Emerging Pharmacologic Treatments for Alcohol-Associated Hepatitis: Current Status and Future Landscape.

Several treatments have shown efficacy in preliminary alcohol-associated hepatitis trials. Interleukin-22 improved Model of End-stage Liver Disease score and aminotransferases in a phase II trial. The endogenous cholesterol derivative, larsucosterol, improved outcomes in a multi-center United States or European phase II trial. The antioxidants N-acetylcysteine and metadoxine improved survival in large trials. Trials from India report improved survival with granulocyte-colony stimulating factor, as well as improved outcome among patients receiving fecal microbiota transfer. Translational studies suggest that phage treatment of cytolytic Enterococcus faecalis may reduce liver injury.

Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort.

BACKGROUND: Hepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection. METHODS: In a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection. RESULTS: HDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p<0.001), and 10 years (19.14 vs. 10.18, p<0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p<0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p<0.001). CONCLUSION: In a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.

Management of coagulopathy among patients with cirrhosis undergoing upper endoscopy and paracentesis: Persistent gaps and areas of consensus in a multispecialty Delphi.

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of 286 possible measures, 33 measures made the final set. International normalized ratio testing was not required for diagnostic or therapeutic paracentesis as well as diagnostic endoscopy. Plasma transfusion should be avoided for all paracenteses and diagnostic endoscopy. No consensus was achieved for these items in therapeutic intent or emergent endoscopy. The risks of prophylactic platelet transfusions exceed their benefits for outpatient diagnostic paracentesis and diagnostic endosopies. For the other procedures examined, the risks outweigh benefits when platelet count is >20,000/mm 3 . It is uncertain whether risks outweigh benefits below 20,000/mm 3 in other contexts. No consensus was achieved on whether it was permissible to continue or stop systemic anticoagulation. Continuous aspirin was permissible for each procedure. Clopidogrel was permissible for diagnostic and therapeutic paracentesis and diagnostic endoscopy. We found many areas of consensus that may serve as a foundation for a common set of practice metrics for the periprocedural management of coagulopathy in cirrhosis.

Organizational and Implementation Factors Associated with Cirrhosis Care in the Veterans Health Administration.

BACKGROUND: The Veterans Health Administration provides care to more than 100,000 Veterans with cirrhosis. AIMS: This implementation evaluation aimed to understand organizational resources and barriers associated with cirrhosis care. METHODS: Clinicians across 145 Department of Veterans Affairs (VA) medical centers (VAMCs) were surveyed in 2022 about implementing guideline-concordant cirrhosis care. VA Corporate Data Warehouse data were used to assess VAMC performance on two national cirrhosis quality measures: HCC surveillance and esophageal variceal surveillance or treatment (EVST). Organizational factors associated with higher performance were identified using linear regression models. RESULTS: Responding VAMCs (n = 124, 86%) ranged in resource availability, perceived barriers, and care processes. In multivariable models, factors independently associated with HCC surveillance included on-site interventional radiology and identifying patients overdue for surveillance using a national cirrhosis population management tool ("dashboard"). EVST was significantly associated with dashboard use and on-site gastroenterology services. For larger VAMCs, the average HCC surveillance rate was similar between VAMCs using vs. not using the dashboard (47% vs. 41%), while for smaller and less resourced VAMCs, dashboard use resulted in a 13% rate difference (46% vs. 33%). Likewise, higher EVST rates were more strongly associated with dashboard use in smaller (55% vs. 50%) compared to larger (57% vs. 55%) VAMCs. CONCLUSIONS: Resources, barriers, and care processes varied across diverse VAMCs. Smaller VAMCs without specialty care achieved HCC and EVST surveillance rates nearly as high as more complex and resourced VAMCs if they used a population management tool to identify the patients due for cirrhosis care.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Steroid responsiveness in alcohol-associated hepatitis is linked to glucocorticoid metabolism, mitochondrial repair, and heat shock proteins.

