High adiponectin in chronic liver disease and cholestasis suggests biliary route of adiponectin excretion in vivo

BACKGROUND/AIMS: Models of fatty liver diseases and fibrosis suggest a hepatoprotective effect of adiponectin, an adipocyte-derived hormone with antidiabetic, antiobesity, antiatherogenic and anti-inflammatory effects. METHODS: We studied adiponectin serum levels in 111 chronic liver disease (CLD) patients and 226 healthy controls and the impact of cholestasis on adiponectin by bile duct ligation experiments in mice. RESULTS: Adiponectin was significantly elevated in CLD, and correlated with stage of liver cirrhosis, liver cell injury, e.g. aminotransferase activity, and inflammatory markers, but not with liver synthesis capacity, insulin sensitivity (HOMA index) or clinical complications. As patients with biliary liver diseases and cholestasis exhibited the highest adiponectin levels, we experimentally investigated a potential biliary route of adiponectin excretion. Following bile duct ligation in mice adiponectin levels rapidly increased without affecting hepatic adiponectin gene expression. Also, adiponectin was detectable in human bile. High adiponectin concentrations were associated with severe cholangitis and/or cholestasis on liver histology. CONCLUSIONS: Adiponectin is elevated in chronic liver disease and correlates with inflammation and liver damage. High adiponectin levels after bile duct ligation in mice and in human bile from cholestatic patients suggest that biliary secretion is involved in adiponectin clearance and that adiponectin could serve as a novel marker indicating cholestasis in liver cirrhosis.     

脂联素/瘦素比值用于判断非酒精性脂肪肝严重程度的可行性研究

目的 研究非酒精性脂肪性肝病(NAFLD)患者血清脂联素/瘦素(A/L)与胰岛素抵抗(IR)的关系,探讨血清A/L在NAFLD严重程度分级中的意义.方法 将78例确诊NAFLD患者,依据彩色超声诊断仪显像结果,分为轻度NAFLD组31例,平均年龄为(50±14)岁,男女比例为19∶12;中重度NAFLD组47例,平均年龄为(49±14)岁,男女比例为27∶20.同期观察体检健康志愿者30例作为对照组,平均年龄(48±10)岁,男女比例为18∶12.ELISA法测定血清瘦素(LP)、脂联素(APN)水平,并检测体质量指数(BMI)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、三酰甘油(TG)、总胆固醇(CHO)、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)、空腹血糖/胰岛素、稳态模型评估的胰岛素抵抗指数(HOMA-IR).采用SPSS17.0软件包进行统计学分析,计量资料差异性比较用方差分析,多因素相关性用Pearson分析.结果 血清LP与HOMA-IR、LDL和BMI均呈正相关(r=0.296,P=0.000;r=0.327,P=0.000;r=0.282,P=0.001),血清APN与HOMA-IR、LDL和BMI均呈负相关(r=-0.375,P=0.000;r=-0.368,P=0.000;r=-0.285,P=0.001).A/L与HOMA-IR、LDL和BMI均呈显著负相关(r=-0.398,P=0.000;r =-0.374,P =0.000;r=-0.307,P=0.000),且NAFLD轻度组的相关系数(r=-0.311)大于中重度组(r=-0.486).结论本研究对NAFLD患者检测发现,A/L与HOMA-IR呈显著负相关.初步提示血清A/L比值可作为一种非侵入性检测指标,有助于NAFLD严重程度的临床分级.     

