The delta neutrophil index is an early predictive marker of severe acute cholecystitis

BackgroundPredicting severe acute cholecystitis (SAC) is important because the mortality rate is higher for patients with SAC than for non-SAC (NSAC) patients. We evaluated the predictive value of the delta neutrophil index (DNI), which is greater in patients with infectious and inflammatory conditions, for SAC among patients in the emergency department (ED).MethodsThis retrospective observational study included 379 consecutive adult patients with AC admitted to the ED from January 2015 to December 2016. The included patients were classified into 2 groups (NSAC and SAC) according to the Tokyo Guidelines 2018. White blood cell (WBC) count, C-reactive protein (CRP) levels, and DNI values were assessed at ED admission.ResultsThe SAC group contained 28 patients (7.4%). DNI was among the early predictors of SAC and was an inflammatory marker with a significantly higher predictive value than WBC count or CRP level for detecting SAC. The predictive power of DNI was significantly higher than that of CRP when used in conjunction with WBC count, abdominal computed tomography, and clinical variables.ConclusionsDNI measured at ED admission may serve as an early predictor of SAC.     

Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C

BACKGROUND/AIMS: Patients with chronic hepatitis C have frequently mild to moderate liver iron overload which increases with fibrosis stage. Thus, it has been postulated that iron could enhance the progression of fibrosis. However, the real impact of iron is still controversial. The study was undertaken to determine the effect of confounding variables. All factors known to influence both iron overload and fibrosis were taken into account. METHODS: Five hundred and eighty-six patients, who had liver biopsy performed prior to antiviral treatment, were included. Serum ferritin and liver iron were correlated with clinical, biological and histological variables in univariate and multivariate analysis. The impact of iron on fibrosis was evaluated in multivariate analysis in the whole group and in the subgroup of 380 patients with available date of infection. RESULTS: Hyperferritinemia, encountered in 27%, was associated with liver iron deposits in only 46% of cases. Liver iron was elevated in 17%, and correlated with age, male sex, and alcohol intake. The univariate strong link which existed between liver iron and fibrosis disappeared after adjustment for confounding variables. CONCLUSIONS: According to the results of this study, liver iron should be considered more as a surrogate marker for disease severity than as a fibrogenic factor per se.     

Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease.

AIM: To determine whether serum hyaluronic acid reliably predicts the severity of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We studied 79 patients with histologically confirmed NAFLD. Hyaluronic acid was measured in serum obtained at the time of liver biopsy. Severity of fibrosis was staged based on Brunt's classification. The prediction levels for fibrosis were determined by area under the receiver operating characteristic curve (AUC). RESULTS: The logarithm of serum hyaluronic acid was significantly different among the stages of fibrosis (P<0.0001, analysis of variance) and had a significant positive correlation with the degrees of fibrosis after adjusting for age and serum albumin (partial r=0.44, P<0.0001). AUCs were 0.67, 0.87, 0.89, and 0.92 for any levels of fibrosis, > or =moderate fibrosis, > or =severe fibrosis, and cirrhosis, all of which were significantly higher than 0.5 (P<0.05). The cut-off value of serum hyaluronic acid of 46.1 mug/l was associated with the highest AUC for severe fibrosis, yielding a sensitivity of 85% and a specificity of 80%. The corresponding positive and negative predictive values were 51% and 96%, when assuming prevalence of severe fibrosis in NAFLD patients of 20% at referral centers. CONCLUSIONS: Measurement of serum hyaluronic acid is useful to identify NAFLD patients with severe fibrosis.     

A simple index of lipid overaccumulation is a good marker of liver steatosis

Background  

Liver steatosis is often found in association with common cardiometabolic disorders, conditions that may all occur in a shared context of abdominal obesity and dyslipidemia. An algorithm for identifying liver steatosis is the fatty liver index (FLI). The lipid accumulation product (LAP) is an index formulated in a representative sample of the US population to identify cardiometabolic disorders. Because FLI and LAP share two components, namely waist circumference and fasting triglycerides, we evaluated the ability of LAP to identify liver steatosis in the same study population from the Northern Italian town where FLI was initially developed.     

Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection

Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis in other settings. In a prospective study in 130 chronic HCV carriers therefore, serum HA concentrations were compared with conventional liver function tests (including alanine aminotransferase (ALT), a-glutathione-S transferase (GST) and serum HCV RNA in order to determine which identified the stage of liver fibrosis as assessed by liver biopsy most accurately. The median HA concentrations according to the stage of fibrosis 0, 1&2, 3 and 4&5 were 17gl^–1 (range 5– 37), 17gl^–1 (5–80), 30gl^–1 (10–105) and 350gl^–1 (20–800) respectively. The median HA concentration in stage 4&5 was significantly greater than in stages 0, 1&2 or 3. Serum HA concentration rose with age, but even when adjusted for age the median HA at stage 4&5 was greater than all other groups (95% CI of difference between the medians exceeded 0). Thus, serum HA gave a sensitivity and specificity for stage 4&5 fibrosis of 85% and 88% respectively, exceeding those for ALT or GST. In contrast, serum ALT or GST levels were not correlated with the stage of fibrosis although ALT was significantly greater in the cirrhotic group when compared to the group with no fibrosis (stage 0). There was no correlation between serum HA and either the grade of inflammatory changes or serum HCV RNA. These results suggest that serum hyaluronic acid is a useful marker of liver fibrosis in patients with chronic HCV infection. It could therefore be used to monitor patients at risk of progressive fibrosis, in controlled clinical trials, as a measure of response to antifibrotic therapy and in those in whom liver biopsy is difficult or contraindicated.     

不同Child-Pugh分级肝硬化患者血胆碱酯酶和肝纤维化标志物的变化

目的探讨肝硬化患者血胆碱酯酶(CHE)和肝纤维化标志物的变化规律。方法 94例肝硬化患者根据Child-Pugh分级分为Child-Pugh A组(n=35例)、Child-Pugh B组(n=32例)和Child-Pugh C组(n=27例),同期选择30例健康体检者作为对照组。常规检测血清CHE和透明质酸(HA)、IV型胶原(IV-C)、层粘蛋白(LN)和Ⅲ型前胶原(PCⅢ)水平。结果 94例肝硬化患者血清CHE水平(4.37±2.77 ku/L)明显低于30例健康人(8.26±2.98 ku/L,P0.05),血清HA、IV-C、LN、PCⅢ[分别为(824.04±442.21)μg/L、(155.08±45.09)μg/L、(133.17±47.87)μg/L和(230.65±92.12)μg/L]明显高于健康人[分别为(98.35±72.15)μg/L、(58.91±20.36)μg/L、(74.32±22.67)μg/L和(78.11±59.54)μg/L,P0.05];随着Child-Pugh分级的逐渐递增,血清HA、IV-C、LN、PCⅢ水平呈进行性升高(P0.05),而血清CHE水平呈进行性降低(P0.05);血清CHE水平与血清HA、IV-C、LN、PCⅢ呈负相关(r1=-0.482,r2=-0.364,r3=-0.718,r4=-0.780,P0.01)。结论肝硬化患者CHE水平降低,肝纤维化标志物升高,对评估肝硬化严重程度和判断预后具有较高的临床价值。     

