Longitudinal relationship of liver injury with inflammation biomarkers in COVID-19 hospitalized patients using a joint modeling approach.

The mechanisms underlying liver disease in patients with COVID-19 are not entirely known. The aim is to investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19. The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy. The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19.

Clinical and capillaroscopic findings in patients with liver disease and proximal apparent leukonychia (Terry nails and its variants).

ABSTRACT: Terry nails and Lindsay nails are similar forms of proximal apparent leukonychia (PAL). A change in nail bed vascularity is thought to be responsible for PAL. The study was aimed at investigating the frequency of PAL in patients attending a liver disease clinic, the factors associated with its presence, its value for detecting cirrhosis, its prognostic value for mortality, and associated capillaroscopic findings.A total of 521 patients were included (age range, 18-94 years; 69% men). Systematic nail photographs were evaluated by 2 independent investigators. Disease-related data were obtained from the medical records. Mortality was evaluated after 7 years of follow-up. Nailfold capillaroscopy was performed on a subset of 80 patients.PAL was present in 228 patients (43.8%; Terry nails in 205, Lindsay nails in 20, and both in 3). The kappa-coefficient of interobserver agreement was 0.82. The presence of PAL was associated with cirrhosis and, accordingly, with portal hypertension and hepatocellular dysfunction. The positive likelihood ratio of PAL for the diagnosis of cirrhosis was 1.6 (95% CI 1.3-1.92). PAL was independently associated with chronic alcohol abuse and was not a significant predictor of mortality. Venous loop dilatation and prominence of the venous plexus were observed on capillaroscopy in patients with cirrhosis but were not significantly associated with PAL.In summary, PAL is a common finding in patients from a liver clinic; it is associated with liver cirrhosis and with alcohol abuse. PAL is not associated with specific capillaroscopic findings. We propose the generic term proximal apparent leukonychia instead of classic eponymous titles to avoid confusion in the literature.

Time-Course Changes of Serum Keratin Concentrations after Liver Transplantation: Contrasting Results of Keratin-18 and Keratin-19 Fragments.

OBJECTIVE: Under normal conditions, adult hepatocytes express only keratin-8 (K8) and keratin-18 (K18), whereas cholangiocytes also express K19. In this study, we delineate the pattern of normal time-course changes in serum K19 and K18 levels after liver transplantation. Patients and Methods. Serum levels of the K19 fragment CYFRA 21-1 and the K18 fragments tissue polypeptide specific antigen (TPS) and M30 (a neoepitope that is generated after caspase cleavage during apoptosis) were measured at baseline and at regular intervals (up to 6 months) after liver transplantation in 11 adult patients. RESULTS: There was a gradual decrease in serum K19 concentrations from baseline values after transplantation, following a time-course pattern similar to that of serum bilirubin. In contrast, serum concentrations of K18 fragments increased markedly shortly after transplantation and gradually decreased thereafter, following a time-course pattern similar to that of serum transaminases. The increase in TPS tended to occur earlier than that in M30, suggesting an initial predominance of hepatocyte necrosis followed by a predominance of apoptosis in the first days after transplantation. Five patients presented posttransplant complications (acute rejection in three cases and HCV recurrence in two cases). An early increase in serum K19 concentrations was observed in all cases. An increase in serum concentrations of K18 fragments (M30 and TPS) was observed in the two cases with HCV recurrence and was more variable in the three cases with acute rejection. CONCLUSIONS: Serum concentrations of K19 and K18 fragments follow a dissimilar pattern of time-course changes after liver transplantation. The diagnostic value of variations in these normal patterns should be addressed in future studies.

Cardiovascular morbidity and mortality after liver transplantation: The protective role of mycophenolate mofetil.

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials.

BACKGROUND: Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower. METHODS: All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure. RESULTS: A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3-F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4. CONCLUSIONS: Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.

