Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Older Patients With Acute on Chronic Liver Failure Have a Higher Waitlist Mortality, but Acceptable Post Liver Transplantation Survival When Compared To Younger Patients.

BACKGROUND & AIMS: There is a paucity of studies on older patients (≥65 years) who develop acute on chronic liver failure (ACLF). The objectives of our study were to determine clinical characteristics and outcomes of older patients listed for liver transplantation (LT). METHODS: Adults listed for LT with estimated ACLF (Est-ACLF) between 2005 and 2021 were identified using the United Network for Organ Sharing database and subdivided into older and younger age (18-64 years) groups. Kaplan-Meier survival analyses were used to evaluate survival, and a competing-risk model (Fine-Gray) was used to evaluate risk factors for survival on the waitlist. Logistic regression was done to evaluate risk factors. RESULTS: A total of 4313 older (14%) and 26,628 younger (86%) patients were listed for LT, and 2142 (49.6%) and 16,931 (63.5%) were transplanted, respectively. Older patients had a higher 30-day waitlist mortality than younger patients (20.4% vs 16.7%; P < .0001); this was more pronounced in Est-ACLF-2 (23.7% vs 14.8%; P < .0001) and Est-ACLF-3 (43.3% vs 29.9%; P < .0001). One-year post-LT, patient survival in older patients with Est-ACLF grades 1, 2, and 3 were 86.4%, 85.5%, and 77% respectively; younger patients had better survival across all Est-ACLF grades. When adjusted for transplant eras, respiratory failure was the only independent risk factor for increased 1-year post-LT mortality in older patients. CONCLUSION: Older patients with Est-CLF had significantly higher waitlist mortality than younger patients, but had acceptable 1-year post-LT survival including those with Est-ACLF-3; therefore, age alone should not be considered as a contraindication for LT. Older patients with respiratory failure should be carefully selected for LT.

Validation of a Clinical Risk-based Classification System in a Large Nonalcoholic Fatty Liver Disease Real-world Cohort.

BACKGROUND & AIMS: There is an unmet need to validate simple and easily available methods that can be used in routine practice to identify those at risk of adverse outcomes from nonalcoholic fatty liver disease (NAFLD). A retrospective-prospective analysis of NAFLD patients enrolled in a longitudinal noninterventional study (TARGET-NASH) was performed to validate the prognostic utility of the following risk-categories: (A) Fibrosis-4 (FIB-4) <1.3 and/or liver-stiffness measurement (LSM) measured by Fibroscan <8 kp, (B) FIB-4 1.31‒2.6 and/or LSM 8.1-12.5 kp, and (C) FIB-4 >2.6 and/or LSM >12.5 kp. METHODS: Those in class A with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3, or class B with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3 were upstaged by one class. Fine-Gray competing risk analyses were performed for all outcomes. RESULTS: A total of 2523 individuals (class A = 555, B = 879, C = 1089) were followed for a median duration of 3.74 years. Adverse outcomes increased from class A to C in all-cause mortality (0.07 vs 0.3 vs 2.5/100 person-years [PY], hazard ratio [HR], 3.0 and 16.3 class B and C vs A), liver-associated clinical events (0.2 vs 1 vs 8/100 PY, HR, 4.3 and 36.6 B and C vs A), major adverse cardiovascular events (0.69 vs 0.87 vs 2.02/100 PY, HR, 0.78 and 1.55 B and C vs A), hepatocellular carcinoma (0 vs 0.09 vs 0.88/100 PY, HR, 8.32 C vs B), and chronic kidney disease (1.24 vs 2.48 vs 3.51/100 PY). Those who were upstaged had outcome rates similar to the lower class defined by their FIB-4. CONCLUSIONS: These data support a FIB-4-based risk-stratification of NAFLD that can be used in routine clinical practice. CLINICALTRIALS: gov Identifier: NCT02815891.

Liver Transplantation Within 7-Days of Listing Improves Survival in ACLF-3.

