Virus-related Cirrhosis Research Articles

A case of gastric cancer after living donor liver transplantation

As newer immunosuppressive regimens have steadily reduced in the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant de novo malignancies have become an important cause of death in cadaveric donor transplantation. Also, according with the recent accumulation of living donor liver transplantation (LDLT), the number of posttransplant recipients with de novo malignancy will be anticipated to increase. A 60 year-old man underwent LDLT for hepatitis C virus-related cirrhosis with hepatocellular carcinoma. Thirty months after LDLT, he was found to have gastric cancer by upper gastrointestinal endoscopy. He underwent segmental gastrectomy with lymph node dissection. Histopathological examination of the explanted stomach revealed poorly differentiated adenocarcinoma with subserosal invasion in the gastric wall and perigastric lymph node metastasis. Three years and eight months after the gastric surgery, the patient is alive with no recurrence of gastric cancer or HCC under no adjuvant chemotherapy. Considering that early detection is the only key in curing cancer in general, we should make effort to detect cancer in their early stage, especially in case of LDLT recipients.

A Rare Case of Hepatocellular Carcinoma Accompanied by Metastasis of a Cervical Lymph Node

Metastasis to lymph nodes in patients with hepatocellular carcinoma (HCC) is generally observed to occur in regional chains of involvement. We encountered a HCC patient who had hepatitis C virus-related liver cirrhosis and portal vein tumor thrombosis, accompanied by metastasis to only a single cervical lymph node, skipping the common intermediate routes of involvement. It is noteworthy, so as not to miss the clinical diagnosis, to remark that metastasis to the cervical lymph node is rarely observed in patients with HCC, and that the metastasis can skip to the regional lymph nodes.

Entecavir Therapy for Patients with Hepatitis B Virus-related Decompensated Cirrhosis

Entecavie (ETV) has a potent antiviral effect and low rates of resistance in hepatitis B virus (HBV) and is the first-line monotherapy in patients with HBV-related decompensated cirrhosis. We evaluated the efficacy of 12 months treatment with ETV and tried to determine predictive factors of response. Forty-five consecutive decompensated cirrhotic patients who received ETV (0.5 mg/day) for more than six months were included. All patients were positive for HBV DNA, and the Child-Turcotte-Pugh (CTP) scores were over 8 point. Seventeen patients were HBeAg-positive. CTP score, model for end-stage liver disease (MELD) score, serum markers of liver function and HBV DNA were assessed every 3 months. ETV treatment for 12 months resulted in improvement of CTP and MELD scores. Pre-treatment mean CTP and MELD score were decreased from 10.1 (±2.0) and 13.48 (±4.05) to 7.24 (±2.0) and 9.68 (±4.85) at 12 months, respectively. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 88.9% and 52.9%, respectively, by intention-to-treat analysis. Thirty-two (71.1%) showed improvement in CTP score. Eleven patients did not show change, and 2 patients got worse. The AST/ALT, albumin, bilrubin, prothrombin time were significantly normalized within six months. The good responder group had high level of prothrombin time than the poor responder group (p=0.004). Our result shows that entecavir can improve liver function in about 70% of patients with HBV related decompensated liver cirrhosis. INR may be a predictive factor of good response with entecavir in these patients.

Efficacy of Entecavir Treatment in Hepatitis B Virus-related Decompensated Cirrhosis

Efficacy of Entecavir Treatment in Hepatitis B Virus-related Decompensated Cirrhosis

Successful use of danaparoid in the treatment of portal vein thrombosis that developed in a warfarin-administered hepatitis C virus-related cirrhosis patient

Successful use of danaparoid in the treatment of portal vein thrombosis that developed in a warfarin-administered hepatitis C virus-related cirrhosis patient

Decrease in Size of Non-Treated Lesions after Cryoablation for Hepatocellular Carcinoma

We present the case of one 58-year-old man with advancd hepatocellular carcinoma and hepatitis-B virus-related liver cirrhosis who received hepatic cryoablation. Magnetic resonance imaging (MRI) showed multiple liver tumors and the diameter of the largest tumor was more than 10cm. The patient received 2 percutaneous cryoablations in December 2009 and January 2010. Ten months later, MRI showed that not only the treated areas underwent necrosis but also the non-treated area decreased. The a-fetoprotein (AFP) level and the frequency of circulated regulatory T cell (Treg) before treatment were 13,800ng/mL and 15.6%, respectively. Following the cryoablations they dropped to 436ng/mL and 7.6%, respectively, 10 months later. The patient remains in good condition until now.

