Review article: Oesophageal disorders in chronic liver disease.

BACKGROUND: Oesophageal disorders and chronic liver disease are common worldwide and significantly impact quality of life. The intricate link between these conditions, including how oesophageal disorders like GERD, Barrett's oesophagus and oesophageal cancer affect and are affected by chronic liver disease, remains poorly understood. AIMS: To review the relationship between oesophageal disorders and chronic liver disease, evaluating epidemiology, pathophysiology and therapeutic factors. METHODS: We reviewed the literature on the relationship between oesophageal disorders and chronic liver disease, including cirrhosis, using the PubMed database RESULTS: Oesophageal disorders such as gastroesophageal reflux disease, Barrett's oesophagus, oesophageal cancer, oesophageal motor disorders and oesophageal candidiasis are prevalent among individuals with cirrhosis, exacerbating the burden of liver disease. These diseases have a multifaceted symptomatology and pathogenic basis, posing a significant challenge in cirrhotic patients that necessitates careful diagnosis and management. Additionally, therapies frequently used for these diseases, such as proton pump inhibitors, require careful consideration in cirrhotic patients due to potential adverse effects and altered pharmacokinetics. Managing oesophageal disorders in cirrhotic patients requires a cautious approach due to possible interactions with medications and the risk of adverse effects. Furthermore, symptoms associated with these conditions are often exacerbated by common interventions in patients with cirrhosis, such as band ligation for oesophageal varices. CONCLUSIONS: Oesophageal disorders are common in cirrhosis and increase the disease burden. These conditions require careful management due to complex symptoms and treatment risks. Proton pump inhibitors and other therapies must be used cautiously, as cirrhosis interventions can worsen symptoms.

Different combinations of the GLIM criteria for patients awaiting a liver transplant: Poor performance for malnutrition diagnosis but a potentially useful prognostic tool.

BACKGROUND & AIMS: Studies using the Global Leadership Initiative on Malnutrition (GLIM) criteria for patients with liver cirrhosis are limited. This study aimed to assess the impact of malnutrition according to the GLIM criteria on the outcomes of patients awaiting a liver transplant (LTx) and compare these criteria with Subjective Global Assessment (SGA). METHODS: This retrospective observational study included adult patients awaiting LTx. Patient clinical data, nutritional status according to various tools including SGA, and resting energy expenditure were assessed. The distinct phenotypic and etiologic criteria provided 36 different GLIM combinations. The GLIM criteria and SGA were compared using the kappa coefficient. The variables associated with mortality before and after the LTx and with a longer length of stay (LOS) after LTx (≥18 days) were assessed by Cox regression and logistic regression analyses, respectively. RESULTS: A total of 152 patients were included [median age 52.0 (interquartile range: 46.5-59.5) years; 66.4% men; 63.2% malnourished according to SGA]. The prevalence of malnutrition according to the GLIM criteria ranged from 0.7% to 30.9%. The majority of the GLIM combinations exhibited poor agreement with SGA. Independent predictors of mortality before and after LTx were presence of ascites or edema (p = 0.011; HR:2.58; CI95%:1.24-5.36), GLIM 32 (PA-phase angle + MELD) (p = 0.026; HR:2.08; CI95%:1.09-3.97), GLIM 33 (PA + MELD-Na≥12) (p = 0.018; HR:2.17; CI95%:1.14-4.13), and GLIM 34 (PA + Child-Pugh) (p = 0.043; HR:1.96; CI95%:1.02-3.77). Malnutrition according to GLIM 28 (handgrip strength + Child-Pugh) was independently associated with a longer LOS (p = 0.029; OR:7.21; CI95%:1.22-42.50). CONCLUSION: The majority of GLIM combinations had poor agreement with SGA, and 4 of the 36 GLIM combinations were independently associated with adverse outcomes.

Eficacia y seguridad de Sofosbuvir/Velpatasvir en pacientes postrasplante renal con infección crónica por el virus de la hepatitis C genotipos 1 o 4, con grado de fibrosis hepática F0 o F1 / Efficacy and safety of Sofosbuvir/Velpatasvir in post-kidney transplant patients with chronic hepatitis C virus infection genotypes 1 or 4, with liver fibrosis grade F0 or F1

