Serum progranulin as an independent marker of liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

Background: Elevated progranulin levels are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. Progranulin has not been previously investigated as a biomarker of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether serum progranulin levels are altered in patients with biopsy-proven NAFLD and if they are associated with their clinical, biochemical, and histological characteristics. Subjects and methods: We measured serum progranulin levels in 95 patients with biopsy-proven NAFLD and 80 age- and sex-matched controls. The potential associations between progranulin and the characteristics of NAFLD patients were examined by multiple linear regression analysis. Results: Serum progranulin levels were significantly higher in NAFLD patients (34 ± 13 ng/mL) than in controls (28 ± 7 ng/mL, P < 0.001). In NAFLD patients, serum progranulin levels were associated with lipid levels and the degree of hepatic fibrosis. After adjustment for potential confounders, serum progranulin remained an independent predictor of the degree of hepatic fibrosis in NAFLD patients (β = 0.392; t =2.226, P < 0.01). Conclusions: Compared with controls, NAFLD patients have higher serum progranulin concentrations, which are closely associated with lipid values and the extent of hepatic fibrosis.     

Clinicopathological correlations in a series of adult patients with non‐alcoholic fatty liver disease

Possible correlations among clinical data, serum aminotransferase levels and histological features were assessed in a series of 37 adult patients with non‐alcoholic fatty liver disease (NAFLD), consisting of nine patients with fatty liver (FL) and 28 with non‐alcoholic steatohepatitis (NASH). In each liver biopsy, the NAFLD activity score (NAS) and the stage of fibrosis were determined. Additionally, the number of Kupffer cell aggregates (microgranulomas) per centimeter of biopsy length (MG/cm ratio) was assessed on immunohistochemical stains for CD68 antigen. Definite NASH (NAS ≥ 5) was strongly correlated with serum aspartate aminotransferase (AST) level (P= 0.003), stage of fibrosis (P= 0.003) and age (P= 0.014). On multivariate analysis, age >46 years and AST level above normal values were found to be independent clinical predictors of established NASH. The MG/cm ratio increased from control liver to FL to NASH (P < 0.001), and was correlated with the NAS (P= 0.003) and with the stage of fibrosis (P= 0.004), but not with the serum aminotransferase levels. In conclusion, persistent AST elevation in patients with suspected NAFLD should be an indication for liver biopsy, in order to determine the severity of necroinflammatory activity and the stage of fibrosis. Microgranuloma counting may represent a useful complementary marker of necroinflammatory activity in patients with NAFLD.     

血浆Hcy和肝纤维化指标检测在NAFLD患者中的临床应用

目的：探讨血浆同型半胱氨酸（Hcy）和肝纤维化指标检测在非酒精脂肪性肝病（NAFLD）患者中的临床意义。方法：对符合临床诊断标准的257例非酒精脂肪肝患者进行Hcy、HA、PCⅢ、CⅣ、LN检测,并以同期体检健康者作为对照。结果：单纯性NAFLD患者Hcy、HA、PCⅢ结果高于对照组,差异有显著性（P〈0.05）,而CⅣ、LN结果虽高于对照组,但增高不明显,差异无显著性（P〉0.05）,非酒精性脂肪性肝炎（NASH）患者Hcy、HA、PCⅢ、CⅣ、LN结果明显高于对照组,差异有显著性（P〈0.01）或（P〈0.05）。NAFLD患者重度组与轻、中度组之间Hcy、HA、PCⅢ、CⅣ、LN差异均有显著性（P〈0.01）,中度脂肪肝与轻度脂肪肝之间Hcy、HA、PCⅢ、CⅣ、LN差异无显著性（P〉0.05）。结论：重度NAFLD患者存在不同程度的肝纤维化趋向,Hcy、HA、PCⅢ、CⅣ、LN结果是NAFLD筛查的实验室重要指标,可作为NAFLD病情监控和疗效评估的重要依据。     

慢性乙型肝炎患者血清TGF-β、CTGF、HA和PⅢP检测的临床意义

目的：探讨了慢性乙型肝炎患者血清TGF-B、CTGF、HA和PIIIP的水平变化及其临床意义。方法：应用放射免疫分析和酶联法对36例慢性乙型肝炎患者进行了血清TGF．13、CTGF、HA和PnlP检测,并与35名正常健康人作比较。结果：慢性乙型肝炎患者血清TGF．13、CTGF、HA和PⅢP水平均非常显著地高于正常人组（P〈0．01）。且血清TGF-B水平与CTGF、HA、P11IP水平呈正相关（r=0．6018、0．5784、0．5584,P〈0．01）。结论：检测慢性乙型肝炎患者血清TGF-Ⅲ、CTGF、HA和PIIIP的水平具有重要的临床价值,这些生物标志物的变化,可提高对病情及预后评估的认识。     

Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease

Background/Aims

Serum bilirubin exerts antioxidant and cytoprotective effects. In addition, elevated serum bilirubin levels are associated with a decreased risk of metabolic and cardiovascular diseases. However, few studies have evaluated whether serum bilirubin is associated with non-alcoholic fatty liver disease (NAFLD), which is closely associated with other metabolic diseases. The aim of this study was thus to elucidate the association between serum total bilirubin levels and NAFLD.

Methods

A cross-sectional study of 17,348 subjects undergoing a routine health check-up was conducted. Subjects positive for hepatitis B or hepatitis C virus, or with other hepatitis history were excluded. NAFLD was diagnosed on the basis of typical ultrasonographic findings and an alcohol consumption of less than 20 g/day.

Results

The mean age of the subjects was 49 years and 9,076 (52.3%) were men. The prevalence of NAFLD decreased steadily as the serum bilirubin level increased in both men and women (P<0.001 for both). Multivariate regression analysis adjusted for other metabolic risk factors showed that serum bilirubin level was inversely associated with the prevalence of NAFLD [odds ratio (OR)=0.88, 95% confidence interval (CI)=0.80-0.97]. Furthermore, there was an inverse, dose-dependent association between NAFLD and serum total bilirubin levels (OR=0.83, 95% CI=0.75-0.93 in the third quartile; OR=0.80, 95% CI=0.71-0.90 in the fourth quartile vs. lowest quartile, P for trend <0.001).

Conclusions

Serum bilirubin levels were found to be inversely associated with the prevalence of NAFLD independent of known metabolic risk factors. Serum bilirubin might be a protective marker for NAFLD.     

慢性丙型肝炎患者血清TGF-β1、CTGF和SS测定的临床意义

目的:探讨慢性丙型肝炎患者血清转化生长因子-β1(TGF-β1),结缔组织生长因子(CTGF)和生长抑素(SS)水平的变化及临床意义.方法:应用放射免疫分析和酶联法对38例丙型肝炎患者进行血清TGF-β1、CTGF和SS检测并与35名正常健康人作比较.结果:慢性丙型肝炎患者血清TGF-β1、CTGF和SS水平均非常显著...     

血清YKL-40对非酒精性脂肪肝肝纤维化的预测作用

目的探讨非酒精性脂肪肝患者血清中YKL-40水平及在肝纤维化程度评价中的价值。方法2017年7月至2019年7月于我院就诊的NAFLD患者142例,根据是否发生肝纤维化分为纤维化组(n=60)与非纤维化组(n=82),另纳入40例健康体检者作为健康对照组,采用放射免疫分析法测定血清中透明质酸(HA)、III型前胶原(PC III)、IV型胶原(CIV)及层粘连蛋白(LN)水平。采用双夹心抗体ELISA法检测血清YKL-40水平。结果三组研究对象年龄、性别、BMI指数等一般性资料差异无统计学意义(P>0.05);健康对照组、S0~S4期血清YKL-40水平随着肝纤维化分期的不断增加而不断升高(P<0.05)。血清YKL-40水平与NFS、FIB-4、APRI评分均呈显著正相关关系,具有统计学意义(P<0.05)。ROC分析结果表明,当Cutoff值为158 ng/mL时,YKL-40对NAFLD患者肝纤维化诊断价值最高,其AUC、灵敏度、特异性、PPV、NPV等均高于传统肝纤维化指标,差异具有统计学意义(P<0.05)。结论血清YKL-40在非酒精性脂肪肝患者中水平明显升高,对肝纤维化具有良好的预测价值。     

