Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Racial and ethnic disparities in alcohol-associated liver disease in the United States: A systematic review and meta-analysis.

BACKGROUND: Alcohol-associated liver disease (ALD), encompassing alcohol-associated hepatitis and alcohol-associated cirrhosis, is rising in the United States. Racial and ethnic disparities are evident within ALD; however, the precise nature of these disparities is poorly defined. METHODS: We conducted a search of the PubMed/MEDLINE and EMBASE databases to identify studies published from inception through September 2023 that reported ALD incidence, prevalence, and mortality within the United States, stratified by race and ethnicity. We calculated pooled prevalence and incidence by race and ethnicity, including risk ratios and ORs for ALD pooled prevalence and alcohol-associated hepatitis/alcohol-associated cirrhosis pooled proportions, and OR for ALD mortality using the DerSimonian and Laird method for random-effect models. RESULTS: We identified 25 relevant studies (16 for quantitative meta-analysis), comprising 76,867,544 patients. ALD prevalence was highest in Hispanic (4.5%), followed by White (3.1%) and Black (1.4%) individuals. Pooled risk ratios of ALD prevalence were 1.64 (95% CI: 1.12-2.39) for Hispanic and 0.59 (95% CI: 0.35-0.87) for Black compared to White individuals. Mortality among those with ALD did not significantly differ between White and Hispanic (OR: 1.54, 95% CI: 0.9-2.5; I2=0%), Black (OR: 1.2, 95% CI: 0.8-1.6; I2=0%), or Native American (OR: 2.41, 95% CI: 0.9-2.9) individuals, while there was a significant difference between White and Asian (OR: 0.1; 95% CI: 0.03-0.5) individuals. Most data were cross-sectional and assessed to be of poor or fair quality. CONCLUSIONS: Differences were observed in ALD epidemiology, including higher prevalence among Hispanic and lower prevalence among Black individuals, although there were smaller differences in ALD mortality. Differences in ALD prevalence and prognosis remain poorly defined based on existing data, highlighting a need for higher-quality epidemiological studies in this area.

Early Graft Failure After Living-Donor Liver Transplant.

BACKGROUND: Living-donor liver transplantation (LDLT) has been increasing in the USA. While data exist on longer-term patient and graft outcomes, a contemporary analysis of short-term outcomes is needed. AIM: Evaluate short-term (30-day) graft failure rates and identify predictors associated with these outcomes. METHODS: Adult (≥ 18) LDLT recipients from 01/2004 to 12/2021 were analyzed from the United States Scientific Registry of Transplant Recipients. Graft status at 30 days was assessed with graft failure defined as retransplantation or death. Comparison of continuous and categorical variables was performed and a multivariable logistic regression was used to identify risk factors of early graft failure. RESULTS: During the study period, 4544 LDLTs were performed with a graft failure rate of 3.4% (155) at 30 days. Grafts from male donors (aOR: 0.63, CI 0.44-0.89), right lobe grafts (aOR: 0.40, CI 0.27-0.61), recipients aged > 60 years (aOR: 0.52, CI 0.32-0.86), and higher recipient albumin (aOR: 0.73, CI 0.57-0.93) were associated with superior early graft outcomes, whereas Asian recipient race (vs. White; aOR: 3.75, CI 1.98-7.10) and a history of recipient PVT (aOR: 2.7, CI 1.52-4.78) were associated with inferior outcomes. LDLTs performed during the most recent 2016-2021 period (compared to 2004-2009 and 2010-2015) resulted in significantly superior outcomes (aOR: 0.45, p < 0.001). CONCLUSION: Our study demonstrates that while short-term adult LDLT graft failure is uncommon, there are opportunities for optimizing outcomes by prioritizing right lobe donation, improving candidate nutritional status, and careful pre-transplant risk assessment of candidates with known PVT. Notably, a period effect exists whereby increased LDLT experience in the most recent era correlated with improved outcomes.

Racial and Ethnic Disparities in Liver Transplantation for Alcohol-associated Liver Diseases in the United States.

