Serum Cytokeratin-18 levels as a prognostic biomarker in advanced liver disease: a comprehensive meta-analysis.

Cytokeratin-18 (CK-18) is a marker of hepatic cell death. Serum CK-18 could serve as a prognostic marker for patients with advanced liver disease (ALD). This meta-analysis aims to explore the association between total CK-18 (M65) and caspase-cleaved CK-18 (M30) levels with the prognosis of ALD patients. Relevant longitudinal observational studies were identified through comprehensive searches of the Medline, Web of Science, and Embase databases. A random-effects model was utilized to synthesize the findings, accommodating heterogeneity among studies. The analysis included 14 datasets from 11 studies. Elevated serum CK-18 levels at admission were linked to a higher risk of death or liver transplantation during follow-up. This association was consistent for both M65 (risk ratio [RR] 1.99, 95% confidence interval [CI] 1.65 to 2.40, p < 0.001; I2 = 43%) and M30 (RR 1.94, 95% CI 1.57 to 2.40, p < 0.001; I2 = 46%). Subgroup analysis revealed that the relationship between serum M65 levels and adverse outcomes was attenuated in studies using multivariate analysis compared to those using univariate analysis (RR 1.78 vs. 2.80, p for subgroup difference = 0.03). Further subgroup analyses indicated that the prognostic significance of CK-18 for ALD patients was not significantly influenced by study design, methods of determining CK-18 cutoff values, or follow-up durations. Elevated serum CK-18 levels at admission indicate a poor prognosis in patients with ALD. This finding holds for both M65 and M30.

Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD. METHODS: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI. RESULTS: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD. CONCLUSION: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population.

BACKGROUND & AIMS: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. METHODS: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. RESULTS: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. CONCLUSION: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Hepatofugal portal flow is highly predictive of acute-on-chronic liver failure: A new hemodynamic patho-physiological hypothesis.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a severe complication of advanced liver disease. A significant number of ACLF patients have not clear precipitating factors. The aim of the study was to investigate the role of alterations in porto-hepatic hemodynamics, especially non-forward portal flow (NFPF), in ACLF and liver-related mortality. METHODS: 233 cirrhotic patients were included in the study with a median follow-up of 24 months. Color-Doppler ultrasound was used to assess portal vein patency, flow direction and significant porto-systemic collaterals (>8 mm). Patients with active cancer, both at baseline and during follow-up and severe non liver-related comorbidities were excluded. ACLF and liver-related mortality were recorded during follow-up. RESULTS: Fifty-six patients (24%) developed ACLF; 24 (10,3%) had baseline NFPF. In survival analysis, NFPF, but not portal vein thrombosis, was independently associated with ACLF development (HR 2.85 95% C.I. [1.49-5.42], p = 0.001) and liver-related mortality (HR 2.24 95% C.I. [1.16-4.28], p = 0.015), even after adjustment for liver disease severity scores, age and etiology of liver disease. CONCLUSION: NFPF is independently associated with ACLF development and liver-related mortality, regardless of etiology, severity disease scores and portal vein thrombosis. Although there is no specific measure to reverse NFPF, patients with NFPF should receive prompt intensive management and urgent prioritization for liver transplantation. CLINICAL TRIAL NUMBER: 2730 CESC.

Asociación de fibrosis hepática mediante elastografía por shear wave 2D y score APRI

