Hyaluronic acid algorithm-based models for assessment of liver fibrosis： translation from basic science to clinical application

BACKGROUND： The estimation of liver fibrosis is usually dependent on liver biopsy evaluation. Because of its disadvantages and side effects, researchers try to find non-invasive methods for the assessment of liver injuries. Hyaluronic acid has been proposed as an index for scoring the severity of fibrosis, alone or in algorithm models. The algorithm model in which hyaluronic acid was used as a major constituent was more reliable and accurate in diagnosis than hyaluronic acid alone. This review described various hyaluronic acid algorithm-based models for assessing liver fibrosis.DATA SOURCE： A Pub Med database search was performed to identify the articles relevant to hyaluronic acid algorithmbased models for estimating liver fibrosis.RESULT： The use of hyaluronic acid in an algorithm model is an extra and valuable tool for assessing liver fibrosis.CONCLUSIONS： Although hyaluronic acid algorithm-based models have good diagnostic power in liver fibrosis assessment, they cannot render the need for liver biopsy obsolete and it is better to use them in parallel with liver biopsy. They can be used when frequent liver biopsy is not possible in situations such as highlighting the efficacy of treatment protocol for liver fibrosis.

Serum hyaluronic acid, procollagen type Ⅲ and Ⅳ in histological diagnosis of liver fibrosis

OBJECTIVE: To assess the significance of serum hyaluronic acid (HA), proeollagen type Ⅲ (PCⅢ), collagen type Ⅳ (CⅣ) in the histological diagnosis of liver fibrosis. METHODS: The concentrations of serum HA, PCⅢ, CⅣ in 253 patients with chronic liver diseases were measured by radioimmunoassay. Liver biopsies were performed in all patients at the same time. The liver was pathologically evaluated by a pathologist according to a scoring system. Combined with the results of liver pathological diagnosis, the accuracy of serum HA, PCⅢ, CⅣ in diagnosing patients with hepatic fibrosis (staging≥S_2) or cirrhosis (S_4) was assessed using the receiver operating curve (ROC). RESULTS: The cutoff values of serum HA, PCⅢ and CⅣ for identifying patients with hepatic fibrosis (≥S_2) or cirrhosis (S_4) were determined. The cutoff values of serum HA, PCⅢ and CⅣ for detecting patients with fibrosis (stage≥S_2) were 90μg/L, 90μg/L, 75μg/L, respectively; their sensitivity (Se) was 80.4%, 82%, 63.1%; their specificity (Spe) was 70.2%, 60.8%, 83.8%; their positive predictive values (PPV) were 86.7%, 83.5%, 90.4%; their negative predictive values (NPV) were 59.8%, 58.4%, 48.4%, respectively. The cutoff values for detecting patients with liver cirrhosis were 210μg/L for HA, 96.2% for Se, 85.3% for Spe, 65.4% for PPV, 98.8% for NPV; 150μg/L for PCⅢ, 76.4% for Se, 68.7% for Spe, 40.4% for PPV, 91.3% for NPV; 90μg/L for CⅣ, 80% for Se, 75.8% for Spe, 47.8% for PPV, 93.2% for NPV, respectively. CONCLUSIONS: Serum HA, PCⅢ and CⅣ can be determined for an accurate diagnosis of hepatic fibrosis in various stages. HA is the best for screening liver cirrhosis.

Non-invasive assessment of liver fibrosis in chronic liver diseases:Implementation in clinical practice and decisional algorithms

Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications,including decompensation,bleeding and liver cancer.Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease.Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis,while cirrhosis requires a specif ic follow-up including screening for esophageal varices and hepatocellular carcinoma.Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive,costly and prone to sampling errors.Recently,blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis.However,there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available.This is due to an unsatisfactory accuracy for some of them,and to an incomplete validation for others.Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they are combined.Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement non-invasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies.

