Daclatasvir and Sofosbuvir With or Without Ribavirin in Liver Transplant Recipients: A Single-Center Real-World Study.

BACKGROUND: Treatment with direct-acting antiviral drugs in interferon-free regimens is currently recommended for viral hepatitis C recurrence after liver transplantation. There are limited data regarding its results in this population, and no optimal treatment scheme has yet been singled out. METHODS: We report our real-world results in liver transplant (LT) recipients. All patients were hepatitis C virus (HCV) monoinfected and completed a 12-week treatment course, followed 12 weeks later by HCV polymerase chain reaction testing with 12 IU/mL sensibility. Liver fibrosis was graded with the use of biopsies taken <12 months before treatment and stratified as early (0-1) or moderate to advanced (2-4) according to the Metavir score. RESULTS: Median postoperative time was 5.2 years. Genotype 3 was found in 66.7% of the sample. The following regimens were prescribed: daclatasvir-sofosbuvir with (n = 11) or without (n = 28) ribavirin. Genotypes 1 and 3 were evenly distributed between the regimens. Sustained virologic response (SVR) was obtained in 24 out of 28 patients (85.7%) who received daclatasvir-sofosbuvir and in all patients (100%) who received daclatasvir-sofosbuvir-ribavirin (global SVR 89.7%). All patients that failed treatment had genotype 3 HCV. Fibrosis was evaluated in 79.5% of the sample: 48.4% had early and 51.6% had moderate to advanced fibrosis, for which ribavirin was more commonly prescribed (P = .001). CONCLUSIONS: The SVR rate in our LT recipients was similar to that previously reported in the literature. The addition of ribavirin to DAA treatment appears to be justified in this population.

Evaluation of the protective effects of quercetin in the hepatopulmonary syndrome.

The hepatopulmonary syndrome (HPS) occurs when intrapulmonary dilatation causes hypoxemia in cirrhosis. The free radicals may play a significant contributory role in the progression of HPS, and flavonoid agents could protect against deleterious effects of free radicals. The flavonoid quercetin was evaluated in an experimental model of biliary cirrhosis induced by bile duct ligation (BDL) in rats. Quercetin was administered at 50mg/kg for 14 days to cirrhotic and non-cirrhotic rats. Bone marrow was extracted from animals to analyze micronuclei. Lung, liver and blood were extracted to detect DNA damage using the comet assay. The results showed that the micronuclei and DNA damages to lung and liver were increased in BDL rats. Quercetin caused no damage to the DNA while decreasing the occurrence of micronucleated cells in bone marrow as well as DNA damage to lung and liver in cirrhotic rats. Quercetin showed antimutagenic activity against hydroperoxides as evaluated by the oxidative stress sensitive bacterial strains TA102 Salmonella typhimurium and IC203 Escherichia coli, suggesting protection by free radical scavenging. In Saccharomyces cerevisie yeast strains lacking mitochondrial or cytosolic superoxide dismutase, these results indicate that quercetin protects cells by induction of antioxidant enzymes. The present study is the first report of genotoxic/antigenotoxic effects of quercetin in a model of animal cirrhosis. In this model, quercetin was not able to induce genotoxicity and, conversely, it increased the genomic stability in the cirrhotic rats, suggesting beneficial effects, probably by its antioxidant properties.

Octreotide for esophageal variceal bleeding treated with endoscopic sclerotherapy: a randomized, placebo-controlled trial.

BACKGROUND/AIMS: Endoscopic sclerotherapy is considered a first line therapy to stop bleeding from esophageal varices, but acute variceal bleeding is still associated with high risk of rebleeding and death. We compared the use of octreotide with endoscopic sclerotherapy versus sclerotherapy alone to control acute variceal bleeding and prevent rebleeding in patients with cirrhosis. METHODOLOGY: In a prospective controlled trial, 68 patients with cirrhosis and acute variceal bleeding who underwent emergency sclerotherapy were randomly assigned to receive a continuous infusion of octreotide or placebo for two days. The primary outcome measure was 7-day mortality. RESULTS: After seven days the overall mortality was 19.1%, and the proportion of patients who died in octreotide group (8 of 40, or 20%) was similar to the placebo group (5 of 28, or 17.85%; p = 0.74). Rebleeding occurred in 20.6% (14 of 68 patients), being 20% (8 of 40) in the octreotide group vs. 21.4% (6 of 28) in the placebo group (p = 0.88). The mean number of units of blood transfused after sclerotherapy was 2.05 units in the octreotide group vs. 2.08 units in the placebo group (p = 0.96). Thirty patients needed intensive care support (20 of 40 in the octreotide group vs. 10 of 28 in the placebo group; p = 0.24). The differences remained without statistical significance even after adjustment for hepatic function and endoscopic bleeding stigmata by a linear regression model analysis test. CONCLUSIONS: In patients with cirrhosis, octreotide intravenous per 48h associated with sclerotherapy is not superior to sclerotherapy alone in terms of 7-day mortality, frequency of rebleeding, number of units of packet red blood cell transfusion and length of stay in intensive care setting.

