Fibrosis Progression Rate Research Articles

The effect of weight gain and metabolic dysfunction-associated steatotic liver disease on liver fibrosis progression and regression in people with HIV.

People with HIV (PWH) have high risk of liver fibrosis. We investigated the effect of weight gain and metabolic dysfunction-associated steatotic liver disease (MASLD) on liver fibrosis dynamics. Multicenter cohort study. Fibrosis progression was defined as development of significant fibrosis [liver stiffness measurement (LSM) ≥8 kPa], or transition to cirrhosis (LSM ≥13 kPa), for those with significant fibrosis at baseline. Fibrosis regression was defined as transition to LSM less than 8 kPa, or to LSM less than 13 kPa for those with cirrhosis at baseline. MASLD was defined as hepatic steatosis (controlled attenuation parameter >248 dB/m) with at least one metabolic abnormality. A continuous-time multistate Markov model was used to describe transitions across fibrosis states. Among 1183 PWH included from three centers (25.2% with viral hepatitis coinfection), baseline prevalence of significant fibrosis and MASLD was 14.4 and 46.8%, respectively. During a median follow-up of 2.5 years (interquartile range 1.9-3.5), the incidence rate of fibrosis progression and regression was 2.8 [95% confidence interval (CI) 2.3-3.4] and 2.2 (95% CI 1.9-2.6) per 100 person-years, respectively. In Markov model, weight gain increased the odds of fibrosis progression [odds ratio (OR) 3.11, 95% CI 1.59-6.08], whereas weight gain (OR 0.30, 95% CI 0.10-0.84) and male sex (OR 0.32, 95% CI 0.14-0.75) decreased the odds of fibrosis regression. On multivariable Cox regression analysis, predictors of fibrosis progression were weight gain [adjusted hazard ratio (aHR) 3.12, 95% CI 1.41-6.90] and MASLD (aHR 2.72, 95% CI 1.05-7.02). Fibrosis transitions are driven by metabolic health variables in PWH, independently of viral hepatitis coinfection and antiretroviral class therapy.

A259 METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE IS ASSOCIATED WITH MULTI-ORGAN COMORBIDITIES AND FIBROSIS PROGRESSION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD)

Abstract Background Patients with IBD are at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) due to chronic inflammation, hepatotoxic drugs, alteration of gut microbiota. MASLD, formerly known as non-alcoholic fatty liver disease, provides a positive rather than negative diagnosis, appropriately assigns a metabolic basis for hepatic steatosis (HS), avoids any potentially stigmatizing term, and excludes alcohol abuse. MASLD carries higher risk of both liver fibrosis progression and extra-hepatic involvement, including cardiovascular disease , extra-hepatic cancer, hypothyroidism, chronic kidney disease (CKD). Data on the effect of MASLD on fibrosis progression and multi-organ co-morbidities are lacking in this population. Aims We aimed to determine if MASLD and liver fibrosis carry a higher risk of extra-hepatic co-morbidities in IBD. Methods We prospectively included consecutive IBD patients who underwent liver stiffness measurement (LSM) with controlled attenuation parameter (CAP) by Fibroscan at a single centre. MASLD was defined as any grade HS without alcohol abuse and viral hepatitis. HS progression was defined as any grade HS (CAPampersand:003E270 dB/m), or transition to severe HS (CAPampersand:003E330 dB/m) with CAPampersand:003E270 but ampersand:003C330 dB/m at baseline. Fibrosis progression was defined as significant liver fibrosis (LSM≥8 kPa), or transition to cirrhosis (LSM≥13 kPa) with LSMampersand:003E8 but ampersand:003C13 kPa at baseline. We estimated incidence rates of HS and fibrosis progression by dividing participants with the outcome by number of person-years (PY) of follow-up. Covariate adjustments for HS progression were evaluated by multivariable Cox regression models and predictors of extra-hepatic conditions by multivariable logistic regression analysis. Results 430 patients were included with mean age 43 years, BMI 25 Kg/m2, IBD duration 14 years, CRP 5.2, ALT 22; females 45%, ulcerative colitis (UC) 31.8%, T2DM 4.7%. Patients with MASLD had higher proportion of CV events (12% vs. 6%), CKD (8% vs. 3%) and hypothyroidism (12% vs. 6%) vs. those without. After adjusting for age, male sex and Crohn’s IBD subtype, MASLD remained an independent predictor of extra-hepatic comorbidities (aOR 1.79, 95% CI 1.15–2.78; p=0.01) with T2DM (aOR 3.53, 95% CI 1.68-7.42; p=0.001). Patients were followed for 26 months (SD 16.4). Rate of HS progression was 16.2 per 100 PY (95% CI, 11.5-22.8) and liver fibrosis progression was 6.12 per 100 PY (95% CI 3.48-10.44). In multivariable analysis, after adjusting for IBD duration and BMI,UC was associated with faster progression of HS (aHR 2.21, 95% CI 1.02-4.91). Conclusions MASLD is associated with extra-hepatic diseases in patients with IBD and can progress to liver fibrosis and cirrhosis. Figure 1. Evolution of NAFLD and associated liver fibrosis in patients with IBD. Funding Agencies CIHR