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de sofosbuvir/velpatasvir, comparado con la mejor terapia de soporte, en pacientes postrasplante renal con infección crónica por el virus de la hepatitis C genotipos 1 o 4, con grado de fibrosis hepática F0 o F1. Los pacientes con enfermedad renal adquieren la infección por el virus de la hepatitis C (VHC) durante la diálisis. En Perú, en el año 2000, se reportó una prevalencia de infección del VHC del 59 % en pacientes con insuficiencia renal crónica terminal que recibieron hemodiálisis. La infección por el VHC tiene un efecto negativo en la sobrevida del paciente y en la probabilidad de rechazo del injerto renal. Además, la infección crónica del VHC sigue un curso progresivo por muchos años, que puede terminar en cirrosis, carcinoma hepatocelular y la necesidad de trasplante hepático. Dicha progresión es más acelerada en pacientes con trasplante renal. El objetivo de la terapia antiviral en pacientes con infección crónica por VHC es alcanzar una carga viral indetectable. Esta puede ser medida por la respuesta virológica sostenida a las 12 semanas (RVS12) después del tratamiento. La selección del tratamiento en pacientes postrasplante renal dependerá del genotipo del VHC, el grado de fibrosis hepática, el tratamiento recibido previamente y las potenciales interacciones con inmunosupresores. En los últimos años, los esquemas combinados con antivirales de acción directa (AAD), como sofosbuvir/velpatasvir, han mostrado ser eficaces (RSV12 > 90.0 %) y bien tolerados en los pacientes con infección por VHC. EsSalud cuenta con sofosbuvir/velpatasvir para el tratamiento de pacientes con infección crónica por el VHC asociado a fibrosis hepática ≥ F21 sin tratamiento sistémico previo (IETSI 2019a), y pacientes con coinfección del virus de inmunodeficiencia humana (VIH) y el VHC, fibrosis hepática F0 o F1 y sin tratamiento sistémico previo (IETSI 2020). No obstante, los pacientes postrasplante renal con infección crónica por el VHC (genotipos 1 o 4) y con fibrosis hepática de grado F0 o F1 no cuentan con una opción de tratamiento (vacío terapéutico). Por esta razón, los especialistas de EsSalud proponen que el uso sofosbuvir/velpatasvir en este grupo de pacientes podría mejorar la sobrevida del paciente y del injerto renal; así como la RVS y la calidad de vida del paciente. METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de sofosbuvir/velpatasvir en pacientes postrasplante renal con infección crónica por el virus de la hepatitis C genotipos 1 o 4, con grado de fibrosis hepática F0 o F1. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Lilacs y The Cochrane Library. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Haute Autorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), y Comissão nacional de incorporação de tecnologías no sus (CONITEC). También se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y se colectó información sobre el medicamento de interés del presente dictamen en las páginas web de la European Medicines Agency (EMA), y Food and Drug Administration (FDA). Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: Se llevó a cabo la búsqueda de evidencia científica relacionada al uso de sofosbuvir/velpatasvir en pacientes postrasplante renal con infección crónica por el virus de la hepatitis C genotipos 1 o 4, con grado de fibrosis hepática F0 o F1. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA). CONCLUSIONES:  En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad sobre la eficacia y seguridad sofosbuvir/velpatasvir, comparado con la mejor terapia de soporte, en pacientes postrasplante renal con infección crónica por el VHC genotipos 1 o 4, con grado de fibrosis hepática F0 o F1. En contexto de EsSalud, para pacientes postrasplante renal con infección crónica por el VHC genotipos 1 o 4, con grado de fibrosis hepática F0 o F1 no se cuenta con una opción de tratamiento dentro del Petitorio de EsSalud. Por lo tanto, la población de interés del presente dictamen se enmarca en un contexto de vacío terapéutico. La búsqueda sistemática de la evidencia culminó con la selección de dos GPC elaboradas por la AASLD-IDSA y EASL, y uno de los estudios pivotales de sofosbuvir/velpatasvir, denominado ASTRAL-1. Las GPC de AASLD-IDSA y EASL recomiendan el uso de sofosbuvir/velpatasvir en pacientes con infección por VHC y trasplante renal. Además, el uso de sofosbuvir/velpatasvir no requeriría el ajuste de las dosis de inmunosupresores que suelen recibir los pacientes con trasplante de órganos. Las recomendaciones de ambas guías se basaron en estudios que evaluaron el uso de sofosbuvir/velpatasvir en pacientes sin trasplante o con trasplante hepático, y estudios que evaluaron el uso de sofosbuvir en combinación con otros AAD (incluyendo inhibidores de NS5A como velpatasvir) en pacientes postrasplante renal. El ECA de fase III, doble-ciego, ASTRAL-1 evaluó el uso de sofosbuvir/velpatasvir vs. placebo por 12 semanas en 740 pacientes con infección crónica de VHC genotipo 1, 2, 4, 5 o 6 sin cirrosis descompensada. El ECA ASTRAL-1 reportó tasas de RVS12 ≥ 98 %, en el conjunto de todos los pacientes tratados con sofosbuvir/velpatasvir, y en análisis por genotipos (1a, 1b y 4). En contraste, en el grupo placebo ningún paciente alcanzó la RSV12. En relación con los desenlaces de seguridad, no se observaron diferencias estadísticamente significativas en el reporte de EAS entre los grupos de tratamiento. El ECA ASTRAL-1 presentó limitaciones, tales como: la inserción de un grupo de pacientes sin aleatorizar al grupo de sofosbuvir/velpatasvir y el patrocinio del estudio por parte de la empresa farmacéutica Gilead Sciences, fabricante del medicamento de sofosbuvir/velpatasvir. Estas limitaciones aumentan el riesgo de sesgo y afectan la validez de los resultados. Aun así, la diferencia en la RVS12 entre sofosbuvir/velpatasvir y es tan grande que resulta poco probable que estas limitaciones cambien el sentido de las conclusiones. El desenlace de RVS es considerado por el IETSI como un desenlace final para evaluar la eficacia del tratamiento antiviral de pacientes con infección por VHC. Esto tiene sustento en la plausibilidad biológica del efecto de una carga viral baja, dado que la reducción de la carga viral hasta niveles indetectables impediría el daño del tejido hepático causado por el VHC. Además, existe evidencia que sugiere que el inicio de la terapia con antivirales guarda correlación con cambios en la epidemiología del cáncer y trasplante hepático (desenlaces a largo plazo). En relación con las interacciones entre sofosbuvir/velpatasvir y otros medicamentos, la evidencia sugiere que no se esperan interacciones clínicamente significativas entre sofosbuvir/velpatasvir y los inmunosupresores comunes. Asimismo, en la etiqueta comercial de sofosbuvir/velpatasvir aprobadas por la FDA y EMA, y en las guías de AASLD-IDSA y EASL, se señala que el uso de sofosbuvir/velpatasvir no requeriría que se hagan ajustes a las dosis de los medicamentos inmunosupresores. En la evaluación de la tecnología de interés del presente dictamen, se tomaron en cuenta: 1) el vacío terapéutico en EsSalud, 2) las tasas de RVS12 ≥ 98 % en pacientes con infección crónica en los grupos de genotipo 1 y 4 y sin cirrosis descompensada, 3) el bajo riesgo de EA relacionados al uso de sofosbuvir/velpatasvir, 4) la baja probabilidad de interacciones entre sofosbuvir/velpatasvir e inmunosupresores, 5) las recomendaciones de uso de sofosbuvir/velpatasvir en pacientes postrasplante renal y en pacientes con un mayor grado de fibrosis señaladas en las GPC internacionales y la guía de IETSI-EsSalud, y 6) la experiencia de uso de sofosbuvir/velpatasvir en EsSalud, ya que se utiliza para el tratamiento de otras poblaciones de pacientes con infecciones por VHC. Por lo expuesto, el IETSI aprueba el uso de sofosbuvir/velpatasvir en pacientes postrasplante renal con infección crónica por el VHC genotipos 1 o 4, con grado de fibrosis hepática F0 o F1. La vigencia del presente dictamen es de dos años, según lo establecido en el Anexo N° 1. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Alterações hidroeletrolíticas em pessoas com cirrose / Hydroelectrolytic alterations in cirrhotic patients

