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.

Impact of Karnofsky performance status on outcomes of patients with severe alcohol-associated hepatitis: a propensity-matched analysis.

BACKGROUND AND AIMS: Severity scores, including the model for end-stage liver disease (MELD) and discriminant function score, guide the treatment of patients with severe alcohol-associated hepatitis (AH). We aimed to investigate the impact of functional status on outcomes of patients with AH. METHODS: Medically managed patients (n = 133) with AH from 1 January 2019 to 31 December 2022 were included in this prospective study. The objectives were to compare the long-term survival, recompensation rates, corticosteroid response, incidence of infections, hepatic encephalopathy (HE) and acute kidney injury (AKI) among propensity score-matched patients with good Karnofsky performance status (KPS) (score ≥50) and poor KPS (score <50) using Kaplan-Meier analysis. RESULTS: Twenty-five patients with good KPS were matched with 25 patients with poor KPS and followed up for a median duration of 10 (0.5-33) months. Survival was 76% (19/25; 95% confidence interval (CI), 54.9-90.6) in patients with good KPS compared to 42.3% (11/25; 95% CI, 23.4-63.1) patients with poor KPS (P = 0.001) at 10 months. The recompensation rate was higher in the good KPS group than in the poor KPS group (68% vs 44%; P = 0.04). A higher proportion of patients in the good KPS group (78.9%) than in the poor KPS group (42.8%; P = 0.03) responded to corticosteroids. Survival was lower among non-responders in the poor KPS group (0% vs 75%; P = 0.01). The proportion of patients who developed infection (36% vs 28%; P = 0.051), HE (36% vs 12%; P = 0.01) and AKI (60% vs 16%; P < 0.001) was higher in patients with poor KPS than in good KPS. CONCLUSIONS: KPS is an important determinant of outcomes in patients with AH, including survival, recompensation, response to corticosteroids and complications.

The Value of Medical Registries and Observational Studies Early in Pandemics: The Coronavirus Disease 2019 (COVID-19) Experience.

Whereas randomized clinical trials remain the gold standard for evaluating new therapies for infections, we argue that registries and observational studies early in the coronavirus disease 2019 (COVID-19) pandemic provided invaluable understanding of the natural history and preliminary data on risk factors and possible treatments. We review the data from the current pandemic, the history of registries in general, and their value in public health emergencies. Lessons from these experiences should be incorporated into rigorous planning for the next pandemic.

Impact of Antibiotic Resistance Genes in Gut Microbiome of Patients With Cirrhosis.

BACKGROUND AND AIMS: Cirrhosis is associated with changes in intestinal microbiota that can lead to hepatic encephalopathy (HE) and infections, especially with antibiotic-resistant organisms. However, the impact of gut microbial antibiotic resistance gene (ARG) burden on clinical outcomes is unclear. The aims of the study were to determine the impact of ARGs in cirrhosis-related gut metagenome on outcomes and disease progression, study the effect of rifaximin on ARG burden, and compare ARGs in cirrhosis with chronic kidney disease (CKD) and diabetes. METHODS: In outpatients with cirrhosis who underwent metagenomics, we evaluated change in ARG abundances with progression and their multivariable impact on 90-day hospitalizations and deaths over 1 year. We also studied ARGs pre- and 8 weeks post-rifaximin in patients with compensated cirrhosis in an open-label trial. Finally, ARGs from CKD and diabetes studies were compared with cirrhosis on machine learning. RESULTS: A total of 163 patients with cirrhosis (43 compensated, 20 ascites-only, 30 HE-only, 70 both) and 40 controls were included. ARG abundances were higher in cirrhosis versus controls and worsened with advancing cirrhosis severity; 44 patients were hospitalized and 14 died. ARG abundances were associated with hospitalizations and mortality while controlling for cirrhosis complications, medications, and demographics. Rifaximin trial: ARG abundance patterns were minimally affected in 19 patients post-rifaximin. CKD/diabetes comparison: ARG abundance patterns in cirrhosis are distinguishable on machine learning and include more gram-positive ARGs. CONCLUSIONS: Cirrhosis is associated with high gut microbial ARG gene burden compared with controls, which worsens with disease progression and may be different from CKD and diabetes. ARGs are not affected by rifaximin and are associated with hospitalizations and death.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Gut Microbial Signature of Hepatocellular Cancer in Men With Cirrhosis.

