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Cholestatic hepatitis C (CHC) is a severe form of hepatitis C virus (HCV) infection recurrence that leads to high graft loss rates early after liver transplantation (LT). To investigate the pathogenic mechanisms of CHC, we analysed HCV quasispecies in CHC patients compared to a control group (mild hepatitis C recurrence) by deep pyrosequencing. At the time of LT, NS5B quasispecies complexity was similar between the two groups but, after LT, it decreased more sharply in CHC patients than in the control group. Interestingly, the major variant before LT propagated efficiently and remained as the dominant sequence after LT in 62 % of CHC patients versus 11 % of controls (P=0.031). Sequence analysis of the complete non-structural region in a limited number of patients revealed a potential 12 as signature specific to the CHC group. These data suggest that intrinsic molecular determinants in the circulating HCV quasispecies may provide a fitness advantage, contributing to the development of CHC.

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

This document provides a detailed description of the position of the Catalan Society of Gastroenterology on the accuracy and utility of elastography in the non-invasive diagnosis of liver fibrosis. The document was written by a group of experts in chronic liver diseases and liver transplantation and reflects the consensus reached on the methodology and indications of transient elastography. This document was reviewed and presented in an abbreviated form at the XX Congress of the Catalan Society of Gastroenterology and included on the website http://www.scdigestologia.org/index.php?link=docs_posicio (C) 2011 Elsevier Espana, S.L. All rights reserved.

⇓“The tantalizing problem of the connective link in cirrhotic patients between oxygen unsaturation and possible arteriovenous shunting in the lungs remains unsolved, and any relation between arterial unsaturation and pulmonary vasodilation remains obscure.” Fig. 1.— Working model of molecular alterations in the pulmonary microcirculation in experimental hepatopulmonary syndrome (HPS). a) In the normal microvasculature, a balance of vasoconstrictive and vasodilatory factors, including paracrine endothelin (ET)-1-mediated vasoconstriction through the ETA receptor (▪) on smooth muscle cells (SMCs) and ET-1-mediated vasodilatation mediated through the ETB receptor (□) linked to endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs), maintain tone. b) During the development of HPS, a number of alterations, both directly and indirectly related to hepatic injury and portal hypertension, result in the production or release of mediators into the venous circulation, where they influence the pulmonary microcirculation. Increased expression of pulmonary endothelial ETB receptors and increased hepatic production and release of ET-1 contribute to an increase in eNOS expression and enhanced nitric oxide (NO) production in the microvascular endothelium during the initiation of HPS. Tumour necrosis factor (TNF)-α-mediated accumulation of intravascular macrophage-like cells also occurs after chronic common bile duct ligation. Haem oxygenase (HO)-1 and inducible nitric oxide synthase (iNOS) expression increase in these cells and contribute to the progression of HPS. CO: carbon monoxide. Fig. 2.— Algorithm for screening and therapeutic decisions in hepatopulmonary syndrome (HPS). OLT: orthotopic liver transplantation; P a,O2: arterial oxygen tension; P A–a,O2: alveolar–arterial oxygen tension difference; CEE: contrast-enhanced echocardiography; PFT: pulmonary function test; MAA: macroaggregated albumin. #: high-resolution thoracic computed tomographic scanning is highly recommended in order to exclude chronic respiratory comorbid conditions; ¶: high risk for post-operative OLT mortality. 1 mmHg=0.133 kPa. Fig. 3.— Plot demonstrating the relationship between cardiac output ( Q ') and transpulmonary pressure gradient (TPG; mean pulmonary arterial …

The incidence of de novo neoplasms was analyzed in 340 patients with liver transplantation who survived more than 2 months post transplantation. Sixteen (4.7%) patients developed a new tumor following transplantation. The most frequent tumor observed was a lymphoma which was detected in four patients (1.2%). In three of the four lymphomas histologic diagnosis of non Hodgkin phenotype B lymphoma was confirmed and in three patients the central nervous system was involved. The remaining tumors consisted of two cases of adenocarcinoma of the colon, papillary carcinoma of the urinary bladder and ductal breast cancer (0.6%) for each of these tumors and one case of cervical cancer, adenocarcinoma of the small intestine, Kaposi sarcoma, laryngeal carcinoma, pharyngeal carcinoma and malignant melanoma (0.3% for each tumor). None of the patients developed more than one tumor. The mean time to the appearance of the tumors was 28 months (range: 3-52 months). These results suggest that de novo neoplasms in patients with liver transplantation are relatively frequent, particularly lymphoma.

With the aim of evaluating liver disturbances after BMT in 76 patients, the hepatic venous pressure gradient was measured and a transvenous liver biopsy was performed through the jugular vein. Catheterization was successful in 71 patients (93%). In 11 cases the procedure was performed twice, yielding a total number of 82 studies. In five (6%) liver biopsies were non-evaluable. Complications were rare (7%), minor and reversible. As a result of this procedure, the diagnosis was modified in 45%, with both the diagnosis and treatment being modified in 30% of patients. Veno-occlusive disease (VOD) was histologically demonstrated in 15 out of 26 patients (58%) in whom this complication was suspected and in two out of 33 (6%) in whom it was not. Acute GVHD of the liver was confirmed in 15 out of the 35 patients (43%) in whom this complication was suspected and in four of 24 (17%) in whom it was not. The hepatic venous pressure gradient was significantly higher in VOD than in liver GVHD. Whereas 14/17 (82%) patients with VOD had a gradient pressure higher than 9 mmHg, no patient with GVHD had a gradient above this value. We conclude that transjugular liver biopsy is an effective, safe, and useful technique to evaluate BMT related liver dysfunction.