BACKGROUND: Alcohol-associated hepatitis (AH) is one of the clinical presentations of alcohol-associated liver disease. AH has poor prognosis, and corticosteroids remain the mainstay of drug therapy. However, ~40% of patients do not respond to this treatment, and the mechanisms underlying the altered response to corticosteroids are not understood. The current study aimed to identify changes in hepatic protein expression associated with responsiveness to corticosteroids and prognosis in patients with AH. METHODS: Patients with AH were enrolled based on the National Institute on Alcohol Abuse and Alcoholism inclusion criteria for acute AH and further confirmed by a diagnostic liver biopsy. Proteomic analysis was conducted on liver samples acquired from patients with AH grouped as nonresponders (AH-NR, n = 7) and responders (AH-R, n = 14) to corticosteroids, and nonalcohol-associated liver disease controls (n = 10). The definition of responders was based on the clinical prognostic model, the Lille Score, where a score < 0.45 classified patients as AH-R and a score > 0.45 as AH-NR. Primary outcomes used to assess steroid response were Lille Score (eg, improved liver function) and survival at 24 weeks. RESULTS: Reduced levels of the glucocorticoid receptor and its transcriptional co-activator, glucocorticoid modulatory element-binding protein 2, were observed in the hepatic proteome of AH-NR versus AH-R. The corticosteroid metabolizing enzyme, 11-beta-hydroxysteroid dehydrogenase 1, was increased in AH-NR versus AH-R along with elevated mitochondrial DNA repair enzymes, while several proteins of the heat shock pathway were reduced. Analysis of differentially expressed proteins in AH-NR who survived 24 weeks relative to AH-NR nonsurvivors revealed several protein expression changes, including increased levels of acute phase proteins, elevated coagulation factors, and reduced mast cell markers. CONCLUSIONS: This study identified hepatic proteomic changes that may predict responsiveness to corticosteroids and mortality in patients with AH.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Identification of integrated proteomics and transcriptomics signature of alcohol-associated liver disease using machine learning.

Distinguishing between alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC) remains a diagnostic challenge. In this study, we used machine learning with transcriptomics and proteomics data from liver tissue and peripheral mononuclear blood cells (PBMCs) to classify patients with alcohol-associated liver disease. The conditions in the study were AH, AC, and healthy controls. We processed 98 PBMC RNAseq samples, 55 PBMC proteomic samples, 48 liver RNAseq samples, and 53 liver proteomic samples. First, we built separate classification and feature selection pipelines for transcriptomics and proteomics data. The liver tissue models were validated in independent liver tissue datasets. Next, we built integrated gene and protein expression models that allowed us to identify combined gene-protein biomarker panels. For liver tissue, we attained 90% nested-cross validation accuracy in our dataset and 82% accuracy in the independent validation dataset using transcriptomic data. We attained 100% nested-cross validation accuracy in our dataset and 61% accuracy in the independent validation dataset using proteomic data. For PBMCs, we attained 83% and 89% accuracy with transcriptomic and proteomic data, respectively. The integration of the two data types resulted in improved classification accuracy for PBMCs, but not liver tissue. We also identified the following gene-protein matches within the gene-protein biomarker panels: CLEC4M-CLC4M, GSTA1-GSTA2 for liver tissue and SELENBP1-SBP1 for PBMCs. In this study, machine learning models had high classification accuracy for both transcriptomics and proteomics data, across liver tissue and PBMCs. The integration of transcriptomics and proteomics into a multi-omics model yielded improvement in classification accuracy for the PBMC data. The set of integrated gene-protein biomarkers for PBMCs show promise toward developing a liquid biopsy for alcohol-associated liver disease.

Undiagnosed Cirrhosis and Hepatic Encephalopathy in a National Cohort of Veterans With Dementia.

