Risk Of Fibrosis Progression Research Articles

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions.

Chronic liver disease (CLD) and its complications constitute a significant cause of mortality and morbidity worldwide. Most deaths are secondary to the decompensation of cirrhosis and evolution of portal hypertension (PHTN). Since disease progression reversal is hardly attainable after decompensated cirrhosis develops, it is essential to intervene early with a therapeutic agent or regimen that could prevent or slow disease evolution. Thus far, there has been no agreed-upon medication to help in the fight against the development of cirrhosis or its decompensation. While early data depicted statins as harmful agents for the liver, current evidence from preclinical and clinical studies suggests that they might have positive impact on CLD. Low-quality evidence supports the fact that statins reduce mortality in CLD. Moderate-quality evidence suggests that statins reduce the risk of hepatic decompensation, variceal bleeding, and mortality, especially among patients with compensated cirrhosis. Combining this data with the long track-record of safety and tolerability of statins and their potential benefits in hepatocellular carcinoma (HCC) risk reduction, hepatologists might soon rely on statins to achieve better outcomes in their CLD and cirrhotic patients without significant additional costs. This review describes the rationale behind the use of statins in patients with CLD and cirrhosis. It sheds light on the current preclinical and clinical studies that reflect beneficial effects of the use of different types and doses of statins in the treatment of patients with different types and stages of CLD and cirrhosis. It also emphasizes the need for designing and developing additional large prospective interventional randomized control trials (RCTs) to better evaluate the association between statin exposure and the risk of fibrosis progression and development of cirrhosis in patients with non-cirrhotic CLDs, the risk of progression of PHTN in patients with cirrhosis, and the mortality rates in patients with cirrhotic or non-cirrhotic CLDs.

Statins for the Treatment of Liver Fibrosis in Chronic Hepatitis-C Patients

Background: Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Chronic hepatitis C (CHC) leads to cirrhosis and hepatocellular carcinoma (HCC). Statins have gained attention for their pleiotropic effects. There is mounting evidence that statins offer chemoprevention against many malignancies. The aim of this was to determine the efficacy of the statin for the treatment of liver fibrosis in chronic hepatitis C patients.
 Methodology: A randomized control trial was conducted at Hepatitis Clinic, People Medical College Hospital, Nawabshah from August 20, 2020, to February 20, 2021. Non-probability, consecutive sampling was adapted. Patients with chronic hepatitis C infection and liver fibrosis were included. Group-A was administered statins in addition to antiviral treatment while Group-B was given anti-viral medications only. Stages of fibrosis were determined by shear wave elastography at the start of the study and after 6 months. All the data were entered and analyzed in Statistical Packages for Social Sciences (SPSS) v25.0.
 Results: There were 73 patients in each group. Fibrosis progression occurred in 7(9.6%) patients in group-A and 23(31.5%) in group-A. The link between the efficacy of the treatment given with the group-A and group-B was significant with a p-value of 0.001.
 Conclusion: Findings demonstrate a significant reduction in the risk of fibrosis progression among statin users with advanced chronic hepatitis C. These results support a possible role for statins in the prevention of liver disease progression.

Анализ результатов противовирусной терапии хронического гепатита С на стадии цирроза печени у пациентов с ВИЧ-инфекцией