Disease severity and antiviral response in patients with chronic hepatitis B with non-obese NAFLD

BackgroundThe burden of nonalcoholic fatty liver disease (NAFLD) is growing in patients with chronic hepatitis B (CHB). NAFLD is typically associated with obesity, however, it is increasingly being identified in non-obese patients. This study aimed to investigate disease severity and antiviral response in non-obese patients with CHB with NAFLD (CHB + NAFLD). MethodsA total of 809 patients with CHB + NAFLD were prospectively recruited and followed up for 3 years. NAFLD was diagnosed by transient elastography and defined as controlled attenuation parameter ≥248 dB/m, in the absence of excessive alcohol intake. Obesity status was defined by the Asian body mass index (BMI) cutoff of 25 kg/m2. Metabolic abnormality was defined by the presence of dyslipidemia, hypertension or diabetes. Fibrosis staging was defined according to the EASL-ALEH guidelines, with fibrosis progression defined as ≥1-stage increment. ResultsIn the total cohort (median age 40 years, 59.0% antiviral-treated), 33.3% were non-obese. Non-obese patients were less metabolically abnormal than obese patients (60.2% vs 72.0%, P = 0.003). After 3-year follow up, the rate of fibrosis progression was comparable between non-obese and obese patients (17.5% vs 21.9% in the total cohort, P = 0.145; 15.7% vs 14.6% in antiviral-treated cohort with persistent viral suppression, P = 0.795). No significant differences in virological and biochemical responses were observed between non-obese and obese patients (P >0.05 for all). ConclusionApproximately one third of CHB + NAFLD patients were non-obese. Non-obese patients, while less metabolically abnormal, had a similar risk for fibrosis progression as obese patients. Obesity status did not impact the efficiency of antiviral therapy.

Clinical and psychopathological features of the course and outcome of the first psychotic episode.

Recently it has been established that cytokines are involved in the regulation of the body’s defense reactions in response to a pathogen and form an independent system for regulating homeostasis. The aim of this work is to study the relationship of the polymorphic marker TNFα (rs1800620) with its quantitative content and the degree of liver fibrosis in patients with various chronic hepatitis (VHC, VHB, VHB+C). The 82 patients with chronic hepatitis B, 62 patients with hepatitis B+C, and 100 patients with chronic hepatitis C were examined. GGTNFα (rs1800620) genotype is protective for patients with various viral hepatitis, and the GATNFα (rs1800620)and AATNFα (rs1800620)genotypes are profibrogenic for patients with chronic hepatitis B, chronic hepatitis B+C and chronic hepatitis C, respectively, since a high degree of fibrosis than in carriers of the homozygous GGTNFα (rs1800620)genotype. It is possible that the rate of fibrosis progression is influenced not only by the qualitative content of TNFα, but also by a certain genotype.

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

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

Antibody designing against IIIabc junction (JIIIabc) of HCV IRES through affinity maturation; RNA-Antibody docking and interaction analysis.

