Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

Outcomes in Patients with Liver Dysfunction Post SARS-CoV-2 Infection: What Should We Measure?

Aim: Since 2019, the COVID-19 pandemic wreaked havoc all over the world. Early in the course of the pandemic, multiple hepatic manifestations of COVID-19 were noted. We aim to categorize hepatic dysfunction and its outcome in COVID-19 infection. Methods: This is a review article based on a literature search in PubMed and Medline databases for articles detailing short-term and long-term outcomes of COVID-19 related liver dysfunction. Results: The most common hepatic manifestation of COVID-19 was aspartate amino transferase (AST) predominant transaminase elevation. Transaminases improve once the COVID-19 infection resolves. In addition, COVID-19 cholangiopathy, autoimmune hepatitis associated COVID-19, and splanchnic venous thrombosis triggered by COVID-19 are other manifestations. Patients with preexisting liver disease, especially those with cirrhosis, have poor prognosis with COVID-19 infections compared to the general population. Elevations in liver tests were associated with severe COVID-19 infections. Patients with chronic liver disease have a higher risk of morbidity and mortality from COVID-19 infection. Among patients with chronic liver disease, decompensated liver cirrhosis, hepatocellular carcinoma and alcohol-associated liver disease were associated with an increased risk of severity and mortality from COVID-19 infection. Interactions between antiviral therapy for COVID-19 and hepatitis B/hepatitis C medications must be considered in patients with chronic viral hepatitis and COVID-19 infection. COVID-19 vaccination-related hepatic dysfunction has been reported. Conclusion: COVID-19 is here to stay. Hepatic dysfunction in COVID-19 signals severe COVID-19 infections. Patients with chronic liver disease have higher mortality from COVID-19 than general population. It is important to remember the lessons learned throughout the covid pandemic to take care of patients with COVID-19 now and in the future. Further studies are needed to document long-term outcomes in patients with COVID-19 who developed hepatic dysfunction.

Epidemiology and outcomes of non-alcoholic fatty liver disease in African Americans.

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Comparison of Guidelines for the Screening, Diagnosis, and Noninvasive Assessment of Nonalcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. However, there is no clear consensus on optimal screening strategies and risk stratification. We conducted a systematic review of society guidelines to identify differences in recommendations regarding the screening, diagnosis, and assessment of NAFLD. Methods: We searched PubMed, Web of Science, and Embase databases from January 1, 2015, to August 2, 2022. Two researchers independently extracted information from the guidelines about screening strategies, risk stratification, use of noninvasive tests (NITs) to assess hepatic fibrosis, and indications for liver biopsy. Results: Twenty clinical practice guidelines and consensus statements were identified in our search. No guidelines recommended routine screening for NAFLD, while 14 guidelines recommended case finding in high-risk groups. Of the simple risk stratification models to assess for fibrosis, the fibrosis-4 score was the most frequently recommended, followed by the NAFLD fibrosis score. However, guidelines differed on which cutoffs to use and the interpretation of "high-risk" results. Conclusion: Multiple guidelines exist with varying recommendations on the benefits of screening and interpretation of NIT results. Despite their differences, all guidelines recognize the utility of NITs and recommend their incorporation into the clinical assessment of NAFLD.

The Impact of Renal Function on Hepatic Encephalopathy Following TIPS Placement for Refractory Ascites.

BACKGROUND: The impact of renal function on hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites is poorly understood. We investigated the role of renal function on HE following TIPS placement. METHODS: A retrospective study was performed for patients undergoing TIPS for refractory ascites from 2007-2019. Patients were stratified by GFR at time of TIPS placement and by whether they were on hemodialysis (HD). Chronic kidney disease (CKD) stage 3 or higher was defined as pre-TIPS GFR < 60 for at least 3 months. Logistic regression analyses were used to identify the role of GFR and CKD at time of TIPS placement on HE within 60 days post TIPS placement. RESULTS: Among 201 TIPS patients for refractory ascites (61% male; mean age 59.1), 78 (39%) patients were in CKD, and 16 (21%) were on HD. Mean GFR at time of TIPS placement was 62.7 ± 28.2 for all non-HD patients (n = 185). Compared with the GFR ≥ 90 group, GFR < 30 or HD (OR, 3.56; 95%CI, 1.19-10.7; p = 0.023) and CKD (OR, 2.52; 95%CI, 1.40-4.53; p = 0.002) at time of TIPS placement were significant predictors of post-TIPS placement HE within 60 days. GFRs between 30-60 and 60-90 were not significant predictors. CONCLUSIONS: In TIPS patients for recurrent ascites, patients with acutely impaired renal function or chronic renal dysfunction were at an increased risk for HE after TIPS.

