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Graft macrosteatosis can predispose to a higher risk of graft loss so we sought to redefine acceptable cutoffs for graft steatosis.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% and20% 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.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 (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".Da BL, Satiya J, Heda RP

Patients with chronic liver disease (CLD) with or without cirrhosis remain at risk of developing hepatic decompensation when infected with viral or bacterial pathogens. The Advisory Committee on Immunization Practices (ACIP) currently recommends vaccination in CLD against hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcus, herpes zoster, tetanus, diphtheria, pertussis, and SARS-CoV-2. Inactivated vaccines are preferred over live attenuated ones, especially in transplant recipients where live vaccines are contraindicated. As the severity of the liver disease progresses, vaccine efficacy declines, and therefore, vaccines should be ideally administered early in the disease course for optimal immune response. Despite the strong recommendations, overall vaccination coverage in CLD remains poor; however, it is encouraging to note that in recent years coverage against influenza and pneumococcus has shown some improvement. Inadequate access to healthcare, lack of information on vaccine safety, poor financial reimbursement for healthcare providers, and vaccine misinformation are often responsible for low immunization rates. This review summarizes the impact of vaccine-preventable illness in those with CLD, updated vaccine guidelines, seroconversion rates in the vaccinated, and barriers faced by healthcare professionals in immunizing those with liver disease.

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

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.To simplify EASL-CLIF criteria for ease of use without sacrificing its sensitivity and prognostic capability.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.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 (Our study showed that EASL-CLIF criteria for ACLF grades could be simplified for ease of use without losing its prognostication capability and sensitivity.

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

There are discordant reports on N-acetylcysteine (NAC) efficacy in non-acetaminophen acute liver failure (ALF).To determine whether NAC is beneficial in non-acetaminophen ALF.We performed a systemic review and meta-analysis of published data to address the question. PubMed and MEDLINE were searched using the terms non-acetylcysteine and ALF due to non-acetaminophen, viral infection, drug-induced or autoimmune hepatitis. The primary outcome was overall mortality. Secondary outcomes were transplant-free survival and length of hospital stay. Risk ratios were calculated using a random model for meta-analysis.A total of 672 patients were included in this meta-analysis from 5 prospective studies (NAC group:The treatment of patients with acute liver failure with N-acetylcysteine improved transplant-free survival and length of stay.

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

Background/Objective Our objective was to assess the impact of mass mailing and the inclusion of Best Practice Advisory (BPA) ‘Pop-Up’ tool in the electronic medical record (EMR) on HCV screening rates. Methods Between June 2015 and March 2020, two interventions were developed for primary care physicians (PCP). An educational letter along with a blood requisition form, signed on behalf of the PCP’s, was sent to patients. We also developed a BPA ‘Pop-Up’ screening tool to alert PCP’s to order HCV screening tests on patients with no previous screening. Data were collected and analyzed prospectively. Results When we started the screening program in June 2015, 33,736 baby boomers were eligible for screening and the hospital system added an additional 26,027 baby boomers between June 2015 and March 2020. Of the 89 primary care providers employed by the hospital, 75 agreed to participate at different time periods. We screened 23,291 (43.5%) of 53,526 eligible patients during study period. Of these 399 (1.7%) had HCV antibody, but HCV RNA was positive in only 195 (1%). HCV antibody positivity rates were higher in men, blacks and in 1951-1960 birth cohorts. Spontaneous clearance rates appeared to be lower in men (OR 0.59, 95% CI 0.39-0.90, p=0.015) and in blacks (OR 0.31, 95% CI 0.20-0.50, p Conclusion Although a formal screening program increased screening rates for HCV among baby boomers, about 50% of baby boomers remained unscreened. In this community screening program, we found that men and blacks are less likely to have spontaneous HCV clearance.