Objective. To analyze the features of the course of chronic hepatitis С virus (HCV) and effectiveness of its treatment in patients with HIV infection. Patients and methods. The study was conducted on the basis of the State Budgetary Health Institution “Samara Regional Clinical Center for AIDS Prevention and Control”. Twenty-two HIV-infected patients with HCV genotype 2 and 3 and HCV-related liver cirrhosis were observed. All patients had compensated cirrhosis (class A according to the Child-Pugh classification). Patients were aged between 33 and 65 years, with an average age of 46.5 years. There were 17 (77.3%) male and 5 (22.7%) female patients. Results. The effectiveness of antiviral therapy (AT) for HCV with progression to liver cirrhosis and the dynamics of clinical and laboratory parameters in 22 HIV-infected patients were assessed. HCV genotypes were distributed as follows: genotype 3 was detected in 20 patients (91%), genotype 2 – in 2 patients (9%). According to the results of elastometry, the stages of fibrosis were distributed as follows: F0–F2 – in 0 (0.0%) patients, F3 – in 3 (13.6%) patients, F4 – in 19 (86.4%) patients. Serum levels of HCV RNA prior to treatment averaged 310,335 copies/mL (1,020 to 795,000 copies/mL). After 8 and 12 weeks of antiviral therapy for HCV, all 22 patients had no HCV RNA in the blood. However, in one patient HCV RNA levels reached 53,856 copies/mL 24 weeks after the end of antiviral therapy (reinfection due to the injection of psychoactive substances). Conclusion. Thus, all 22 treated patients with HIV infection and HCV with progression to liver cirrhosis achieved sustained virologic response 12 (SVR12) after an 8-week course of antiviral therapy for HCV (glecaprevir/pibrentasvir). Hepatitis C virus eradication is likely to reduce the risk of fibrosis progression, decompensated cirrhosis, and hepatocellular carcinoma formation. In turn, laboratory manifestations in the form of hepatocyte cytolysis syndrome (AST/ALT) and intrahepatic cholestasis (GGT) ceased by the end of treatment. Against the background of antiviral therapy for HCV, CD4 cell count tended to increase in patients, which would subsequently reduce the risk of severe opportunistic infections and complications. There were no adverse events during treatment with glecaprevir/pibrentasvir (neither clinical symptoms nor change in clinical and biochemical blood tests), which confirms the safety of the chosen treatment regimen. The only problem remains the adherence to treatment of such a complex group of patients as HCV/HIV co-infected, as well as the possibility of HCV reinfection through sexual contact with HCV patients and/or through injecting psychoactive substances. Key words: antiretroviral therapy, HIV infection, direct-acting antivirals, chronic hepatitis C, liver cirrhosis

One liver, two samples and two diagnoses-An example of how multiple samples by laparoscopically guided liver biopsy can be decisive.

Laparoscopically-guided liver biopsy was performed to make the diagnosis in a 54-year old female patient with clinical and serological signs of both non-alcoholic fatty liver disease and autoimmune hepatitis (AIH). Figure A shows a sample from the right liver lobe (HE, 20x) with a blue-boxed area (Figure B) (HE, 100x) demonstrating a total of eight portal tracts. Macrovesicular steatosis of about 50% of hepatocytes and mild lymphocyte infiltration were detected.

The usefulness of noninvasive liver stiffness assessment using shear-wave elastography for predicting liver fibrosis in children

BackgroundPediatric patients with liver disease require noninvasive monitoring to evaluate the risk of fibrosis progression. This study aimed to identify the significant factors affecting liver stiffness values using two-dimensional shear-wave elastography (2D-SWE), and determine whether liver stiffness can predict the fibrosis stage of various childhood liver diseases.MethodsThis study included 30 children (22 boys and 8 girls; mean age, 5.1 ± 6.1 years; range, 7 days–17.9 years) who had undergone biochemical evaluation, 2D-SWE examination, histopathologic analysis of fibrosis grade (F0 to F3), assessment of necroinflammatory activity, and steatosis grading between August 2016 and March 2020. The liver stiffness from 2D-SWE was compared between fibrosis stages using Kruskal–Wallis analysis. Factors that significantly affected liver stiffness were evaluated using univariate and multivariate linear regression analyses. The diagnostic performance was determined from the area under the receiver operating curve (AUC) values of 2D-SWE liver stiffness.ResultsLiver stiffness at the F0-1, F2, and F3 stages were 7.9, 13.2, and 21.7 kPa, respectively (P < 0.001). Both fibrosis stage and necroinflammatory grade were significantly associated with liver stiffness (P < 0.001 and P = 0.021, respectively). However, in patients with alanine aminotransferase (ALT) levels below 200 IU/L, the only factor affecting liver stiffness was fibrosis stage (P = 0.030). The liver stiffness value could distinguish significant fibrosis (≥ F2) with an AUC of 0.950 (cutoff value, 11.3 kPa) and severe fibrosis (F3 stage) with an AUC of 0.924 (cutoff value, 18.1 kPa). The 2D-SWE values for differentiating significant fibrosis were 10.5 kPa (≥ F2) and 18.1 kPa (F3) in patients with ALT levels below 200 IU/L.ConclusionThe liver stiffness values on 2D-SWE can be affected by both fibrosis and necroinflammatory grade and can provide excellent diagnostic performance in evaluating the fibrosis stage in various pediatric liver diseases. However, clinicians should be mindful of potential confounders, such as necroinflammatory activity or transaminase level, when performing 2D-SWE measurements for liver fibrosis staging.

Perspectives of nonalcoholic fatty liver disease research: a personal point of view

Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.

Patients with suboptimal hepatitis B virus diagnostic characterization are at risk of liver fibrosis progression.