Introducción: Las hepatopatías son un problema prevalente a nivel mundial. La biopsia hepática ha sido hasta la fecha el gold standard para valorar el grado de fibrosis, sin embargo, con el advenimiento de nuevos métodos no invasivos, costo-efectivos para el sistema sanitario, cada vez recurrimos menos a esta. En nuestro medio se introdujo recientemente la elastografía por onda cizallamiento con imagen biplanar, lo que implica una curva de aprendizaje por parte de los técnicos. Objetivo: Valorar la asociación de los grados de fibrosis hepática determinado por la elastografía por onda de cizallamiento con imagen biplanar (2D-SWE) y el score APRI en pacientes portadores de enfermedad hepática asistidos en el servicio de hepatología del Hospital Pasteur.Médica 2. Metodología: Se incluyeron los pacientes con enfermedad hepática de cualquier etiología, asistidos entre el 01/10/21 al 31/08/22, mayores de 15 años, de ambos sexos y que han sido valorados con elastografía por onda de cizallamiento con imagen biplanar (2D-SWE) y analítica sanguínea realizado por el equipo médico del servicio mencionado en los últimos 6 meses. Resultados: Se incluyeron 158 pacientes. Se encontró mayor prevalencia de enfermedad hepática en mujeres, con predominio de la etiología de enfermedad por hígado graso no alcohólico (EHGNA) e infección por virus de hepatitis C (VHC). Se evidenció asociación positiva entre la elastografía (2D-SWE) y el score APRI para el diagnóstico o exclusión de enfermedad hepática avanzada, sin diferencia estadísticamente significativa entre los dos médicos hepatólogos. Conclusiones: Existe asociación entre la elastografía por SWE y el score APRI para el diagnóstico de enfermedad hepática avanzada en la población general y por etiología.

Introduction: Liver diseases are a prevalent problem worldwide. To date, liver biopsy has been the gold standard for assessing the degree of fibrosis; however, with the advent of new non-invasive, cost-effective methods for the healthcare system, we are resorting to it less and less. Shear wave elastography with biplanar imaging was recently introduced in our setting, which implies a learning curve for technicians. Objective: To assess the association of the degrees of liver fibrosis determined by shear wave elastography with biplanar imaging (2D-SWE) and the APRI score in patients with liver disease treated in the hepatology service of the Pasteur Hospital. Methodology: Patients with liver disease of any etiology, attended between 01/10/21 and 08/31/22, over 15 years of age, of both sexes and who have been evaluated with shear wave elastography with biplanar image were included. (2D-SWE) and blood analysis performed by the medical team of the aforementioned service in the last 6 months. Results: 158 patients were included. A higher prevalence of liver disease was found in women, with a predominance of the etiology of nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection. A positive association was evident between elastography (2D-SWE) and the APRI score for the diagnosis or exclusion of advanced liver disease, with no statistically significant difference between the two hepatologists. Conclusions: There is an association between SWE elastography and the APRI score for the diagnosis of advanced liver disease in the general population and by etiology.

Introdução: As doenças hepáticas são um problema prevalente em todo o mundo. Até o momento, a biópsia hepática tem sido o padrão ouro para avaliar o grau de fibrose, porém, com o advento de novos métodos não invasivos e de baixo custo para o sistema de saúde, recorremos cada vez menos a ela. A elastografia por onda de cisalhamento com imagem biplanar foi introduzida recentemente em nosso meio, o que implica uma curva de aprendizado para os técnicos. Objetivo: Avaliar a associação dos graus de fibrose hepática determinados pela elastografia por ondas de cisalhamento com imagem biplanar (2D-SWE) e o escore APRI em pacientes com hepatopatia atendidos no serviço de hepatologia do Hospital Pasteur. Metodologia: Foram incluídos pacientes portadores de doença hepática de qualquer etiologia, atendidos entre 10/01/21 e 31/08/22, maiores de 15 anos, de ambos os sexos e que foram avaliados com elastografia por onda de cisalhamento com imagem biplanar. ( 2D-SWE) e análises sanguíneas realizadas pela equipa médica do referido serviço nos últimos 6 meses. Resultados: foram incluídos 158 pacientes. Foi encontrada maior prevalência de doença hepática em mulheres, com predomínio da etiologia da doença hepática gordurosa não alcoólica (DHGNA) e da infecção pelo vírus da hepatite C (HCV). Foi evidente uma associação positiva entre a elastografia (2D-SWE) e o escore APRI para o diagnóstico ou exclusão de doença hepática avançada, sem diferença estatisticamente significativa entre os dois hepatologistas. Conclusões: Existe associação entre a elastografia SWE e o escore APRI para o diagnóstico de doença hepática avançada na população geral e por etiologia.

Prognostic value of procalcitonin in patients with cirrhosis hospitalized for acute infection.

