Characteristics and risk factors for invasive fungal infection in hospitalized patients with acute-on-chronic hepatitis B liver failure: a retrospective cohort study from 2010 to 2023.

Background and aim: The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients. Methods: A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method. Results: There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990). Conclusion: IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.

Palliative Care for Patients with End-Stage Liver Disease.

End-stage liver disease (ESLD) is the culmination of progression of chronic liver disease to cirrhosis, decompensation, and chronic liver failure, featuring portal hypertension or hepatocellular failure-related complications. Liver transplantation offers improved long-term survival for these patients but is negatively influenced by donor availability, financial constraints in developing countries, active substance abuse, progression of disease or malignancy on wait-list, sepsis and extrahepatic organ involvement. In this context, palliative care (PC), an interdisciplinary medical practice that aim to prevent and relieve suffering, offers best possible quality of life and is not limited to end-of-life care. It also encompasses achievable goals such as symptom control and aggressive disease-modifying treatments or interventions that beneficially alter the natural course of the disease to offer curative intend. In this narrative review, we discuss the prognostic factors that define disease course in ESLD, various indications and challenges in PC for advanced cirrhosis and management options for major symptom burden in patients with ESLD based on evidence-based best practice.

Implications of anaemia and response to anaemia treatment on outcomes in patients with cirrhosis.

Background & Aims: Anaemia is frequently observed in patients with cirrhosis and was identified as a predictor of adverse outcomes, such as increased mortality and occurrence of acute-on-chronic liver failure. To date, the possible effects of iron supplementation on these adverse outcomes are not well described. We therefore aimed to assess the role of iron supplementation in patients with cirrhosis and its capability to improve prognosis. Methods: Laboratory diagnostics were performed in consecutive outpatients with cirrhosis admitted between July 2018 and December 2019 to the University Hospital Essen. Associations with transplant-free survival were assessed in regression models. Results: A total of 317 outpatients with cirrhosis were included, of whom 61 received a liver transplant (n = 19) or died (n = 42). In multivariate Cox regression analysis, male sex (hazard ratio [HR] = 3.33, 95% CI [1.59, 6.99], p = 0.001), model for end-stage liver disease score (HR = 1.19, 95% CI [1.11, 1.27], p <0.001) and the increase of haemoglobin levels within 6 months (ΔHb6) (HR = 0.72, 95% CI [0.63, 0.83], p <0.001) were associated with transplant-free survival. Regarding the prediction of haemoglobin increase, intake of rifaximin (beta = 0.50, SD beta = 0.19, p = 0.007) and iron supplementation (beta = 0.79, SD beta = 0.26, p = 0.003) were significant predictors in multivariate analysis. Conclusions: An increase of haemoglobin levels is associated with improvement of transplant-free survival in patients with cirrhosis. Because the prediction of haemoglobin increase significantly depends on rifaximin and iron supplementation, application of these two medications can have an important impact on the outcome of these patients. Impact and implications: Anaemia is very common in patients with cirrhosis and is known to be a predictor of negative outcomes, but little is known about the effect of iron substitution in these individuals. In our cohort, increase of haemoglobin levels improved transplant-free survival of patients with cirrhosis. The increase of haemoglobin levels was mainly induced by iron supplementation and was even stronger in the case of concomitant use of iron and rifaximin. Clinical trial registration: UME-ID-10042.

Artificial Intelligence in Hepatology- Ready for the Primetime.

Artificial Intelligence (AI) is a mathematical process of computer mediating designing of algorithms to support human intelligence. AI in hepatology has shown tremendous promise to plan appropriate management and hence improve treatment outcomes. The field of AI is in a very early phase with limited clinical use. AI tools such as machine learning, deep learning, and 'big data' are in a continuous phase of evolution, presently being applied for clinical and basic research. In this review, we have summarized various AI applications in hepatology, the pitfalls and AI's future implications. Different AI models and algorithms are under study using clinical, laboratory, endoscopic and imaging parameters to diagnose and manage liver diseases and mass lesions. AI has helped to reduce human errors and improve treatment protocols. Further research and validation are required for future use of AI in hepatology.

Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease.

Background & Aims: Ammonia levels predicted hospitalisation in a recent landmark study not accounting for portal hypertension and systemic inflammation severity. We investigated (i) the prognostic value of venous ammonia levels (outcome cohort) for liver-related outcomes while accounting for these factors and (ii) its correlation with key disease-driving mechanisms (biomarker cohort). Methods: (i) The outcome cohort included 549 clinically stable outpatients with evidence of advanced chronic liver disease. (ii) The partly overlapping biomarker cohort comprised 193 individuals, recruited from the prospective Vienna Cirrhosis Study (VICIS: NCT03267615). Results: (i) In the outcome cohort, ammonia increased across clinical stages as well as hepatic venous pressure gradient and United Network for Organ Sharing model for end-stage liver disease (2016) strata and were independently linked with diabetes. Ammonia was associated with liver-related death, even after multivariable adjustment (adjusted hazard ratio [aHR]: 1.05 [95% CI: 1.00-1.10]; p = 0.044). The recently proposed cut-off (≥1.4 × upper limit of normal) was independently predictive of hepatic decompensation (aHR: 2.08 [95% CI: 1.35-3.22]; p <0.001), non-elective liver-related hospitalisation (aHR: 1.86 [95% CI: 1.17-2.95]; p = 0.008), and - in those with decompensated advanced chronic liver disease - acute-on-chronic liver failure (aHR: 1.71 [95% CI: 1.05-2.80]; p = 0.031). (ii) Besides hepatic venous pressure gradient, venous ammonia was correlated with markers of endothelial dysfunction and liver fibrogenesis/matrix remodelling in the biomarker cohort. Conclusions: Venous ammonia predicts hepatic decompensation, non-elective liver-related hospitalisation, acute-on-chronic liver failure, and liver-related death, independently of established prognostic indicators including C-reactive protein and hepatic venous pressure gradient. Although venous ammonia is linked with several key disease-driving mechanisms, its prognostic value is not explained by associated hepatic dysfunction, systemic inflammation, or portal hypertension severity, suggesting direct toxicity. Impact and implications: A recent landmark study linked ammonia levels (a simple blood test) with hospitalisation/death in individuals with clinically stable cirrhosis. Our study extends the prognostic value of venous ammonia to other important liver-related complications. Although venous ammonia is linked with several key disease-driving mechanisms, they do not fully explain its prognostic value. This supports the concept of direct ammonia toxicity and ammonia-lowering drugs as disease-modifying treatment.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Spectrum of Autoimmune Liver Disease and Real-World Treatment Experience from a Tertiary Care Hospital.

