AIM: To investigate the population-based prevalence of fatty liver disease (FLD) and its risk factors in Guangdong Province,China. METHODS: A cross-sectional survey with multiple-stage stratified cluster and random sa...AIM: To investigate the population-based prevalence of fatty liver disease (FLD) and its risk factors in Guangdong Province,China. METHODS: A cross-sectional survey with multiple-stage stratified cluster and random sampling of inhabitants over 7-year-old was performed in 6 urban and rural areas of Guangdong Province,China. Questionnaires,designed by co-working of epidemiologists and hepatologists,included demographic characteristics,current medication use,medical history and health-relevant behaviors,i.e. alcohol consumption,smoking habits,dietary habits and physical activities. Anthropometric measurements,biochemical tests and abdominal ultrasonography were carried out. RESULTS: Among the 3543 subjects,609 (17.2%) were diagnosed having FLD (18.0% males,16.7% females,P > 0.05). Among them,the prevalence of confirmed alcoholic liver disease (ALD),suspected ALD and nonalcoholic fatty liver disease (NAFLD) were 0.4%,1.8%,and 15.0%,respectively. The prevalence rate (23.0%) was significantly higher in urban areas than (12.9%) in rural areas. After adjustment for age,gender and residency,the standardized prevalence of FLD in adults was 14.5%. Among them,confirmed ALD,suspected ALD and NAFLD were 0.5%,2.3%,and 11.7%,respectively,in adults and 1.3% (all NAFLD) in children at the age of 7-18 years. The overall prevalence of FLD increased with age in both genders to the peak of 27.4% in the group of subjects at the age of 60-70 years. The prevalence rate was significantly higher in men than in women under the age of 50 years (22.4% vs 7.1%,P < 0.001). However,the opposite phenomenon was found over the age of 50 years (20.6% vs 27.6%,P < 0.05). Multivariate and logistic regression analysis indicated that male gender,urban residency,low education,high blood pressure,body mass index,waist circumference,waist to hip ratio,serum triglyceride and glucose levels were the risk factors for FLD. CONCLUSION: FLD,especially NAFLD,is prevalent in South China. There are many risk factors for FLD.展开更多
Redox state constitutes an important background of numerous liver disorders. The redox state participates in the course of inflammatory, metabolic and proliferative liver diseases. Reactive oxygen species(ROS) are pri...Redox state constitutes an important background of numerous liver disorders. The redox state participates in the course of inflammatory, metabolic and proliferative liver diseases. Reactive oxygen species(ROS) are primarily produced in the mitochondria and in the endoplasmic reticulum of hepatocytes via the cytochrome P450 enzymes. Under the proper conditions, cells are equipped with special molecular strategies that control the level of oxidative stress and maintain a balance between oxidant and antioxidant particles. Oxidative stress represents an imbalance between oxidant and antioxidant agents. Hepatocytic proteins, lipids and DNA are among the cellular structures that are primarily affected by ROS and reactive nitrogen species. The process results in structural and functional abnormalities in the liver. Thus, the phenomenon of oxidative stress should be investigated for several reasons. First, it may explain the pathogenesis of various liver disorders. Moreover, monitoring oxidative markers among hepatocytes offers the potential to diagnose the degree of liver damage and ultimately to observe the response to pharmacological therapies. The present report focuses on the role of oxidative stress in selected liver diseases.展开更多
AIM To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. METHODS Male C57BL/6J mice we...AIM To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. METHODS Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation-or metabolism-associated genes were quantified by real-time PCR. RESULTS NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae, Blautia and Lactobacillus. These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-alpha, IL-1, IL-2, IL-6 and IFN-gamma in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group. CONCLUSION NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.展开更多
Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease(NAFLD).The change in gut microbiota may alter nutritional absorption...Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease(NAFLD).The change in gut microbiota may alter nutritional absorption and storage.In addition,gut microbiota are a source of Toll-like receptor(TLR)ligands,and their compositional change can also increase the amount of TLR ligands delivered to the liver.TLR ligands can stimulate liver cells to produce proinflammatory cytokines.Therefore,the gut-liver axis has attracted much interest,particularly regarding the pathogenesis of NAFLD.The abundance of the major gut microbiota,including Firmicutes and Bacteroidetes,has been considered a potential underlying mechanism of obesity and NAFLD,but the role of these microbiota in NAFLD remains unknown.Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD.For instance,a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability,which allows the leakage of bacterial components.Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD.In children,the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis(NASH)compared with those in obese control.Escherichia can produce ethanol,which promotes gut permeability.Thus,normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD.In addition,TLR signaling in the liver is activated,and its downstream molecules,such as proinflammatory cytokines,are increased in NAFLD.To data,TLR2,TLR4,TLR5,and TLR9 have been shown to be associated with the pathogenesis of NAFLD.Therefore,gut microbiota and TLRs are targets for NAFLD treatment.展开更多