Risk factors associated with cytomegalovirus infection in orthotopic liver transplant patients.

UNLABELLED: Our objective was to investigate the potential risk factors associated with cytomegalovirus (CMV) infection. PATIENTS AND METHODS: From January 1999 to December 2001, 163 liver transplantations were performed in 154 patients. The study inclusion criteria were absence of retransplantation and survival of more than 6 months. One hundred fifteen patients met the inclusion criteria. We determined variables such as age, gender, and number of hemecomponents as well as serum IgG CMV status of donors and recipients. We recorded the immunosuppression used by each patient. CMV infection was detected by positive antigenemia. RESULTS: Recipient mean age was 50 years. The etiology of cirrhosis was viral (n = 57; 49.6%), alcoholic (n = 20; 17.4%), virus and alcohol (n = 15; 13.0%), cryptogenic (n = 14; 12.2%), or other causes (n = 9; 7.8%). CMV infection was positive in 75 patients (65.8%). There was no relation between infection and age, gender, or CMV IgG donor recipient status, or the number of hemecomponent units. The risk was 3.8-fold higher for patients receiving a three-drug compared with a two-drug regimen. When cyclosporine was used instead of tacrolimus, the risk of CMV infection was 4.3-fold higher. Logistic regression analysis revealed cyclosporine (OD=5.8) and a three-drug regimen (OD=6.7) to have stronger associations with CMV infection. CONCLUSION: The use of cyclosporine (OD=5.8) and a three-drug regimen (OD=6.7) are risk factors for CMV infection.

Impact of cytomegalovirus infection on long-term survival after orthotopic liver transplantation.

UNLABELLED: Cytomegalovirus (CMV) is one of the most common and serious opportunistic infections in solid organ transplant patients. In different series the incidence of CMV infection ranges from 25% to 85%. An indirect effect of infection includes reduced long-term patient and allograft survival. Our objective was to determine the relationship between CMV infection and patient survival after orthotopic liver transplantation. PATIENTS AND METHODS: From January 1999 to December 2001, 163 orthotopic liver transplantations were performed in 154 patients. The inclusion criteria for this analysis were the absence of retransplantation and survival of more than 6 months. One hundred fifteen patients met the inclusion criteria. CMV infection was detected by positive antigenemia. RESULTS: CMV infection occurred in 65.8% of patients after orthotopic liver transplantation. Their 5-year survival was 85%, with no difference observed between patients with or without infection (P = .8). CONCLUSION: CMV infection did not interfere with patient survival after orthotopic liver transplantation.

Enteric-coated mycophenolate sodium experience in liver transplant patients.

Mycophenolate sodium (EC-MPS) has been shown to be as effective and as safe as mycophenolate mofetil (MMF) in renal transplant patients. Nevertheless, compared to MMF its use in liver transplant patients has been limited. The purpose of this study was to analyze the efficacy of EC-MPS as a primary immunosuppressant or as a replacement for MMF in liver transplant patients. Ninety among 470 liver transplant recipients were receiving or had added an antimetabolite to their immunosuppressant therapy. The most common reason for this change was renal dysfunction (47.8%) or diabetes (32.2%). EC-MPS was started at a median of 30 months after liver transplantation. The mean administered daily dose was 720 mg/d. At least one gastrointestinal symptom was reported by 25 patients. Abdominal pain (16.6%) and diarrhea (14.5%) were the most frequent. EC-MPS had to be discontinued in two patients, while six others required dose reduction to resolve the symptoms. Hematological adverse events were infrequent: three patients had leukopenia and one, anemia, all of which responded to dosage reduction. There was a creatinine reduction within 6 months of drug commencement and maintenance of the lower creatinine levels at 1 year among patients who began EC-MPS for renal dysfunction. Serum low-density lipoprotein cholesterol and triglyceride levels were significantly lower among patients on EC-MPS than on MMF. In conclusion, EC-MPS appears to have a similar efficacy and safety profile as MMF in liver transplant patients. Hematological and gastrointestinal adverse events were infrequent; seldom had the drug to be discontinued.