Background and aims: Autoimmune liver disease (AILD) comprises of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) with a spectrum of overlap amongst the three. We analyzed the spectrum and treatment outcomes of patients with AILD presenting to a tertiary care center in India. Methods: A retrospective analysis of AILD patients from June 2008 to April 2021 was performed. The diagnosis was based on clinical, biochemical, imaging, serological, and histological characteristics. Eligible patients received treatment depending on the disease stage. Biochemical response to treatment was defined as normalization of AST, ALT, bilirubin, and immunoglobulin G levels at 6 months in AIH, normalization of total bilirubin and/or albumin at 1 year in PBC and decrease in alkaline phosphatase (ALP) levels by 40% in PSC. Results: Two hundred seventy-five patients were analyzed. AIH (58.54%) was most common, followed by an overlap of AIH-PBC (24%) and AIH-PSC (6.54%), PSC (6.18%), and PBC (4.72%). Most patients presented in 3rd or 4th decade, except PBC which occurred predominantly in 5th decade. The majority of patients were females (72.72%). Jaundice was the most common presentation seen in 60% of patients. Cirrhosis was present in 57.47% of patients. Patients with overlap had more pruritus (54.76 vs 6.83%), fatigue (63.1% vs 49.7%), hepatomegaly (52.4% vs 25.5%), and higher ALP (80.9% vs 37.7%) than patients with AIH alone. Acute presentation was seen in 33 patients (13.5%) with most having AIH flare. Five patients had acute liver failure (ALF) and 9 had acute-on-chronic liver failure (ACLF). ALF was associated with 80% mortality while 55.56% of patients with ACLF had a complete biochemical response to immunosuppression. Among patients with AIH and/or overlap who received immunosuppression, a complete biochemical response to immunosuppression was seen in 60.69% of patients. High ALT (OR 1.001 [1.000-1.003], P = 0.034), high albumin (OR 1.91 [1.05-3.48], P = 0.034) and low fibrosis on biopsy (OR 0.54 [0.33-0.91], P = 0.020) predicted complete response. Conclusion: AIH is the most common AILD followed by overlap syndromes, PSC and PBC in our cohort. Biochemical response to immunosuppression is seen in 60% of patients with AIH & low fibrosis score on histopathology predicts a complete response.

National Liver Allocation Policy-Consensus Document by the Liver Transplantation Society of India for a Nationally Uniform System of Allocation of Deceased Donor Liver Grafts.

Background: Deceased donor liver transplantation (DDLT) is increasing in India and now constitutes nearly one-third of all liver transplantation procedures performed in the country. There is currently no uniform national system of allocation of deceased donor livers. Methods: A national task force consisting of 19 clinicians involved in liver transplantation from across the country was constituted under the aegis of the Liver Transplantation Society of India to develop a consensus document addressing the above issues using a modified Delphi process of consensus development. Results: The National Liver Allocation Policy consensus document includes 46 statements covering all aspects of DDLT, including minimum listing criteria, listing for acute liver failure, DDLT wait-list management, system of prioritisation based on clinical urgency for adults and children, guidelines for allocation of paediatric organs and allocation priorities for liver grafts recovered from public sector hospitals. Conclusion: This document is the first step in the setting up of a nationally consistent policy of deceased donor liver allocation.

Acute Kidney Injury (AKI) at Admission Predicts Mortality in Patients With Severe Alcoholic Hepatitis (SAH).

Background & aims: Severe alcoholic hepatitis (SAH) is a grave condition, and the presence of acute kidney injury (AKI) further jeopardizes patient survival. However, the impact of AKI on survival in SAH has not been assessed from this region of Asia. Materials and methods: This study was conducted on consecutive alcohol-associated liver disease (ALD) patients hospitalized in Gastroenterology Department, SCB Medical College, Cuttack, India, between October 2016 and December 2018. On diagnosis of SAH (mDF score ≥32), demographic, clinical, and laboratory parameters were recorded, and survival was compared between patients with and without AKI (AKIN criteria). In addition, survival was compared among SAH patients defined by other criteria and prognostic models in the presence and absence of AKI. Results: 309 (70.71%) of ALD patients had SAH, and 201 (65%) of them had AKI. SAH patients with AKI had higher total leucocyte count, total bilirubin, serum creatinine, serum urea, INR, MELD (UNOS), MELD (Na+), CTP score, mDF score, Glasgow score, ABIC score, and increased prevalence of acute on chronic liver failure (ACLF) as per EASL-CLIF Consortium criteria (P < 0.001). Further, they had prolonged hospital stay, and increased death during hospitalization, at 28 days as well as 90 days (P < 0.001). Significant differences in survival were also seen in SAH (as per MELD, ABIC, and GAHS criteria) patients above the marked cut offs in respect to AKI. Conclusions: Over two-thirds of ALD patients had SAH, and about two-thirds had AKI. Patients with SAH and AKI had an increased prevalence of ACLF, longer hospital stay, and increased mortality during hospitalization at 28 days and 90 days. Lay summary: SAH is a critical condition, and the presence of AKI negatively affects their survival. Hence, early identification of SAH and AKI, as well as early initiation of treatment, is crucial for better survival. Our study from the coastal part of eastern India is the first to demonstrate the prevalence of SAH among patients with ALD along with the prevalence of AKI among SAH patients in this region. This knowledge will be helpful in managing these patients from this region of world.