Kupffer cells, the resident liver macrophages have long been considered as mostly scavenger cells responsible for removing particulate material from the portal circulation. However, evidence derived mostly from animal...Kupffer cells, the resident liver macrophages have long been considered as mostly scavenger cells responsible for removing particulate material from the portal circulation. However, evidence derived mostly from animal models, indicates that Kupffer cells may be implicated in the pathogenesis of various liver diseases including viral hepatitis, steatohepatitis, alcoholic liver disease, intrahepatic cholostasis, activation or rejection of the liver during liver transplantation and liver fibrosis. There is accumulating evidence, reviewed in this paper, suggesting that Kupffer cells may act both as effector cells in the destruction of hepatocytes by produdng harmful soluble mediators as well as antigen presenting cells during viral infections of the liver. Moreover they may represent a significant source of chemoattractant molecules for cytotoxic CD8 and regulatory T cells. Their role in fibrosis is well established as they are one of the main sources of TGFβ1 production, which leads to the transformation of stellate cells into myofibroblasts. Whether all these variable functions in the liver are mediated by different Kupffer cell subpopulations remains to be evaluated. In this review we propose a model that demonstrates the role of Kupffer cells in the pathogenesis of liver disease.展开更多
Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although th...Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing prote展开更多
Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 ...Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.展开更多
目的为深入研究酒精性肝病的发病机制,提供一个简单可行的动物模型,并利用此模型检测血浆PDGF含量在酒精性肝病发生发展中的变化。方法本研究在平衡饮食的条件下,以400mL·L^(-1)乙醇,8g·kg^(-1)·d^(-1),日3次灌胃至4wk末...目的为深入研究酒精性肝病的发病机制,提供一个简单可行的动物模型,并利用此模型检测血浆PDGF含量在酒精性肝病发生发展中的变化。方法本研究在平衡饮食的条件下,以400mL·L^(-1)乙醇,8g·kg^(-1)·d^(-1),日3次灌胃至4wk末,自5wk,以500 mL·L^(-1)乙醇,9g·kg^(-1)·d^(-1),日3次灌胃至8 wk末,自9 wk,以500mL·L^(-1)乙醇,10g·kg^(-1)·d^(-1)日3次灌胃至12wk末,诱导酒精性肝病大鼠动物模型,分别于4wk末、8wk末、12wk末观察肝脏病理学改变,并用生物活性法测定了对照组及实验组不同病理阶段血浆中血小板源性生长因子(PDGF)的含量。结果光镜显示对照组肝细胞以中央静脉为中心呈放射状排列,酒精摄入4wk末,肝细胞中重度脂肪变性,8wk末肝细胞变性坏死,炎性细胞浸润,Mallory染色可见胶原于中央静脉沉积增加,12wk末变性坏死及炎性细胞浸润明显,Mallory染色可见胶原自中央静脉向窦周隙伸展,呈现轻度肝纤维化改变,PDGF含量结果可见与同时期对照组相比,实验组PDGF含量(kU·L^(-1))均有显著增高,4,8,12wk分别为67±15 vs 31±18(P<0.05),130±30vs33±19(P<0.001),202±20 vs 36±6(P<0.001);实验组不同时期差异明显,随病程进展病变加重,8wk与4wk相比,P<0.01,12wk与8wk相比,P<0.001。结论灌胃为一种简单可行的造模方法;PDGF可能在酒精性肝纤维化的发生发展中起重要作用,但详细机制有待进一步探讨。展开更多
AIM: To evaluate safety and feasibility of autologous bone marrow-enriched CD34+ hematopoietic stem cell Tx through the hepatic artery in patients with decompensated cirrhosis.METHODS: Four patients with decompensated...AIM: To evaluate safety and feasibility of autologous bone marrow-enriched CD34+ hematopoietic stem cell Tx through the hepatic artery in patients with decompensated cirrhosis.METHODS: Four patients with decompensated cirrhosis were included. Approximately 200 mL of the bone marrow of the patients was aspirated, and CD34+ stem cells were selected. Between 3 to 10 million CD34+ cells were isolated. The cells were slowly infused through the hepatic artery of the patients.RESULTS: Patient 1 showed marginal improvement in serum albumin and no significant changes in other test results. In patient 2 prothrombin time was decreased; however, her total bilirubin, serum creatinine, and Model of End-Stage Liver Disease (MELD) score worsened at the end of follow up. In patient 3 there was improvement in serum albumin, porthrombin time (PT), and MELD score. Patient 4 developed radiocontrast nephropathy after the procedure, and progressed to type 1 hepatorenal syndrome and died of liver failure a few days later. Because of the major side effects seen in the last patient, the trial was prematurely stopped.CONCLUSION: Infusion of CD34+ stem cells through the hepatic artery is not safe in decompensated cirrhosis. Radiocontrast nephropathy and hepatorenal syndrome could be major side effects. However, this study doesnot preclude infusion of CD34+ stem cells through other routes.展开更多
基金Supported by a Grant from Guangzhou Health Bureau Project, No. 2004-Z001
