Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

BACKGROUND AND AIMS: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and as such was assessed in a population comprised of liver transplant (LT) candidates. METHODS AND RESULTS: Fifty hospitalized, LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. ACLF grade 3, serum creatinine (SCr)>5.0 mg/dL, or MELD≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide (M&O) or norepinephrine (NorEpi) for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as ≥30% decrease in SCr with EOT SCr≤1.5, partial response (PR) as ≥30% decrease in SCr with EOT SCr>1.5, and non-response (NR) as <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p<0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. CONCLUSIONS: With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical M&O/NorEpi cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Decreased need for RRT in liver transplant recipients after pretransplant treatment of hepatorenal syndrome-type 1 with terlipressin.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin ( p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo ( p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Racial and ethnic disparities in psychosocial evaluation and liver transplant waitlisting.

Health disparities have been well-described in all stages of the liver transplantation (LT) process. Using data from psychosocial evaluations and the Stanford Integrated Psychosocial Assessment, our objective was to investigate potential racial and ethnic inequities in overall LT waitlisting and not waitlisting for medical or psychosocial reasons. In a cohort of 2271 candidates evaluated for LT from 2014 to 2021 and with 1-8 years of follow-up, no significant associations were noted between race/ethnicity and overall waitlisting and not waitlisting for medical reasons. However, compared with White race, Black race (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.07-2.56) and Hispanic/Latinx ethnicity (OR, 2.10; 95% CI, 1.16-3.78) were associated with not waitlisting for psychosocial reasons. After adjusting for sociodemographic variables, the relationship persisted in both populations: Black (OR, 1.95; 95% CI, 1.12-3.38) and Hispanic/Latinx (OR, 2.29; 95% CI, 1.08-4.86) (reference group, White). High-risk Stanford Integrated Psychosocial Assessment scores were more prevalent in Black and Hispanic/Latinx patients, likely reflecting upstream factors and structural racism. Health systems and LT centers should design programs to combat these disparities and improve equity in access to LT.

Clinical Predictors of Intensive Care Unit Transfer in Admitted Patients with Cirrhosis.

BACKGROUND: Patients with cirrhosis are at high risk of mortality after organ failure that requires ICU care. There have been attempts to predict which patients are at highest risk, with some success found in adapting liver disease-specific scoring systems with clinical variables commonly associated with critical illness. However, the clinical factors predictive of which patients with cirrhosis are most at-risk of needing ICU level care are unknown. AIMS: Our study set out to better understand which clinical variables were associated with need for ICU care in patients with cirrhosis. METHODS: Retrospective analysis of admitted patients with cirrhosis at single tertiary care center. RESULTS: Patients with cirrhosis admitted to our center were categorized into three groups: those without ICU transfer, those admitted to the ICU directly from the emergency department (ED), and those admitted to the ICU from the medicine floor. These groups differed in mortality at 30 days (3.5% vs. 15% vs. 25%, P < 0.001) and at subsequent intervals up to 1 year. These groups differed in indication for ICU transfer, with GI bleed, hemorrhagic shock, hepatic encephalopathy, and hyponatremia occurring more in the ED-to-ICU group, while respiratory failure was more common in the floor-to-ICU group. In multivariable analysis, factors associated with ICU transfer included worsened kidney function, anemia, hyponatremia, leukocytosis, and the decision to obtain a lactate level. Similar analysis with only floor-to-ICU patients found that ICU transfer was associated with hypoalbuminemia, hyponatremia, hypotension, and SIRS score. CONCLUSION: Our study found significant differences in mortality among three distinct groups of patients with cirrhosis. A risk factor model for ICU transfer found that variables both specific and nonspecific to liver disease were associated with ICU transfer, with between-group differences supporting the idea of different clinical phenotypes and suggesting factors that should be considered in early triage and assessment of hospitalized patients with cirrhosis.

Autoimmune hepatitis and metabolic syndrome-associated disease development: a U.S. cohort study.

BACKGROUND: Autoimmune hepatitis (AIH) may coexist with metabolic syndrome-associated diseases (MSADs) given patients' inherent need for corticosteroid therapy, as well as general population trends. AIM: To examine the impact of MSAD risk factors on AIH or its treatment, and vice versa METHODS: This was a multi-centre retrospective cohort study of 552 patients with AIH diagnosed between January 2000 and December 2019. Data relating to demographic factors, laboratory values, AIH medications and MSADs were collected at diagnosis and at 1- and 3-year follow-up. Statistical relationships were analysed and reported. RESULTS: We included 552 patients in the study cohort (median age 50 years, 76.1% female). All MSADs, including hypertension, dyslipidaemia, diabetes and a gain of BMI ≥3 kg/m2 , increased within the AIH cohort over time. Initial treatment regimen impacted de novo diabetes but not other MSAD development. AIH biochemical remission was less frequent at 3 years post-diagnosis among patients with ≥1 MSAD. The incidence of new MSADs could be predicted by baseline factors in certain cases. CONCLUSION: In the largest US-based cohort of patients newly diagnosed with AIH, there was a considerable burden of pre-existing and de novo MSADs that may affect AIH treatment outcomes. Identifying those at highest risk of co-morbid MSADs allows for an individualised approach to management to reduce its long-term sequelae in patients with AIH.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Rising Trend in Waitlisting for Alcoholic Hepatitis With More Favorable Outcomes Than Other High Model for End-stage Liver Disease in the Current Era.