Background Patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage ≥2 comprise a target population for pharmacotherapy. Liver biopsy, the reference standard for identifying this population, requires complete and accurate assessment of steatohepatitis and fibrosis. Aims To investigate the completeness of real-world NASH-related pathology reports, assess concordance between site pathologists and central expert interpretation of the histologic elements of NASH, and determine concordance between biopsy-diagnosed NASH and a pragmatic clinical definition of NASH. Methods Liver pathology reports from 222 patients across 38 TARGET-NASH sites were analysed for documentation of the histologic features of NASH. Biopsy slides were over-read by a blinded central expert pathologist. Concordance of histologic scores and interpretation was assessed. Histologic concordance with a clinical definition of NASH was determined. TARGET-NASH clinically defined NASH: elevated ALT, hepatic steatosis on biopsy or imaging and ≥1 of the following: BMI ≥30 kg/m2 , type 2 diabetes mellitus and dyslipidaemia. Results Documentation of steatosis, lobular inflammation, portal inflammation and ballooning were missing from 21%, 35%, 46% and 40% of reports, respectively. There was slight-to-fair concordance (weighted kappa 0.01-0.35) between site and central pathologists for inflammatory features, and moderate concordance (weighted kappa 0.56-0.57) for fibrosis staging. Clinical definition of NASH was 75%-91% concordant (94%-95% sensitive) with biopsy-diagnosed NASH. Conclusions There is substantial variability in reporting and grading NASH and fibrosis staging in clinical practice. This heterogeneity may adversely impact patient assessment and translation of practice guidelines into reality. The TARGET-NASH pragmatic clinical definition may serve as a valuable tool to accurately identify NASH patients in clinical practice.

In this study, our objective was to determine gender differences in the outcomes of patients with PLD undergoing liver (LT) or liver/kidney transplantation (SLK). We analyzed the UNOS datasets of all adults who had transplanted for PLD between 1988 and 2018. During the study period, 663 LT/SLK (51% LT only and 49% SLK) were done for PLD patients and of these 500 (75%) were in women. Women were younger (52.8 vs. 56.7 years, p

BACKGROUND The Budd Chiari syndrome (BCS) is a rare and potentially fatal disease, but there is a paucity of data on the in- hospital mortality as well its economic burden on the health care system. AIM To evaluate trends in mortality, length of hospital stays and resource utilization among inpatients with BCS. METHODS Data on all adult patients with a diagnosis of BCS were extracted from the National Inpatient Sample (NIS) from 1998 to 2017. To make inferences regarding the national estimates for the total number of BCS discharges across the study period, sample weights were applied to each admission per recommendations from the NIS. RESULTS During the study period, there were 3591 (8.73%) in-patient deaths. The overall in-hospital mortality rates among BCS patients decreased from 18% in 1998 to 8% in 2017; the mortality decreased by 4.41% (P < 0.0001) every year. On multivariate analysis, older age, higher comorbidity score, acute liver failure, acute kidney injury, acute respiratory failure, hepatic encephalopathy, hepatorenal syndrome, inferior vena cava thrombosis, intestinal infarct, sepsis/septic shock and cancer were associated increased risk of mortality. The average of length of stay was 8.8 d and it consistently decreased by 2.04% (95%CI: -2.67%, -1.41%, P < 0.001) from 12.7 d in 1998 to 7.6 d in 2017.The average total charges after adjusted for Medical Care Consumers Price Index to 2017 dollars during the time period was $94440 and the annual percentage change increased by 1.15% (95%CI: 0.35%, 1.96%, P = 0.005) from $95515 in 1998 to $103850 in 2017. CONCLUSION The in-hospital mortality rate for patients admitted with BCS in the United States has reduced between 1998 and 2017 and this may a reflection of better management of these patients.

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

With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.

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

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.

The 2019 novel coronavirus disease (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to global public health. Although primarily, the infection causes lung injury, liver enzyme abnormalities have also been reported to occur during the course of the disease. We conducted an extensive literature review using the PubMed database on articles covering a broad range of issues related to COVID-19 and hepatic injury. The present review summarizes available information on the spectrum of liver involvement, the possible mechanisms and risk factors of liver injury due to SARS-CoV-2 infection, and the prognostic significance of the presence of liver injury. Hopefully, this review will enable clinicians, especially the hepatologists, to understand and manage the liver derangements they may encounter in these patients better and provide guidance for further studies on the liver injury of COVID-19.

Hepatic hydrothorax (HH) remains a difficult-to-treat complication of cirrhosis. To define the mortality, length of stay (LOS), and risk of ACLF in patients admitted with HH. 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. There were no differences between the groups in age, gender, or liver disease etiology. Admission MELD (20.5, 21.6 vs. 18.7; p

