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Indirect drug-induced liver toxicity (IDLT) refers to the condition that the use of some therapeutic drugs may induce new liver diseases or exacerbate the original liver disease, with the phenotype of underlying or predisposed liver diseases. IDLT may induce persistent liver injury or even acute liver failure and affect the pharmacotherapy for tumor or other comorbidities, leading to the suspension or termination of ongoing chemotherapy, immunotherapy, and targeted therapy, and therefore, it should be taken seriously in clinical practice. This article elaborates on the mechanisms and prevention strategies of several types of IDLT.
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Liver fibrosis is a pathophysiological process characterized by abnormal accumulation of connective tissues in the liver caused by chronic liver injuries, in which the activation and migration of hepatic stellate cells (HSCs) play a central role. Extracellular vesicles (EVs) are a class of nanoscale, bilayer lipid enveloped vesicles secreted by almost all cells. EVs are of great interest in liver pathology because they have been found to mediate the communication between cells and regulate cellular microenvironment via horizontal transfer of their cargoes. EVs carry bioactive cargoes including proteins, lipids and RNA molecules, and are involved in the activation of HSCs during liver fibrogenesis.
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The application of modern bioinformatics, 'omics’ and molecular biology to research of fibrotic liver diseases holds promise to accelerate the development of new therapeutic targets and therapies for hepatic fibrosis. Specifically, progress is anticipated in delineating pathways of fibrosis reversal and functional compensation, and defining key determinants and presenting factors associated with fibrosis progression and reversion. These efforts will also lead to develop accurate biomarkers and methods for early noninvasive diagnosis, and to accelerate the testing of anti-fibrotic drugs.
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Portal hypertension is the major cause of complications in decompensated liver cirrhosis. Research results showed that non-selective β-blockers, angiotensin receptor antagonists, and statins can improve portal hypertension by reducing portal vein blood flow and intrahepatic resistance, and have certain prevention and treatment effect on hemodynamic disorders and portal hypertensive complications in chronic liver diseases. Herein, we review the mechanism of action, clinical effects and limitations of these three types of drugs on portal hypertension of cirrhosis.
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Liver fibrosis is the scar repairing reaction in response to chronic liver injury due to various etiologies. It has been considered as the early and reversible stage of liver cirrhosis. This article points out the distinction between liver fibrosis and cirrhosis, introduces the current staging system of chronic liver diseases, and recent progress in diagnosing and evaluating liver fibrosis, as well as the medical treatment.The critical importance of diagnosing and treating liver fibrosis in preventing liver diseases progression into decompensated liver cirrhosis is emphasized.
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Epigenetic modification refers to a variety of regulating processes that may induce the changes in gene expression without altering DNA sequence. Epigenetic mechanisms including DNA methylation, histone modification, and regulatory non-coding RNAs are involved in hepatic stellate cell activation and liver fibrogenesis. A deep understanding of epigenetic mechanisms in liver fibrosis helps to identify new markers and therapies for liver fibrosis.
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Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. Most of the HCC occur in developing countries. Chronic hepatitis B virus (HBV) infection is an important risk factor for HCC development. HBV induces immune-mediated chronic hepatitis, liver injury, regeneration and scar forming responses, leading to an inflammatory, fibrotic and immune deficient microenvironment. HBV may integrate into host genome, inducing genetic abnormality and altering the expression of HCC-related genes. HBV also expresses active proteins such as X (HBx) and S proteins, which may trans-activate HCC-related proteins expression, interact with intracellular specific proteins, activate a variety of signaling pathways, and induce aberrant epigenetic modifications. HBV mutation also has impact on HBV related HCC development.
Subject(s)
Humans , Carcinoma, Hepatocellular , Pathology , Virology , Epigenesis, Genetic , Hepatitis B virus , Hepatitis B, Chronic , Pathology , Liver Neoplasms , Pathology , Virology , Mutation , Signal Transduction , Trans-ActivatorsABSTRACT
The development of hepatocellular carcinoma (HCC) is closely related to the precancerous microenvironment of inflammation and fibrosis. The activated hepatic stellate cells (HSCs) are the major source of extracellular matrix in the development of liver fibrosis and the key effective cells of hepatic inflammatory responses. HSCs have an intact Toll-like receptor 4 (TLR4) signaling pathway, which mediates important biological properties of HSCs such as fibrogenesis, inflammatory phenotype, and immunoregulatory function. The TLR4 signaling pathway is involved in the development and progression of chronic liver diseases, and mediates liver fibrogenesis and HCC. HSCs produce several cytokines and growth factors by TLR4 signaling pathway, which has been confirmed to be related to the development of HCC.