Noninvasive assessment of liver fibrosis with combined serum aminotransferase/platelet ratio index and hyaluronic acid in patients with chronic hepatitis B

AIM： To construct a noninvasive assessment model consisting of routine laboratory data to predict significant fibrosis and cirrhosis in patients with chronic hepatitis B （CHB）. METHODS： A total of 137 consecutive patients with CriB who underwent percutaneous liver biopsy were retrospectively analyzed. These patients were divided into two groups according to their aminotransferase （ALT） level. The sensitivity, specificity, positive predictive value （PPV）, negative predictive value （NPV）, the likelihood ratio （LR） of aminotransferase/platelet ratio index （APRI） ≥ 1.5 or 〈 1.5 in combination with different hyaluronic acid （HA） cut-off points were calculated for the presence of moderate to severe fibrosis/cirrhosis （fibrosis stages 2 and 4） and no to mild fibrosis/cirrhosis （fibrosis stages 0 and 1）. RESULTS： The APRI correlated with fibrosis stage in CriB patients. The APRI ≥1.5 in combination with a cut-off HA cut-off point 〉 300 ng/mL could detect moderate to severe fibrosis （stages 2-4） in Crib patients. The PPV was 93.7%, the specificity was 98.9%. The APRI 〈 1.5 in combination with different HA cut-off points could not detect no to mild fibrosis in CHB patients. CONCLUSION： The APRI ≥ 1.5 in combination with a HA cut-off point 〉 300 ng/mL can detect moderate to severe fibrosis （stages 2-4） in Crib patients.

Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease. However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type VI collagen 7S domain and hyaluronic acid. METHODS: One hundred and twelve patients with histologically proven NAFLD were studied. RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type VI collagen 75 domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type VI collagen 7S domain, 86% and hyaluronic acid, 92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type VI collagen 7S domain (≥5.0 ng/mL), 84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis. CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the commonest chronic liver disease and its prevalence is increasing driven by the pandemic of obesity and type 2 diabetes mellitus. NAFLD can progress to cirrhosis and is associated with increased risk for cardiovascular disease and hepatocellular cancer. Diet and exercise are limited by suboptimal long-term adherence in patients with NAFLD. On the other hand, current pharmacological treatment of NAFLD has limited efficacy and unfavorable safety profile. In this context, obeticholic acid(OCA), a selective agonist of the farnesoid X receptors, might represent a useful option in these patients. Preclinical studies suggest that OCA improves hepatic steatosis, inflammation and fibrosis. A proof-of-concept study and the randomized, placebo-controlled Farnesoid X Receptor Ligand Obeticholic Acid in non-alcoholic steatohepatitis Treatment(FLINT) trial also showed improvements in liver histology in patients with NAFLD who received OCA. Weight loss and reduction in blood pressure were also observed. However, the effects of OCA on insulin resistance are conflicting and the lipid profile is adversely affected by this agent. In addition, pruritus is frequently observed during treatment with OCA and might lead to treatment discontinuation. However, given the limitations of existing treatments for NAFLD, OCA might represent a useful therapeutic option in selected patients with NAFLD.

Clinical Evaluation of Hepatic Fibrosis in Chinese Patients with Nonalcoholic Fatty Liver Disease with FibroScan

Aim: The clinical value of FibroScan in evaluation of hepatic fibrosis was assessed in Chinese patients with nonalcoholic fatty liver disease (NAFLD). Methods: Liver stiffness and other NAFLD related variables were measured in NAFLD patients with either elevated or normal hyaluronic acid (HA) levels, and in healthy volunteers respectively. Moreover, hepatic fibrosis rat model was used for the correlation analysis between the measured liver elasticity and its corresponding pathological changes. Results: The severity of NAFLD in patients was positively correlated with both HA level and FibroScan values suggesting that fibrosis occured along with the progression of NAFLD. Interestingly, the FibroScan value was found to change at an earlier stage of the disease than that of HA level. The mean liver elasticity in the sampling volume of the region of interest in experimental rats, which were subject to the induction of liver fibrosis using peritoneal injection of carbon tetrachloride (CCl4) for 6 or 9 weeks respectively, was measured using Fibroscan. The examination of pathological changes of these experimental rats demonstrated the positive correlation of the measured elasticity values with the extent (severity) of the corresponding pathological changes in the rats of 6 weeks post induction of liver fibrosis with a moderate liver fibrosis, or 9 weeks with a severe liver fibrosis. The average liver stiffness for the normal liver (S0) was 4.51 ± 0.82 kPa, for moderate liver fibrosis (S2) was 6.91 ± 1.32 kPa, and for severe liver fibrosis (S3) 9.62 ± 1.82 kPa. Conclusion: FibroScan can be used to objectively and quantitatively identify the trend in the changing stiffness of the liver and noninvasively detect the development of liver fibrosis.