O objetivo deste estudo foi evidenciar e discutir as principais alterações hidroeletrolíticas em pessoas com cirrose. Trata-se de uma revisão integrativa, de natureza qualitativa. Os artigos foram selecionados por meio da plataforma Medical Literature Analysis and Retrievel System Online. Os principais achados identificados a partir dos artigos selecionados foram a ocorrência de hiponatremia, o mau prognóstico diante da presença de distúrbios hidroeletrolíticos em relação à sobrevida em pessoas com cirrose e a importância da albumina. Indivíduos com cirrose são suscetíveis ao desenvolvimento de distúrbios hidroeletrolíticos devido às mudanças fisiopatológicas da doença e às condições clínicas apresentadas. A hiponatremia e a hipocalemia são os mais recorrentes, destacando, porém, a necessidade de atenção aos demais distúrbios. (AU)

The objective of this study was to show and discuss the main hydroelectrolytic alterations in cirrhotic patients. This is an integrative review, a qualitative study, in which articles were selected at the Medical literature Analysis and Retrieval System Online. The main findings identified in the articles selected were the occurrence of hyponatremia, the poor prognostic, due to the presence of hydroelectrolytic disorders, regarding cirrhotic individuals survival and the importance of albumin. Individuals with cirrhosis are susceptible to the development of hydroelectrolytic disorders due to the pathophysiological alterations of the disease and because of the clinical status presented. Hyponatremia and hypokalemia are the most recurrent, but attention shall be given to the other disorders too. (AU)

Six-Minute Walking Test as a Predictor of Clinical Decompensation in Patients with Cirrhosis.