BACKGROUND: Emerging data suggest disparities exist in liver transplantation (LT) for alcohol-associated liver disease (ALD). As the incidence of ALD increases, we aimed to characterize recent trends in ALD LT frequency and outcomes, including racial and ethnic disparities. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data (2015 through 2021), we evaluated LT frequency, waitlist mortality, and graft survival among US adults with ALD (alcohol-associated hepatitis [AH] and alcohol-associated cirrhosis [AAC]) stratified by race and ethnicity. We used adjusted competing-risk regression analysis to evaluate waitlist outcomes, Kaplan-Meier analysis to illustrate graft survival, and Cox proportional hazards modeling to identify factors associated with graft survival. RESULTS: There were 1211 AH and 26 526 AAC new LT waitlist additions, with 970 AH and 15 522 AAC LTs performed. Compared with non-Hispanic White patients (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (subdistribution hazard ratio [SHR] = 1.23, 95% confidence interval [CI]: 1.16-1.32), Asian (SHR = 1.22, 95% CI:1. 01-1.47), and American Indian/Alaskan Native (SHR = 1.42, 95% CI: 1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in non-Hispanic Black (HR = 1.32, 95% CI: 1.09-1.61) and American Indian/Alaskan Native (HR = 1.65, 95% CI: 1.15-2.38) patients with AAC than NHWs. We did not observe differences in waitlist or post-LT outcomes by race or ethnicity in AH, although analyses were limited by small subgroups. CONCLUSIONS: Significant racial and ethnic disparities exist for ALD LT frequency and outcomes in the United States. Compared with NHWs, racial and ethnic minorities with AAC experience increased risk of waitlist mortality and graft failure. Efforts are needed to identify determinants for LT disparities in ALD that can inform intervention strategies.

Increasing practice and acceptable outcomes of high-MELD living donor liver transplantation in the USA.

Recent deceased-donor allocation changes in the United States may have increased high-Model for End-Stage Liver Disease (MELD) living donor liver transplantation (LDLT); however, outcomes in these patients remain poorly defined. We aimed to examine the impact of the MELD score on LDLT outcomes. Using UNOS data (January 1, 2010-December 31, 2021), LDLT recipients were identified and stratified into low-MELD (<15), intermediate-MELD (15-24), and high-MELD (≥25) groups. We compared outcomes between MELD-stratified LDLT groups and between MELD-stratified LDLT and donation after brain death liver transplantation recipients. We used Kaplan-Meier analysis to compare graft survival rates and multivariable Cox proportional hazards modeling to identify factors associated with graft outcomes. Of 3558 LDLTs, 1605 (45.1%) were low-MELD, 1616 (45.4%) intermediate-MELD, and 337 (9.5%) high-MELD. Over the study period, the annual number of LDLTs increased from 282 to 569, and the proportion of high-MELD LDLTs increased from 3.9% to 7.7%. Graft survival was significantly higher in low-MELD versus high-MELD LDLT recipients (adjusted HR = 1.36, 95% CI: 1.03-1.79); however, 5-year survival exceeded 70.0% in both groups. We observed no significant difference in graft survival between high-MELD LDLT and high-MELD donation after brain death liver transplantation recipients (adjusted HR: 1.25, 95% CI:0.99-1.58), with a 5-year survival of 71.5% and 77.3%, respectively. Low LDLT center volume (<3 LDLTs/year) and recipient life support requirement were both associated with inferior graft outcomes among high-MELD LDLT recipients. While higher MELD scores confer graft failure risk in LDLT, high-MELD LDLT outcomes are acceptable with similar outcomes to MELD-stratified donation after brain death liver transplantation recipients. Future practice guidance should consider the expansion of LDLT recommendations to high-MELD recipients in centers with expertise to help reduce donor shortage.

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure.

BACKGROUND AND AIMS: Patients with acetaminophen-induced acute liver failure are more likely to die while on the liver transplant waiting list than those with other causes of acute liver failure. Therefore, there is an urgent need for prognostic biomarkers that can predict the need for liver transplantation early after an acetaminophen overdose. APPROACH AND RESULTS: We evaluated the prognostic potential of plasma chemokine C-X-C motif ligand 14 (CXCL14) concentrations in patients with acetaminophen (APAP) overdose (n=50) and found that CXCL14 is significantly higher in nonsurviving patients compared to survivors with acute liver failure ( p < 0.001). Logistic regression and AUROC analyses revealed that CXCL14 outperformed the MELD score, better discriminating between nonsurvivors and survivors. We validated these data in a separate cohort of samples obtained from the Acute Liver Failure Study Group (n = 80), where MELD and CXCL14 had similar AUC (0.778), but CXCL14 demonstrated higher specificity (81.2 vs. 52.6) and positive predictive value (82.4 vs. 65.4) for death or need for liver transplantation. Next, combining the patient cohorts and using a machine learning training/testing scheme to mimic the clinical scenario, we found that CXCL14 outperformed MELD based on AUC (0.821 vs. 0.787); however, combining MELD and CXCL14 yielded the best AUC (0.860). CONCLUSIONS: We find in 2 independent cohorts of acetaminophen overdose patients that circulating CXCL14 concentration is a novel early prognostic biomarker for poor outcomes, which may aid in guiding decisions regarding patient management. Moreover, our findings reveal that CXCL14 performs best when measured soon after patient presentation to the clinic, highlighting its importance for early warning of poor prognosis.

