Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease

Background. Visfatin is a proinflammatory and insulin-mimetic adipokine contributing to whole body glucose and lipid metabolism. Studies to date are conflicting regarding the relationship between visfatin and non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the relationship of circulating visfatin with NAFLD. Material and methods. The study included 114 NAFLD patients and 60 healthy non-diabetic controls. Plasma visfatin, adiponectin, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels were measured by ELISA. High sensitive C-reactive protein (hsCRP) levels were measured by immunoturbidimetric fixed rate method. Insulin sensitivity determined by homeostasis model assessment (HOMA-IR) index. Results. TNF-α, IL-6 and hsCRP levels were higher and, Adiponectin levels were lower in NAFLD group when compared to healthy controls (p < 0.001, for all). However, no difference was found regarding to visfatin levels between two groups. Different histologic subgroups of NAFLD had a significantly higher TNF-α, IL-6 and hsCRP, and lower adiponectin levels than those with controls (p < 0.001, for all). On the other hand, no statistically significant difference was found regarding to visfatin levels among different histologic groups. Visfatin was found to be negatively correlated with TNF-α (r = −0.236, p = 0.011) in NAFLD group. However, no association was found between visfatin and histological findings. Conclusion. Our findings show that plasma visfatin levels are not altered in the early stages of NAFLD. However, it is inversely associated with TNF-α. These findings suggest a role for visfatin in protection against liver injury in this widespread disease.     

Visfatin、Acrp30与非酒精性脂肪性肝病及肝纤维化指标的关系

目的研究Visfatin、Acrp30水平与非酒精性脂肪性肝病（NAFLD）及肝纤维化指标的关系。方法采用酶联免疫吸附法检测NAFLD患者和正常对照组的Visfatin、Acrp30水平及Ⅲ型前胶原（PCⅢ）、透明质酸（HA）、Ⅳ型胶原（CIV）、层粘连蛋白（LN）水平。结果NAFLD组hcrp30显著低于对照组,Visfatin水平显著高于对照组（P〈0.05）,Visfatin水平与WHR、BMI、FBG、TG、FINS、HOMA-IRI、PCⅢ、PCⅣ、HA、LN呈显著正相关（P〈0.05）,Acrp30水平与WHR、BMI、FBG、TG、FINS、HOMA-IRI、PCⅢ、PCⅣ、HA、LN呈显著负相关（P〈0.01或〈0.05）,Visfatin与Acrp30水平呈显著负相关（P〈0.05）。结论NAFLD患者血清Visfatin水平增高,Acrp30水平降低;Visfatin与Acrp30在NAFLD患者肝纤维化进程中可能起重要作用。     

Association between small dense LDL levels and hepatic fibrosis in patients with nonalcoholic fatty liver disease

While patients with nonalcoholic fatty liver disease (NAFLD) continue to increase worldwide, few hematological biomarkers are helpful. This study examined the potential of small dense low density lipoprotein (sdLDL) as a noninvasive biomarker for NAFLD and investigated the relevance of liver fibrosis. One hundred seventy two patients were enrolled: 121 NAFLD patients and 51 healthy controls. The lipoprotein profiles of NAFLD patients and controls were analyzed, and transient elastography (Fibroscan®) was performed to evaluate the degree of NAFLD. The liver biopsy results in some NAFLD patients were also analyzed. Age-gender matching was performed among the 172 patients, and a comparison with 46 NAFLD patients with the control group confirmed that the sdLDL (P < .001) is significantly higher in the NAFLD group. A liver fibrosis test performed on 121 NAFLD patients confirmed a positive correlation between the degree of hepatic fibrosis and the sdLDL/LDL ratio (R = 0.215, P = .017). The area under the curve of the sdLDL for the diagnosis of NAFLD was 0.734 (95% CI, 0.631–0.838), and the area under the curve of the sdLDL/LDL ratio was 0.730 (95% CI, 0.621–0.829). The sdLDL and NAFLD activity scores of the 11 NAFLD patients who underwent liver biopsy showed a positive correlation, but it was not statistically significant. The sdLDL was higher in NAFLD patients than in controls and showed a tendency to increase gradually with increasing degree of hepatic steatosis and fibrosis. In particular, the sdLDL/LDL ratio showed a significant correlation with the degree of hepatic fibrosis, and the sdLDL measurement could be useful in NAFLD patients.     

Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease

Previous studies examining the relationship between hepatic iron deposition and histological severity in nonalcoholic fatty liver disease (NAFLD) have been inconclusive. The goal of this study was to examine the relationship between hepatic iron deposition and liver histology in 849 patients enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatic iron staining was performed in a central laboratory, and the stains were scored for grade and cellular and parenchymal localization by a central pathology committee; the relationship between the grade and pattern of iron deposition and the clinical, laboratory, and histological variables was examined with univariate and multivariate analyses. Stainable hepatic iron was present in 293 of 849 patients (34.5%) in one of three histological patterns: a hepatocellular (HC) pattern [63/849 (7.4%)], a reticuloendothelial system (RES) cell pattern [91/849 (10.7%)], or a mixed RES/HC pattern [139/849 (16.4%)]. Patients with the RES iron-staining pattern were more likely to have advanced fibrosis compared to those with those with HC iron (P = 0.01). Patients with RES iron were also more likely to have advanced histological features such as fibrosis (P = 0.049), portal inflammation (P = 0.002), HC ballooning (P = 0.006), and definite nonalcoholic steatohepatitis (P = 0.007) compared to those with patients with HC or mixed iron patterns. The presence of RES iron (odds ratio = 1.60, 95% confidence interval = 1.10-2.33, P = 0.015) was independently associated with advanced hepatic fibrosis on multiple regression analysis after adjustments for age, gender, diabetes status, and body mass index. CONCLUSION: The presence and pattern of hepatic iron deposition are associated with distinct histological features in patients with NAFLD and may have implications for pathophysiology and therapy.     

Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease

AIM: To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD).METHODS: A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated.RESULTS: No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 ± 0.54 vs 0.78 ± 0.38, P = 0.032 and FIB4: 0.24 ± 0.12 vs 0.31 ± 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41).CONCLUSION: APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD.     

非酒精性脂肪性肝病患者肝纤维化指标与血清尿酸水平关系分析

[目的]分析非酒精性脂肪性肝病（nonalcoholicfattyliverdisease,NAFLD）患者肝纤维化指标与血清尿酸水平的相关性。[方法]人选符合B超诊断的60例NAFLD患者,其中脂肪肝程度轻度者21例、中度22例、重度17例,并选取40例健康体检者为正常对照组,对所有入选者进行血液生化指标[三酰甘油（TG）、总胆固醇（Tc）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血清肌酐（SCr）、血清尿酸（SUA）、谷草转氨酶（AST）和丙氨酸转移酶（ALT）]和肝纤维化指标[透明质酸（HA）、层黏蛋白（LN）、Ⅲ型前胶原肽（PCm）、Ⅳ型胶原（CⅣ）]检测,并将血清SUA与肝纤维化指标进行偏相关性分析。[结果]与正常对照组相比,NAFLD组中脂肪肝中度患者TG、SUA、AST水平均显著升高;重度患者TC、LDL-C、SCr、AST、ALT、TG、SUA水平均显著升高,HDL-C水平极显著降低。NAFLD组患者的Pcm和HA均显著升高;脂肪肝中、重度患者CⅣ显著升高。NAFLD组患者SUA水平均与Pcm有显著正相关性,脂肪肝中度患者SUA水平与HA呈显著正相关。[结论]NAFLD患者多项血液生化指标及肝纤维化指标异常,其中,SUA与肝纤维化指标PCIII有正相关性。     

非酒精性脂肪肝与血清脂联素及胰岛素抵抗的关系

NAFLD通常与超重或肥胖、2型糖尿病、高血压和高脂血症等代谢紊乱有关,胰岛素抵抗可能在脂肪肝形成过程中起重要作用。而脂联素作为一种新发现的由脂肪细胞分泌的激素,具有降低血脂、降低血糖、改善胰岛素敏感性以及拮抗动脉粥样硬化的作用,能拮抗胰岛素低抗。但是目前这     

Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis

Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). CONCLUSION: Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients.     

Metabolic inflammation as an instigator of fibrosis during nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells(qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors(PRRs),expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes,Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.     

Treatment of fibrosis in nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH) is one of the most common liver disorders in North America. The mechanism of liver injury in NASH involves insulin resistance and oxidative stress as well as cytokine release. Therapeutic interventions aimed at enhancing insulin sensitivity or reducing oxidative stress have been studied. The role of peptide hormones secreted by adipose tissue—adipocytokines—in the potential pathogenesis of NASH is an area of intense research. As the function of adipokines in modulating hepatic inflammation and fibrosis is elucidated, the potential for novel treatment strategies in patients with NASH is likely to be realized.     

Association of serum C-peptide with all-cause and cardiovascular disease mortality in ultrasound-defined nonalcoholic fatty liver disease

ObjectiveTo determine the prognostic value of C-peptide in long-term nonalcoholic fatty liver disease (NAFLD) mortality.MethodsA total of 4670 participants with NAFLD were enrolled in this study. Multivariable Cox regression models evaluated the links between C-peptide levels and all-cause and cardiovascular disease (CVD) mortality risk using adjusted hazard ratios (aHR). In addition, a two?piecewise Cox model with penalized splines was adapted to investigate the nonlinear relationships between C-peptide and mortality.ResultsAfter a mean follow?up period of 20 years, 1714 deaths from all causes were recorded. In an adjusted Cox regression analysis, using the low C-peptide group as the reference (quartile 1), higher C-peptide (quartile 4) was notably associated with increased all-cause mortality (aHR =1.39; 95% CI: 1.18–1.65) and CVD death (aHR = 1.97; 95% CI: 1.41–2.76). Spline analyses demonstrated that the association between C-peptide levels and all-cause mortality was U-shaped, with a threshold value of 0.41 nmol/L. Below the threshold, every one-unit increment in C-peptide had a 70% reduced risk of all-cause death (aHR = 0.30, 95% CI: 0.1–0.7). Above the threshold, the C-peptide levels were associated with a higher probability of all-cause death (aHR = 1. 3, 95% CI:1.2–1.4).ConclusionsIn the US NAFLD population defined by ultrasound, a U-shaped association was detected between baseline serum C-peptide level and all-cause mortality.     

Association of nonalcoholic fatty liver disease and liver cancer

AIM:To investigate the association between nonalcoholic fatty liver disease(NAFLD) and liver cancer,and NAFLD prevalence in different liver tumors.METHODS:This is a retrospective study of the clinical,laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation,with subsequent evaluation of the explant or liver biopsy.The following criteria were used to exclude patients from the study:a history of alcohol abuse,hepatitis B or C infection,no tumor detected in the liver tissue examined by histological analysis,and the presence of chronic autoimmune hepatitis,hemochromatosis,Wilson’s disease,or hepatoblastoma.The occurrence of NAFLD and the association with its known risk factors were studied.The risk factors considered were diabetes mellitus,impaired glucose tolerance,impaired fasting glucose,body mass index,dyslipidemia,and arterial hypertension.Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson’s trichrome and silver impregnation.Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade.RESULTS:No difference was found in the association of NAFLD with the general population(34.2% and 30.0% respectively,95%CI:25.8-43.4).Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma(OR = 3.99,95%CI:1.78-8.94,P < 0.001 vs OR = 0.60,95%CI:0.18-2.01,P = 0.406 and OR = 0.70,95%CI:0.18-2.80,P = 0.613,respectively).There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma(OR = 3.50,95%CI:1.06-11.57,P = 0.032).Evaluation of the relationship between the presence of NAFLD,nonalcoholic steatohepatitis,and liver fibrosis,and their risk factors,showed no significant statistical association for any of the tumors studied.CONCLUSION:NAFLD is more common in patients with liver metastases caused by colorectal cancer.     

Hepatic iron and nonalcoholic fatty liver disease.

Increased iron is suspected to enhance hepatic injury associated with nonalcoholic fatty liver disease (NAFL). We evaluated the impact of iron accumulation on the outcome of NAFL. Patients with NAFL were identified from our database. Twenty-two clinicodemographic and 19 pathological features were available for each patient. Histological staining (Perls' Prussian blue), hepatic iron concentration (HIC), and hepatic iron index (HII) were determined. Data on follow-up, mortality, and cause of death were analyzed. In 65 patients with available liver biopsy blocks, HIC and HII were 1,171 +/- 717 microgram/g dry weight and 0.43 +/- 0.30 micromol/g/yr, respectively. Males had more iron accumulation (HIC: 1,514 +/- 836 vs. 859 +/- 389, P =.0001; and HII: 0.58 +/- 0.35 vs. 0.29 +/- 0.16, P =.0001). In type II diabetics, both HIC (977 +/- 769 vs. 1,301 +/- 659; P <.05) and HII (0.30 +/- 0.23 vs. 0.52 +/- 0.32; P <.05) were lower. Iron accumulation was not related to other variables analyzed. Increased iron was not seen in those with higher grades of fibrosis or other pathological features associated with the aggressive form of NAFL (hepatocyte necrosis, fibrosis, ballooning degeneration, and Mallory hyaline). Iron accumulation was not associated with increased overall mortality, liver-related mortality, or development of cirrhosis. In summary, in most patients with NAFL, significant iron accumulation is not seen. Additionally, in our series of patients with NAFL, iron is not associated with poor clinical or pathological outcomes.     