Many patients with chronic hepatitis B virus infection remain infradiagnosed and untreated. In a national health system with unrestricted access to treatment, our aims were to assess the level of compliance with clinical guidelines and the characteristics and risk of fibrosis progression in patients with suboptimal diagnosis. In a cohort of patients with positive hepatitis B surface antigen from January 2011 to December 2013, data were registered to assess characteristics and compliance with guidelines. For assessing the risk of liver fibrosis, positive hepatitis B surface antigen patients from January 2008 to December 2013 were grouped depending on DNA request. Liver fibrosis was estimated by serological scores. Of 41 158 subjects with hepatitis B surface antigen request, 351 (0.9%) tested positive, and DNA was not available from 110 patients (66.4% male, mean 42.4 ± 14.5 years) after a median of 25.6 months (range 12.0-43.5). Most of these patients (76%) were assessed by primary care. Half of the patients (47.2%) showed hypertransaminasemia, at least significant fibrosis, or both conditions. After long follow-up (mean 90.1 ± 45.2 months), these patients had a higher risk of achieving at least significant fibrosis during follow-up (log-rank 8.73; P = 0.003). In more than one-third of patients with positive hepatitis B surface antigen, DNA was not requested despite showing hypertransaminasemia and significant fibrosis. Patients without DNA request are at high risk of liver fibrosis progression. Thus, educational measures and other strategies are necessary, especially targeting primary care, to improve access to treatment.

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

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

Tricyclic antidepressant use and the risk of fibrosis progression in hepatitis C-infected persons: Results from ERCHIVES.

Recent preclinical studies have suggested an antifibrotic role for tricyclic antidepressants (TCA). Using the Electronically Retrieved Cohort of hepatitis C virus (HCV) Infected Veterans, we aimed to evaluate the impact of TCA use on fibrosis progression and development of hepatocellular carcinoma (HCC) among HCV-infected persons. Subjects were categorized according to use of TCAs, selective serotonin reuptake inhibitors (SSRI) or no antidepressants. TCAs or selective serotonin uptake inhibitors use was defined according to cumulative defined daily dose (cDDD), and categories were mutually exclusive. Subjects with HIV coinfection, hepatitis B surface antigen (HbsAg) positivity, cirrhosis or HCC at baseline were excluded. Outcomes were liver fibrosis progression measured by APRI scores and incident HCC. We utilized Cox proportional hazards regression to determine predictors of cirrhosis, defined as APRI>2, and incident hepatocellular carcinoma (iHCC). Among 128201 eligible HCV+ persons, 4% received TCAs, 43% received selective serotonin uptake inhibitors, and 53% received no antidepressants. Fewer TCAs users had drug abuse (34% and 43%) and alcohol abuse (32% vs 42%) compared to selective serotonin uptake inhibitor users. After adjusting for age, baseline APRI score, diabetes, hypertension, alcohol use, drug abuse and HCV RNA levels, TCAs use was associated with decreased risk of cirrhosis (hazard ratio [HR]=0.77, 95% CI=0.60, 0.99) and delayed time to development of cirrhosis, but not with decreased iHCC. In conclusion among a large cohort of HCV-positive Veterans, TCAs use was associated with decreased fibrosis progression and lower risk of developing cirrhosis. These data provide supportive evidence for the beneficial effects of TCAs on progression of liver fibrosis in patients with chronic HCV infection.

HIV virological rebounds but not blips predict liver fibrosis progression in antiretroviral-treated HIV/hepatitis C virus-coinfected patients.

