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| 1 | Cellular and molecular mechanisms in the pathogenesis of liver fibrosis:An update显示文摘There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis. | Gülsüm ?zlem Elpek | 2014 | World Journal of Gastroenterology2014，20，23： | 82 |
| 2 | Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets显示文摘Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis. | Chong-Yang Zhang Wei-Gang Yuan Pei He Jia-Hui Lei Chun-Xu Wang | 2016 | World Journal of Gastroenterology2016，22，48： | 114 |
| 3 | Inhibiting effect of antisense oligonucleotides phosphorthioate on gene expression of TIMP-1 in rat liver fibrosis显示文摘AIM To observe the inhibition of antisenseoligonucleotides (asON) phosphorthioate to thetissue inhibitors metalloproteinase-1 (TIMP-1)gene and protein expression in the liver tissue ofimmunologically induced hepatic fibrosis rats.The possibility of reversing hepatic fibrosisthrough gene therapy was observed.METHODS Human serum albumin (HSA) wasused to attack rats, as hepatic fibrosis model, inwhich asONs were used to block the gene andprotein expressing TIMP-1. According to theanalysis of modulator, structure protein, codingseries of TIMP-1 genome, we designed fourdifferent asONs. These asONs were injected intothe hepatic fibrosis models through coccygealvein. The results was observed by RT-PCR formeasuring TIMP-1 mRNA expression,immunohistochemistry and in situ hybridizationfor collagen Ⅰ, Ⅲ, special staining of collagenfiber, and electron microscopic examination.RESULTS Hepatic fibrosis could last within 363days in our modified model. The expressinglevel of TIMP-1 was high during hepatic fibrosisprocess. It has been proved by theimmunohistochemical and the electronmicroscopic examination that the asONphosphorthioate of TIMP-1 could exactly expressin vivo. The effect of colchicine wasdemonstrated to inhibit the expressing level ofmRNA and the content of collagen Ⅰ, Ⅲ in theliver of experimental hepatic fibrosis rats.However, the electron microscopy research andthe pathologic grading of hepatic fibrosisshowed that there was no significant differencebetween the treatment group and the modelgroup (P>0.05).CONCLUSION The experimental rat model ofhepatic fibrosis is one of the preferable modelsto estimate the curative effect of anti-hepaticfibrosis drugs. The asON phosphorthioate ofTIMP-1 could block the gene and proteinexpression of TIMP-1 in the liver of experimentalhepatic fibrosis rats at the mRNA level. It ispossible to reverse hepatic fibrosis, and it isexpected to study a new drug of anti-hepaticfibrosis on the genetic level. Colchicine has verylimited therapeutic effect on hepatic fibrosis,furthermore, its toxicity and side effects areobvious. | Qing He Nie Yong Qian Cheng Yu Mei Xie Yong Xing Zhou Yi Zhan Cao The Center of Infectious Disease Diagnosis and Treatment of PLA,Tangdu Hospital,Forth Military Medical University,Xi’an 710038,Shaanxi Province,ChinaDr,Qing He Nie graduated from Qinghai Medical College as a doctor in 1983,got master degree at Beijing 302 Army Hospital in 1993,got doctor degree at the Third Military Medical University in 1998,engaged in postdoctoral research at the Fourth Military Medical University from 1998 to 2000,now an associate professor,specialized in clinical and experimental research of infectious diseases,had more than 90 papers published,coauthor of ten books,first author of one book. | 2001 | World Journal of Gastroenterology2001，7，3： | 73 |
| 4 | Clinical epidemiology and disease burden of nonalcoholic fatty liver disease显示文摘Nonalcoholic fatty liver disease(NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis(NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma(HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type Ⅱ diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear toexperience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis. | Brandon J Perumpail Muhammad Ali Khan Eric R Yoo George Cholankeril Donghee Kim Aijaz Ahmed | 2017 | World Journal of Gastroenterology2017，23，47： | 70 |
