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Hepatology (Baltimore, Md.) May 2022Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive...
BACKGROUND AND AIMS
Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis.
APPROACH AND RESULTS
Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events.
CONCLUSIONS
In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.
Topics: Collagen; Fibrosis; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 34662449
DOI: 10.1002/hep.32204 -
Journal of Medical Genetics Aug 2015Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control...
BACKGROUND
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.
METHODS
We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.
RESULTS
We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.
CONCLUSIONS
This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.
Topics: Abnormalities, Multiple; Cerebellum; Cohort Studies; DNA Mutational Analysis; Eye Abnormalities; Genetic Association Studies; Genetic Heterogeneity; Humans; Kidney Diseases, Cystic; Models, Theoretical; Pedigree; Retina; Sequence Analysis, DNA
PubMed: 26092869
DOI: 10.1136/jmedgenet-2015-103087 -
Journal of Hepatology Dec 2022Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial.
METHODS
After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis.
RESULTS
A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results.
CONCLUSIONS
ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention.
LAY SUMMARY
Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.
Topics: Humans; Male; Adult; Female; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Liver Neoplasms; Liver Cirrhosis; Antiviral Agents; China
PubMed: 35985545
DOI: 10.1016/j.jhep.2022.07.018 -
Hepatology (Baltimore, Md.) Aug 2003Information on the stage of liver fibrosis is essential in managing chronic hepatitis C (CHC) patients. However, most models for predicting liver fibrosis are...
Information on the stage of liver fibrosis is essential in managing chronic hepatitis C (CHC) patients. However, most models for predicting liver fibrosis are complicated and separate formulas are needed to predict significant fibrosis and cirrhosis. The aim of our study was to construct one simple model consisting of routine laboratory data to predict both significant fibrosis and cirrhosis among patients with CHC. Consecutive treatment-naive CHC patients who underwent liver biopsy over a 25-month period were divided into 2 sequential cohorts: training set (n = 192) and validation set (n = 78). The best model for predicting both significant fibrosis (Ishak score > or = 3) and cirrhosis in the training set included platelets, aspartate aminotransferase (AST), and alkaline phosphatase with an area under ROC curves (AUC) of 0.82 and 0.92, respectively. A novel index, AST to platelet ratio index (APRI), was developed to amplify the opposing effects of liver fibrosis on AST and platelet count. The AUC of APRI for predicting significant fibrosis and cirrhosis were 0.80 and 0.89, respectively, in the training set. Using optimized cut-off values, significant fibrosis could be predicted accurately in 51% and cirrhosis in 81% of patients. The AUC of APRI for predicting significant fibrosis and cirrhosis in the validation set were 0.88 and 0.94, respectively. In conclusion, our study showed that a simple index using readily available laboratory results can identify CHC patients with significant fibrosis and cirrhosis with a high degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among CHC patients.
Topics: Adult; Biopsy; Female; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Models, Statistical; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index
PubMed: 12883497
DOI: 10.1053/jhep.2003.50346 -
Hepatology (Baltimore, Md.) Apr 2022Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. We evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis.
APPROACH AND RESULTS
NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the United States. Patients with HCV-SVR (for ≥ 1 year) and advanced fibrosis received once-weekly i.v. infusions of placebo or BMS-986263 (45 or 90 mg) for 12 weeks. The primary endpoint was ≥ 1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment, and 2/15 (13%, placebo), 3/18 (17%, 45 mg), and 6/28 (21%, 90 mg) had METAVIR improvements of ≥ 1 stage at Week 12. Five patients in the 90-mg arm had Ishak improvements by ≥ 2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients.