Management of Patients After Treatment of Severe Alcohol-associated Hepatitis.

Alcohol-associated liver disease is the leading indication for hospitalization among patients with chronic liver disease. Rates of hospitalization for alcohol-associated hepatitis have been rising over the last 2 decades. Patients with alcohol-associated hepatitis carry significant morbidity and mortality, but there is a lack of standardized postdischarge management strategies to care for this challenging group of patients. Patients warrant management of not only their liver disease but also their alcohol use disorder. In this review, we will discuss outpatient management strategies for patients who were recently hospitalized and discharged for alcohol-associated hepatitis. We will discuss short management of their liver disease, long-term follow-up, and review-available treatment options for alcohol use disorder and challenges associated with pursuing treatment for alcohol use disorder.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation.

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

The Evolution of Redo Liver Transplantation Over 35 Years: Analysis of 654 Consecutive Adult Liver Retransplants at a Single Center.

OBJECTIVE: To examine liver retransplantation (ReLT) over 35 years at a single center. BACKGROUND: Despite the durability of liver transplantation (LT), graft failure affects up to 40% of LT recipients. METHODS: All adult ReLTs from 1984 to 2021 were analyzed. Comparisons were made between ReLTs in the pre versus post-model for end-stage liver disease (MELD) eras and between ReLTs and primary-LTs in the modern era. Multivariate analysis was used for prognostic modeling. RESULTS: Six hundred fifty-four ReLTs were performed in 590 recipients. There were 372 pre-MELD ReLTs and 282 post-MELD ReLTs. Of the ReLT recipients, 89% had one previous LT, whereas 11% had ≥2. Primary nonfunction was the most common indication in the pre-MELD era (33%) versus recurrent disease (24%) in the post-MELD era. Post-MELD ReLT recipients were older (53 vs 48, P = 0.001), had higher MELD scores (35 vs 31, P = 0.01), and had more comorbidities. However, post-MELD ReLT patients had superior 1, 5, and 10-year survival compared with pre-MELD ReLT (75%, 60%, and 43% vs 53%, 43%, and 35%, respectively, P < 0.001) and lower in-hospital mortality and rejection rates. Notably, in the post-MELD era, the MELD score did not affect survival. We identified the following risk factors for early mortality (≤12 months after ReLT): coronary artery disease, obesity, ventilatory support, older recipient age, and longer pre-ReLT hospital stay. CONCLUSIONS: This represents the largest single-center ReLT report to date. Despite the increased acuity and complexity of ReLT patients, post-MELD era outcomes have improved. With careful patient selection, these results support the efficacy and survival benefit of ReLT in an acuity-based allocation environment.

Clinical Impact and Safety of Non-Target Punctures (NTP) during Portal Vein Access in TIPS Procedure.

BACKGROUND: Although non-target puncture (NPT)-related complications are well known to clinicians performing TIPS, there is no NTP-focused study to assess the true clinical sequalae of NTP-related complications. In this study, the aim was to evaluate the incidence, safety, clinical outcomes and complications related to NTPs during the portal access of TIPS procedures. METHODS: A retrospective review of 369 TIPS procedures from October 2007 to September 2019 was performed. We identified inadvertent NTPs, including biliary, hepatic artery, lymphatic and capsular punctures. Next, the medical records and images were reviewed and analyzed to assess the safety and clinical outcomes of these cohorts. RESULTS: A total of 71 NTPs were identified in 56 patients (15.18% of 369 patients). Of 369 TIPS patients, there were (1) 28 biliary punctures (7.6%), (2) 16 extracapsular punctures (4.3%), (3) 15 lymphatic punctures (4.1%) and (4) 12 hepatic artery punctures (3.3%). The overall complication rate was 2.2% (8/369). Based on the Clavien-Dindo classification, three patients (0.8%) had a minor complication. In addition, five patients (1.4%) experienced grade II-V major complications, such as symptomatic hemoperitoneum, arterio-biliary fistula or hemorrhagic shock leading to death. Mortality (0.5%) was only caused by extracapsular puncture combined with other NTP. CONCLUSIONS: NTPs during the portal access of TIPS procedures are associated with low complication risk. However, when extracapsular punctures are combined with other NTPs, a more severe complication, including mortality, can occur. Nevertheless, all patients with NTP should be closely monitored at a higher level of care after TIPS placement.

