Prophylaxis and treatment of hepatitis B infection in the setting of liver transplantation

Without any treatment, the prognosis of hepatitis B in liver transplant recipients is very poor. So, antiviral prophylaxis is very important in patients with hepatitis B who undergo liver transplantation. Before liver transplantation, a suppression of viral replication has to be achieved by nucleos(t)ide analogs. Drugs used in the prophylaxis of post-transplant hepatitis B include immunoglobulin against HBV and nucleos(t)ide analogs. Prophylaxis against graft infection must be based on the individual risk of recurrence. When prophylactic measures have failed and graft infection has occurred, treatment of recurrent hepatitis B may be based on the resistance profile of the virus and previous antiviral exposure. Finally, lamivudine seems to be very effective in the prevention of de novo hepatitis B in patients transplanted with a graft from an anti-HBc positive donor

Interactive Role of Surrogate Liver Fibrosis Assessment and Insulin Resistance on the Incidence of Major Cardiovascular Events

Introduction: The combination of easy-to-obtain validated biomarkers is interesting in the prognostic evaluation of patients at cardiovascular risk in a precision medicine scenario. The evaluation of the effect modification of insulin resistance and liver fibrosis with the Triglyceride-Glucose index (TyG) and Fibrosis-4 index (FIB4) might provide prognostic information in patients at cardiovascular risk. Patients and methods: A retrospective cohort study was performed with 2055 patients recruited in the Vascular Metabolic CUN cohort. The studied outcome was the incidence rate of major cardiovascular events (MACE). The Systematic Coronary Risk Evaluation (SCORE), FIB4 and TyG indexes were calculated according to validated formulas. Results: FIB4 and TyG showed a synergistic interaction using validated cut-offs for both indexes in the prediction of MACE (Hazard ratio (HR) 1.05 CI95% 1.01–1.08) which remained after adjustment by age, sex, SCORE subgroup, presence of diabetes, or previous MACE using standardized cut-off (HR 2.29 CI95% 1.33–3.94). Finally, a subgroup with significant TyG and FIB4 showed a higher cardiovascular risk in the study population (adjusted HR 3.34 CI 95% 1.94–5.77). Conclusion: The combined interpretation of TyG and FIB4 indexes might have a potential predictive value of major cardiovascular events

Risk factors of lung, head and neck, esophageal, and kidney and urinary tract carcinomas after liver transplantation: the effect of smoking withdrawal

Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking-related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow-up of 7.5 years, 26 patients were diagnosed with 29 smoking-related malignancies. The 5- and 10-year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

Background and aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods and results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAX? expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.Funding information: This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI-100, PID2020-115055RB-I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A-2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article

Prophylaxis and treatment of hepatitis B infection in the setting of liver transplantation Profilaxis y tratamiento de la infección por el virus de la hepatitis B en relación con el trasplante hepático

Without any treatment, the prognosis of hepatitis B in liver transplant recipients is very poor. So, antiviral prophylaxis is very important in patients with hepatitis B who undergo liver transplantation. Before liver transplantation, a suppression of viral replication has to be achieved by nucleos(t)ide analogs. Drugs used in the prophylaxis of post-transplant hepatitis B include immunoglobulin against HBV and nucleos(t)ide analogs. Prophylaxis against graft infection must be based on the individual risk of recurrence. When prophylactic measures have failed and graft infection has occurred, treatment of recurrent hepatitis B may be based on the resistance profile of the virus and previous antiviral exposure. Finally, lamivudine seems to be very effective in the prevention of de novo hepatitis B in patients transplanted with a graft from an anti-HBc positive donor.<br>La infección por el virus de la hepatitis B en los receptores de trasplante hepático tiene un pronóstico malo en ausencia de tratamiento farmacológico. Por ello, en los pacientes trasplantados por una hepatopatía por virus B, la profilaxis de esta infección es imprescindible. Antes del trasplante, debe intentarse suprimir la replicación viral con un análogo de nucleót(s)idos. Tras el trasplante, la profilaxis de la recidiva de la hepatitis B se basa en el uso de los análogos de nucleót(s)idos y la inmunoglobulina frente al virus de la hepatitis B; la pauta de profilaxis debe basarse en el riesgo de recidiva de la hepatitis B que tenga cada paciente. En el caso de que se produzca una hepatitis B tras el trasplante, el tratamiento con análogos de nucleót(s)idos debe basarse en los estudios de resistencia. Por último, en los pacientes trasplantados que reciben un injerto de un donante antiHBc-positivo, la profilaxis con lamivudina parece ser muy eficaz

Prophylaxis and treatment of hepatitis B infection in the setting of liver transplantation

Without any treatment, the prognosis of hepatitis B in liver transplant recipients is very poor. So, antiviral prophylaxis is very important in patients with hepatitis B who undergo liver transplantation. Before liver transplantation, a suppression of viral replication has to be achieved by nucleos(t)ide analogs. Drugs used in the prophylaxis of post-transplant hepatitis B include immunoglobulin against HBV and nucleos(t)ide analogs. Prophylaxis against graft infection must be based on the individual risk of recurrence. When prophylactic measures have failed and graft infection has occurred, treatment of recurrent hepatitis B may be based on the resistance profile of the virus and previous antiviral exposure. Finally, lamivudine seems to be very effective in the prevention of de novo hepatitis B in patients transplanted with a graft from an anti-HBc positive donor

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease

Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood

International audienceThe analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising highthroughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cutoff value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirmhighly efficient CTC isolation with a stringent cut-off value and better separationresults than the state of the art