Metabolomics profiles in acute-on-chronic liver failure: Unveiling pathogenesis and predicting progression.

Acute-on-chronic liver failure (ACLF) usually develops based on acute decompensation (AD) of cirrhosis and is characterized by intense systemic inflammation, multiple organ failure, and high short-term mortality. Validated biomarkers for the diagnosis and prognosis of ACLF remain to be clarified. Metabolomics is an emerging method used to measure low-molecular-weight metabolites and is currently frequently implemented to understand pathophysiological processes involved in disease progression, as well as to search for new diagnostic or prognostic biomarkers of various disorders. The characterization of metabolites in ACLF has recently been described via metabolomics. The role of metabolites in the pathogenesis of ACLF deserves further investigation and improvement and could be the basis for the development of new diagnostic and therapeutic strategies. In this review, we focused on the contributions of metabolomics on uncovering metabolic profiles in patients with ACLF, the key metabolic pathways that are involved in the progression of ACLF, and the potential metabolite-associated therapeutic targets for ACLF.

Long-term Outcomes of Stool Transplant in Alcohol-associated Hepatitis-Analysis of Clinical Outcomes, Relapse, Gut Microbiota and Comparisons with Standard Care.

Background: Healthy donor fecal microbiota transplantation (FMT) was preliminarily shown to have clinical benefits in hepatic encephalopathy (HE), severe alcohol-associated hepatitis (SAH), and alcohol use disorder. However, the long-term outcomes of FMT and the gut microbiota (GM) changes in patients with SAH are unknown. Methods: Patients with SAH who underwent FMT (N = 35) or standard of care (SoC, N = 26) from May 2017 to June 2018 were included, and their stored stool samples were analyzed prospectively. Clinical outcomes, including infections, hospitalizations, critical illness, alcohol relapse, and survival, were evaluated. Metagenomic analysis was undertaken to identify the relative abundances (Ras) and significant taxa at baseline and post-therapy (up to three years) among survivors between the two groups. Results: At follow-up, the incidences of ascites, HE, infections, and major hospitalizations were significantly higher in the SoC than in the FMT group (P < 0.05). Alcohol relapse was lower (28.6% versus 53.8%), and the time to relapse was higher in the FMT than in the SoC group (P = 0.04). Three-year survival was higher in the FMT than in the SoC group (65.7% versus 38.5%, P = 0.052). Death due to sepsis was significantly higher in the SoC group (N = 13/16, 81.2%; P = 0.008). GM analysis showed a significant increase in the RA of Bifidobacterium and a reduction in the RA of Acinetobacter in the FMT group. Beyond one to two years, the RA of Porphyromonas was significantly higher and that of Bifidobacterium was lower in the SoC than in the FMT group. Conclusions: In terms of treatment for patients with SAH, healthy donor FMT is associated with significantly lesser ascites, infections, encephalopathy, and alcohol relapse (with a trend toward higher survival rates) than SoC, associated with beneficial GM modulation. Larger controlled studies on FMT are an unmet need.

Liver Transplant Society of India Guidelines for Liver Transplant During COVID-19 times.

Coronavirus disease-2019 (COVID-19) pandemic has affected liver transplantation in many ways. There is risk of infection to the transplant recipients; and COVID-19 is associated with significant risk of mortality in patients on wait list. The Liver Transplant Society of India (LTSI) has prepared guidelines regarding selection of adult and pediatric patients for liver transplantation, transplant for acute liver failure, use of deceased donor organs, transplant techniques and minimally invasive donor hepatectomy, pre- and postsurgery testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related coronavirus disease 2019 in donors and recipients, role of COVID-19 antibody testing, shifting of recipients from COVID-19 to non-COVID-19 areas after recovery, isolation policy of team members exposed to COVID-19 patients, drug therapy of proven or suspected COVID-19 infection early posttransplant, care of SARS-CoV-2 positive donors and recipients and a separate COVID-19 consent for surgery.

