Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis

Purpose: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. Methods: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (±SD) length of follow-up was 60.3 ± 51.7 months (range 6–258). Results: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. Conclusions: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.     

Non-invasive diagnosis of advanced fibrosis and cirrhosis

Liver cirrhosis is a common and growing public health problem globally.The diagnosis of cirrhosis portends an increased risk of morbidity and mortality.Liver biopsy is considered the gold standard for diagnosis of cirrhosis and staging of fibrosis.However,despite its universal use,liver biopsy is an invasive and inaccurate gold standard with numerous drawbacks.In order to overcome the limitations of liver biopsy,a number of non-invasive techniques have been investigated for the assessment of cirrhosis.This review will focus on currently available non-invasive markers of cirrhosis.The evidence behind the use of these markers will be highlighted,along with an assessment of diagnostic accuracy and performance characteristics of each test.Non-invasive markers of cirrhosis can be radiologic or serum-based.Radiologic techniques based on ultrasound,magnetic resonance imaging and elastography have been used to assess liver fibrosis.Serum-based biomarkers of cirrhosis have also been developed.These are broadly classified into indirect and direct markers.Indirect biomarkers reflect liver function,which may decline with the onset of cirrhosis.Direct biomarkers,reflect extracellular matrix turnover,and include molecules involved in hepatic fibrogenesis.On the whole,radiologic and serum markers of fibrosis correlate well with biopsy scores,especially when excluding cirrhosis or excluding fibrosis.This feature is certainly clinically useful,and avoids liver biopsy in many cases.     

Treatment of patients with HCV related cirrhosis: many rewards with very few risks

Antiviral treatment of chronic hepatitis C virus (HCV) is aimed at the persistent eradication of the virus, the so-called sustained virological response (SVR), with the aim ultimately being to prevent the development of liver-related complications and improve patients' survival. Patients with HCV-related compensated cirrhosis are the group most likely to benefit from viral clearance, as several retrospective studies have shown liver complications rates to be positively modified by the achievement of a SVR. Whether these benefits rely on viral clearance or on the histological improvements seen following successful interferon (IFn)-based therapies has recently been a matter for debate, as studies have shown cirrhosis to regress in some patients with a SVR. Whatever the mechanisms, cirrhosis has the uncanny ability to be both a dominant indication for therapy, as well as one of the strongest baseline factors associated with reduced efficacy of any IFn-based regimen. This has led to the development of alternative treatment strategies, such as low dose pegylated IFn (PegIFn) monotherapy, that unfortunately has proven to be of limited efficacy. For this reason regimens able to clear the virus without relying on the broad antiviral effect of IFN are eagerly awaited.     

Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin

AIM： To assess the long-term clinical benefit of sustained virological response （SVR） in patients with hepatitis C virus （HCV） cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated.METHODS： One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment ≥ 3 mo and followed ≥ 30 mo were included. The occurrence of clinical events [hepatocellular carcinoma （HCC）, decompensation and death] was compared in SVR and non SVR patients.RESULTS： Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients （33%）. During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC （24/76 vs 1/37, P = 0.01）. No SVR patient died while 20/76 non-SVR did （P = 0.002）, mainly in relation to HCC （45%）.CONCLUSION： In patients with HCV-related cirrhosis, $VR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.     

拉米夫定治疗活动性肝硬化疗效观察

目的 观察拉米夫定治疗活动性肝硬化患者的疗效。方法 随机选择活动性肝硬化患者57例，其中29例作为观察组，对照组28例使用常规综合治疗。观察组在此基础上加用拉米夫定100mg／，口服，治疗8个月。观察临床症状和肝功能、Child-Push积分、肝纤维化指标以及HBVDNA、e系统血清转换等。结果 治疗8个月时，临床症状改善、HBVDNA阴转、肝功能改善，以及有无合并症的出现，观察组均明显优于对照组。结论 拉米夫定治疗活动性肝硬化，能抑制病毒复制，改善肝功能，稳定病情，改善预后。     

Novel non-invasive score to predict cirrhosis in the era of hepatitis C elimination: A population study of ex-substance users in Singapore