瘦素及脂联素与非酒精性脂肪性肝病

非酒精性脂肪性肝病（NAFLD）作为代谢综合征在肝脏的表现,是一个多因素共同作用的结果,近年来已成为临床高发疾病之一。除了胰岛素抵抗（IR）在本病发生发展过程中起着重要作用外,脂联素（APN）、瘦素（LP）水平变化与胰岛素抵抗以及与NAFLD的关系受到关注。本文就脂联素（APN）、瘦素（LP）在NAFLD发病中的作用予以综述。     

Acute kidney injury in patients with chronic liver disease

Acute kidney injury(AKI) is a frequent clinical event in patients with liver disease, compounding their prognosis. Furthermore, it is likely that the occurrence of AKI has a detrimental impact on the subsequent renal function and the long-term survival of these patients. Recently, some authors advocated the use of new diagnostic criteria for detecting acute kidney injury in patients with cirrhosis. These criteria are based on the rapidity and extent of the creatinine increase comparing to the basal creatinine and also on the kinetics of diuresis decrease. Although their validity in this population requires further studies to be clearly established, these new criteria could have two advantages:(1) to allow earlier diagnosis of AKI and, thus, hepatorenal syndromefor which earlier intervention could improve patients' survival; and(2) to promote more intensive monitoring of renal function in these patients with high risk of AKI. Finally, recent practice guidelines about the prevention and treatment of general AKI have been published which should be useful in optimising the management of AKI in cirrhotic patients.     

慢性淤胆型肝炎高压氧治疗前后肝组织超微结构的变化

目的 观察慢性淤胆型肝炎（ＣＣＨ）高压氧（ＨＢＯ）治疗前后肝组织超微结构的变化。方法 用纯氧单仓治疗（２．５Ｍｐａ,２ｈ／ｄ,１０ｄ／ｃｙｃ,６ｃｙｃ）１０例ＣＣＨ。治疗前后肝穿,透射电镜观察。结果 ９例肝组织汇管区淋巴细胞浸润和肝细胞淤胆减轻;８例肝细胞线粒体肿胀和ｋｕｐｆｆｅｒ细胞增生减轻;７例肝组织毛细胆管淤胆减轻和溶酶体数量减少;６例肝组织内毛细血管增生明显（Ｐ〈０．０５）;３例肝细胞内内     

脂联素及其受体在酒精性肝病中的作用

脂联素是脂肪细胞特异分泌的一种脂肪因子,具有抗炎、促进脂肪酸氧化、减轻胰岛素抵抗等作用,在酒精性肝病患者及动物模型中,脂联素水平均下降,提示脂联素在酒精性肝病的发病中可能起重要作用,进一步研究其具体作用将为酒精性肝病的防治提供新的思路.     

合并非酒精性脂肪性肝病的HBeAg阴性慢性乙型肝炎患者临床特征和肝组织中脂联素的表达

目的：研究合并非酒精性脂肪性肝病（NAFLD）的HBeAg阴性慢性乙型肝炎（CHB）患者临床特点及脂变对肝组织中脂联素表达的影响。方法：以组织学检查证实存在肝细胞脂肪变性的39例HBeAg阴性的CHB患者为脂变纽,同期接受肝组织学检查不伴有肝细胞脂肪变性的54例HBeAg阴性CHB患者为对照组,比较其临床特征的差异并通过多因素分析判断HBeAg阴性CHB患者合并NAFLD的有关因素。结果：单因素分析显示,脂变组男性比例、肥胖者比例、BMI、血清ALT、总胆固醇（TCh）、甘油三酯（TG）水平均高于对照组,两组比较差异有显著性意义（P=0．026,0．048,0．045,0．022,0．047和〈0．001）;多因素分析显示,男性及高血清TG水平是与对脂变有意义的影响因素,比值比OR（95％CI）分别为6．105（1．185,31．448）和17．364（3．060,98．536）,P=0．031,0．001。两组患者脂联素表达水平的差异无显著性意义;对照组患者肝脏炎症分级G1及G1以下者脂联素表达强于G2及G2以上者,P=0．026。结论：HBeAg阴性CHB合并NAFLD的发生是宿主代谢因素所致而非病毒因素影响的结果,脂联素可能是肝损伤的防护性因子。     