Gut Microbiome and Alcohol-associated Liver Disease.

Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD.

CLIF-C AD score predicts survival benefit from pre-emptive TIPS in individuals with Child-Pugh B cirrhosis and acute variceal bleeding.

Background & Aims: Among individuals with Child-Pugh B cirrhosis and acute variceal bleeding (AVB), the Baveno VII workshop recommended pre-emptive TIPS in those with a Child-Pugh score of 8-9 and active bleeding at initial endoscopy (Child B8-9 + AB criteria). Nevertheless, whether this criterion is superior to the CLIF-Consortium acute decompensation score (CLIF-C ADs) remains unclear. Methods: Data on 1,021 consecutive individuals with Child-Pugh B cirrhosis and AVB from 13 university hospitals in China who were treated with pre-emptive TIPS (n = 297) or drug plus endoscopic treatment (n = 724) between 2010 to 2019 were retrospectively analysed. A competing risk regression model was used to compare the outcomes between the two groups after adjusting for confounders. The concordance-statistic for benefit (c-for-benefit) was used to evaluate a models' ability to predict treatment benefit (risk difference between treatment groups). Results: Pre-emptive TIPS was associated with reduced mortality compared to drug plus endoscopic treatment (adjusted hazard ratio 0.62, 95% CI 0.44 to 0.88). A higher baseline CLIF-C AD score was associated with greater survival benefit (i.e., larger absolute mortality risk reduction). After adjusting for confounders, a survival benefit was observed in individuals with CLIF-C ADs ≥48 or Child-Pugh B8-9 with active bleeding, but not in those with CILF-C ADs <48, no active bleeding or Child-Pugh B7 with active bleeding. The c-for-benefit of CILF-C ADs for predicting survival benefit was higher than that of Child B8-9+AB criteria. Conclusions: In individuals with Child-Pugh B cirrhosis and AVB, CLIF-C ADs predicts survival benefit from pre-emptive TIPS and outperforms the Child B8-9+AB criteria. Prospective validation should be performed to confirm this result, especially for other aetiologies of cirrhosis. Impact and implications: In this study, among individuals with Child-Pugh B cirrhosis and acute variceal bleeding, the CLIF-Consortium acute decompensation (CLIF-C AD) score could predict the survival benefit from pre-emptive TIPS, with patients with higher CLIF-C AD scores benefiting more from pre-emptive TIPS. Furthermore, the CLIF-C AD score outperformed the Child B8-9 plus active bleeding criteria in terms of discriminating between those who obtained more benefit vs. less benefit from pre-emptive TIPS. Depending on prospective validation, the CLIF-C AD score could be used as the model of choice to determine who should undergo pre-emptive TIPS.

Rifaximin Vs. Norfloxacin for Spontaneous Bacterial Peritonitis Prophylaxis: A Randomized Controlled Trial.