Impact of delayed diagnosis time in estimating progression rates to hepatitis C virus-related cirrhosis and death

Delay of the diagnosis of hepatitis C virus (HCV), and its treatment to avert cirrhosis, is often present sincethe early stage of HCV progression is latent. Current methods to determine the incubation time to HCV-related cirrhosis and the duration time from cirrhosis to subsequent events (e.g. complications or death) used to be based on the time of liver biopsy diagnosis and ignore this delay which led to an interval censoring for the first event time and a double censoring for the subsequent event time. To investigate the impact of this delay in estimating HCV progression rates and relevant estimating bias, we present a correlated two-stage progression model for delayed diagnosis time and fit the developed model to the previously studied hepatitis C cohort data from Edinburgh. Our analysis shows that taking the delayed diagnosis into account gives a mildly different estimate of progression rate to cirrhosis and significantly lower estimated progression rate to HCV-related death in comparison with conventional modelling. We also find that when the delay increases, the bias in estimating progression increases significantly.

Assessment of the Fecal Lactobacilli Population in Patients with Hepatitis B Virus-Related Decompensated Cirrhosis and Hepatitis B Cirrhosis Treated with Liver Transplant

This study aims to provide an overview of the diversity of intestinal Lactobacillus among Chinese patients with hepatitis B virus (HBV)-related decompensated cirrhosis and who received liver transplant for hepatitis B cirrhosis. Fecal samples were collected from 38 healthy volunteers, 61 patients with HBV-related decompensated cirrhosis (group LC) and 74 patients who had liver transplant for hepatitis B cirrhosis (group LT). Quantitative polymerase chain reaction technology with species-specific primers was applied to investigate lactobacilli 16S rDNA in crude DNA, extracted from fecal samples. Software package Statistical Package for the Social Sciences and Palaeontological Statistics for Windows was used to analyze the data. Lactobacilli population of the two patient groups was different from the healthy control subjects, principal differences being marked decrease in the population of Lactobacillus rhamnosus (p < 0.001 for both patient groups) and reduction in the frequency of Lactobacillus fermentus (p < 0.001 for group LC and p < 0.01 for group LT). Our findings on the frequency of lactobacilli population suggested decreased diversity in groups LC and LT (compared with the healthy controls (p < 0.001 and p < 0.01, respectively)). Patients tended to have less complex fecal lactobacilli composition than the healthy controls, especially in the group LC.

Vitamin D3 modulates T lymphocyte responses in hepatitis C virus-infected liver transplant recipients

Background Aim of the present study was to investigate whether 1,25(OH)(2)D(3) (Vitamin D3) modulates T lymphocyte functions in patients transplanted for hepatitis C virus-related cirrhosis. Methods Sixteen patients and ten healthy subjects were investigated. T lymphocytes were activated in vitro in the presence or absence of Vitamin D3 and then the proliferative response and IFN-γ and TNF-α production were assessed. Results Vitamin D3 potently reduced T-lymphocyte proliferation in a dose-related fashion. Similarly, FACS analysis and ELISA testing demonstrated that Vitamin D3 significantly decreased the response frequency and the response intensity of IFN-γ and TNF-α production in the whole CD3-positive T lymphocyte population as well as in “naive” CD4+ CD45RA+ and “memory” CD4+ CD45RO+ T lymphocyte subsets. The inhibitory effect of Vitamin D3 on T-cell proliferation and cytokine production was not different between patients and controls. No toxic effects were exerted by Vitamin D3 even at the higher concentration used (10 nM). Finally, no statistically significant correlation was found between 25(OH)D serum levels and the proliferative response or cytokine production of T lymphocytes from transplanted patients. Conclusions This study demonstrates that in patients transplanted for hepatitis C virus-related cirrhosis Vitamin D3 modulates T lymphocyte activation, and provides a rationale for the evaluation of this compound as an immunosuppressive agent in liver-transplanted patients.