Exploratory assessment: Nurse-led community health worker delivered HCV intervention for people experiencing homelessness.

BACKGROUND: Getting and maintaining Hepatitis C Virus (HCV) cure is challenging among people experiencing homelessness (PEH) as a result of critical social determinants of health such as unstable housing, mental health disorders, and drug and alcohol use. OBJECTIVES: The purpose of this exploratory pilot study was to compare a registered nurse/community health worker (RN/CHW)-led HCV intervention tailored for PEH, "I am HCV Free," with a clinic-based standard of care (cbSOC) for treating HCV. Efficacy was measured by sustained virological response at 12 weeks after stopping antivirals (SVR12), and improvement in mental health, drug and alcohol use, and access to healthcare. METHODS: An exploratory randomized controlled trial design was used to assign PEH recruited from partner sites in the Skid Row Area of Los Angeles, California, to the RN/CHW or cbSOC programs. All received direct-acting antivirals. The RN/CHW group received directly observed therapy in community-based settings, incentives for taking HCV medications, and wrap-around services, including connection to additional healthcare services, housing support, and referral to other community services. For all PEH, drug and alcohol use and mental health symptoms were measured at month 2 or 3 and 5 or 6 follow-up, depending on HCV medication type, while SVR12 was measured at month 5 or 6 follow-up. RESULTS: Among PEH in the RN/CHW group, 75% (3 of 4) completed SVR12 and all three attained undetectable viral load. This was compared with 66.7% (n = 4 of 6) of the cbSOC group who completed SVR12; all four attained undetectable viral load. The RN/CHW group, as compared to the cbSOC, also showed greater improvements in mental health, and significant improvement in drug use, and access to healthcare services. DISCUSSION: While this study shows significant improvements in drug use and health service access among the RN/-CHW group, the sample size of the study limits the validity and generalizability of the results. Further studies using larger sample sizes are necessitated.

Anticoagulation for the Treatment of Portal Vein Thrombosis in Cirrhosis: A Systematic Review and Meta-Analysis of Comparative Studies.

Background: Portal vein thrombosis (PVT) leads to significant morbidity and mortality burden in patients with cirrhosis. An improved understanding of the utility of anticoagulation in patients with PVT will aid clinical decision making and inform future research. This meta-analysis aimed to evaluate the association between anticoagulation therapy and clinical outcomes in the context of treatment for PVT in cirrhosis. Methods: Pubmed, Embase, and Web of Science were searched from inception to February 13, 2022, for studies comparing the use of anticoagulation to other modalities as treatment for PVT in cirrhosis. Pooled odds ratios (OR) were calculated using a random-effects model for PVT improvement, recanalization, progression, bleeding events, and all-cause mortality in treatment studies. Results: We identified 944 records, of which 16 studies (n = 1126) examining anticoagulation as PVT treatment were included for subsequent analysis. Anticoagulation as PVT treatment was associated with PVT improvement (OR 3.64; 95% CI 2.56-5.17), PVT recanalization (OR 3.73; 95% CI 2.45-5.68), decreased PVT progression (OR 0.38; 95% CI 0.23-0.63), and decreased all-cause mortality (OR 0.47; 95% CI 0.29-0.75). The use of anticoagulation was not associated with bleeding events (OR 0.80; 95% CI 0.39-1.66). All analyses demonstrated low heterogeneity. Conclusions: These results support the use of anticoagulation in cirrhosis as treatment for PVT. These findings may inform the clinical management of PVT and highlight the need for further studies such as large randomized controlled trials characterizing the safety and efficacy of anticoagulation for PVT in cirrhosis.

Role of Biomarkers to Assess the Use of Alcohol.

Alcohol-associated liver disease has seen a significant rise in the last 2 decades, with an associated rise in the need for accurate alcohol use assessment. Alcohol use has been associated with poor outcomes in both the pre-liver transplant and post-liver transplant patients. Patients with alcohol use disorder often under-report their alcohol consumption because of varying factors, highlighting the need for objective assessment of alcohol use. Aside from the available self-report questionnaires, multiple serologic biomarkers are currently available to assist clinicians to assess recent alcohol consumption among patients with chronic liver disease, liver transplant candidates, and recipients. In this review, we will assess some of these alcohol biomarkers, discuss their strengths and weakness, and review-available data to discuss their role in pre-liver transplant and post-liver transplant population.

Expert perspectives for the pharmacist on facilitating and improving the use of albumin in cirrhosis.