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

Introduction Readmission and death in cirrhosis are common, expensive, and difficult to predict. Our aim was to evaluate the abilities of multiple artificial intelligence (AI) techniques to predict clinical outcomes based on variables collected at admission, during hospitalization, and at discharge. Methods We used the multicenter North American Consortium for the Study of End-Stage Liver Disease (NACSELD) cohort of cirrhotic inpatients who are followed up through 90-days postdischarge for readmission and death. We used statistical methods to select variables that are significant for readmission and death and trained 3 AI models, including logistic regression (LR), kernel support vector machine (SVM), and random forest classifiers (RFC), to predict readmission and death. We used the area under the receiver operating characteristic curve (AUC) from 10-fold crossvalidation for evaluation to compare sexes. Data were compared with model for end-stage liver disease (MELD) at discharge. Results We included 2,170 patients (57 ± 11 years, MELD 18 ± 7, 61% men, 79% White, and 8% Hispanic). The 30-day and 90-day readmission rates were 28% and 47%, respectively, and 13% died at 90 days. Prediction for 30-day readmission resulted in 0.60 AUC for all patients with RFC, 0.57 AUC with LR for women-only subpopulation, and 0.61 AUC with LR for men-only subpopulation. For 90-day readmission, the highest AUC was achieved with kernel SVM and RFC (AUC = 0.62). We observed higher predictive value when training models with only women (AUC = 0.68 LR) vs men (AUC = 0.62 kernel SVM). Prediction for death resulted in 0.67 AUC for all patients, 0.72 for women-only subpopulation, and 0.69 for men-only subpopulation, all with LR. MELD-Na model AUC was similar to those from the AI models. Discussion Despite using multiple AI techniques, it is difficult to predict 30- and 90-day readmissions and death in cirrhosis. AI model accuracies were equivalent to models generated using only MELD-Na scores. Additional biomarkers are needed to improve our predictive capability (See also the visual abstract at http://links.lww.com/AJG/B710).

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.

Abnormal liver enzymes are seen in 20% of hospitalized patients with COVID-19. The etiology of elevated liver enzymes is thought to be multifactorial including medications and underlying liver disease. The true prevalence and clinical significance of underlying chronic liver diseases (CLD) in COVID-19 remains poorly defined. In this systematic review and meta-analysis, we included 74 clinical studies that were identified after a thorough literature search across three databases. The prevalence of CLD patients (73 studies, 24,299 patients) was 3% among all COVID-19 patients. The prevalence of CLD patients was similar in COVID-19 positive and negative population (pooled OR 0.79 [95% CI 0.60, 1.05], p = 0.10). The presence of CLD was significantly associated with more severe COVID-19 infection (pooled OR 1.48 [95% CI 1.17, 1.87], p = 0.001) and overall mortality (pooled OR 1.78 [95% CI 1.09, 2.93], p = 0.02). Additionally, there was a non-significant trend noted for increased ICU admissions and need for invasive mechanical ventilation among COVID-19 patients with CLD. To date, the clinical importance of chronic liver diseases among COVID-19 infection has remained undefined. In this novel systematic review and meta-analysis, the presence of underlying chronic liver disease was significantly associated with more severe COVID-19 infections and mortality. Electronic supplementary material The online version of this article (10.1007/s12072-020-10078-2) contains supplementary material, which is available to authorized users.

Background/Aims Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death among patients with type 2 diabetes mellitus (T2DM). We aimed to assess the independent role of T2DM on HCC risk among patients with different liver disease etiologies. Methods We analyzed the United Network for Organ Sharing database of all adults registered for liver transplantation (LT) between February 27, 2002 and December 31, 2017. For initial analyses, patients were divided into four groups: nonalcoholic steatohepatitis (NASH) and all other etiologies with or without T2DM. For additional analyses, we divided them based on underlying etiology. Logistic regression was used to evaluate the impact of T2DM with NASH and other etiologies on HCC risk. Results Overall, 24,149 (21.6%) of the listed patients had HCC. Of those, 23.9% had T2DM. When compared with nondiabetics, patient with NASH and T2DM had the highest risk of HCC (odds ratio [OR] 1.68; 95% confidence interval [CI] 1.52–1.86), followed by patients with other etiologies and diabetes. After adjusting for other risk factors, these associations remained unchanged. Registrants with T2DM and NASH, cryptogenic cirrhosis, hepatitis C, and alcoholic liver disease were at higher risk of HCC than those without diabetes, but in patients with chronic hepatitis B or primary biliary cholangitis, diabetes did not increase the HCC risk. Between 2004 and 2016, the annual percentage change of HCC incidence increased for all patients with NASH and hepatitis C regardless of their diabetes status. For those with hepatitis B, this trend was significant only for diabetics. Conclusions The additive risk of T2DM for HCC development was highest in patients with NASH. HCC risk may vary depending on the underlying etiology.

Background & Aims Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. Methods We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. Results There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (−0.21, −0.45, −0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. Conclusions Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. Lay summary Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. Clinical Trial Number Clinical Trials.gov #NCT02960204.