血清HBsAg与HBV DNA水平与乙肝患者肝纤维化程度的相关性分析

目的 探讨血清HBsAg与HBV DNA对乙肝患者肝纤维化的相关性分析.方法 选取2010年5月至2014年9月在我院进行治疗的100例肝脏穿刺活组织学检查的患者,根据肝脏炎症程度将患者分为G0-G1、G2、G3-G4三组,根据不同纤维化分期将患者分为S0-S1、S2、S3、S4四组,根据丙氨酸转氨酶(ALT)水平,将患者分为A1 (ALT≤40U/L)组、A2(40＜ALT≤80U/L)组,对不同分组患者进行血清HBsAg测定、HBV DNA测定及ALT测定,分析其含量与肝脏炎症程度及纤维化程度的相关性.结果 G0-G1组、G2组、G3-G4组HBsAg定量分别为(3.85±0.87)U/ml、(3.54±0.79) U/ml、(2.79 ±0.58) U/ml,三组间具有统计学差异(P＜0.05).G0-G1组、G2组、G3-G4组HBV DNA定量分别为(6.27±1.67) U/ml、(5.68±1.49) U/ml、(5.84±1.59) U/ml,三组间差异无统计学差异(P＞0.05).S0-S1组、S2组、S3组、S4组患者HBsAg定量分别为(3.95±0.93) U/ml、(3.62±0.86) U/ml、(3.55±0.62) U/ml、(3.35 ±0.54) U/ml,四组差异有统计学差异(P＜0.05).S0-S1组、S2组、S3组、S4组患者HBV DNA定量分别为(6.23±1.72) U/ml、(5.79±1.62U/ml)、(5.50±1.48) U/ml、(5.48±1.35U/ml),四组差异有统计学意义(P＜0.05).ALT水平与炎症程度及纤维化程度没有相关性(P＞0.05).结论 HBsAg、乙肝病毒随着肝纤维化程度的加重逐渐减低,血清HBsAg结合HBV DNA载量作为检测乙肝病毒感染者肝纤维化指标更为可靠.     

Non‐alcoholic fatty liver disease – histological scoring systems: a large cohort single‐center,evaluation study

Non‐alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow‐up studies of non‐alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS‐CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS‐CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS‐CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3–4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt‐out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0.001), with higher fibrosis stages (p < 0.001) and higher serum ALT levels (p < 0.001). NAFLD classifications based on histological scoring NAS‐CRN and SAF algorithm are concordant for the category of definite NASH and not NASH, while borderline NASH shows discrepant interpretation. There was highly significant correlation between the NAS and SAF categories with high grades of histological characteristics, with serum ALT and with higher stages of fibrosis. Exclusion of fibrosis is a limitation with both scores.     

结缔组织生长因子在慢性肝病诊断中的应用研究

探讨结缔组织生长因子(CTGF)在慢性肝病诊断中的应用价值。运用ELISA方法检测198例研究对象,观察血清CTGF水平的变化,分析CTGF水平与临床特征及实验室指标的相关性;运用实时荧光定量RT-PCR方法检测组织中CT-GF mRNA的表达量,比较各组间表达量的变化。乙肝后重度肝纤维化组、肝硬化组、原发性肝细胞癌(HCC)组的血清CTGF水平均显著高于正常对照组,且具有统计学意义(P<0.05);血清CTGF水平与部分临床实验室特征存在相关性,在区分早晚期肝纤维化上具有诊断提示作用;癌旁组织的CTGF mRNA相对表达量显著高于正常对照和癌组织的表达量且具有统计学差异(P<0.05)。血清CTGF水平与肝纤维化、肝硬化及肝癌的发生发展关系密切,有望成为一个新的无创性肝纤维化检测诊断指标,为临床诊断提供依据。     

Pathologic features associated with fibrosis in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress. This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis). Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis. We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.     

血清APN及CG水平对非酒精性脂肪肝肝纤维化患者的诊断价值

目的：研究脂联素（APN）与甘胆酸（CG）的水平对非酒精性脂肪肝肝纤维化（NAFLD）诊断。方法：采用ELISA检测NAFLD患者和正常对照组的血清APN水平及放免法检测CG水平,并以NEFLD和正常对照组作比较。结果：NAFLD组APN水平显著低于正常对照组（P〈0.05）,CG水平显著高于正常对照组（P〈0.05）,APN水平与CG水平呈显著负相关（P〈0.05）。结论：NAFLD患者血清APN水平降低,APN的表达在NAFLD患者肝纤维化进程中可能起重要作用。     

Serum transferrin as a liver fibrosis biomarker in patients with chronic hepatitis B

Background/Aims

Transferrin and alpha-1 antitrypsin are reportedly associated with liver fibrosis. We evaluated the usefulness of serum transferrin and alpha-1 antitrypsin as new liver fibrosis markers in patients with chronic hepatitis B.