A cis-acting regulatory variation of the estrogen receptor α (ESR1) gene is associated with hepatitis B virus-related liver cirrhosis

The hepatic fibrogenesis and sexual dimorphism of hepatitis B virus-related liver cirrhosis (HBV-LC) are related to estrogen and its receptors. Abnormal expression of estrogen receptor α (ESR1) is implicated in the development of cirrhosis in both animal models and humans. Here, we examine whether the ESR1 polymorphisms are related to HBV-LC risk among chronic HBV carriers, and we investigate the functional significance of positively associated polymorphisms. A total of 2,404 unrelated Chinese HBV carriers were recruited to conduct the two-stage designed case-control study. Two ESR1 haplotype tagging polymorphisms, c.30T>C (rs2077647) and c.453-397T>C (rs2234693), were genotyped in 1,285 patients with HBV-LC and in 1,119 asymptomatic HBV carriers. We observed a significantly increased susceptibility to HBV-LC associated with the c.30C allele (P = 4.2 × 10(-8) ), c.453-397C allele (P = 2.0 × 10(-8) ), and [c.30C; c.453-397C] haplotype (Dominant model, P = 8.85 × 10(-10) , odds ratio = 1.50, 95% CI 1.32∼1.71) compared with the T alleles and (c.30T; c.453-397T) haplotype of c.30T>C and c.453-397T>C polymorphisms, respectively. Functional analyses were conducted to verify the biological functions of the associated genetic variations and showed that the c.453-397T>C polymorphism is a novel c.453-397C allele-specific and c-myb-dependent enhancer-like cis-acting regulatory variation and could be part of the genetic variations underlying the susceptibility of individuals to HBV-LC.

Safety of Complete and Sustained Prophylaxis Withdrawal in Patients Liver-transplanted for Hepatitis B Virus-related Cirrhosis at Low Risk of Hepatitis B Virus Recurrence

BackgroundHBV (hepatitis B virus) reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. MethodsThirty patients transplanted 64-195 months earlier (23 males, median age 56 years), HBsAg-positive, HBeAg, and HBV-DNA-negative at transplant (43% HCV/HDV coinfected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetect-ability 24 weeks after stopping HBIg also underwent lamivudine withdrawal and were followed up without prophylaxis. ResultsTwenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7 months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIg and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild alanine transaminase elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs se-roconversion; thus no antiviral treatment was needed. ConclusionPatients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and ccc-DNA may safely undergo cautious weaning of prophylaxis, showing the low rate of HBV recurrence after a 2-year follow-up. Undetectability of intrahepatic ccc-DNA may help to identify patients at low risk of recurrence; yet studies with longer follow-up are needed.

First Report of Disseminated Mycobacterium Skin Infections in Two Liver Transplant Recipients and Rapid Diagnosis by hsp65 Gene Sequencing

We present here the first report of disseminated skin Mycobacterium infections in two liver transplant recipients, in which hsp65 gene sequencing was used for rapid species identification. Both patients had hepatitis B virus-related cirrhosis and diabetes mellitus and presented with progressive generalized, nodular skin lesions. In one patient, a 50-year-old woman who had frequent contact with marine fish, an acid-fast bacillus was isolated from skin biopsy tissue after 2 months of culture. While awaiting phenotypic identification results, hsp65 gene sequencing showed that it was most closely related to that of Mycobacterium marinum with 100% nucleotide identity. The patient was treated with oral rifampin, ethambutol, and moxifloxacin. In the other patient, a 59-year-old woman, direct PCR for Mycobacterium using hsp65 gene from skin biopsy tissue was positive, with the sequence most closely related to that of M. haemophilum with 100% nucleotide identity. Based on PCR results, the patient was treated with clarithromycin, ethambutol, moxifloxacin, and amikacin. A strain of M. haemophilum was only isolated after 3 months. Skin lesions of both patients resolved after 1 year of antimycobacterial therapy. Nontuberculous Mycobacterium infections should be considered in liver transplant recipients presenting with chronic, nodular skin lesions. This report highlights the crucial role of hsp65 gene PCR and sequencing on both cultured isolates and direct clinical specimens for rapid diagnosis of slow-growing Mycobacterium infection.

Changes of Fecal Bifidobacterium Species in Adult Patients with Hepatitis B Virus-Induced Chronic Liver Disease