ObjectivesAntiretroviral interruption is associated with liver fibrosis progression in HIV/hepatitis C virus (HCV) coinfection. It is not known what level of HIV viraemia affects fibrosis progression.MethodsWe evaluated 288 HIV/HCV-coinfected cohort participants with undetectable HIV RNA (< 50 HIV-1 RNA copies/mL) on two consecutive visits while on combination antiretroviral therapy (cART) without fibrosis [aspartate aminotransferase to platelet ratio index (APRI) < 1.5], end-stage liver disease or HCV therapy. An HIV blip was defined as a viral load of ≥ 50 and < 1000 copies/mL, preceded and followed by undetectable values. HIV rebound was defined as: (i) HIV RNA ≥ 50 copies/mL on two consecutive visits, or (ii) a single HIV RNA measurement ≥ 1000 copies/mL. Multivariate discrete-time proportional hazards models were used to assess the effect of different viraemia levels on liver fibrosis progression (APRI ≥ 1.5).ResultsThe mean age of the patients was 45 years, 74% were male, 81% reported a history of injecting drug use, 51% currently used alcohol and the median baseline CD4 count was 440 [interquartile range (IQR) 298, 609] cells/μL. Fifty-seven (20%) participants [12.4/100 person-years (PY); 95% confidence interval (CI) 9.2−15.7/100 PY] progressed to an APRI ≥ 1.5 over a mean 1.1 (IQR 0.6, 2.0) years of follow-up time at risk. Virological rebound [hazard ratio (HR) 2.3; 95% CI 1.1, 4.7] but not blips (HR 0.5; 95% CI 0.2, 1.1) predicted progression to APRI ≥ 1.5. Each additional 1 log10 copies/mL HIV RNA exposure (cumulative) was associated with a 20% increase in the risk of fibrosis progression (HR 1.2; 95% CI 1.0–1.3).ConclusionsLiver fibrosis progression was associated with HIV rebound, but not blips, and with increasing cumulative exposure to HIV RNA, highlighting the importance of achieving and maintaining HIV suppression in the setting of HIV/HCV coinfection.

S11 * ALCOHOL AS A MODULATOR OF LIVER DISEASE PROGRESSION ESBRA &amp; EASL JOINT SYMPOSIUM

S11 * ALCOHOL AS A MODULATOR OF LIVER DISEASE PROGRESSION ESBRA &amp; EASL JOINT SYMPOSIUM

Strategies in secondary biliary fibrosis

The cellular and molecular mechanisms that mediate hepatic fibrosis have provided a framework of different therapeutic foci to prevent, delay or in such case revert fibrosis and cirrhosis. The fundamental event in development of hepatic fibrosis caused by secondary biliary cholestasis is based on activation of the hepatic stellar cells (HSC) which the primary function is forming fibrosis. The activated HSC cells transform into myofibroblasts with capacity to produce alpha smooth muscle actin (α-SMA). As a result, the HSC activates proliferation of the cholangiocytes and epithelial cells whose functions represent important anti-fibrotic objectives. Some strategies are described as targeting against molecule involved in fibrosis production; and some medications with anti-fibrotic functions that are actually available in the medical arsenal have been tested in experimental animal models and in few clinical studies, and their components act in relation to the fibrotic cascade. In the end, the treatment strategies for hepatic fibrosis can vary on an individual basis depending on the etiology, the risk of fibrosis progression and the predominant pathogenic medium, which indicates that a multi-factorial approach could be necessary. Orthotopic liver transplant continues being the last final alternative for hepatic insufficiency from any cause; however, in no way does it supersede healthy natural liver in survival and adequate function. The investigative arsenal continues to develop rapidly, giving rise to other possible objectives in pre-clinical studies of conceptual trials, such as the utilization of molecular, cellular, drugs therapy and Chinese herbs. Despite being aforementioned, there are no existing ideal alternatives that completely reverse fibrosis in humans. Future usefulness of the majority of management alternatives seems probable and could be feasible.

Predicting cirrhosis and clinical outcomes in patients with advanced chronic hepatitis C with a panel of genetic markers (CRS7)

Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a predictor of clinical outcomes in patients with CHC. A total of 938 patients (677 Caucasians, 165 African-Americans, and 96 Hispanic/Other) in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial were studied. CRS7 was categorized a priori as high risk (n=440), medium risk (n=310), or low risk (n=188). Patients were assessed for four possible outcomes: fibrosis progression, cirrhosis, clinical outcomes [decompensation or hepatocellular carcinoma (HCC)], or HCC alone. Twenty-nine percent (142/493) developed an increase in fibrosis score by greater than or equal to 2 points on follow-up biopsies, 58% had cirrhosis on one or more biopsies, 35% developed at least one clinical outcome, and 13% developed HCC. CRS7 (trend test) was associated with risk for fibrosis progression (P=0.04) with adjusted hazard ratio of 1.27 (95% confidence interval: 1.01-1.58) and with cirrhosis (P=0.05) with adjusted odds ratio of 1.19 (1.00-1.41). Rates of HCC and clinical outcomes were increased in patients with higher CRS7 scores, but were not statistically significant (P=0.12 clinical outcomes, and P=0.07 HCC). A single nucleotide polymorphism in AZIN1 was significantly associated with fibrosis progression. CRS7 was validated as a predictor of fibrosis progression and cirrhosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, who all had advanced fibrosis. CRS7 was not predictive of clinical outcome.