CONCLUSIONS
In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepacivirus; Hepatitis C, Chronic; Humans; Liposomes; Liver Cirrhosis; Liver Neoplasms; Nanoparticles; Treatment Outcome
PubMed: 34605045
DOI: 10.1002/hep.32181 -
Clinical and Experimental Medicine Jun 2023The world-wide increase in chronic liver disease (CLD) calls for refinement of diagnostic and prognostic measures for early and accurate disease detection and... (Review)
Review
The world-wide increase in chronic liver disease (CLD) calls for refinement of diagnostic and prognostic measures for early and accurate disease detection and management. Regardless of the aetiology, liver biopsy allows direct visualisation of specimen under the microscope. It facilitates histological evaluation of disease-specific morphological alterations. Thereby, it aids in disease diagnosis, prognosis, and assessment of treatment compliance/response. Indeed, with the advent of non-invasive methods, liver biopsy is used less frequently than before, but it is still considered as a gold standard for staging and grading several CLDs. This short review revisits liver biopsy. It highlights the significance of liver biopsy in evaluating CLDs and explains the commonly used Ishak, METAVIR and Batts-Ludwig scoring systems for grading and staging CLDs. The utility of liver biopsy in examining alcohol-related liver disease and non-alcoholic fatty liver disease (NAFLD) is discussed along with the disease-specific alcoholic hepatitis histology score (AHHS) and non-alcoholic fatty liver disease activity score (NAS). Additionally, the review elaborates on the role of liver biopsy in evaluating viral hepatitis, haemochromatosis, and hepatocellular carcinoma. Contextual explanation on the diagnosis of metabolic dysfunction-associated liver disease (MAFLD) is provided. The significance and clinical indications of repeat biopsy are also explained. Lastly, caveats and limitations associated with liver biopsy are reviewed. Essentially, this review collates the application of liver biopsy in assessing various CLDs and provides succinct explanations of the core scoring systems, all under one roof. It is clinically relevant and provides a useful synopsis to budding scientists and hepato-pathologists.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Liver; Biopsy; Liver Neoplasms
PubMed: 35192111
DOI: 10.1007/s10238-022-00799-z -
Innovations in Clinical Neuroscience Apr 2020: This paper sought to identify the instruments used to measure depression in heart failure (HF) and elucidate the impact of treatment interventions on depression in HF.... (Review)
Review
: This paper sought to identify the instruments used to measure depression in heart failure (HF) and elucidate the impact of treatment interventions on depression in HF. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. Studies published from 1988 to 2018 covering depression and HF were identified through the review of the PubMed and PsycINFO databases using the keywords: "depres*" AND "heart failure." Two authors independently conducted a focused analysis, identifying 27 studies that met the specific selection criteria and passed the study quality checks. Patient-reported questionnaires were more commonly adopted than clinician-rated questionnaires, including the Beck Depression Inventory, the Patient Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale. Six common interventions were observed: antidepressant medications, collaborative care, psychotherapy, exercise, education, and other nonpharmacological interventions. Except for paroxetine, selective serotonin reuptake inhibitors failed to show a significant difference from placebo. However, the collaborative care model including the use of antidepressants showed a significant decrease in PHQ-9 score after one year. All of the psychotherapy studies included a variation of cognitive behavioral therapy and patients showed significant improvements. The evidence was mixed for exercise, education, and other nonpharmacological interventions. This study suggests which types of interventions are more effective in addressing depression in heart failure patients.
PubMed: 32802590
DOI: No ID Found -
World Journal of Gastroenterology Feb 2021Histological changes after direct-acting antivirals (DAAs) therapy in hepatitis C virus (HCV) patients has not been elucidated. Whether the predominantly progressive,...
BACKGROUND
Histological changes after direct-acting antivirals (DAAs) therapy in hepatitis C virus (HCV) patients has not been elucidated. Whether the predominantly progressive, indeterminate and predominately regressive (P-I-R) score, evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.
AIM
To identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.
METHODS
Chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. Sustained virologic response (SVR) was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation. The Ishak system and P-I-R score were assessed. Inflammation improvement and fibrosis regression were defined as a ≥ 2-points decrease in the histology activity index (HAI) score and a ≥ 1-point decrease in the Ishak fibrosis score, respectively. Fibrosis progression was defined as a ≥ 1-point increase in the Ishak fibrosis score. Histologic improvement was defined as a ≥ 2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy. The P-I-R score was also assessed. "absolutely reversing or advancing" was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score; and "probably reversing or advancing" was defined as only one parameter showing directionality.
RESULTS
Thirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. The mean age of these patients was 40.9 ± 14.6 years and there were 53% (20/38) males. Thirty-four percent (13/38) of patients were cirrhotic. Eighty-two percent (31/38) of patients achieved inflammation improvement. The median HAI score decreased significantly after SVR (pretreatment 7.0 posttreatment 2.0, = -5.146, = 0.000). Thirty-seven percent (14/38) of patients achieved fibrosis improvement. The median Ishak score decreased significantly after SVR (pretreatment 4.0 posttreatment 3.0, = -2.354, = 0.019). Eighty-two percent (31/38) of patients showed histological improvement. The P-I-R score was evaluated in 61% (23/38) of patients. The progressive group showed lower platelet ( = 0.024) and higher HAI scores ( = 0.070) before treatment. In patients with stable Ishak stage after treatment: Progressive injury was seen in 22% (4/18) of patients, 33% (6/18) were classified as indeterminate and regressive changes were seen in 44% (8/18) of patients who were judged as probably reversing by the Ishak and P-I-R systems.
CONCLUSION
Significant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy. The P-I-R score has potential in predicting fibrosis in HCV patients.