Significance of hepatic fibrosis markers in early diagnosis of type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease

Objective:Hyaluronic acid (HA), laminin (LN), and collagen IV (CIV) are major serum markers of liver fibrosis. This study evaluated the diagnostic value of various noninvasive indicators for hepatic fibrosis in patients with T2DM and NAFLD.Methods: Between January 2016 and September 2018, a total of 278 patients, which were grouped to normal, NAFLD and T2DM with NAFLD. Routine clinical and laboratory examinations were collected, including age, sex, blood routine, HbA1C, FBG, FCP, AST, AST, ALB, PLT, TC, TG, HDL, LDL, serum fibrosis C-IV, HA, LN. NFS, APRI and FIB4 scores were calculated.Results: No statistical difference was found on age, ALT, AST, GGT, BMI, TG, CHOL, and Glu, APRI, FIB4, CIV, LN, and HA exhibited statistical significance. Further correlation analysis showed that HA, IV-C, LN, were positively correlated with NFS, APRI, and FIB4.Conclusions:Compared with healthy control group, ALT, AST, TC, TG, HDL and LDL in NAFLD group, T2DM patients with NAFLD group increased to different degrees, and the difference was statistically significant. The HA, C-IV, LN, NFS, APRI ratio index and FIB-4 index of T2DM patients with NAFLD were higher than those of NAFLD group and healthy control group, and the HA, C-IV and LN of NAFLD group were higher than those of healthy control group. Compared with non-fibrosis group, HA, LN, C-IV, ALT and AST in fibrosis group were significantly higher. Moreover, HA, LN and C-IV were positively correlated with NFS, APRI ratio index and FIB-4 index.

Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease

High prevalence of non-alcoholic fatty liver disease (NAFLD) and very diverse outcomes that are related to disease form and severity at presentation have made the search for noninvasive diagnostic tools in NAFLD one of the areas with most intense development in hepatology today.Various methods have been investigated in the recent years,including imaging methods like ultrasound and magnetic resonance imaging,different forms of liver stiffness measurement,various biomarkers of necroinflammatory processes (acute phase reactants,cytokines,markers of apoptosis),hyaluronic acid and other biomarkers of liver fibrosis.Multicomponent tests,scoring systems and diagnostic panels were also developed with the purposes of differentiating non-alcoholic steatohepatitis from simple steatosis or discriminating between various fibrosis stages.In all of the cases,performance of noninvasive methods was compared with liver biopsy,which is still considered to be a gold standard in diagnosis,but is by itself far from a perfect comparative measure.We present here the overview of the published data on various noninvasive diagnostic tools,some of which appear to be very promising,and we address as well some of still unresolved issues in this interesting field.

Association of CX3CL1 and CX3CR1 Expression with Liver Fibrosis in a Mouse Model of Schistosomiasis