BACKGROUND AND AIMS: Patients with acute on chronic liver failure (ACLF-3) have a very high short-term mortality without liver transplantation (LT). Our objective was to determine whether early LT (ELT; ≤ 7 days from listing) had an impact on 1 year patient (PS) in patients with ACLF-3 compared to late LT (LLT; days 8-28 from listing). METHODS: All adults with ACLF-3 listed for LT with the United Network for Organ Sharing (UNOS) between 2005 and 2021 were included. We excluded status one patients and those with liver cancer or listed for multi-organ or living donor transplants. ACLF patients were identified using the European Association for the Study of the Liver-Chronic Liver Failure criteria. Patients were categorized as ACLF-3a and ACLF-3b. RESULTS: During the study period, 7607 patients were listed with ACLF-3 (3a-4520, 3b-3087); 3498 patients with ACLF-3 underwent ELT and 1308 had LLT. The overall 1 year PS after listing was 64.4% in ACLF-3a and 50% in ACLF-3b. In 4806 ACLF-3 patients who underwent LT, 1 year PS was 86.2%, but those who had ELT had higher survival (87.1 vs. 83.6%, P = 0.001) than the LLT group. These survival benefits were seen in both ACLF-3a and ACLF-3b. On multivariable analysis, age (HR 1.02, CI 1.01-1.03), diabetes (HR 1.40, CI 1.16-1.68), respiratory failure (HR 1.76, CI 1.50-2.08), donor risk index > 1.7 (HR 1.24, CI 1.06-1.45), and LLT (HR 1.20, CI 1.02-1.43) were independent predictors of higher 1 year mortality while higher albumin (HR 0.89, CI 0.80-0.98) was associated with reduced mortality. CONCLUSION: Early LT (≤ 7 days from listing) in ACLF-3 is associated with better 1 year survival compared to late LT (days 8-28 from listing).

Combined effects of hyponatremia and hepatic encephalopathy on inpatient mortality.

INTRODUCTION AND OBJECTIVES: Although hyponatremia and hepatic encephalopathy (HE) are known independent predictors of mortality, their combined effect is unknown. We investigated whether the inpatient mortality differed among patients with both hyponatremia and HE compared to those with either hyponatremia or HE alone. MATERIALS AND METHODS: In this retrospective study, data were extracted from the National Inpatient Sample (NIS) to identify US adults (aged ≥18 years) with cirrhosis between January 1st, 2016, and December 31st, 2017. We analyzed the effects of hyponatremia, HE, or a combination of hyponatremia and HE on inpatient mortality using logistic regression. RESULTS: Among 309,841 cirrhosis-related admissions, 22,870 (7%) patients died during hospitalization. Those with a combination of hyponatremia and HE had higher mortality (14%) than those with HE only (11%), hyponatremia only (9%), and neither hyponatremia nor HE (6%) (p<0.001). When compared to patients without hyponatremia or HE, patients with both hyponatremia and HE had the highest odds (adjusted odds ratio or aOR) of inpatient mortality (aOR 1.90, 95% CI: 1.79 - 2.01) followed by patients with HE only (aOR 1.75, 95% CI: 1.69 - 1.82) and patients with hyponatremia only (aOR 1.17, 95% CI: 1.12 - 1.22). Patients with HE only had 50% higher odds of inpatient mortality when compared to those with hyponatremia only (aOR: 1.50, 95% CI: 1.43 - 1.57). CONCLUSIONS: In this nationwide study, the presence of both hyponatremia and HE was associated with higher inpatient mortality than either hyponatremia or HE alone.

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.

BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. METHODS: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. GOV NUMBER: NCT02955602 CLINICALTRIALSREGISTER. EU NUMBER: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.

Association of serum metabolites and gut microbiota at hospital admission with nosocomial infection development in patients with cirrhosis.

Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography-mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End-Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1-linolenoyl-glycerolphosphocholine (GPC) and 1-stearoyl-GPC and higher N-acetyltryptophan and N-acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial-metabolite correlation networks were complex and dense in patients with NIs, especially sub-networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial-metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

