Liver Fibrosis

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Knowledge of the cellular and molecular events associated with the formation of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-ᵝ1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has encougaged researchers to continue their research for potent and safer antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown.

Autophagy is a metabolic process that degrades and recycles intracellular organelles and proteins with many connections to human disease and physiology. We studied the role of autophagy during hepatic stellate cell (HSC) activation, a key event in liver fibrogenesis. Analysis of the autophagic flux during in vitro activation of primary mouse HSCs was performed using a DsRed-GFP-LC3B encoding plasmid. The effect of autophagy inhibition by bafilomycin A1 on the in vitro activation process of human and mouse HSCs was examined by measuring proliferation, presence of activation markers by RT-qPCR, immunofluorescence, and Western blotting. Analysis of lipid droplet and microtubule-associated protein light chain 3 beta (LC3B) colocalization in the presence of PDGF-BB was investigated by immunocytochemistry. A significant increased autophagic flux was observed during culture induced mouse HSC activation. Treatment of mouse HSCs and human HSCs with autophagy inhibitor bafilomycin A1 results in a significant decreased proliferation and expression of activation markers. In addition, lipid droplets and LC3B colocalization was increased after PDGF-BB treatment in quiescent HSCs. During HSC activation, autophagic flux is increased. The demonstration of partly inhibition of in vitro HSC activation after treatment with an autophagy inhibitor unveils a potential new therapeutic strategy for liver fibrosis.

OBJECTIVE To review evidence on the diagnosis and management of nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in human beings. SOURCES OF INFORMATION The literature was searched for clinical trials and review articles on NAFLD. Levels I and II evidence indicates the benefit of both lifestyle and pharmacologic interventions for NAFLD and nonalcoholic steatohepatitis

Chinese herbal medicine (CHM), an alternative and complementary medicine, has been applied in various diseases. Recently, a number of anti-liver fibrogenesis compounds exhibiting antiliver fibrosis effects have been discovered in CHM. In this review, we reviewed the published data on their anti-fibrosis effects and discussed the possible underlying mechanisms. More investigations are needed to improve the insight into therapeutic effect of CHM on liver fibrosis.

Aim To find out the association of common HFE mutations (viz., C282Y and H63D) with primary iron overload (PIL) in liver cirrhosis (CLD) patients of Indian origin. Methods Polymerase chain reaction-restriction fragment length polymorphism method was used for screening C282Y and H63D mutation in 496 CLD patients (hepatitis B virus associated cirrhosis (HBVc) = 74, hepatitis C virus associated cirrhosis (HCV) = 50, alcoholic cirrhosis with hepatitis (ALcW)  =  38, alcoholic cirrhosis without hepatitis (ALc) = 92, cryptogenic cirrhosis (CC) = 242) and 502 healthy controls. Transferrin saturation of >45 or serum ferritin of >300 ng/mL (males)/>200 ng/mL (females) with normal total exogenous iron intake was suggestive of PIL. Histological liver iron grading was done by Perl’s Prussian blue stain. Results Of 496 patients, 13 (2.6; 9 CC, 2 ALc, 1 HBVc, 1 AlcW) had PIL. However, only two (15.3) of 13 patients (1 CC and 1 HBVc) were positive for H63D heterozygous mutation. All the subjects were found to be C282Y wild type, except a single case of double heterozygous (C282Y/H63D) who however, did not have PIL. Overall frequency of H63D allele in patients and controls was not significantly different (5.95 and 4.58 respectively, p = 0.17). A highly significant H63D allele frequency (p  <  0.005) was observed in HBVc (10.82) and ALcW (11.84) groups but they were not associated with PIL. Conclusion The frequency of PIL, and the HFE gene mutaion (C282Y) are both rare in Indian patients and explain why hemochromatosis is a rare cause of liver cirrhosis in India. A highly significant H63D allele frequency in HBV and alcohol-related cirrhosis suggest a possible predisposing role for liver fibrosis of this allele.

Introduction: Transient Elastography is a promising form of non-invasive assessment of fibrosis in chronic hepatitis B. The diagnostic accuracy and usefulness of TE is evaluated and compared with FIB 4 index, Aspartate Platelet Ratio Index (APRI), Aspartate Alanine aminotransferase Ratio (AAR), Age Platelet Index (API) and Fibrosis Index (FI).

The presence and degree of hepatic fibrosis is crucial in order to make therapeutic decisions and predict clinical outcomes. Currently, the place of liver biopsy as the standard of reference for assessing liver fibrosis has been challenged by the increasing awareness of a number of drawbacks related to its use (invasiveness, sampling error, inter-/intraobserver variability). In parallel with this, noninvasive assessment of liver fibrosis has experienced explosive growth in recent years and a wide spectrum of noninvasive methods ranging from serum assays to imaging techniques have been developed. Some are validated methods, such as the Fibrotest/ Fibrosure and transient elastography in Europe, and are gaining a growing role in routine clinical practice, especially in chronic hepatitis C. Large-scale validation is awaited in the setting of other chronic liver diseases. However, noninvasive tests used to detect significant fibrosis and cirrhosis, the two major clinical endpoints, are n...

