Association between sarcopenia and hepatic encephalopathy: A systematic review and meta-analysis

Studies have suggested that the presence of sarcopenia in patients with cirrhosis could be a predisposing risk factor for hepatic encephalopathy. This systematic review and meta-analysis were conducted to summarize all available evidence on this relationship. A systematic review was carried out in Medline and EMBASE database through December 2018 to identify studies that recruited patients with cirrhosis from any causes and collected data on the presence of minimal or overt hepatic encephalopathy as well as sarcopenia. All study designs (case–control, cohort and cross-sectional studies) were eligible for the meta-analysis. Odds ratio (OR) and 95% confidence interval (CI) were extracted from the included studies and were pooled together using random-effect, generic inverse variance method of DerSimonian and Laird. Five cross-sectional studies with a total of 1,713 patients met our eligibility criteria and were included into the meta-analysis. We found a significantly higher risk of both mild and overt hepatic encephalopathy among cirrhotic patients with sarcopenia when compared with cirrhotic patients without sarcopenia with the pooled OR of 3.34 (95% CI: 1.68–6.67; I² = 37%) and 2.05 (95% CI: 1.28–3.29; I² = 61%), respectively. This systematic review and meta-analysis demonstrated a significant association between sarcopenia and hepatic encephalopathy among patients with cirrhosis.     

Novel Agents in the Management of Hepatic Encephalopathy: A Review

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.     

肝硬化患者的神经心理测验及轻微肝性脑病调查

轻微肝性脑病(minimal hepatic encephalopathy,MHE)是指在没有临床证据证实肝性脑病的肝硬化患者中可观测到的认知功能、电生理学参数、大脑神经化学/神经传递稳态、大脑血流、新陈代谢和体液稳态的轻微改变[1].近来的调查显示,半数以上肝病医生未进行MHE的检查[2].     

慢性肝病患者肝脏卵圆细胞的定位和定量研究--29例慢性肝病患者肝组织病理学分析

目的 观察慢性肝病患者肝脏卵圆细胞的形态学特征,并探讨卵圆细胞数量和肝纤维化分级的相关性。方法 以免疫组织化学染色法在３例正常人和２９例慢性肝病患者的肝脏切片中寻找卵圆细胞,对符合卵圆细胞的形态学特征并呈胞浆阳性染色的细胞进行计数。结果 正常肝脏组织中未见到卵圆细胞。在慢性肝病患者肝脏组织中,卵圆细胞主要存在于汇管区和纤维隔内,以细胞核呈卵圆形、细胞体积小和胞浆量少为特征。０～４期肝纤维化组的卵圆     

Non-invasive tests for predicting liver outcomes in chronic hepatitis C patients: A systematic review and meta-analysis

