The Liver Cirrhosis Network Cohort Study: Cirrhosis Definition, Study Population, and Endpoints.

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

Short-Term Out-of-Pocket and Total Costs of Care After Ablation, Resection, or Transplant for Early-Stage Hepatocellular Carcinoma: A National SEER-Medicare Cost Comparison.

BACKGROUND. Differences in survival and morbidity among treatment options (ablation, surgical resection, and transplant) for early-stage hepatocellular carcinoma (HCC) have been well studied. Additional understanding of the costs of such care would help to identify drivers of high costs and potential barriers to care delivery. OBJECTIVE. The purpose of this article was to quantify total and patient out-of-pocket costs for ablation, surgical resection, and transplant in the management of early-stage HCC and to identify factors predictive of these costs. METHODS. This retrospective U.S. population-based study used the SEER-Medicare linked dataset to identify a sample of 1067 Medicare beneficiaries (mean age, 73 years; 674 men, 393 women) diagnosed with early-stage HCC (size ≤ 5 cm) treated with ablation (n = 623), resection (n = 201), or transplant (n = 243) between January 2009 and December 2016. Total costs and patient out-of-pocket costs for the index procedure as well as for any care within 30 and 90 days after the procedure were identified and stratified by treatment modality. Additional comparisons were performed among propensity score-matched subgroups of patients treated by ablation or resection (each n = 172). Multivariable linear regression models were used to identify factors predictive of total costs and out-of-pocket costs for index procedures as well as for 30- and 90-day post-procedure periods. RESULTS. For ablation, resection, and transplant, median index-procedure total cost was US$6689, US$25,614, and US$66,034; index-procedure out-of-pocket cost was US$1235, US$1650, and US$1317; 30-day total cost was US$9456, US$29,754, and US$69,856; 30-day out-of-pocket cost was US$1646, US$2208, and US$3198; 90-day total cost was US$14,572, US$34,984, and US$88,103; and 90-day out-of-pocket cost was US$2138, US$2462, and US$3876, respectively (all p < .001). In propensity score-matched subgroups, ablation and resection had median index-procedure, 30-day, and 90-day total costs of US$6690 and US$25,716, US$9995 and US$30,365, and US$15,851 and US$34,455, respectively. In multivariable analysis adjusting for socioeconomic factors, comorbidities, and liver-disease prognostic indicators, surgical treatment (resection or transplant) was predictive of significantly greater costs compared with ablation at all time points. CONCLUSION. Total and out-of-pocket costs for index procedures as well as for 30-day and 90-day postprocedure periods were lowest for ablation, followed by resection and then transplant. CLINICAL IMPACT. This comprehensive cost analysis could help inform future cost-effectiveness analyses.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Predictors for Early Liver Cancer Survival After Ablation and Surgical Resection: A Surveillance, Epidemiology, and End Results Program-Medicare Study.

OBJECTIVE: To identify independent predictors of all-cause and cancer-specific mortality after ablation or surgical resection (SR) for small hepatocellular carcinomas (HCCs), after adjusting for key confounders. METHODS: Using Surveillance, Epidemiology, and End Results Program-Medicare, HCCs less than 5 cm treated with ablation or SR in 2009 to 2016 (n = 956) were identified. Univariate and multivariable Cox regression models for all-cause and cancer-specific mortality were performed including demographics, clinical factors (tumor size, medical comorbidities, and liver disease factors), social determinants of health, and treatment characteristics. We also determined the most influential predictors of survival using a random forest analysis. RESULTS: Larger tumor size (3-5 cm) is predictive of all-cause (hazard ratio [HR] 1.31, P = .002) and cancer-specific mortality (HR 1.59, P < .001). Furthermore, chronic kidney disease is predictive of all-cause mortality (HR 1.43, P = .013), though it is not predictive of cancer-specific death. Multiple liver disease factors are predictive of all-cause and cancer-specific mortality including portal hypertension and esophageal varices (HRs > 1, P < .05). Though Asian race is protective in univariate models, in fully adjusted, multivariable models, Asian race is not a significant protective factor. Likewise, other social determinants of health are not significantly predictive of all-cause or cancer-specific mortality. Finally, treatment with SR, in later procedure years or at high-volume centers, is protective for all-cause and cancer-specific mortality. In machine learning models, year procedure was performed, ascites, portal hypertension, and treatment choice were the most influential factors. DISCUSSION: Treatment characteristics, liver disease factors, and tumor size are more important predictors of all-cause and cancer-specific death than social determinants of health for small HCCs.