Hepatitis C virus is a single-stranded RNA based virus which can cause chronic HCV and hepatocellular carcinoma. HCV genotype 3a has relatively higher rate of fibrosis progression, prevalence of steatosis and incidence of HCC. Despite HCVs variation in genomic sequence, the 5' untranslated region containing internal ribosome entry site (IRES) is highly conserved among all genotypes. It is responsible for translation and initiation of the viral protein. In present study, IRES was targeted by designing variants of reported antigen binding fragment (Fab) through affinity maturation approach. Affinity maturation strategy allowed the rational antibody designing with better biophysical properties and antibody-antigen binding interactions. Complementarity determining regions of reported Fab (wild type) were assessed and docked with IRES. Best generated model of Fab was selected and subjected to alanine scanning Three sets of insilico mutations for variants (V) designing were selected; single (1-71), double (a-j) and triple (I-X). Redocking of IRES-Fab variants consequently enabled the discovery of three variants exhibiting better docking score as compared to the wild type Fab. V1, V39 and V4 exhibited docking scores of -446.51, -446.52 and-446.29 kcal/mol respectively which is better as compared to the wild type Fab that exhibited the docking score of -351.23 kcal/mol. Variants exhibiting better docking score were screened for aggregation propensity by assessing the aggregation prone regions in Fab structure. Total A3D scores of wild type Fab, V1, V4 and V39 were predicted as -315.325, -312.727, -316.967 and -317.545 respectively. It is manifested that solubility of V4 and V39 is comparable to wild type Fab. In future, development and invitro assessment of these promising Fab HCV3 variants is aimed.

Long-term outcomes after EUS-guided antegrade intervention for benign bilioenteric anastomotic stricture

Background and aimsBilioenteric anastomotic stricture (BES) is a well-known adverse event after bilioenterostomy. Recently, endoscopic ultrasound-guided antegrade intervention (EUS-AI) has been developed for cases that are difficult to treat by balloon enteroscopy-assisted ERCP. However, there have been no data on the long-term outcomes after EUS-AI. The main goal of the present study was to clarify the long-term outcomes of EUS-AI in such patients. Methods and patientsBetween November 2013 and November 2021, 34 patients who were followed for more than 1 year after EUS-AI for BES were identified. The primary endpoint was the rate of stricture resolution. The secondary endpoints were factors associated with stricture resolution, the rate of BES recurrence, the rate of conversion to surgery, and the rate of hepatic fibrosis progression during follow-up. ResultsThe median follow-up period was 56.7 months. Stricture resolution was achieved in 17 of 34 cases (50%). A multivariate analysis confirmed that the presence of bile duct stones (odds ratio: 9.473; 95% confidence interval (CI): 1.66–53.98; P=0.01) was significantly associated with stricture resolution. The stricture recurrence rate was 33%, and the median time from stent removal to recurrence was 31.2 months. A total of 4 patients underwent surgery due to recurrent cholangitis. During the median follow-up period of 56.7 months, 25% progressed to hepatic fibrosis based on the Fib4 grade. Interestingly, the cases without cholangitis during follow-up did not show progression of hepatic fibrosis. ConclusionEUS-AI has achieved acceptable long-term clinical outcomes. EUS-AI can be a viable alternative treatment of choice before surgical treatment in patients who are difficult to treat by conventional approaches.

Diagnostic values of MMP-9 and TGF-1β in assessing the severity of liver fibrosis and the rate of its progression in patients with chronic hepatitis C GT 1 infection

Aim. The purpose of our work is to find out diagnostic values of serum MMP-9 and TGF-1β determination for assessing the severity of liver fibrosis and the rate of its progression in patients with chronic hepatitis C genotype 1 (CHC GT1) infection. Materials and methods. 92 patients with CHC GT1 were examined. The severity of liver fibrosis was assessed by elastometry. The rate of liver fibrosis progression was calculated using the T. Poynard formula. Serum levels of TGF-1β and MMP-9 were measured by ELISA method. Results. In patients with CHC GT1, the most noticeable changes in the serum parameters of fibrogenesis / fibrinolysis were observed in the presence of F 3–4. The probability of liver fibrosis stages F 3–4 was high at the serum levels of TGF-1β >12.03 pg/ml (p < 0.001), MMP-9 ≤987.20 pg/ml (p = 0.016), TGF-1β/MMP-9 ratio >0.011 (p < 0.001). Fast liver fibrosis progression was more often registered in F 3–4 than in F 0–2 (62.9 % vs. 16.7 %, p < 0.0001). Increasing rate of liver fibrosis progression in these patients was confirmed by a higher ratio of TGF-1β/MMP-9 compared to that in patients with a slow rate of liver fibrosis progression (p < 0.05). The probability of fast liver fibrosis progression was high at the serum levels of TGF-1β >8.69 pg/ml (p < 0.001), MMP-9 ≤920.65 (p = 0.005), TGF-1β/MMP-9 ratio > 0.011 (p < 0.001). Conclusions. The diagnostic value of MMP-9 and TGF-1β in assessing the liver fibrosis severity and the rate of its progression in patients with CHC GT1 has been defined. Cut-off levels of MMP-9, TGF-1β and the TGF-1β/MMP-9 ratio for stratification of patients with severe liver fibrosis and the fast rate of its progression have been proposed.