BACKGROUNDLiver fibrosis leads to liver-related events in patients with chronic hepatitis C (CHC) infection. Although non-invasive tests (NITs) are critical to early detection of the development of liver fibrosis, the prognostic role of NITs remains unclear due to the limited types of NITs and liver outcomes explored in previous studies.AIMTo determine the prognostic value of NITs for risk stratification in CHC patients.METHODSThe protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42019128176). The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search was performed using MEDLINE and EMBASE databases under a timeframe from the inception of the databases through February 25, 2020. We restricted our search to CHC cohort studies reporting an association between liver fibrosis assessed by NITs and the development of hepatocellular carcinoma, decompensation, or mortality. Pooled hazard ratios (HR) and area under the receiver operating characteristic (AUROC) for each NIT were estimated using a random effects model. Subgroup analyses were performed for NITs assessed at pre-treatment or post-treatment with sustained virologic response (SVR), treatment with either pegylated interferon and ribavirin or direct acting antiviral, Eastern or Western countries, and different cutoff points.RESULTSThe present meta-analysis included 29 cohort studies, enrolling 69339 CHC patients. Fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio (APRI) score, and liver stiffness measurement (LSM) were found to have hepatocellular carcinoma predictive potential with pooled adjusted HRs of 2.48 [95% confidence interval (CI): 1.91-3.23, I² = 96%], 4.24 (95%CI: 2.15-8.38, I² = 20%) and 7.90 (95%CI: 3.98-15.68, I² = 52%) and AUROCs of 0.81 (95%CI: 0.73-0.89, I² = 77%), 0.81 (95%CI: 0.75-0.87, I² = 68%), and 0.79 (95%CI: 0.63-0.96, I² = 90%), respectively. Pooled adjusted HR with a pre-treatment FIB-4 cutoff of 3.25 was 3.22 (95%CI: 2.32-4.47, I² = 80%). Pooled adjusted HRs for post-treatment with SVR FIB-4, APRI, and LSM were 3.01 (95%CI: 0.32-28.61, I² = 89%), 9.88 (95%CI: 2.21-44.17, I² = 24%), and 6.33 (95%CI: 2.57-15.59, I² = 17%), respectively. Pooled adjusted HRs for LSM in patients with SVR following direct acting antiviral therapy was 5.55 (95%CI: 1.47-21.02, I² = 36%). Pooled AUROCs for post-treatment with SVR FIB-4 and LSM were 0.75 (95%CI: 0.55-0.95, I² = 88%) and 0.84 (95%CI: 0.66-1.03, I² = 88%), respectively. Additionally, FIB-4 and LSM were associated with overall mortality, with pooled adjusted HRs of 2.07 (95%CI: 1.49-2.88, I² = 27%) and 4.04 (95%CI: 2.40-6.80, I² = 63%), respectively. CONCLUSIONFIB-4, APRI, and LSM showed potential for risk stratification in CHC patients. Cutoff levels need further validation.     

血清肝细胞生长因子在慢性肝病中的意义

目的 肝细胞生长因子(HGF)能促进上皮细胞增生、运动、变形，是肝再生的起始因子之一，近来发现其在肝硬化和肝肿瘤的发生发展中也有重要作用。现主要探讨血清HGF水平在慢性肝病中的意义。方法 检测197例个体血清HGF水平，包括肝细胞癌(HCC)80例，肝硬化(LC)57例，慢性肝炎(CH)22例，正常对照38例。ELISA法检测血清HGF水平，并描绘受试者工作曲线(ROC)，确定HCC和LC患者HGF水平的最佳临界点。运用Spearman相关分析HGF水平和ALT、AST、GGT、白蛋白、总胆红索、凝血时间、肝癌大小、病理分级的相关性。结果 HCC、LC、CH和正常对照组的血清HGF中位值分别是6．767、151．200、7．017和3．476pg／m1。其中HCC组(P＜0．05)和比组(P＜0．01)的血清HGF水平显著高于正常对照组。LC组根据Child分级分层发现，Child C级患者的HGF水平明显高于Child A、B级。肝硬化ROC曲线显示，14pg／m1为临界值时效率最高。血清HGF水平仅发现与凝血时间有相关性(r=0．45，P＜0．01)。在HCC组中，未发现血清HGF水平与肿瘤大小、病理分级有任何相关。结论 血清中HGF水平增高与LC程度有关。     

microRNA-335在慢性肝病中的作用

近年来,microRNA(miRNA)在肝脏病理过程中的调控作用备受关注。在病毒性及脂肪性肝炎中,miRNA-335通过Y盒上的性别决定区(SOX)4转录因子调控肝炎进展;在进展性肝纤维化及肝癌发生发展过程中,miRNA-335通过缺氧诱导因子1α、磷酸酶和紧张素同系物、靶向Rho蛋白激酶1、纤溶酶原激活物抑制剂1、碱性螺旋-环-螺旋转录因子家族1及间质-上皮细胞转化因子等靶基因调控肝脏中胶原的产生、沉积和降解,从而调控肝星状细胞或肝癌细胞的迁移和侵袭等生物学行为。主要归纳了近几年报道的miRNA-335在肝炎、肝纤维化和肝癌中作用的研究进展,同时,结合现有研究,提出miRNA-335/巯基氧化酶1调控轴可能通过抑制肝星状细胞活化介导青蒿琥酯抗血吸虫性肝纤维化的猜想,以期为抗肝纤维化及其他肝病治疗提供新思路。     

Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis

BACKGROUND Several studies have been conducted to explore the association between the use of proton pump inhibitors (PPIs) and hepatic encephalopathy (HE) risk in patients with liver cirrhosis. However, their results are controversial. AIM To perform a systematic review and meta-analysis to evaluate the HE risk among PPI users. METHODS A systematic search on PubMed, Web of Science, EMBase, and ScienceDirect databases was conducted up to December 31, 2018 for eligible studies involving PPI use and HE risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed or random effects model. Publication bias was evaluated using Begg’s test, Egger’s test, and trim-and-fill method. RESULTS Seven studies with 4574 patients were included in the present meta-analysis. The meta-analysis results indicated a significant association between the PPI use and HE risk (OR = 1.50;95%CI: 1.25-1.75) with low heterogeneity (I2 = 14.2%, P = 0.321). Although publication bias existed when Egger’s tests were used (P = 0.005), the trim-and-fill method verified the stability of the pooled result. Sensitivity analyses suggested that the results of this meta-analysis were robust. CONCLUSION The current evidence indicates that PPI use increases HE risk in patients with liver cirrhosis. Further studies with a large data set and well-designed models are needed to validate our findings.     

Selection of a TIPS stent for management of portal hypertension in liver cirrhosis: An evidence-based review

Nowadays,transjugular intrahepatic portosystemic shunt(TIPS)has become a mainstay treatment option for the management of portal hypertension-related complications in liver cirrhosis.Accumulated evidence has shown that its indications are being gradually expanded.Notwithstanding,less attention has been paid for the selection of an appropriate stent during a TIPS procedure.Herein,we attempt to review the current evidence regarding the diameter,type,brand,and position of TIPS stents.Several following recommendations may be considered in the clinical practice:(1)a 10-mm stent may be more effective than an 8-mm stent for the management of portal hypertension,and may be superior to a 12-mm stent for the improvement of survival and shunt patency;(2)covered stents are superior to bare stents for reducing the development of shunt dysfunction;(3)if available,Viatorr stent-grafts may be recommended due to a higher rate of shunt patency;and(4)the placement of a TIPS stent in the left portal vein branch may be more reasonable for decreasingthe development of hepatic encephalopathy.However,given relatively low quality of evidence,prospective well-designed studies should be warranted to further confirm these recommendations.     

Role of fibroscan and APRI in detection of liver fibrosis: A systematic review and meta-analysis

Background and study aimsFibroscan and APRI are promising noninvasive alternatives to liver biopsy for detecting hepatic fibrosis. However, their overall test performance in various settings remains questionable. The aim of our study was to perform a systematic review and meta-analysis of diagnostic accuracy studies comparing fibroscan and APRI with liver biopsy for hepatic fibrosis.Patients and methodsElectronic and manual bibliographic searches to identify potential studies were performed. Selection of studies was based on reported accuracy of fibroscan and APRI compared with liver biopsy. Data extraction was performed independently by two reviewers. Meta-analysis combined the sensitivities, specificities, and likelihood ratios of individual studies. Extent and reasons for heterogeneity were assessed.Results23 studies for fibroscan and 20 studies for APRI in full publication were identified. For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of fibroscan were 83.4% (95% confidence interval [CI], 71.7–95.0%) and specificity 92.4% (95% CI, 85.6–99.2%). For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of APRI at cutoff point of 1.5 were 66.5% (95% CI, 25.0–100%) and specificity 71.7% (95% CI, 35.0–100%). Diagnostic threshold bias was identified as an important cause of heterogeneity for pooled results in both patient groups.ConclusionsFibroscan and APRI appear to be clinically useful tests for detecting cirrhosis however not useful tools in early stages of fibrosis.     

Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

AIM: To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients.METHODS: We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk.RESULTS: We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001).CONCLUSION: Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.     

Chinese guidelines on management of hepatic encephalopathy in cirrhosis

The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy(HE) including minimal hepatic encephalopathy(MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.     