Factores de riesgo relacionados con la prevalencia de sobrepeso y obesidad en adolescentes / Risk factors associated with the prevalence of overweight and obesity among adolescent / Os fatores de risco associados com a prevalência de sobrepeso e obesidade entre adolescentes

Objetivo: identificar los factores de riesgo relacionados con la prevalencia de sobrepeso y obesidad en adolescentes entre 10 y 18 años que pertenecen a los colegios públicos de la ciudad de Cúcuta, durante el primer semestre del 2014. Materiales y Métodos: estudio descriptivo de corte transversal; con una población: 61.172 adolescentes y una muestra de 382 estudiantes matriculados en los colegios públicos de Cúcuta. El instrumento fue diseñado por las investigadoras para valorar las características sociodemográficas, medidas antropométricas, factores endógenos, exógenos y percepción del exceso de peso y de su imagen. Resultados: el exceso de peso presento alta proporción en la adolescencia temprana y en el estrato socioeconómico 2. Predominio de sobrepeso en mujeres y obesidad en hombres. En los factores endógenos asociados con estos trastornos, prevaleció el antecedente familiar de sobrepeso y obesidad, además recibieron otra alimentación y no leche materna durante los primeros seis meses, y como antecedentes personales presentaron ansiedad y parto prematuro. En los factores exógenos la alimentación de los adolescentes con sobrepeso es alta en grasas y en los obesos es alta en azúcares, baja en verduras y fibra. Los estudiantes con déficit y con peso normal, se sienten flacos y sanos; los adolescentes con sobrepeso perciben su silueta mayor, y los obesos la perciben menor a la establecida para su índice de masa corporal. Conclusiones: los adolescentes escolarizados presentan una alta prevalencia de sobrepeso y obesidad, observándose una mayor preponderancia de factores de riesgo endógenos y exógenos. De igual manera, presentan una imagen corporal que no corresponde a su estado nutricional.

Objective: to identify risk factors associated with the prevalence of overweight and obesity in adolescents aged 10 to 18 who belong to public schools in Cucuta city, in the first half of 2014. Materials and Methods: a descriptive cross-sectional study; population: 61,172 adolescents as a sample: 382 students enrolled in public schools in Cúcuta. The instrument was designed by the researchers to assess sociodemographic, anthropometric measurements, endogenous factors, exogenous and perception of overweight and image. Results: there was a high overweight proportion in early adolescence and socioeconomic level 2: prevalence of overweight in women and obesity in men. According to endogenous factors associated with these disorders, the prevailing factors were: family history of overweight and obesity in addition they didn`t have other food and breast milk for the first six months, and as personal history showed anxiety and prematurity. In the exogenous factors, the adolescent feeding is high in fat and in obese adolescents is high in sugar, low in vegetables and fiber. Students with deficit and normal weight, feel thin and healthy; overweight adolescents perceive their greater size shape, obese students perceive a lower size than the established one for BMI. Conclusions: school teenagers have a high prevalence of overweight and obesity, showing a greater preponderance of endogenous and exogenous risk factors. Similarly, the body image of the adolescents does not correspond to their nutritional state.

Objetivo: identificar fatores de risco associados com a prevalência de sobrepeso e obesidade em adolescentes de 10 a 18 anos que pertencem a escolas públicas na cidade de Cucuta, no primeiro semestre de 2014. Materiais e Métodos: um estudo descritivo transversal ; População: 61,172 adolescentes mostra: 382 alunos matriculados em escolas públicas de Cúcuta. O instrumento foi projetado pelos pesquisadores para avaliar sociodemográficas, medidas antropométricas, fatores endógenos, exógeno e percepção de excesso de peso e sua imagem. Resultados: sobrepeso alta proporção presente no início da adolescência e estratos sócio-econômicos 2: prevalência de excesso de peso em mulheres e obesidade em homens. Em fatores endógenos associados a esses distúrbios, a história da família predominante do sobrepeso e obesidade, além recebeu nenhum outro leite alimentos e de mama para os primeiros seis meses e, como história pessoal mostrou ansiedade e prematuridade. Nos factores exógenos alimentação adolescentes com sobrepeso é rico em gordura e obesidade é rico em açúcar, pobre em vegetais e fibras. Estudantes défice e de peso normal, se sentir magra e saudável; adolescentes com sobrepeso percebem sua maior silhueta, obesos e perceber inferiores aos estabelecidos para o IMC. Conclusões: adolescentes escola tem uma alta prevalência de sobrepeso e obesidade, mostrando uma maior preponderância de fatores de risco endógeno e exógeno. Da mesma forma, uma imagem do corpo que não corresponde ao seu estado nutricional é apresentada.

Improvement of renal function after the switch from a calcineurin inhibitor to everolimus in liver transplant recipients with chronic renal dysfunction.

Chronic renal dysfunction is a frequent and severe complication in solid-organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty-one liver transplant recipients (19 males, mean age = 60.6 +/- 7.8 years) with chronic renal dysfunction (creatinine >or= 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 +/- 0.39 mg/dL (range = 1.50-2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft-Gault formula, was 54.64 +/- 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow-up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 +/- 0.40 (P = 0.012 with respect to basal values), 1.67 +/- 0.34 (P = 0.107), 1.70 +/- 0.41 (P = 0.521), and 1.57 +/- 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 +/- 16.50 (P = 0.013 with respect to basal values), 59.49 +/- 13.27 (P = 0.028), 59.82 +/- 16.83 (P = 0.124), and 64.46 +/- 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection.

Epithelioid hemangioendothelioma in the posterior mediastinum.

Epithelioid hemangioendothelioma is a rare neoplasm usually presenting in soft tissues. A case of epithelioid hemangioendothelioma arising in the posterior mediastinum and presenting as a large pleural effusion in a young woman is presented.

Serum levels of cytokeratin-18 (tissue polypeptide-specific antigen) in liver diseases.

OBJECTIVE: The tissue polypeptide-specific antigen (TPS, cytokeratin-18, a normal constituent of the hepatocyte cytoskeleton) is a standard tumour marker. This study aimed to evaluate serum TPS levels in patients with liver disease. METHODS: Serum TPS was measured with a commercial immunoassay in 884 individuals (753 outpatients from a liver disease clinic, 131 patients admitted to the hospital with acute liver disease). RESULTS: Abnormally high (> 80 U/l) TPS levels were found in 57.7% (95% CI 54.0-61.3%) of outpatients with liver disease. Elevated TPS levels were observed for all liver diseases, including fatty liver, alcoholic disease, chronic viral hepatitis, autoimmune hepatitis, cholestasis, transplantation, and hepatocarcinoma. TPS levels correlated with liver markers, particularly serum AST. In addition, TPS levels correlated with Knodell's score in patients with chronic hepatitis. TPS was increased in one-third of patients with normal liver enzyme values. Serum TPS levels decreased after specific therapy in patients with hepatitis C and autoimmune hepatitis. Abnormally high TPS levels were found in the vast majority of patients admitted to the hospital, with markedly high (> 800 U/l) values being observed in 47.5% (95% CI 36.1-55.7%) of patients with alcoholic liver disease and in 80.8% (95% CI 60.0-92.7%) of patients with acute hepatitis. CONCLUSIONS: Serum TPS (cytokeratin-18) is elevated in patients with non-malignant liver diseases, particularly in those with prominent cytolysis. Further studies are needed to evaluate the use of TPS as a marker of liver disease.

Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease.

BACKGROUND/AIMS: Alcoholic cirrhosis is a common indication for liver transplantation. The present study was aimed to assess the influence of superimposed alcoholic hepatitis on the outcome of liver transplantation in patients with alcoholic cirrhosis. METHODS: Survival rates of 68 patients transplanted for alcoholic cirrhosis were compared with those of 101 patients transplanted for miscellaneous causes. Within the alcoholic group, explanted livers were searched for data of acute alcoholic hepatitis. The survival rate of patients with alcoholic hepatitis superimposed on liver cirrhosis was compared to that of patients with liver cirrhosis alone. Clinical severity of alcoholic hepatitis was assessed with Maddrey's score. RESULTS: Survival was similar in alcoholics and patients with other causes of liver disease. Among patients transplanted for alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis (n=36) and in cases with liver cirrhosis alone (n=32). There was no difference in survival between patients with mild (n=26) and severe (n=10) alcoholic hepatitis. Seven alcoholics (10%) returned to ethanol consumption. Recidivism was not associated with either alcoholic hepatitis in the explanted liver or graft loss. CONCLUSIONS: Survival after liver transplantation in patients with alcoholic cirrhosis plus alcoholic hepatitis detected in the explanted liver is similar to that of patients transplanted for other reasons. Even the presence of severe alcoholic hepatitis does not worsen the outcome of liver transplantation for end-stage alcoholic liver disease.