FIB 4 Score (Liver Fibrosis) and Attending Level of Vitamin D in Chronic Hepatitis C Patients

Millions of people around the world are affected by chronic hepatitis C (HCV), which is a global health issue. It is a major contributor to chronic liver conditions such as cirrhosis, hepatocellular carcinoma, and liver fibrosis. For optimal therapy and intervention, prompt identification of liver fibrosis is essential. The rate of hepatic fibrosis progression in HCV-infected patients varies substantially. Objective: To evaluate the vitamin D level and liver fibrosis degree by non-invasive Fib 4 score among chronic hepatitis patients. Methods: This Cross-sectional study was conducted at a tertiary care hospital in Karachi, Pakistan, from August 2020 to September 2022. 65 participants were recruited through a non-probability sampling technique. Results: Study findings show that 21.9% of the patients have low risk for advanced fibrosis, whereas 9.2% have an Intermediate risk for advanced fibrosis, and 69.2% have a high risk for advanced fibrosis. Moreover, findings also revealed that among 65 patients, 66.2% have a deficient amount of Vitamin D, whereas 16.9% have an insufficient amount of Vitamin D level and 16.9% have a sufficient amount of vitamin D. Furthermore, the findings also showed significant association based on p-value (0.001) between Age and Fib4 score of the participant. Conclusions: In conclusion, the study revealed that a significant proportion of chronic hepatitis C patients were at high risk for advanced fibrosis, while vitamin D deficiency/ insufficiency were prevalent among the majority of the patients.

Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

A continuous-time Markov chain model of fibrosis progression in NAFLD and NASH.

The specific pathways, timescales, and dynamics driving the progression of fibrosis in NAFLD and NASH are not yet fully understood. Hence, a mechanistic model of the pathogenesis and treatment of fibrosis in NASH will necessarily have significant uncertainties. The rate of fibrosis progression and the heterogeneity of pathogenesis across patients are not thoroughly quantified. To address this problem, we have developed a continuous-time Markov chain model that is able to capture the heterogeneity of fibrosis progression observed in the clinic. We estimated the average time of disease progression through various stages of fibrosis using seven published clinical studies involving paired liver biopsies. Sensitivity analysis revealed therapeutic intervention at stage F1 or stage F2 results in greatest potential improvement in the average fibrosis scores for a typical patient cohort distribution. These results were in good agreement with a retrospective analysis of placebo-controlled pioglitazone clinical trials for the treatment of NAFLD and NASH. This model provides support for determining patient populations, duration, and potential successful endpoints for clinical trial design in the area of NAFLD and NASH.

Clinical aspects of the use of erdosteine in respiratory diseases

Erdosteine is a drug based on thiol and used at the beginning only as a mucolytic. The main indication for it is the treatment of acute and chronic lung diseases, accompanied by difficult sputum discharge. The therapeutic effect of erdosteine is due to the action of thiol metabolites, which, in addition to mucoactive, have antioxidant, anti-inflammatory and antibacterial activities. Experimental studies have shown that this drug reduces the degree of damage to lung tissue caused by oxidative stress, primarily by reducing the production of reactive oxygen species. It increases the concentration of IgA in the respiratory mucosa, thereby reducing the damaging effect of tobacco smoke on endothelial and macrophage cells. In the RESTORE clinical study, which studied the effect of erdosteine on the frequency of exacerbations of chronic obstructive pulmonary disease, it was demonstrated that it significantly reduces the risk, frequency and severity of COPD exacerbations, regardless of patients taking inhaled corticosteroids and eosinophil levels. Recent experimental studies have shown that erdosteine also has the ability to slow the progression rate of fibrosis in pulmonary tissue. It has been shown to inhibit the development of bleomycin-induced fibrosis. The authors of the study suggested that this effect may be related to the suppression of neutrophil migration metabolite erastheine, the inhibition of lipid peroxidation and, in general, the regulation of antioxidant protection mechanisms Data obtained in recent studies also open up new possibilities for the use of erdosteine in patients with bronchial asthma and idiopathic pulmonary fibrosis, significantly expanding the indications for its use.

Prognostic impact of steatosis in the clinical course of chronic HCV infection-Results from the German Hepatitis C-Registry.

BackgroundLiver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients.MethodsThe German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores.ResultsAt the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m2) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT.ConclusionClinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.