Elevated Liver Biochemistries in Hospitalized Chinese Patients With Severe COVID-19: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Several recent studies have reported an abnormal liver chemistry profile among patients with coronavirus disease 2019 (COVID-19), although its clinical significance remains unknown. APPROACH AND RESULTS: This systematic review and meta-analysis identified six studies of 586 patients delineating liver chemistries among patients with severe/critical illness versus mild cases of COVID-19 infection. Patients with severe/critical illness with COVID-19 infection have increased prevalence of coronary artery disease, cerebrovascular disease, and chronic obstructive pulmonary disease as compared with mild cases. A significant association between severe/critical COVID-19 infections with elevations in aspartate aminotransferase (pooled mean difference [MD], 11.70 U/L; 95% confidence interval [CI], 2.97, 20.43; P = 0.009), elevated total bilirubin (pooled MD, 0.14 mg/dL; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled MD, -0.68 g/L; 95% CI, -0.81, -0.55; P < 0.00001) was noted. There was also a trend toward elevated alanine aminotransferase levels among these severe cases (pooled MD, 8.84 U/L; 95% CI, -2.28, 19.97; P = 0.12); however, this did not reach statistical significance. More severe/critically ill cases were associated with leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase, elevated lactate dehydrogenase (LDH), and elevated prothrombin time (PT). CONCLUSIONS: Comorbidities, including coronary artery disease, cerebrovascular disease and chronic obstructive pulmonary disease, are more prevalent in hospitalized Chinese patients with severe/critical illness from COVID-19, and these patients are more likely to manifest with abnormal liver chemistries. Further prospective studies are crucial to understand the pathophysiologic mechanisms underlying the hepatic manifestations of the novel COVID-19 infection and its clinical significance.

Prognosis of hospitalized patients with cirrhosis and acute kidney disease.

BACKGROUND: The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known. AIM: To study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD. METHODS: The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes. RESULTS: 1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in-hospital and 30-day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53). CONCLUSIONS: Patients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.

Bariatric Surgery in NAFLD.

Currently, there are no approved medications to treat patients with nonalcoholic steatohepatitis (NASH) with fibrosis or cirrhosis. Although the management goal in these patients is weight reduction by 7-10% with lifestyle modifications, only less than 10% of patients achieve this target at 1-year, and fewer maintain the weight loss at 5 years. Bariatric surgery is an option that may be considered in those who fail to lose weight by lifestyle changes. Bariatric surgery has been shown to improve liver histology including fibrosis secondary to NASH, in addition to other benefits including an improvement or resolution of type 2 diabetes mellitus, dyslipidemia, and hypertension, and a reduction of cardiovascular morbidity or mortality. There are no guidelines of bariatric surgery indications for the management of NASH. The purpose of this review is to critically appraise the current knowledge of the role of bariatric surgery and the potential mechanisms for its perceived benefits in the management of patients with NASH-related liver disease.

Gender Differences in Liver Transplantation Outcomes in Polycystic Liver Disease.

BACKGROUND: In this study, our objective was to determine gender differences in the outcomes of patients with PLD undergoing liver (LT) or liver/kidney transplantation (SLK). METHODS: We analyzed the UNOS datasets of all adults who had transplanted for PLD between 1988 and 2018. RESULTS: During the study period, 663 LT/SLK (51% LT only and 49% SLK) were done for PLD patients and of these 500 (75%) were in women. Women were younger (52.8 vs. 56.7 years, p < 0.001), had lower MELD at transplant (16.6 vs. 19.4, p < 0.001), had higher serum albumin (3.7 vs. 3.5, p < 0.001), and had a lower CTP class (p < 0.008). During the follow-up, 18% (n = 89) women and 29% (n = 47) men died (p = 0.002). Kaplan-Meier (KM) survival estimates showed similar survival rate for patients who had LT and SLK (p = 0.459), but survival rate was significantly higher for women compared to men (p < 0.001). Multivariable analysis showed that female gender (aHR 0.54, 95% CI 0.33-0.90) was associated with a lower mortality. Moreover, Karnofsky Performance Status was excellent for 70% of women and 55% of men (p = 0.03) after LT. Women had better survival whether they received liver or SLK. The era of transplant, whether they were transplanted with MELD exception points or whether they were on dialysis at the time of transplant, did not have an effect on the gender differences in outcomes. CONCLUSIONS: Women had 46% lower risk of mortality after adjusting for other covariates compared to men after LT/SLK for PLD.

Antibody response after a booster dose of SARS-CoV-2 vaccine in liver transplant recipients and those with chronic liver diseases.