Therapeutic targets in liver fibrosis

Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

Medication treatment of alcohol use disorders in veterans with Hepatitis C

Hepatitis C viral infection (HCV) is the most common chronic blood borne viral infection in the world and in the United States affects approximately 1.8% of the general population. The prevalence of hepatitis C viral infection (HCV) is 3-4 times higher among veterans who use VA services than the general population rate of 1.8% and is estimated to be approximately 5 to 6%. A national VA study found that over 75% of veterans had some Substance Use Disorder. At the Portland VAMC, 57.6% (n = 783) of veterans with HCV recently seen in the hepatology clinic reported consuming alcohol in the past year and approximately 25% reported heavy alcohol use (AUDIT C score of 4 or greater). Alcohol use and HCV are thought to act synergistically to accelerate liver damage and cirrhosis. Several studies show heavy alcohol consumption increases the risk of fibrosis progression as well as the risk of end stage liver disease and cirrhosis in HCV patients. Among them Corrao and Arico (1998) found, among all patients who do not drink alcohol, HCV-infected patients are 9.2 times more likely to develop liver cirrhosis than non-HCV-infected patients. They also found that there is a dose-dependent relationship between lifetime daily alcohol intake, HCV infection, and risk of developing cirrhosis. Compared to HCV patients who do not drink, the risk of cirrhosis was three times higher in HCV patients who drank 75 to 100 grams per day, 16 times higher in HCV patients who drank ≥175 grams per day of alcohol than HCV patients who did not drink and over 140 times higher than people who did not have HCV or drink alcohol. Effective treatments for alcohol use have not been studied in patients chronically infected with HCV and current FDA-approved medications for AUD can adversely affect the liver and are generally not well tolerated. The presentation will review current FDA -approved as well as off-label use medication studies for Alcohol Use Disorders and their utility for people who have hepatitis C and co-morbid Alcohol Use Disorders. The various treatment options will be discussed.

Immunopathogenesis of hepatitis C virus infection and hepatic fibrosis: New insights into antifibrotic therapy in chronic hepatitis C

Fibrosis and cirrhosis represent the consequences of a sustained wound-healing response to chronic liver injury of any cause. Chronic hepatitis C virus (HCV) has emerged as a leading cause of cirrhosis in the USA and throughout the world. HCV may induce fibrogenesis directly by hepatic stellate cell activation or indirectly by promoting oxidative stress and apoptosis of infected cells. The ultimate result of chronic HCV injury is the accumulation of extracellular matrix with high density type I collagen within the subendothelial space of Disse, culminating in cirrhosis with hepatocellular dysfunction. The treatment of hepatitis C with the combination of pegylated interferon and ribavirin is still both problematic and costly, has suboptimal efficacy, serious side effects and a high level of intolerance, and is contraindicated in many patients. Hence, new approaches have assumed greater importance, for which there is an urgent need. The sustained progress in understanding the pathophysiology of hepatic fibrosis in the past two decades has increased the possibility of developing drugs specifically targeting the fibrogenic process. Future efforts should identify genetic markers associated with fibrosis risk in order to tailor the treatment of HCV infection based on genetically regulated pathways of injury and/or fibrosis. Such advances will expand the arsenal to overcome liver fibrosis, particularly in patients with hepatic diseases who have limited treatment options, such as those patients with chronic hepatitis C who have a high risk of fibrosis progression and recurrent HCV disease after liver transplantation.

Influence of age and date of infection on distribution of hepatitis C virus genotypes and fibrosis stage.

The objective of this study was to assess the influence of age and date of acquisition of hepatitis C virus (HCV) infection on the distribution of genotypes and the progression of fibrosis in HCV-infected patients who were born in Spain and had their habitual place of residence in this country. Genotypic analysis was performed in 375 patients in whom it was possible to establish the year of HCV infection because the mode of transmission was known (transfusion, injection drug use, blood donor, or epidemic outbreak). In 298 patients with liver biopsy, fibrosis stage was related to age at infection, duration of infection, alcohol consumption, and HCV genotype. HCV subtype 1b was almost exclusively detected among transfusion recipients, but the onset of intravenous drug addiction was associated with the introduction of HCV genotypes other than 1b among injecting users with subsequent spread to other exposure risk groups. Fibrosis progression was influenced by alcohol consumption, increased duration of infection, and older age at infection. In summary, spread of intravenous drug use determined HCV infection by genotypes other than 1b. The risk of fibrosis progression was influenced more by age at viral acquisition and alcohol consumption than by the infecting genotype.