BackgroundChronic hepatitis C infection is common among people with history of substance use. Liver fibrosis assessment is a barrier to linkage to care, particularly among those with history of substance users. The use of non-invasive scores can be helpful in predicting liver cirrhosis in the era of HCV elimination, especially in countries where transient elastography (TE) is not available. We compared the commonly used non-invasive scores with a novel non-invasive score in predicting liver cirrhosis in this population.MethodsHCV patients with history of substance use between 2011 and 2016 were analyzed. All patients had TE for liver fibrosis assessment. Clinical performance of established non-invasive scores for fibrosis assessment and novel score were compared. Youden's index was used to determine optimal cut-off of the novel score.ResultsA total of 579 patients were included. In multivariate logistic regression, cirrhosis on TE was associated with age (P = 0.002), aspartate aminotransferase (AST) (P = 0.004), and platelet count (P < 0.001), but not alanine aminotransferase (ALT) (P = 0.896). These form the components of modified AST-to-platelet ratio index (APRI) score. Modified APRI was superior to APRI in predicting cirrhosis (AUROC, 0.796 vs. 0.770, P = 0.007), but not fibrosis-4 score (FIB-4) (P = 1.00). Modified APRI at cut-off of 4 has sensitivity, specificity and negative predictive value (NPV) of 94.4%, 26.9% and 92.6%, respectively, and at 19, has sensitivity, specificity and positive predictive value (PPV) of 33.3%, 96.2% and 77.1%, respectively. FIB-4 has a NPV and PPV of 88.6%, 41.8% and 78.5%, 77.6%, at cut-off of 1.45 and 3.25, respectively. Using the cut-off of 4 and 14 for modified APRI, 32.5% of patients can be correctly classified and misses out only 5.6% of cirrhosis patients.ConclusionsModified APRI score is superior in predicting cirrhosis in HCV population, with 32.5% of the population being correctly classified using cut-off of 4 and 14. Further studies are required to validate the findings.     

Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis

Interferon(IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma(HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus(HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer.Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated(PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.     

原发性胆汁性肝硬化失代偿期的临床特征

目的了解原发性胆汁性肝硬化(PBC)失代偿期的临床特征。方法回顾性分析204例PBC患者(包括代偿期113例,失代偿期91例)的人口统计学、实验室检查、临床表现及预后模型积分等,研究失代偿期PBC的临床特征,并且与乙型肝炎肝硬化失代偿期(乙肝组,51例)、丙型肝炎肝硬化失代偿期(丙肝组,20例)、酒精性肝硬化失代偿期(ALD组,51例)患者的临床特征进行比较。统计学处理采用t检验、方差分析及χ2检验。结果 (1)PBC失代偿期患者往往高龄,血细胞计数、血脂水平、白蛋白、胆碱酯酶及凝血酶原活动度明显降低,国际标准化比值、总胆红素及直接胆红素水平显著升高,Child-Pugh分级、终末期肝病模型、Mayo等模型积分均明显升高(P<0.05)。(2)与乙肝、丙肝及ALD组失代偿期肝硬化相比,PBC失代偿期患者女性比例较多,血清碱性磷酸酶显著升高,凝血酶原时间延长较少,更常见瘙痒症状(与ALD、丙肝组相比,P<0.05),上消化道出血发生率较高(与乙肝、丙肝组相比,P<0.05),更常合并干燥综合征、骨质疏松,但肝细胞癌发生率较低。结论 PBC多发于中老年女性,与其他病因所致肝硬化失代偿期患者相比,失代偿期PBC有一些显著不同的临床特征。     

拉米夫定治疗乙型肝炎肝硬化的临床观察

目的观察拉米夫定治疗乙型肝炎肝硬化的临床疗效。方法选择Child-Pugh A、B级乙型肝炎肝硬化70例,36例接受拉米夫定治疗2~3年,另34例不规则口服护肝药物。结果治疗或随访至3年时,接受拉米夫定治疗的患者HBeAg阴转、HBeAg/抗HBe血清转换和HBV DNA阴转率分别为50%、44.4%和77.3%,显著高于对照组;Child-Pugh计分为7.5±1.1,而对照组为9.1±1.3(P<0.05);两组ALT复常率和发生肝衰竭和肝细胞癌情况无显著性相差。2例HBV相关性肾病患者病情恢复、稳定。结论拉米夫定治疗乙型肝炎肝硬化的临床效果肯定,可以延缓病情进展。     

Lipid dysregulation in hepatitis C virus,and impact of statin therapy upon clinical outcomes

The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.     

Chemokine system polymorphisms, survival and hepatocellular carcinoma occurrence in patients with hepatitis C virus-related cirrhosis