BACKGROUND: In patients with cirrhosis, infections significantly increase the risk of short and long-term mortality. During infection, the levels of procalcitonin increase, but it has not yet been clarified its prognostic value in subjects with cirrhosis. Therefore, the aim of this study was to evaluate the prognostic role of procalcitonin in patients with liver cirrhosis hospitalized for acute infection, and to compare it with other markers of infection. PATIENTS: We included 279 patients hospitalized because of infection, 133 with liver cirrhosis. At admission the levels of the main biochemical parameters of infection, i.e. leukocytes, procalcitonin, C reactive protein and lactate, were considered. RESULTS: The duration of hospitalization and antibiotic therapy were longer in patients with cirrhosis, while no difference was observed for mortality. In both groups, a correlation with the duration of hospitalization and antibiotic therapy was observed for high levels of procalcitonin. In the cirrhotic population, in particular, higher procalcitonin values were associated with an increase in the length of hospitalization and antibiotic therapy, suggesting an even greater predictive value for those patients. High levels of leucocytes and lactate were positively associated with the duration of hospitalization, but not with the duration of antibiotic therapy. For mortality, the strongest correlation was found for high serum lactate levels, regardless of the presence of cirrhosis. CONCLUSION: In patients with cirrhosis and acute infection, the value of procalcitonin at admission is a good prognostic indicator for the course of hospitalization, and could be useful for guiding the management and treatment of hospitalized patients.

Ultrasonography as a diagnostic tool for sarcopenia in patients with cirrhosis: Examining the pros and cons.

Sarcopenia has emerged as a significant prognostic factor in liver disease, posing a significant risk to patients in terms of morbidity and mortality. However, the evaluation of skeletal muscle mass and quality remains challenging, as cross-sectional imaging is not a suitable screening tool. In order to better include this crucial variable in the routine risk stratification of patients with chronic liver disease, there is an urgent need for simple and reliable non-invasive diagnostic tools for sarcopenia. Therefore, the use of ultrasound techniques has garnered attention as a promising alternative for detecting sarcopenia and muscle abnormalities. This narrative review aims to provide an overview of the current literature on the use of ultrasound as a diagnostic tool for sarcopenia, with particular focus on patients with cirrhosis, emphasizing its potential limitations and future prospects.

Economic Burden and Patient-Reported Outcomes of Nonalcoholic Fatty Liver Disease.

In addition to adverse clinical outcomes such as liver-related morbidity and mortality, nonalcoholic fatty liver disease (NAFLD) is associated with a substantial public health and economic burden and could also potentially impair health-related quality of life and other patient-reported outcomes. The disease also affects multiple aspects of patients' quality of life which are the most pronounced in physical health-related and fatigue domains as well as work productivity, and get more severe in patients with advanced liver disease or with non-hepatic comorbidities. The economic burden of NAFLD is substantial and is increasing, with the highest costs in those with advanced disease.

Epidemiology, characteristics, and outcomes of patients with acute-on-chronic liver failure in Australia.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is distinct from acute decompensation (AD) of cirrhosis in its clinical presentation, pathophysiology, and prognosis. There are limited published Australian ACLF data. METHODS: We performed a single-center retrospective cohort study of all adults with cirrhosis admitted with a decompensating event to a liver transplantation (LT) centre between 2015 and 2020. ACLF was defined using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) definition while those who did not meet the definition were classified as AD. The primary outcome of interest was 90-day LT-free survival. RESULTS: A total of 615 patients had 1039 admissions for a decompensating event. On their index admission, 34% (209/615) of patients were classified as ACLF. Median admission model for end-stage liver disease (MELD) and MELD-Na scores were higher in ACLF patients compared with AD (21 vs 17 and 25 vs 20 respectively, both P < 0.001). Both the presence and severity of ACLF (grade ≥ 2) significantly predicted worse LT-free survival compared with patients with AD. The EASL-CLIF ACLF score (CLIF-C ACLF), MELD and MELD-Na scores performed similarly in predicting 90-day mortality. Patients with index ACLF had a higher risk of 28-day mortality (28.1% vs 5.1%, P < 0.001) and shorter times to readmission compared with those with AD. CONCLUSION: ACLF complicates over a third of hospital admissions for cirrhosis with decompensating events and is associated with a high short-term mortality. The presence and grade of ACLF predicts 90-day mortality and should be identified as those at greatest risk of poor outcome without intervention such as LT.

Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension.

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5 mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience.

BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.

Magnitude and genotype of hepatitis delta virus among chronic hepatitis B carriers with a spectrum of liver diseases in Ethiopia.

INTRODUCTION AND OBJECTIVES: Chronic hepatitis D infection contributes substantially to the progression of chronic liver disease, especially in most low and middle-income countries, where hepatitis B virus-related chronic liver disease is endemic. Therefore, this study aimed to determine the magnitude and genotype of hepatitis delta virus (HDV) among patients with chronic hepatitis B (CHB)-related liver diseases in Ethiopia. PATIENTS AND METHODS: In this cross-sectional study, 323 known HBsAg positive individuals comprising 220 patients with CHB-related liver diseases [121 advanced liver diseases (hepatocellular carcinoma /HCC/ and non-HCC) and 99 chronic hepatitis (CH)], and 103 symptomless blood donors (BD) were enrolled. An ELISA kit was employed to determine HDV infection, and quantitative real-time PCR was used to detect HDV RNA. In addition, a non-coding genomic RNA region was sequenced for genotyping and phylogenetic analysis. RESULTS: Irrespective of the stage of liver disease, the overall magnitude of HDV was 7.7% (25/323). The frequency of anti-HDV increases with the severity of liver disease, 1.9%, 4%, 10%, and 21.3% among BD, CH, non-HCC, and HCC patients, respectively. HDV RNA has been detected in 1.54 %(5/323) cases with a mean viral load of 4,010,360 IU/ml. All isolates were found to be HDV genotype 1. CONCLUSIONS: The magnitude of HDV infection increased with the severity of liver disease, indicating HDV infection is more common among patients with CHB-related liver diseases in Ethiopia.

Co-infections, comorbidities, and alcohol or other substances abuses in chronic hepatitis C-related hospitalisations in Spain / Coinfecciones, comorbilidades y abuso de alcohol u otras sustancias en las hospitalizaciones por hepatitis C crónica en España

Background: The Strategic Plan for Tackling Hepatitis C launched in 2015 in Spain has led to an important nationwide decrease in hepatitis C related hospitalisation rates. However, patients’ infection progression during decades could increase their health status complexity and challenge patient's prognosis after hepatitis C eradication. Methods: We carried out an observational retrospective study evaluating the prevalence of the main co-infections, comorbidities (risk factors and extrahepatic manifestations), and alcohol or other substances abuses in chronic hepatitis C related hospitalised patients in Spain. Data were obtained from the National Hospitalisation Registry discharges from January 1st of 2012 to December 31st of 2019. Results: Between 2012 and 2019 there were 356,197 chronic hepatitis C-related hospitalisations. In-hospital deaths occurred in 11,558 (4.6%) non-advanced liver disease and in 10,873 (10.4%) advanced liver disease-related hospitalisations. Compared to 2012–2015, in 2016–2019 the proportion of hospitalisations related to non-advanced liver disease increased from 69.4% to 72.4%, while the advanced disease-related hospitalisations decreased from 30.6% to 27.6% (P<.001). In spite of the decrease in severe cases among hospitalisations, all comorbidities evaluated, and alcohol abuse increased in 2016–2019 compared to 2012–2015, while co-infections and other substances abuses decreased in the same period.In the latest period (2016–2019): 28,679 (18.3%) of the hospitalised patients had a HIV, 6928 (4.4%) a hepatitis B, and 972 (.6%) a tuberculosis co-infection. Most frequent comorbidities were diabetes (N=33,622; 21.5%); moderate to severe renal disease (N=28,042; 17.9%), chronic obstructive pulmonary disease and asthma (N=25,559; 16.3%), and malignant neoplasms (excluding hepatocellular carcinoma) (N=19,873; 12.7%).(AU)