The gut microbiome is altered in cirrhosis. Recent evidence has suggested a key role for the gut microbiota in the progression of cirrhosis and the development of hepatocellular carcinoma (HCC). We studied the differences in the microbial composition in patients with cirrhosis with prior and future HCC in the context of other complications (eg, infections, hepatic encephalopathy). The following 2 cohorts were recruited prospectively: the prior HCC cohort, in which outpatients with HCC within 2 years were age-matched, sex-matched, and Model for End-Stage Liver Disease (MELD) score-matched with those without HCC; and the future HCC cohort, in which patients were followed for 2 years and divided into future HCC versus no HCC after age, sex, and MELD-score matching and other complications were also recorded. Microbiota composition and predicted function were analyzed with ribosomal RNA sequencing and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PiCRUST)and compared between (1) prior HCC versus none and (2) future HCC versus none, and in the future cohort, comparisons were also made between those patients who developed (1) HCC only versus without complications, (2) HCC only versus non-HCC complications only, and (3) HCC + other complications versus non-HCC complications only. A total of 142 men (76 total in the prior cohort [38 with/38 without HCC] and 66 total in the future cohort [33 with/33 without future HCC]) were included. The groups had similar etiology, lactulose/rifaximin/proton pump inhibitor use, diabetes mellitus, and non-HCC complications. Microbial diversity was similar between prior HCC/not or future HCC/not. On DESeq2 higher Clostridium sensu stricto and Anaerotruncus were significantly associated with protection from HCC, whereas the reverse was seen with Raoultella and Haemophilus regardless of prior/future HCC comparisons. Functions focused on urea cycle, bioenergetics, tryptophan, and toluene metabolism were different between the groups. Rothia was specific for other complications. Despite age, sex, and MELD-score matching and accounting for other complications, gut microbiota composition and the predicted function are different in men with cirrhosis with and without prior HCC and can be extended toward future HCC development.

New drugs for NASH.

Non-alcoholic steatohepatitis (NASH) is a result of inflammation and hepatocyte injury in the presence of hepatic steatosis which can progress to cirrhosis. NASH is the most rapidly growing aetiology for liver failure and indication for liver transplantation in the United States. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, type 2 diabetes, dyslipidaemia and metabolic syndrome. Because of the absence of approved pharmacotherapy, weight loss and lifestyle modifications remain the safest and most effective first-line treatment. However, this may not be effective in patients with advanced fibrosis or cirrhosis and long-term adherence is difficult to achieve. Therefore, effective drugs are urgently needed for the treatment of NASH. Drug development targeting pathological pathways in NASH have exploded in the past decade, with numerous new drugs under investigation. This review summarizes the results of pivotal finalized phase 2 studies and provides an outline of key active studies with trial data of drugs under development.

Role of gut microbiota in liver disease.

The gut microbiome is the natural intestinal inhabitant that has been recognized recently as a major player in the maintenance of human health and the pathophysiology of many diseases. Those commensals produce metabolites that have various effects on host biological functions. Therefore, alterations in the normal composition or diversity of microbiome have been implicated in various diseases, including liver cirrhosis and nonalcoholic fatty liver disease. Moreover, accumulating evidence suggests that progression of dysbiosis can be associated with worsening of liver disease. Here, we review the possible roles for gut microbiota in the development, progression, and complication of liver disease.

Hospitalized Women With Cirrhosis Have More Nonhepatic Comorbidities and Associated Complications Than Men.

Gender differences in the natural history of chronic liver disease have been well-described. Women have lower rates of chronic liver disease and slower fibrosis progression, yet higher rates of waitlist mortality.1,2 Although previous studies have identified several clinical factors including height and creatinine that explain some of this transplant disparity, most have used data from administrative records, which are limited in their ability to identify clinically relevant differences and opportunities for intervention to reduce disparities.3-5 Additionally, most studies have focused on the period between waitlist and transplant, failing to capture gender differences in access to transplant.3,6 In the present study, we took advantage of a multicenter inpatient cohort with granular clinical data to characterize how women and men with cirrhosis differ, to stimulate future research aimed at reducing the well-established gender disparity in liver transplantation.

Small Dense Low-Density Lipoprotein Cholesterol Predicts Cardiovascular Events in Liver Transplant Recipients.

Cardiovascular disease (CVD) is an important cause of morbidity and mortality after liver transplantation (LT). Although LT is associated with dyslipidemia, particularly atherogenic lipoprotein subparticles, the impact of these subparticles on CVD-related events is unknown. Therefore, the aim of the current study was to evaluate the impact of small dense (sdLDL-C) low-density lipoprotein (LDL) cholesterol (LDL-C) on CVD events. Prospectively enrolled patients (N = 130) had detailed lipid profile consisting of traditional lipid parameters and sdLDL-C and were followed for CVD events. The primary endpoint was a CVD composite consisting of myocardial infarction (MI), angina, need for coronary revascularization, and cardiac death. Mean age of the cohort was 58 ± 11 years, and the most common etiology of liver disease (LD) was hepatitis C virus (N = 48) and nonalcoholic steatohepatitis (N = 23). A total of 20 CVD events were noted after median follow-up of 45 months. The baseline traditional profile was similar in patients with and without CVD events. A serum LDL-C cutoff of 100 mg/dL was unable to identify individuals at risk of a CVD event (P = 0.86). In contrast, serum concentration of atherogenic sdLDL-C >25 mg/dL was predictive of CVD events with a hazard ratio of 6.376 (95% confidence interval, 2.65, 15.34; P < 0.001). This relationship was independent of diabetes, hypertension, sex, ethnicity, LD, obesity, and statin use. Conclusion: sdLDL-C independently predicted CVD events whereas LDL-C did not. Thus, sdLDL-C may provide a useful clinical tool in risk stratifying and managing patients after LT.

Digital therapeutics lead to clinically significant body weight loss in patients with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis.

BACKGROUND: Most patients with metabolic dysfunction-associated steatotic liver disease are unable to achieve clinically significant body weight loss with traditional in-person approaches. Digital therapeutic (DTx)-delivered interventions offer promise to remove barriers to weight loss success inherent to traditional resource-heavy in-person programs and at a population level, but their efficacy remains relatively unknown. METHODS: Published studies were identified through May 2023 by searching the following electronic databases: PubMed and Embase (Ovid). DTx intervention was compared to standard of care. The primary outcome was a change in body weight. Secondary outcomes included clinically significant body weight loss (≥5%) and change in liver enzymes. RESULTS: Eight studies comprising 1001 patients met inclusion criteria (mean age: 47 y; body mass index: 33.2 kg/m2). The overall rate of clinically significant body weight loss was 33%, with DTx lifestyle interventions ranging from 4 to 24 months in length. DTx lifestyle intervention achieved statistically significant body weight loss (absolute change -3.4 kg, 95% CI: -4.8 to -2.0 kg, p < 0.01, relative change -3.9%, 95% CI: -6.6 to -1.3, p < 0.01) as well as clinically significant body weight loss of ≥5% (risk ratio: 3.0, 95% CI: 1.7-5.5, p < 0.01) compared to standard of care. This was seen alongside improvement in liver enzymes. CONCLUSIONS: DTx-delivered lifestyle intervention programs lead to greater amounts of body weight loss than traditional in-person lifestyle counseling. These results further support the role of DTx in delivering lifestyle intervention programs to patients with metabolic dysfunction-associated steatotic liver disease and suggest that this scalable intervention offers promise to benefit the billions of patients worldwide with this condition.

Fibrosis-4 index is associated with the risk of hepatocellular carcinoma in patients with cirrhosis and nonalcoholic steatohepatitis.

Background and aims: Identification of high-risk patients for hepatocellular carcinoma (HCC) is essential for long term monitoring of nonalcoholic steatohepatitis (NASH) cirrhosis progression. We sought to evaluate the association between Fibrosis-4 (FIB-4) index and incidence of HCC risk among patients with NASH cirrhosis. Methods: We conducted a retrospective cohort study of adult patients with NASH cirrhosis (n= 1,338) who were evaluated in a single medical center between 2005 and 2015. Those who developed HCC were identified through electronic medical records using International Classification of Diseases (ICD) 9 and 10 codes until the end of September 2021. Results: During a median follow-up time of 3.7 years, 157 (11.7%) patients with NASH cirrhosis developed HCC. At index visit, the study population had a median age 57 years, 43% males, 78.8% White, and mean FIB-4 index 4.2. The final multivariable Cox regression model revealed that male sex, BMI 25-29.9 kg/m2, and hypertension were independent factors associated with development of HCC in patients with NASH cirrhosis. Compared to patients with FIB-4 ¾ 1.45, patients with FIB-4 between 1.45-3.25 had a similar hazard of HCC (Hazard Ratio [HR] 1.12, 95% CI: 0.67-1.86, p=0.670), whereas patients with FIB-4 >3.25 had a 1.93 (95% CI: 1.22-3.05, p=0.005) increased hazard of HCC. Conclusion: FIB-4 > 3.25 was an independent factor associated with increased HCC risk among NASH cirrhosis patients. FIB-4 index is a promising tool for determining high-risk patients and may be used in routine clinical practice to monitor risk of HCC in patients with NASH cirrhosis.

Subjective and objective burden on providers from a multicenter app-based study of patients with cirrhosis and caregivers.