AIM： To explore the influence of polymorphisms in genes encoding for the chemokines Stromal cell-Derived Factor-1 （SDF-1）/CXCL12 and Monocyte Chemotactic Protein-1 （MCP-1）/CCL2, or for the chemokine receptor CCR5 on the risks of liver-related death and hepatocellular carcinoma （HCC） occurrence in hepatitis C virus （HCV）-infected patients.
METHODS： SDF-1 3＇A, MCP-1 （-2518） and CCRS-△32 polymorphisms, SDF-1α, Regulated upon Activation Normal T cells Expressed and Secreted （RANTES）/CCL5 and MCP-1 serum levels were determined in 120 HCV- infected patients, included at time of cirrhosis diagnosis and prospectively followed-up.
RESULTS： During follow-up, 23/120 （19.1%） patients died and 47/120 （39.1%） developed HCC. Carriers and noncarriers of each genetic marker had similar baseline characteristics estimating the severity of liver disease. The occurrence of death or HCC during follow-up was similar among carriers and noncarriers of each polymorphism. There was no association between the carriage of mutated alleles and chemokine serum levels and the latter were not associated with the risks of death or HCC.
CONCLUSION： This study suggests the lack of association of SDF-1 3＇A, MCP-1 （-2518）, CCRS-△32 polymorphisms with death and HCC occurrence in cirrhotic HCV-infected patients.     

Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients

Purpose  

Chronic hepatitis C progression is commonly attributed to the continuous activation of the immune response with an increased production of pro-inflammatory cytokines, leading to fibrosis and ultimately to cirrhosis. On the contrary, anti-inflammatory cytokines, mainly interleukin (IL)-10 have a modulatory effect on hepatic fibrogenesis. The association between individual polymorphisms within cytokine genes and hepatitis C outcome is often weak and non-informative. Interestingly, it has been demonstrated that a combination of specific genotypes may be a more significant and powerful approach for predicting disease risk.     

Inflammatory status in human hepatic cirrhosis

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus(HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcoholinduced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis(HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared withHCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gutmesenteric lymph nodes-peritoneal-systemic axis.     

Relationship between the severity of hepatitis C virus-related liver disease and the presence of Helicobacter species in the liver： A prospective study

INTRODUCTION Chronic hepatitis C virus (HCV) infection is a major public health problem with over 170 million people infected worldwide. It is the leading cause of chronic liver disease and the main indication for liver transplantation in the Western worl…     

视黄醇脂对慢性酒精性肝病患者肝脏纤维化的抑制作用

目的:证明维生素A(Vit A)对慢性酒精性肝病 (ALD)患者的肝脏纤维化形成有抑制作用,为肝纤维化的治疗提供一条简便有效的新途径．方法:选择58例ALD患者,采用临床观察的方法,通过外源性的给予Vit A,以酶联免疫吸附法检查ALD患者血清Ⅲ型前胶原肽(PⅢP)及血清透明质酸(HA)的变化．结果:Vit A可以降低ALD患者血清Ⅲ型前胶原肽及血清透明质酸水平．Vit A治疗后 18 mo,血清Ⅲ型前胶原肽(16．9±6．8 μg/L vs 28．2±9．7 μg/L)及透明质酸(132．3±71 μg/L vs 210．0±87 μg／L)水平均较治疗前显著降低 (均P<0．01),且较对照组也有显著降低(PⅢP: 16．9±6．8μg/L vs 23．6±9．6μg/L,P<0．01:HA: 132．3±71 μg/L vs 192．0±97 μg／L,P<0．05)．结论:Vit A可以抑制ALD患者肝脏纤维化的形成,其机制可能是Vit A参与肝星状细胞 (HSC)的代谢,从而抑制胶原的释放．     

Hepatitis C cirrhosis: New perspectives for diagnosis and treatment

Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.     

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study

AIM To evaluate waiting list(WL) registration and liver transplantation(LT) rates in patients with hepatitis C virus(HCV)-related cirrhosis since the introduction of direct-acting antivirals(DAAs).METHODS All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectivelyupdated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/hepatocellular carcinoma(HCC)] and into two interval times(2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS One thousand one hundred and ninty-four [male(M)/female(F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration(490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction(from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst decHCV(from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time(289/666, 43.4%), there was a trend towards a decrease after DAAs introduction(from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients(M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival(log-rank test P = 0.02) and delisting rate(P = 0.002) than untreated HCV patients. CONCLUSION Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.     

Portal vein thrombosis in a patient with hepatitis C virus-related cirrhosis complicated with antiphospholipid syndrome

We report a rare case of portal vein thrombosis (PVT) associated with antiphospholipid syndrome (APS) and hepatitis C virus-related cirrhosis. A 59-year-old woman with hepatitis C virus (HCV) infection was admitted because of coma. The blood test showed a typically cirrhosis pattern including an elevated serum ammonia level. Abdominal computed tomography showed liver cirrhosis and thrombus in the right branch of the portal vein. To elucidate the cause of PVT, antiphospholipid antibodies were examined. Both IgG anti-cardiolipin antibody (ELISA) and IgG anti-cardiolipin-β2 -glycoprotein I complex antibody (ELISA) were positive. When PVT is detected in a patient with cirrhosis, it might be necessary to examine antiphospholipid antibodies to clarify the cause of PVT.