INTRODUCTION AND OBJECTIVES: Lower antibody (Ab) responses after SARS-CoV-2 vaccination have been reported in liver transplant (LT) recipients and those with chronic liver diseases (CLD). The role of a booster dose in those with poor responses to initial vaccination is not well defined. METHODS: In this prospective study, we determined antibody (Ab) response to spike protein after a booster dose in LT recipients and those with chronic liver diseases (CLD) with and without cirrhosis after they had a poor response to an initial standard regimen. RESULTS: Of the 80 patients enrolled, 45 had LT, and 35 had CLD (18 with cirrhosis). A booster dose was given at a median of 138.5 days after the completion of the standard regimen. After the booster dose, 58 (73%, 31 LT, 27 CLD) had good response (≥250 U/mL), and 22 (28%, 14 LT, and 8 CLD) had poor response (7 undetectable and 15 with low Ab levels). No patient had any serious adverse events. The antibody responses were lower in those who had undetectable Ab (80 U/mL) than those who had low levels of Ab (0.80-249 U/mL) after the standard vaccination regimen (42% vs. 87%, p=0.0001). The antibody responses after homologous and heterologous booster doses were similar. CONCLUSIONS: We have shown that a booster dose will enhance Ab responses in LT recipients and those with CLD who had poor responses after an initial vaccine regimen.

Outcomes of status 1 liver transplantation for Budd-Chiari Syndrome with fulminant hepatic failure.

There is a paucity of data on the outcome of liver transplantation (LT) in Budd-Chiari Syndrome (BCS) patients who are listed as status 1. The objective of our study was to determine patient or graft survival following LT in status 1 BCS patients. We utilized United Network for Organ Sharing (UNOS) database to identify all adult patients (> 18 years of age) listed as status 1 with a primary diagnosis of BCS in the United States from 1998 to 2018, and analyzed their outcomes and compared it to non-status 1 BCS patients. Four hundred and forty-six patients with BCS underwent LT between 1998 and 2018, and of these 55 (12.3%) were listed as status 1. There was no difference in long-term post-liver transplant or "intention-to-treat" survival from the time of listing to death or the last day of follow-up between status 1 and non-status 1 groups. Graft and patient survival at 5 years for status 1 patients were 75% and 82%, respectively. Cox regression analysis showed that patients listed as status 1 (aHR: 0.45, p < .02) were associated with a better survival. BCS patients listed as status 1 have excellent survival following emergency LT.

EASL-CLIF criteria outperform NACSELD criteria for diagnosis and prognostication in ACLF.

BACKGROUND & AIMS: There is no consensus on the best definition for acute-on-chronic liver failure (ACLF). In this study, we compared the prevalence and 30-day all-cause and transplant-free mortality of patients with ACLF identified by European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) and North American Consortium for the Study of End-stage Liver Disease (NACSELD) criteria. METHODS: We performed this comparative analysis using the United Network for Organ Sharing (UNOS) data from January 11, 2016 to August 31, 2020. RESULTS: A total of 10,198 (21%) adult patients had EASL-CLIF ACLF grade 1-3, but of these only 15.3% had ACLF by NACSELD. Of the 2,562 with EASL-CLIF ACLF grade 3, only 48.8% had NACSELD-ACLF, 16.8% had no organ failure (OF) and 34.4% had 1 OF. The 30-day all-cause mortality was 1.5%, 7.7%, 13.3% and 25.8% for EASL-CLIF grade 0-3, respectively, and it was 15.4% and 28.1% in those without and with NACSELD-ACLF. When EASL-CLIF grade 3 patients were stratified by NACSELD OF, the mortality ranged from 18.6% with no OF to 41.0% with 4 OFs. The 30-day transplant-free mortality in those with no OF by NACSELD was 2.7%, but when the same group is stratified by EASL-CLIF grades 0-3, the mortality rates were 1.5%, 10.5%, 43.5% and 86%, respectively; the mortality rates ranged from 3.0% to 75.7% in those with 1 OF by NACSELD. CONCLUSIONS: There is a clear discordance in the prevalence and 30-day mortality rates of patients with ACLF identified by the EASL-CLIF and NACSELD criteria. EASL-CLIF criteria have a better sensitivity to detect ACLF and have a better prognostic capability. LAY SUMMARY: There is no consensus on the definition of acute-on-chronic liver failure. European (EASL-CLIF) and North American (NACSELD) consortia have each proposed a commonly used definition. In this study, we compared the prevalence and short-term (30-day) mortality based on these definitions. Using a very large data set, we observed that there was a significant discordance in the prevalence and mortality based on these criteria. EASL-CLIF criteria appeared to be more sensitive to identify acute-on-chronic liver failure, and were better at predicting all-cause and short-term mortality.

Analysis of antibody responses after COVID-19 vaccination in liver transplant recipients and those with chronic liver diseases.