BACKGROUND AND AIMS: The 6-minute walk test (6MWT) is a measure of the overall functional capacity and is associated with the risk of mortality in patients with liver cirrhosis and in those listed for liver transplantation. Nevertheless, physical performance has not yet been established as a predictor of the risk of clinical decompensation in patients with cirrhosis. We aimed to determine the capacity of the 6MWT to predict the clinical decompensation in patients with cirrhosis after 1 year of follow-up. METHODS: This prospective cohort study included patients with compensated cirrhosis of several etiologies. All participants had stable clinical conditions for at least 6 months prior to baseline. At baseline, patients performed the 6MWT and were followed up for 1 year to detect the decompensation outcomes. RESULTS: A total of 55 participants completed the evaluation and follow-up. The mean age was 56.3±10.5 years, and 65% were men. Around 65.4% were classified as Child-Pugh class A. In the receiver operating characteristic analysis, a walking distance ≤ 401.8 m during the 6MWT was set as the threshold for predicting clinical decompensation with 64% sensitivity and 82% specificity. Kaplan-Meier curve analysis revealed that patients who covered a distance of < 401.8 m during the test had a decompensation-free outcome rate of 30% as compared to the rate of 75% of those who walked > 401.8 m (p<0.001). CONCLUSIONS: The 6MWT was a significant predictor of clinical decompensation in patients with cirrhosis. A cutoff of 401.8 m was related to an increased risk of clinical decompensation in cirrhotic patients with a stable clinical condition at baseline. The 6MWT should be added to the clinical assessment of the cirrhotic population.

Impact of hypoxemia on pediatric liver transplantation for hepatopulmonary syndrome.

BACKGROUND: The treatment of choice for patients with cirrhosis and HPS is LT. The clinical manifestations associated with hypoxemia result in limitations and a poor health-related quality of life of affected patients. The present report aims to study the differences in outcomes between patients with PaO2  < 50 mm Hg and those with PaO2  ≥ 50 mm Hg. METHODS: This was a retrospective study of 21 patients under 18 years of age conducted from 2001 to 2018; the patients were divided into 2 groups: G1-PaO2  ≥ 50 mm Hg, 11 patients, and G2-PaO2  < 50 mm Hg, 10 patients. Demographic, clinical, laboratory, and perioperative data; outcome variables; and post-transplant survival were compared between the groups. RESULTS: In total, 2/11 (18.2%) patients in G1 and 8/10 (80%) patients in G2 required supplemental oxygen therapy at home (P = .005). Patients in G2 required prolonged MV (median 8.5 days in G2 vs 1 day in G1, P = .015) and prolonged ICU and hospital stays (P = .002 and P = .001, respectively). Oxygen weaning time was longer in G2 (median 127.5 days) than in G1 (median 3 days; P = .004). One (9.1%) patient in G1 and three (30%) patients in G2 died (P = .22). The survival at 90 months was 90.9% in G1 and 70% in G2 (P = .22). CONCLUSION: The survival between groups was similar. Patients with very severe HPS required a longer MV time, longer ICU and hospital stays, and a longer O2 weaning time than those with mild, moderate, or severe HPS.

Blunted blood pressure response to exercise and isolated muscle metaboreflex activation in patients with cirrhosis.

We sought to test the hypothesis that the cardiovascular responses to isolated muscle metaboreflex activation would be blunted in patients with cirrhosis. Eleven patients with cirrhosis and 15 healthy controls were evaluated. Blood pressure (BP; oscillometric method), contralateral forearm blood flow (FBF; venous occlusion plethysmography), and heart rate (HR; electrocardiogram) were measured during baseline, isometric handgrip at 30% of maximal voluntary contraction followed by postexercise ischemia (PEI). Forearm vascular conductance (FVC) was calculated as follows: (FBF / mean BP) × 100. Changes in HR during handgrip were similar between groups but tended to be different during PEI (controls: Δ 0.5 ± 1.1 bpm vs. cirrhotic patients: Δ 3.6 ± 1.0 bpm, P = 0.057). Mean BP response to handgrip (controls: Δ 20.9 ± 2.7 mm Hg vs. cirrhotic patients: Δ 10.6 ± 1.5 mm Hg, P = 0.006) and PEI was attenuated in cirrhotic patients (controls: Δ 16.1 ± 1.9 mm Hg vs. cirrhotic patients: Δ 7.2 ± 1.4 mm Hg, P = 0.001). In contrast, FBF and FVC increased during handgrip and decreased during PEI similarly between groups. These results indicate that an abnormal muscle metaboreflex activation explained, at least partially, the blunted pressor response to exercise exhibited by cirrhotic patients. Novelty: Patients with cirrhosis present abnormal muscle metaboreflex activation. BP response was blunted but forearm vascular response was preserved. HR response was slightly elevated.