老年人代谢综合征的相关代谢指标和脂联素水平的临床观察

目的 观察老年代谢综合征（MS）患者相关代谢指标和脂联素的变化.方法 对我院就诊的老年患者进行问卷调查、体格检查及血液生化指标测定,了解代谢综合征组与非代谢综合征组的相关代谢指标和脂联素值.结果 代谢综合征患者年龄、体重、体质量指数、腰围、舒张压、收缩压、空腹血糖、餐后2h血糖、甘油三酯、高密度脂蛋白胆固醇、脂联素水平比无代谢综合征者明显升高,差异有统计学意义;脂联素水平随MS代谢紊乱数目的增多而明显升高（P＜0.01）.结论 患有代谢综合征的老年患者相关代谢指标明显升高,脂联素也明显升高,提示脂联素与MS的发生可能相关,应加强对老年患者代谢综合征相关代谢指标及脂联素的监测.     

Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease

Background and Aim:  Obesity is one of the risk factors for non-alcoholic fatty liver disease (NAFLD) and a common disease that comprises simple steatosis and non-alcoholic steatohepatitis (NASH), and can eventually lead to liver cirrhosis. Adiponectin is an adipocyte-derived protein that has anti-obesity, antidiabetic and anti-inflammatory properties, and is considered to possess a hepatoprotective function. Its role in the development and progression of NAFLD in morbidly obese patients is unknown. In this study, we examined the expression levels of adiponectin and its receptors in liver biopsies of morbidly obese patients and then determined whether there was an association with the disease severity.
Methods:  Liver biopsies from 30 morbidly obese patients (18 NASH vs 12 steatosis) were analyzed. The needle core biopsies were subjected to routine histological examination and stained immunohistochemically for adiponectin, adiponectin receptor I (adipoRI) and receptor II (adipoRII).
Results:  The two groups were comparable with respect to body mass index, age and gender distribution. The expression of adiponectin decreased in liver biopsies with NASH as compared to those with simple steatosis (1.61 ± 0.70 vs 2.25 ± 0.75, P  = 0.028). Spearman's rank correlation coefficient analysis showed that the staining intensity of adiponectin negatively correlated with the grade of inflammation ( r  = −0.368, P  = 0.045) and stage of fibrosis ( r  = −0.380, P  = 0.038). There was no significant difference in expression of adipoRI and adipoRII between the two groups.
Conclusion:  These findings indicate that decreased liver adiponectin expression may play a role in the development and progression of NAFLD, from simple steatosis to NASH, in morbidly obese patients.     

脂联素与慢性肝病研究进展

脂联素(adiponectin)是脂肪细胞因子家族的重要成员之一,具有增强胰岛素敏感性、抗炎、抗动脉粥样硬化及负性调节免疫功能等多种作用。随着对脂联素研究的深入,发现其与慢性肝病的发生密切相关。文章就脂联素的来源、结构、生物学功能及其在慢性肝病中的表达情况和其在慢性肝病治疗中的潜在效应作一综述。     

Gut flora and bacterial translocation in chronic liver disease

Increasing evidence suggests that derangement of gut flora is of substantial clinical relevance to patients with cirrhosis. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen, in particular, predispose to an increased potential for bacterial infection in this group. Recent studies suggest that, in addition to their role in the pathogenesis of overt infective episodes and the clinical consequences of sepsis, gut flora contributes to the pro-inflammatory state of cirrhosis even in the absence of overt infection. Furthermore, manipulation of gut flora to augment the intestinal content of lactic acid-type bacteria at the expense of other gut flora species with more pathogenic potential may favourably influence liver function in cirrhotic patients. Here we review current concepts of the various inter-relationships between gut flora, bacterial translocation, bacterial infection, pro-inflammatory cytokine production and liver function in this group.     

血清内脏脂肪素、脂联素与非酒精性脂肪性肝病临床病理的关系

目的探讨NAFLD临床病理改变与血清内脏脂肪素（visfatin）、脂联素（adiponectin）水平的相关性。方法取54例患者肝组织标本,根据其病理改变分为正常对照组（Control组）、单纯性脂肪肝组（ss组）、非酒精性脂肪性肝炎（NASH组）。酶联免疫法测定所有患者的血清visfatin、adiponectin水平,并比较各组之间visfatin、adiponectin的差异。结果54例标本中：Control组23例,SS组11例,NASH组20例。NASH组血清visfatin{k~于Control组（P=O．012）和sS组（P=0．021）;SS组血清visfatin较Control组有降低的趋势;Control组血清adiponectin高于NASH组（P=0．024）和sS组（P=0．039）：NASH组较Ss组有降低的趋势。结论在NAFLD患者中,随着肝组织脂肪变及炎症的加重,其血清visfatin、adiponectin水平逐渐降低。     

Osteoporosis in chronic liver disease

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end‐stages and in chronic cholestasis, in addition to non‐alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/β‐catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease.     

Endoscopic ultrasound in chronic liver disease

Endoscopic ultrasound(EUS) is a minimally invasive diagnostic and therapeutic modality with a number of established as well as evolving uses in patients with chronic liver disease. Compared to other diagnostic tools such as cross-sectional imaging or conventional endoscopy, EUS has been shown to increase diagnostic sensitivity and therapeutic success for many clinical scenarios and applications with a low rate of adverse events. In this review, we discuss and focus on the current and growing role of EUS in the evaluation and/or treatment of hepatobiliary masses, hepatic parenchymal disease, portal hypertension,esophageal and other varices, and indeterminate biliary strictures.     

血清脂联素的表达及肝功能、肝脾CT值等联合检测对非酒精性脂肪肝诊断的临床意义

目的探讨血清脂联素的表达及肝功能、肝脾CT值等联合检测对非酒精性脂肪性肝病（NAFLD）诊断的临床意义。方法选取NAFLD患者71例,分为轻、中、重三组;对照组41例。检测ALT、AST、GGT、TG、TC、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）及脂联素,分析脂联素与各临床指标的相关性,NAFLD组与对照组、NAFLD不同组间上述指标的变化。结果（1）与对照组比较,NAFLD组的脂联素水平、肝脏CT值、CT肝脾比值、HDL-C明显降低（P〈0.01）,BMI、ALT、AST、TG、TC、GGT、LDL-C明显增高（P〈0.01）;（2）脂联素与BMI、ALT、AST、GGT、LDL-C呈负相关,与肝脏CT值、HDL-C呈正相关;（3）ALT在轻度与中度、轻度与重度组间表达有统计学意义（P〈0.05）,而中度与重度组间差异表达无统计学意义（P〉0.05）。结论联合检测脂联素、ALT对于NAFLD的诊断和鉴别诊断有临床意义。     

脂联素在肝纤维化发生中的作用

脂联素（ADN）具有多种生物学作用。近年研究表明其可抑制肝纤维化的发展。一些动物实验显示ADN基因敲除（ADN-KO）鼠易发生纤维化,可能与ADN具有抗氧化应激及抗炎作用有关。肝星状细胞（HSC）在肝纤维化中起核心作用,ADN可抑制HSC增殖、迁移,促进其凋亡。临床研究报道ADN与慢性肝病的纤维化进展有关,为肝纤维化的无创性诊断提供新的方向。进一步分析ADN的抗肝纤维化机制有重要意义。     

Association between HMW adiponectin,HMW-total adiponectin ratio and early-onset coronary artery disease in Chinese population

Objective

Adiponectin is an adipose-secreting protein that shows atheroprotective property and has inverse relation with coronary artery disease (CAD). High-molecular weight (HMW) adiponectin is reported as the active form of adiponectin. In the present study, we aimed to investigate the association between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis, and to compare their evaluative power for the risk of CAD.

Methods

Serum levels of total and HMW adiponectin were measured in 382 early-onset CAD (EOCAD) patients and 305 matched controls undergoing coronary angiography by enzyme-linked immunosorbent assay (ELISA). Gensini score was used to evaluate the severity of coronary atherosclerosis.

