center for hemodialysis in Lima remains high, with GT1a predominance, viral load usually below 800,000 IU/mL and significant liver fibrosis.

Use of shear wave elastography for the diagnosis and follow-up of biliary atresia: A meta-analysis.

BACKGROUNDTimely differentiation of biliary atresia (BA) from other infantile cholestatic diseases can impact patient outcomes. Additionally, non-invasive staging of fibrosis after Kasai hepatoportoenterostomy has not been widely standardized. Shear wave elastography is an ultrasound modality that detects changes in tissue stiffness. The authors propose that the utility of elastography in BA can be elucidated through meta-analysis of existing studies.AIMTo assess the utility of elastography in: (1) BA diagnosis, and (2) post-Kasai fibrosis surveillance.METHODSA literature search identified articles that evaluated elastography for BA diagnosis and for post-Kasai follow-up. Twenty studies met criteria for meta-analysis: Eleven for diagnosis and nine for follow-up post-Kasai. Estimated diagnostic odds ratio (DOR), sensitivity, and specificity of elastography were calculated through a random-effects model using Meta-DiSc software.RESULTSMean liver stiffness in BA infants at diagnosis was significantly higher than in non-BA, with overall DOR 24.61, sensitivity 83%, and specificity 79%. Post-Kasai, mean liver stiffness was significantly higher in BA patients with varices than in patients without, with DOR 16.36, sensitivity 85%, and specificity 76%. Elastography differentiated stage F4 fibrosis from F0-F3 with DOR of 70.03, sensitivity 96%, and specificity 89%. Elastography also differentiated F3-F4 fibrosis from F0-F2 with DOR of 24.68, sensitivity 85%, and specificity 81%.CONCLUSIONElastography has potential as a non-invasive modality for BA diagnosis and surveillance post-Kasai. This paper’s limitations include inter-study method heterogeneity and small sample sizes. Future, standardized, multi-center studies are recommended.

Association Between Skeletal Muscle Mass and Severity of Steatosis and Fibrosis in Non-alcoholic Fatty Liver Disease.

BackgroundSarcopenia is known to be the risk factor of non-alcoholic fatty liver disease (NAFLD). However, studies evaluating the association of skeletal muscle mass (SMM) with liver fibrosis by transient elastography are limited. Here, we investigated the association of SMM with hepatic steatosis and fibrosis assessed in Chinese adults.MethodsPatients who underwent liver ultrasonography at the Health Promotion Center of the First Affiliated Hospital of Nanjing Medical University between January 2020 to June 2021 were enrolled. We used transient elastography to evaluate the degree of hepatic fat and liver stiffness. Appendicular skeletal muscle mass was determined by bioelectrical impedance and was adjusted for body weight to derive the skeletal muscle mass index (SMI).ResultsOf 3,602 finally enrolled individuals, 1,830 had NAFLD and 1,772 did not have NAFLD. SMI gradually decreased as the severity of hepatic steatosis increased (40.47 ± 3.94% vs. 39.89 ± 3.57% vs. 39.22 ± 3.46% vs. 37.81 ± 2.84%, P < 0.001). Individuals with F3-F4 and F2 liver fibrosis groups had significantly lower SMI than individuals with F0-F1 stages (37.51 ± 3.19% vs. 38.06 ± 3.51% vs. 39.36 ± 3.38%, P < 0.001). As the SMI increased, the percentages of subjects with mild and severe NAFLD, and the percentages of subjects in F2 and F3-F4 stage were gradually decreased. SMI was independently associated with the severity of hepatic steatosis and fibrosis by logistic regression analysis. Moreover, decreased SMI was an independent risk factor for NAFLD and fibrosis.ConclusionSMI is closely associated with liver fat content and liver fibrosis in Chinese adults with NAFLD.

Predicting NAFLD prevalence in the United States using National Health and Nutrition Examination Survey 2017-2018 transient elastography data and application of machine learning.

This cohort analysis investigated the prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD with fibrosis at different stages, associated clinical characteristics, and comorbidities in the general United States population and a subpopulation with type 2 diabetes mellitus (T2DM), using the National Health and Nutrition Examination Survey (NHANES) database (2017–2018). Machine learning was explored to predict NAFLD identified by transient elastography (FibroScan®). Adults ≥20 years of age with valid transient elastography measurements were included; those with high alcohol consumption, viral hepatitis, or human immunodeficiency virus were excluded. Controlled attenuation parameter ≥302 dB/m using Youden’s index defined NAFLD; vibration‐controlled transient elastography liver stiffness cutoffs were ≤8.2, ≤9.7, ≤13.6, and >13.6 kPa for F0–F1, F2, F3, and F4, respectively. Predictive modeling, using six different machine‐learning approaches with demographic and clinical data from NHANES, was applied. Age‐adjusted prevalence of NAFLD and of NAFLD with F0–F1 and F2–F4 fibrosis was 25.3%, 18.9%, and 4.4%, respectively, in the overall population and 54.6%, 32.6%, and 18.3% in those with T2DM. The highest prevalence was among Mexican American participants. Test performance for all six machine‐learning models was similar (area under the receiver operating characteristic curve, 0.79–0.84). Machine learning using logistic regression identified male sex, hemoglobin A1c, age, and body mass index among significant predictors of NAFLD (P ≤ 0.01). Conclusion: Data show a high prevalence of NAFLD with significant fibrosis (≥F2) in the general United States population, with greater prevalence in participants with T2DM. Using readily available, standard demographic and clinical data, machine‐learning models could identify subjects with NAFLD across large data sets.