BACKGROUND & AIMS: Liver transplant (LT) recipients or other immunocompromised patients were not included in the registration trials studying the efficacy of vaccines against SARS-CoV-2. Although the clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown, many societies have recommended vaccination of this highly vulnerable patient population. METHODS: In this prospective study, we determined antibody responses to spike protein, 4 weeks after the 2nd dose of mRNA vaccines or after the single dose of Johnson & Johnson vaccine, in LT recipients and those with chronic liver disease (CLD) with and without cirrhosis. RESULTS: Of the 233 patients enrolled so far, 62 were LT recipients, 79 had cirrhosis (10 decompensated) and 92 had CLD without cirrhosis. Antibody titers were defined as undetectable (<0.40 U/ml), suboptimal (0.40-250 U/ml) and adequate (>250 U/ml). Of the 62 patients who had LT, antibody levels were undetectable in 11 patients and suboptimal (median titer 17.6, range 0.47-212 U/ml) in 27 patients. Among 79 patients with cirrhosis, 3 had undetectable antibody levels and 15 had suboptimal (median titer 41.3, range 0.49-221 U/L) antibody responses. Of the 92 patients without cirrhosis, 4 had undetectable antibody levels and 19 had suboptimal (median titer 95.5, range 4.9-234 U/L) antibody responses. Liver transplantation, use of 2 or more immunosuppression medications and vaccination with a single dose of the Johnson & Johnson vaccine were associated with poor immune response on multivariable analysis. No patient had any serious adverse events. CONCLUSIONS: Poor antibody responses after SARS-CoV-2 vaccination were seen in 61% of LT recipients and 24% of those with CLD. LAY SUMMARY: The clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown. We performed a prospective study to evaluate immune responses to COVID-19 vaccines (Moderna, Pfizer or Johnson & Johnson) in 62 liver transplant recipients, 79 patients with cirrhosis and 92 with chronic liver diseases without cirrhosis. We found that 17.8% of liver transplant recipients, 3.8% of those with cirrhosis and 4.3% of those with chronic liver diseases without cirrhosis had undetectable antibody levels. In total, 61.3% of liver transplant recipients and 24% of those with chronic liver diseases (with or without cirrhosis) had poor antibody responses (undetectable or suboptimal). Liver transplantation, use of immunosuppressive medications and vaccination with a single dose of Johnson & Johnson vaccine were associated with poor antibody responses when adjusted for other factors.

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.

Insurance Status But Not Race and Ethnicity Are Associated With Outcomes in a Large Hospitalized Cohort of Patients With Cirrhosis.

BACKGROUND & AIMS: Insurance, race, and ethnicity can affect outcomes of patients with cirrhosis, but findings from prospective studies are unclear. We investigated the role of insurance status and race and ethnicity (race/ethnicity) on inpatient and 90-day postdischarge outcomes in a large inpatient cohort of patients with cirrhosis. METHODS: We used data from the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) database, from 13 tertiary care centers. Insurance status (uninsured, Medicare, Medicaid, private, and Canadian), race, and ethnicity, were analyzed independent of clinical covariates for their association with transfer to the intensive care unit, acute on chronic liver failure (ACLF), length of hospital stay, inpatient and 90-day death or liver transplantation, and readmission to the hospital within 90 days. Multi-variable analyses and interaction terms were created for insurance, race/ethnicity, and for each outcome, with or without Canadian patients. RESULTS: We analyzed data from 2640 patients in the NACSELD database (971 with private insurance, 770 with Medicare, 456 Canadians, 265 with Medicaid, 178 uninsured, 540 non-Caucasian and 220 Hispanic); 23% required admittance to the intensive care unit, 12% developed NACSELD-defined ACLF, 7% died, 5% underwent liver transplantation. Of the 2288 patients discharged from hospital, 13% underwent liver transplantation, 19% died, and 42% were readmitted within 90 days. In the univariate model, uninsured patients accounted for the highest percentage of alcohol- or bleeding-related admissions and the lowest proportion of outpatient cirrhosis-related medication users. Canadians had the lowest rifaximin use and but higher proportions had hepatic encephalopathy, compared with other groups. Lack of insurance was higher among non-Caucasians, regardless of Hispanic ethnicity. In multi-variable analysis, lack of insurance was associated with ACLF (P = .02) and inversely associated with inpatient liver transplant (P = .05) and 90-day liver transplant (P = .02), regardless of whether Canadians were included or specific insurance type. Race or ethnicity were not significantly associated with outcomes. CONCLUSIONS: In analyzing the NACSELD database, we found that insurance status, but not race or ethnicity, were independently associated with ACLF and inpatient or 90-day liver transplantation, regardless of inclusion of Canadian patients.