| 5 | Immune suppression in chronic hepatitis B infection associated liver disease: A review显示文摘Hepatitis B virus(HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer(HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer(NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC),NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBVinduced immune dysfunction and HBV-related liver diseases are not understood.In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC. | Tian-Yang Li Yang Yang Guo Zhou Zheng-Kun Tu | 2019 | World Journal of Gastroenterology2019，25，27： | 69 |
| 6 | Animal experiment and clinical study of effect of gamma-interferon on hepatic fibrosis显示文摘AIM To evaluate the antifibrotic effect ofdifferent doses of recombinant human Gamma-Interferon (IFN-γ) intwo rat models of hepaticfibrosis, and to observe its effect on moderatechronic hepatitis B virus fibrosis.METNODS Hepatic fibrosis was successfullyinduced in 150 and 196 rats by subcutaneousinjection of carbon tetrachloride (CCl4) andintraperitoneal injection of dimethylnitrosamine(DMN), respectively. Each of the two modeldose IFN-γ group (15 MU/kg per day, i.m. for 8group (1.67 MU/kg daily, i.m. for 8 weeks).Another group of 10 rats without any treatmentwas used as normal controls. At the end of theexperiment, semi-quantitative histopathologicalscores of inflammation and fibrosis, liver (αsmooth muscle actin (α-SMA) expression level,liver hydroxyl proline content and serumhyaluronic acid levels were compared. And 47medium chronic hepatitis B viral fibrosispatients were studied. They were given IFN-γtreatment, 100MU/day i.m. for the first threemonths and 100MU qod i.m. for the next sixmonths. Semi-quantitative pathological scoresof inflammation and fibrosis and serum hepaticfibrosis indices were compared within the 9months.RESULTS In animal experiment, thepathological fibrosis scores and liver hydroxylproline content were found to be significantlylower in rats treated with different doses of IFN-γ as compared with rats in fibrotic model groupinduced by either CCI4 or DMN, in a dose-dependent manner. For CCI4-induced model,pathological fibrosis scores in high, medium andIow doses IFN-γ groups were 5.10 ± 2.88, 7.70 ±3.53 and 8.00 ± 3.30, respectively, but the scorewas 14.60 ± 7.82 in fibrotic model group.Hydroxyl proline contents were 2.83 ± 1.18, 3.59± 1.22 and 4.80 ± 1.62, in the three IFN-γgroups, and 10.01 ± 3.23 in fibrotic model group.The difference was statistically significant(P<0.01). Similar results were found in DMN-induced model. Pathological fibrosis scoreswere 6.30±0.48, 8.10 ±2.72 and 8.30 ±2.58, inhigh, medium and Iow doses IFN-γ groups, and12.60 ± 3.57 in fibrotic model group. Hydroxylproline contents were 2.72 ± 0.58, 3.14 ± 0.71and 3.62 ± 1.02, in the three IFN-γ groups, and12.79 ± 1.54 in fibrotic model group. Thedifference was statistically significant(P<0.01). Serum hepatic fibrosis indicesdecreased significantly in the 47 patients afterIFN-γ treatment (HA: 433.38 ± 373.00 vs 281.57± 220.48; LN: 161.22± 41.02 vs 146.35 ± 44.67;PCⅢ: 192.59 ± 89.95 vs 156.98 ± 49.22; C-Ⅳ:156.30 ± 44.01 vs 139.14 ± 34.47) and thedifferences between the four indices weresignificant (P<0.05). Thirty-three patientsCONCLUSION All the three doses of IFN-γ areeffective in treating rat liver fibrosis induced byeither CCl4 or DMN, the higher the dose, thebetter the effect. And IFN-γ is effective forpatients with moderate chronic hepatitis B viralfibrosis. | Hong Lei Weng Wei Min Cai Rong Hua Liu Institute of Infectious Diseases, First Affiliated Hospital. Medical School. Zhejiang University, Hangzhou 310003, Zhejiang Province. China | 2001 | World Journal of Gastroenterology2001，7，1： | 53 |