BACKGROUND: In the appropriate candidate, liver transplantation (LT) is a viable treatment for alcoholic hepatitis (AH). We compared the waitlisting trends and outcomes of AH patients in the context of others with high Model for End-stage Liver Disease (MELD) score. METHODS: LT listings for AH between January 1, 2008, and June 12, 2020 were identified in the United Network for Organ Sharing database. Temporal trends in listings for AH were assessed. Covariate adjusted competing risks models evaluated waitlist mortality and LT rates between AH candidates and others with listing native MELD ≥30. RESULTS: Between 2008 and 2019, waitlist additions for AH increased 6.5-fold. Waiting time for AH candidates was short (median 10 d). Delisting for clinical improvement was infrequent in AH, albeit higher than MELD ≥30 patients (3.3% versus 0.8%; P < 0.001). Among 99 centers with ≥1 AH listing, AH patients accounted for 0.2%-18.2% of all alcohol-related listings and 0.6%-25.0% of those with native listing MELD ≥30. Overall listing volume was larger at these 99 centers than the 40 with no AH listings (P < 0.001). AH candidates in 2014-2020 experienced improved waitlist survival (adjusted subhazard ratio, 0.67; 95% confidence interval, 0.52-0.86; P = 0.002) and higher transplant rates (adjusted subhazard ratio, 1.14; 95% confidence interval, 1.04-1.25; P = 0.006) versus other MELD ≥30 candidates. CONCLUSIONS: There has been a rising trend in waitlisting patients with AH and high MELD score. Liver disease causes influence waitlist outcomes and those of AH candidates are more favorable. Further research and allocation adjustments may be needed to ensure equitable organ allocation, based on liver disease cause, for those on the LT waitlist.

Radiologically Placed Peritoneovenous Shunt is an Acceptable Treatment Alternative for Refractory Ascites Due to End-Stage Liver Disease.

PURPOSE: To compare patients treated with large-volume paracentesis (LVP), transjugular intrahepatic portosystemic shunt (TIPS), and peritoneovenous shunt (PVS) for ascites. MATERIALS AND METHODS: A retrospective study of 192 patients treated with LVP (94), TIPS (75), or PVS (23) was performed. Records were reviewed for patient characteristics and outcomes. The patients' age differed (LVP, 59.5 years; TIPS, 58.8 years; and PVS, 65.6 years; P = .003). Nonalcoholic steatohepatitis was the most common etiology in the PVS cohort (11/23, 47%), and hepatitis C in the TIPS (27/75, 36%), and LVP cohorts (43/94, 46%) (P = .032). The model for end-stage liver disease score was significantly different (LVP, 14; TIPS, 13; and PVS, 8; P = .035). Hepatocellular carcinoma was higher in the PVS cohort (6/23 patients, 25%) than in the TIPS (4/75, 5%), and LVP (12/94, 12%) cohorts (P = .03). RESULTS: Emergency department visits and hospital readmissions were the highest in the LVP cohort (40%, ≥2 readmissions, P < .001). Patients required fewer LVPs after TIPS (1.5 to 0.14, P < .001) or PVS (2.1 to 0.5, P = .019). In an unadjusted Cox model, patients in the TIPS cohort were found to have a 58% reduction in the risk of death compared with patients in the LVP cohort (P = .003). Transplant-free survival (PVS, 44 days; TIPS, 155 days; and LVP, 213 days) differed (log rank = 0.001). CONCLUSIONS: The survival in the PVS and TIPS cohorts was similar, with less healthcare utilization than the LVP cohort. PVS is a satisfactory alternative to LVP.

Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening.

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.This article is highlighted in the In This Issue feature, p. 2355.

Blinding in Clinical Trials for Chronic Liver Diseases.

Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical therapy in a single trial. While many RCTs are conducted without blinding (open label), it is rare to encounter a blinded trial that does not randomize its subjects. Clinical trials for chronic liver diseases have adopted many of the practices set forth by RCTs in other chronic diseases, but blinding has often been difficult to properly implement. This review examines the rationale for blinding, common challenges to successful blinding, different mechanisms of unintentional unblinding in clinical trials for viral hepatitis and nonalcoholic steatohepatitis, and recommendations for blinding and design in future trials of treatments for liver disease.

Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI). METHODS: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type. RESULTS: Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P < .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77). CONCLUSIONS: More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.

Mortality and Hepatic Decompensation in Patients With Cirrhosis and Atrial Fibrillation Treated With Anticoagulation.

BACKGROUND AND AIMS: Outcomes with anticoagulation (AC) are understudied in advanced liver disease. We investigated effects of AC with warfarin and direct oral anticoagulants (DOACs) on all-cause mortality and hepatic decompensation as well as ischemic stroke, major adverse cardiovascular events, splanchnic vein thrombosis, and bleeding in a cohort with cirrhosis and atrial fibrillation (AF). APPROACH AND RESULTS: This was a retrospective, longitudinal study using national data of U.S. veterans with cirrhosis at 128 medical centers, including patients with cirrhosis with incident AF, from January 1, 2012 to December 31, 2017 followed through December 31, 2018. To assess the effects of AC on outcomes, we applied propensity score (PS) matching and marginal structural models (MSMs) to account for confounding by indication and time-dependent confounding. The final cohort included 2,694 veterans with cirrhosis with AF (n = 1,694 and n = 704 in the warfarin and DOAC cohorts after PS matching, respectively) with a median of 4.6 years of follow-up. All-cause mortality was lower with warfarin versus no AC (PS matched: hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55-0.76; MSM models: HR, 0.54; 95% CI, 0.40-0.73) and DOACs versus no AC (PS matched: HR, 0.68; 95% CI, 0.50-0.93; MSM models: HR, 0.50; 95% CI, 0.31-0.81). In MSM models, warfarin (HR, 0.29; 95% CI, 0.09-0.90) and DOACs (HR, 0.23; 95% CI, 0.07-0.79) were associated with reduced ischemic stroke. In secondary analyses, bleeding was lower with DOACs compared to warfarin (HR, 0.49; 95% CI, 0.26-0.94). CONCLUSIONS: Warfarin and DOACs were associated with reduced all-cause mortality. Warfarin was associated with more bleeding compared to no AC. DOACs had a lower incidence of bleeding compared to warfarin in exploratory analyses. Future studies should prospectively investigate these observed associations.

Multicenter, Double-Blind, Randomized Trial of Emricasan in Hepatitis C-Treated Liver Transplant Recipients With Residual Fibrosis or Cirrhosis.

Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan.

The Stanford Integrated Psychosocial Assessment for Transplant Is Associated With Outcomes Before and After Liver Transplantation.

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a standardized psychosocial evaluation tool used in liver transplantation (LT) evaluation. We assessed the impact of the SIPAT score and subdomains on transplant waitlisting decisions and post-LT outcomes including immunosuppression (IS) nonadherence, biopsy-proven rejection, andmortality/graft failure. We conducted a single-center observational cohort study of 1430 patients evaluated for LT. Patients were divided in 2 groups based on a SIPAT cutoff score of <21 or ≥21 (higher SIPAT scores indicate higher psychosocial risk). Regression models assessed relationships between total SIPAT score and domain scores and waitlisting decisions, IS nonadherence, allograft rejection, and death/graft failure. Elevated total SIPAT and SIPAT domain scores were associated not being added to the waitlist (total SIPAT core ≥21 adjusted odds ratio [aOR], 1.78 [95% confidence interval, CI, 1.36-2.33]; readiness score ≥5 aOR, 2.01 [95% CI, 1.36-2.76]; social support score ≥4aOR, 1.50 [95% CI, 1.15-1.94]; psychopathology score ≥7 aOR, 1.45 [95% CI, 1.07-1.94]; lifestyle/substance abuse score ≥12 aOR, 1.72 [95%CI, 1.23-2.39]) and were more likely to experience IS nonadherence as measured by the tacrolimus coefficient of variation (CoV) (total SIPAT score ≥21 aOR, 2.92 [95% CI, 1.69-5.03]; readiness score ≥5 aOR, 3.26 [95% CI, 1.63-6.52]; psychopathology score ≥7 aOR, 1.88 [95% CI, 1.00-3.50]; lifestyle substance abuse score ≥12 aOR, 3.03 [95% CI, 1.56-5.86]). SIPAT readinessscore ≥5 was associated with biopsy-proven allograft rejection (aOR, 2.66; 95% CI, 1.20-5.91). The SIPAT score was independently associated with LT listing decisions and IS nonadherence, and the readiness domain was associated with the risk of allograft rejection. These findings offer insights into higher risk recipients who require additional support before and aftertransplantation.