A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Effects of Food Insecurity on Hepatic Steatosis and Fibrosis in People With HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥ 18 years on antiretroviral therapy, HIV RNA <200 copies/mL, and without other known liver diseases were screened for NAFLD (controlled attenuated parameter ≥263 decibels/meter) and advanced fibrosis (liver stiffness measurement ≥11 kilopascals) by vibration controlled transient elastography at 8 U.S. CENTERS: Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 of participants (31%), including 97/348 with NAFLD (28%) and 18/41 with advanced fibrosis (44%). In multivariable analysis, FI was associated with lower odds of NAFLD (OR, 0.57; 95% CI, 0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR, 1.38; 95% CI, 0.65-2.90). We identified a significant interaction between FI and diabetes (P = .02) on fibrosis risk, with greater odds of fibrosis among food insecure PWH and diabetes (OR, 3.83; 95% CI, 1.15-12.73) but not among food insecure nondiabetics (OR, 1.12; 95% CI, 0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, there is greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis.

BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS: In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS: Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS: Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS: There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION: NCT04072822.

Occult liver disease: A multinational perspective.

Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020. Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption. Screening for NAFLD in high-risk subjects and screening for excessive drinking and alcohol use disorders at every level of medical care is relevant. Efforts should also focus on the early treatment of occult liver disease to try to reduce liver disease burden and, in the case of occult viral hepatitis infection, prevent further spreading.

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease.

Introduction: To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. Methods: Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. Results: In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. Conclusions: There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.

GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting.

Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFß ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver-muscle negative crosstalk along with liver injury progression.

Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis.

BACKGROUND AND AIMS: In cirrhotic nonalcoholic steatohepatitis (NASH) clinical trials, primary efficacy endpoints have been hepatic venous pressure gradient (HVPG), liver histology and clinical liver outcomes. Important histologic features, such as septa thickness, nodules features and fibrosis area have not been included in the histologic assessment and may have important clinical relevance. We assessed these features with a machine learning (ML) model. METHODS: NASH patients with compensated cirrhosis and HVPG ≥6 mm Hg (n = 143) from the Belapectin phase 2b trial were studied. Liver biopsies, HVPG measurements and upper endoscopies were performed at baseline and at end of treatment (EOT). A second harmonic generation/two-photon excitation fluorescence provided an automated quantitative assessment of septa, nodules and fibrosis (SNOF). We created ML scores and tested their association with HVPG, clinically significant HVPG (≥10 mm Hg) and the presence of varices (SNOF-V). RESULTS: We derived 448 histologic variables (243 related to septa, 21 related to nodules and 184 related to fibrosis). The SNOF score (≥11.78) reliably distinguished CSPH at baseline and in the validation cohort (baseline + EOT) [AUC = 0.85 and 0.74, respectively]. The SNOF-V score (≥0.57) distinguished the presence of varices at baseline and in the same validation cohort [AUC = 0.86 and 0.73, respectively]. Finally, the SNOF-C score differentiated those who had >20% change in HVPG against those who did not, with an AUROC of 0.89. CONCLUSION: The ML algorithm accurately predicted HVPG, CSPH, the development of varices and HVPG changes in patients with NASH cirrhosis. The use of ML histology model in NASH cirrhosis trials may improve the assessment of key outcome changes.

Review article: the safety of anticoagulants and antiplatelet agents in patients with cirrhosis.

Patients with cirrhosis were long thought to be coagulopathic. However, this paradigm has changed in recent years and currently, cirrhosis is recognised as a prothrombotic state. Due to the increasing incidence of cirrhosis from nonalcoholic steatohepatitis which is closely associated with cardiac disease, patients with cirrhosis increasingly require therapy with anticoagulants and antiplatelet agents. However, their potential for causing catastrophic and life-threatening bleeding in patients with cirrhosis leads to hesitancy about their use in patients with cirrhosis. Overall, traditional anticoagulation is safe for all Child-Pugh classes while newer direct oral anticoagulants (DOACs) are mostly safe in Child-Pugh class A/B and contraindicated in severe hepatic impairment. For different indications, published data to date suggest that anticoagulation is overall safe for patients with cirrhosis who have venous thromboembolism, atrial fibrillation and portal vein thrombosis, and does not increase the risk of variceal bleeding. Moreover, DOACs appear to have similar safety profiles as traditional anticoagulants. Finally, most studies suggest that antiplatelet agents are also safe to use in patients with cirrhosis although they are mostly contraindicated in severe hepatic impairment. For both anticoagulants and antiplatelet agents, severe thrombocytopaenia presents a relative contraindication to their use. More prospective trials and large cohort studies are needed to advance our understanding of the safety and nuances of DOACs and antiplatelet agents in patients with advanced cirrhosis.

Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis.

Background: Chronic excessive alcohol consumption leads to a spectrum of alcohol-associated liver diseases (ALD), including alcoholic hepatitis (AH). AH is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is an actively regulated process, primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from ω-6 and ω-3 poly-unsaturated fatty acids (PUFAs). We investigated the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the ω-6 and ω-3 PUFA metabolic pathways and examined the impact of alcohol abstinence on rectifying the dysregulated biosynthesis of PLMs and SPMs in AH patients. Methods: LC-MS/MS and ELISA were used to quantify levels of bioactive lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and various markers of inflammatory cascade andmicrobial translocation. Furthermore, we conducted a longitudinal study to track changes in levels of LMs over 6- and 12-month follow-ups in AH patients who underwent alcohol abstinence. Results: AH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD 2 and LTB 4 ) and SPM RvE1 compared to HDCs and/or HCs. Conversely, key SPMs such as LXA4, RvD1, and several precursors in the ω-3 pathway were significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity, clinical parameters, and various inflammatory cytokines. In particular, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score, suggesting its potential utility as an indicator of disease severity in AH patients. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence. Conclusion: Our study reveals significant dysregulation in the levels of PLM metabolites and anti-inflammatory SPMs in both ω-6 and ω-3 PUFA pathways in AH patients. This disrupted biosynthesis, characterized by an overabundance of PLMs and a deficiency in SPMs, is linked to the heightened inflammation observed in AH patients. Importantly, our findings suggest an important role of alcohol abstinence in restoring the balance of these LMs and the potential therapeutic benefits of SPM supplements in alleviating the inflammatory cascade in AH patients.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

BACKGROUND AND AIMS: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. APPROACH AND RESULTS: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. CONCLUSIONS: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.

Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis.

BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

Validation of a Novel Multitarget Blood Test Shows High Sensitivity to Detect Early Stage Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. METHODS: Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex. RESULTS: In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). CONCLUSIONS: The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651.

Practice patterns and outcomes associated with intravenous albumin in patients with cirrhosis and acute kidney injury.

BACKGROUND & AIMS: Guidelines recommend albumin as the plasma-expander of choice for acute kidney injury (AKI) in cirrhosis. However, the impact of these recommendations on patient outcomes remains unclear. We aimed to determine the practice-patterns and outcomes associated with albumin use in a large, nationwide-US cohort of hospitalized cirrhotics with AKI. METHODS: A retrospective cohort study was performed in hospitalized cirrhotics with AKI using Cerner-Health-Facts database from January 2009 to March 2018. 6786 were included for analysis on albumin-practice-patterns, and 4126 had available outcomes data. Propensity-score-adjusted model was used to determine the association between albumin use, AKI-recovery and in-hospital survival. RESULTS: Median age was 61-years (60% male, 70% white), median serum-creatinine was 1.8 mg/dL and median Model for End-stage Liver Disease Sodium (MELD-Na) score was 24. Albumin was given to 35% of patients, of which 50% received albumin within 48-hours of AKI-onset, and 17% received appropriate weight-based dosing. Albumin was used more frequently in patients with advanced complications of cirrhosis, higher MELD-Na scores and patients admitted to urban-teaching hospitals. After propensity-matching and multivariable adjustment, albumin use was not associated with AKI-recovery (odds ratio [OR] 0.70, 95% confidence-interval [CI]: 0.59-1.07, P = .130) or in-hospital survival (OR 0.76 [95% CI: 0.46-1.25], P = .280), compared with crystalloids. Findings were unchanged in subgroup analyses of patients with varying cirrhosis complications and disease severity. CONCLUSIONS: USA hospitalized patients with cirrhosis and AKI frequently do not receive intravenous albumin, and albumin use was not associated with improved clinical outcomes. Prospective randomised trials are direly needed to evaluate the impact of albumin in cirrhotics with AKI.

ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.

Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. METHODS: A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. RESULTS: We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15-2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04-1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921). CONCLUSION: PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.

Circulating Extracellular Vesicles Carrying Sphingolipid Cargo for the Diagnosis and Dynamic Risk Profiling of Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. APPROACH AND RESULTS: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol-associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011 /mL) compared to healthy controls (4.38 × 1010 /mL; P < 0.0001), heavy drinkers (1.28 × 1011 /mL; P < 0.0001), ESLD (5.35 × 1010 /mL; P < 0.0001), and decompensated AC (9.2 × 1010 /mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End-Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high-EV group and 90.0% in the low-EV group (log-rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. CONCLUSIONS: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90-day survival permitting dynamic risk profiling.

A Novel Blood-Based Panel of Methylated DNA and Protein Markers for Detection of Early-Stage Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) can be treated effectively if detected at an early stage. Recommended surveillance strategies for at-risk patients include ultrasound with or without α-fetoprotein (AFP), but their sensitivity is suboptimal. We sought to develop a novel, blood-based biomarker panel with improved sensitivity for early-stage HCC detection. METHODS: In a multicenter, case-control study, we collected blood specimens from patients with HCC and age-matched controls with underlying liver disease but without HCC. Ten previously reported methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins, including AFP, were assayed and analyzed by a logistic regression algorithm to predict HCC cases. The accuracy of the multi-target HCC panel was compared with that of other blood-based biomarkers for HCC detection. RESULTS: The study included 135 HCC cases and 302 controls. We identified a multi-target HCC panel of 3 MDMs (HOXA1, EMX1, and TSPYL5), B3GALT6 and 2 protein markers (AFP and AFP-L3) with a higher sensitivity (71%, 95% CI: 60-81%) at 90% specificity for early-stage HCC than the GALAD score (41%, 95% CI: 30-53%) or AFP ≥7.32 ng/mL (45%, 95% CI: 33-57%). The AUC for the multi-target HCC panel for detecting any stage HCC was 0.92 compared with 0.87 for the GALAD score and 0.81 for AFP alone. The panel performed equally well in important subgroups based on liver disease etiology, presence of cirrhosis, or sex. CONCLUSIONS: We developed a novel, blood-based biomarker panel that demonstrates high sensitivity for early-stage HCC. These data support the potential for liquid biopsy detection of early-stage HCC to clinically benefit at-risk patients. This study was registered on ClinicalTrials.gov (NCT03628651).

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.