The aim of this study was to investigate the effects of S-adenosylmethionine on liver peroxidation and liver fibrogenesis in carbon tetrachloride-induced cirrhosis. Cirrhosis was induced in three groups of six rats by repeated injections of carbon tetrachloride over 9 weeks. One group of animals was treated only with carbon tetrachloride, and the other two received carbon tetrachloride plus S-adenosylmethionine (10 mg/kg intramuscularly daily) from week 3 to week 9, and from week 6 to week 9 of the study, respectively. Two additional groups of six rats, a control group and a group treated only with S-adenosylmethionine, were also studied. Glutathione concentration, thiobarbituric acid-reactive substances, collagen content, prolyl hydroxylase activity, and procollagen type I mRNA expression were determined in liver samples. All carbon tetrachloride-treated rats had cirrhosis at the end of the study. Cirrhosis was also present in five of the six carbon tetrachloride-treated rats receiving S-adenosylmethionine for 3 weeks, but in only one of the six rats that received S-adenosylmethionine for 6 weeks. Hepatic glutathione was significantly diminished in carbon tetrachloride-treated rats (2.7 +/- 0.3 mumol/g tissue) and returned to normal in rats receiving S-adenosylmethionine for 3 or 6 weeks (3.7 +/- 0.13 and 3.9 +/- 0.11 mumol/g tissue, respectively). The hepatic thiobarbituric acid-reactive substances were significantly lower in rats treated with carbon tetrachloride and S-adenosylmethionine for 6 weeks (98 +/- 5 nmol/g) than in rats treated with carbon tetrachloride (134 +/- 12 nmol/g) and in those treated with carbon tetrachloride and S-adenosylmethionine for 3 weeks (127 +/- 13 nmol/g). There were no differences in either hepatic collagen and prolyl hydroxylase activity between rats that received only carbon tetrachloride and those treated with S-adenosylmethionine for 3 weeks. In contrast, carbon tetrachloride-treated rats receiving S-adenosylmethionine for 6 weeks had significantly lower collagen and prolyl hydroxylase activity than the other two groups. A much greater increase in procollagen type I mRNA was found in carbon tetrachloride-treated rats than in rats treated with carbon tetrachloride and S-adenosylmethionine for 6 weeks. Furthermore, there was a significant correlation between the hepatic thiobarbituric acid-reactive substances and prolyl hydroxylase activity and hepatic collagen. We conclude that the early administration of S-adenosylmethionine in a model of carbon tetrachloride-induced liver injury restores glutathione levels and reduces lipid peroxidation, resulting in less advanced liver fibrosis.

Hepatocellular carcinoma (HCC) is the main tumor of the liver and is the sixth most frequently diagnosed tumor in the world. It is the evolution of chronic hepatic injury secondary to different etiologies. Chronic hepatitis B virus and hepatitis C virus infection, chronic alcoholic hepatitis, as well as non-alcoholic fatty liver disease are the most common causes behind the development of HCC. The introduction of effective prophylaxis and treatment against hepatitis B, the recent use of highly effective hepatitis C treatments, as well as lifestyle changes observed in recent decades in the general population causing an increase in obesity and metabolic syndrome have led to significant epidemiological change in HCC in relation to the changed etiologic prevalence of liver injury. Increasing evidence was emerging, emphasizing how the development of HCC is a complex and multifactorial process. The knowledge of the molecular mechanisms involved is important for the understanding of the basic factors of the development of hepatocarcinogenesis and of possible therapeutic approaches. Several pathogenic mechanisms and clinical expression of HCC occur in relation to the different etiologies of the underlying liver disease. The different clinical behavior of HCC often makes diagnosis difficult at an early stage, that is necessary for an effective therapeutic approach. This review analyzes the possible different pathogenic mechanisms involved in the development of HCC and emphasizes the different epidemiological and clinical aspects of HCC observed in the most common forms of liver diseases of viral and non-viral origin.

F2-isoprostanes are considered as the most reliable markers of oxidative stress and can be used to evaluate the oxidative status in a number of human pathologies. Besides being markers of oxidative stress, F2-isoprostanes proved to be mediators of important biological effects and would act through the activation of receptors analogous to those for thromboxane A2. In a previous work, we provided evidence that F(2)-isoprostanes, generated during carbon tetrachloride-induced hepatic fibrosis, mediate hepatic stellate cell (HSC) proliferation and collagen hyperproduction. To investigate whether TxA2 receptor (TxA2r or TPr) is involved in the effects of F2-isoprostanes on HSC, experiments on DNA synthesis were carried out in the presence of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) or the TxA2r-specific agonist I-BOP ([1S-[1alpha,2alpha(Z),3beta(1E,3S*), 4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid). Both agonists significan...