| 7 | Dynamic changes of typeⅠ,Ⅲand N collagen synthesis and distribution of collagen-producing cells in carbon tetrachloride-induced rat liver fibrosis显示文摘AIM To find out the relationship between the gene transcription of different types ofprocollagen and the deposition of the relevant collagens in the liver tissue and to confirm the types of collagen producing cells in liverfibrogenesis.METHODS Dynamic changes of the expression of α1(Ⅰ ), α1 (Ⅲ ) and α1 (Ⅳ) procollagen mRNAand relevant collagens and the distribution ofcollagen producing cells during liver fibrogenesis of rat induced by CCl4 (20 weeks)were investigated with Northern blot analysis,in situ hybridization and immunohistochemicaltechniques.RESULTS The increased expression of α1 (Ⅲ)procollagen mRNA by Northern blot analysis was the most predominant one among the threemRNAs during fibrogenesis. However, theenhanced expression of al (Ⅳ) procollagenmRNA occurred very early while the expressionof α1 (Ⅰ) mRNA was not enhanced much until themiddle stage of the exPeriment. D6smin (Dm)positive hepatic stellate cells (HSCs) and fewmyofibroblasts (MFs) in and around the necrotic areas expressed α1 (Ⅰ), α1 (Ⅲ) and α1 (Ⅳ)procollagen mRNA signals detected by in situhybridization at the early stage of theexperiment. All the three procollagen mRNAsignals thereafter mainly localized in fibroblasts (Fbs) and MFs in fibrotic septa during the middle and late stages of fibrosis, which distributedparallel to the corresponding collagens detected by immunohistochemical study. ln addition, the endothelial cells of sinusoids and the small blood vessels within the septa also showed α1(Ⅳ) procollagen mRNA and type Ⅳ collagen expressionCONCLUSION It is considered that 'HSC-MF-Fb' effect cell system is the major cellularsource of collagen production in liver fibrosis, in which HSCs are collagen producing precursor cells in the early liver fibrogenesis, thereafter the synthesis of type Ⅰ, Ⅲ and Ⅳ collagens (Col Ⅰ, Col Ⅲ and Col Ⅳ) mainly derives fromMFs and Fbs, which play a very important role in the progress of liver fibrosis. The endothelialcells along sinusoids, as another source of Col Ⅳ production, might participate in the capillization of liver sinusoids. | DU Wei-Dong ZHANG Yue-E ZHAl Wei-Rong and ZHOU Xiao-Mei(Department of Pathology, Shanghai Medical University, Shanghai200032, China)(National Laboratory for Oncogenes and Related Genes, ShanghaiCencer Institute)See invited commentary on page 388 | 1999 | World Journal of Gastroenterology1999，5，5： | 47 |
| 8 | Gut microbiota dysbiosis in patients with nonalcoholic fatty liver disease显示文摘BACKGROUND:Gut microbiota plays a significant role in the pathogenesis of non-alcoholic fatty liver disease(NAFLD)This study aimed to assess the contribution of gut microbiota dysbiosis to the pathogenesis of NAFLD.METHODS:Forty-seven human feces samples(25 NAFLD patients and 22 healthy subjects) were collected and 16 S r DNA amplicon sequencing was conducted on Hiseq 2000 platform Discrepancy of species composition between controls and NAFLD group was defined by Metastats analysis under P value<0.01.RESULTS:NAFLD patients harbored lower gut microbiota diversity than healthy subjects did.In comparison to the control group,the Proteobacteria(13.50%) and Fusobacteria(2.76%) phyla were more abundant in NAFLD patients.Additionally,the Lachnospiraceae(21.90%),Enterobacteriaceae(12.02%),Erysipelotrichaceae(3.83%),and Streptococcaceae(1.39%) families,as well as the Escherichia_Shigella(10.84%)Lachnospiraceae_Incertae_Sedis(7.79%),and Blautia(4.95%)genera were enriched in the NAFLD group.However,there was a lower abundance of Prevotella in the NAFLD group than that in the control group(5.83% vs 27.56%,P<0.01)The phylum Bacteroidetes(44.63%) also tended to be more abundant in healthy subjects,and the families Prevotellaceae(28.66%) and Ruminococcaceae(26.44%) followed the same trend.Compared to those without non-alcoholic steatohepatitis(NASH),patients with NASH had higher abundance of genus Blautia(5.82% vs 2.25%;P=0.01) and the corresponding Lachnospiraceae family(24.33% vs 14.21%;P<0.01).Patients with significant fibrosis had a higher abundance of genus Escherichia_Shigella(12.53% vs 1.97%;P<0.01) and the corresponding Enterobacteriaceae family(13.92% vs 2.07%;P<0.01) compared to those with F0/F1 fibrosis.CONCLUSIONS:NAFLD patients and healthy subjects harbor varying gut microbiota.In contrast to the results of previous research on children,decreased levels of Prevotella might be detrimental for adults with NAFLD.The increased level of the genus Blautia,the family Lachnospiraceae,the genus Escherichia_Shigella,and the family Enterobacteriaceae may be a primary contributor to NAFLD progression. | Feng Shen Rui-Dan Zheng Xing-Qiang Sun Wen-Jin Ding Xiao-Ying Wang Jian-Gao Fan | 2017 | Hepatobiliary & Pancreatic Diseases International2017，16，4： | 46 |
