柞蚕雄蛾液对酒精性肝病小鼠Toll样受体4的影响

目的:探讨柞蚕雄蛾液对小鼠酒精性肝病TLR -4的影响及对肝脏保护作用机制。方法:40只昆明种小鼠随机分为4组,柞蚕雄蛾大、小剂量组小鼠每日在酒精灌胃前给予不同剂量柞蚕雄蛾液灌胃,4周后处死,取血及肝组织,常规病理学观察及脂肪肝评分;免疫组织化学方法检测肝组织TLR-4、TNF-α、NF-κb表达情况;检测肝细胞线粒体MDA含量, SOD活性。结果:模型组小鼠肝组织明显脂肪变性,TLR -4、TNF-α表达较正常组明显增高;柞蚕雄蛾小剂量组与模型组比较,脂肪变性有不同程度减轻,TLR-4、TNF-α表达较模型组降低(P<0.01),SOD活性明显升高,MDA浓度降低(P<0.01)。结论:柞蚕雄娥液能够降低小鼠早期酒精性肝病Kupffer细胞的Toll样受体4及肝组织TNF-α的表达,对肝组织有一定的保护作用,小剂量作用更为显著。

酒精性肝病

还原型谷胱甘肽治疗酒精性肝病46例——邵寿祺等（浙江宁海县第一医院感染科315600）；《中国药业》，2005，14（9）：86[目的：观察还原型谷胱甘肽注射液对洒精性肝病的疗效。方法：将92例酒精性肝病（酒精性脂肪肝、酒精性肝炎、酒精性肝硬化）患者，随机分为两组对照组（46例）用基础治疗，治疗组（46例）给予基础治疗并加用还原型谷胱甘肽注射液，每日1．2g，静脉滴注。治疗期间均戒酒，4周为1个疗程，观察肝功能变化。结果：与对照组比较，治疗组综合疗效，有显著性差异伊〈0．05）。结论：还原型谷胱苷肽注射液在酒精性肝病患者具有良好的疗效。]

酒精性肝病患者酒精戒断综合征的中医护理

目的:探讨酒精性肝病患者酒精戒断综合征的中医护理方法和效果。方法:综合运用护理评估、心理护理、健康教育、结合辨证药膳的饮食调护。结果:患者均能以积极的心态和行为应对、减轻、克服戒断症状带来的负性心理情绪反应,减轻患者"心病发作",提高戒酒成功率。结论:采取积极有效的中医护理干预措施,对减轻戒断症状的不适感是有效的。

凯西莱治疗酒精性肝病50例疗效观察

目的研究凯西莱治疗酒精性肝病的疗效。方法观察组给予凯西莱0.2g静点,对照组给予强力宁100ml静点。两组均连用4周。结果观察组痊愈64%,好转30%,无效6%,总有效率94%。对照组痊愈27%,好转53%,无效20%,总有效率80%。观察组血脂均正常,对照组有10例血脂异常。结论凯西莱对洒精性肝病有一定疗效。

六味五灵片治疗非洒精性脂肪性肝病随机对照试验Meta分析

目的:对六味五灵片治疗非洒精性脂肪性肝病临床疗效及安全性进行Meta分析。方法:检索电子数据库包括Cochrane Central Register of Controlled Trials(CENTRAL)、Pubmed、万方数据库、中文科技期刊全文数据库、中国学术期刊全文数据库和中国生物医学文献数据库已发表的关于六味五灵片治疗非洒精性脂肪性肝病的随机对照试验。采用Review Manager 5.1软件对数据进行分析。结果:共纳入5篇文献,312名患者,研究间无明显异质性,结果显示试验组与对照组在疗效方面差异有统计学意义。结论:六味五灵片治疗非洒精性脂肪性肝病临床疗效明显优于常规治疗,较安全,值得推广应用。

中西药联用治疗酒精肝病疗效观察

目的:观察中西药联用治疗酒精肝病的疗效及机理。方法:将65例酒精性肝病患者随机分为2组,治疗组33例,应用中药(自拟护酒肝饮)联合西药(水林佳)治疗,对照组32例,单纯服用西药(水林佳)治疗,疗程6周,观察2组临床疗效与治疗前后外周血白细胞介素-8(IL-8)、超氧化物歧化酶(SOD)、丙二醛(MDA)水平及肝功能(ALT、AST、GGT)变化。结果:治疗组病人外周血IL-8、MDA水平均明显下降(P<0.05,P<0.01),SOD活性明显上升(P<0.05);对照组病人外周血MDA水平下降(P<0.05),2组患者肝功能有不同程度的恢复,治疗组总有效率90.01%,对照级总有效率71.87%;2组总有效率差异有显著性(P<0.05)。

Comprehensive Understanding of Immune Cells in The Pathogenesis of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.