Topics: Adult; Antiviral Agents; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged
PubMed: 33584072
DOI: 10.3748/wjg.v27.i5.404 -
Computers in Biology and Medicine Aug 2022Prevalently considered as the "gold-standard" for diagnosis of hepatic fibrosis and cirrhosis, the clinical liver needle biopsy is known to be subject to inadequate...
INTRODUCTION
Prevalently considered as the "gold-standard" for diagnosis of hepatic fibrosis and cirrhosis, the clinical liver needle biopsy is known to be subject to inadequate sampling and a high mis-sampling rate. However, quantifying such sampling bias has been difficult as generating a large number of needle biopsies from the same living patient is practically infeasible. We construct a three-dimension (3D) virtual liver tissue volume by spatially registered high resolution Whole Slide Images (WSIs) of serial liver tissue sections with a novel dynamic registration method. We further develop a Virtual Needle Biopsy Sampling (VNBS) method that mimics the needle biopsy sampling process. We apply the VNBS method to the reconstructed digital liver volume at different tissue locations and angles. Additionally, we quantify Collagen Proportionate Area (CPA) in all resulting virtual needle biopsies in 2D and 3D.
RESULTS
The staging score of the center 2D longitudinal image plane from each 3D biopsy is used as the biopsy staging score, and the highest staging score of all sampled needle biopsies is the diagnostic staging score. The Mean Absolute Difference (MAD) in reference to the Scheuer and Ishak diagnostic staging scores are 0.22 and 1.00, respectively. The absolute Scheuer staging score difference in 22.22% of sampled biopsies is 1. By the Ishak staging method, 55.56% and 22.22% of sampled biopsies present score difference 1 and 2, respectively. There are 4 (Scheuer) and 6 (Ishak) out of 18 3D virtual needle biopsies with intra-needle variations. Additionally, we find a positive correlation between CPA and fibrosis stages by Scheuer but not Ishak method. Overall, CPA measures suffer large intra- and inter- needle variations.
CONCLUSIONS
The developed virtual liver needle biopsy sampling pipeline provides a computational avenue for investigating needle biopsy sampling bias with 3D virtual tissue volumes. This method can be applied to other tissue-based disease diagnoses where the needle biopsy sampling bias substantially affects the diagnostic results.
Topics: Biopsy; Biopsy, Needle; Collagen; Humans; Liver; Liver Cirrhosis; Selection Bias
PubMed: 35797891
DOI: 10.1016/j.compbiomed.2022.105764 -
Acta Gastro-enterologica Belgica 2022In this study, we investigated the efficacy of nine non-invasive fibrosis markers in the assessment of the degree of fibrosis in patients with chronic Hepatitis B (CHB)...
BACKGROUND AND STUDY AIMS
In this study, we investigated the efficacy of nine non-invasive fibrosis markers in the assessment of the degree of fibrosis in patients with chronic Hepatitis B (CHB) in comparison with liver biopsy.
PATIENTS AND METHODS
A total of 1454 untreated CHB patients from two different centers who underwent liver biopsy were included in the study. Laboratory results of patients were reviewed retrospectively and the pathology slides were re-evaluated in accordance with the Ishak score. Degree of fibrosis ≥ 3 was accepted as "significant fibrosis", ≥ 4 as "advanced fibrosis", and ≥ 5 as cirrhosis. The diagnostic performance of the markers Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 score (FIB-4), Aspartate aminotransferase to Alanine aminotransferase Ratio (AAR), AAR to Platelet Ratio Index (AAPRI), Gamma-glutamyl transpeptidase to Platelet Ratio (GPR), King's Score, Fibro quotient (Fibro-Q), S Index and Platelet to Lymphocyte Ratio (PLR) were evaluated with ROC analysis.
RESULTS
In detecting significant fibrosis, APRI, GPR, King's Score and S Index had AUROC values over 0.70. For advanced fibrosis, all of the models except AAPRI; and for cirrhosis, all of the models had AUROC values over 0.70. In accordance with the chosen staging system, GPR, King's Score and S Index had high diagnostic efficacy whereas APRI, FIB-4, FibroQ and PLR had moderate diagnostic efficacy, AAR and AAPRI had low diagnostic efficacy.
CONCLUSIONS
GPR, King's Score and S Index had moderate diagnostic performance in detecting significant fibrosis and advanced fibrosis, and high diagnostic performance in detecting cirrhosis.
Topics: Hepatitis B, Chronic; Humans; Liver Cirrhosis; Platelet Count; Retrospective Studies; Severity of Illness Index
PubMed: 35304995
DOI: 10.51821/85.1.9156