Myocardial Dysfunction in Cirrhotic Cardiomyopathy is Associated with Alterations of Phospholamban Phosphorylation and IL-6 Levels.

BACKGROUND: Decreased cardiac contractility has been observed in cirrhosis, but the mechanisms that initiate and maintain cardiac dysfunction are not entirely understood. AIM OF THE STUDY: We test the hypothesis that cirrhotic cardiomyopathy is related to deterioration of myocardial contractility due to alterations in calcium-handling proteins expression. In addition, we evaluated whether cardiac pro-inflammatory cytokine levels are associated with this process. METHODS: Cirrhosis was induced by thioacetamide (TAA, 100 mg/kg/i.p., twice weekly for eight weeks). The myocardial performance was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic challenge. The cardiac calcium handling protein expression was detected by Western blotting. Cardiac TNF-α and IL-6 levels were measured by ELISA. RESULTS: Thioacetamide induced liver cirrhosis, which was associated with cirrhotic cardiomyopathy characterized by in vivo left ventricular diastolic and systolic dysfunction as well as cardiac hypertrophy. In vitro baseline myocardial contractility was lower in cirrhosis. Also, myocardial responsiveness to post-rest contraction stimulus was declined. Protein expression for RYR2, SERCA2, NCX, pPBL Ser16 and L-type calcium channel was quantitatively unchanged; however, pPBL Thr17 was significantly lower while IL-6 was higher. CONCLUSIONS: Our study demonstrates that cirrhotic cardiomyopathy is associated with decreased cardiac contractility with alteration of phospholamban phosphorylation in association with higher cardiac pro-inflammatory IL-6 levels. These findings provided molecular and functional insights about the effects of liver cirrhosis on cardiac function.

Pro-Resolving Lipid Mediator Resolvin E1 Mitigates the Progress of Diethylnitrosamine-Induced Liver Fibrosis in Sprague-Dawley Rats by Attenuating Fibrogenesis and Restricting Proliferation.

Liver fibrosis is a complex process associated to most types of chronic liver disease, which is characterized by a disturbance of hepatic tissue architecture and the excessive accumulation of extracellular matrix. Resolvin E1 (RvE1) is a representative member of the eicosapentaenoic omega-3 lipid derivatives, and is a drug candidate of the growing family of endogenous resolvins. Considering the aforementioned, the main objective of this study was to analyze the hepatoprotective effect of RvE1 in a rat model of liver fibrosis. Male Sprague-Dawley rats received diethylnitrosamine (DEN, 70 mg/mg body weight intraperitoneally (i.p)) as an inductor of liver fibrosis once weekly and RvE1(100 ng/body weight i.p) twice weekly for four weeks. RvE1 suppressed the alterations induced by DEN, normalizing the levels of alanine aminotransferase (ALT), albumin, and lactate dehydrogenase (LDH), and ameliorated DEN injury by decreasing the architecture distortion, inflammatory infiltration, necrotic areas, and microsteatosis. RvE1 also limited DEN-induced proliferation through a decrease in Ki67-positive cells and cyclin D1 protein expression, which is related to an increase of the levels of cleaved caspase-3. Interestingly, we found that RvE1 promotes higher nuclear translocation of nuclear factor κB (NF-κB)p65 than DEN. RvE1 also increased the levels of nuclear the nuclear factor erythroid 2-related factor 2 (Nrf2), but with no antioxidant effect, measured as an increase in glutathione disulfide (GSSG) and a decrease in the ratio of glutathione (GSH)/GSSG. Taken together, these results suggest that RvE1 modulates the fibrogenesis, steatosis, and cell proliferation in a model of DEN induced fibrosis.

Hepatic manifestations and impact of COVID-19 on the cirrhotic patient. / Manifestaciones hepáticas y repercusión en el paciente cirrótico de COVID-19.

The novel SARS-CoV-2 coronavirus is responsible for the infectious disease caused by coronavirus 19 (COVID-19). The current pandemic is growing worldwide and could affect 50-60% of the world population in the months to come. The most severe disease manifestations are atypical pneumonia and sepsis, but the gastrointestinal tract, particularly the liver, has recently been reported to be affected by SARS-CoV-2. Therefore, the aim of the present work was to review the literature available on the topic and provide information about COVID-19, in both healthy and diseased livers, and issue recommendations. The incidence of liver injury specifically associated with COVID-19 varies from 14.8-53%. The majority of case series have reported altered ALT and AST, elevated total bilirubin, and low serum albumin and liver compromise has been associated with the most severe cases of COVID-19. Cirrhosis of the liver has a recognized immune dysfunction status that includes immunodeficiency and systemic inflammation, making it reasonable for those patients to be more susceptible to SARS-CoV-2 infection. The recommendations for those patients, in addition to the general measures of physical distancing and handwashing for all persons, include social, medical, and psychologic support during the period of home quarantine to prevent lapses in treatment. Patients should be made aware that they need to keep abreast of changes in recommendations and social policies.

