Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis

BACKGROUND AND AIMS: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy, but also has pleiotropic deleterious effects on several organ systems, impacting on immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS: We collected data from 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analysis and fast unified random forest were performed to predict complications and mortality. External validation was carried out using prospective data from 130 cirrhotic patients in an independent tertiary liver centre. RESULTS: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (HR=2.13; 95%CI=1.89-2.40; p<0.001) and mortality (HR=1.45; 95%CI=1.20-1.76; p<0.001). AUROC of AMM-ULN was 77.9% for 1-year complications, higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p<0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients

Hepatitis C Virus Clearance by Direct-Acting Antivirals Agents Improves Endothelial Dysfunction and Subclinical Atherosclerosis: HEPCAR Study

© 2020 The Author(s).[INTRODUCTION]: Hepatitis C virus (HCV) infection has been related to increased cardiovascular (CV) risk. The aim of this study was to analyze the impact of sustained virological response (SVR) on endothelial dysfunction and subclinical atherosclerosis in patients with hepatitis C virus treated with direct-acting antiviral agents. [METHODS]: A total of 114 patients were prospectively recruited and underwent CV risk assessment including (i) endothelial dysfunction determined through laser Doppler flowmetry and (ii) subclinical atherosclerosis, elucidated by the ankle-brachial index (ABI). Atherogenic lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides); markers of oxidative stress (oxidized low-density lipoprotein antibodies [OLAbs]), soluble markers of adhesion (vascular cell adhesion molecule [VCAM], e-selectin, and soluble markers of angiogenesis; and vascular endothelial growth factor, endothelial [EMPs] and platelet [PMPs] apoptotic microparticles, and cell-free DNA [cfDNA]) were measured. All determinations were performed at baseline, 12 weeks (SVR time), and 1 year after treatment. [RESULTS]: In patients with endothelial dysfunction, area of hyperemia improved after virus clearance (P = 0.013) and was related to significant decrease in VCAM, e-selectin (P < 0.001), and cfDNA (P = 0.017) and to increased OLAb levels (P = 0.001). In patients with subclinical atherosclerosis at baseline, a significantly improved ABI was seen after HCV clearance (P < 0.001). Levels of both EMPs and PMPs also decreased after SVR and at follow-up (P = 0.006 and P = 0.002, respectively). [DISCUSSION]: HCV clearance improved not only liver function but also endothelial dysfunction and subclinical atherosclerosis promoted by decrease in levels of VCAM, e-selectin, cfDNA, and PMPs and EMPs.Postdoctoral fellowship from the Spanish Government (Juan de la Cierva fellowship FJC1-2014-21675). Instituto de Salud Carlos III Project GLD17/00203

Predictores de reingreso precoz en población con cirrosis hepática

La cirrosis hepática es una enfermedad crónica que se asocia a una gran morbi-mortalidad, a menudo con requerimiento de ingreso hospitalario si aparece una complicación, y a un gran coste socio-económico. En este sentido, es crucial determinar qué pacientes van a reingresar tras una hospitalización. Sin embargo, no existen escalas pronósticas que determinen dicho riesgo en la actualidad. Objetivos: a) Identificar factores de riesgo asociados a reingreso a los 30 días en pacientes con cirrosis; b) Establecer grupos de riesgo para reingreso y mortalidad en 7, 30 y 90 días; c) Valorar la aplicabilidad del modelo predictivo en la gestión de consultas tras el alta. Métodos: Estudio multicéntrico retrospectivo con 1257 pacientes con cirrosis que tuvieron ingreso en Aparato Digestivo y fueron seguidos durante 90 días posteriores al alta. Se recogieron reingresos vía urgente durante el seguimiento, y el éxitus de cualquier causa. Se calculó el índice LACE que comprende el índice Charlson, número de veces en urgencias 6 meses antes, ingreso urgente vs. programado y duración del ingreso. Resultados: Se incluyeron finalmente 1123 pacientes, que se dividieron en cohorte de estimación (fase I), de 818 pacientes, y en cohorte de validación (fase II), de 305 pacientes, para confirmar los resultados obtenidos previamente. De los 818 pacientes de la cohorte de estimación, el 23,2% (190/818) y el 42,4% (347/818) reingresaron en 30 y 90 días, respectivamente, mientras que el 13,6% (111/818) fallecieron. El principal motivo de ingreso fue la ascitis (49,8%), seguida de insuficiencia renal (35,1%), y la hemorragia digestiva alta (26,5%), y el de reingreso en <30 días fue encefalopatía (35%). El índice LACE (HR 1,11 (IC95% 1,07-1,16); p=0,001), MELD al alta (HR 1,05 (IC95% 1,01-1,05); p=0.,01) y descompensación previa al ingreso (HR 1,35 (IC95% 1,09-1,65); p=0,005) se asociaron independientemente al reingreso en <30 días, mientras que el sodio sérico resultó ser un factor protector (HR 0,98 (IC95% 0,96-0,99); p=0,002). El modelo obtenido a partir de estas variables presentó curvas ROC para predecir el reingreso en torno a 0,95 para ambas cohortes, de forma estadísticamente significativa, y con valores muy superiores al índice de LACE, y las escalas MELD y Child-Pugh de forma aislada. Además, predijo dos grupos de riesgo de reingreso según 95% de especificidad, así como para supervivencia durante el seguimiento, observando una diferencia estadísticamente significativa entre los grupos de alto y bajo riesgo, desde el inicio del seguimiento. Aunque el tiempo hasta consulta de revisión post-hospitalización fue similar entre grupos (48,9 vs. 46,8 días) (p=0.593), el 75%% (177/220) del grupo de alto riesgo reingresó antes de acudir a la consulta frente al 10,5% (91/867) del grupo bajo riesgo. Conclusión: La combinación del índice LACE, la existencia de descompensación previa al ingreso, y el MELD y los niveles séricos de sodio al alta predijo e identificó grupos de riesgo de reingreso y mortalidad en <30 y <90 días en pacientes con cirrosis. Este modelo predictivo debería considerarse en práctica clínica para programar las consultas de revisión tras la hospitalización