The beneficial effects of Bifidobacteria on health have been widely accepted. Patients with chronic liver disease have varying degrees of intestinal microflora imbalance with a decrease of total Bifidobacterial counts. Since different properties have been attributed to different Bifidobacterium species and there is no information available for the detailed changes in the genus Bifidobacterium in patients with chronic liver disease heretofore, it is meaningful to investigate the structure of this bacterium at the species level in these patients. The aim of this study was to characterize the composition of intestinal Bifidobacterium in patients with hepatitis B virus-induced chronic liver disease. Nested-PCR-based denaturing gradient gel electrophoresis (PCR-DGGE), clone library, and real-time quantitative PCR were performed on the fecal samples of 16 patients with chronic hepatitis B (CHB patients), 16 patients with hepatitis B virus-related cirrhosis (HBV cirrhotics), and 15 healthy subjects (Controls). Though there was no significant difference in the diversity among the three groups (P = 0.196), Bifidobacterium dentium seems to be specifically enhanced in patients as the PCR-DGGE profiles showed, which was further validated by clone library and real-time quantitative PCR. In contrast to the B. dentium, Bifidobacterium catenulatum/Bifidobacterium pseudocatenulatum were detected less frequently in the predominant profile and by quantitative PCR in HBV cirrhotics than in the controls, and the level of this species was also significantly different between these two groups (P = 0.023). Although having no quantitative difference among the three groups, Bifidobacterium longum was less commonly detected in HBV cirrhotics than in CHB patients and Controls by quantitative PCR (P = 0.011). Thus, the composition of intestinal Bifidobacterium was deeply altered in CHB and HBV cirrhotic patients with a shift from beneficial species to opportunistic pathogens. The results provide further insights into the dysbiosis of the intestinal microbiota in patients with hepatitis B virus-induced chronic liver disease and might potentially serve as guidance for the probiotics interventions of these diseases.

Hepatectomy for Hepatocellular Carcinoma in Patients with Severe Thrombocytopenia

Hepatic resection for hepatocellular carcinoma (HCC) is risky for cirrhotic patients with severe thrombocytopenia. Among 23 patients with histologically proven cirrhosis who underwent hepatic resection for HCC at our hospital since 2006, 7 had severe thrombocytopenia (platelet count <5×104/mm3). The clinical background and surgical outcomes of these 7 patients were retrospectively evaluated and compared to those of the 16 cirrhotic patients without severe thrombocytopenia. All 7 patients had hepatitis C virus-related liver cirrhosis. The median preoperative platelet count was 4.3×104/mm3 (range, 3.9-4.9×104/mm3) and the median operative time and intraoperative bleeding were 77min and 193cc, respectively. Postoperative complications were observed in 4 patients (57%) and all were managed conservatively. Four patients received an intraoperative platelet-rich transfusion, but this had no beneficial effect on intraoperative bleeding or postoperative changes in platelet counts. The cirrhotic patients with severe thrombocytopenia were significantly younger and had a significantly shorter operative time compared to those without severe thrombocytopenia. There were no other differences between the groups. Our results suggest that the indication for hepatectomy in cirrhotic patients should not be based on platelet counts alone. However, we note that the younger age and shorter operative time for the patients with severe thrombocytopenia might have contributed to the safety of hepatectomy.

Spontaneous portal vein arterialization in hepatic artery thrombosis

A 56-year-old male with hepatitis B virus-related cirrhosis nderwent liver transplantation. At transplantation the arterial nflow to the liver graft was achieved using an iliac artery conduit nastomosed to the infrarenal aorta and to the hepatic artery (HA) f the graft. By postoperative day 60 all liver function tests were normal; ubsequent Doppler testing demonstrated normal arterial inflow o the liver. Seven months later the patient was readmitted to the Hosital due to fever (39 ◦C) and elevated white blood cell count. oppler investigation failed to detect arterial flow to the graft; comuted tomography (CT) confirmed occlusion of the HA and showed ecrosis of the left lateral segment with normal appearance of the emaining liver. The patient underwent surgery and necrosis of the left lateral epatic segment was found; left lateral segmentectomy was perormed; a liver biopsy was taken from the right lobe. The arterial onduit was not patent and the exploration of its origin from the nfrarenal aorta revealed a spontaneous shunt between the inferior esenteric artery and the inferior mesenteric vein, that was clearly ulsatile (Fig. 1). Histology of the right remnant liver was normal. Despite an occluded HA, the patient is alive and well one year fter resection and his liver function tests, in particular total biliruin, gamma-GT and alkaline phosphatase are normal; ERCP shows normal biliary tree (Fig. 2).