PURPOSE: Albumin, the most abundant and arguably most important protein in the human body, plays a unique role in decompensated cirrhosis because its structure and function are quantitatively and qualitatively affected. A literature review was performed to provide insights into albumin use. The manuscript was developed using a multidisciplinary approach; 2 hepatologists, a nephrologist, a hospitalist, and a pharmacist, who are all members of or work closely with the Chronic Liver Disease Foundation, collaborated to write this expert perspective review. SUMMARY: Cirrhosis represents the potential end in the spectrum of all chronic liver diseases. Decompensated cirrhosis, defined by the overt manifestation of liver failure (eg, ascites, hepatic encephalopathy, variceal bleeding), is the inflection point associated with increased mortality. Human serum albumin (HSA) infusion serves an important role in the treatment of advanced liver disease. The benefits of HSA administration in patients with cirrhosis are widely accepted, and its use has been advocated by several professional societies. However, inappropriate HSA use can lead to significant adverse patient events. This paper discusses the rationale for the administration of HSA in the treatment of complications of cirrhosis, analyzes the data on the use of HSA in cirrhosis, and streamlines practical recommendations set forth in published guidance. CONCLUSION: Use of HSA in clinical practice needs to be improved. The objective of this paper is to empower pharmacists to facilitate and improve the use of HSA in patients with cirrhosis at their practice sites.

Comparative Efficacy of Treatment Options for the Prevention of Post-TIPS Hepatic Encephalopathy: A Systematic Review and Network Meta-analysis.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is often used in patients with cirrhosis to manage portal hypertension-related complications. Unfortunately, 35-50% of patients develop overt hepatic encephalopathy (HE) after TIPS. However, data on lactulose and rifaximin to prevent post-TIPS HE is limited. Therefore, we aimed to perform a network meta-analysis to investigate the efficacy of multiple pharmacological regimens in the prevention of post-TIPS HE. METHODS: A comprehensive search strategy to identify reports of studies of rifaximin use on post-TIPS hepatic encephalopathy was constructed using truncated keywords, phrases, and subject headings developed in Embase. This strategy was translated to MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, with all searches performed on 10 February 2022. No publication date or language limits were used. RESULTS: The initial search identified 72 studies, and 56 studies were screened after removing duplicates. Five studies, two randomized controlled trials (RCTs) and three retrospective studies, met our inclusion criteria and were included in the final analysis. A total of 840 patients were included, with 65% male. Our meta- analysis did not find a statistically significant difference between lactulose vs placebo/no prophylaxis, nor rifaximin vs placebo/no prophylaxis, nor rifaximin plus lactulose vs placebo/no prophylaxis in the reduction of post-TIPS HE. CONCLUSIONS: Rifaximin alone, lactulose alone, and rifaximin plus lactulose did not significantly reduce the development of post-TIPS HE. Based on the P-scores of the three treatment groups, the combination of rifaximin plus lactulose showed the most promising trend towards preventing post-TIPS HE. More studies, especially large RCTs, are warranted.

Barriers to Lactulose Adherence in Patients with Cirrhosis and Hepatic Encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a major cause of mortality and morbidity in patients with cirrhosis. Lactulose non-adherence is one of the most frequently reported precipitants of hospital admission for HE. AIMS: We aimed to identify which factors contribute most to lactulose non-adherence and propose strategies to promote greater adherence and utilization of lactulose. METHODS: Participants in this study consisted of patients with cirrhosis who were taking lactulose for prevention of HE. Subjects were administered the Morisky Adherence Scale 8 (MAS-8) and a customized 16-question survey that assessed barriers to lactulose adherence. Results from the MAS-8 were used to stratify subjects into "adherent" and "non-adherent" groups. Survey responses were compared between groups. RESULTS: We enrolled 129 patients in our study, of whom 45 were categorized as "adherent and 72 were categorized as "non-adherent." Barriers to adherence included large volumes of lactulose, high frequency of dosing, difficulty remembering to take the medication, unpleasant taste, and medication side-effects. Most patients (97%) expressed understanding of the importance of lactulose, and 71% of patients felt that lactulose was working to manage their HE. Hospital admission rates for HE was higher in non-adherent patients, although this difference was not statistically significant. CONCLUSION: We identified several factors that contribute to lactulose non-adherence among patients treated for HE. Many of these factors are potentially modifiable. Patient and care-giver education are critical to assure adherence. Pharmacists and nurses are an essential but underutilized aspect of education regarding proper medication use.