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.

The Lower Survival in Patients With Alcoholism and Hepatitis C Continues in the DAA Era.

BACKGROUND: Alcohol liver disease (ALD) may coexist with hepatitis C (HCV) in many transplant recipients (alcoholic cirrhosis with hepatitis C [AHC]). Our objective was to determine whether there were differences in postliver transplantation outcomes of patients with AHC when compared with those with alcoholic cirrhosis (AC) and/or alcoholic hepatitis (AH). METHODS: Using UNOS explant data sets (2016-2020), the survival probabilities of AC, AH, and AHC were compared by Kaplan-Meier survival analysis. Cox proportional-hazard regression analysis was used to determine outcomes after adjusting for disease confounders. The outcomes were also compared with predirect antiviral agent (DAA) period. RESULTS: During study period, 8369 biopsy-proven ALD liver transplant recipients were identified. Of those, 647 had AHC (HCV + alcohol), 353 had AH, and 7369 had AC. MELD-Na score (28.7 ± 9.5 versus 23.8 ± 10.7; P < 0.001) and presence of ACLF-3 (19% versus 11%; P < 0.001) were higher in AC + AH as compared with AHC. AHC and AC+AH has similar adjusted mortality at 1-y, but 3-y (hazard ratios, 1.76; 95% confidence intervals, 1.32-2.35; P < 0.0001) and 5-y (hazard ratios, 1.64; 95% confidence intervals, 1.24-2.15; P = 0.0004) mortality rates were higher in AHC. Survival improved in the DAA era (2016-2020) compared with 2009 to 2013 in AHC, but remained worse in AHC group versus AC and/or AH. Malignancy-related mortality was higher in AHC (15% versus 9.3% in AC) in the DAA era. CONCLUSIONS: AHC was associated with lower 3- and 5-y post-LT survival as compared with ALD without HCV and the worse outcomes in AHC group continued in the DAA era.

The Role of Endoscopy for Primary and Secondary Prophylaxis of Variceal Bleeding.

Cirrhosis is associated with a high morbidity and mortality. One of the most serious and unpredictable complication of cirrhosis, with a high mortality rate, is bleeding from esophagogastric varices. Endoscopic screening of varices followed by primary prophylactic treatment with beta blockers or band ligation in the presence of large esophageal varices will reduce the variceal bleeding rates and thereby reduce mortality risks in those with advanced cirrhosis. There is a paucity of data on primary prophylaxis of gastric varices but secondary prophylaxis includes glue injection, balloon-occluded retrograde transvenous obliteration, or transjugular intrahepatic portosystemic shunting with coil embolization.

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. CLINICALTRIALS: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.

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.

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).

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.

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.

Outcomes after Liver Transplantation with Steatotic Grafts: Redefining Acceptable Cutoffs for Steatotic Grafts.

Background: Graft macrosteatosis can predispose to a higher risk of graft loss so we sought to redefine acceptable cutoffs for graft steatosis. Methods: Data of 26,103 donors who underwent liver transplantation (LT) between January 2004 and December 2018 from the UNOS-STAR database were utilized. A high-risk steatotic (HRS) graft and a low-risk steatotic (LRS) graft were defined as ≥20% and <20% macrosteatosis, respectively. High-risk steatotic grafts were further classified as grafts with 20-29% (G1S grafts), 30-39% (G2S grafts), and ≥40% steatosis (G3S grafts). Outcomes between groups were compared. Results: LRS grafts had excellent graft (93.3 and 87.7%) and overall survival (95.4 and 90.5%) at 90 days and 1 year. Compared to LRS grafts, G1S, G2S, and G3S grafts had worse graft and overall survival at 90 days and 1-year (p <0.001). There was no difference in graft or overall survival of G1S or G3S grafts compared to G2S grafts until after adjustment in which G3S grafts were found to be associated with an increased risk of graft loss-aHR 1.27 (1.03-1.57), p = 0.02. Discussion: Liver grafts can be categorized into three categories: (1) <20% or "very low risk", (2) 20-39% or "low-to-moderate risk", and usually acceptable, and (3) ≥40% steatosis or "moderate-to-high risk". How to cite this article: Da BL, Satiya J, Heda RP, et al. Outcomes after Liver Transplantation with Steatotic Grafts: Redefining Acceptable Cutoffs for Steatotic Grafts. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S5-S14.

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.

Purely endoscopic appendectomy.

Video 1Submucosal nodule in the cecum. After submucosal injection, a circumferential incision of the mucosa surrounding the lesion is performed with DualKnife (Olympus America, Center Valley, Pa, USA). The fore-balloon of the double-balloon endoluminal interventional platform (DBEIP) is deployed and the edges of the circumferential incision are attached with 2 endoscopic clips to the long suture-loop mounted on the fore-balloon of the DBEIP. The fore-balloon is retracted in anal direction, pulling the lesion into the cecum. Careful endoscopic submucosal dissection is performed with DualKnife and HookKnife (Olympus America). Dissection is markedly facilitated by traction and continued until the entire appendix is pulled into the cecum. The tip of the appendix is separated from surrounding tissues, resulting in a full-thickness cecal wall defect. The suture-loop holding the resected appendix is cut with LoopCutter (Olympus America). The resected appendix is removed through DBEIP and the Overstitch endoscopic suturing device (Apollo Endosurgery, Austin, Tex, USA) is advanced into the cecum. The full-thickness defect in the cecal wall is completely closed with 2 continuous sutures. The final view demonstrates the entire resected appendix.

Liver transplantation in patients with acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a dynamic syndrome associated with a very high short-term mortality. Hence, the ongoing assessment of treatment response, an expedited liver transplant evaluation and listing, and the determination of futility of treatment are critical for optimal outcomes. In this review, we appraise our current understanding of the timing and futility of liver transplantation, and the short- and long-term outcomes including the quality of life after deceased or live donor liver transplantation in those with ACLF.

Impact of Hyponatremia on Morbidity, Mortality, and Resource Utilization in Portal Hypertensive Ascites: A Nationwide Analysis.

Background and aims: Ascites and hyponatremia are important milestones of worsening portal hypertension in those with cirrhosis. The objective of our study was to evaluate the differences in clinical characteristics, resource utilization, and disposition of hospitalized cirrhotic patients with ascites with and without hyponatremia. Methods: The National Inpatient Sample (NIS) database was used to identify all adult hospitalized patients with a diagnosis of cirrhosis and ascites with or without hyponatremia from 2016 to 2017 using ICD-10 codes. Results: During the study period, 10,187 (7.6%) hospitalized patients with cirrhosis had ascites and hyponatremia and 34,555 (24.3%) had ascites but no hyponatremia. Elixhauser comorbidity score, excluding liver disease, was higher in hyponatremic patients (median 21 vs. 12, P < 0.001). Acute kidney injury (50.3% vs. 32.8%, P < 0.001) and sepsis (16.8% vs. 11.8%, P < 0.001) were more common in hyponatremic patients compared to those without hyponatremia. Similarly, acute respiratory failure, coagulopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, acute (on chronic) liver failure, and liver cancer were more common in hyponatremic patients. Hyponatremia patients had a higher number of inpatient procedures, longer (6 days vs. 4 days, P < 0.001) hospital stay, and had higher hospital charges ($97,327 vs. $72,278, P < 0.01) than those without hyponatremia. Inpatient mortality was 38% higher in hyponatremic patients (9.8% vs. 7.1%, P < 0.001) compared to those without hyponatremia. Additionally, hyponatremic patients were less likely to have routine home discharges with self-care. Conclusion: In conclusion, using a large and diverse national cohort of unselected patients, we were able to show that hyponatremia in patients with cirrhosis and ascites is associated with poor clinical outcomes and increased resource utilization.

Effect of Sofosbuvir/Ledipasvir and Glecaprevir/Pibrentasvir on Serum Creatinine.

Background & objectives: There are reports of worsening renal functions with sofosbuvir, but there are no comparative data of different direct-acting antivirals (DAAs) on serum creatinine. In this retrospective cohort analysis, we examined the treatment effect of two commonly used regimens, sofosbuvir/ledipasvir (SOF/LDV) and glecaprevir/pibrentasvir (GLE/PIB), on serum creatinine. Methods: We included all patients treated with SOF/LDV (n = 825) and GLE/PIB (n = 116) between December 1, 2014, and December 31, 2018. An increase of serum creatinine ≥0.3 mg/dL was considered clinically significant. The change of creatinine values from pretreatment to posttreatment between two treatment groups was tested in unadjusted and adjusted generalized linear model, and risk factors associated with creatinine change were assessed. In addition, GLE/PIB-treated patients were matched 1:2 to SOF/LDV-treated patients using propensity scores, and then serum creatinine changes were compared. Results: The mean baseline creatinine was higher in the GLE/PIB group vs. SOF/LDV group (1.39 ± 1.86 vs. 0.91 ± 0.24, P = 0.007). When compared to baseline, serum creatinine at posttreatment week 4 was significantly higher in SOF/LDV group (0.97 ± 0.4 vs.0.91 ± 0.24, P < 0.001), but there was no significant change in the GLE/PIB group (1.41 ± 1.73 vs. 1.39 ± 1.86, P = 0.52). Overall, there was no significant change in serum creatinine between posttreatment week 4 and week 24 (P = 0.6). Clinically significant increase in serum creatinine was seen in 6% (46/825) of SOF/LDV and 7% (8/116) of GLE/PIB (P = 0.6). The unadjusted and adjusted models indicated that the changes in creatinine from baseline to posttreatment week 4 and week 24 were not associated with the type of DAA combination. Conclusion: Treatment of chronic hepatitis C infection with both SOF/LDV and GLE/PIB regimens may result in an increase of creatinine, and 6-7% will have an increase in serum creatinine of ≥0.3 mg/dL. The increase in creatinine, however, is unrelated to the type of DAA combination.

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.

Modified EASL-CLIF criteria that is easier to use and perform better to prognosticate acute-on-chronic liver failure.

BACKGROUND: We have recently shown that the European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) criteria showed a better sensitivity to detect acute-on-chronic liver failure (ACLF) with a better prognostic capability than the North American Consortium for the Study of End-Stage Liver Disease criteria. AIM: To simplify EASL-CLIF criteria for ease of use without sacrificing its sensitivity and prognostic capability. METHODS: Using the United Network for Organ Sharing data (January 11, 2016, to August 31, 2020), we modified EASL-CLIF (mEACLF) criteria; the modified mEACLF criteria included six organ failures (OF) as in the original EASL-CLIF, but renal failure was defined as creatinine ≥ 2.35 mg/dL and coagulation failure was defined as international normalized ratio (INR) ≥ 2.0. The mEACLF grades (0, 1, 2, and ≥ 3) directly reflected the number of OF. RESULTS: Of the 40357 patients, 14044 had one or more OF, and 9644 had ACLF grades 1-3 by EASL-CLIF criteria. By the mEACLF criteria, 15574 patients had one or more OF. The area under the receiver operating characteristic (AUROC) for 30-d all-cause mortality by OF was 0.842 (95%CI: 0.831-0.853) for mEACLF and 0.835 (95%CI: 0.824-0.846) for EASL-CLIF (P = 0.006), and AUROC for 30-d transplant-free mortality by OF was 0.859 (95%CI: 0.849-0.869) for mEACLF and 0.851 (95%CI: 0.840-0.861) for EASL-CLIF (P = 0.001). The AUROC of 30-d all-cause mortality by ACLF grades was 0.842 (95%CI: 0.831-0.853) for mEACLF and 0.793 (95%CI: 0.781-0.806) for EASL-CLIF (P < 0.0001). The AUROC of 30-d transplant-free mortality by ACLF was 0.859 (95%CI: 0.848-0.869) for mEACLF and 0.805 (95%CI: 0.793-0.817) for EASL-CLIF (P < 0.0001). CONCLUSION: Our study showed that EASL-CLIF criteria for ACLF grades could be simplified for ease of use without losing its prognostication capability and sensitivity.

Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19). METHODS: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed. FINDINGS: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups. INTERPRETATION: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials. FUNDING: NGM Biopharmaceuticals.