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

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

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

Hepatocellular carcinoma in patients without advanced fibrosis after HCV eradication antiviral treatment.

From the last few years, hepatitis C virus and the new direct antiviral treatments are being more and more important. In consequence, case studies like the one we present, the appearance of hepatocelullar carcinoma after its eradication with fibrosis grade 2, are getting special interest. In 2007, our patient was treated with pegylated interferon α-2a and ribavirin, having a sustained virological response after it. In this way, liver fibrosis grade 2 was confirmed by a biopsy. Finally, after corroborating a good liver functioning, the patient was discharged (as, according to the guidebooks, an ultrasound scan of screeing every 6 months was not required). In 2014, the patient came to hospital because of a pain at right hypochondrium and he was diagnosed with hepatocelullar carcinoma. A hepatectomy was done objectifying the surgical piece, liver fibrosis grade 2, one more time. Subsequently, a tumour relapse through an abdominal CT scan, a tumour relapse was found and despite the Sorafenib treatment, the patient died on January 2015. This case study provokes curiosity and uncertainty about the attitude which should be taken respect to the monitoring, and hepatocelullar carcinoma screening overall, in patients with a sustained virological response after eradicator treatment and without advanced fibrosis. Nowadays, with the benefits of the new treatments, the amount of patients in this situation is increasing significantly

New therapeutic perspectives in non-alcoholic steatohepatitis

Management of non-alcoholic steatohepatitis is focused on restitution of metabolic derangement, weight loss and drugs able to improve steatosis, ballooning and fibrosis. Life-style interventions based on Mediterranean diet and increasing physical activity are the first line ther apy. In patients with unsuccessful life-style intervention several drugs are under development: agonist PPAR, agonist GLP-1R and agonist FXR together with drugs focussing on inflammation, ballooning, apoptosis and fibrosis. Bariatric surgery or advanced endoscopy are reserved for morbid obese without response to life-style intervention and weighting loss drugs

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

Analysis of the burden and variability in the management of NAFLD patients in the clinical practice: unifying the required criteria

[Aim] to assess the prevalence of non-alcoholic fatty liver disease (NAFLD) in the gastroenterology outpatient clinic and describe the use of the resources accordingly. Methods: a prospective and observational study of 403 patients seen in the gastroenterology outpatient clinic to rule out liver disease during three randomized months in 2016. The overall prevalence of NAFLD, disease severity, heterogeneity of the final diagnosis, the use of medical resources and their respective cost were analyzed.[Results] the main reason for consultation was hypertransaminasemia (42.9%, 173/403), followed by hepatitis C virus (HCV) (28.5%, 115/403). NAFLD was identified as the definitive diagnosis in 29.8% (120/403) of the cohort, 69.2% (83/120) derived by hypertransaminasemia and 24.2% (29/120) by steatosis. Laboratory tests were performed in 96.7% (116/120), abdominal ultrasound in 88.3% (106/120), viral serology in 79.2% (95/120) and autoimmunity in 70% (84/120) of patients with NAFLD. Liver fibrosis was not assessed in 87.5% of cases. In a post-hoc analysis, 12.1% (17/120) had advanced fibrosis by FIB-4. On ultrasound, 65% (73/106) had hepatic steatosis and 15% (17/106) chronic liver disease (significant fibrosis). The mean time for diagnosis was 2.23 ± 0.8 visits. The terminology used to define the clinical diagnosis was heterogeneous as follows: a) 48.3% (58/120) hepatic steatosis; b) 15% (18/120) non-alcoholic steatohepatitis; c) 15.8% (19/120) fatty liver; d) 13.3% (16/120) metabolic syndrome; and e) 7.5% (9/120) dual liver disease (fatty liver and alcohol). A pharmacological intervention was performed in six patients, a liver biopsy in two patients and another six were referred to another specialist. The average cost per patient until diagnosis was €570.78, which included analytical, autoantibodies, viral serology and abdominal ultrasound, with a mean of 2.5 consultations. Thus, the total expense in patients with NAFLD was €68,493.6.[Conclusion] NAFLD is a frequent cause of hypertransaminasemia. However, the heterogeneity in the management and terminology of the disease makes it necessary to initiate medical training actions in order to unify the criteria for disease control.Peer reviewe