Results

CAD onset age was positively correlated with HMW adiponectin (r = 0.383, P < 0.001) and HMW-total adiponectin ratio (r = 0.429, P < 0.001) in EOCAD patients. Total and HMW adiponectin and HMW-total adiponectin ratio were all inversely correlated with Gensini score (r = −0.417, r = −0.637, r = −0.578, respectively; all P < 0.001). Multivariate binary logistic regression analysis demonstrated that HMW adiponectin and HMW-total adiponectin ratio were both inversely correlated with the risk of CAD (P < 0.05). ROC analysis indicated that areas under the ROC curves of HMW adiponectin and HMW-total adiponectin ratio were larger than that of total adiponectin (P < 0.05).

Conclusions

Adiponectin is cardioprotective against coronary atherosclerosis onset in EOCAD patients. HMW adiponectin and HMW-total adiponectin ratio show stronger negative associations with the severity of coronary atherosclerosis than total adiponectin does. HMW adiponectin and HMW-total adiponectin ratio are effective biomarkers for the risk of CAD in Chinese population.     

肥胖相关性肝肾疾病的新机制

肥胖是肥胖相关性肾病和非酒精性脂肪肝病的重要危险因素。近年来研究表明,组织内的血清胎球蛋白A和脂联素,以及5’-AMP激活的蛋白激酶(AMPK)的协同作用是肥胖相关性肝肾疾病的共同机制,在肾脏足细胞和肝实质细胞的损伤中发挥枢纽作用,引发组织炎症、纤维化,以及终末期硬化。深入研究该早期共同通路,有助于发现肥胖相关性疾病治疗的新靶标。     

慢性乙型肝炎患者血清脂联素水平与肝功能及相关因素的关系

目的探讨慢性乙型肝炎（CHB）患者血清脂联素水平与肝功能及相关因素的关系。方法选择77例不同类型CHB患者,应用ELISA法检测血清脂联素水平;同时检测肝功能、血脂、空腹血糖（FBG）、HBVDNA等。测量人体身高、体重,计算体重指数（BMI）。30例健康体检者为正常对照组。结果各组CHB患者血清脂联素水平明显高于正常对照组（P〈0.01）,随肝损害加重而上升。脂联素与AST、TBil和ALP均正相关,与白蛋白（ALB）负相关。结论CHB患者血清脂联素水平升高与肝脏炎症活动有关,可能是机体抵抗炎症的一种机制。     

Increased liver stiffness in extrahepatic cholestasis caused by choledocholithiasis

Background

Extrahepatic cholestasis that is caused by benign and malignant diseases has been reported to increase liver stiffness (LS), as measured by transient elastography (TE).

Objectives

The aim of this study was to evaluate LS in patients with extrahepatic cholestasis due to choledocholithiasis before and after endoscopic sphincterotomy and stone removal.

Patients and Methods

LS was measured by TE (Fibroscan) in patients with extrahepatic cholestasis that was caused by choledocholithiasis before and 1 month after endoscopic sphincterotomy and successful stone removal.

Results

We studied 12 patients (7 females, 5 males), aged 36 to 76 years (mean age 57.1 ± 11.6 years), with extrahepatic cholestasis that was caused by choledocholithiasis. LS was increased in all patients (range: 6.2-18.4 kPa; mean: 8.9 ± 3.5 kPa) before endoscopic therapy. Successful biliary drainage was effected by sphincterotomy and stone removal in all patients, which led to a significant decline in LS to 3.9-8.1 kPa (Mean: 5.6 ± 1.2 kPa; p < 0.001) within a mean observation time of 29 days. The decrease in LS values correlated significantly with a decline in serum total bilirubin levels (r = 0.691; p < 0.0001).

Conclusions

Extrahepatic cholestasis due to choledocholithiasis increases LS and should be excluded before assesing liver fibrosis by transient elastography.