Randomized clinical assay for hepatic grafts preservation with University of Wisconsin or histidine-tryptophan-ketoglutarate solutions in liver transplantation.

University of Wisconsin (UW) solution has been the standard for preservation of liver transplantation grafts since 1989. However, some studies demonstrated that histidine-tryptophan-ketoglutarate (HTK) solution is also effective. The purpose of this study was to compare the efficacy of both solutions in liver transplantation. From January 2003 to August 2004 the livers of deceased donors were randomized into HTK and UW groups. The 102 studied patients included 65 (63.7%) in the UW group and 37 (36.3%) in the HTK group. Sex, race, hemodynamic state, use of adrenergic drugs, and presence of steatosis in the donor were similarly distributed in the two groups (P > .05). The mean age of the donors was 38.1 years (SD +/-14.4) in the UW group and 44.6 years (SD +/-14.2) in the HTK cohort (P = .036). Sex, race, age, etiology of the cirrhosis, retransplant, acute liver failure, portal thrombosis, and Child-Pugh and MELD scores in the recipients were similarly distributed in the two recipient samples (P > .05). Among 89 patients who completed 4 months of follow-up, the HTK group included eight cases (25.8%) of biliary complications versus five cases (8.6%) in the UW group (P = .033; OR = 2.0 95% CI = 1.2-3.5). The incidence of graft dysfunction was 2.8% in the HTK group and 9.4% in the UW group (P = .15). In conclusion, UW and HTK solutions were equally effective for the preservation of the hepatic graft. The routine use of HTK solution can reduce the costs of liver transplantation.

Comparison Between IGL-1 and HTK Preservation Solutions in Deceased Donor Liver Transplantation.

The effectiveness of liver preservation solutions remains in evidence. Cold ischemia time, steatosis, expanded criterion donors, operational cost, and survival represent important roles in its success. In a prospective cohort study between August 2009 and April 2014, 178 patients were allocated into an Institut Georges Lopez - 1 (IGL-1) solution group (63.5%) or histidine-tryptophan-ketoglutarate (HTK) group (36.5%). There were no differences among recipient's characteristics including age, skin color, gender, Model for End-stage Liver Disease score, acute rejection, cholestasis, and reperfusion syndrome incidences. Also, donors, age average, skin color, donor risk index, time in intensive care unit, hemodynamic variables, infections, and steatosis incidences were similar. The average cold ischemia time was 494 minutes in the IGL-1 group and 489 minutes in the HTK group (P = .77). Alanine aminotransferase and aspartate aminotransferase serum levels on the first postoperative day were 707 and 1185 mg/dL, respectively, with IGL-1 and 1298 and 2291 mg/dL, respectively, with HTK (P = .016) and similar at day 15 (P > .88). The incidence of delayed graft function was 4.5% with IGL-1 and 4.6% with HTK (P = .90). The incidence primary nonfunction was 2.7% with IGL-1 and 3.1% with HTK (P = .71). The incidence of perioperative death was 11.5% with IGL-1 and 13.8% with HTK (P = .94). The survival in 30 months was 86% in IGL-1 group and 82% in HTK group (P = .66). Both preservation solutions are efficient to liver transplantations with deceased donors. Major prospective trials are necessary to evaluate each preservation solution's particularities. The preservation solution availability in each transplantation center must guide its use at the present moment.

Risk factors associated with cytomegalovirus-positive antigenemia in orthotopic liver transplant patients.

The aim of the study was to investigate risk factors associated with cytomegalovirus (CMV)-positive antigenemia in orthotopic liver transplant (OLT) patients. Sixty-nine patients undergoing OLT during 2001 were retrospectively evaluated for CMV antigenemia during a follow-up of 6 months after transplantation for demographic variables, pretransplant donor and recipient CMV serologic status, etiology of liver disease, number of blood transfusions, and type of immunosuppression. Among the 69 patients who underwent 71 OLT in this period, 43 met study criteria. Mean age was 49.7 +/- 10.8 years and 60.5% were men. End-stage liver disease was the indication for liver transplant, except in one case. The most prevalent etiology of liver disease was hepatitis C and/or alcohol in 66% of the cases. CMV-positive status was recorded in 74% of donors and 95% of recipients. None of the CMV-negative recipients received a positive donor allograft. CMV-positive antigenemia was 84% with 12% having two episodes of infection. There was no correlation between CMV infection and age, gender, etiology of liver disease, or number of blood transfusions. However, all patients using cyclosporine had CMV-positive antigenemia compared with 61% using tacrolimus (P <.032). In this study, the incidence of CMV infection after OLT in adult patients was slightly higher than reported in literature. No risk factor was associated with CMV antigenemia; however, this study suggests a higher probability of CMV infection among patients treated with cyclosporine.