Log-Linear Model and Multistate Model to Assess the Rate of Fibrosis in Patients With NAFLD

In this paper, the deleterious effects of obesity, type II diabetes, and insulin resistance, systolic and diastolic hypertension on the rate of progression of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) are illustrated using a new approach utilizing the Poisson regression to model the transition rate matrix. The observed counts in the transition count matrix are used as the response variables and the covariates are the risk factors for fatty liver. Then, the estimated counts from running the Poisson regression are used to estimate the transition rates using the continuous-time Markov chains (CTMCs) followed by exponentiation of the estimated rate matrix to obtain the transition probability matrix at specific time points. A depicted, hypothetical, observational, prospective longitudinal study of 150 participants followed up every year for a total of 29 years recording their demographic characteristics and their timeline follow-up is demonstrated. The findings revealed that insulin resistance expressed by HOMA2-IR had the most deleterious effects among other factors on increasing the rate of fibrosis progression from state 1 to state 2, from state 2 to state 3, and from state 3 to state 4. The higher the level of HOMA2-IR is, the more rapid the rate of progression is. This analysis helps the health policymakers and medical insurance managers to allocate the financial and human resources for investigating and treating high-risk patients with NAFLD. In addition, this analysis can be used by pharmaceutical companies to conduct longitudinal studies to assess the effectiveness of the newly emerging anti-fibrotic drugs.

PREVALENCE OF COMBINED LIVER DAMAGE IN MEXICAN POPULATION

Metabolic syndrome and alcohol consumption are the two main causes of liver steatosis. Often, one of them predominates for its development and the other acts as a cofactor. The impact of these entities separately and their damage in synergy in the Mexican population is currently unknown. Our objective is to determine the prevalence of non-alcoholic liver steatosis, alcoholic liver steatosis, and dual damage in donors from the blood bank of the Hospital General de México “Dr. Eduardo Liceaga” (HGMEL) using transient elastography (TE). Pilot study. prospective, transversal, descriptive, and analytical. Healthy donors from the HGMEL blood bank who attended from June 8 to 29 2021 ≥18 years old, of any gender, will be included with a body mass index (BMI) ≥18.5. Donors with liver disease of any etiology and liver malignancy will be excluded. Donors who did not attend TE will be eliminated. The equipment used for TE was FibroScan® 502 Touch. Descriptive statistics will be used with measures of central tendency and dispersion. 30 donors were recruited, four were eliminated for not having performed TE. The age of the subjects was 36.53 ± 12.13 years. There were 13 female subjects and 13 males. Seven (26.92%) donors were classified with non-alcoholic fatty liver disease (NAFLD), 2 (7.69%) with alcoholic fatty liver disease (ALD), and 1 (3.84%) subject with liver steatosis due to combined damage; the 16 (61.55%) remaining subjects corresponded to a healthy population. From the NAFLD group, S1 steatosis was documented in 1 subject (14.28%), S2 in 2 (28.56%), and S3 in 4 (57.16%); F0-F1 liver stiffness was found in 6 (85.72%) subjects, and F4 in 1 (14.28%); Of this group, 3 (42.86%) subjects were classified as overweight, 3 (42.86%) with grade 2 obesity, and 1 (14.28%) with grade 3 obesity. On the other hand, from the ALD group, one donor was found with steatosis S1, and 1 with S2; one of them had liver stiffness F0-F1 with an AUDIT score of 17 and a risk pattern for excessive alcohol consumption (117 g 2 to 4 times a month), while the other subject had F4 fibrosis with an AUDIT score of 7 and a pattern risk of excessive consumption (208 g 2 to 4 times per month), both consume beer. Finally, one donor had liver steatosis due to combined damage, with S3 for steatosis and F4 liver stiffness (27.4 kPa, the highest record in the study); He has grade 3 obesity (BMI 44.41), an AUDIT score of 4, and a pattern of excessive consumption (78 g 2 to 4 times a month) of distillates. What is relevant about this work is that it studies an apparently healthy population and, according to our results, 38.45% (10) of the subjects already have a degree of liver steatosis and even 11.53% (3) showed advanced fibrosis. Our findings are similar to others about the prevalence of nonalcoholic liver steatosis, such as the work of the López-Velázquez group (26%) in 2014. Our study is novel in the investigation of alcoholic liver steatosis and the combined damage. Those issues are scarce addressed in our country. We also collect additional information, such as the identification of the consumption pattern of people with risky alcohol intake and the type of drink they consume. Our study shows that liver steatosis in this sample of the Mexican population is predominantly non-alcoholic; all subjects within this group have high BMI. Excessive risk consumption is prevalent in subjects with alcohol-related steatosis, and beer is the most frequent drink. In combined damage, obesity and excessive consumption of distillates seem to be the cause of severe steatosis. The only patient in this group already shows advanced fibrosis, which makes us suspect that dual damage accelerates the rate of fibrosis progression. The authors declare that there is no conflict of interest.