Immunopathological mechanisms of schistosomiasis,a debilitating parasitic disease,are still unclear.In this study,we investigated the involvement of CX3C chemokine ligand 1(CX3CL1)and its sole receptor CX3CR1 in the development of liver fibrosis in schistosomiasis.The animal model of schistosomiasis was established by infection of C57BL/6 mice with Schistosoma japonicum cercariae;mice injected with carbon tetrachloride(CCl4)were used as positive control of liver injury.After 4 and 8 weeks,the degree of liver lesions was assessed by hematoxylin and eosin staining,serum levels of hyaluronic acid(HA)were analyzed by a chemiluminescence immunoassay,liver fibrosis was evaluated by immunohistochemistry analysis ofα-smooth muscle actin(α-SMA)expression,and CX3CL1 and CX3CR1 expression in the liver was measured by immunohistochemistry and real-time PCR.The results showed that at 8 weeks after Schistosoma infection,serum HA levels were increased andα-SMA-expressing cells appeared in the liver,indicating fibrogenesis.CX3CL1-and CX3CR1-positive cells were observed in the outer layer of granulomas formed around Schistosoma eggs in liver tissues,which was consistent with the significant upregulation of hepatic CX3CL1 and CX3CR1 mRNA expression at 4 and 8 weeks post-infection.Furthermore,correlation analysis revealed positive association between CX3CL1 and CX3CR1 expression and serum HA levels at 8 weeks post-infection,indicating a link between fibrogenesis and the CX3CL1/CX3CR1 axis in schistosomiasis.In conclusion,our data suggest the involvement of CX3CL1 and CX3CR1 in the progression of liver fibrosis caused by Schistosoma infection.

Animal experiment and clinical study of effect of gamma-interferon on hepatic fibrosis

AIM: To evaluate the antifibrotic effect of different doses of recombinant human Gamma-Interferon (IFN-gamma) in two rat models of hepatic fibrosis, and to observe its effect on moderate chronic hepatitis B virus fibrosis. METHODS: Hepatic fibrosis was successfully induced in 150 and 196 rats by subcutaneous injection of carbon tetrachloride (CCl4) and intraperitoneal injection of dimethylnitrosamine (DMN), respectively. Each of the two model groups was divided into: (1) fibrotic model group; (2) colchicine treatment group (0.1 mg/kg/day, gastrogavage for 8 weeks); (3) high-dose IFN-gamma group (15 MU/kg per day, i.m. for 8 weeks); (4) medium-dose IFN-gamma group (5 MU/kg daily, i.m. for 8 weeks); and (5) Y low-dose IFN-gamma group (1.67 MU/kg daily, i.m. for 8 weeks). Another group of 10 rats without any treatment was used as normal controls. At the end of the experiment, semi-quantitative histopathological scores of inflammation and fibrosis, liver alpha smooth muscle actin (alpha-SMA) expression level, liver hydroxyl proline content and serum hyaluronic acid levels were compared. And 47 medium chronic hepatitis B viral fibrosis patients were studied. They were given IFN-gamma treatment, 100 MU/day i.m. for the first three months and 100 MU qod i.m. for the next six months. Semi-quantitative pathological scores of inflammation and fibrosis and serum hepatic fibrosis indices were compared within the 9 months. RESULTS: In animal experiment, the pathological fibrosis scores and liver hydroxyl proline content were found to be significantly lower in rats treated with different doses of IFN-gamma as compared with rats in fibrotic model group induced by either CCl4 or DMN, in a dose-dependent manner. For CCl4-induced model, pathological fibrosis scores in high, medium and low doses IFN-gamma groups were 5.10 +/- 2.88, 7.70 +/- 3.53 and 8.00 +/- 3.30, respectively, but the score was 14.60 +/- 7.82 in fibrotic model group. Hydroxyl proline contents were 2.83 +/- 1.18, 3.59 +/- 1.22 and 4.80 +/- 1.62, in the three IFN-gamma groups, and 10.01 +/- 3.23 in fibrotic model group. The difference was statistically significant (P【0.01). Similar results were found in DMN-induced model. Pathological fibrosis scores were 6.30 +/- 0.48, 8.10 +/- 2.72 and 8.30 +/- 2.58, in high, medium and low doses IFN-gamma groups, and 12.60 +/- 3.57 in fibrotic model group. Hydroxyl proline contents were 2.72 +/- 0.58, 3.14 +/- 0.71 and 3.62 +/- 1.02, in the three IFN-gamma groups, and 12.79 +/- 1.54 in fibrotic model group. The difference was statistically significant (P【0.01).Serum hepatic fibrosis indices decreased significantly in the 47 patients after IFN-gamma treatment (HA: 433.38 +/- 373.00 vs 281.57 +/- 220.48; LN: 161.22 +/- 41.02 vs 146 +/- 35 +/- 44. 67; PC III: 192.59 +/- 89.95 vs 156.98 +/- 49.22; C-I: 156.30 +/- 44.01 vs 139.14 +/- 34.47) and the differences between the four indices were significant (P 【0.05). Thirty-three patients received two liver biopsies, one before and one after IFN-gamma treatment. In thirty of 33 patients IFN-gamma had better effects according to semi-quantitative pathological scores (8.40 +/- 5.83 vs 5.30 +/- 4.05, P【0.05). CONCLUSION: All the three doses of IFN-gamma are effective in treating rat liver fibrosis induced by either CCl4 or DMN, the higher the dose, the better the effect. And IFN-gamma is effective for patients with moderate chronic hepatitis B viral fibrosis.