Antecedentes: El Plan Estratégico para el Abordaje de la Hepatitis C lanzado en España en 2015ha supuesto una importante disminución a nivel nacional de las tasas de hospitalización relacionadas con la hepatitis C. Sin embargo, la progresión de la infección en los pacientes durante décadas podría aumentar la complejidad de su estado de salud y desafiar el pronóstico del paciente después de la erradicación de la hepatitis C. Métodos: Se realizó un estudio observacional retrospectivo evaluando la prevalencia de las principales coinfecciones, comorbilidades (factores de riesgo y manifestaciones extrahepáticas) y abuso de alcohol u otras sustancias en pacientes hospitalizados relacionados con hepatitis C crónica en España. Los datos se obtuvieron del Registro de altas hospitalarias entre el 1 de enero de 2012 y el 31 de diciembre de 2019. Resultados: Entre 2012 y 2019 hubo 356.197 hospitalizaciones relacionadas con hepatitis C crónica y se registraron 11.558 (4,6%) muertes intrahospitalarias relacionadas con hospitalizaciones por enfermedad hepática no avanzada y 10.873 (10,4%) por enfermedad hepática avanzada. En comparación con 2012-2015, en 2016-2019 la proporción de hospitalizaciones relacionadas con enfermedad no avanzada aumentó del 69,4% al 72,4%, mientras que las relacionadas con enfermedad avanzada disminuyeron del 30,6% al 27,6% (P <0,001). A pesar de la disminución de casos graves entre las hospitalizaciones, todas las comorbilidades evaluadas y el abuso de alcohol aumentaron en 2016-2019 en comparación con 2012-2015, mientras que las coinfecciones y el abuso de otras sustancias disminuyeron en el mismo período. En el último período (2016-2019): 28.679 (18,3%) de los pacientes hospitalizados tenían VIH, 6928 (4,4%) hepatitis B y 972 (0,6%) coinfección tuberculosa. (AU)

Pulmonary complications of portal hypertension: The overlooked decompensation.

The systemic nature of cirrhosis and portal hypertension has long been recognized, and the amount of data characterizing the interplay between each system is becoming ever so complex. Lung involvement was among the first described associated entities in cirrhosis, with reports dating back to the late nineteenth century. However, it appears that throughout the years, interest in the pulmonary complications of portal hypertension has generally faded, especially in contrast to other decompensating events, as expertise in this field has primarily been concentrated in highly experienced tertiary care facilities and liver transplantation centers. Despite affecting up to 10%-15% of patients with advanced liver disease and having a proven prognostic impact, hepato-pulmonary syndrome, porto-pulmonary hypertension, and hepatic hydrothorax are frequently misdiagnosed, mistreated, or misinterpreted. This lack of precision might adversely impact patient care, referral to expert centers, and, ultimately, liver disease-related mortality and successful transplantation odds. The present minireview aims to increase awareness of the pulmonary complications of chronic liver disease by providing a brief overview of each of the three entities. The paper focuses on the essential theoretical aspects, addressing the most critical knowledge gaps on the one hand and, on the other hand, critically discussing one key issue for each complication.

Bicyclol ameliorates advanced liver diseases in murine models via inhibiting the IL-6/STAT3 signaling pathway.

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Saudi association for the study of liver diseases and transplantation position statement on the hepatology workforce in Saudi Arabia.

The field of hepatology has evolved significantly over the last two decades. Hepatology practice in Saudi Arabia (SA) was dominated by hepatitis B and C viruses but is now being overtaken by patients with non-alcoholic fatty liver disease. These patients require greater medical attention as their care is more complex compared to patients with viral hepatitis. In addition, liver transplantation (LT) has expanded significantly in SA over the last three decades. There is a necessity to increase the hepatology workforce to meet the demand in SA. The time has come to reinforce the transplant hepatology fellowship program, that was launched recently, and to develop a nurse practitioner practice model to meet these demands. In addition, SA is going through a health care reform to enhance health care delivery which may affect the financial compensation polices of various specialties including gastroenterology and hepatology. Therefore, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) established a task force to discuss the current and future demands in the hepatology workforce in SA, as well as to discuss different avenues of financial compensation for transplant hepatologists in LT centers.

Beneficial Effects of Silybin Treatment After Viral Eradication in Patients With HCV-Related Advanced Chronic Liver Disease: A Pilot Study.