BACKGROUND: App-based technologies could enhance patient and caregiver communication and provide alerts that potentially reducing readmissions. However, the burden of App alerts needs to be optimized to reduce provider burnout. AIM: The purpose of this study was to determine subjective and objective burden of using the Patient Buddy App, a health information technology (HIT) on providers in a randomized multicenter trial, who completed a semi-quantitative Likert scale survey regarding training procedures, data and privacy concerns, follow-up details, and technical support. This randomized multicenter trial recruits cirrhosis inpatients and their caregivers, and randomizes them into standard-of-care, HIT (communication only via App) and HIT+visits (App+phone calls/visits) for 30 days after discharge. The alerts are monitored by providers through a central iPad. The reason(s) and number of alerts were recorded as the objective burden. A total of 1442 messages were sent as alerts from the 103 dyads (patient + caregiver) (n=206) randomized to HIT arms. The most common messages related to Hepatic Encephalopathy (HE) (high or low bowel movement=50% or orientation tests=37%). Twelve providers completed the surveys reflecting the following themes-92% and 100%, felt adequately trained and confident about educating the patients and caregivers before roll out of App and had no concerns related to data and privacy; 70%, felt that appropriate time was spent on pursuing reason for data not being logged; 60% each, had issues with availability of adequate technical support and connectivity. CONCLUSION: The Patient Buddy App randomized multicenter trial till date shows an overall favorable rating regarding training procedures/education, privacy concerns, and ease of message follow-up, from providers. However, it is important to gauge and address subjective and objective burdens of monitoring human resources in current and future HIT studies to avoid burnout and to ensure successful study completion.

The association between serum liver enzymes and cancer mortality.

Interpreting levels of liver enzymes is often challenging because they may be influenced by metabolic processes beyond the liver. Given their pathophysiologic roles in inflammation and oxidative stress, higher levels of these enzymes may be associated with increased risk of mortality. However, studies have found inconsistent results. Thus, we examined the association of liver enzymes levels with cancer mortality in the general US adult population. We used the US National Health and Nutrition Examination Survey from 1999 to 2016. Kaplan-Meier survival curve comparisons were examined across quartiles of liver enzymes. Cox proportional hazards models were built to examine the relationship between cancer mortality and liver enzymes quartiles without and with adjustment for potential confounding factors. During the 338,882 person-years follow-up, 1059 participants had cancer-related deaths. There was a nonlinear U-shaped relationship between serum alanine and aspartate aminotransferase (ALT and AST) levels and cancer mortality. There was no relationship between cancer mortality and gamma-glutamyltransferase (GGT); however, each 10 IU/L increase in GGT after median was associated with 1% higher mortality risk (HR = 1.01; 95% CI = 1.00, 1.02; P = 0.001). Only subjects with high levels of alkaline phosphatase (ALP) had higher cancer mortality (HR = 1.63; 95CI = 1.30, 2.05; P < 0.001 and HR = 1.52; 95%CI = 1.20, 1.94; P = 0.001, respectively). Only the lowest and highest serum ALT and AST levels are associated with increased cancer mortality. For ALP, the relationship is present at higher levels. The association with GGT was not robust to different analyses. The mechanisms underlying the observed relationships need further exploration.

Behavioral health disorders related to nonalcoholic steatohepatitis.

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Treatments for obesity in the context of nonalcoholic steatohepatitis and mental health.

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Nonalcoholic fatty liver disease is specifically related to the risk of hepatocellular cancer but not extrahepatic malignancies.

Objective: We performed a matched cohort study among individuals with and without nonalcoholic fatty liver disease (NAFLD) to determine: 1) the incidence of cancers (extrahepatic and liver) and their spectrum and 2) if NAFLD increases the risk of extrahepatic cancers. Methods: The NAFLD and non-NAFLD (control) cohorts were identified from electronic medical records via International Classification of Diseases (ICD) codes from a single center and followed from 2010 to 2019. Cohorts were matched 1:2 for age, sex, race, body mass index (BMI), and type 2 diabetes. Results: A total of 1,412 subjects were included in the analyses. There were 477 individuals with NAFLD and 935 controls (median age, 52 years; women, 54%; white vs. black: 59% vs. 38%; median BMI, 30.4 kg/m2; type 2 diabetes, 34%). The cancer incidence (per 100,000 person-years) was 535 vs. 1,513 (NAFLD vs. control). Liver cancer incidence (per 100,000 person-years) was 89 in the NAFLD group vs. 0 in the control group, whereas the incidence of malignancy was higher across other types of cancer in the control group vs. in the NAFLD group. Conclusions: The overall extrahepatic cancer risk in NAFLD is not increased above and beyond the risk from background risk factors such as age, race, sex, BMI, and type 2 diabetes.

Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.

Current and Potential Therapies Targeting Inflammation in NASH.

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD). It is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. Inflammation plays a key role in the progression of NASH and can be provoked by intrahepatic (e.g., lipotoxicity, immune responses, oxidative stress and cell death) and extrahepatic sources (adipose tissue or gut). The identification of triggers of inflammation is central to understanding the mechanisms in NASH development and progression and in designing targeted therapies that can halt or reverse the disease. In this review, we summarize the current and potential therapies targeting inflammation in NASH.