Non-invasive diagnosis of liver fibrosis in chronic hepatitis C

Assessment of liver fibrosis in chronic hepatitis C virus(HCV)infection is considered a relevant part of patient care and key for decision making.Although liver biopsy has been considered the gold standard for staging liver fibrosis,it is an invasive technique and subject to sampling errors and significant intra-and inter-observer variability.Over the last decade,several noninvasive markers were proposed for liver fibrosis diagnosis in chronic HCV infection,with variable performance.Besides the clear advantage of being noninvasive,a more objective interpretation of test results may overcome the mentioned intra-and inter-observer variability of liver biopsy.In addition,these tests can theoretically offer a more accurate view of fibrogenic events occurring in the entire liver with the advantage of providing frequent fibrosis evaluation without additional risk.However,in general,these tests show low accuracy in discriminating between intermediate stages of fibrosis and may be influenced by several hepatic and extrahepatic conditions.These methods are either serum markers(usually combined in a mathematical model)or imaging modalities that can be used separately or combined in algorithms to improve accuracy.In this review we will discuss the different noninvasive methods that are currently available for the evaluation of liver fibrosis in chronic hepatitis C,their advantages,limitations and application in clinical practice.     

Role of two-dimensional shear wave elastography in chronic liver diseases: A narrative review

Liver biopsy is the gold standard for evaluating the degree of liver fibrosis in patients with chronic liver disease. However, due to the many limitations of liver biopsy, there has been much interest in the use of noninvasive techniques for this purpose. Among these techniques real-time two-dimensional shear wave elastography(2D-SWE) has the advantage of measuring tissue elasticity with the guidance of B-mode images. Recently, many studies have been conducted on the application of 2D-SWE in patients with various liver diseases, and their validity has been confirmed. Here, we briefly discuss the role of 2D-SWE in patients with chronic liver diseases, particularly aspects of the examination techniques and clinical applications.     

Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties

Liver cirrhosis is commonly associated with nutritional alterations,reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids(BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications,such as hepatic e...     

Role of hepatitis B virus infection in chronic liver disease of diabetic patients: A case-control study

Summary In the literature there is no agreement on the prevalence of chronic liver disease (CLD) and the role of hepatitis B virus (HBV) infection in diabetics. We undertook an epidemiological case-control study of the prevalence of CLD and HBV infection in 394 diabetics and 265 healthy subjects from Seriate and Como. The results did not show any significant differences between: 1) the prevalence of CLD in the diabetic population and in controls (4.8%vs 4.5%); 2) the prevalence of HBV infection in diabetics (HBsAg+: 8.3%: HBVAb+: 55.8%) and in controls (HBsAg+: 8.6%; HBVAb+: 54.7%); 3) the prevalence of HBV infection in diabetics with CLD (HBsAg+: 21%; HBVAb+: 52.6%) and in controls with CLD (HBsAg+: 16.6%; HBVAb+: 50%); 4) the prevalence of HBV infection in diabetics with and without CLD (HBsAg+: 21%vs 7.7%; HBVAb+: 52.6%vs 56%); 5) the prevalence of HBV infection in diabetics treated by injection and orally (HBsAg+: 6.9%vs 8.6%; HBVAb+: 58.3%vs 55.2%). The relative risk of CLD for the factor HBsAg+ was 3.2 in the diabetic populationvs 1.4 in controls. In view of the presence of antidelta antibodies (HDVAb) in 25% of HBsAg+ diabetics with CLD and the lack of HBV markers in 26.3% of diabetics with CLD, we assume that other viruses (Delta, nonA-nonB) may play roles. Probably the interaction of all possible etiopathogenetic factors (alcohol, viruses, glycometabolic derangement) is determinant for CLD in diabetics.     

Role of living donor liver transplantation in the treatment of hepatitis C virus infection

Hepatitis C virus (HCV) infection is one of the most common indications for liver transplantation worldwide. Because of the existing organ shortage, adult-to-adult living donor liver transplantation (LDLT) has become an important method of expanding the donor pool to meet the ever-increasing need. However, despite advantages such as the quality of the hepatic graft and the timing of the transplant, the exact role of LDLT in the treatment of HCV is still unclear. In this review, we aim to address some of these issues in an effort to highlight both the advantages and disadvantages, as well as to identify the main challenges, of using LDLT for treating patients with HCV infection.     