Introduction and Aims: HCV eradication by direct-acting antivirals (DAAs) improves liver outcomes and reduces overall liver mortality. However, patients with advanced chronic liver disease (ACLD) may experience a progression of liver disease despite viral clearance. Silybin has shown hepatoprotective effects in experimental models, but clinical data are limited. The aim of this study is to evaluate the effect of a highly bioavailable form of silybin on liver fibrosis in patients with HCV-related ACLD after viral eradication with DAAs, in comparison with the standard of care. Methods: In this multicenter and prospective study, HCV patients with ACLD achieving SVR12 were treated with the combination of silybinphospholipid complex with vitamin D and vitamin E (Realsil 100D®, Ibi Lorenzini S.p.A., Aprilia, Italy) for 12 months (R group) compared to controls (C group). Patients were submitted to transient elastography (TE) and to the enhanced liver fibrosis (ELF) test at baseline, week 24, and week 48. Results: One hundred sixteen patients were enrolled, 56 in the R group and 60 in the C group. The median age was 68 years, and 53% were male, with no differences between groups. In both groups, liver stiffness improved at 6 and 12 months compared to baseline. However, patients in the R group compared to those in the C group showed a higher reduction of liver stiffness after 6 months (-2.05, 95% CI -3.89 to -0.22, p < 0.05) and 12 months of treatment (-2.79, 95% CI -4.5 to -1.09, p < 0.01) in comparison with baseline. No significant difference in the reduction of ELF was observed between the two groups. During the follow-up, four patients developed HCC, all in the C group. Conclusions: In HCV-related ACLD, the hepatoprotective effects of silybin may represent a tool to counteract liver disease progression.

Co-infections, comorbidities, and alcohol or other substances abuses in chronic hepatitis C-related hospitalisations in Spain.

BACKGROUND: The Strategic Plan for Tackling Hepatitis C launched in 2015 in Spain has led to an important nationwide decrease in hepatitis C related hospitalisation rates. However, patients' infection progression during decades could increase their health status complexity and challenge patient's prognosis after hepatitis C eradication. METHODS: We carried out an observational retrospective study evaluating the prevalence of the main co-infections, comorbidities (risk factors and extrahepatic manifestations), and alcohol or other substances abuses in chronic hepatitis C related hospitalised patients in Spain. Data were obtained from the National Hospitalisation Registry discharges from January 1st of 2012 to December 31st of 2019. RESULTS: Between 2012 and 2019 there were 356,197 chronic hepatitis C-related hospitalisations. In-hospital deaths occurred in 11,558 (4.6%) non-advanced liver disease and in 10,873 (10.4%) advanced liver disease-related hospitalisations. Compared to 2012-2015, in 2016-2019 the proportion of hospitalisations related to non-advanced liver disease increased from 69.4% to 72.4%, while the advanced disease-related hospitalisations decreased from 30.6% to 27.6% (P<.001). In spite of the decrease in severe cases among hospitalisations, all comorbidities evaluated, and alcohol abuse increased in 2016-2019 compared to 2012-2015, while co-infections and other substances abuses decreased in the same period. In the latest period (2016-2019): 28,679 (18.3%) of the hospitalised patients had a HIV, 6928 (4.4%) a hepatitis B, and 972 (.6%) a tuberculosis co-infection. Most frequent comorbidities were diabetes (N=33,622; 21.5%); moderate to severe renal disease (N=28,042; 17.9%), chronic obstructive pulmonary disease and asthma (N=25,559; 16.3%), and malignant neoplasms (excluding hepatocellular carcinoma) (N=19,873; 12.7%). Alcohol or substances abuse was reported in 48,506 (31.0%) hospitalisations: 30,782 (19.7%) with alcohol; 29,388 (18.8%) with other substances; and 11,664 (7.5%) with both, alcohol and other substances, abuses. CONCLUSIONS: Despite the reduction in advanced liver disease hepatitis C-related hospitalisations due to prioritisation of treatment to the more severe cases, high and increasing prevalence of comorbidities and risks factors among hepatitis C-related hospitalisations have been found.

Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules.

BACKGROUND & AIMS: Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population. METHODS: We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months. RESULTS: A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified. CONCLUSIONS: Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs. LAY SUMMARY: Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients.