Severe Liver Disease Research Articles

Analysis of clinical and genetic characteristics of the severe liver disease phenotype in patients with hepatolenticular degeneration

Objective: To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD). Methods: Inpatients with HLD confirmed at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine from January 1989 to December 2022 were selected as the research subjects. Clinical classification was performed according to the affected organs. Patients with liver disease phenotypes were classified into the liver disease group and further divided into the severe liver disease group and the ordinary liver disease group. The clinical characteristics and genetic variations were compared in each group of patients. The predictive indicators of patients with severe liver disease were analyzed by multiple regression. Statistical analysis was performed using the t-test, Mann-Whitney U test, or χ(2) test according to different data. Results: Of the 159 HLD cases, 142 were in the liver disease group (34 in the severe liver disease group and 108 in the ordinary liver disease group), and 17 were in the encephalopathy group. The median age of onset was statistically significantly different between the liver disease group and the encephalopathy group [12.6 (7.0, 13.3) years versus 16.9 (11.0, 21.5) years, P<0.01]. 156 ATP7B gene mutation sites were found in 83 cases with genetic testing results, of which 54 cases carried the p.Arg778Leu gene mutation (allele frequency 46.2%). Compared with patients with other types of gene mutations (n=65), patients with homozygous p.Arg778Leu mutations (n=18) had lower blood ceruloplasmin and albumin levels, a higher prognostic index, Child-Pugh score, an international normalized ratio, and prothrombin time (P<0.05). Hemolytic anemia, corneal K-F ring, homozygous p.Arg778Leu mutation, and multiple laboratory indexes in the severe liver disease group were statistically significantly different from those in the ordinary liver disease group (P<0.05). Multivariate logistic regression analysis showed that the predictive factors for severe liver disease were homozygous p.Arg778Leu mutation, total bilirubin, and bile acids (ORs=16.512, 1.022, 1.021, 95% CI: 1.204-226.425, 1.005-1.039, and 1.006-1.037, respectively, P<0.05). The drawn ROC curve demonstrated a cutoff value of 0.215 3, an AUC of 0.953 2, and sensitivity and specificity of 90.91% and 92.42%, respectively. Conclusion: Liver disease phenotypes are common in HLD patients and have an early onset. Total bilirubin, bile acids, and the homozygous p.Arg778Leu mutation of ATP7B is related to the severity of liver disease in HLD patients, which aids in predicting the occurrence and risk of severe liver disease.

Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19

The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment. IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. Invitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules. SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.

Impact of pre-existing medical conditions on mortality in geriatric trauma: a nationwide study in Japan.

To investigate the relationship between pre-existing medical conditions and outcomes in elderly trauma patients in Japan. This multicenter observational study utilized data from the Japan Trauma Data Bank (JTDB) from 2019 to 2020. The primary outcome was in-hospital mortality. Factors associated with in-hospital mortality were identified using multivariate logistic regression analysis, from which adjusted odds ratios (AOR) and 95% confidence intervals (CI) were determined. Of the participants during the study period, 19,598 patients were included in the analysis. Among the pre-existing medical conditions, moderate or severe liver disease showed the strongest positive association with in-hospital mortality (AOR: 7.087, 95% CI: 3.194-15.722), followed by multiple malignancies (AOR: 3.490, 95% CI: 1.046-11.641), congestive heart failure (AOR: 2.572, 95% CI: 1.920-3.445), and moderate or severe renal disease (AOR: 2.256, 95% CI: 1.584-3.215). Data from JTDB suggests that pre-existing conditions like moderate or severe liver disease, congestive heart failure, and moderate or severe renal disease in elderly trauma patients are positively correlated with in-hospital mortality.

Physical frailty, genetic predisposition, and the risks of severe non-alcoholic fatty liver disease and cirrhosis: a cohort study.