The imperative for an updated cirrhosis surgical risk score.

The burden of cirrhosis is increasing, as is the need for surgeries in patients with cirrhosis. These patients have increased surgical risk relative to non-cirrhotic patients. Unfortunately, currently available cirrhosis surgical risk prediction tools are non-specific, poorly calibrated, limited in scope, and/or outdated. The Mayo score is the only dedicated tool to provide discrete post-operative mortality predictions for patients with cirrhosis, however it has several limitations. First, its single-center nature does not reflect institution-specific practices that may impact surgical risk. Second, it pre-dates major surgical changes that have changed the landscape of patient selection and surgical risk. Third, it has been shown to overestimate risk in external validation. Finally, and perhaps most importantly, the score does not account for differences in risk based on surgery type. The clinical consequences of inaccurate prediction and risk overestimation are significant, as patients with otherwise acceptable risk may be denied elective surgical procedures, thereby increasing their future need for higher-risk emergent procedures. Confident evaluation of the risks and benefits of surgery in this growing population requires an updated, generalizable, and accurate cirrhosis surgical risk calculator that incorporates the type of surgery under consideration.

Mitochondrial oxidative injury: a key player in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. NAFLD is tightly linked to the metabolic syndrome, insulin resistance, and oxidative stress. Globally, its inflammatory form, nonalcoholic steatohepatitis (NASH), has become the main cause of liver-related morbidity and mortality, mainly due to liver cirrhosis and primary liver cancer. One hallmark of NASH is the presence of changes in mitochondrial morphology and function that are accompanied by a blocked flow of electrons in the respiratory chain, which increases formation of mitochondrial reactive oxygen species in a self-perpetuating vicious cycle. Consequences are oxidation of DNA bases and mitochondrial DNA depletion that are coupled with genetic and acquired mitochondrial DNA mutations, all impairing the resynthesis of respiratory chain polypeptides. In general, several maladaptations of pathways that usually maintain energy homeostasis occur with the early and late excess metabolic stress in NAFLD and NASH. We discuss the interplay between hepatocyte mitochondrial stress and inflammatory responses, focusing primarily on events initiated and maintained by mitochondrial free radical-induced damage in NAFLD. Importantly, mitochondrial oxidative stress and dysfunction are modulated by key pharmacological targets that are related to excess production of reactive oxygen species, mitochondrial turnover and the mitochondrial unfolded protein response, mitophagy, and mitochondrial biogenesis. However, the efficacy of such interventions depends on NAFLD/NASH disease stage.

RESPIRATORY AND SYMPTOMATIC IMPACT OF ASCITES RELIEF BY PARACENTESIS IN PATIENTS WITH HEPATIC CIRRHOSIS.

BACKGROUND: Liver cirrhosis is a highly prevalent disease that, at an advanced stage, usually causes ascites and associated respiratory changes. However, there are few studies evaluating and quantifying the impact of ascites and its relief through paracentesis on lung function and symptoms such as fatigue and dyspnea in cirrhotic patients. OBJECTIVE: To assess and quantify the impact of acute reduction of ascitic volume on respiratory parameters, fatigue and dyspnea symptoms in patients with hepatic cirrhosis, as well as to investigate possible correlations between these parameters. METHODS: Thirty patients with hepatic cirrhosis and ascites who underwent the following pre and post paracentesis evaluations: vital signs, respiratory pattern, thoracoabdominal mobility (cirtometry), pulmonary function (ventilometry), degree of dyspnea (numerical scale) and fatigue level (visual analog scale). RESULTS: There was a higher prevalence of patients classified as CHILD B and the mean MELD score was 14.73±5.75. The comparison of pre and post paracentesis parameters evidenced after paracentesis: increase of predominantly abdominal breathing pattern, improvement of ventilatory variables, increase of the differences obtained in axillary and abdominal cirtometry, reduction of dyspnea and fatigue level, blood pressure reduction and increased peripheral oxygen saturation. Positive correlations found: xiphoid with axillary cirtometry, degree of dyspnea with fatigue level, tidal volume with minute volume, Child "C" with higher MELD score, volume drained in paracentesis with higher MELD score and with Child "C". We also observed a negative correlation between tidal volume and respiratory rate. CONCLUSION: Since ascites drainage in patients with liver cirrhosis improves pulmonary volumes and thoracic expansion as well as reduces symptoms such as fatigue and dyspnea, we can conclude that ascites have a negative respiratory and symptomatological impact in these patients.