Oxidative stress, hepatocellular integrity, and hepatic function after initial reperfusion in human hepatic transplantation.

BACKGROUND: The mechanisms underlying liver graft dysfunction are not completely defined, although much of the injury derives from oxidative stress in organ reperfusion. The antioxidant glutathione in its reduced form (GSH) is an important agent to detoxify oxygen species after reperfusion. However, this effect might be limited by low concentrations at the end of cold storage. The objective of this study was to evaluate GSH and glutathione oxidized (GSSG) hepatic levels pre- and postreperfusion and correlate with hepatocellular injury and liver function in the 5 subsequent days after transplantation. METHODS: Liver biopsies were taken immediately before implant and 2 hours after venous reperfusion in 34 grafts, determining GSH, GSSG levels, and GSSG/GSH ratio. Aminotransferases (ALT, AST) and PT were measured for 5 days. RESULTS: There was a strong decrease in GSH concentration (P <.0001), increase of GSSG levels (P <.01), and increase of the GSSG/GSH ratio (P <.0001). No correlations were found between GSH, GSSG, or GSH/GSSH levels and AST, ALT, and PT. CONCLUSION: Glutathione levels showed significant changes after 2 hours of reperfusion, due to intense oxidative stress. Therapies to replenish GSH should be considered as a protective measure to avoid liver graft dysfunction after transplantation.

[Chronic anemia protects against gastric damage by alcohol and aspirin. The role of the toxic radicals and lipid peroxidation]. / La anemia crónica protege el daño gástrico por alcohol y aspirina. Papel de los radicales tóxicos y de la peroxidación lipídica.

The effects of chronic anemia on gastric damage induced by ethanol or aspirin have been investigated in rats. The role of free radicals and lipid peroxidation in that circumstance was also assessed. Chronic anemia was induced by replacement of 1.5 ml of blood by a plasma expander during 5 days. Under anesthesia, the stomach was perfused with 100% ethanol or acidified aspirin during 30 minutes. Thereafter, the rats were sacrificed, the stomachs removed and analyzed planimetrically for macroscopic damage. In addition, gastric tissue was collected and homogenized for assessment of toxic free radicals generation by chemoluminicense and lipid peroxidation by measuring reactive species of thiobarbituric acid (TBA-RS). Chronic anemia significantly protected against damage induced by ethanol or aspirin. The rate of toxic free radicals and the TBA-RS in the gastric mucosa was significantly reduced by anemia, either under ethanol or aspirin injury. It is concluded that anemia offers a general protection against gastric mucosal damage and that this protection is in part mediated by limitations on lipid peroxidation and toxic free radicals generation.

[Neurologic disorders in patients submitted to liver transplantation: analysis of 30 consecutive cases]. / Alterações neurológicas em pacientes submetidos a transplante hepático: análise de 30 casos consecutivos.

Neurologic complications are important source of morbi-mortality, in liver transplantation. They result from previous factors, alterations during the surgical procedure, effects from immunosuppressor drugs, coagulopathy and infections. We analyzed, retrospectively, the chronology, causes, and frequencies of neurologic alterations in thirty adult patients submitted to liver transplantation, and our results differ slightly from those registered in other series.

[Experimental cirrhosis induced by carbon tetrachloride inhalation: adaptation of the technique and evaluation of lipid peroxidation]. / Cirrose experimental induzida pela inalação de tetracloreto de carbono: adaptação da técnica e avaliação da peroxidação lipídica.

BACKGROUND: Long-term administration of carbon tetrachloride is an accepted experimental model to produce hepatic fibrosis. Oxidative stress has been postulated as a major molecular mechanism involved in carbon tetrachloride hepatotoxicity, where the reactive oxygen species play an important role in the pathogenesis of liver fibrosis. AIMS: This study was conducted to evaluate the effectiveness of an experimental model of hepatic cirrhosis induced by carbon tetrachloride inhalation as well as the importance of lipid peroxidation and the characteristics of the ascitic fluid in this model. METHODS: At first the hepatic histologic findings were assessed using the hematoxilineosin technique in different moments of carbon tetrachloride inhalation (5th, 7th, 9th, 12th weeks). Later, at the end of 15 weeks of the study the rats were divided in three groups (control; control + phenobarbital; and carbon tetrachloride + phenobarbital) for lipid peroxidation, ascitic fluid and histologic characteristics evaluation. For the lipid peroxidation analysis, thiobarbituric acid and QL techniques were used. Cytologic and bacteriologic parameters were analysed in the ascitic fluid. RESULTS: Cirrhosis was established in 100% of carbon tetrachloride rats between the 12th and 15th weeks with an elevation in the lipid peroxidation carbon tetrachloride rats' livers. Ascitic fluid infection was observed in one of seven rats who has developed ascites. CONCLUSIONS: The carbon tetrachloride inhalation method developed in this study is effective in cirrhosis induction and ascites formation, and the carbon tetrachloride cirrhosis physiopathogenesis is probably related to the oxidative stress installation.