| 9 | Hepatic inflammation and progressive liver fibrosis in chronic liver disease显示文摘Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory actions.Responses,however,are commonly incomplete and inconsistently achieved.The fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive therapies.Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes.Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species.Anti-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental therapies.Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease. | Albert J Czaja | 2014 | World Journal of Gastroenterology2014，20，10： | 46 |
| 10 | Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice显示文摘With the increasing number of individuals with diabetes and obesity,nonalcoholic fatty liver disease(NAFLD) is becoming increasingly prevalent,affecting one-quarter of adults worldwide. The spectrum of NAFLD ranges from simple steatosis or nonalcoholic fatty liver(NAFL) to nonalcoholic steatohepatitis(NASH). NAFLD, especially NASH, may progress to fibrosis, leading to cirrhosis and hepatocellular carcinoma. NAFLD can impose a severe economic burden,and patients with NAFLD-related terminal or deteriorative liver diseases have become one of the main groups receiving liver transplantation. The increasing prevalence of NAFLD and the severe outcomes of NASH make it necessary to use effective methods to identify NAFLD. Although recognized as the gold standard, biopsy is limited by its sampling bias, poor acceptability, and severe complications, such as mortality, bleeding, and pain. Therefore, noninvasive methods are urgently needed to avoid biopsy for diagnosing NAFLD. This review discusses the current noninvasive methods for assessing NAFLD,including steatosis, NASH, and NAFLD-related fibrosis, and explores the advantages and disadvantages of measurement tools. In addition, we analyze potential noninvasive biomarkers for tracking disease processes and monitoring treatment effects, and explore effective algorithms consisting of imaging and nonimaging biomarkers for diagnosing advanced fibrosis and reducing unnecessary biopsies in clinical practice. | Jiang-Hua Zhou Jing-Jing Cai Zhi-Gang She Hong-Liang Li | 2019 | World Journal of Gastroenterology2019，25，11： | 42 |
| 11 | Portal hypertensive gastropathy:A systematic review of thepathophysiology,clinical presentation,natural history andtherapy显示文摘AIM: To describe the pathophysiology, clinical presentation, natural history, and therapy of portal hypertensive gastropathy(PHG) based on a systematic literature review.METHODS: Computerized search of the literature was performed via Pub Med using the following medical subject headings or keywords: 'portal' and 'gastropathy'; or 'portal' and 'hypertensive'; or 'congestive' and 'gastropathy'; or 'congestive' and 'gastroenteropathy'. The following criteria were applied for study inclusion: Publication in peer-reviewed journals, and publication since 1980. Articles were independently evaluated by each author and selected for inclusion by consensus after discussion based on the following criteria: Well-designed, prospective trials; recent studies; large study populations; and study emphasis on PHG. RESULTS: PHG is diagnosed by characteristic endoscopic findings of small polygonal areas of variable erythema surrounded by a pale, reticular border in a mosaic pattern in the gastric fundus/body in a patient with cirrhotic or non-cirrhotic portal hypertension. Histologic findings include capillary and venule dilatation, congestion, and tortuosity, without vascular fibrin thrombi or inflammatory cells in gastric submucosa. PHG is differentiated from gastric antral vascular ectasia by a different endoscopic appearance. The etiology of PHG is inadequately understood. Portal hypertension is necessary but insufficient to develop PHG because many patients have portal hypertension without PHG.PHG increases in frequency with more severe portal hypertension, advanced liver disease, longer liver