During the XXII Congress of the Spanish Association for the Study of the Liver a questionnaire was distributed with the aim of describing the current therapeutic attitude of those attending the meeting, concerning two of the most frequent complications of cirrhosis: ascites and spontaneous bacterial peritonitis (SBP). One hundred twelve of the 135 physicians who answered the questionnaire (83%) use to treat tense ascites by therapeutic paracentesis, while 86 physicians (63.7%) managed moderate ascites with diuretics, with spironolactone being the drug most commonly used (n = 117; 87.3%). The most used diuretic schedule for the treatment of ascites was the isolated administration of spironolactone. Frusemide was associated with spironolactone only when moderate or high doses of the latter were found to be insufficient for increasing urinary sodium excretion and eliminating ascites. Following therapeutic paracentesis however, 79 of those surveyed (58.3%) administered a combination of both diuretics on initiation to avoid reaccumulation of ascitic fluid. Sixty-eight of the physicians (50.3%) used transhepatic intrajugular portosystemic shunt in the treatment of refractory ascites. Cefotaxime was the antibiotic most widely used in the treatment of SBP (n = 119; 88%). Most of the physicians surveyed performed prophylaxis of this infection (generally by the oral administration of norfloxacin) in patients with a previous history of SBP (n = 125; 92.6%) or an episode of gastrointestinal hemorrhage (n = 108; 80%) but not in those patients with no previous history of SBP and with low protein concentrations in the ascitic fluid (n = 40; 29.6%). On the appearance of SBP in patients undergoing prophylactic treatment, cefotaxime remained the antibiotic of choice (n = 104; 79%).

Hepatic angiosarcoma is an infrequent neoplasm representing 1-3% of all the primary liver cancers. One fourth of the cases have demonstrated a relation with chemical carcinogens with the most frequent being thorium dioxide (thorotrast) and vinyl chloride. The case of an hepatic angiosarcoma which presented as an intraperitoneal hemorrhage in a patient who had undergone treatment with Neosalvarsán (dioxidiaminoarsenobenzol) 46 years beforehand is reported. The previous published reports include 6 cases of hepatic angiosarcoma related with treatment with arsenic salts and 4 cases in whom exposure was environmental.

Portal hypertension is characterized by a chronic increase in portal venous pressure. This is initiated by an increased vascular resistance to portal blood flow. In advanced stages, however, blood flow increases and contributes to worsen and maintain portal hypertension. Increased pressure and blood flow within the portal system promotes the appearance and dilation of portal-systemic collaterals and oesophageal varices, which are responsible for the main complication of portal hypertension: massive gastrointestinal haemorrhage. In recent years there have been several major innovations in the evaluation of portal hypertension. These include the application of new endoscopic, ultrasonographic and haemodynamic techniques that allow a better evaluation of the portal hypertensive patient, especially when prophylactic medical therapy is considered. Ultrasonography is very useful to assess the patency of the portal vein. The association of a pulsed Doppler flowmeter increases its accuracy and allows the non-invasive estimation of the direction and magnitude of portal blood flow. In addition to the measurement of portal pressure, measurement of azygos venous blood flow has proven very useful in the haemodynamic evaluation of portal hypertension. Azygos blood flow represents an index of blood flow through gastro-oesophageal collaterals and varices draining in the azygos vein. Its main application has been the assessment of the effects of pharmacological therapy. Endoscopic measurements of variceal pressure, either by direct puncture or using non-invasive pressure gauges, have contributed significantly to the understanding of the mechanism of variceal haemorrhage. This technique allows the calculation of the variceal wall tension as the product of the transmural pressure at the varices and the radius of the varix.(ABSTRACT TRUNCATED AT 250 WORDS)

Background : Pretransplant renal function is the major determinant of survival after liver transplantation (LTx). Patients with hepatorenal syndrome (HRS) have a poor outcome after LTx compared with patients transplanted without HRS. Aim : To analyze the impact of treatment of HRS before LTx on outcome after transplantation. Methods : The outcome of patients with HRS ( n =9) treated with vasopressin analogues before LTx was compared with that of a contemporary control group of patients without HRS ( n =27) matched by age, severity of liver failure, and type of immunosuppression. Results : Cases and controls were similar with respect to pretransplantation characteristics. Three-year survival probability was similar between the two groups (HRS-treated: 100% vs control: 83%, P =0.15). No significant differences were found between the two groups with respect to the incidence of impairment of renal function after LTx (HRS-treated: 22% vs control: 30%), severe infections (22 vs 33%), acute rejection (33 vs 41%), days in Intensive Care Unit (6±1 vs 8±1), days in hospital (27±4 vs 31±4), and transfusion requirements (11±3 vs 10±2 units). Conclusions : Patients with HRS treated with vasopressin analogues before LTx have a posttransplantion outcome similar to that of patients transplanted with normal renal function. These results suggest that HRS should be treated before LTx.

Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 mu g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. Results: In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. Conclusion: Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.