Methods

The study included 293 patients with chronic hepatitis B who underwent a liver biopsy between October 2005 and June 2009, and who had no history of hepatocellular carcinoma. Serum markers and liver fibrosis stages were compared.

Results

Univariate analysis revealed that age (P<0.001), serum platelet count (P<0.001), and serum alkaline phosphatase level (P=0.003) differed significantly between the patients with and without liver cirrhosis. Serum transferrin levels were significantly lower in advanced fibrosis than in mild fibrosis in both univariate analysis (P=0.002) and multivariate analysis (P=0.009). In addition, the serum transferrin level was significantly lower in cirrhotic patients than in noncirrhotic patients (P=0.020). However, the serum level of alpha-1 antitrypsin was not significantly associated with liver cirrhosis in patients with chronic hepatitis B.

Conclusions

Serum transferrin could be promising serum marker for predicting advanced liver fibrosis in patients with chronic hepatitis B.     

Intrahepatic HCV RNA loads in 37 HIV-HCV co-infected patients with controlled HIV infection

Serum and intrahepatic hepatitis C virus (HCV) RNA were measured in 37 HIV-HCV co-infected patients with controlled human immunodeficiency virus (HIV) infection and correlated with clinical, biological, and histological parameters. Thirty-seven interferon-naive patients underwent liver biopsy. HCV-induced activity (A) and fibrosis (F) were evaluated with METAVIR score. The 37 patients included had HIV plasma loads < 10,000 copies/ml, CD4(+) count > 250/microl. All the patients but two were receiving antiretroviral treatment. Liver tissue and sera were used for measurement of HCV RNA by the Cobas Amplicor HCV Monitor. All patients had serum and liver HCV RNA, and both levels were correlated (r = 0.47; P = 0.003). Intrahepatic HCV load did not depend on age, sex, duration of HCV infection, CD4(+), HCV genotype, or fibrosis. AST levels correlated with intrahepatic HCV load (r = 0.52; P = 0.001). Patients with METAVIR A1/A2 had significantly lower levels of liver HCV-RNA than were found in patients with METAVIR A3 (P = 0.026). Highly active antiretroviral therapy (HAART) including protease inhibitors(PI)-treated patients had significantly lower intrahepatic HCV load (P = 0.04). A weak but significant correlation between serum and liver HCV RNA was found. The amount of hepatic HCV RNA was correlated with AST levels, histological activity, but not with HCV genotype or fibrosis. The immune improvement associated with PI regimens could help reduce HCV load, supporting a protective effect of PI-induced immune restoration.     

脂联素与非酒精性脂肪肝肝纤维化及胰岛素抵抗的关系

目的：研究脂联素水平与非酒精性脂肪肝（NAFLD）患者肝纤维化指标及胰岛素抵抗指数（IRI）的关系。方法：采用ELISA法检测NAFLD患者和正常对照组的脂联素水平及Ⅲ型前胶原（PCⅢ）、透明质酸（HA）、Ⅳ型胶原（CⅣ）、层黏蛋白（LN）水平,采用稳态模式胰岛素抵抗指数（HOMA IRI）评估胰岛素抵抗。结果：NAFLD组脂联素水平显著低于对照组,胰岛素抵抗指数与肝纤维化指标显著高于对照组（P〈0.05）,IRI与PCⅢ、PCⅣ、HA和LN呈显著正相关（P〈0.05）,脂联素水平与WHR、BMI、FBG、Tg、FINS、HOMA-IRI、PCⅢ、PCⅣ、HA和LN呈显著负相关（P〈0.01或〈0.05）。结论：NAFLD患者血清脂联素水平降低,脂联素的表达在NAFLD患者肝纤维化与胰岛素抵抗进程中可能起重要作用。     

不稳定型心绞痛患者血清Hcy和sFas的水平及相关分析

目的:探讨不稳定型心绞痛(unstable angina pectoris,UAP)患者血清Hcy水平的变化和可溶性Fas(sFas)水平的相关性.方法:应用酶联免疫吸附法(ELISA)对60例UAP患者进行了血清Hcy和血清sFas检测并与40例正常健康人做比较.结果:危险分层为Ⅱ、Ⅲ级的UAP患者血清Hcy与sFa...     