Importance: Dementia and hepatic encephalopathy (HE) are challenging to distinguish clinically. Undiagnosed cirrhosis in a patient with dementia can lead to missed opportunities to treat HE. Objective: To examine the prevalence and risk factors of undiagnosed cirrhosis and therefore possible HE in veterans with dementia. Design, Setting, and Participants: A retrospective cohort study was conducted between 2009 and 2019 using data from the Veterans Health Administration (VHA) and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Data analysis was conducted from May 20 to October 15, 2023. Participants included 177 422 US veterans with a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) score. Exposures: Demographic and clinical characteristics. Main Outcomes and Measures: An FIB-4 score (>2.67 suggestive of advanced fibrosis and >3.25 suggestive of cirrhosis), capped at age 65 years even for those above this cutoff who were included in the analysis. Results: Among 177 422 veterans (97.1% men; 80.7% White; mean (SD) age, 78.35 [10.97] years) 5.3% (n = 9373) had an FIB-4 score greater than 3.25 and 10.3% (n = 18 390) had an FIB-4 score greater than 2.67. In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with older age (odds ratio [OR], 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17), and inversely associated with White race (OR, 0.79; 95% CI, 0.73-0.85), diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and rural residence (OR, 0.92; 95% CI, 0.87-0.97). Similar findings were associated with the FIB-4 greater than 2.67 threshold. These codes were associated with cirrhosis on local validation. A local validation cohort of patients with dementia showed a similar percentage of high FIB-4 scores (4.4%-11.2%). Conclusions and Relevance: The findings of this cohort study suggest that clinicians encountering patients with dementia should be encouraged to screen for cirrhosis using the FIB-4 score to uncover reversible factors associated with cognitive impairment, such as HE, to enhance outcomes.

Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project.

BACKGROUND & AIMS: The coronavirus disease-2019 pandemic profoundly disrupted preventative health care services including cancer screening. As the largest provider of cirrhosis care in the United States, the Department of Veterans Affairs (VA) National Gastroenterology and Hepatology Program aimed to assess factors associated with hepatocellular carcinoma (HCC) stage at diagnosis, treatment, and survival. METHODS: Veterans with a new diagnosis of HCC in 2021 were identified from electronic health records (N = 2306). Structured medical record extraction was performed by expert reviewers in a 10% random subsample of Veterans with new HCC diagnoses. Factors associated with stage at diagnosis, receipt of treatment, and survival were assessed using multivariable models. RESULTS: Among 199 patients with confirmed HCC, the average age was 71 years and most (72%) had underlying cirrhosis. More than half (54%) were at an early stage (T1 or T2) at diagnosis. Less-advanced liver disease, number of imaging tests adequate for HCC screening, HCC diagnosis in the VA, and receipt of VA primary care were associated significantly with early stage diagnosis. HCC-directed treatments were administered to 145 (73%) patients after a median of 37 days (interquartile range, 19-54 d) from diagnosis, including 70 (35%) patients who received potentially curative treatments. Factors associated with potentially curative (vs no) treatments included HCC screening, early stage at diagnosis, and better performance status. Having fewer comorbidities and better performance status were associated significantly with noncurative (vs no) treatment. Early stage diagnosis, diagnosis in the VA system, and receipt of curative treatment were associated significantly with survival. CONCLUSIONS: These results highlight the importance of HCC screening and engagement in care for HCC diagnosis, treatment, and survival while demonstrating the feasibility of developing a national quality improvement agenda for HCC screening, diagnosis, and treatment.

Comparing the CFIR-ERIC matching tool recommendations to real-world strategy effectiveness data: a mixed-methods study in the Veterans Health Administration.