Non-Alcoholic Cirrhosis and Heart Rate Variability: A Systematic Mini-Review.

. Background and Objectives: Cirrhosis is a liver disease that causes about one million deaths annually worldwide. The estimated cirrhosis prevalence ranges from 4.5-9.5% in the general population. Up to 40% of cirrhotic patients are asymptomatic and may be diagnosed late. Studies have described the importance of the functions of the liver and autonomic nervous system (ANS) and their relationship. There is limited information available on non-alcoholic cirrhosis and heart rate variability (HRV), which is a measure of the ANS. This study aimed to evaluate cardiac autonomic modulation through HRV in non-alcoholic cirrhosis individuals reported in previous observational and clinical trial studies. Materials and Methods: We performed a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement using the Medline, Scopus, and Web of Science electronic databases. Five studies were identified and reviewed. Results: HRV was decreased in patients with non-alcoholic cirrhosis, even in the first stage. Conclusions: HRV could be used as a complementary method to improve both the diagnosis and prognosis of non-alcoholic cirrhosis.

Eficacia y seguridad de sofosbuvir/velpatasvir en pacientes con infección crónica por el virus de la hepatitis c sin tratamiento sistémico previo, con grado de fibrosis hepática F0 y F1, y con coinfección por el virus de la inmunodeficiencia humana / Efficacy and safety of sofosbuvir/velpatasvir in patients with chronic hepatitis C virus infection without prior systemic treatment, with liver fibrosis grade F0 and F1, and with human immunodeficiency virus co-infection

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de sofosbuvir/velpatasvir (SOF/VEL), comparado con la mejor terapia de soporte (MTS) en pacientes con la infección crónica por el virus de la hepatitis C (VHC), sin tratamiento sistémico previo, con grado de fibrosis hepática F0 y F1 y con coinfección por el virus de la inmunodeficiencia humana (VIH). En el Perú, los pacientes con infección crónica por el virus de la hepatitis C (VHC) con coinfección con el virus de la inmunodeficiencia humana (VIH) (coinfección VIH/VHC) representan alrededor del 1 % al 4 % de la población total de los pacientes seropositivos para el VIH. Los pacientes con la coinfección VIH/VHC presentan una progresión más rápida de daño hepático (i. e. fibrosis hepática o cirrosis) que aquellos con infección única con el VHC, por lo cual, la Organización Mundial de la Salud (OMS) ha sugerido la priorización de los tratamientos antivirales en el primer grupo de pacientes. Para el tratamiento de pacientes con la coinfección VIH/VHC, el Petitorio Farmacológico de EsSalud cuenta con diversos medicamentos de terapia antiretroviral (TARV) para el VIH. Además, el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 0

Non-Alcoholic Fatty Liver Disease Is Associated with Impairment of Ejection Fraction Among Individuals with Obesity Undergoing Bariatric Surgery: Results of a Cross-Sectional Study.

BACKGROUND: The relationship between non-alcoholic fatty liver disease (NAFLD) and myocardial function seems to be more than just the effect of mutual metabolic risk factors. OBJECTIVE: To determine whether there is a significant association between NAFLD assessed by means of liver biopsy and left ventricular function expressed by the estimated ejection fraction among individuals with obesity. METHODS: This is a cross-sectional study which enrolled individuals who consecutively underwent bariatric surgery. NAFLD was assessed by means of liver biopsies which were systematically collected during the procedures. The estimated ejection fraction was obtained by means of transthoracic echocardiograms. The main outcome evaluated was a possible association between NAFLD features and ejection fraction. The results of liver biopsies and the respective degrees of severity of each NAFLD feature were also correlated with the ejection fraction and main anthropometric, biochemical, and clinical variables. RESULTS: Of 112 individuals, 86.6% were female and the mean age was 38.5 ± 9.3 years. It was observed that the average estimated ejection fraction (EEF) was significantly lower among individuals with liver fibrosis (67.6 ± 5.5% vs. 70.8 ± 4.9%, p = 0.008). After adjustment for confounding variables in a multivariate model, the degree of liver fibrosis was independently associated with the EEF (R = - 0.3, p = 0.02). CONCLUSION: Among individuals with morbid obesity, the findings of this study are suggestive that liver fibrosis confirmed by histopathological examination is associated with a slight impairment of left ventricular function. Further studies are needed to confirm this association.