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Narrative review of management of cirrhosis during the treatment of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: The management of hepatocellular carcinoma (HCC) and cirrhosis are closely linked. HCC most often occurs in the background of cirrhosis and can also lead to decompensation of underlying liver disease. The treatment of complications of cirrhosis is important to help reduce morbidity and mortality and allow for expanded treatment options of HCC. METHODS: We searched PubMed using search terms for cirrhosis and HCC. From this search, we selected references which appeared to be primary studies preferentially within the last 5 years, although also included select landmark studies which have shaped guidelines and recommendations. KEY CONTENT AND FINDINGS: The development of HCC and treatment of HCC can both cause decompensation of liver disease and worsening of liver function. For most patients, the development of HCC or progression of disease are the drivers of morbidity and mortality. However, it is important to closely monitor patients for complications of liver disease that develop either as a result of HCC or as a complication of HCC treatment, and this can have important implications on treatment options. Multidisciplinary team involvement including hepatologists, surgeons, radiologists, interventional radiologists, medical oncologists, and palliative care is essential in the care of patients with cirrhosis and HCC to help guide management decisions and treatment. CONCLUSIONS: The management of cirrhosis and HCC are both complex and interrelated. Through a multidisciplinary team approach we can best treat the complications of cirrhosis, allow for expanded treatment options, and improve quality of life through symptom management.

Beyond Survival: Adverse Events and Care Delivery Outcomes after Early Liver Cancer Treatment in a Nationally Representative Cohort.

PURPOSE: To compare secondary outcomes after ablation (AB), surgical resection (SR), and liver transplant (LT) for small hepatocellular carcinomas (HCCs), including resource utilization and adverse event (AE) rates. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results Program (SEER)-Medicare, HCCs <5 cm that were treated with AB, SR, or LT in 2009-2016 (n = 1,067) were identified using Healthcare Common Procedure Coding System codes through Medicare claims. Index procedure length of stay, need for intensive care unit (ICU) level care, readmission rates, and AE rates at 30 and 90 days were compared using chi-square tests or Fisher exact tests. Examined AEs included hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, liver failure, and anesthesia-related AEs, identified by International Classification of Diseases, Ninth/10th Revision, codes. RESULTS: The median length of stay for initial treatment was 1 day, 6 days, and 7 days for AB, SR, and LT, respectively (P < .001). During initial hospital stay, 5.0%, 40.8%, and 63.4% of AB, SR, and LT cohorts, respectively, received ICU-level care (P < .001). By 30 and 90 days, there were significant differences among the AB, SR, and LT cohorts in the rate of postprocedural hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, and anesthesia-related AEs (P < .05). By 90 days, the readmission rates after AB, SR, and LT were 18.6%, 28.2%, and 40.6% (P < .001), respectively. CONCLUSIONS: AB results in significantly less healthcare utilization during the initial 90 days after procedure compared with that after SR and LT due to shorter length of stay, lower intensity care, fewer readmissions, and fewer AEs.

Nonviral or Drug-Induced Etiologies of Acute-on-Chronic Liver Failure (Autoimmune, Vascular, and Malignant).

Vascular, autoimmune hepatitis, and malignant causes of acute-on-chronic liver failure are rare but important to consider and investigate in patients with underlying liver disease who present with acute deterioration and other more common etiologies have been excluded. Vascular processes including Budd-Chiari syndrome and portal vein thrombosis require imaging for diagnosis and anticoagulation is the mainstay of therapy. Patients may require advanced interventional therapy including transjugular intrahepatic portosystemic shunt or consideration of liver transplantation. Autoimmune hepatitis is a complex disease entity that requires a high degree of clinical suspicion and can present heterogeneously.

Opportunities to address gaps in early detection and improve outcomes of liver cancer.

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.

Management and Risks Before, During, and After Liver Transplant in Individuals With Obesity.

Obesity has become a global epidemic, adding to the burden of chronic diseases and disabilities. Metabolic syndrome, especially obesity, is a significant risk factor for nonalcoholic fatty liver disease, which is the most common indication for liver transplant (LT). The prevalence of obesity among the LT population is growing. Obesity increases the necessity of LT by playing a role in the development of nonalcoholic fatty liver disease, decompensated cirrhosis, and hepatocellular carcinoma, and it can also coexist with other diseases requiring LT. Therefore, LT teams must identify key aspects required to manage this high-risk population, but there are currently no defined recommendations for managing obesity in LT candidates. Although body mass index is often used to assess the weight of patients and classify them as overweight or obese, this measure may be inaccurate to use in patients with decompensated cirrhosis, as fluid overload or ascites can significantly add to the weight of patients. Diet and exercise remain the cornerstone of obesity management. Supervised weight loss before LT, without worsening frailty and sarcopenia, may be beneficial in reducing surgical risks and improving long-term LT outcomes. Bariatric surgery is another effective treatment for obesity, with sleeve gastrectomy currently conferring the best outcomes in LT recipients. However, evidence supporting the timing of bariatric surgery is lacking. Long-term patient and graft survival data in individuals with obesity following LT are scarce. Class 3 obesity (body mass index ≥40) further complicates the treatment of this patient population. This article discusses the impact of obesity on the outcome of LT.