Association of nonalcoholic fatty liver disease with insulin resistance

BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia, but some patients have normal glucose tolerance or normal weight. We tested the hypothesis that there is an association between nonalcoholic fatty liver disease and insulin resistance that is independent of diabetes and obesity. SUBJECTS AND METHODS: We measured anthropometric and metabolic variables in 46 patients with chronically elevated serum aminotransferase levels, "bright liver" on ultrasound scan, and normal glucose tolerance. Indexes of insulin resistance and secretion were determined using the homeostasis model assessment method. They were compared with 92 normal subjects who were matched for age and sex. RESULTS: Patients with nonalcoholic fatty liver disease were characterized by fasting and glucose-induced hyperinsulinemia, insulin resistance, postload hypoglycemia, and hypertriglyceridemia. Insulin resistance [odds ratio (OR) = 15 per percent increase, 95% confidence interval (CI): 3.0 to 70], fasting triglyceride level (OR = 3.1 per mmol/liter increase, 95% CI: 1.1 to 8.9), 180-minute blood glucose level (OR = 4.3 per mmol/ liter decrease, 95% CI: 1.6 to 12), and average insulin concentration in response to oral glucose (OR = 3.0 per 100 pmol/liter increase, 95% CI: 1.5 to 6.2) were independently associated with nonalcoholic fatty liver disease. The exclusion of overweight and obese subjects did not change the results. CONCLUSION: Nonalcoholic fatty liver disease is associated with insulin resistance and hyperinsulinemia even in lean subjects with normal glucose tolerance. Genetic factors that reduce insulin sensitivity and increase serum triglyceride levels may be responsible for its development.     

非酒精性脂肪性肝病患者血清preptin水平与胰岛素抵抗的相关性分析

目的探讨非酒精性脂肪性肝病(NAFLD)患者血清preptin水平的变化及其与胰岛素抵抗(IR)的相关性。方法选取2014年4-8月在上海中医药大学附属普陀医院、同济大学附属东方医院门诊、住院的72例NAFLD患者(NAFLD组),53例年龄、性别匹配的正常对照者(正常对照组)为研究对象。所有受试者进行B超检查,根据B超检查结果将NAFLD组患者分为轻度组(n=20)、中度组(n=30)和重度组(n=22)3个亚组。分别测量身高、体质量、收缩压、舒张压、腰围、臀围、肝功能、血脂、高敏C反应蛋白、空腹血糖、空腹胰岛素(FINS)、糖化血红蛋白、血清preptin水平,并计算BMI、腰臀比及稳态模型胰岛素抵抗指数(HOMAIR)。计量资料两组间均数比较采用两独立样本t检验,多组间比较采用单因素方差分析,进一步两两比较采用SNK-q检验;相关性分析采用Pearson相关系数法;采用多元线性回归分析各变量与preptin之间的关系,采用logistic回归分析各变量与NAFLD之间的关系。结果 NAFLD组preptin水平(385.54±72.78)pg/ml较正常组(303.85±57.54)pg/ml显著升高(t=-6.76,P0.001);轻度、中度和重度NAFLD组preptin水平逐渐升高,分别为(328.58±53.51)pg/ml﹑(376.71±57.77)pg/ml﹑(449.35±56.95)pg/ml,3组间比较差异有统计学意义(F=3.08,P0.001)。Pearson相关分析显示血清preptin水平与BMI(r=0.475,P0.001)、HOMA-IR(r=0.671,P0.001),FINS(r=0.763,P0.001)成正相关。多元线性回归分析显示FINS和HOMA-IR是影响血清preptin水平的独立相关因素,logistic回归分析显示preptin与NAFLD密切相关。结论 Preptin与NAFLD的发生密切相关,可能通过影响IR而参与NAFLD的发生发展。