不同医院无创性肝纤维化指标预测慢性乙型肝炎患者肝纤维化效能差异分析*

目的 探讨应用谷草转氨酶/血小板比值（APRI）、基于4因子的纤维化指数（FIB-4）和瞬时弹性成像技术评判不同医院慢性HBV感染者肝纤维化的效能差异。方法 在2所大学附属医院收治的慢性HBV携带者或慢性乙型肝炎（CHB）行肝穿刺,并获得APRI、FIB-4和肝脏硬度检测（LSM）值,采用ROC曲线分析指标的诊断效能。结果 两组分别纳入327例（A组）和250例（B组）患者,两组患者肝组织病理学检查肝纤维化分期和LSM值存在极显著差异（P值均<0.001）,而APRI和FIB-4值无显著性统计学差异（P=0.547和0.578）;就区分S0-1和≥S2期肝纤维化而言,A组APRI分别为0.14和0.18,B组分别为0.15和0.24,A组FIB-4分别为0.98和1.26,B组分别为0.93和1.50,而A组LSM分别为5.2 kPa和6.8 kPa,B组分别为7.2 kPa和9.0 kPa（P<0.001）;A组和B组APRI诊断的截断点分别为0.105和0.145,FIB-4分别为0.675和0.775,而LSM分别为4.650和6.345,其诊断两家医院患者显著性肝纤维化的灵敏度在85%左右,而特异性在24%~46%之间。结论 可能由于一些不可控制的因素存在,导致临床数据的获得在不同医院间不可比,因此也需要经组织病理学检查,以确定APRI、FIB-4和LSM 诊断显著性肝纤维化的截断点,达到最佳诊断效果。     

A new index for non-invasive assessment of liver fibrosis

AIM:To construct and evaluate a new non-invasive fibrosis index for assessment of the stage of liver f ibrosis. METHODS:A new f ibrosis index (Fibro-Stiffness index) was developed in 165 of 285 patients with chronic hepatitis C, and was validated in the other 120 patients where liver biopsy was performed. Its usefulness was compared with liver stiffness (LS) measured by FibroScan, the aminotransferase-to-platelet ratio index, the Forns index and the FibroIndex. RESULTS: The Fibro-Stiffness index consists of...     

肝纤维化血清学检测指标的研究进展

肝纤维化是肝细胞发生坏死及炎症刺激时,肝脏内纤维结缔组织异常增生的病理过程,而且是慢性肝病发展为肝硬化的重要中间环节。目前,肝纤维化诊断的金标准仍然是病理组织活检,但其有很多缺点和不足,难以在临床广泛开展。血清学相关检测指标简便快速,创伤小,尤其适用于不能进行肝脏穿刺的患者。现就血清学检测指标在肝纤维化诊断中的进展作一综述。     

Liver fibrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population

BackgroundA growing body of evidence suggests that Non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are associated with cardiovascular disease (CVD). However, the independent role of liver fibrosis markers in the prediction of CVD in the general population is seldom tested.AimsTo assess whether a marker of liver fibrosis predicts the first occurrence of a CVD event in a large sample of community-based general population.MethodsHistorical cohort using data from a large health provider that operates a centralized computerized medical record. The level of liver fibrosis was measured by the fibrosis-4 (FIB-4) score, and the association with CVD was adjusted for the European Systematic Coronary Risk Evaluation calculator (SCORE).ResultsThe study included 8,511 individuals, 3,292 with inconclusive fibrosis and 195 with advanced fibrosis (FIB-4 ≥ 2.67). People with advanced fibrosis had higher risk for CVD, after adjustment for sociodemographic characteristics, the SCORE, use of statins and aspirin (HR [95%CI], 1.63 [1.29–2.06]). The association persisted in both women and men. Using age-specific cut-offs, there was a dose-response association between inconclusive and advanced fibrosis and CVD (HR [95%CI], 1.15 [1.01–1.31]) and HR [95%CI], 1.60 [1.27–2.01], respectively, P for trend<0.001).ConclusionsA simple fibrosis score is independently associated with CVD, suggesting that fibrosis markers should be considered in primary-care risk assessment.     

肝纤维化血清学诊断指标的临床流行病学评价

目的 评价血清透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原肽(PⅢP)和Ⅳ型胶原(Ⅳ-C)在肝纤维化诊断中的临床应用价值。方法 采用ELISA法分别检测慢性肝炎组(30例)和肝硬化组(30例)及正常对照组(30例)四项肝纤维化血清学指标,并采用ROC曲线分析进行临床意义评价。结果 各组间各指标分别存在有统计学显著性差异(FHA=139.9,FLN=52.8,FPⅢP=146.7,FⅣ-C=37.2,P<0.01),表现为肝硬化组>慢性肝炎组>对照组(q检验,P<0.01)。HA和PⅢP指标具有较高的特异性,而HA和LN及Ⅳ-C则具有较高的敏感性,表明HA对肝纤维化或肝硬化的临床诊断价值优于其它三项指标。结论 四项指标联合应用有助于临床肝纤维化的筛检和初诊。     

Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis

BACKGROUND Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension(HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts(PTC), when still within the normal range, and the risk of cirrhosis.AIM To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases.METHODS A nested case-control study utilizing a large computerized database. Cirrhosis cases(n = 5258) were compared to controls(n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores(fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated.RESULTS The mean age in both groups was 56(SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who's PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis(95%CI 1.25-1.35).CONCLUSION In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.     

Performance of serum marker panels for liver fibrosis in chronic hepatitis C

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is characterised by hepatic fibrosis, used as a proxy measure of prognosis. Liver biopsy is a flawed reference standard and serum markers of fibrosis offer an attractive alternative. METHODS: A systematic review was conducted to assess the performance of panels of serum markers of hepatic fibrosis in CHC, incorporating analyses placing markers in a clinical context. RESULTS: 14 studies were included with 10 different panels. Median AUC in validation populations was 0.77 and training populations 0.81. Likelihood ratios (LR) ranged from -LR 0.1 to 0.9, + LR 1.2 to 33.1, diagnostic odds ratios (DOR) were 9.0 (median) with a range of 5 to 27- mostly below values of robust tests. Tests perform with either high sensitivity with low specificity or vice versa. Cut-off levels that gave clinically relevant predictive values for the presence/absence of significant fibrosis were applicable to 35% of the population. CONCLUSIONS: Serum markers can rule-in or rule-out fibrosis in up to 35% of patients, but cannot differentiate stages of fibrosis reliably. Improvement of index and reference test in needed including evaluation of clinical outcomes as reference. Improved test reporting is needed to derive LR and DOR as performance indicators.     

Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice

AIM:To investigate the role of human platelets in liver fibrosis.METHODS:Severe combined immunodeficiency(SCID)mice were administered CCl4and either phosphate-buffered saline(PBS group)or human platelet transfusions(hPLT group).Concentrations of hepatocyte growth factor(HGF),matrix metallopeptidases(MMP)-9,and transforming growth factor-β(TGF-β)in the liver tissue were compared between the PBS and the hPLT groups by enzyme-linked immunosorbent assay(ELISA)and Western blotting.The effects of a human platelet transfusion on liver fibrosis included the fibrotic area,hydroxyproline content,and-smooth muscle actin(α-SMA)expression,which were evaluated by picrosirius red staining,ELISA,and immunohistochemical staining using an anti-mouse-SMA antibody,respectively.Phosphorylations of mesenchymal-epithelial transition factor(Met)and SMAD3,downstream signals of HGF and TGF-β,were compared between the two groups by Western blotting and were quantified using densitometry.Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling.Furthermore,the accumulation of human platelets in the liver 2 h after platelet transfusion was compared between normal and fibrotic livers by immunohistochemical staining using an anti-human CD41 antibody.RESULTS:The fibrotic area and hydroxyproline content in the liver were both significantly lower in the hPLT group when compared to the PBS group(fibrotic area,1.7%±0.6%vs 2.5%±0.6%,P=0.03;hydroxyproline content,121±26 ng/g liver vs 156±47 ng/g liver,P=0.04).There was less α-smooth muscle actin staining in the hPLT group than in the PBS group(0.5%±0.1%vs 0.8%±0.3%,P=0.02).Hepatic expression levels of mouse HGF and MMP-9were significantly higher in the hPLT group than in the PBS group(HGF,109±13 ng/g liver vs 88±22 ng/g liver,P=0.03;MMP-9,113%±7%/GAPDH vs 92%±11%/GAPDH,P=0.04).In contrast,the concentration of mouse TGF-β in the liver tissue was significantly lower in the hPLT group than in the PBS group(22±5ng/g liver vs 39±6 ng/g liver,P=0.     

Increased susceptibility to liver fibrosis with age is correlated with an altered inflammatory response

It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15-month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age.