Dietary total antioxidant capacity is positively associated with muscular strength in cirrhotic outpatients: a cross-sectional study.

BACKGROUND: Cirrhosis is the end-stage of progressive fibrosis, in which oxidative stress and inflammation-related pathways can modulate the cellular and tissue events involved in the pathogenesis of liver fibrosis. Dietary intake of antioxidants has been suggested to protect against oxidative damage and related clinical complications. The present study aimed to investigate the potential association of the dietary total antioxidant capacity (dTAC) with anthropometric, functional and biochemical markers, as well as the severity of the disease, in cirrhotic outpatients. METHODS: Sixty-two outpatients (38 men and 24 women) with a mean (SD) age of 59.1 (9.9) years were evaluated. Dietary TAC was estimated from a food frequency questionnaire. Aetiology and severity of liver cirrhosis, lifestyle characteristics, occurrence of comorbidities and oedema, and anthropometric, functional and biochemical markers were all assessed. RESULTS: Cirrhotic outpatients with higher dTAC also had higher values of the hand-grip strength (P = 0.029) and arm muscle area (P = 0.027). After adjusting by sex, age, smoking and alcohol intake, the addition of 1 mmol day-1 of dTAC contributed to increase 0.552 kg f-1 in hand-grip strength (P < 0.05). The addition of one mmol day-1 of dTAC contributed to an arm muscle area increase 0.565 cm2 (P < 0.05) on average. CONCLUSIONS: The dTAC was positively associated with hand-grip strength and arm muscle area in cirrhotic outpatients. The implications of the present study are important in clinical practice because a diet rich in antioxidants may be an ally in the control of excessive reactive oxygen species production in cirrhotic outpatients with repercussion on muscle mass and strength.

Mechanisms of kidney dysfunction in the cirrhotic patient: Non-hepatorenal acute-on-chronic kidney damage considerations.

Renal dysfunction is a common finding in cirrhotic patients and has a great physiologic, and therefore, prognostic relevance. The combination of liver disease and renal dysfunction can occur as a result of systemic conditions that affect both the liver and the kidney, although primary disorders of the liver complicated by renal dysfunction are much more common. As most of the renal dysfunction scenarios in cirrhotic patients correspond to either prerenal azotemia or hepatorenal syndrome (HRS), physicians tend to conceive renal dysfunction in cirrhotic patients as mainly HRS. However, there are many systemic conditions that may cause both a "baseline" chronic kidney damage and a superimposed kidney dysfunction when this systemic condition worsens. The main aim of this article is to review some of the most important non prerenal non-HRS considerations regarding acute on chronic kidney dysfunction in cirrhotic patients, including renal manifestation of related to non-alcoholic steatohepatitis (NASH) viral hepatitis, the effect of cardiorenal syndrome in cirrhotics and corticosteroid-deficiency associated renal dysfunction.

Liver transplant candidates have impaired quality of life across health domains as assessed by computerized testing.

INTRODUCTION AND OBJECTIVES: Liver transplantation candidates are among the most comorbid patients awaiting lifesaving intervention. Health related quality of life (HRQOL) measured by instruments that incorporate dynamic computerized adaptive testing, could improve their assessment. We aimed to determine the feasibility of administration of the Patient-Reported Outcomes Measurement Information System (PROMIS-CAT) in liver transplant candidates. MATERIALS AND METHODS: Liver transplantation candidates were prospectively enrolled following a review of their available medical history. Subjects were given a tablet computer (iPad) to access the pre-loaded PROMIS CAT. RESULTS: 109 candidates with mean age 55.6±8.6 years were enrolled in this pilot study. Mean MELD-Na score was 16.3±6.3; 92.6% had decompensated liver disease. Leading etiologies of cirrhosis included hepatitis C (34.8%), nonalcoholic steatohepatitis (25.7%) and alcohol (21.1%). Subjects with MELD-Na score>20 had the most significant impairment in HRQOL (anxiety/fear+5.9±2.7, p=0.0289, depression+5.1±2.5, p=0.0428, fatigue+4.3±2.6, p=0.0973) and physical impairment (-7.8±2.5, p=0.0022). Stage of cirrhosis and decompensated liver disease were predictive of impaired HRQOL but Child-Pugh Turcotte score was not. Hepatic encephalopathy was the strongest independent predictor of impaired HRQOL, with significant impairment across all domains of health. CONCLUSIONS: Liver transplant candidates have significantly impaired HRQOL across multiple domains of health as measured by PROMIS-CAT. HRQOL impairment parallels disease severity. Future study is needed to determine how best HRQOL could be systematically included in liver transplantation listing policy, especially in those candidates with hepatic encephalopathy.