disease duration, presence of esophageal varices, and endoscopic variceal obliteration. PHG pathogenesis is related to a hyperdynamic circulation, induced by portal hypertension, characterized by increased intrahepatic resistance to flow, increased splanchnic flow, increased total gastric flow, and most likely decreased gastric mucosal flow. Gastric mucosa in PHG shows increased susceptibility to gastrotoxic chemicals and poor wound healing. Nitrous oxide, free radicals, tumor necrosis factor-alpha, and glucagon may contribute to PHG development. Acute and chronic gastrointestinal bleeding are the only clinical complications. Bleeding is typically mild-to-moderate. Endoscopic therapy is rarely useful because the bleeding is typically diffuse. Acute bleeding is primarily treated with octreotide, often with concomitant proton pump inhibitor therapy, or secondarily treated with vasopressin or terlipressin. Nonselective β-adrenergic receptor antagonists, particularly propranolol, are used to prevent bleeding after an acute episode or for chronic bleeding. Iron deficiency anemia from chronic bleeding may require iron replacement therapy. Transjugular-intrahepaticportosystemic-shunt or liver transplantation is highly successful ultimate therapies because they reduce the underlying portal hypertension.CONCLUSION: PHG is important to recognize in patients with cirrhotic or non-cirrhotic portal hypertension because it can cause acute or chronic GI bleeding that often requires pharmacologic therapy. | Mihajlo Gjeorgjievski Mitchell S Cappell | 2016 | World Journal of Hepatology2016，8，4： | 38 |
| 12 | Iron and liver fibrosis: Mechanistic and clinical aspects显示文摘Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore,understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly,highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis. | Kosha J Mehta Sebastien Je Farnaud Paul A Sharp | 2019 | World Journal of Gastroenterology2019，25，5： | 39 |
| 13 | Non-invasive diagnosis of liver fibrosis and cirrhosis显示文摘The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this 'gold-standard' is imperfect; even according to its proponents, it is only 'the best' among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future. | Yoav Lurie Muriel Webb Ruth Cytter-Kuint Shimon Shteingart Gerardo Z Lederkremer | 2015 | World Journal of Gastroenterology2015，21，41： | 36 |
| 14 | Beneficial effects of naringenin in liver diseases: Molecular mechanisms显示文摘Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix(ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma(HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor(TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells(HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase(MAPK), toll-like receptor(TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease(NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor(VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases. | Erika Hernández-Aquino Pablo Muriel | 2018 | World Journal of Gastroenterology2018，24，16： | 31 |
| 15 | Natural history of chronic hepatitis B:Phases in a complex relationship显示文摘Chronic hepatitis B(CHB)is a condition of globalprevalence and its sequelae include cirrhosis and hepatocellular carcinoma.The natural history of CHB isa complex interplay of virological,environmental andhost factors.The dynamic relationship between thevirus and host evolves over the duration of the infection and different phases of the disease have been observed and described.These have been conceptualizedin terms of the state of balance between the host immune system and the hepatitis B virus and have beengiven the labels immune tolerant,immune clearance,immune control and immune escape although othernomenclature is also used.Host factors,such as age atinfection,determine progression to chronicity.Virological factors including hepatitis B viral load,mutationsand genotype also have an impact on the adverseoutcomes of the infection,as do hepatotoxic cofactorssuch as alcohol.Our understanding of the natural history of CHB has evolved significantly over the past fewdecades and characterizing the phase of disease ofCHB remains an integral part of managing this virus in the clinic. | Catherine MN Croagh John S Lubel | 2014 | World Journal of Gastroenterology2014，20，30： | 32 |