Modeling HCV elimination recovery following the COVID-19 pandemic in the United States: Pathways to regain progress.

BACKGROUND: As of 2019, the United States (US) was not on track to achieve targets for elimination, due to increasing incidence and treatment barriers. In 2020, the COVID-19 pandemic disrupted HCV services globally and in the US. As healthcare services normalize, there is an urgent need to reassess progress and evaluate scenarios that restore a pathway toward HCV elimination. METHODS: We updated a validated Markov model to estimate HCV-related morbidity and mortality in the US. Five scenarios were developed to bookend possible HCV outcomes in the wake of the pandemic. These included 1) return to pre-COVID-19 treatment forecasts; 2) achieve elimination targets through treatment and harm reduction; 3) long-term treatment disruptions; 4/5) achieve elimination targets through increased treatment without increased harm reduction, starting in either 2022 or 2025. FINDINGS: From 2014-2019, more than 1.2 million patients were treated for HCV in the US. Elimination targets in 2030 could be achieved in the US by treating an additional 3.2-3.3 million patients from 2020 to 2030, or by preventing new infections through expanded harm reduction programs and treating up to 2.7 million patients. Intervention scenarios could prevent over 30,000 HCC cases and over 29,000 liver-related deaths. INTERPRETATION: The US has made strides toward HCV elimination, but gains could be lost in the wake of the pandemic. However, it is still possible to avert nearly 30,000 deaths through increased harm reduction and increased treatment rates. This requires a coordinated effort from the entire HCV community.

Noninvasive Fibrosis Testing in Chronic Liver Disease Including Caveats.

Assessment of liver fibrosis is important as the range of liver disease management has expanded, rendering biopsy both imperfect and impractical in many situations. Noninvasive tests of fibrosis leverage laboratory, imaging and elastography techniques to estimate disease extent, often with the goal of identifying advanced fibrosis. This review attempts to summarize their utility across a broad range of possible clinical scenarios while considering the central tenets of health care quality: access, quality, and cost. For each test, it also discusses the caveats whereby each test may have reduced effectiveness and how to consider each in a typical clinical setting.

Practice patterns of the medical evaluation of living liver donors in the United States.

Living donor liver transplantation (LDLT) can help address the growing organ shortage in the United States, yet little is known about the current practice patterns in the medical evaluation of living liver donors. We conducted a 131-question survey of all 53 active LDLT transplant programs in the United States to assess current LDLT practices. The response rate was 100%. Donor acceptance rate was 0.33 with an interquartile range of 0.33-0.54 across all centers. Areas of high intercenter agreement included minimum age cutoff of 18 years (73.6%) and the exclusion of those with greater than Class 1 obesity (body mass index, 30.0-34.9 m/kg 2 ) (88.4%). Diabetes mellitus was not an absolute exclusion at most centers (61.5%). Selective liver biopsies were performed for steatosis or iron overload on imaging (67.9% and 62.3%, respectively) or for elevated liver enzymes (60.4%). Steatohepatitis is considered an exclusion at most centers (84.9%). The most common hypercoagulable tests performed were factor V Leiden (FVL) (88.5%), protein C (73.1%), protein S (71.2%), antithrombin III (71.2%) and prothrombin gene mutation (65.4%). At 41.5% of centers, donors were allowed to proceed with donation with FVL heterozygote status. Most programs discontinue oral contraceptive pills at least 28 days prior to surgery. At most centers, the need for cardiovascular ischemic risk testing is based on age (73.6%) and the presence of one or more cardiac risk factors (68.0%). Defining areas of practice consensus and variation underscores the need for data generation to develop evidence-based guidance for the evaluation and risk assessment of living liver donors.

Long-Term Survival After Surgery Versus Ablation for Early Liver Cancer in a Large, Nationally Representative Cohort.