Post-transfusion hyperhemolysis syndrome following gastrointestinal bleeding secondary to prehepatic portal hypertension.

Supportive transfusion represents a basic tool in the management of gastrointestinal (GI) bleeding. However, the use of hemoderivatives is not exempt from risks such as development of hemolysis. We report a case of post-transfusion hyperhemolysis syndrome in a female patient with prehepatic portal hypertension

Impact of liver injury on the severity of COVID-19: Systematic Review with Meta-analysis

Background and Aims SARS-CoV-2 is mainly a respiratory virus that has relevant systemic effects. We assessed the impact of the baseline liver function (AST, ALT, and bilirubin) on COVID-19-related outcomes, including on mortality, intensive care unit admission, and non-fatal severe complications. Methods After a systematic review of the relevant studies, odds ratio, mean difference, sensitivity, specificity, and positive and negative likelihood ratios, were calculated for the prediction of relevant COVID-19 outcomes by performing a meta-analysis using fixed and random effects models. A Fagan nomogram was used to assess the clinical utility. Heterogeneity was explored by sensitivity analysis and univariable meta-regression. Results Twenty-six studies were included (22 studies and 5271 patients for AST, 20 studies and 5440 subjects for ALT, and 9 studies and 3542 patients for bilirubin). The outcomes of the studies were: survival (n=8), intensive care unit admission (n=4), and non-fatal severe complications (n=16). AST>ULN (OR 3.10 (95 %CI 2.61-3.68)), ALT>ULN (OR 2.15 (95 %CI 1.43-3.23)), and bilirubin >ULN (OR 2.78 (95 %CI 1.88-4.13)) were associated with an increased prevalence of severe complications, with 78 %, 77 % and 94 % of specificity, respectively. The mean difference between mild and severe COVID-19 was 10.7 U/L (95 %CI 5.8-15.6) for AST, 8 U/L (95 %CI 1.0-15) for ALT, and 0.3 mg/dL (95 %CI 0.16-0.45) for bilirubin. Conclusions Patients showing liver injury had significantly higher risks of developing severe COVID-19 compared to those with normal liver function tests at admission. We should include the assessment of AST, ALT, and total bilirubin routinely in patients affected by SARS-CoV-2 in order to anticipate those at risk of developing COVID-19-related outcomes.This project has been partially funded by the “Consejería de Salud de la Junta de Andalucía” (PI-0075-2014), the “Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).Peer reviewe

Performance of different biomarkers for the management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second cause of cancer related death due to latent liver disease, late diagnosis and non-available therapeutic treatment. Liver biopsy is still the gold standard in order to know the molecular biology of the tumor, its behaviour and invasive characteristics. Conventional diagnosis methods for HCC detection include imaging and serological tests with low sensitivity and specificity. In this review, we focus on the potential utility of certain serum biomarkers and a new approach, “liquid biopsy”, in the management of HCC patients

Long non-coding RNA H19 as a biomarker for hepatocellular carcinoma

[Background and Aims] Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer.[Methods] LncRNA-H19 expression levels and the functional assays were conducted in EpCAM+CD133+ CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort.[Results] EpCAM+CD133+ cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025).[Conclusion] LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC.The research leading to these results has received funding from the Ministry of Health of the Government of Andalusia under grant agreement PC-0033-2017 and from the Instituto de Salud Carlos III under grant agreements PI16/01842, PI19/01404 and PI19/00589. Ángela Rojas has received the Sara Borrell postdoctoral fellowships from Instituto de Salud Carlos III CD18/00126 to support her postdoctoral contract.Peer reviewe

Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study

Background and aims: To assess whether corticosteroids improve prognosis in patients with AS-AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids. Methods: This was a retrospective cohort study including all patients with AS-AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan-Meier and Cox regression methods were used for data analysis. Results: Of 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90-day transplant-free survival was 61.6% (95% confidence interval [CI] 55.4-67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2-0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C-index 0.82; [95% CI 0.8-0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non-responders. MELD on day 7 with a cut-off of 25 (sensitivity 62.5%[95% CI: 47.0-75.8]; specificity 95.2% [95% CI: 89.9-97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3-2.1). Conclusion: Older patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided.This study was supported in part by grants from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, number PI20/01302, awarded to Agustín Albillos and number PI 21/01310, awarded to Luis Téllez. CIBEREHD is funded by the Instituto de Salud Carlos III using grants cofinanced by the European Development Regional Fund “A way to achieve Europe” (EDRF). María Carlota Londoño received support from the Plan Nacional de I+D+I co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa") (PI17/00955). Laura Patricia Llovet received the Resident Award “Clínic-La Pedrera” granted by the Hospital Clínic de Barcelona, Research, Innovation and Education Department