Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients with Unresectable HCC.

BACKGROUND AND AIMS: Non-invasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a non-invasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the US including adult patients with unresectable HCC and Child Pugh A5-B7 cirrhosis diagnosed between 2007 and2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but prior to HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age 64.6 years, 80.6% male and 74.0% White). Median time from HCC diagnosis to EGD was 47 (IQR: 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved a NPV of 86.3% in the validation cohort, while a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in over half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSION: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients prior to the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.

Association of Baseline Hepatitis B Virus DNA and On-Treatment Risk of Cirrhosis and Hepatocellular Carcinoma.

Background: Recent studies suggest an inverse relationship between baseline levels of hepatitis B virus (HBV) DNA and on-treatment risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, data are limited to Asian cohorts, and it is unclear if similar associations hold true for non-Asians with CHB. We aimed to evaluate association of baseline HBV DNA with long-term risks of cirrhosis and HCC among a predominantly non-Asian cohort of CHB patients in the USA. Methods: Using longitudinal data from the national Veterans Affairs database, we evaluated the risk of cirrhosis or HCC among adults with non-cirrhotic CHB who are on continuous antiviral therapy, stratified by moderate levels of baseline HBV DNA (4.00 - 6.99 log10 IU/mL) vs. high levels of baseline HBV DNA (7.00 log10 IU/mL or higher). Propensity score weighting was applied, and competing risks cumulative incidence functions and Cox proportional hazards models were utilized. Results: Among 1,129 non-cirrhotic CHB patients (41% non-Hispanic White, 36% African American, mean age 57.0 years, 62.2% hepatitis B e antigen (HBeAg) positive), 585 had moderate levels of baseline HBV DNA and 544 had high HBV DNA. After propensity score weighting, no significant difference in risk of cirrhosis was observed between moderate vs. high baseline HBV DNA (4.55 vs. 5.22 per 100 person-years, hazard ratio (HR): 0.87, 95% confidence interval (CI): 0.69 - 1.09, P = 0.22), but risk of HCC was significantly higher in patients with moderate vs. high baseline HBV DNA (0.84 vs. 0.69 per 100 person-years, HR: 1.33, 95% CI: 1.09 - 1.62, P < 0.01). Conclusions: Among a national cohort of predominantly non-Asian US veterans with non-cirrhotic CHB on antiviral therapy, moderate levels of baseline HBV DNA was associated with higher risk of HCC than high HBV DNA.

Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project.

BACKGROUND & AIMS: The coronavirus disease-2019 pandemic profoundly disrupted preventative health care services including cancer screening. As the largest provider of cirrhosis care in the United States, the Department of Veterans Affairs (VA) National Gastroenterology and Hepatology Program aimed to assess factors associated with hepatocellular carcinoma (HCC) stage at diagnosis, treatment, and survival. METHODS: Veterans with a new diagnosis of HCC in 2021 were identified from electronic health records (N = 2306). Structured medical record extraction was performed by expert reviewers in a 10% random subsample of Veterans with new HCC diagnoses. Factors associated with stage at diagnosis, receipt of treatment, and survival were assessed using multivariable models. RESULTS: Among 199 patients with confirmed HCC, the average age was 71 years and most (72%) had underlying cirrhosis. More than half (54%) were at an early stage (T1 or T2) at diagnosis. Less-advanced liver disease, number of imaging tests adequate for HCC screening, HCC diagnosis in the VA, and receipt of VA primary care were associated significantly with early stage diagnosis. HCC-directed treatments were administered to 145 (73%) patients after a median of 37 days (interquartile range, 19-54 d) from diagnosis, including 70 (35%) patients who received potentially curative treatments. Factors associated with potentially curative (vs no) treatments included HCC screening, early stage at diagnosis, and better performance status. Having fewer comorbidities and better performance status were associated significantly with noncurative (vs no) treatment. Early stage diagnosis, diagnosis in the VA system, and receipt of curative treatment were associated significantly with survival. CONCLUSIONS: These results highlight the importance of HCC screening and engagement in care for HCC diagnosis, treatment, and survival while demonstrating the feasibility of developing a national quality improvement agenda for HCC screening, diagnosis, and treatment.

Liver Stiffness Measurement and Risk Prediction of Hepatocellular Carcinoma After HCV Eradication in Veterans With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. METHODS: This was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. RESULTS: The risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01-1.04; P < .001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70-0.90; P = .0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10-14.9 kPa (aHR, 1.71; 95% CI, 1.01-2.88; P = .046), 3.22% for LSM 15-19.9 kPa (aHR, 1.59; 95% CI, 0.78-3.20; P = .20), 5.07% among LSM 20-24.9 kPa (aHR, 2.55; 95% CI, 1.30-5.01; P = .01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74-5.26; P < .0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. CONCLUSIONS: LSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension-related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued.