Effects of Dan-Shao-Hua-Xian on the expression of collagen type I and III in rats with hepatic fibrosis

BACKGROUND: Hepatic fibrosis is the common patholo gical change in various chronic liver diseases,and its major cause is the imbalance between the production and degra dation of the extracellular matrix, which is mainly com posed of collagens. Dan-Shao-Hua-Xian ( DSHX) cap sule, a traditional Chinese herbal compound, has shown marked preventive effects on hepatic fibrosis in rats in our previous studies. The present study was designed to further investigate its therapeutic actions on hepatic fibrosis in rats and its possible mechanisms. METHODS: Eighty male Wistar rats were randomly divid- ed into normal control group, hepatic fibrosis group, non DSHX-treated group, low-dose-treated group, and high dose-treated group. The rat models of hepatic fibrosis were established by subcutaneous injecton of CC14 , drinking al- cohol , giving diet of hyperliprosis and hypoprotein for 8 weeks. The two DSHX-treated groups were treated respec- tively with low dose (0.5 g/kg) and high dose (1.0 g/kg) of DSHX capsule p. o. everyday for 8 weeks. At the end of the experiment, liver indexes were calculated in each group in addition to the levels of the serum hyaluronic acid and alanine aminotransferase. Their degree of hepatic fibrosis and urinary excretion of hydroxyproline and expression of collagen , were detected. RESULTS: Comparison of the indexes of the hepatic fibro- sis group and non-DSHX-treated group revealed that the liver indexes, levels of serum hyaluronic acid and alanine aminotransferase, and stage of hepatic fibrosis were all sig- nificantly reduced in the two DSHX treated groups. The urinary excretion of hydroxyproline was increased and the expression of collagen I and HI in liver tissue was lessened. These alterations were more obviously observed in the high-dose-treated group. CONCLUSION: DSHX capsule has certain therapeutic effect on hepatic fibrosis in rats.

Determining the role for uric acid in non-alcoholic steatohepatitis development and the utility of urate metabolites in diagnosis:An opinion review

There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD.There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD.Given the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and necessary.In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.

入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平与CHB肝纤维化严重程度的相关性及对疾病预后的预测价值

目的探讨入院时血清转化生长因子-β1(TGF-β1)、Smad同源蛋白2(Smad2)、Smad同源蛋白3(Smad3)及透明质酸(HA)、Ⅲ型前胶原(PCⅢ)、层黏连蛋白(LN)、Ⅳ型胶原(CⅣ)水平与慢性乙型肝炎(CHB)肝纤维化严重程度的相关性及联合检测对疾病预后的预测价值。方法选取河南省中医院2021年3月至2022年3月收治的78例CHB肝纤维化患者作为研究组,选择同期78名健康体检者作为对照组。比较研究组和对照组及不同肝纤维化分期、不同炎症活动分级CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平;分析入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平与肝纤维化分期、炎症活动分级的相关性。CHB肝纤维化患者治疗3个月后,根据患者预后分为预后良好和预后不良亚组,比较预后良好和预后不良患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平;分析入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平联合检测对CHB肝纤维化患者预后不良的预测价值。结果研究组入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ高于对照组(P<0.05);不同肝纤维化分期、炎症活动分级CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ比较:S1<S2<S3<S4、G1<G2<G3<G4,差异有统计学意义(P<0.05);入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平与肝纤维化分期、炎症活动分级均呈正相关(P<0.05)。预后良好患者入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平均低于预后不良患者(P<0.05);入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平联合预测肝纤维化患者预后不良的曲线下面积(AUC)优于各指标单一检测(P<0.05)。结论CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平均呈现高表达,且与肝纤维化分期、炎症活动分级密切相关,其联合检测对CHB肝纤维化患者预后有较高的预测价值,可用于评估CHB肝纤维化患者病情严重程度和预后,为制定针对性治疗措施提供参考。

超声实时剪切波弹性成像、血清透明质酸对非酒精性脂肪性肝病的诊断价值

目的探究超声实时剪切波弹性成像、血清纤维化标志物透明质酸对非酒精性脂肪性肝病的诊断价值。方法选取2020年4月-2023年4月在皖南医学院附属宣城医院(宣城市人民医院)就诊的非酒精性脂肪性肝病患者112例作为肝病组,另取同期该院肝功能正常的健康体检者112例作为对照组。收集所有受试者的病历/体检资料,行超声实时剪切波弹性成像检查及血清透明质酸检测。非酒精性脂肪性肝病均以肝组织活检作为诊断金标准。比较两组杨氏模量值及血清透明质酸水平;评估超声实时剪切波弹性成像、血清透明质酸对非酒精性脂肪性肝病的诊断效能。结果肝病组透明质酸、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平均高于对照组(P<0.05),杨氏模量值高于对照组(P<0.05)。多因素逐步Logistic回归分析结果显示:杨氏模量值[OR=4.627(95%CI:1.627,13.159)]是非酒精性脂肪性肝病的保护因素;透明质酸[OR=4.116(95%CI:1.924,8.807)]、ALT[OR=3.691(95%CI:1.725,7.898)]和AST[OR=3.846(95%CI:1.798,8.229)]是非酒精性脂肪性肝病的危险因素(P<0.05)。受试者工作特征曲线分析结果显示,杨氏模量值、透明质酸及其联合诊断非酒精性脂肪性肝病的敏感性分别为68.9%(95%CI:0.591,0.752)、76.2%(95%CI:0.695,0.843)、84.3%(95%CI:0.726,0.935),特异性分别为83.1%(95%CI:0.723,0.921)、68.4%(95%CI:0.571,0.794)、83.5%(95%CI:0.719,0.926)。结论超声实时剪切波弹性成像联合血清透明质酸可辅助诊断非酒精性脂肪性肝病,诊断效能良好。