Long-term surveillance of liver histological changes in chronic hepatitis C patients completing pegylated interferon-α plus ribavirin therapy: an observational cohort study.

Background:For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored.Methods:This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63–7.54).Results:In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n = 77), cases achieving sustained virological response (SVR) (n = 52) had a significantly lower rate of fibrosis progression than non-SVR cases (n = 25) (3.8% versus 24.0%, p = 0.012). Among the entire cohort (n = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases (n = 59) was significantly higher than that in non-SVR cases (n = 26) (94.9% versus 65.4%, p = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p = 0.049) and activity response (OR = 17.741, p = 0.047), respectively.Conclusions:Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development

There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n= 421) and was validated in an independent NAFLD cohort (n= 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic exvivo cultures of clinical fibrotic liver tissues (n= 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n= 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n= 122). A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic exvivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in exvivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Presence of CAT genetic markers as an indicator of accelerated rate of liver fibrosis progression in patients with chronic hepatitis

Goal. To evaluate the genetic profi le of patients with chronic hepatitis C (CHC) by the CAT gene polymorphism in the region-262G/A (rs1001179), GPX4 in the region-718C/T (rs713041), IL28B in the region C/T (rs12979860) and VEGFA in the region- 634G/C (rs2010963) to analyze the association of the rate of progression of liver fi brosis with polymorphic genetic markers.Materials and methods. We examined 36 patients with CHC with a rapidly progressive rate of fi brosis (up to 10 years) and 56 patients with a slowly progressive course of the disease (more than 10 years). The study of single- nucleotide polymorphisms of genes was carried out by the method of polymerase chain reaction.Results. In the group with rapid progression of liver fi brosis, individuals with multiple risk alleles for the studied polymorphisms were more common, which confi rms the association of the risk of liver fi brosis progression with the genetic markers CAT in the region-262G/A (rs1001179) and GPX4 in the region-718C/T (rs713041) with their combined carrier. Among patients with rapid progression of fi brosis, a greater number of individuals had simultaneously 4–6 risk alleles in 27.5%, while patients with slow progression of the process only in 11% of cases.Conclusion. This set of genetic markers can be used as genetic testing of patients with liver fibrosis to determine the prognosis of the disease.

Transition of Care Model for Pediatric Patients With Nonalcoholic Fatty Liver Disease.

Transition of Care Model for Pediatric Patients With Nonalcoholic Fatty Liver Disease.

Fontan-Associated Anatomical Variants and Hepatic Fibrosis.

We hypothesized that a relationship between post-Fontan hepatic fibrosis and anatomical variants might exist. Attempting to limit confounding variables, we analyzed data from living, stable, post-extracardiac Fontan patients who underwent cardiac catheterization and transvenous hepatic biopsy procedures between March 2012 and June 2020. We identified 120 patients who met the inclusion criteria. Of the 120, 35 (29%) had pulmonary artery stents. For the 35 with pulmonary artery stents, the average total fibrosis score was 3.2 ± 1.9 and the fibrosis progression rate was 0.36 ± 0.33, and for those with no pulmonary artery stents, the total fibrosis score was 2.6 ± 1.8 and the fibrosis progression rate was 0.27 ± 0.33 (P = .13 and P = .11, respectively). Of the 120, 65 had functional univentricles of right ventricular type. Of these 65, 27 had pulmonary artery stents. For the 27 with pulmonary artery stents, the average total fibrosis score was 3.4 ± 1.8 and the average fibrosis progression rate was 0.39 ± 0.30, and for the 38 without pulmonary artery stents, the average fibrosis score was 2.3 ± 1.5 and the average fibrosis progression rate was 0.23 ± 0.21 (P = .01 for comparison of both values). This study's findings suggest that a post-extracardiac Fontan with a functional univentricle of right ventricular type plus a pulmonary artery stent may have more advanced liver pathology than those without a pulmonary artery stent at similar Fontan duration years and ages at liver biopsy.