| 16 | Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-nave patients显示文摘AIM: To determine whether adding vitamin D, a potent immunomodulator, improves the hepatitis C virus (HCV) response to antiviral therapy. METHODS: Seventy-two consecutive patients with chronic HCV genotype 1 were randomized into two groups: the treatment group (n = 36, 50% male, mean age 47 ± 11 years) received Peg-α-2b interferon (1.5 μg/kg per week) plus ribavirin (1000-1200 mg/d) together with vitamin D3 (2000 IU/d, target serum level > 32 ng/mL), and the control group (n = 36, 60% male, mean age 49 ± 7 years) received identical therapy without vitamin D. HCV-RNA was assessed by realtime polymerase chain reaction (sensitivity, 10 IU/mL). The sustained virologic response (SVR) was defined as undetectable HCV-RNA at 24 wk post-treatment. RESULTS: Clinical characteristics were similar in both groups. The treatment group had a higher mean bodymass index (27 ± 4 kg/m2 vs 24 ± 3 kg/m2, P < 0.01), viral load (50% vs 42%, P < 0.01), and fibrosis score (> F2: 42% vs 19%, P < 0.001) than the controls. At week 4, 16 (44%) treated patients and 6 (17%) controls were HCV-RNA negative (P < 0.001). At week 12, 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001). At 24 wk post-treatment (SVR), 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001). Viral load, advanced fibrosis and vitamin D supplementation were strongly and independently associated with SVR (multivariate analysis). Adverse events were mild and typical of Peg-α-2b/ribavirin. CONCLUSION: Adding vitamin D to conventional Peg-α-2b/ribavirin therapy for treatment-na■ve patients with chronic HCV genotype 1 infection significantly improves the viral response. | Saif Abu-Mouch Zvi Fireman Jacob Jarchovsky Abdel-Rauf Zeina Nimer Assy Liver Unit | 2011 | World Journal of Gastroenterology2011，17，47： | 29 |
| 17 | Quantitative assessment of hepatic fibrosis in chronic hepatitis B and C: T1 mapping on Gd-EOB-DTPA-enhanced liver magnetic resonance imaging显示文摘AIM To assess the accuracy of Look-Locker on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(GdEOB-DTPA)-enhanced magnetic resonance imaging(MRI) for staging liver fibrosis in chronic hepatitis B/C(CHB/C).METHODS We prospectively included 109 patients with CHB or CHC who underwent a 3.0-Tesla MRI examination, including T1-weighted and Look-Locker sequences for T1 mapping. Hepatocyte fractions(He F) and relaxation time reduction rate(RE) were measured for staging liver fibrosis. A receiver operating characteristic analysis using the area under the receiver operating characteristic curve(AUC) was used to compare thediagnostic performance in predicting liver fibrosis between He F and RE.RESULTS A total of 73 patients had both pathological results and MRI information. The number of patients in each fibrosis stage was evaluated semiquantitatively according to the METAVIR scoring system: F0, n = 23(31.5%); F1, n = 19(26.0%); F2, n = 13(17.8%); F3, n = 6(8.2%), and F4, n = 12(16.4%). He F by EOB enhancement imaging was significantly correlated with fibrosis stage(r =-0.808, P < 0.05). AUC values for diagnosis of any(≥ F1), significant(≥ F2) or advanced(≥ F3) fibrosis, and cirrhosis(F4) using He F were 0.837(0.733-0.913), 0.890(0.795-0.951), 0.957(0.881-0.990), and 0.957(0.882-0.991), respectively. He F measurement was more accurate than use of RE in establishing liver fibrosis staging, suggesting that calculation of He F is a superior noninvasive liver fibrosis staging method.CONCLUSION A T1 mapping-based He F method is an efficient diagnostic tool for the staging of liver fibrosis. | Shen Pan Xiao-Qi Wang Qi-yong Guo | 2018 | World Journal of Gastroenterology2018，24，18： | 30 |