Frailty, defined as a phenotype of decreased physiological reserves and diminished ability to respond to stressors, has been linked to the development of chronic diseases. Epidemiological evidence connecting frailty to non-alcoholic fatty liver disease (NAFLD) and cirrhosis risks remain sparse. We aimed to assess the longitudinal associations of frailty with the risks of severe NAFLD and cirrhosis in middle-aged to older adults and further explore the modification role of genetic risk on these associations. This study included a total of 398386 participants from the UK Biobank. Incident cases of severe NAFLD and cirrhosis were ascertained through linked hospital records and death registries. Frailty status was assessed by a modified version of the frailty phenotype, encompassing five key components: weight loss, tiredness, physical activity, gait speed, and grip strength. Participants were classified as pre-frailty if they met one or two of these criteria, and as frailty if they met three or more. Genetic predisposition to NAFLD and cirrhosis was estimated by genetic risk score (GRS) and further categorized into high, intermediate, and low genetic risk levels according to tertiles of GRSs. Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for their associations. The mean (standard deviation) age of the study population was 56.6 (8.03) years. 214408 (53.8%) of the participants was female; 14924 (3.75%) of participants met the criteria for frailty, 170498 (42.8%) for pre-frailty, and 212964 (53.5%) for non-frailty. Over a median follow-up of 12.0years, we documented 4439 incident severe NAFLD and 3323 incident cirrhosis cases, respectively. Compared with non-frailty, both pre-frailty (HR: 1.50; 95% CI: 1.40-1.60) and frailty (HR: 1.98; 95% CI: 1.77-2.21) were associated with increased risk of NAFLD. Similar associations were observed for cirrhosis, the corresponding HRs (95% CIs) for non-frailty, pre-frailty, and frailty were 1.00 (reference), 1.29 (1.20, 1.38), and 1.90 (1.66, 2.18). Such associations were consistent across all genetic risk levels, with no observed interactions between frailty and GRSs (all P for interactions ≥0.10). Compared with participants with frailty and a low level of genetic risk, the greatest risk increasement in developing severe NAFLD (HR: 3.36; 95% CI: 2.83-3.99) and cirrhosis (HR: 2.81; 95% CI: 2.29-3.44) was both observed in those with frailty and a high level of genetic risk. Our findings indicate that frailty is a significant predictor of severe NAFLD and cirrhosis, irrespective of genetic predisposition.

Dynamic Exception Points for Fair Liver Allocation

There are disparities in access to livers based on transplant patients’ height, which disproportionately affects Hispanics, Asians, and women (across all ethnicities), because short patients can receive transplants from a smaller pool of available deceased donors for medical reasons. Reduced likelihood of transplantation leads to higher mortality rates and longer waiting times. We analyze fairness within the current U.S. liver allocation system where patients receive priority dynamically, based on their model for end-stage liver disease (MELD) scores, which reflect the severity of liver disease. We propose a simple adjustment, providing additional (exception) points based on height and MELD score, that can be easily implemented in practice, which materially reduces the disparity without sacrificing overall efficiency. We model the liver allocation system as a multiclass fluid model of overloaded queues with heterogeneous servers. We impose explicit equity constraints for all static patient classes, that is, height. We characterize the optimal solution under the objective of minimizing pretransplant mortality. The discretized version of the optimal policy is numerically solved using estimates from clinical data and a detailed simulation study demonstrates its effectiveness. The optimal policy, called the equity adjusted mortality risk policy, advocates ranking patients based on their short-term mortality risk adjusted for equity among height classes. Interpretation of the shadow prices of equity constraints in the optimal control problem as MELD exception points is novel in the transplant context since they can be seamlessly mapped into the existing system. Our simulations show that for women, the disparity can be almost completely eliminated. Hispanics and Asians greatly benefit from receiving these MELD exception points also. Our work provides a remedy to reduce the disparities in access to liver transplantation within the MELD-based allocation. Our approach can help the on-going analysis of the continuous distribution model for livers because it also considers aspects of candidate biology, notably height and body surface area. Funding: M. Akan was supported by the National Science Foundation [Grant CMMI-1334194] and the Carnegie Mellon University (CMU) [Onetto Fellowship in Operations Management]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/serv.2023.0092 .

Model for end-stage liver disease-dependent prognostic capacity of platelet-to-lymphocyte ratio following liver transplantation for hepatocellular carcinoma

