Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT mRNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg. The primary endpoint was percentage change in serum Z-AAT concentration from baseline to Week 16. Patients with fibrosis on baseline liver biopsy received treatment on Day 1, Week 4, and then every 12 weeks, and had a second liver biopsy at or after Weeks 48, 72, or 96. Patients without fibrosis received two doses on Day 1 and Week 4. RESULTS: At Week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83% and -94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001). Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden. Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively. Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292).

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

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

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

Hepatorenal Syndrome-Acute Kidney Injury in Liver Transplantation.

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis. HRS nomenclature has recently changed to HRS-AKI (acute kidney injury). HRS is a complex response to chronic vasodilatory changes brought about by portal hypertension and exacerbated by inflammatory responses that portends poor prognosis to patients with cirrhosis. This syndrome is commonly seen in the setting of infections, particularly spontaneous bacterial peritonitis. Because of the frequency of renal injury in the patient with cirrhosis, HRS-AKI has to be considered high in the differential diagnosis of AKI. Discontinuation of potential triggering agents and elimination of pre-renal AKI, intrinsic renal disease, and structural uropathy as causes of injury are imperative on presentation. Volume expansion with albumin and vasoconstrictive drugs to counteract the underlying splanchnic vasodilation constitutes the most effective medical modality to manage this process. Although the most effective therapy is generally considered to be liver transplantation (LT), the logistic barriers of offering this life-saving therapy on time to all needing it is a major limitation. Terlipressin has been shown to reverse HRS-AKI in a significant proportion of those treated and consequently can lead to increased LT patient survival and freedom from renal replacement therapy. We will review the impact of HRS on the management of patients awaiting LT, present strategies to prevent this significant complication, and discuss major implications of recent therapeutic advances in the setting of LT.

Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort.

BACKGROUND & AIMS: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation. METHODS: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited. RESULTS: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity. CONCLUSIONS: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.

Role of Oral Health, Frailty, and Minimal Hepatic Encephalopathy in the Risk of Hospitalization: A Prospective Multi-Center Cohort of Outpatients With Cirrhosis.

BACKGROUND & AIMS: Hospitalizations are a sentinel event in cirrhosis; however, the changing demographics in patients with cirrhosis require updated hospitalization prediction models. Periodontitis is a risk factor for liver disease and potentially progression. The aim of this study was to determine factors, including poor oral health, associated with 3-month hospitalizations in a multi-center cohort of outpatients with cirrhosis. METHODS: North American Consortium for Study of End-stage Liver Disease (NACSELD-3), a new study cohort, recruits outpatients with cirrhosis. Cirrhosis details, demographics, minimal hepatic encephalopathy (MHE), frailty, and comorbid conditions including oral health were collected. All patients were followed for 3 months for nonelective hospitalizations. Multi-variable models were created for this outcome using demographics, cirrhosis details, oral health, MHE, frailty, and comorbid conditions with K-fold internal validation using 25%/75% split. RESULTS: A total of 442 outpatients (70% men; 37% compensated; Model for End-stage Liver Disease-Sodium, 12; 42% ascites; and 33% prior HE) were included. MHE was found in 70%, frailty in 10%; and both in 8%. In terms of oral health, 15% were edentulous and 10% had prior periodontitis. Regarding 3-month hospitalizations, 14% were admitted for mostly liver-related reasons. These patients were more likely to be decompensated with higher cirrhosis complications, MHE, frailty and periodontitis history. Multi-variable analysis showed prior periodontitis (P = .026), composite MHE + frailty score (P = .0016), ascites (P = .004), prior HE (P = .008), and hydrothorax (P = .004) were associated with admissions using the training and validation subsets. CONCLUSIONS: In a contemporaneous, prospective, multi-center cohort study in outpatients with cirrhosis, poor oral health is significantly associated with 3-month hospitalizations independent of portal hypertensive complications, MHE, and frailty. Potential strategies to reduce hospitalizations should consider oral evaluation in addition to MHE and frailty assessment in practice pathways.

Admission Urinary and Serum Metabolites Predict Renal Outcomes in Hospitalized Patients With Cirrhosis.

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

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.

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection.

BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).