BACKGROUND: Practical and feasible methods for matching implementation strategies to diagnosed barriers of evidence-based interventions in real-world contexts are lacking. This evaluation compared actual implementation strategies applied with those recommended by an expert opinion-based tool to improve guideline-concordant cirrhosis care in a Veterans Health Administration national learning collaborative effort. METHODS: This convergent parallel mixed-methods study aimed to (1) identify pre-implementation Consolidated Framework for Implementation Research (CFIR) barriers to cirrhosis care through focus groups with frontline providers, (2) generate 20 recommended strategies using focus group identified barriers entered into the CFIR-Expert Recommendations for Implementing Change (ERIC) Implementation Strategy Matching Tool, (3) survey providers over two consecutive years on the actual use of 73 ERIC strategies and determine strategy effectiveness, (4) compare actual versus recommended strategy use, and (5) compare actual versus expected barriers by reverse applying the CFIR-ERIC Matching Tool. RESULTS: Eighteen semi-structured focus groups were conducted with 197 providers representing 95 VA sites to identify barriers to quality improvement, including cirrhosis care complexity, clarity of national goals, and local leadership support. The CFIR-ERIC Matching Tool recommended strategies such as assessing for readiness and needs, promoting adaptability, building local groups, preparing champions, and working with opinion leaders and early adopters. Subsequent strategy surveys found that sites used the top 20 "recommended" strategies no more frequently than other strategies. However, 14 (70%) of the top recommended strategies were significantly positively associated with cirrhosis care compared to 48% of actual strategies. Reverse CFIR-ERIC matching found that the strategies most used in the first year corresponded to the following barriers: opinion leaders, access to knowledge and information, and resources. The strategies most frequently employed in the second year addressed barriers such as champions, cosmopolitanism, readiness for implementation, relative priority, and patient needs and resources. Strategies used in both years were those that addressed adaptability, trialability, and compatibility. CONCLUSIONS: This study is among the first to empirically evaluate the relationship between CFIR-ERIC Matching Tool recommended strategies and actual strategy selection and effectiveness in the real world. We found closer connections between recommended strategies and strategy effectiveness compared to strategy frequency, suggesting validity of barrier identification, and application of the expert-informed tool.

The road to pandemic recovery: Tracking COVID-19's impact on cirrhosis care and outcomes among 111,558 Veterans.

BACKGROUND AIMS: This study aimed to evaluate quarterly trends in process and health outcomes among Veterans with cirrhosis and assess the factors associated with cirrhosis outcomes before and during the COVID-19 pandemic. APPROACH RESULTS: US Veterans with cirrhosis were identified using the Veterans Health Administration Corporate Data Warehouse. Quarterly measures were evaluated from September 30, 2018, through March 31, 2022, including twice yearly screening for hepatocellular carcinoma (HCC-6), new HCC, surveillance for or treatment of esophageal varices, variceal bleeding, all-cause hospitalization, and mortality. Joinpoint analyses were used to assess the changes in trends over time. Logistic regression models were used to identify the demographic and medical factors associated with each outcome over time. Among 111,558 Veterans with cirrhosis with a mean Model for End-stage Liver Disease-Sodium of 11±5, rates of HCC-6 sharply declined from a prepandemic peak of 41%, to a nadir of 28%, and rebounded to 36% by March 2022. All-cause mortality did not significantly change over the pandemic, but new HCC diagnosis, EVST, variceal bleeding, and all-cause hospitalization significantly declined over follow-up. Quarterly HCC diagnosis declined from 0.49% to 0.38%, EVST from 50% to 41%, variceal bleeding from 0.15% to 0.11%, and hospitalization from 9% to 5%. Rurality became newly, significantly associated with nonscreening over the pandemic (aOR for HCC-6=0.80, 95% CI 0.74 to 0.86; aOR for EVST=0.95, 95% CI 0.90 to 0.997). CONCLUSIONS: The pandemic continues to impact cirrhosis care. Identifying populations at the highest risk of care disruptions may help to address ongoing areas of need.

CSF from a puppy with a cerebral vascular hamartoma.