BackgroundTo improve liver organ allocation, the model for end-stage liver disease (MELD) score was adopted in candidates reflecting the severity of liver disease and the physical condition of patients. Inflammatory markers are prognostic factors for various cancers and play prognostic roles in patients after liver transplantation (LT) for hepatocellular carcinoma (HCC). Researchers focused more on pre-LT inflammatory markers, while the role of dynamic change of these inflammatory markers is still unknown. The purpose of this study was to estimate the prognostic value of pre-LT and post-LT inflammatory markers. Material and methodsWe collected the pre-LT complete blood count and the post-LT result with highest count of white blood cells within 48 h. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and systemic immune-inflammation index were calculated, and their prognostic roles were analyzed for their MELD scores. ResultsThis retrospective two-center cohort study enrolled 290 patients after LT for HCC. Multivariate analysis identified pre-LT PLR as independent risk factor for recurrence-free survival (RFS) [HR (95%CI): 1.002 (1.000–1.003), p = 0.023]. A high pre-LT PLR or post-LT PLR were associated with poorer RFS (p < 0.001 and p = 0.004, respectively). Based on the MELD scores, the pre-LT PLR value was able to predict the RFS in high MELD group (p < 0.001) but had no predictive power in low MELD group (p = 0.076). On the contrary, the post-LT PLR value was better to predict the overall RFS value in low MELD group (p = 0.007) but could not predict the overall RFS value in high MELD group (p = 0.136). ConclusionsBoth pre-LT PLR and post-LT PLR demonstrated prognostic value in patients following LT for HCC. Monitoring PLR values based on the MELD score can improve the predictive prognosis and more effectively guide the individual decisions for the postoperative intervention.

Sarcopenia in cirrhosis: Unraveling the prevalence and relationships with liver disease severity and complications.

Sarcopenia in cirrhosis is associated with poor survival and adverse pre and post-transplant outcomes. The study aimed at determining the prevalence of sarcopenia and its association with the severity, complications and etiology of liver disease. As many as 416 cirrhotic patients who met the inclusion criteria underwent muscle strength testing using a dynamometer. As many as 109 probable sarcopenia patients underwent computed tomography (CT) scan to measure skeletal muscle index (SMI) at the L3 vertebral level and gait-speed testing. The gender-specific cut-offs used to define sarcopenia were an SMI of 36.54 cm2/m2 in males and 30.21 cm2/m2 in females. A gait speed ≤ 0.8m/s was taken as a cut-off to define severe sarcopenia in both genders. The mean age was 54.7 ± 9.51years and male:female ratio was 2.2:1.The mean body mass index (BMI) was 24.2 ± 1.34kg/m2. Alcohol and non-alcoholic steatohepatitis (NASH) were the two most common etiologies (45.9% and 31.2%). The proportion of patients belonging to Child-Pugh class A, B and C was 26.6%, 48.6% and 24.8%, respectively. Forty out of 109 (36.7%) patients had a model for end-stage liver disease (MELD) > 14. Ascites, upper gastrointestinal bleeding and hepatic encephalopathy (HE) were present in 59 (54.1%), 60 (55.0%) and 24 (22.0%) patients, respectively. The prevalence of probable sarcopenia, sarcopenia and severe sarcopenia was found to be 26.20%, 10.09% and 6.73%, respectively. Sarcopenia and severe sarcopenia were associated with Child-Pugh class (p < 0.001, p < 0.001), MELD (p = 0.007, 0.002), upper gastrointestinal bleed (p = 0.007, 0.004), ascites (p = 0.038, 0.025) and HE (0.001, < 0.001). The prevalence of sarcopenia and severe sarcopenia was found to be 10.09% and 6.73%, respectively. Sarcopenia and severe sarcopenia had a significant association with the severity and complications of cirrhosis. However, no association was observed with etiology of liver disease.

Distinct Gut Microbial Signature and Host Genetic Variants in Association with Liver Fibrosis Severity in Patients with MASLD.

Gut microbiota might affect the severity and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to characterize gut dysbiosis and clinical parameters regarding fibrosis stages assessed by magnetic resonance elastography. This study included 156 patients with MASLD, stratified into no/mild fibrosis (F0-F1) and moderate/severe fibrosis (F2-F4). Fecal specimens were sequenced targeting the V4 region of the 16S rRNA gene and analyzed using bioinformatics. The genotyping of PNPLA3, TM6SF2, and HSD17B13 was assessed by allelic discrimination assays. Our data showed that gut microbial profiles between groups significantly differed in beta-diversity but not in alpha-diversity indices. Enriched Fusobacterium and Escherichia_Shigella, and depleted Lachnospira were found in the F2-F4 group versus the F0-F1 group. Compared to F0-F1, the F2-F4 group had elevated plasma surrogate markers of gut epithelial permeability and bacterial translocation. The bacterial genera, PNPLA3 polymorphisms, old age, and diabetes were independently associated with advanced fibrosis in multivariable analyses. Using the Random Forest classifier, the gut microbial signature of three genera could differentiate the groups with high diagnostic accuracy (AUC of 0.93). These results indicated that the imbalance of enriched pathogenic genera and decreased beneficial bacteria, in association with several clinical and genetic factors, were potential contributors to the pathogenesis and progression of MASLD.

Alpha-1-Antitrypsin Deficiency in Children-Unmet Needs Concerning the Liver Manifestation.

This study aimed to analyse the clinical course of 45 children with severe alpha-1-antitrypsin deficiency (AATD) registered in our clinic to detect possible predictors of poor outcomes. The clinical and biological data of 45 patients with homozygous or compound heterozygous AATD were analysed. The data were collected retrospectively going back to 2005 and prospectively from May 2020 until October 2021. It was based on questionnaires, laboratory values, sonography, and biopsy findings. Liver disease was classified into four grades depending on the grade of liver disease: mild or no liver disease, moderate disease, severe disease, and liver transplantation. Thirty-nine patients (86.7%) had a Pi*ZZ and five (11.1%) a Pi*SZ genotype. One patient showed a new, not-yet-described compound heterozygous genotype (Pi*Z + Asp95Asn). A total of 66.7% of the cohort showed mild or no liver disease, 20% moderate, and 13.3% severe. AATD was diagnosed in most cases because of liver abnormalities, such as the elevation of transaminases (42.2%). A total of 29.4% of the patients with neonatal icterus prolongatus developed severe liver disease, and 25.7% were born small for their gestational age (SGA). Diseases of the atopic type were reported in 47.4% of the cases. The presence of neonatal icterus prolongatus in the first weeks of life was significantly more likely in severe courses of liver disease (r = 0.371, p = 0.012). A tendency toward atopic comorbidity in AAT-deficient children needs to be further evaluated.

Gynostemma pentaphyllum Extract Alleviates NASH in Mice: Exploration of Inflammation and Gut Microbiota.

NASH (non-alcoholic steatohepatitis) is a severe liver disease characterized by hepatic chronic inflammation that can be associated with the gut microbiota. In this study, we explored the therapeutic effect of Gynostemma pentaphyllum extract (GPE), a Chinese herbal extract, on methionine- and choline-deficient (MCD) diet-induced NASH mice. Based on the peak area, the top ten compounds in GPE were hydroxylinolenic acid, rutin, hydroxylinoleic acid, vanillic acid, methyl vanillate, quercetin, pheophorbide A, protocatechuic acid, aurantiamide acetate, and iso-rhamnetin. We found that four weeks of GPE treatment alleviated hepatic confluent zone inflammation, hepatocyte lipid accumulation, and lipid peroxidation in the mouse model. According to the 16S rRNA gene V3-V4 region sequencing of the colonic contents, the gut microbiota structure of the mice was significantly changed after GPE supplementation. Especially, GPE enriched the abundance of potentially beneficial bacteria such as Akkerrmansia and decreased the abundance of opportunistic pathogens such as Klebsiella. Moreover, RNA sequencing revealed that the GPE group showed an anti-inflammatory liver characterized by the repression of the NF-kappa B signaling pathway compared with the MCD group. Ingenuity Pathway Analysis (IPA) also showed that GPE downregulated the pathogen-induced cytokine storm pathway, which was associated with inflammation. A high dose of GPE (HGPE) significantly downregulated the expression levels of the tumor necrosis factor-α (TNF-α), myeloid differentiation factor 88 (Myd88), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4) genes, as verified by real-time quantitative PCR (RT-qPCR). Our results suggested that the therapeutic potential of GPE for NASH mice may be related to improvements in the intestinal microenvironment and a reduction in liver inflammation.

Renal impairment is prevalent in pediatric NAFLD/MASLD and associated with disease severity.