Risk factors for hepatotoxicity in solid organ transplants recipients being treated for tuberculosis.

BACKGROUND: Tuberculosis (TB) is associated with high morbidity and mortality in solid organ transplant (SOT) recipients. Also, SOT patients have a 20- to 74-fold increase in the chance of developing TB compared to the general population. Here we evaluated the incidence of hepatotoxicity in SOT recipients on treatment for TB and determined risk factors for liver toxicity in these patients. PATIENTS AND METHODS: Retrospective cohort conducted in a reference hospital for SOT in Southern Brazil. All SOT recipients who underwent TB treatment during the years 2000-2012 were considered for the study. RESULTS: A total of 69 patients were included in the study and 23 had liver toxicity (incidence 33.3%). Independent risk factors for hepatotoxicity were rifampin use at doses of ≥600 mg daily (P = .016; OR 2.47; 95% CI, 1.18-5.15) and lung transplantation (P = .017; OR 2.05; 95% CI, 1.14-3.70). Kidney transplantation appeared as a protective factor (P = .036; OR 0.50; 95% CI, 0.26-0.96). Mortality was higher in the patients who had hepatotoxicity (43.5%), compared with those who did not (19.6%). CONCLUSION: In this study, the use of rifampin at doses of 600 mg daily or higher was found to be an independent risk factor for liver toxicity in SOT recipients. The importance of additional risk factors for hepatotoxicity, such as lung transplantation as well as the protective role of kidney transplantation, should be better investigated in SOT recipients being treated for TB.

Relationship between MELD severity score and the distance walked and respiratory muscle strength in candidates for liver transplantation.

The model end-stage liver disease (MELD) severity scoring system is used in the allocation of organs for liver transplantation. However, there is no evidence of its relationship with the functionality and respiratory muscle strength in these patients. The aim of this study was to analyze the correlation of MELD with distance walked and respiratory muscle strength in patients awaiting liver transplantation. We performed a cross-sectional analysis of 24 individuals (16 male and 8 female) with mean age of 51.8 +/- 10.4 years. The MELD score inversely correlated with the 6-minute walking test (6MWT) (r = -0.85; P < .001) and with the maximal inspiratory pressure (MIP) (r = -0.69; P < .001). In addition, there was a correlation between 6MWT and MIP (r = 0.77; P < .001). Thus, MELD scores can be considered to be effective tools to predict the functional capacity and respiratory muscle strength in candidates for liver transplantation.

Endoscopic dilation of benign esophageal strictures: report on 1043 procedures.

OBJECTIVE: Endoscopic dilation is considered the best treatment for most cases of benign esophageal stricture, although the best dilation technique and the kind of stricture is the most amenable to treatment is still controversial. We report on our experience on a large series of patients treated by dilation without the aid of fluoroscopy and compare the results of this therapy among patients with strictures from different causes. METHODS: Between 1992 and 1997, we performed 1043 dilation sessions on 153 patients. Treatment was considered adequate if the esophageal lumen could be dilated up to the size of a 42F catheter. If the stricture recurred after initial successful treatment, the stricture was dilated again up to a 42F catheter. RESULTS: One hundred forty patients (96 men, 44 women; mean age, 54.1 yr) were followed-up for a mean of 20.5 months (4 to 62 months). Stricture's etiology was postsurgical in 80 patients, peptic in 37, caustic in 12, and from other causes in 11 patients. Adequate dilation was achieved in 93.5% of the patients (131 of 140). Patients with peptic strictures needed a median of three sessions to be adequately dilated during follow-up in comparison to five sessions among patients with postsurgical or caustic strictures (p = 0.07). There were four perforations, with one death (2.8% and 0.7% per patient and 0.4% and 0.1% per session, respectively). CONCLUSIONS: Endoscopic dilation without the aid of fluoroscopy is safe and effective in relieving dysphagia caused by benign strictures of different causes, although repeated sessions are necessary because of stricture recurrence.