Background: Spontaneous bacterial peritonitis (SBP) heralds increased mortality in cirrhosis, mandating strategies for prophylaxis. Norfloxacin has been the recommended choice for SBP prevention. However, its use has raised concerns about antibiotic resistance. Rifaximin has been suggested as an alternative. We investigated the efficacy of rifaximin against norfloxacin in primary and secondary prophylaxis of SBP. Methods: In this open-labeled randomized trial, patients with either advanced cirrhosis having ascitic fluid protein levels (<1.5 g/l), Child-Pugh score ≥9 points, serum bilirubin ≥3 mg/dl or impaired renal function (primary prophylaxis group), or those with prior SBP (secondary prophylaxis group) received either norfloxacin (400 mg once daily) or rifaximin (550 mg twice daily). All patients were followed for six months, with the primary endpoint being the development of incident SBP. Results: 142 patients were assessed for eligibility, of which 132 met the enrolment criteria; 12 were lost to follow-up, while 4 discontinued treatment. In patients on primary prophylaxis, occurrence of SBP was similar (14.3% vs. 24.3%, P = 0.5), whereas in secondary prophylaxis SBP recurrence was lower with rifaximin (7% vs. 39% P = 0.004). Rifaximin significantly reduced the odds for SBP development in secondary prophylaxis [OR (95% CI0.14 (0.02-0.73; P = 0.02)]. Patients receiving rifaximin as secondary prophylaxis also had fewer episodes of hepatic encephalopathy (23.1% vs. 51.5%, P = 0.02). 180-day survival between the arms in either group was similar (P = 0.5, P = 0.2). Conclusion: In comparison to norfloxacin, rifaximin significantly reduces incident events of SBP, as well as HE when used as a secondary prophylaxis, whereas for primary prophylaxis both have similar effects (NCT03695705). Clinical trial registration: ClinicalTrials.gov number: NCT03695705.

Principles, Interpretation, and Evidence-Based Role of Viscoelastic Point-of-Care Coagulation Assays in Cirrhosis and Liver Failure.

Background and Aims: Standard coagulation tests such as prothrombin time, activated partial thromboplastin time, and international normalized ratio are determined by liver-synthesized coagulation factors. Despite an increased international normalized ratio, patients with cirrhosis are in a "rebalanced" state of hemostasis as the concomitant effect of reduced protein C, protein S, and thrombomodulin is not evaluated in standard coagulation tests. The cell-based model of hemostasis indicates additional mechanisms such as systemic inflammation, sepsis, and organ failures tip the delicate coagulation balance to an anticoagulant type in acute-on-chronic liver failure. In acute liver failure, thrombin generation and platelet function remain intact despite a marked prolongation in prothrombin time. We aimed to explain the principles, application, and utility of viscoelastic tests such as thromboelastography, rotational thromboelastometry, and Sonoclot. Methods: We reviewed the available literature from MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trial with the search terms 'coagulation', 'cirrhosis', 'acute-on-chronic liver failure', 'thromboelastography', 'thromboelastometry' and 'sonoclot' for cross sectional studies, cohort studies and randomized trials. Results: The point-of-care viscoelastic tests provide actionable targets for correcting the coagulation defect in a patient with bleeding and provide evidence-based algorithms for use in liver disease. A limitation of these tests is the inability to assess vessel injury and endothelial elements. Conclusion: Global coagulation tests provide a comprehensive estimate of coagulation in vitro; however, their use has only been validated in the setting of liver transplantation. Newer guidelines for hemostatic resuscitation are now accepting these POC tests, but additional data are required to validate their use as standard of care.

Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.

Patients with alcohol-associated liver disease may develop severe forms of presentation of acute-on-chronic liver failure, with a high risk for short-term mortality. Alcoholic hepatitis should be suspected among patients with alcohol-associated liver disease who present with acute-on-chronic liver failure. In this review, we discuss the need and feasibility of liver biopsy in the diagnosis of alcoholic hepatitis and predicting its prognosis among decompensated patients with alcohol-associated liver disease and acute-on-chronic liver failure.

Public Health Measures and Prevention of Alcohol-Associated Liver Disease.