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<p><b>OBJECTIVE</b>To identify risk factors of hepatocellular carcinoma (HCC) in cirrhotic patients with chronic hepatitis B (CHB).</p><p><b>METHODS</b>A total of 715 cirrhotic patients with CHB were recruited from the Zhongshan Hospital Affiliated to Fudan University and enrolled in this case-control study between January 2009 and September 2014. All participants were Chinese Han residing in Shanghai and the surrounding areas. The patients were divided into a cirrhosis group (n =281) and a HCC group (n=434). History of hepatitis B infection and HCC, as well as clinical data from serological, imaging and pathological examinations were collected for analysis.SPSS software, version 19.0, was used for all statistical comparisons.</p><p><b>RESULTS</b>Single factor analysis indicated that development of HCC in cirrhotic patients with CHB was significantly associated with male sex, age of 50 years or more, family history of HCC, alcohol consumption,fatty liver, detectable levels of hepatitis B virus (HBV) DNA, and history of HBV infection without effective antiviral treatment. Multivariate logistic regression analysis indicated that age of 50 years or more (P =0.005, odds ratio [OR] =1.766), history of alcohol consumption (P =0.002, Or = 2.570), family history of HCC (P =0.014, Or = 2.268), fatty liver (P =0.023, Or = 3.390), and history of HBV infection without effective antiviral treatment (P < 0.001,Or = 5.389) were risk factors of HCC.The risk factors for development of HCC in cirrhotic patients with hepatitis B after achieving sustained virologic suppression (SVS) were family history of HBV infection (P =0.014, Or = 2.537), family history of HCC (P =0.037,Or = 3.339) and fatty liver (P =0.018, Or = 11.646).</p><p><b>CONCLUSION</b>Risk factors of HCC in cirrhotic patients with CHB include age,drinking history,family history of HCC, fatty liver, and ineffective antiviral treatment of CHB.Family history of HBV infection or HCC, and fatty liver disease, were significantly associated with HCC development after SVS in patients with hepatitis B-related cirrhosis.</p>
Subject(s)
Humans , Male , Alcohol Drinking , Antiviral Agents , Carcinoma, Hepatocellular , Case-Control Studies , China , Fatty Liver , Hepatitis B virus , Hepatitis B, Chronic , Liver Cirrhosis , Liver Neoplasms , Odds Ratio , Risk FactorsABSTRACT
Objective To investigate the role of cyclooxygenase-2 (COX-2) in sinusoidal capillarization in liver cirrhotic rats. Methods The SD rats were intraperitoneally injected with carbon tetrachloride (CCl4) twice a week for 8 weeks to induce liver cirrhosis. The rats were randomly divided into three groups: normal control group (n= 10), model control group (n= 15) and rofecoxib treated group (received 10 mg/kg of rofecoxib daily, n = 15). Liver histopathology was examined by light microscopy, and sinusoidal ultrastructure was observed by transmission electron microscopy. Furthermore, the level of basement membrane proteins (collagen type Ⅳ, laminin) and their localizations in liver were determined by Western blotting and immunohistochemistry, respectively, and the microvessel density was detected following vWF (yon Willebrand factor) immunolabeling on liver tissue sections. Results Fibrotic areas were reduced in rofecoxib treated group compared with that in model group (30.7±8.9 vs 23.5±6.5,P<0. 05). The light and electron microscopy showed that the pathologic changes including loss or reduction in number of sinusoidal endothelial fenestrate, the accumulation of extracellular matrix in the Disse's space and development of subendothelial basal lamina (basement membrane formation) were more severe in model group than those in rofecoxib treated group. Compared with model group, administration of rofecoxib resulted in significant decrease in microvessel density (11.3 ± 1.6 vs. 6.4 ±0. 7, P<0. 01). Rofecoxib could significantly decrease the expression of type Ⅳ collagen and laminin at protein levels (3.0±0.5 and 3.0±0.5, respectively) when compared with model group (3.8±0.4 and 3.7±0. 5, respectively). Conclusion The results indicate that early administration of rofecoxib may reduce sinusoidal capillarization.
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Objective To investigate the role of cyclooxygenase 2 (COX 2) in the forming of portal hypertension and whether a selective COX 2 inhibitor can reduce the portal hypertension or not. Methods Cirrhotic Sprague Dawley rat was induced by carbon tetrachloride (CCl 4) intraperitoneally for 8 weeks. The animals were divided into three groups: 10 normal rats served as control group; the other 15 rats, which received CCl 4 intraperitoneally twice a week and rofecoxib (10 mg/kg) by gavages daily, served as treatment group; another 15 rats, which were induced cirrhosis by CCl 4 but given placebo (saline solution ) instead of rofecoxib, served as placebo group. After 8 weeks of CCl 4 induction, portal pressure was measured, and the levels of thromboxane B 2 (TXB 2), and prostaglandin (PG)E 2 in the liver tissues were determined by enzyme immunoassay. Furthermore, liver histopathological analysis was performed in H E and Masson's trichrome staining sections. Results Portal pressure in the rats of rofecoxib group was significantly decreased compared to that in the placebo group [(11.95?1.05) mm Hg vs. (13.45?1.15) mm Hg; P
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Objective To observe the effects of recombinant plasmid of rat's interstitial collagenase on experimental liver fibrosis. Methods We constructed the recombinant plasmid of rat's interstitial collagenase fused Flag peptide which can be expressed in eucaryotic cells. After bound to galactose terminal glyco poly L lysine(G PLL), we transferred the recombinant plasmid to the rat's fibrotic liver in vivo by intravenous injection, then observed the effects of the plasmid on the fibrotic liver by RT PCR, immunohistochemistry and the observation of pathology. Results The recombinant plasmid of interstitial collagenase could be expressed in rat liver, the expression of the plasmid could increase the degradation of type Ⅰ and type Ⅲ collagen in the rat's fibrotic liver compared with fibrotic modal group ( P 0.05). Conclusion The recombinant plasmid of interstitial collagenase have some effects on liver fibrosis, but this effects is limited.