THIS ARTICLE HAS BEEN RETRACTED: Haemodynamic derangement in human immunodeficiency virus-infected patients with hepatitis C virus-related cirrhosis: the role of bacterial translocation

Background and aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)-infected patients with decompensated hepatitis C virus (HCV)-related liver disease. Methods: Forty HIV/HCV co-infected patients and 40 HCV mono-infected patients, 20 of them with compensated cirrhosis and 20 with a previous decompensation, and 20 healthy controls, were studied. Intestinal permeability was determined by serum levels of lipopolysaccharide-binding protein (LBP). Monocyte expression of toll-like receptor 4 (TLR-4), serum levels of interleukin (IL)-6 and soluble receptors of tumour necrosis factor (sTNFRI) were analysed. Cardiac index, systemic vascular resistance (SVR), plasma renin activity (PRA) and aldosterone concentration were also determined in cirrhotic patients. Results: Serum levels of LBP, TLR-4, IL-6 and sTNFRI were significantly higher in HIV–HCV co-infected and HCV mono-infected patients with decompensated cirrhosis compared with those with compensated liver disease. Significantly lower values of SVR and higher values of cardiac index, PRA and aldosterone concentration were observed in patients with decompensated cirrhosis compared with those with compensated liver disease, particularly in those with elevated levels of IL-6. There were no significant differences between HIV/HCV co-infected and HCV mono-infected patients. Conclusions: Higher intestinal permeability and consequent macrophage activation is observed in patients with cirrhosis; this permeability is even higher in those with portal hypertension. Serum values of IL-6 are associated with the characteristic haemodynamic derangement observed in advanced phases of cirrhosis. HIV/HCV co-infected cirrhotic patients present inflammatory and systemic haemodynamic alterations similar to those observed in HCV mono-infected patients.

Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis

Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4(+) T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4(+) T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4(+) regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-γ to interleukin (IL)-10 and a reduction of PD-1-expressing CD4(+) T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.

957 THE CLINICAL SIGNIFICANCE OF PLASMA OSTEOPONTIN LEVEL IN EGYPTIAN PATIENTS WITH HEPATITIS C VIRUS-RELATED HEPATOCELLULAR CARCINOMA

Background and Aims. Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Osteopontin (OPN) is a secreted glycoprotein frequently associated with various tumors. This study aimed to investigate the clinical usefulness of plasma OPN level as a biomarker for HCC among high-risk patients compared to alpha-fetoprotein (AFP) and to evaluate its relationship with clinicopathological features of HCC patients. Methods. Plasma levels of OPN and AFP were measured in 60 Egyptian patients with hepatitis C virus-related liver cirrhosis (30 with HCC, 30 without HCC) and 20 healthy controls. Results. Plasma OPN levels in cirrhotic patients with HCC were significantly higher than in those without HCC and controls (p !0.001). Among HCC patients, plasma levels of OPN increased significantly with advanced Child-Pugh class (BeC, p !0.001), late tumor stage (IIIeIV, p !0.001), larger tumor size ($5 cm, p !0.01), and high tumor grade (p !0.01). The sensitivity and specificity of OPN for HCC were 88.3% and 85.6%, respectively, at a cut-off value of 9.3 ng/mL. OPN had a greater area under curve value (0.918) than AFP (0.712), suggesting superior diagnostic accuracy of OPN. Moreover, no significant correlation was found between OPN and AFP levels in HCC patients. Conclusions. Plasma OPN can be regarded as a promising diagnostic biomarker for HCC in the surveillance of Egyptian patients with HCV infection. It could also serve as an adverse prognostic factor for HCV-related HCC patients. 2010 IMSS. Published by Elsevier Inc.

Interferon therapy following treatment of recurrent hepatocellular carcinoma in an 83-year-old man with hepatitis C virus-related liver cirrhosis.

A sustained virological response and improvement of liver function were achieved by low-dose interferon (IFN) therapy following curative treatment of initial and recurrent hepatocellular carcinoma (HCC) in an 83-year-old man with hepatitis C virus (HCV)-related liver cirrhosis (CLC). Although a fourth HCC episode recurred 16months after IFN therapy, it was successfully treated. The patient is still alive 6years and 7months after diagnosis of the initial HCC and has been in a tumor-free state for 19months following treatment of the last HCC. The results of this case suggest that, given sufficient consideration of adverse effects, IFN therapy for HCV and repeated local treatment for HCC contribute to improving the prognosis even in the case of a CLC patient over 80years of age whose condition is complicated by recurrent HCC.

T-46 Erythropoietin administration seems to improve the decrease in platelet count observed during pegylated interferon and ribavirin treatment of patients with hepatitis C virus-related cirrhosis

T-46 Erythropoietin administration seems to improve the decrease in platelet count observed during pegylated interferon and ribavirin treatment of patients with hepatitis C virus-related cirrhosis