Alcoholic liver disease and hepatitis C:A frequently underestimated combination

Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epidemiology and combined impact of ALD and HCV on the progres sion of liver disease.ALD and HCV affect the progres sion of liver disease to liver cirrhosis and hepatocellular carcinoma(HCC) in a synergistic manner.Thus, the risk for HCC increases f ive times with a daily alcohol con sumption of 80 g;in the presence of HCV it is increased 20fold, and a combination of both risk factors leads to a more than 100fold risk for HCC development.Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication.Several molecu lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression.They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron.Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liversecreted systemic iron hormone hepcidin.A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future.For now, it can be generally concluded that HCVinfect ed patients should abstain from alcohol and alcoholicsshould be encouraged to participate in detoxification programs.

Ethanol induced mitochondria injury and permeability transition pore opening: Role of mitochondria in alcoholic liver disease

AIM: To observe changes of mitochondria and investigate the effect of ethanol on mitochondrial perme- ability transition pore (PTP), mitochondrial membrane potential (MMP, ΔΨm) and intracellular calcium concentration in hepatocytes by establishing an animal model of alcoholic liver disease (ALD). METHODS: Fourty adult male Wistar rats were randomly divided into two groups, the model group (20) was administered alcohol intragastrically plus an Oliver oil diet to establish an ALD model, and the control group (20) was given an equal amount of normal saline. The ultramicrostructural changes of mitochondria were observed under electron microscopy. Mitochondria of liver was extracted, and patency of PTP, mitochondrial membrane potential (ΔΨm), mitochondrial mass and intracellular calcium concentration of isolated hepacytes were detected by flow cytometry using rhodamine123 (Rh123), Nonyl-Acridine Orange and calcium fluorescent probe Fluo-3/AM, respectively. RESULTS: Membrane and cristae were broken or disappeared in mitochondria in different shapes under electron microscopy. Some mitochondria showed U shape or megamitochondrion. In the model group, liver mitochondria PTP was broken, and mitochondria swelled, the absorbance at 450 nm, A540 decreased (0.0136 ± 0.0025 vs 0.0321 ± 0.0013, model vs control, P < 0.01); mitochondria transmembrane potential (239.4638 ± 12.7263 vs 377.5850 ± 16.8119, P < 0.01) was lowered; mitochondrial mass (17.4350 ± 1.9880 vs 31.6738 ± 3.4930, P < 0.01); and [Ca2+]i was increased in liver cells (7.0020 ± 0.5008 vs 10.2050 ± 0.4701, P < 0.01).CONCLUSION: Chronic alcohol intake might lead to broken mitochondria PTP, decreased mitochondria membrane potential and injury, and elevated intracellular Ca2+ production. Ethanol-induced chondriosome injury may be an important mechanism of alcoholic diseases.

Alcohol metabolites and lipopolysaccharide: Roles in the development and/or progression of alcoholic liver disease

The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts, and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore, the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflamma-tion and fi brosis, and play a role in the development and/or progression of ALD.

Hepatic stellate cells and innate immunity in alcoholic liver disease

Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

AIM: To determine the role of leptin system in non-al- coholic fatty liver disease (NAFLD) development by deli- neating the changes in serum levels of leptin and soluble leptin receptor (sOB-R). METHODS: Blood samples were collected from 30 consecutive patients with liver-biopsy-proven NAFLD and 30 patients with cholecystolithiasis (stationary phase) as controls. Serum leptin levels were determined by radio- immunoassay and concentration of sOB-R was measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected. RESULTS: Mean serum leptin level and BMI in the NAFLD group were significantly higher than in the con- trols (both P < 0.001), but mean sOB-R level was lower in the NAFLD group when compared to the controls. Both men and women in the NAFLD group had higher mean serum leptin levels and lower sOB-R levels than did the men and women in the control group (all P < 0.001). The- re was a significant negative correlation between serum leptin and sOB-R levels (r = -0.725, P < 0.001). Multiva- riate analysis showed that the percentage of hepatocyte steatosis, sex, BMI, and homeostasis model assessment of insulin resistance (HOMA IR) were independently rela- ted to serum leptin levels. CONCLUSION: Elevated serum leptin seems to be afeature of steatosis, and serum leptin seems to increase as hepatocyte steatosis develops. An enhanced release of leptin is accompanied by an decrease in sOB-R con- centration, which suggests higher resistance of periphe- ral tissues towards the action of leptin.

Targeting collagen expression in alcoholic liver disease

Alcoholic liver disease （ALD） is a leading cause of liver disease and liver-related deaths globally, particularly in developed nations. Liver fibrosis is a consequence of ALD and other chronic liver insults, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Liver fibrosis is characterized by accumulation of excess extracellular matrix components, including type I collagen, which disrupts liver microcirculation and leads to injury. To date, there is no therapy for the treatment of liver fibrosis; thus treatments that either prevent the accumulation of type I collagen or hasten its degradation are desirable. The focus of this review is to examine the regulation of type I collagen in fibrogenic cells of the liver and to discuss current advances in therapeutics to eliminate excessive collagen deposition.

Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver, which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes. It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-α signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease.

Pediatric nonalcoholic fatty liver disease,metabolic syndrome and cardiovascular risk

Nonalcoholic fatty liver disease(NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use.The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes.A more advanced form of NAFLD,nonalcoholic steatohepatitis,includes inflammation and liver cell injury,progressive to cryptogenic cirrhosis.NAFLD has become the most common cause of chronic liver disease in children and adolescents.The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide.NAFLD is strongly associated with abdominal obesity,type 2 diabetes,and dyslipidemia,and most patients have evidence of insulin resistance.Thus,NAFLD shares many features of the metabolic syndrome(MetS),a highly atherogenic condition,and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis.Accumulating evidence suggests thatNAFLD is associated with a significantly greater overall mortality than in the general population,as well as with increased prevalence of cardiovascular disease(CVD),independently of classical atherosclerotic risk factors.Yet,several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS.Therefore,the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes.In children,the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively.Therapeutic goals for NAFLD should address nutrition,physical activity,and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

AIM： To assess whether treatment with insulinsensitizing agents （ISAs） in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet （MCDD） rat model of non-alcoholic fatty liver disease （NAFLD）. METHODS： Rats （n = 6 per group） were treated with different drugs, including MCDD only, MCDD diet with either metformin （200 mg/kg）, rosiglitazone （3 mg/kg）, metformin plus rosiglitazone （M＋R）, ezetimibe （2 mg/ kg）, valsartan （2 mg/kg）, or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS： Fatty liver （FL） rats demonstrated severe hepatic fatty infiltration （〉 91% fat）, with an increase in hepatic TG （＋1263%, P 〈 0.001）, hepatic cholesterol （＋245%, P 〈 0.03）, hepatic MDA levels （＋225%, P 〈 0.001）, serum TNF-alpha （17.8 ＋ 10 vs 7.8 ＋ 0.0, P 〈 0.001）, but a decrease in hepatic alpha tocopherol （-74%, P 〈 0.001） as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis （-54%）, hepatic TG （-64%）, hepatic cholesterol （-31%） and hepatic MDA （-70%）, but increased hepatic alpha tocopherol （＋443%） as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis （-32% vs -54%, P 〈 0.001） and in hepatic MDA levels （-55% vs -70%, P 〈 0.01）, but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION： Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.

Liver histology according to the presence of metabolic syndrome in nonalcoholic fatty liver disease cases

AIM:To investigate the histologic features of the liver in nonalcoholic fatty liver disease (NAFLD) cases according to the presence of metabolic syndrome or its individual components. METHODS:We enrolled 81 patients (40 male,41 fe-male) who were diagnosed with fatty liver by ultraso-nographic scan and fulfi lled the inclusion criteria. First anamnesis,anthropometric,clinical,laboratory and imaging features of all participants were recorded and then liver biopsy was performed after gaining consent from patients. Diagnosis of metabolic syndrome was dependent on patients having 3 or more out of 5 risk criteria defined by the WHO. Biopsy specimens were assessed according to Brunt et al's classification. RESULTS:Sixty-nine of the 81 patients had nonalco-holic steatohepatitis (NASH),11 had simple fatty liver and 1 had cirrhosis according to histologic evaluation. Comparisons were made between two groups of NASH patients,those with and without metabolic syndrome. We did not detect statistically significant differences in liver histology between NASH patients with and wit-hout metabolic syndrome. CONCLUSION:NASH can progress without metabolic risk factors or the presence of metabolic syndrome.

T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease

AIM： To determine in obese children with nonalcoholic fatty liver disease （NAFLD） the accuracy of magnetic resonance imaging （MRI） in assessing liver fat concentration. METHODS： A case-control study was performed. Cases were 25 obese children with biopsy-proven NAFLD. Controls were 25 obese children matched for age and gender, without NAFLD at ultrasonography and with normal levels of aminotransferases and insulin. Hepatic fat fraction （HFF） by MRI was obtained using a modification of the Dixon method.RESULTS： HFF ranged from 2% to 44% [mean, 19.0% （95% CI, 15.1-27.4）] in children with NAFLD, while in the controls this value ranged from 0.08% to 4.69% [2.0% （1.3-2.5）, P 〈 0.0001]. HFF was highly correlated with histological steatosis （r = 0.883, P 〈 0.0001） in the NAFLD children. According to the histological grade of steatosis, the mean HFF was 8.7% （95% CI, 6.0-11.6） for mild, 21.6% （15.3-27.0） for moderate, and 39.7% （34.4-45.0） for severe fatty liver infiltration. With a cutoff of 4.85%, HFF had a sensitivity of 95.8% for the diagnosis of histological steato- sis ≥ 5%. All control children had HFF lower than 4.85%; thus, the specificity was 100%. Alter 12 mo, children with weight loss displayed a significant decrease in HFF. CONCLUSION： MRI is an accurate methodology for liver fat quantification in pediatric NAFLD.