Background/Aim: Using machine learning approaches as non-invasive methods have been used recently as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy. This study aims to evaluate different machine learning techniques in prediction of advanced fibrosis by combining the serum bio-markers and clinical information to develop the classification models. Methods: A prospective cohort of 39,567 patients with chronic hepatitis C was divided into two sets-one categorized as mild to moderate fibrosis (F0-F2), and the other categorized as advanced fibrosis (F3-F4) according to METAVIR score. Decision tree, genetic algorithm, particle swarm optimization, and multilinear regression models for advanced fibrosis risk prediction were developed. Receiver operating characteristic curve analysis was performed to evaluate the performance of the proposed models. Results: Age, platelet count, AST, and albumin were found to be statistically significant to advanced fibrosis. The machine learning algorithms under study were able to predict advanced fibrosis in patients with HCC with AUROC ranging between 0.73 and 0.76 and accuracy between 66.3% and 84.4%. Conclusions: Machine-learning approaches could be used as alternative methods in prediction of the risk of advanced liver fibrosis due to chronic hepatitis C.

To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft. Ninety consecutive patients (63 males, median age 53 years; 55 with HCV-related liver disease), transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single, experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis. The SFP was quantified in fibrosis units/month (FU/mo). The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it. In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point, a SFP &lt;=0.100 FU/mo was observed more frequen...

Background: Assessment of liver fibrosis is a vital need for enabling therapeutic decisions and prognostic evaluations of chronic hepatitis. Liver biopsy is considered the definitive investigation for assessing the stage of liver fibrosis but it carries several limitations. FIB-4 and APRI also have a limited accuracy. The National Committee for Control of Viral Hepatitis (NCCVH) in Egypt has supplied a valuable pool of electronic patients' data that data mining techniques can analyze to disclose hidden patterns, trends leading to the evolution of predictive algorithms. Aim: to collaborate with physicians to develop a novel reliable, easy to comprehend noninvasive model to predict the stage of liver fibrosis utilizing routine workup, without imposing extra costs for additional examinations especially in areas with limited resources like Egypt. Methods: This multi-centered retrospective study included baseline demographic, laboratory, and histopathological data of 69106 patients with chronic hepatitis C. We started by data collection preprocessing, cleansing and formatting for knowledge discovery of useful information from Electronic Health Records EHRs. Data mining has been used to build a decision tree (Reduced Error Pruning tree (REP tree)) with 10-fold internal cross-validation. Histopathology results were used to assess accuracy for fibrosis stages. Machine learning feature selection and reduction (CfsSubseteval / best first) reduced the initial number of input features (N=15) to the most relevant ones (N=6) for developing the prediction model. Results: In this study, 32419 patients had F(0-1), 25073 had F(2) and 11615 had F(3-4). FIB-4 and APRI revalidation in our study showed low accuracy and high discordance with biopsy results, with overall AUC 0.68 and 0.58 respectively. Out of 15 attributes machine learning selected Age, AFP, AST, glucose, albumin, and platelet as the most relevant attributes. Results for REP tree indicated an overall classification accuracy up to 70% and ROC Area 0.74 which was not nearly affected by attribute reduction, and pruning. However attribute reduction, and 316 Computer Science & Information Technology (CS & IT) tree pruning were associated with simpler model easy to understand by physician with less time for execution. Conclusion: This study we had the chance to study a large cohort of 69106 chronic hepatitis patients with available liver biopsy results to revise and validate the accuracy of FIB-4 and APRI. This study represents the collaboration between computer scientist and hepatologists to provide clinicians with an accurate novel and reliable, noninvasive model to predict the stage of liver fibrosis.

Erythema induratum, or nodular vasculitis, was initially described as a type of cutaneous tuberculosis. Currently, it is considered a multifactorial syndrome of lobular panniculitis of unknown cause. An association between erythema induratum and hepatitis C virus (HCV) has been suggested in previous reports.We report the case of a 49-year-old male presenting with a 3-year history of itchy, painful red to violaceous cutaneous nodules and plaques on both legs that had been unresponsive to topical dermatologic treatments. Evaluation of persistent serum transaminase elevations led to a diagnosis of chronic hepatitis C with bridging liver fibrosis. A thorough evaluation to exclude mycobacterial infection was performed, and anti-tuberculosis treatment was started based on a positive QuantiFERON test. There was no improvement in the skin lesions with this treatment. The patient then received standard antiviral therapy with pegylated interferon and ribavirin for 48 weeks. Treatment produced an early virologic response with significant improvement in the skin lesions, pain and pruritus. Six months after antiviral treatment, virologic relapse occurred without recurrence of the cutaneous lesions.There appears to be an association between erythema induratum and hepatitis C infection, probably mediated by circulating immune complexes. Interestingly, lesions improve with antiviral treatment and, as shown in this case, the effect may be sustained after stopping treatment despite virologic relapse.