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.

Progression of Stage 2 and 3 Acute Kidney Injury in Patients With Decompensated Cirrhosis and Ascites.

BACKGROUND & AIMS: Progression of stages 2 and 3 acute kidney injury (AKI) in cirrhosis has not been characterized adequately. Patients with higher stages of AKI are believed to have worse outcomes. We assessed outcomes and factors associated with stages 2 and 3 AKI in patients with cirrhosis in the North American Consortium for the Study of End-stage Liver Disease cohort. METHODS: We collected data from 2297 hospitalized patients with cirrhosis and ascites from December 2011 through February 2017. Our final analysis included 760 patients who developed AKI per the International Ascites Club 2015 definition (419 with maximum stage 1 and 341 with maximum stage 2 or 3; 63% male; mean age, 58 y). We compared demographic features, laboratory values, AKI treatment response, and survival between patients with maximum stage 1 vs patients with stage 2 or 3 AKI. RESULTS: Patients with stage 2 or 3 AKI had higher Model for End-Stage Liver Disease scores (25.9 ± 7.3) than patients with stage 1 AKI (21.9 ± 7.5) (P < .0001). More patients fulfilled systemic inflammatory response syndrome criteria on admission, and more developed a second nosocomial infection (P < .05 for both comparisons). More patients with stage 2 or 3 AKI also had progression of AKI and required dialysis and admission into intensive care units when compared to stage 1 AKI patients (P < .0001 for both). A lower proportion of patients with stage 2 or 3 AKI survived their hospital stay (80% vs 99% with stage 1 AKI; P < .0001), or survived for 30 days without a liver transplant (56% vs 81%; P < .0001). The development of stage 2 or 3 AKI was associated with a higher Model for End-Stage Liver Disease score at the time of admission (P < .0001), presence of systemic inflammatory response on admission (P = .039), and second infection (P < .0001). CONCLUSIONS: Based on an analysis of data from the North American Consortium for the Study of End-stage Liver Disease cohort, we found that patients with cirrhosis and more advanced liver disease, as well as a second infection, are more likely to develop stages 2 or 3 AKI, with a progressive course associated with decreased 30-day transplant-free survival. Prevention of AKI progression in patients with cirrhosis and stage 2 or 3 AKI might improve their outcomes.

Serum Levels of Metabolites Produced by Intestinal Microbes and Lipid Moieties Independently Associated With Acute-on-Chronic Liver Failure and Death in Patients With Cirrhosis.

BACKGROUND & AIMS: Inpatients with cirrhosis have high rates of acute-on-chronic failure (ACLF) development and high mortality within 30 days of admission to the hospital. Better biomarkers are needed to predict these outcomes. We performed metabolomic analyses of serum samples from patients with cirrhosis at multiple centers to determine whether metabolite profiles might identify patients at high risk for ACLF and death. METHODS: We performed metabolomic analyses, using liquid chromatography, of serum samples collected at time of admission to 12 North American tertiary hepatology centers from 602 patients in the North American Consortium for the Study of End-Stage Liver Disease sites from 2015 through 2017 (mean age, 56 years; 61% men; mean model for end-stage liver disease score, 19.5). We performed analysis of covariance, adjusted for model for end-stage liver disease at time of hospital admission, serum levels of albumin and sodium, and white blood cell count, to identify metabolites that differed between patients who did vs did not develop ACLF and patients who did vs did not die during hospitalization and within 30 days. We performed random forest analysis to identify specific metabolite(s) that were associated with outcomes and area under the curve (AUC) analyses to analyze them in context of clinical parameters. We analyzed microbiomes of stool samples collected from 133 patients collected at the same time and examined associations with serum metabolites. RESULTS: Of the 602 patients analyzed, 88 developed ACLF (15%), 43 died in the hospital (7%), and 72 died within 30 days (12%). Increased levels of compounds of microbial origin (aromatic compounds, secondary or sulfated bile acids, and benzoate) and estrogen metabolites, as well as decreased levels of phospholipids, were associated with development of ACLF, inpatient, and 30-day mortality and were also associated with fecal microbiomes. Random forest analysis and logistic regression showed that levels of specific microbially produced metabolites identified patients who developed ACLF with an AUC of 0.84 (95% confidence interval [CI] 0.78-0.88; P = .001), patients who died while in the hospital with an AUC of 0.81 (95% CI 0.74-0.85; P = .002), and patients who died within 30 days with an AUC of 0.77 (95% CI 0.73-0.81; P = .02). The metabolites were significantly additive to clinical parameters for predicting these outcomes. Metabolites associated with outcomes were also correlated with microbiomes of stool samples. CONCLUSIONS: In an analysis of serum metabolites and fecal microbiomes of patients hospitalized with cirrhosis at multiple centers, we associated metabolites of microbial origin and lipid moieties with development of ACLF and death as an inpatient or within 30 days, after controlling for clinical features.