Renal impairment is prevalent in adults with nonalcoholic fatty liver disease (NAFLD/metabolic dysfunction associated steatotic liver disease [MASLD])and is associated with increased mortality. Pediatric data are limited. Our objective was to determine the prevalence of hyperfiltration or chronic kidney disease (CKD) in children with NAFLD/MASLD and determine links with liver disease severity. Data from children who had previously participated in prospective, multicenter, pediatric studies by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) were collected. Renal function was determined using the calculated glomerular filtration rate (cGFR). Hyperfiltration was defined as cGFR > 135 mL/min/1.73m2, while CKD stage 2 or higher as cGFR < 90 mL/min/1.73 m2. Renal dysfunction progression was defined as transition from normal to hyperfiltration or to CKD stage ≥ 2, or change in CKD by ≥1 stage. Multinomial logistic regression models were used to determine the prevalence of CKD and independent associations between CKD and liver disease severity. The study included 1164 children (age 13 ± 3 years, 72% male, 71% Hispanic). The median cGFR was 121 mL/min/1.73 m2; 12% had CKD stage 2-5, while 27% had hyperfiltration. Hyperfiltration was independently associated with significant liver fibrosis (odds ratio: 1.45).Baseline renal function was not associated with progression in liver disease over a 2-year period (n = 145). Renal dysfunction worsened in 19% independently of other clinical risk factors. Progression of renal impairment was not associated with change in liver disease severity. Renal impairment is prevalent in children with NAFLD/MASLD and hyperfiltration is independently associated with significant liver fibrosis. Almost 1/5 children have evidence of progression in renal dysfunction over 2 years, not associated with change in liver disease severity. Future assessments including additional renal impairment biomarkers are needed.

Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction.

The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.

The impact of genetic risk on the prevalence of advanced fibrosis and cirrhosis in prospectively assessed patients with type 2 diabetes.

Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised. To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines. We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis. Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk. Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction.

Predictors of Non-Variceal Hemorrhage in a National Cohort of Patients With Chronic Liver Disease.

Non-variceal hemorrhage in patients with chronic liver disease (CLD) increases morbidity, mortality, and healthcare costs. There are limited data on risk factors for non-variceal hemorrhage in the CLD population. The aim of this study was to assess the predictive value of various clinical and laboratory parameters for non-variceal hemorrhage in CLD patients. We conducted a retrospective cohort study of US veterans diagnosed with CLD between 2002 and 2018 within the Veterans Health Administration database. We derived candidate variables from existing risk prediction models for hemorrhage, risk calculators for severity of liver disease, Charlson index of prognostic comorbidities, and prior literature. We used a competing risk analysis to study the relationship between putative risk factors and incidence of non-variceal hemorrhage in patients with CLD. Of 15,183 CLD patients with no history of cancer or anticoagulation use, 674 experienced non-variceal hemorrhage within 1 year of CLD diagnosis. In multivariable analysis, 11 of the 26 candidate variables independently predicted non-variceal hemorrhage: race, international normalized ratio (INR) > 1.5, bilirubin ≥ 2 mg/dL, albumin ≤ 3.5 g/dL, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, proton pump inhibitor prescription, and recent infection. In this study of almost 15,000 veterans, risk factors for non-variceal bleeding within the first year after diagnosis of CLD included non-Caucasian race, laboratory parameters indicating severe liver disease and recent infection in addition to the risk factors for bleeding observed in a general non-CLD population.

OS-072-YI Identifying patterns of steatotic liver disease severity: a multiomic analysis of 834 distinct omics features from healthy to end-stage liver disease in 854 individuals

OS-072-YI Identifying patterns of steatotic liver disease severity: a multiomic analysis of 834 distinct omics features from healthy to end-stage liver disease in 854 individuals

Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis.

Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms. We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort. Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm. Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.

THU-058 Portal vein thrombosis increases short-term mortality independent of liver disease severity score among hospitalized patients of decompensated cirrhosis-result from CLEARED consortium

THU-058 Portal vein thrombosis increases short-term mortality independent of liver disease severity score among hospitalized patients of decompensated cirrhosis-result from CLEARED consortium

A deep learning approach for acute liver failure prediction with combined fully connected and convolutional neural networks.

Acute Liver Failure (ALF) is a critical medical condition with rapid development, often caused by viral infections, hepatotoxic drug abuse, or other severe liver diseases. Timely and accurate prediction of ALF occurrence is clinically crucial. However, predicting ALF poses challenges due to the diverse physiological differences among patients and the dynamic nature of the disease. This study introduces a deep learning approach that combines fully connected and convolutional neural networks for effective ALF prediction. The goal is to overcome limitations of traditional machine learning methods and enhance predictive model performance and generalization. The proposed model integrates a fully connected neural network for handling basic patient features and a convolutional neural network dedicated to capturing temporal patterns in patient data. The combination allows automatic learning of complex patterns and abstract features present in highly dynamic medical data associated with ALF. The model's effectiveness is demonstrated through comprehensive experiments and performance evaluations. It outperforms traditional machine learning methods, achieving 94.8% accuracy and superior generalization capabilities. The study highlights the potential of deep learning in ALF prediction, emphasizing the importance of considering individualized medical factors. Future research should focus on improving model robustness, addressing imbalanced data, and further exploring personalized features for enhanced predictive accuracy in real-world clinical scenarios.