Hazardous alcohol consumption causes approximately 4% of deaths globally, constituting one of the leading risk factors for the burden of the disease worldwide. Alcohol has several health consequences, such as alcohol-associated liver disease, hepatocellular carcinoma, nonliver neoplasms, physical injury, cardiac disease, and psychiatric disorders. Alcohol misuse significantly affects workforce productivity, with elevated direct and indirect economic costs. Due to the high impact of alcohol consumption on the population, public health has led to the development of a range of strategies to reduce its harmful effects. Regulatory public health policies (PHP) for alcohol can exist at the global, regional, international, national, or subnational levels. Effective strategies incorporate a multilevel, multicomponent approach, targeting multiple determinants of drinking and alcohol-related harms. The World Health Organization categorizes the PHP into eight categories: national plan to fight the harmful consequences of alcohol, national license and production and selling control, taxes control and pricing policies, limiting drinking age, restrictions on alcohol access, driving-related alcohol policies, control over advertising and promotion, and government monitoring systems. These policies are supported by evidence from different populations, demonstrating that determinants of alcohol use depend on several factors such as socioeconomic level, age, sex, ethnicity, production, availability, marketing, and others. Although most policies have a significant individual effect, a higher number of PHP are associated with a lower burden of disease due to alcohol. The excessive consequences of alcohol constitute a call for action, and clinicians should advocate for developing and implementing a new PHP on alcohol consumption.

Vaccination in Chronic Liver Disease: An Update.

Patients with chronic liver disease (CLD) with or without cirrhosis remain at risk of developing hepatic decompensation when infected with viral or bacterial pathogens. The Advisory Committee on Immunization Practices (ACIP) currently recommends vaccination in CLD against hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcus, herpes zoster, tetanus, diphtheria, pertussis, and SARS-CoV-2. Inactivated vaccines are preferred over live attenuated ones, especially in transplant recipients where live vaccines are contraindicated. As the severity of the liver disease progresses, vaccine efficacy declines, and therefore, vaccines should be ideally administered early in the disease course for optimal immune response. Despite the strong recommendations, overall vaccination coverage in CLD remains poor; however, it is encouraging to note that in recent years coverage against influenza and pneumococcus has shown some improvement. Inadequate access to healthcare, lack of information on vaccine safety, poor financial reimbursement for healthcare providers, and vaccine misinformation are often responsible for low immunization rates. This review summarizes the impact of vaccine-preventable illness in those with CLD, updated vaccine guidelines, seroconversion rates in the vaccinated, and barriers faced by healthcare professionals in immunizing those with liver disease.

Predictors of in-hospital Outcomes in Patients With Cirrhosis and Coronavirus Disease-2019.

Background: Coronavirus disease-2019 (COVID-19) cases continue to increase globally. Poor outcomes in patients with COVID-19 and cirrhosis have been reported; predictors of outcome are unclear. The existing data is from the early part of the pandemic when variants of concern (VOC) were not reported. Aims: We aimed to assess the outcomes and predictors in patients with cirrhosis and COVID-19. We also compared the differences in outcomes between the first wave of pandemic and the second wave. Methods: In this retrospective analysis of a prospectively maintained database, data on consecutive cirrhosis patients (n = 221) admitted to the COVID-19 care facility of a tertiary care center in India were evaluated for presentation, the severity of liver disease, the severity of COVID-19, and outcomes. Results: The clinical presentation included: 18 (8.1%) patients had compensated cirrhosis, 139 (62.9%) acute decompensation (AD), and 64 (29.0%) had an acute-on-chronic liver failure (ACLF). Patients with ACLF had more severe COVID-19 infection than those with compensated cirrhosis and AD (54.7% vs. 16.5% and 33.3%, P < 0.001). The overall mortality was 90 (40.7%), the highest among ACLF (72.0%). On multivariate analysis, independent predictors of mortality were high leukocyte count, alkaline phosphatase, creatinine, child class, model for end-stage liver disease (MELD) score, and COVID-19 severity. The second wave had more cases of severe COVID-19 as compared to the first wave, with a similar MELD score and Child score. The overall mortality was similar between the two waves. Conclusion: Patients with COVID-19 and cirrhosis have high mortality (40%), particularly those with ACLF (72%). A higher leukocyte count, creatinine, alkaline phosphatase, Child class, and MELD score are predictors of mortality.