| 18 | Current status, problems, and perspectives of non-alcoholic fatty liver disease research显示文摘Non-alcoholic fatty liver disease(NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver(NAFL) or non-alcoholic steatohepatitis(NASH) based on the existence of ballooned hepatocytes,although the states have been known to transform into each other. Moreover,since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus,identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs. | Naoki Tanaka Takefumi Kimura Naoyuki Fujimori Tadanobu Nagaya Michiharu Komatsu Eiji Tanaka | 2019 | World Journal of Gastroenterology2019，25，2： | 29 |
| 19 | Alcoholic liver disease显示文摘Alcohol use disorders affect millions of individuals worldwide.Alcohol consumption is directly associated with liver disease mortality and accounts for elevated social and economic costs.Alcoholic liver disease(ALD) may take the form of acute involvement(alcoholic hepatitis)or chronic liver disease(steatosis,steatohepatitis,fibrosis and cirrhosis).The severity and prognosis of alcohol-induced liver disease depends on the amount,pattern and duration of alcohol consumption,as well as on the presence of liver inflammation,diet,nutritional status and genetic predisposition of an individual.While steatosis is an almost completely benign disease,liver cirrhosis is associated with marked morbidity,mortal-ity and life expectancy shortening.The median survival of patients with advanced cirrhosis is 1-2 years.Se-vere acute alcoholic hepatitis(AH)is associated with mortality as high as 50%.It has been managed with corticoids,pentoxifylline and enteral nutrition,although evidence based data are still conflicting.Some author suggest that pentoxifylline could be a better first-line treatment in patients with severe AH.Absolute abstinence is a basic condition for any treatment of acute or chronic ALD,the other therapeutical procedure being of a supportive nature and questionable significance.Acamprosate appears to be an effective treatment strategy for supporting continuous abstinence in alco-hol dependent patients.Patients with advanced liver cirrhosis who demonstrably abstain can be considered for liver transplantation,which leads to a markedly pro-longed life expectancy.The crucial step in ALD preven-tion is in the prevention of alcohol abuse,whereas the prevention of liver injury in active alcohol abusers is not clinically applicable. | Radan Bruha Karel Dvorak Jaromir Petrty | 2012 | World Journal of Hepatology2012，4，3： | 28 |
| 20 | From fatty liver to fibrosis:A tale of “second hit”显示文摘Although much is known about how fat accumulates in the liver,much remains unknown about how this causes sustained hepatocellular injury.The consequences of injury are recognized as nonalcoholic steatohepatitis(NASH) and progressive fibrosis.The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired.An additional stressor is sometimes referred to as a 'second hit' in a paradigm that identifies the accumulation of fat as the 'first hit'.Possible candidates for the second hit include increased oxidative stress,lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal,decreased antioxidants,adipocytokines,transforming growth factor(TGF)-β,Fas ligand,mitochondrial dysfunction,fatty acid oxidation by CYPs(CYP 2E1,4A10 and 4A14),and peroxisomes,excess iron,small intestinal bacterial overgrowth,and the generation of gut-derived toxins such as lipopolysaccharide and ethanol.Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury.Previous studies have specifically observed increased plasma and tissue levels of oxidative stress markers and lipid peroxidation products,with reduced hepatic and plasma levels of antioxidants.There is also some indirect evidence of the benefit of antioxidants such as vitamin E,S-adenosylmethionine,betaine,phlebotomy to remove iron,and N-acetylcysteine in NASH.However,a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far.A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor(TNF)-α,iron overload,overburdened and dysfunctional mitochondria,CYPs,and peroxisomes.Briefly,the pathogenesis of NASH is multifactorial and excess intracellular fatty acids,oxidant stress,ATP depletion,and mitochondrial dysfunction are important causes of hepatocellular injury in the steatotic liver. | Metin Basaranoglu Gkcen Basaranoglu Hakan Sentürk | 2013 | World Journal of Gastroenterology2013，19，8： | 28 |
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