The novel SALT-M score predicts 1-year post-transplant mortality in patients with severe acute-on-chronic liver failure.

BACKGROUND & AIMS: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS). METHODS: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors. RESULTS: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/≥2 inotropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. CONCLUSIONS: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score predicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits. IMPACT AND IMPLICATIONS: Liver transplantation (LT) may be the only life-saving procedure available to patients with acute-on-chronic liver failure (ACLF), but clinically instability can augment the perceived risk of post-transplant mortality at 1 year. We developed a parsimonious score with clinically and readily available parameters to objectively assess 1-year post-LT survival and predict median length of stay after LT. We developed and externally validated a clinical model called the Sundaram ACLF-LT-Mortality score in 521 US patients with ACLF with 2 or ≥3 organ failure(s) and 120 French patients with ACLF grade 3. The c-statistic was 0.72 in the development cohort and 0.80 in the validation cohort. We also provided an estimation of the median length of stay after LT in these patients. Our models can be used in discussions on the risks/benefits of LT in patients listed with severe ACLF. Nevertheless, the score is far from perfect and other factors, such as patient's preference and center-specific factors, need to be considered when using these tools.

Patients With Acute-on-Chronic Liver Failure Have Greater Healthcare Resource Utilization After Liver Transplantation.

BACKGROUND & AIMS: Although liver transplantation (LT) has been demonstrated to provide survival benefit for patients with acute-on-chronic liver failure (ACLF), data are lacking regarding resource utilization for this population after LT. METHODS: We retrospectively reviewed data from 10 centers in North America of patients transplanted between 2018 and 2019. ACLF was identified by using the European Association for the Study of the Liver-Chronic Liver Failure criteria. RESULTS: We studied 318 patients of whom 106 patients (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Healthcare resource utilization after LT was greater among recipients with ACLF compared with patients without ACLF regarding median post-LT length of hospital stay (LOS) (P < .001), length of post-LT dialysis (P < .001), discharge to a rehabilitation center (P < .001), and 30-day readmission rates (P = .042). Multivariable negative binomial regression analysis demonstrated a significantly longer LOS for patients with ACLF-1 (1.9 days; 95% confidence interval [CI], 0.82-7.51), ACLF-2 (6.7 days; 95% CI, 2.5-24.3), and ACLF-3 (19.3 days; 95% CI, 1.2-39.7), compared with recipients without ACLF. Presence of ACLF-3 at LT was also associated with longer length of dialysis after LT (9.7 days; 95% CI, 4.6-48.8) relative to lower grades. Multivariable logistic regression analysis revealed greater likelihood of discharge to a rehabilitation center among recipients with ACLF-1 (odds ratio [OR], 1.79; 95% CI, 1.09-4.54), ACLF-2 (OR, 2.23; 95% CI, 1.12-5.01), and ACLF-3 (OR, 2.23; 95% CI, 1.40-5.73). Development of bacterial infection after LT also predicted LOS (20.9 days; 95% CI, 6.1-38.5) and 30-day readmissions (OR, 1.39; 95% CI, 1.17-2.25). CONCLUSIONS: Patients with ACLF at LT, particularly ACLF-3, have greater post-transplant healthcare resource utilization.

Anticoagulation in Cirrhosis: Evidence for the Treatment of Portal Vein Thrombosis and Applications for Prophylactic Therapy.

The clinical utility of anticoagulation for patients with cirrhosis and asymptomatic portal vein thrombosis (PVT) is widely debated. Complex hemostatic derangements in cirrhosis that increase risk of both bleeding and thrombosis, as well as a lack of randomized controlled data, limit conclusive assessments regarding optimal management of anticoagulation in this setting. In this review, we summarize the relevant literature pertaining to PVT in cirrhosis, including the effect of untreated PVT on the natural progression of liver disease and the overall impact of anticoagulation on clot burden and other relevant clinical outcomes. Apart from patients who are symptomatic or listed for liver transplantation, data supporting anticoagulation for the treatment of PVT is limited and without clear consensus guidelines. In patients with cirrhosis without PVT, emerging evidence for the role of prophylactic anticoagulation to mitigate the progression of fibrosis suggests an optimal risk-benefit tradeoff with decreased rates of liver decompensation and mortality, without a heightened risk of bleeding. In summation, as our understanding of the role of both prophylactic and therapeutic anticoagulation in cirrhosis continues to evolve, ongoing risk stratification of patients with asymptomatic PVT demands further attention.