Indeterminate etiology of acute liver failure in North America: Less common, still grave prognosis.

BACKGROUND: The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF. METHODS: Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS). RESULTS: Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true-IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%). CONCLUSION: We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.

Mortality and Morbidity Among Adult Liver Retransplant Recipients.

BACKGROUND: Liver transplantation (LT) is life-saving procedure for patients with end-stage liver failure with up to 20% of patients suffering graft failure following primary transplantation. Retransplantation (ReLT) remains the only definitive treatment for irreversible graft failure. AIMS: We aimed to explore the postoperative outcomes following liver ReLT. METHODS: Patients who had received a liver transplant between 2003 and 2016 were retrospectively identified using the Scientific Registry of Transplant Recipients (SRTRs). Patients were stratified based on previous liver transplant history. The primary outcomes of this study were 5-year postoperative mortality, morbidity, and length of hospital stay following LT. RESULTS: 60,554 (96%) recipients were first LT recipients and 2524 (4%) were ReLT recipients. Compared with first LT, ReLT recipients had significantly higher rates of mortality (OR 1.93, 95%CI 1.76-2.12), overall morbidity (OR 1.80, 95%CI 1.65-1.96), and prolonged length of stay (OR 1.66, 95%CI 1.52-1.81) on multivariate analysis. Morbidity including cardiovascular (CVD) complications (OR 1.32, 95%CI 1.08-1.60), graft failure (OR 2.18, 95%CI 1.84-2.57), infection (OR 2.13, 95%CI 1.82-2.50), and hemorrhage (OR 2.67, 95%CI 2.00-3.61) were significantly greater in ReLT recipients. Compared to first LT, ReLT patients had a significant increase in overall 5-year mortality (p < 0.001), 5-year mortality due to CVD complications (p < 0.001), infection (p = 0.009), but not graft failure (p = 0.3543). CONCLUSION: ReLT is associated with higher rates of 5-year mortality, overall morbidity, CVD morbidity, infection, and graft failure. Higher 5-year mortality in ReLT is due to CVD and infections. These results could be used in preoperative patient assessment and prognostic counseling for ReLT.

Biliary atresia and liver transplantation in the United States: A contemporary analysis.

BACKGROUND: Biliary atresia (BA) remains the number one indication for paediatric liver transplantation (LT) worldwide but is an uncommon indication for older LT recipients. The impact of recent donor allocation changes, pervasive organ shortage and evolving LT practices on the BA LT population is unknown. METHODS: We identified patients who underwent LT between January 2010 and December 2021 using the UNOS database. We compared clinical outcomes between patients with BA and those with non-BA cholestatic liver disease. Groups were stratified by age, <12 years (allocated via PELD system) and ≥12 years (allocated via MELD system). Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis and Cox proportional hazards modelling provided adjusted estimates. RESULTS: There were 2754 BA LT waitlist additions and 2206 BA LTs (1937 <12 years [younger], 269 ≥12 years [older]). There were no differences in waitlist mortality between BA and non-BA cholestatic patients. Among BA LT recipients, there were 441 (20.0%) living-donor liver transplantations (LDLT) and 611 (27.7%) split deceased-donor LTs. Five-year graft survival was significantly higher among BA versus non-BA cholestatic patients in the older group (88.3% vs. 79.5%, p < .01) but not younger group (89.3% vs. 89.5%). Among BA LT recipients, improved graft outcomes were associated with LDLT (vs. split LT: HR: 2, 95% CI: 1.03-3.91) and higher transplant volume (volume >100 vs. <40 BA LTs: HR: 3.41, 95% CI: 1.87-6.2). CONCLUSION: Liver transplant outcomes among BA patients are excellent, with LDLT and higher transplant centre volume associated with optimal graft outcomes.

Future directions in acute liver failure.

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury-international normalized ratio 2.0 but no encephalopathy-ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG's accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

Use of HBV RNA and to predict change in serological status and disease activity in CHB.

BACKGROUND AND AIMS: Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss. APPROACH AND RESULTS: Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability. CONCLUSION: Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB.

The Role of Carbamoyl Phosphate Synthetase 1 as a Prognostic Biomarker in Patients With Acetaminophen-induced Acute Liver Failure.

BACKGROUND & AIMS: Carbamoyl phosphate synthetase 1 (CPS1) is a highly abundant mitochondrial urea cycle enzyme that is expressed primarily in hepatocytes. CPS1 is constitutively and physiologically secreted into bile but is released into the bloodstream upon acute liver injury (ALI). Given its abundance and known short half-life, we tested the hypothesis that it may serve as a prognostic serum biomarker in the setting of acute liver failure (ALF). METHODS: CPS1 levels were determined using enzyme-linked immunosorbent assay and immunoblotting of sera collected by the ALF Study Group (ALFSG) from patients with ALI and ALF (103 patients with acetaminophen and 167 non-acetaminophen ALF etiologies). A total of 764 serum samples were examined. The inclusion of CPS1 was compared with the original ALFSG Prognostic Index by area under the receiver operating characteristic curve analysis. RESULTS: CPS1 values for acetaminophen-related patients were significantly higher than for non-acetaminophen patients (P < .0001). Acetaminophen-related patients who received a liver transplant or died within 21 days of hospitalization exhibited higher CPS1 levels than patients who spontaneously survived (P = .01). Logistic regression and area under the receiver operating characteristic analysis of CPS1 enzyme-linked immunosorbent assay values improved the accuracy of the ALFSG Prognostic Index, which performed better than the Model for End-Stage Liver Disease, in predicting 21-day transplant-free survival for acetaminophen- but not non-acetaminophen-related ALF. An increase of CPS1 but not alanine transaminase or aspartate transaminase, when comparing day 3 with day 1 levels was found in a higher percentage of acetaminophen transplanted/dead patients (P < .05). CONCLUSION: Serum CPS1 determination provides a new potential prognostic biomarker to assess patients with acetaminophen-induced ALF.

Declining rates of opioid/acetaminophen combination product overdose: 2011-2020.

BACKGROUND: During the opioid epidemic, misuse of acetaminophen-opioid products resulted in supratherapeutic acetaminophen ingestions and cases of hepatotoxicity. In 2014, the US Food and Drug Administration (FDA) limited the amount of acetaminophen in combination products to 325 mg, and the US Drug Enforcement Administration (DEA) changed hydrocodone/acetaminophen from schedule III to schedule II. This study assessed whether these federal mandates were associated with changes in acetaminophen-opioid supratherapeutic ingestions. METHODS: We identified emergency department encounters at our institution of patients with a detectable acetaminophen concentration and manually reviewed these charts. RESULTS: We found a decline in acetaminophen-opioid supratherapeutic ingestions after 2014. A downtrend in hydrocodone/acetaminophen ingestions accompanied a relative increase in codeine/acetaminophen ingestions from 2015 onwards. CONCLUSION: This experience at one large safety net hospital suggests a beneficial impact of the FDA ruling in reducing likely unintentional acetaminophen supratherapeutic ingestions, carrying a risk of hepatotoxicity, in the setting of intentional opioid ingestions.

Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.

Importance: In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014. Objective: To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate. Design, Setting, and Participants: This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG. Exposures: Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products. Main Outcomes and Measures: Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate. Results: In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings. Conclusions and Relevance: The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.

Acute Liver Failure: Biomarkers Evaluated by the Acute Liver Failure Study Group.

There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King's College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.

Role of Hepatitis C Infection in Acute Liver Injury/Acute Liver Failure in North America.

BACKGROUND: While hepatitis A and B are well-known causes of acute liver failure (ALF), few well-documented cases of hepatitis C virus (HCV) infection (absent preexisting liver disease or other liver insults) have been described that result in ALF. We reviewed the Acute Liver Failure Study Group registry for evidence of HCV as a primary or contributing cause to ALF. METHODS: From January 1998 to January 2017, 2,332 patients with ALF (INR ≥ 1.5, any degree of hepatic encephalopathy) and 667 with acute liver injury (ALI; INR ≥ 2.0, no hepatic encephalopathy) were enrolled. Anti-HCV testing was done routinely, with confirmatory RT-PCR testing for HCV RNA where necessary. RESULTS: A total of 136 patients were anti-HCV-antibody positive, as follows: 56 HCV RNA negative, 65 HCV RNA positive, and 8 with no result nor sera available for testing. Only three subjects with ALI/ALF were determined to represent acute HCV infection. Case 1: 47-year-old female with morbid obesity (BMI 52.4) developed ALF and recovered, experiencing anti-HCV seroconversion. Case 2: 37-year-old female using cocaine presented with ALI and fully recovered. Case 3: 54-year-old female developed ALF requiring transplantation and was anti-HCV negative but viremic prior to transplant experiencing anti-HCV seroconversion thereafter. Among 1636 APAP overdose patients, the 52 with concomitant chronic HCV had higher 3-week mortality than the 1584 without HCV (31% vs 17%, p = 0.01). CONCLUSIONS: ALI/ALF solely related to acute hepatitis C infection is very rare. Chronic HCV infection, found in at least 65 (2.2%) of ALI/ALF patients studied, contributed to more severe outcomes in APAP ALI/ALF; ClinicalTrials.gov number, NCT000518440. Trial Registration ClinicalTrials.gov number NCT000518440.