OBJECTIVE: To compare survival outcomes (all-cause, cancer-specific, and disease-free) for small hepatocellular carcinomas (HCCs), less than or equal to 5 cm, after ablation (AB) and surgical resection (SR) after adjusting for key confounders. Secondarily, to understand differential survival outcomes of liver transplant (TR) compared with SR and AB. METHODS: Using Surveillance, Epidemiology, and End Results Program-Medicare, HCCs less than 5 cm that were treated with AB, SR, or TR in 2009 to 2016 (n = 1,215) were identified using Healthcare Common Procedure Coding System codes through Medicare claims. The TR group was subdivided into two groups: TR with prior treatment and TR without prior treatment. All-cause survival, cancer-specific survival, and disease-free survival were analyzed using Kaplan-Meier curves and compared between groups using log-rank tests and Cox regression analyses. Propensity score-matched comparison of AB and SR groups was performed, with groups matched on demographics, social determinants of health, medical comorbidities, and liver disease severity prognostic indicators. RESULTS: Median study follow-up time was 2.71 years (interquartile range 1.25-3.83). Unadjusted 1-, 3-, and 5-year cancer-specific survivals were 85.9%, 67.6%, and 56.3% for the AB group; 91.7%, 82.6%, and 81.7% for the SR group; 93.5%, 88.7%, and 79.4% for TR without prior treatment group; and 96.4%, 93.2%, and 93.2% for TR with prior treatment group (P < .0001). With SR as the reference group, the propensity-matched hazard ratios for AB were 2.04 (95% confidence interval: 1.51-2.77) for all-cause mortality, 2.44 (95% confidence interval: 1.56-3.80) for cancer-specific mortality, and 2.12 (95% confidence interval: 1.61-2.78) for disease recurrence. DISCUSSION: SR is superior to AB for small HCCs in a large, nationally representative, modern cohort, and in secondary analysis TR was superior to both.

Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma.

Importance: National guidelines on transplant selection have adopted successful downstaging to within Milan criteria (MC) as a viable option for the treatment of hepatocellular carcinoma (HCC) before liver transplant (LT). Recurrence of HCC after LT carries a poor prognosis, and treatment modalities remain challenging. Objective: To establish the 10-year outcomes of patients with HCC after LT in a large, multicenter US study based on individual data; provide robust data on the long-term role of downstaging; and evaluate the association of treatment modalities with postrecurrence survival. Design, Setting, and Participants: In this cohort study, a retrospective, multicenter analysis of prospectively collected data was conducted for 2645 adults who had undergone LT for HCC at 5 US academic centers between January 2001 and December 2015. The analysis was performed from May 2019 through June 2021. Outcomes of 341 patients whose disease was downstaged to within MC were compared with those in 2122 patients whose disease was always within MC and 182 patients whose disease was not downstaged. The associations of tumor and treatment factors on postrecurrence survival were analyzed using Cox proportional hazards regression and multivariable logistic regression models. Main Outcomes and Measures: The primary outcome was overall survival for the whole cohort and according to downstaging status. Secondary outcomes were time to recurrence, recurrence-free survival, and recurrence after specific post-LT therapies. Results: Of the 2645 patients studied, the median age was 59.9 years (IQR, 54.7-64.7 years). The majority of the patients were men (2028 [76.7%] vs 617 [23.3%] women). The 10-year post-LT survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within MC; and 43.3% and 41.1% in those whose disease was not downstaged. Independent variables associated with downstaging failure were tumor size greater than 7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P = .02), more than 3 tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P = .01), and α-fetoprotein response of at least 20 ng/mL with less than 50% improvement from maximum α-fetoprotein before LT (OR, 1.99; 95% CI, 1.14-3.46; P = .02). Surgically treated patients with recurrent HCC differed in clinicopathologic characteristics and had improved 5-year postrecurrence survival rates (31.6% vs 7.3%; P < .001). Conclusions and Relevance: In a large, multicenter cohort of patients with HCC successfully downstaged to within MC, 10-year post-LT outcomes were excellent, validating national downstaging policies and showing a clear utility benefit for LT prioritization decision making. Surgical management of HCC recurrence after LT was associated with improved survival in well-selected patients and should be pursued, if feasible.

An Evidence-based Practical Guide to Vaccination for Hepatitis B Virus.

The hepatitis B virus (HBV) is highly infectious, with over 292 million chronically infected people worldwide and up to 2.4 million in the United States. Following infection, clinically silent liver damage can ensue, but symptoms or signs of advanced disease, including cirrhosis and hepatocellular carcinoma, can take decades to emerge. HBV has the heaviest public health burden of all hepatitis viruses and has now surpassed other major communicable diseases (eg, HIV, diarrheal disease, malaria, tuberculosis) as a leading cause of death globally. Preventing transmission is essential, and efforts are in place to reinforce screening, vaccination, and routine follow-up. Three safe and effective vaccines are available in the United States and other countries for HBV prevention, and the benefits of vaccination in preventing infection and its sequelae have been substantiated. For the first time in over 25 years, a new Food and Drug Administration-approved vaccine is available that offers a high degree of immunogenicity after 2, rather than 3, injections. Persistent challenges include the underutilization of vaccination, choice of vaccine, incomplete vaccinations, varying needs in different populations, management of nonresponders or those with undocumented or incompletely documented vaccination courses, and questions about whether and when booster injections may be needed. A panel of US academic hepatologists with expertise and experience in preventing and managing HBV infection have collaborated to write this practical clinical paper intended to guide clinicians in vaccinating for HBV and address questions that regularly arise in the clinic.