Advances in the management of complications from cirrhosis.

Cirrhosis with complications of liver decompensation and hepatocellular carcinoma (HCC) constitute a leading cause of morbidity and mortality worldwide. Portal hypertension is central to the progression of liver disease and decompensation. The most recent Baveno VII guidance included revision of the nomenclature for chronic liver disease, termed compensated advanced chronic liver disease, and leveraged the use of liver stiffness measurement to categorize the degree of portal hypertension. Additionally, non-selective beta blockers, especially carvedilol, can improve portal hypertension and may even have a survival benefit. Procedural techniques with interventional radiology have become more advanced in the management of refractory ascites and variceal bleeding, leading to improved prognosis in patients with decompensated liver disease. While lactulose and rifaximin are the preferred treatments for hepatic encephalopathy, many alternative treatment options may be used in refractory cases and even procedural interventions such as shunt embolization may be of benefit. The approval of terlipressin for the treatment of hepatorenal syndrome (HRS) in the USA has improved the way in which HRS is managed and will be discussed in detail. Malnutrition, frailty, and sarcopenia lead to poorer outcomes in patients with decompensated liver disease and should be addressed in this patient population. Palliative care interventions can lead to improved quality of life and clinical outcomes. Lastly, the investigation of systemic therapies, in particular immunotherapy, has revolutionized the management of HCC. These topics will be discussed in detail in this review.

Hepatitis C Treatment Among Primary Care and Specialty Providers: A Single Center Study, 2015 to 2022.

INTRODUCTION: Despite national goals to eliminate Hepatitis C (HCV) and the advancement of curative, well-tolerated direct-acting antiviral (DAAs) regimens, rates of HCV treatment have declined nationally since 2015. Current HCV guidelines encourage treatment of HCV by primary care providers (PCPs). Payors have reduced restrictions to access DAAs nationally and in California however it remains unclear if the removal of these restrictions has impacted the proportion of PCPs prescribing DAAs at a health system level. Our objective was to examine the proportion of DAAs prescribed by PCPs and specialists and to describe the population receiving treatment in a single health system from 2015 to 2022. METHODS: We examined the proportion of DAAs prescribed by PCPs and specialists and the population receiving treatment through a retrospective analysis of claims data in the University of California, Los Angeles (UCLA) Health System from 2015 to 2022. We described number of prescriptions for HCV medication prescribed by PCPs and specialists by year, medication type, and physician specialty. We also described numbers of prescriptions by patient demographics and comorbidities. RESULTS: A total of 1515 adult patients received a prescription for HCV medication through the UCLA Health System between 2015 and 2022. The proportion of patients receiving prescriptions for PCPs peaked at 19% in 2016, yet decreased to 5.7% in 2022, an average of 13% across all years. Median age of patients receiving treatment was 60 years old, and 56% of patients receiving HCV treatment had commercial insurance as their primary payer. CONCLUSIONS: HCV treatment declined from 2015 to 2022 among specialists and PCPs in our health system. Older patients comprised the majority of patients receiving treatment, suggesting a need for novel approaches to reach patients under 40, an age group with significant increases in HCV transmission.

Lower FIB-4 threshold in patients with diabetes improves diagnostic accuracy of the test in a Hispanic population.

Background: Non-invasive tests (NITs) can be used to estimate the severity of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) but their diagnostic accuracy is variable. Hispanic patients are at increased risk of NAFLD and diabetes. We evaluate the diagnostic performance of the fibrosis index based on 4 factors (FIB-4) in a population of Hispanic patients who underwent vibration-controlled transient elastography (VCTE). Methods: A total of 1,524 patients underwent VCTE at University of California, Los Angeles from July 18, 2019 to June 7, 2022. Ultimately 110 patients were identified as Hispanic, with confirmed NAFLD. Sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 threshold ≥1.3 were calculated. Logistic regression models were used to determine updated thresholds for patients with and without diabetes based on Youden's index. Results: Of the 110 patients, the majority (65%) were female. Prevalence of diabetes was higher in the group with clinically significant fibrosis (76% vs. 36%, P<0.001). Using a FIB-4 threshold ≥1.3 to predict clinically significant fibrosis (F2-F4 on VCTE), area under the receiver operating characteristic (AUROC) was 0.74. By incorporating diabetes status, AUROC was 0.81 when employing a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes. Conclusions: Using a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes improves the diagnostic performance of the test. The new FIB-4 including diabetes status will lead to improved screening in patients who are at risk of clinically significant fibrosis.

Cost effectiveness of hepatitis C direct acting agents.

INTRODUCTION: Introduction of direct acting antivirals (DAA) has transformed treatment of chronic hepatitis C (HCV) and made the elimination of HCV an achievable goal set forward by World Health Organization by 2030. Multiple barriers need to be overcome for successful eradication of HCV. Availability of pan-genotypic HCV regimens has decreased the need for genotype testing but maintained high efficacy associated with DAAs. AREAS COVERED: In this review, we will assess the cost-effectiveness of DAA treatment in patients with chronic HCV disease, with emphasis on general, cirrhosis, and vulnerable populations. EXPERT OPINION: Multiple barriers exist limiting eradication of HCV, including cost to treatment, access, simplified testing, and implementing policy to foster treatment for all groups of HCV patients. Clinically, DAAs have drastically changed the landscape of HCV, but focused targeting of vulnerable groups is needed. Public policy will continue to play a strong role in eliminating HCV. While we will focus on the cost-effectiveness of DAA, several other factors regarding HCV require on going attention, such as increasing public awareness and decreasing social stigma associated with HCV, offering universal screening followed by linkage to treatment and improving preventive interventions to decrease spread of HCV.

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.