Outcomes of patients with acute liver failure listed for liver transplantation: A multicenter prospective cohort analysis.

Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation-related data from the SRTR. Primary outcomes were 1- and 3-year post-LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug-induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1- and 3-year post-LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.04), APAP etiology (aOR 2.72, 95% CI 1.42-5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44-7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29-4.72), and Model for End-Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02-1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post-LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.

Establishing baseline framework for hepatitis B virus micro-elimination in Ho Chi Minh City, Vietnam - A community-based seroprevalence study.

Background: We conducted a community-based seroprevalence study using three HBV seromarkers (HBsAg, anti-HBs, anti-HBc) in Ho Chi Minh City (HCMC), Vietnam, to (1) determine the prevalence of HBV serologic profiles; (2) document factors associated with HBV infection or susceptibility; and (3) propose strategies toward HBV elimination by 2030. Methods: During 2019-2020, we deployed a multistage cluster design with probability proportionate to size, to recruit 20,000 adults for an HBV screening and linkage to care program citywide. Screening results with interpretation, recommendations, and health education materials were returned to participants. Post-study surveys were conducted within three months to identify gaps in linkage to care. Findings: Of the 17,600 adults invited, 15,275 (86.7%) participated in the study, 14,674 (96.1%) completing all data for final analyses. The prevalence of HBsAg (+) and HBV-naïve were 7.5% and 37.7%, respectively. HBV vaccination rates were 18.7% and about 50% of HCMC population had been exposed to HBV. Of the persons with HBsAg (+), 27.1% linked to care (76% used health insurance). There were wide variations in HBsAg (+) and HBV vaccination rates between districts, risk factors, and socio-economic statuses. Interpretation: The significant disease burden of and gaps in the continuum of care highlight the need and urgency to address the HBV public health problem in Vietnam. Using three screening seromarkers that tailor interventions to the needs of HBV micro-populations could be an effective strategy to pursue HBV elimination goals. Funding: Gilead Sciences Inc; Roche Diagnostic International Ltd; Roche Diagnostics-Vietnam; Abbott Diagnostics-Vietnam; Hepatitis B Foundation; Medic MedicalCenter, Vietnam; Center of Excellence for Liver Disease in Vietnam, Johns Hopkins University School of Medicine.

Acute Hepatitis B Virus Infection in North American Adults.

BACKGROUND & AIMS: Acute hepatitis B virus (aHBV) is thought to be self-limited with clearance of hepatitis B surface antigen (HBsAg) within 6 months. There are limited reports of the presenting features and outcomes of adults with symptomatic aHBV in the United States. METHODS: Demographics, clinical features, and 12-month outcomes of patients with adjudicated aHBV were captured prospectively and compared with a contemporaneous cohort of chronic HBV (cHBV) patients enrolled in the Hepatitis B Research Network. RESULTS: Between 2011 and 2018, 60 adjudicated patients with aHBV were compared with 1534 cHBV untreated controls. Although similar in age, other features were dissimilar: aHBV patients were more often male (72% vs 51%), single (72% vs 30%), and non-Hispanic whites or blacks (75% vs 24%). They also were frequently genotype A2 (65% vs 9%), having different risk factors: sexual exposure (75% vs 16%) or injection drug use (10% vs 2%), compared with the cHBV controls. In addition to higher serum aminotransferase and bilirubin levels, acute patients had higher HBV DNA levels (4.8 vs 3.6 log10 IU/mL), whereas quantitative hepatitis B e antigen (HBeAg) levels were lower (1.4 vs 3.0 log10 IU/mL), despite higher rates of HBeAg (73% vs 25%). The median time to HBsAg clearance was 27 weeks and to anti-HBs appearance, 41 weeks. CONCLUSIONS: In the current era, caucasian men infected with genotype A2 as a result of sexual exposure or injection drug use were the predominant group in aHBV, suggesting a potential strategy for adult vaccination in North America. Strikingly, only an estimated 36% of subjects cleared HBsAg by month 6; the definition of resolution in acute hepatitis B may need to be modified. ClinicalTirals.gov number NCT01263587.