Increased Risk of ACLF and Inpatient Mortality in Hospitalized Patients with Cirrhosis and Hepatic Hydrothorax.

BACKGROUND: Hepatic hydrothorax (HH) remains a difficult-to-treat complication of cirrhosis. AIM: To define the mortality, length of stay (LOS), and risk of ACLF in patients admitted with HH. METHODS: We utilized the North American Consortium for the Study of End-stage Liver Disease, a prospective cohort of 2868 non-electively hospitalized patients with cirrhosis from 14 tertiary care hepatology centers in North America. A total of 121 patients who required an inpatient thoracentesis (HH group) were compared to 736 patients with refractory ascites without HH, and to 1639 patients without these complications (Other). Patients with a TIPS before or during admission were excluded. RESULTS: There were no differences between the groups in age, gender, or liver disease etiology. Admission MELD (20.5, 21.6 vs. 18.7; p < 0.0001) was lower in HH than RA patients but lowest in other patients, respectively. In hospital, HH patients' rate of second infections and ICU transfer were the highest, and their LOS was the longest of all groups. Despite a similar mean discharge MELD compared to RA patients, the 90-day transplant rate was lower. Multivariable modeling showed patients with HH had an increased risk of ACLF (HR = 2.37 vs. RA, HR = 2.56 vs. Other; p = 0.01) even when controlling for MELD score, AKI, second infection, and history of prior 6-month hospitalization. Multivariable modeling also showed that HH increased the risk of inpatient mortality (HR = 2.22 vs. RA alone, HR = 2.31 vs. Other; p = 0.04). CONCLUSIONS: HH that required a therapeutic thoracentesis more than doubled the risk of ACLF and inpatient mortality among hospitalized patients with cirrhosis.

Increased access to liver transplantation for patients with acute on chronic liver failure after implementation of Share 35 Rule: An analysis from the UNOS database.

INTRODUCTION AND OBJECTIVES: Acute on chronic liver failure (ACLF), leads to high mortality. These patients are at risk of being delisted for liver transplantation (LT). Emerging data shows 1y post-transplant survival of 80-92%. The Share 35 (S35) policy was implemented to prioritize patients with MELD ≥35 on the LT waitlist. Our aim was to compare the LT outcomes of ACLF patients as a result of S35. MATERIALS AND METHODS: Data from the UNOS scientific registry were used to classify ACLF patients using the NACSELD criteria. For the analyses, data were divided into two eras; 2 years before S35 (Era 1) and 2 years after S35 (Era 2). Waitlist status was classified into categories: Transplanted, Death or Too Sick to Transplant and Still Waiting/Other. LT cumulative incidence between the populations in the eras was calculated using Fine and Gray's method. A proportional hazards model was used to investigate the era effect on cumulative incidence of LT. RESULTS: 46,861 patients were reviewed, of which 817 had ACLF. 366 patients (mean MELD: 37.1) were identified in Era 1 and 451 patients (mean MELD: 37.3) in Era 2. We found that ACLF patients were more likely to receive a liver transplant in Era 2 (p=0.0074). In both eras, transplanted patients had a significantly higher survival than those who were not transplanted (p<0.0001). CONCLUSIONS: Our study shows that S35 improved LT rate for ACLF suggesting that there should be broader recognition of ACLF and early transplantation should be pursued.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Clinical Outcomes of Portosystemic Shunts on the Outcome of Liver Transplantation.

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre-liver transplantation (LT) setting, but little is known about their post-LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post-LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre-LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post-LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan-Meier method and were compared between groups using a log-rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45-2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20-1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38-1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25-1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre-LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.

Underutilization of Hospice in Inpatients with Cirrhosis: The NACSELD Experience.

BACKGROUND: Little is known about patients discharged to hospice following hospitalization for complications of cirrhosis. AIM: We sought to understand the current pattern of hospice utilization in patients with cirrhosis by evaluating the North American Consortium for the Study of End-stage Liver Disease (NACSELD) cohort. METHODS: Patients with cirrhosis from 14 tertiary-care hepatology centers across North America non-electively hospitalized and prospectively enrolled were evaluated. Exclusion criteria included HIV infection, transplantation or non-hepatic malignancy. Random computer-based propensity score matching was undertaken in a 1:2 ratio based on admission MELD score ± 3 points. RESULTS: Totally, 2718 patients were enrolled, 5% (N = 132) were discharged to hospice, 6% (N = 171) died, and the rest were discharged alive. Patients discharged to hospice were older (60 vs. 57 years, p = 0.04), less likely to have had SBP (13% vs. 28%, p = 0.002) and be listed for liver transplantation (11% vs. 26%, p = 0.0007). Features, on multivariable modeling, associated with increased probability of discharge to hospice as opposed to being discharged alive: grade-3-4 hepatic encephalopathy, a higher Child-Turcotte-Pugh (CTP) score, and a higher discharge serum creatinine; however, a higher serum sodium, being listed for transplant and being prescribed rifaximin or a statin were protective from hospice discharge. CONCLUSION: Patients with more advanced liver disease, hepatic encephalopathy, renal dysfunction, and those not candidates for liver transplantation were more likely to be discharged to hospice. However, in this sick multinational cohort of cirrhotic inpatients, it seems that hospice is markedly underutilized (5%) since 25% of patients not discharged to hospice died within 6 months.

Association Between Intestinal Microbiota Collected at Hospital Admission and Outcomes of Patients With Cirrhosis.

BACKGROUND & AIMS: Inpatients with cirrhosis are prone to develop acute-on-chronic liver failure (ACLF). ACLF is associated with dysbiosis of the intestinal microbiota, which might serve as a prognostic factor. We investigated whether features of the intestinal microbiota associate organ failure, transfer to intensive care, and mortality within 30 days in patients admitted to the hospital with cirrhosis. METHODS: Stool samples were collected from 181 patients with cirrhosis (age 56 years; mean model for end-stage liver disease score, 21; 43% with infections) at time of admission, from multiple hospitals in North America. Patients were followed for 30 days for development of ACLF, extra-hepatic organ failures, and death or hospice care. Microbiota were analyzed by 16s rRNA sequencing for alpha diversity (within groups), beta diversity (between groups), cirrhosis dysbiosis ratio (CDR), and taxa that differed between groups with vs without negative outcomes (individual organ failures, transfer to intensive care, ACLF, death, or hospice). Regression analyses were performed using microbial and clinical variables for each outcome. RESULTS: ACLF developed in 8% of study subjects; 16% were transferred to intensive care and 21% died. Beta diversity of the intestinal microbiome was significantly different, whereas alpha diversity was similar, between subjects with vs without outcomes. The CDR was lower in subjects who developed ACLF, especially among those with renal failure. Taxa belonging to phylum Proteobacteria (Enterobacteriaceae, Campylobacteriaceae, and Pasteurellaceae) and Firmicutes (Enterococcaceae and Streptococcaceae) were associated with development of negative outcomes, whereas other Firmicutes members (Lachnospiraceae and Clostridiales) reduced risk of negative outcomes. Changes in the microbiota associated with extra-hepatic organ failure, transfer to intensive care, ACLF, and death, independently on logistic regression analyses. CONCLUSION: In hospitalized patients with cirrhosis, dysbiosis of the intestinal microbiota on admission (particularly changes in Protebacteria constituents) associates with increased risk of extra-hepatic organ failure, ACLF, and death, independent of clinical factors. Strategies to reduce gut dysbiosis might improve outcomes of patients with cirrhosis.