拉米夫定治疗乙型肝炎肝硬化临床随机对照试验国内文献的荟萃分析

目的应用荟萃分析评价拉米夫定治疗乙肝肝硬化国内文献的疗效。方法对2000年1月—2006年12月在国内生物医学期刊有关拉米夫定治疗乙肝肝硬化的临床随机对照试验进行质量评价。结果纳入8个RCT(n=578)研究拉米夫定100mg/d治疗乙肝肝硬化的疗效,纳入文献的总体方法学质量较高,4篇Jadad评分为3分以上,但在随机化方法、分配隐藏和盲法的使用方面重视不够。分析结果显示,使用拉米夫定可明显促使ALT复常,对Child-Pugh评分与对照组相比有统计学意义(P<0.05),短期内使用拉米夫定对HBVDNA转阴率与对照组相比有统计学意义(P<0.05),但长期则无统计学意义(P>0.05)。拉米夫定治疗组的HBeAg转阴率与对照组相比无统计学意义(P>0.05)。结论拉米夫定治疗乙肝肝硬化是安全的,它可使ALT复常,降低Child-Pugh评分,但对远期HBVDNA和HBeAg阴转率尚无足够证据说明。     

Comparing outcomes of donation after cardiac death versus donation after brain death in liver transplant recipients with hepatitis C: A systematic review and meta-analysis

BACKGROUND:

Liver transplantation (LT) using organs donated after cardiac death (DCD) is increasing due, in large part, to a shortage of organs. The outcome of using DCD organs in recipients with hepatits C virus (HCV) infection remains unclear due to the limited experience and number of publications addressing this issue.

OBJECTIVE:

To evaluate the clinical outcomes of DCD versus donation after brain death (DBD) in HCV-positive patients undergoing LT.

METHODS:

Studies comparing DCD versus DBD LT in HCV-positive patients were identified based on systematic searches of seven electronic databases and multiple sources of gray literature.

RESULTS:

The search identified 58 citations, including three studies, with 324 patients meeting eligibility criteria. The use of DCD livers was associated with a significantly higher risk of primary nonfunction (RR 5.49 [95% CI 1.53 to 19.64]; P=0.009; I²=0%), while not associated with a significantly different patient survival (RR 0.89 [95% CI 0.37 to 2.11]; P=0.79; I²=51%), graft survival (RR 0.40 [95% CI 0.14 to 1.11]; P=0.08; I²=34%), rate of recurrence of severe HCV infection (RR 2.74 [95% CI 0.36 to 20.92]; P=0.33; I²=84%), retransplantation or liver disease-related death (RR 1.79 [95% CI 0.66 to 4.84]; P=0.25; I²=44%), and biliary complications.

CONCLUSIONS:

While the literature and quality of studies assessing DCD versus DBD grafts are limited, there was significantly more primary nonfunction and a trend toward decreased graft survival, but no significant difference in biliary complications or recipient mortality rates between DCD and DBD LT in patients with HCV infection. There is insufficient literature on the topic to draw any definitive conclusions.     

临界视觉闪烁频率在肝硬化失代偿期患者轻型肝性脑病诊断中的价值

目的 探讨临界视觉闪烁频率（CFF）对肝硬化失代偿期患者轻型肝性脑病诊断上的应用价值。方法 对160例肝硬化失代偿期患者进行CFF检测,并与对照组进行比较。结果 肝硬化失代偿期患者CFF值＜ 39.0 Hz以下者占多数（76.25%）,而对照组CFF值均＞ 40.0 Hz,两组间比较差异有统计学意义（t = 7.35,P ＜ 0.01）。CFF值＜ 39.0 Hz以下的患者平均血氨异常率为78.96%,分别与CFF值＞ 39.0 Hz各组比较,差异有统计学意义（t = 5.65,P ＜ 0.01）。结论 检测CFF值是肝硬化失代偿期患者及早发现轻型肝性脑病的一项客观而敏感的诊断方法。