Risk Factors for Posttransplantation Mortality in Recipients With Grade 3 Acute-on-Chronic Liver Failure: Analysis of a North American Consortium.

Although liver transplantation (LT) yields survival benefit for patients with acute-on-chronic liver failure grade 3 (ACLF-3), knowledge gaps remain regarding risk factors for post-LT mortality. We retrospectively reviewed data from 10 centers in the United States and Canada for patients transplanted between 2018 and 2019 and who required care in the intensive care unit prior to LT. ACLF was identified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. A total of 318 patients were studied, of whom 106 (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Survival probability 1 year after LT was significantly higher in patients without ACLF (94.3%) compared with patients with ACLF (87.3%; P = 0.02), but similar between ACLF-1 (88.5%), ACLF-2 (87.8%), and ACLF-3 (85.7%; P = 0.26). Recipients with ACLF-3 and circulatory failure (n = 29) had similar 1-year post-LT survival (82.3%) compared with patients with ACLF-3 without circulatory failure (89.6%; P = 0.32), including those requiring multiple vasopressors. For patients transplanted with ACLF-3 including respiratory failure (n = 20), there was a trend toward significantly lower post-LT survival (P =  0.07) among those with respiratory failure (74.1%) compared with those without (91.0%). The presence of portal vein thrombosis (PVT) at LT for patients with ACLF-3 (n = 15), however, yielded significantly lower survival (91.9% versus 57.1%; P < 0.001). Multivariable logistic regression analysis revealed that PVT was significantly associated with post-LT mortality within 1 year (odds ratio, 7.3; 95% confidence interval, 1.9-28.3). No correlation was found between survival after LT and the location or extent of PVT, presence of transjugular intrahepatic portosystemic shunt, or anticoagulation. LT in patients with ACLF-3 requiring vasopressors yields excellent 1-year survival. LT should be approached cautiously among candidates with ACLF-3 and PVT.

The efficacy and safety of thrombopoietin receptor agonists in patients with chronic liver disease undergoing elective procedures: a systematic review and meta-analysis.

Thrombopoietin receptor agonists (TPO-RAs) can mitigate preprocedural thrombocytopenia in patients with chronic liver disease (CLD) however their effects on procedural outcomes is unclear. In this meta-analysis, we aimed to better define the efficacy, thrombotic risk and bleeding mitigation associated with the use of preoperative TPO-RAs in patients with CLD. We performed a systematic review and meta-analysis of randomized placebo-controlled clinical trials to assess the use of preprocedural TPO-RAs in patients with CLD, searching MEDLINE, EMBASE and the Cochrane library database. Six publications comprising eight randomized trials (1229 patients; 717 received TPO-RAs, 512 received placebo) and three unique TPO-RAs were retrieved. The majority of the included procedures were endoscopic. TPO-RAs were significantly more likely to result in a preoperative platelet count greater than 50 x 109/L (72.1% vs 15.6%, RR 4.8, 95% CI 3.6-6.4 p < .00001. NNT 1.8) and reduced the incidence of platelet transfusions (22.5% vs 67.8%, RR 0.33, 95% CI 0.3-0.4 p < .00001. NNT 2.2). Total periprocedural bleeding was decreased in patients who received TPO-RAs (11.6% vs 15.6%, RR 0.64, 95% CI 0.5-0.9 p = .01. NNT 24.7) and there was no increase in the rate of thrombosis (2.2% vs 1.8% RR 1.25, 95% CI 0.6-2.9 p = .60. NNH 211.1). In patients with CLD the use of preprocedural TPO-RAs resulted in significant increased platelet counts, and decreased the incidence of platelet transfusions as compared to placebo. TPO use likewise decreased the incidence of total periprocedural bleeding without increasing the rate of thrombosis.

The hemostatic and thrombotic complications of liver disease.

Hepatic cirrhosis leads to numerous hematologic derangements resulting in a complex and tenuously rebalanced hemostatic milieu. The utility of common hematologic tests including the INR and aPTT in assessing hemostatic and thrombotic risk in patients with cirrhosis is limited, and consensus on transfusion thresholds and proper management of thrombotic complications continues to evolve. This review summarizes the pathophysiology of key derangements of hemostasis including those of platelets, von Willebrand factor, pro- and anticoagulation factors, and fibrin. Additionally, the pathogenesis, consequences, optimal management, and prevention of major thrombotic and bleeding complications in cirrhosis arte discussed.