文摘AIM: To investigate the population-based prevalence of fatty liver disease (FLD) and its risk factors in Guangdong Province,China. METHODS: A cross-sectional survey with multiple-stage stratified cluster and random sampling of inhabitants over 7-year-old was performed in 6 urban and rural areas of Guangdong Province,China. Questionnaires,designed by co-working of epidemiologists and hepatologists,included demographic characteristics,current medication use,medical history and health-relevant behaviors,i.e. alcohol consumption,smoking habits,dietary habits and physical activities. Anthropometric measurements,biochemical tests and abdominal ultrasonography were carried out. RESULTS: Among the 3543 subjects,609 (17.2%) were diagnosed having FLD (18.0% males,16.7% females,P > 0.05). Among them,the prevalence of confirmed alcoholic liver disease (ALD),suspected ALD and nonalcoholic fatty liver disease (NAFLD) were 0.4%,1.8%,and 15.0%,respectively. The prevalence rate (23.0%) was significantly higher in urban areas than (12.9%) in rural areas. After adjustment for age,gender and residency,the standardized prevalence of FLD in adults was 14.5%. Among them,confirmed ALD,suspected ALD and NAFLD were 0.5%,2.3%,and 11.7%,respectively,in adults and 1.3% (all NAFLD) in children at the age of 7-18 years. The overall prevalence of FLD increased with age in both genders to the peak of 27.4% in the group of subjects at the age of 60-70 years. The prevalence rate was significantly higher in men than in women under the age of 50 years (22.4% vs 7.1%,P < 0.001). However,the opposite phenomenon was found over the age of 50 years (20.6% vs 27.6%,P < 0.05). Multivariate and logistic regression analysis indicated that male gender,urban residency,low education,high blood pressure,body mass index,waist circumference,waist to hip ratio,serum triglyceride and glucose levels were the risk factors for FLD. CONCLUSION: FLD,especially NAFLD,is prevalent in South China. There are many risk factors for FLD.
文摘Redox state constitutes an important background of numerous liver disorders. The redox state participates in the course of inflammatory, metabolic and proliferative liver diseases. Reactive oxygen species(ROS) are primarily produced in the mitochondria and in the endoplasmic reticulum of hepatocytes via the cytochrome P450 enzymes. Under the proper conditions, cells are equipped with special molecular strategies that control the level of oxidative stress and maintain a balance between oxidant and antioxidant particles. Oxidative stress represents an imbalance between oxidant and antioxidant agents. Hepatocytic proteins, lipids and DNA are among the cellular structures that are primarily affected by ROS and reactive nitrogen species. The process results in structural and functional abnormalities in the liver. Thus, the phenomenon of oxidative stress should be investigated for several reasons. First, it may explain the pathogenesis of various liver disorders. Moreover, monitoring oxidative markers among hepatocytes offers the potential to diagnose the degree of liver damage and ultimately to observe the response to pharmacological therapies. The present report focuses on the role of oxidative stress in selected liver diseases.
基金the State Key Development Program for Basic Research of China,No.2012CB517501National Natural Science Foundation of China,No.81070322,No.81270491,No.81470840 and No.31400001100 Talents Program,No.XBR2011007h
文摘AIM To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. METHODS Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation-or metabolism-associated genes were quantified by real-time PCR. RESULTS NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae, Blautia and Lactobacillus. These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-alpha, IL-1, IL-2, IL-6 and IFN-gamma in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group. CONCLUSION NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.
基金Supported by JSPS[Grant-in-Aid for Scientific Research(C)](to Miura K)
文摘Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease(NAFLD).The change in gut microbiota may alter nutritional absorption and storage.In addition,gut microbiota are a source of Toll-like receptor(TLR)ligands,and their compositional change can also increase the amount of TLR ligands delivered to the liver.TLR ligands can stimulate liver cells to produce proinflammatory cytokines.Therefore,the gut-liver axis has attracted much interest,particularly regarding the pathogenesis of NAFLD.The abundance of the major gut microbiota,including Firmicutes and Bacteroidetes,has been considered a potential underlying mechanism of obesity and NAFLD,but the role of these microbiota in NAFLD remains unknown.Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD.For instance,a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability,which allows the leakage of bacterial components.Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD.In children,the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis(NASH)compared with those in obese control.Escherichia can produce ethanol,which promotes gut permeability.Thus,normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD.In addition,TLR signaling in the liver is activated,and its downstream molecules,such as proinflammatory cytokines,are increased in NAFLD.To data,TLR2,TLR4,TLR5,and TLR9 have been shown to be associated with the pathogenesis of NAFLD.Therefore,gut microbiota and TLRs are targets for NAFLD treatment.