可溶性血管细胞粘附分子1(sVCAM-1)在紫癜性肾炎发病中的作用探讨

目的:探讨血管细胞粘附分子-1(VCAM-1)在过敏性紫癜性肾炎(HSPN)发病中的作用,并观察其与白介素-6(IL-6)、免疫球蛋白E(IgE)在HSPN发病中的关系。方法:采用酶联免疫吸附法(ELISA)检测27例过敏性紫癜、35例紫癜性肾炎患儿(其中急性期16例,恢复期10例)及20例健康对照儿童的血清sVCAM-1、IL-6、IgE水平。结果:①紫癜性肾炎组较单纯过敏性紫癜组、正常对照组血清sVCAM-1均明显升高,且急性期高于恢复期及正常对照组,差异均有显著性意义(P均<0.001),肾炎组、单纯组分别与对照组比较,血清IL-6、IgE水平升高,差异有显著性意义(P<0.01),恢复期较正常对照组血清sVCAM-1、IL-6水平无很大变化,差异无显著性意义(P均>0.05)。②紫癜性肾炎组、单纯过敏性紫癜组sVCAM-1水平随血清IL-6、IgE水平升高而增加(相关系数分别为0.35、0.38,P均<0.01)。结论:sVCAM-1参与了过敏性紫癜、紫癜性肾炎的发病过程,且可反映其病情程度。     

氟伐他汀对糖尿病心肌病患者血清CTGF及心功能的影响

目的：探讨氟伐他汀治疗对糖尿病心肌病患者血清结缔组织生长因子（CTGF）及心功能的影响。方法：选取2010年1月～2010年12月在黑龙江省医院住院的2型糖尿病（DM2）住院患者,依据糖尿病心肌病诊断标准,筛选出57例（男28,女29）糖尿病心肌病患者,随机分为两组,氟伐他汀治疗组（fluvastatin组）和对照组（control组）。其中fluvastatin组[n=32（男16,女16）,年龄（52±9）岁]和control组[n=25（男12,女13）,年龄（53±8）岁]。fluvastatin组80mg/d氟伐他汀口服6个月,control组不服用fluvastatin。实验进行6个月后,测定两组患者治疗前及治疗后的血糖、血脂等生化指标及血清CTGF值。此外,治疗前后做心脏彩超检查,测定左室后壁厚度（LVPW）,左室舒张末期内径（LVEDD）,射血分数（EF）,二尖瓣环舒张早期血流峰值运动速度（E/A）。比较两组治疗前后患者生化指标、血清CTGF以及心功能变化。结果：①fluvastatin治疗6个月后,flu-vastatin组血清CTGF[（425.78±63.56）ng/L vs（216.55±72.11）ng/L,P〈0.05]显著降低;control组6个月后血清CTGF无显著变化[（436.86±53.21）ng/L vs（429.98±63.77）ng/L,P〉0.05]。治疗后两组间血清CTGF有显著的统计学差异（P〈0.05）。②fluvastatin治疗6个月后,fluvastatin组患者EF[43.65%±3.89%）vs（51.21%±4.92%）,P〈0.05]、E/A[（0.74±0.43）vs（1.06±0.59）,P〈0.05]显著升高;control组6个月后,EF[（41.89%±4.03%）vs（43.65%±5.45%）,P〉0.05],E/A[（0.71±0.54）vs（0.72±0.47）,P〉0.05]变化不显著。治疗后两组间EF、E/A有显著差异（P〈0.05）。结论：：fluvastatin治疗可显著降低糖尿病心肌病患者血清CTGF,并改善心功能。     

肝硬化患者血清TPO水平与APN和HA水平相关性探讨

目的：探讨肝硬化患者血清血小板生成素（TPO）水平与脂联素（APN）和HA的相关性。方法：应用放射免疫分析和酶联法对63例肝硬化患者进行血清TPO、APN和HA检测,并与35名正常健康人作比较。结果：肝硬化患者血清TPO、APN水平均非常显著地低于正常人组（P〈0.01）,而HA水平则显著地高于正常人组（P〈0.01）,血清TPO水平与APN水平呈正相关（r=0.6284,P〈0.01）,与HA水平呈负相关（r=-0.4982,P〈0.01）。结论：肝硬化患者血清TPO、APN和HA水平与疾病的发生、发展密切相关,有重要的临床价值。