树豆酮酸A可减轻db/db小鼠非酒精性脂肪肝损伤

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是指肝中储存过多的脂肪,与肥胖、胰岛素抵抗、2型糖尿病(type-2 diabetes mellitus,T2DM)、血脂异常等代谢综合征密切相关。肝纤维化是NAFLD进一步发展为肝细胞癌(hepatocellular carcinoma,HCC)的关键过程,减少肝内的脂肪积累,从而延缓或阻止NAFLD向纤维化的进展是治疗的关键。树豆酮酸A(cajanonic acid A,CAA)在2型糖尿病中能够有效改善胰岛素抵抗,发挥降糖减脂作用。本研究旨在探究CAA对NAFLD肝损伤的保护作用。通过采用db/db自发性NAFLD小鼠模型,将db/db小鼠分为NAFLD组和CAA给药组,CAA组予50 mg/(kg·d)灌胃给药,同期C57BL小鼠作为正常对照组(NC组),每组6只。小鼠生化指标检测和组织病理染色发现,CAA干预可有效缓解db/db小鼠的糖脂代谢紊乱、肝功能损伤(P<0.05)及肝脂肪变性和减少脂质沉积(P<0.05)。ELISA法结果显示,经过CAA治疗后肝组织上清液中白细胞介素1β(Interlecukin-1β,IL-1β)的水平显著降低(P<0.05),提示CAA具有明显抗炎作用,并且CAA干预显著减轻小鼠肝的纤维化程度,天狼星红染色发现,CAA组胶原沉积显著减少(P<0.05),进一步Western印迹结果表明,CAA组纤维化相关基因纤连蛋白(fibronectin,FN)、α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)蛋白质水平表达降低,E-钙黏着蛋白(E-cadherin,E-ca)的表达升高(P<0.05)。E2F转录因子1(E2F transcription factor 1,E2F1)被证实在肝中是葡萄糖和脂质代谢的主要因子,在肥胖小鼠中表达增加,并且可通过PPARγ的转录调节参与脂肪组织代谢,我们猜测,E2F1是CAA改善NAFLD肝脂质沉积和纤维化的中间作用靶标。通过免疫组织化学染色观察E2F1和其同家族拮抗转录因子E2F转录因子7(E2F transcription factor 7,E2F7)在小鼠经CAA处理后在肝组织核质中均表达,通过Western印迹法和实时荧光定量PCR进一步检测蛋白质和mRNA的表达发现,在CAA组中E2F1较NAFLD组基因表达降低(P<0.05),E2F7基因表达增加(P<0.05),并且spearman秩相关分析提示,E2F1和E2F7呈显著负相关(P<0.05)。以上结果表明,树豆酮酸A可有效减轻db/db小鼠非酒精性脂肪性肝损伤,改善糖脂代谢紊乱,抑制脂质过度沉积,减轻肝纤维化以缓解NAFLD进一步发展,同时E2F1和E2F7可能参与了CAA改善脂质代谢和纤维化的过程。

乙型肝炎肝硬化患者血清LN、HA、CⅣ、PⅢ、CHI3L1水平对肝纤维化程度的评估价值

目的探究乙型肝炎肝硬化患者血清层粘连蛋白(LN)、透明质酸(HA)、Ⅳ型胶原(CⅣ)、Ⅲ型前胶原N端肽(PⅢ)、壳多糖酶3样蛋白1(CHI3L1)水平对肝纤维化程度的评估价值。方法以回顾性研究方式选取2023年9月至2024年3月乙型肝炎肝硬化患者111例,根据肝纤维化程度将其分为无显著纤维化组(50例)、显著纤维化组(61例),另选取同期健康体检者31名为对照组,比较三组血清LN、HA、CⅣ、PⅢ、CHI3L1水平,分析血清LN、HA、CⅣ、PⅢ、CHI3L1水平与肝纤维化程度的相关性及评估价值。结果显著纤维化组血清HA、CⅣ、PⅢ、CHI3L1水平较无显著纤维化组、对照组更高(均P<0.05);通过Spearman相关检验显示,血清HA、CⅣ、PⅢ、CHI3L1水平与乙型肝炎肝硬化患者肝纤维化程度呈正相关(r=0.464、0.591、0.285、0.372,均P<0.05);血清LN、PⅢ、CHI3L1、HA、CⅣ水平及联合检测预测患者显著纤维化的曲线下面积(AUC)分别为0.524、0.665、0.716、0.746、0.843、0.875。结论乙型肝炎肝硬化患者血清HA、CⅣ、PⅢ、CHI3L1水平明显升高,其血清水平与乙型肝炎肝硬化患者肝纤维化程度密切相关,各指标联合检测对评估肝纤维化程度具有一定临床应用价值。