A 9-week-old puppy with refractory seizures and a dome-shaped head presented to the Mississippi State College of Veterinary Medicine Specialty Center for suspected hydrocephalus. Computerized tomography (CT) findings included transtentorial herniation and an intra-axial mass with dystrophic mineralization. Cerebrospinal fluid analysis revealed an increased nucleated cell count of 1100/µl (RI < 5/µl), erythrocyte count of 2.2 × 106 /µl, and markedly increased microprotein of 1939 mg/dl (RI < 30 mg/dl). On cytologic examination of the CSF, numerous erythrophagocytic, and hemosiderin-laden macrophages were observed, which indicated chronic active hemorrhage. Many neutrophils, macrophages, and lymphocytes that contained numerous intracytoplasmic, pleomorphic, bright yellow crystals were observed. Considering the ongoing hemorrhage, the crystals were presumed to be hematoidin. A biopsy with histopathology was performed on the intra-axial mass, and the results were consistent with a vascular hamartoma. We speculate that the formation of these crystals was related to the ongoing hemorrhage associated with the vascular hamartoma. Identification of these crystals may be useful to aid in the identification of chronic hemorrhage associated with vascular malformations or lesions within the central nervous system.

High-grade mucoepidermoid carcinoma of the salivary gland in a bull.

Salivary gland neoplasia is uncommon in veterinary species and has rarely been reported in cattle. Adenocarcinoma, squamous cell carcinoma, and pleomorphic carcinoma have been described in the parotid gland of dairy cows. Here we describe a case of high-grade mucoepidermoid carcinoma in a bull. The bull had a chronic history of caudal mandibular soft tissue swelling. Postmortem examination revealed a 30 × 30-cm mass with a caseonecrotic center, hemorrhage and necrosis of the ipsilateral cervical musculature, osteolysis of the right paracondylar process of the skull and right horn base, pulmonary nodules, and enlarged tracheobronchial lymph nodes. Histology of the mass, lungs, and lymph nodes revealed an invasive neoplasm composed of epithelial cells arranged in nests and ductular structures supported by a spindle cell stroma, with frequent central necrosis. Immunohistochemistry revealed that epithelial cells were diffusely positive for pancytokeratin and p63 with multifocal vimentin positivity; stromal cells were diffusely positive for vimentin and α-SMA. A salivary gland mucoepidermoid carcinoma was diagnosed based on these findings. Although rare, salivary gland neoplasia should be considered a differential diagnosis for mandibular masses in cattle.

All-cause and liver-related mortality risk factors in excessive drinkers: Analysis of data from the UK biobank.

BACKGROUND: High alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts of alcohol. METHODS: We obtained information from the UK Biobank on approximately 500,000 participants aged 40-70 years at baseline assessment in 2006-2010. Habitual alcohol intake, lifestyle and physiological data, laboratory test results, and hospital diagnoses and death certificate data (to June 2020) for 5136 men (2.20% of male participants) and 1504 women (0.60%) who reported consuming ≥80 or ≥50 g/day, respectively, were used in survival analysis. RESULTS: Mortality hazard ratios for these excessive drinkers, compared to all other participants, were 2.02 (95% CI 1.89-2.17) for all causes, 1.89 (1.69-2.12) for any cancer, 1.87 (1.61-2.17) for any circulatory disease, and 9.40 (7.00-12.64) for any liver disease. Liver disease diagnosis or abnormal liver function tests predicted not only deaths attributed to liver disease but also those from cancers or circulatory diseases. Mortality among excessive drinkers was also associated with quantitative alcohol intake; diagnosed alcohol dependence, harmful use, or withdrawal syndrome; and current smoking at assessment. CONCLUSIONS: People with chronic excessive alcohol intake experience decreased average survival, but there is substantial variation in their mortality, with liver abnormality and alcohol dependence or other alcohol use disorders associated with a worse prognosis. Clinically, patients with these risk factors and high alcohol intake should be considered for early or intensive management. Research can usefully focus on the factors predisposing to dependence or liver abnormality.

Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis.

Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent studies have shown that defective function of hepatocyte nuclear factor 4 alpha (HNF4a) and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein, an integrative analysis of hepatic RNA sequencing and liquid chromatography-tandem mass spectrometry was performed to identify plasma protein signatures for patients with mild and severe AH. Alcohol-related liver disease cirrhosis, nonalcoholic fatty liver disease, and healthy subjects were used as comparator groups. Levels of identified proteins primarily involved in hepatocellular function were decreased in patients with AH, which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified, including thrombin, hepatocyte growth factor α, clusterin, human serum factor H-related protein, and kallistatin, which exhibited large abundance shifts between severe and nonsevere AH. The combination of thrombin and hepatocyte growth factor α discriminated between severe and nonsevere AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.

Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples.

Background & Aims: Liver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples. Methods: We collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools. Results: Utilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes. Conclusions: Our machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases. Lay summary: Distinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.

Semiautomated Software to Improve Stability and Reduce Operator-Induced Variation in Vascular Ultrasound Speckle Tracking.

OBJECTIVES: Ultrasound is useful in predicting arteriovenous fistula (AVF) maturation, which is essential for hemodialysis in end-stage renal disease patients. We developed ultrasound software that measures circumferential vessel wall strain (distensibility) using conventional ultrasound Digital Imaging and Communications in Medicine (DICOM) data. We evaluated user-induced variability in measurement of arterial wall distensibility and upon finding considerable variation we developed and tested 2 methods for semiautomated measurement. METHODS: Ultrasound scanning of arteries of 10 subjects scheduled for AVF surgery were performed. The top and bottom of the vessel wall were tracked using the Kanade-Lucas-Tomasi (KLT) feature-tracking algorithm over the stack of images in the DICOM cine loops. The wall distensibility was calculated from the change of vessel diameter over time. Two semiautomated methods were used for comparison. RESULTS: The location of points selected by users for the cine loops varied significantly, with a maximum spread of up to 120 pixels (7.8 mm) for the top and up to 140 pixels (9.1 mm) for the bottom of the vessel wall. This variation in users' point selection contributed to the variation in distensibility measurements (ranging from 5.63 to 41.04%). Both semiautomated methods substantially reduced variation and were highly correlated with the median distensibility values obtained by the 10 users. CONCLUSIONS: Minimizing user-induced variation by standardizing point selection will increase reproducibility and reliability of distensibility measurements. Our recent semiautomated software may help expand use in clinical studies to better understand the role of vascular wall compliance in predicting the maturation of fistulas.

Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

BACKGROUND AND AIMS: HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS: The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION: Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.

Getting to implementation: Adaptation of an implementation playbook.

Introduction: Implementation strategies supporting the translation of evidence into practice need to be tailored and adapted for maximum effectiveness, yet the field of adapting implementation strategies remains nascent. We aimed to adapt "Getting To Outcomes"® (GTO), a 10-step implementation playbook designed to help community-based organizations plan and evaluate behavioral health programs, into "Getting To Implementation" (GTI) to support the selection, tailoring, and use of implementation strategies in health care settings. Methods: Our embedded evaluation team partnered with operations, external facilitators, and site implementers to employ participatory methods to co-design and adapt GTO for Veterans Health Administration (VA) outpatient cirrhosis care improvement. The Framework for Reporting Adaptations and Modifications to Evidenced-based Implementation Strategies (FRAME-IS) guided documentation and analysis of changes made pre- and post-implementation of GTI at 12 VA medical centers. Data from multiple sources (interviews, observation, content analysis, and fidelity tracking) were triangulated and analyzed using rapid techniques over a 3-year period. Results: Adaptations during pre-implementation were planned, proactive, and focused on context and content to improve acceptability, appropriateness, and feasibility of the GTI playbook. Modifications during and after implementation were unplanned and reactive, concentrating on adoption, fidelity, and sustainability. All changes were collaboratively developed, fidelity consistent at the level of the facilitator and/or implementer. Conclusion: GTO was initially adapted to GTI to support health care teams' selection and use of implementation strategies for improving guideline-concordant medical care. GTI required ongoing modification, particularly in steps regarding team building, context assessment, strategy selection, and sustainability due to difficulties with step clarity and progression. This work also highlights the challenges in pragmatic approaches to collecting and synthesizing implementation, fidelity, and adaptation data. Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT04178096).