文摘Kupffer cells, the resident liver macrophages have long been considered as mostly scavenger cells responsible for removing particulate material from the portal circulation. However, evidence derived mostly from animal models, indicates that Kupffer cells may be implicated in the pathogenesis of various liver diseases including viral hepatitis, steatohepatitis, alcoholic liver disease, intrahepatic cholostasis, activation or rejection of the liver during liver transplantation and liver fibrosis. There is accumulating evidence, reviewed in this paper, suggesting that Kupffer cells may act both as effector cells in the destruction of hepatocytes by produdng harmful soluble mediators as well as antigen presenting cells during viral infections of the liver. Moreover they may represent a significant source of chemoattractant molecules for cytotoxic CD8 and regulatory T cells. Their role in fibrosis is well established as they are one of the main sources of TGFβ1 production, which leads to the transformation of stellate cells into myofibroblasts. Whether all these variable functions in the liver are mediated by different Kupffer cell subpopulations remains to be evaluated. In this review we propose a model that demonstrates the role of Kupffer cells in the pathogenesis of liver disease.
文摘Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing prote
文摘Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.
文摘目的为深入研究酒精性肝病的发病机制,提供一个简单可行的动物模型,并利用此模型检测血浆PDGF含量在酒精性肝病发生发展中的变化。方法本研究在平衡饮食的条件下,以400mL·L^(-1)乙醇,8g·kg^(-1)·d^(-1),日3次灌胃至4wk末,自5wk,以500 mL·L^(-1)乙醇,9g·kg^(-1)·d^(-1),日3次灌胃至8 wk末,自9 wk,以500mL·L^(-1)乙醇,10g·kg^(-1)·d^(-1)日3次灌胃至12wk末,诱导酒精性肝病大鼠动物模型,分别于4wk末、8wk末、12wk末观察肝脏病理学改变,并用生物活性法测定了对照组及实验组不同病理阶段血浆中血小板源性生长因子(PDGF)的含量。结果光镜显示对照组肝细胞以中央静脉为中心呈放射状排列,酒精摄入4wk末,肝细胞中重度脂肪变性,8wk末肝细胞变性坏死,炎性细胞浸润,Mallory染色可见胶原于中央静脉沉积增加,12wk末变性坏死及炎性细胞浸润明显,Mallory染色可见胶原自中央静脉向窦周隙伸展,呈现轻度肝纤维化改变,PDGF含量结果可见与同时期对照组相比,实验组PDGF含量(kU·L^(-1))均有显著增高,4,8,12wk分别为67±15 vs 31±18(P<0.05),130±30vs33±19(P<0.001),202±20 vs 36±6(P<0.001);实验组不同时期差异明显,随病程进展病变加重,8wk与4wk相比,P<0.01,12wk与8wk相比,P<0.001。结论灌胃为一种简单可行的造模方法;PDGF可能在酒精性肝纤维化的发生发展中起重要作用,但详细机制有待进一步探讨。
文摘AIM: To evaluate safety and feasibility of autologous bone marrow-enriched CD34+ hematopoietic stem cell Tx through the hepatic artery in patients with decompensated cirrhosis.METHODS: Four patients with decompensated cirrhosis were included. Approximately 200 mL of the bone marrow of the patients was aspirated, and CD34+ stem cells were selected. Between 3 to 10 million CD34+ cells were isolated. The cells were slowly infused through the hepatic artery of the patients.RESULTS: Patient 1 showed marginal improvement in serum albumin and no significant changes in other test results. In patient 2 prothrombin time was decreased; however, her total bilirubin, serum creatinine, and Model of End-Stage Liver Disease (MELD) score worsened at the end of follow up. In patient 3 there was improvement in serum albumin, porthrombin time (PT), and MELD score. Patient 4 developed radiocontrast nephropathy after the procedure, and progressed to type 1 hepatorenal syndrome and died of liver failure a few days later. Because of the major side effects seen in the last patient, the trial was prematurely stopped.CONCLUSION: Infusion of CD34+ stem cells through the hepatic artery is not safe in decompensated cirrhosis. Radiocontrast nephropathy and hepatorenal syndrome could be major side effects. However, this study doesnot preclude infusion of CD34+ stem cells through other routes.