Clinical Study on Relationship between Liver-Blood Stasis and Liver Fibrosis

Objective: Exploring the relationship between Liver-Blood Stasis (LBS) and liver fibrosis(LF) to lay a theoretical foundation of rational using traditional Chinese medicine against LF. Methods: Humanprocollagen peptide ill (hp ill P), hyaluronic acid (HA), laminin in the sera of 35 patients with hepatopathy andblood stasis syndrome (HP-BS) and 35 patients with hepatopathy and non-blood stasis syndrome (HP-NBS)were measured by radioimmunoassay. Thirty healthy subjects were taken as control. Correlation analysis between the degrees of LBS and those of the serum indexes of LF was made. Results: (1 ) hPlll P, HA, laminin inthe sera of the patients with HP-BS were markedly higher than those in the sera of the patients with HP-NBS,but the latter were markedly higher than healthy subjects. (2) Degrees of LBS correlated closely with those ofLF. (3) Xuefu Zhuyu (血府逐瘀) Decoction not only might improve the degrees of LBS but also decline theserum LF indexes. Nevertheless, the curative effects in early period of taking the herbs only showed serum HAdropped. Conclusions: The nature of LF in traditional Chinese medicine is mainly LBS, the degrees of whichmight reflect those of LF to a certain extent. Xuefu Zhuyu Decoction showed effective in reducing serum LF indexes but it needs at least 2 months.

Relationship between obstructive sleep apnea-hypopnea syndrome(OSAHS)and liver fibrosis

Objective:The current study discusses the relationship between sleep apnea-hypopnea syn-drome(OSAHS)and liver fibrosis by determining the level of plasma hyaluronic acid(HA),pro-collagen III(PIII),collagen IV(IVC),and laminin(LN)in OSAHS patients and non-OSAHS patients with obesity and normal body weight.Methods:The patients who underwent polysomnographic(PSG)examinations in the outpatient and inpatient departments of our hospital between December 2010 and June 2013 were selected.The patients were divided into two groups based on the apnea-hypopnea index(AHI;OSAHS and non-OSAHS patients),and both groups were further divided based on obesity and normal body weight based on the body mass index(BMI).Sleep breathing indicators,including BMI,AHI,LSaO_(2),and MSaO_(2),were measured in all patients.All of the patients had their blood drawn on the morning after the day of the PSG examination,and the samples were sent to the biochemical laboratory of our hospital for determination of the levels of HA,PIII,IVC,and LN.Results:Among the obese and normoweight patients,the levels of HA,PIII,IVC,and LN in OSAHS patients were higher than the non-OSAHS patients(P value<0.05).Amongst the OSAHS and non-OSAHS patients,the levels of HA,PIII,IVC,and LN in the obese patients were also higher than the non-obese patients(P value<0.05).The levels of HA,PIII,IVC,and LN in the obese OSAHS patients were higher than the remaining three groups(P value<0.05).The levels of HA,PIII,IVC,and LN had positive correlations with the AHI and BMI(r=0.701,0.523,0.639,and 0.421,respectively,P<0.05;and r=0.565,0.441,0.475,and 0.401,respectively,P<0.05),and nega-tive correlations with the LSaO_(2) and MSaO_(2) in OSAHS patients(r=-0.432,-0.394,-0.403,and-0.267,respectively,P<0.05;and r=-0.591,-0.517,-0.533,and-0.484,respectively,P<0.05).Conclusion:The levels of plasma HA,PIII,IVC,and LN in OSAHS patients were related to OSAHS.OSAHS might lead to liver fibrosis.

大黄素对大鼠肝纤维化形成的影响

研究大黄素对肝纤维化的影响。方法：采用 ４０％的四氯化碳（ ＣＣｌ４）给予大鼠皮下注射诱导肝纤维化，并以小、中和大剂量大黄素（２０、４０和 ８０ｍｇ／ｋｇ体重）干预，测定血清透明质酸、层粘连蛋白及肝组织羟脯氨酸，并通过光镜和电镜观察肝组织病理变化。结果：大黄素组较模型组：（１）血清透明质酸及层粘连蛋白显著降低；（２）肝组织胶原蛋白含量明显减少；（３）肝组织纤维化程度明显改善；（４）肝细胞损伤减轻。结论：大黄素对大鼠肝纤维化具有治疗作用。