The objective of our study was to determine the concordance rates of steatosis staging by controlled attenuation parameter (CAP) scores from transient elastography (TE) in comparison with liver histology in patients with chronic liver disease and to determine the optimal CAP cutoffs to predict the severity of steatosis and identify those with nonalcoholic steatohepatitis (NASH). Patients (n = 217) who had both CAP scores and liver biopsy within a period of 90 days were retrospectively studied. Histology was graded in a blinded fashion by a single pathologist; steatosis was graded on a scale from 0 to 3. Nonalcoholic fatty liver disease activity scores (NAS) scores were calculated for all patients. Optimal CAP cut-points were selected by maximum Youden’s index. Area under receiver operating characteristic curve (AUROC) for CAP (using cutoff value ≥ 278 dB/m) in differentiating steatosis 1–3 from 0 was 0.82 (95% CI 0.75–0.89), and 0.79 (95% CI 0.70–0.88) in differentiating steatosis 0–1 from 2 to 3 using CAP cutoff value ≥ 301 dB/m. With CAP cutoff value ≥ 301 dB/m, CAP identified NAS 3 or above with AUROC of 0.82 (95% CI 0.74–0.89). The AUROC for TE in differentiating fibrosis (cutoff 11.9 kPa) 3–4 from 0 to 2 was 0.85 (95% CI 0.77–0.92), and 0.84 (95% CI 0.74–0.93) in differentiating (cutoff 14.4 kPa) 4 from 0 to 3. Transient elastography is a good modality to accurately diagnose steatosis and NASH and can also differentiate advanced liver fibrosis from early stages.

Multiple listing (ML) at1 transplant center is one mechanism to combat the geographic disparities in liver transplantation (LT) rates. The objective of our study was to determine the impact of multiple listing on LT rates.We examined the United Network of Organ Sharing database from 2002 to 2016 after excluding those listed for multiple organs, hepatocellular carcinoma, or living donor LT. The waitlist mortality and LT rates for the ML groups and the single listed (SL) group were compared after stratifying patients by the Model for End-Stage Liver Disease (MELD) with a cutoff at 15 (15 and ≥15).Of the 83 935 listed during the study period, 80 351 were listed in a single center (SL group), and 3584 were listed in1 center (ML group). Of the ML groups, 2028 (2.4%) were listed at multiple donor service areas but within the same region (ML-SR) and 1556 (1.9%) listed in different regions (ML-DR). The median MELD at LT was 20, 21, and 24 for ML-DR, ML-SR, and SL groups, respectively (P = 0.001). Although the probability of receiving LT was significantly higher for the ML groups relative to the SL group for both MELD groups (15 and ≥15), the impact was the highest for ML-DR group. At MELD score15, the probability of LT was 72% for ML-DR, 38% for ML-SR, and 32% for SL groups. At MELD score ≥15, the probability of LT was 79% for ML-DR, 67% for ML-SR, and 61% for SL groups.Multiple listing appeared to considerably improve a patient's chance of receiving LT and survival with the highest benefit for those with low MELD scores (15) listed at multiple regions.

Little is known about patients discharged to hospice following hospitalization for complications of cirrhosis. 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. 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. 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. 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.

Hypervolemic hyponatremia is a late complication of portal hypertension. Hyponatremia is associated with a higher mortality in hospitalized patients. In this study, we evaluated the risk factors for inhospital mortality and developed a mortality prediction model in patients with cirrhosis and hyponatremia.Using the national inpatient sample data for years 2016 and 2017, we identified cirrhotic patients hospitalized with ascites and hyponatremia (n = 9153). We identified independent risk factors of inhospital mortality and developed a prediction model in a training group and assessed its accuracy in a validation group. To enhance the clinical utility, we further stratified patients into low-, intermediate-, and high-risk mortality risk groups using cutoff points selected by decision tree analysis.The inhospital mortality in our cohort was 10.2% (n = 846). Multivariable analysis showed that age at least 65 years, variceal bleeding, sepsis, coagulopathy, and acute-on-chronic liver failure (ACLF defined as two or more organ failures) were independent risk factors for mortality. The prediction model using these five risk factors had an AUROC of 0.80 [95% confidence interval (CI), 0.78-0.82] for the training data and 0.83 (95% CI, 0.80-0.86) for the validation data. The mortality risks in the low-, intermediate-, and high-risk groups were 4% (95% CI, 3-4), 29% (95% CI, 28-33), and 43% (95% CI, 37-50), respectively.We have developed a clinically meaningful inhospital prognostic model with excellent discrimination that will enable clinicians to risk stratify hospitalized patients with hyponatremia, ascites, and cirrhosis.

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).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.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.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.NGM Biopharmaceuticals.

The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of60 ml/min/1.73 mTo study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD.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.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).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.

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.

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