A Scoring Model to Predict In-Hospital Mortality in Patients With Budd-Chiari Syndrome.

INTRODUCTION: A model that can predict short-term mortality in patients with the Budd-Chiari syndrome (BCS) with a high degree of accuracy is currently lacking. The primary objective of our study was to develop an easy-to-use in-hospital mortality prediction model in patients with BCS using easily available clinical variables. METHODS: Data were extracted from the National Inpatient Sample to identify all adult patients with a listed diagnosis of BCS from 2008 to 2017 using ICD-9 or ICD-10 codes. After identifying independent risk factors of in-hospital mortality, we developed a prediction model using logistic regression analysis. The model was built and validated in a training and a validation data set, respectively. Using the model, we risk stratified patients into low-, intermediate-, and high-risk groups. RESULTS: Between 2008 and 2017, we identified a total of 5,306 (weighted sample size 26,110) discharge diagnosis of patients with BCS, with an overall in-hospital mortality of 7.14%. The independent risk factors that predicted mortality were age of 50 years or older, ascites, sepsis, acute respiratory failure, acute liver failure, hepatorenal syndrome, and cancers. The mortality prediction model that incorporated these risk factors had an area under the receiver operating characteristic curve of 0.87 (95% CI 0.85-0.95) for the training data and 0.89 (95% CI 0.86-0.92) for the validation data. Patients with low-, intermediate-, and high-risk scores had a predicted in-patient mortality of 4%, 30%, and 66%, respectively. DISCUSSION: Using a national administrative database, we developed a reliable in-patient mortality prediction model with an excellent accuracy. The model was able to risk stratify patients into low-, intermediate-, and high-risk groups.

Role of Locoregional Therapies in Patients With Hepatocellular Cancer Awaiting Liver Transplantation.

Hepatocellular cancer (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related deaths. The United Network for Organ Sharing has its own staging criteria for organ allocation, which is a modification of tumor-node-metastasis staging of American Joint Committee on Cancer. For the purpose of clarity, United Network for Organ Sharing staging will be described as uT1, uT2 (Milan criteria), and uT3 (eligible for downstaging) in this review. For those with unresectable HCC or those with advanced liver disease and HCC but within the Milan criteria, liver transplantation is the treatment of choice. Because of prolonged waiting period on the liver transplant list in many parts of the world for deceased donor liver transplantation, there is a serious risk of dropout from the liver transplant list because of tumor progression. For those patients, locoregional therapies might need to be considered, and moreover, there is circumstantial evidence to suggest that tumor progression after locoregional therapies might be a surrogate marker of unfavorable tumor biology. There is no consensus on the role or type of locoregional therapies in the management of patients with uT1 and uT2 eligible for liver transplant and of those with lesions larger than uT2 but eligible for downstaging protocol (uT3 lesions). In this review, we examine the role of locoregional therapies in these patients stratified by staging and propose treatment options based on the current evidence of tumor progression rates while awaiting liver transplantation and tumor recurrence rates after liver transplantation.

Off-Label Use of Multitarget Stool DNA Testing in Primary Care.

INTRODUCTION: We evaluated the off-label use of multitarget stool DNA (mt-sDNA) testing in the primary care setting. METHODS: We reviewed all mt-sDNA orders between July 1, 2018, and June 30, 2019, to determine the frequency of off-label mt-sDNA orders. RESULTS: Nine hundred two patients with mt-sDNA orders were evaluated, of which 160/902 patients (17.7%) met at least 1 criterion for off-label mt-sDNA order. Increasing age was associated with off-label order (Odds Ratio [OR] 2.32 [95% CI, 1.86-2.89] for every 10-year increase in age, P < 0.0001). On multivariate analysis, increased age (OR 1.04 [1.02-1.06], P = 0.001) and need for diagnostic colonoscopy (OR 2.9 [1.01-8.34], P = 0.048) were associated with a positive mt-sDNA result. DISCUSSION: Off-label mt-sDNA testing is common, and further efforts are needed to educate patients and providers on appropriate use of mt-sDNA for colorectal cancer screening.