The association between serum fructosamine and random spot urine fructose levels with the severity of non-alcoholic fatty liver disease - an analytical cross-sectional study.

Non-alcoholic fatty liver disease (NAFLD) in South Africa and Africa at large is considered a hidden threat. Our local population is burdened with increased metabolic risk factors for NAFLD. Our setting requires a reasonable approach to screen for and aid the diagnosis of NAFLD. To investigate serum fructosamine and random spot urine fructose levels as biomarkers for the screening, diagnosis and monitoring of NAFLD. The primary objective of this study was to compare serum fructosamine and random spot urine fructose levels between groups with different levels of NAFLD severity as measured by ultrasound. A secondary objective was to determine the association, if any, between serum transaminases, the aspartate aminotransferase (AST) to platelet ratio index (APRI) score, serum fructosamine and urine fructose in different groups with steatosis. Using a cross-sectional study design, 65 patients with three different levels of NAFLD, as detected by imaging, were enrolled. The primary exposures measured were serum fructosamine with random spot urine fructose, and secondary exposures were the serum transaminases (AST and alanine aminotransferase (ALT)) and the APRI score. Patients identified at the departments of gastroenterology, general internal medicine and diagnostic radiology were invited to participate. There were 38, 17 and 10 patients with mild, moderate and severe steatosis, respectively. There was no significant difference between the groups regarding serum fructosamine, measured as median (interquartile range): mild 257 (241 - 286) μmol/L, moderate 239 (230 - 280) μmol/L and severe 260 (221 - 341) μmol/L, p=0.5; or random spot urine fructose: mild 0.86 (0.51 - 1.30) mmol/L, moderate 0.84 (0.51 - 2.62) mmol/L and severe 0.71 (0.58 - 1.09) mmol/L, p = 0.8. ALT (U/L) differed between groups: mild 19 (12 - 27), moderate 27 (22 - 33), severe 27 (21 - 56), p=0.03, but not AST (U/L) (p=0.7) nor APRI (p=0.9). Urine fructose and ALT were correlated in the moderate to severe steatosis group (R=0.490, p<0.05), but not in the mild steatosis group. Serum fructosamine was associated with age in the mild steatosis group but not the moderate-severe steatosis group (R=0.42, p<0.01). Serum fructosamine and random spot urine fructose did not vary with the severity of NAFLD, indicating that they would not be useful biomarkers in this condition.

A near-infrared fluorescent probe for differentiating cancer cells from normal cells and early diagnosis of liver cirrhosis

BackgroundCirrhosis represents the terminal stage of liver disease progression and timely intervention in a diseased liver can enhance the likelihood of recovery. Viscosity, a crucial parameter of the cellular microenvironment, is intricately linked to the advancement of cirrhosis. However, viscosity monitoring still faces significant challenges in achieving non-invasive and rapid early diagnosis of cirrhosis. Near-infrared (NIR) fluorescence imaging has the advantages of high sensitivity, non-destructive detection, and ignoring background fluorescence interference, plays an important role in diagnosing and treating various biological diseases. Hence, monitoring cellular viscosity changes with NIR fluorescence probe holds great significance in the early diagnosis of cirrhosis. ResultsIn this study, the NIR fluorescence probe based on the intramolecular charge transfer (TICT) mechanism was developed for imaging applications in mouse model of liver cirrhosis. A molecular rotor-type viscosity-responsive probe was synthesized by linking dioxanthracene groups via carbon-carbon double bonds. The probe demonstrated remarkable sensitivity, high selectivity and photostability, with its responsiveness to viscosity largely unaffected by factors such as polarity, pH, and interfering ions. The probe could effectively detect various drug-induced changes in cellular viscosity, enabling the differentiation between normal cells and cancerous cells. Furthermore, the enhanced tissue penetration capabilities of probe facilitated its successful application in mouse model of liver cirrhosis, allowing for the assessment of liver disease severity based on fluorescence intensity and providing a powerful tool for early diagnosis of cirrhosis. SignificanceA NIR viscosity-sensitive fluorescent probe was specifically designed to effectively monitor alterations in cellular and organ viscosity, which could advance the understanding of the biological characteristics of cancer and provide theoretical support for the early diagnosis of cirrhosis. Overall, this probe held immense potential in monitoring viscosity-related conditions, expanding the range of biomedical tools available.