Liver Disease Research Articles

Echocardiographic evaluation in patient candidate for liver transplant: from pathophysiology to hemodynamic optimization

AbstractCardiovascular complications are common in patients with severe liver disease and are an important cause of peri-operative and post-transplant morbidity and mortality. Cirrhotic cardiomyopathy (CCM), often found in advanced liver disease, is characterized by diastolic dysfunction, systolic dysfunction, and electrophysiological abnormalities. While CCM may not cause symptoms at rest, it can become evident during stressful activities, such as surgery. Liver transplantation, while being the definitive treatment for end-stage liver disease (ESLD), carries significant cardiovascular risks. Preoperative cardiac evaluation is essential for assessing these risks and planning appropriate management. Cardiac imaging, particularly echocardiography, plays a crucial role in evaluating liver transplant candidates, helping to identify conditions such as CCM, pulmonary hypertension, hepatopulmonary syndrome, and others. Currently, liver transplant anesthetists must acquire echocardiographic knowledge and skills to evaluate the cardiocirculatory conditions of the transplanted patient, especially in the pre-operative phase, but also intra-operatively and post-operatively.

Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al ’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

Trends in Hospitalizations and Liver Transplants Associated With Alcohol-Induced Liver Disease

This study investigates trends in hospitalization and liver transplant rates in the US from 2005 to 2021 associated with alcohol-induced liver disease.

Association Between Fatty Liver Index and Incidence of Cataract Surgery in Individuals Aged 50 Years and Older Based on the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) Data: Longitudinal Retrospective Cohort Study

Abstract Background Cataract is a leading cause of vision impairment. Obesity-related risk factors, including insulin resistance, increase the risk of cataract. The fatty liver index (FLI) is a biomarker for noninvasive fat layer prediction of nonalcoholic fatty liver disease. The FLI has been used to evaluate the metabolic contribution in other organs besides the eye. However, no study exists on the FLI and eye disease. Objective This retrospective cohort study for the association between the FLI and incidence of cataract surgery in individuals older than 50 years was designed to show that a higher FLI is associated with an increased incidence of cataract surgery in individuals aged 50 years and older. Methods This study was retrospectively designed based on the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) cohort (median follow-up of 9.8 years). Participants were assigned to 1 of 3 groups based on the FLI: low (FLI<30), intermediate (FLI 30-59), or high (FLI≥60). Kaplan-Meier survival analysis was performed on the cumulative incidence of all-cataract and senile-cataract surgery. Multivariable Cox proportional hazards regression models were used to study the association between the FLI group and cataract surgery after adjusting for potential confounders. Results Of the 138,347 included participants, the incidence of cataract surgery was 12.49% (4779/38,274), 13.95% (6680/47,875), and 14.16% (7496/52,930) in the low, intermediate, and high FLI groups, respectively. After adjusting for all confounding factors, hazard ratios (HRs; 95% CIs) in the high FLI group for all-cataract surgery were 1.111 (1.028‐1.199) and 1.184 (1.101‐1.274) in men and women, respectively, when compared with the low FLI group. HRs (95% CIs) in the high FLI group for senile-cataract surgery were 1.106 (1.022‐1.197) and 1.147 (1.065‐1.237) in men and women, respectively, when compared with the low FLI group. The project was conducted between August 2023 and February 2024 without donations from external bodies. Conclusions Individuals with a higher FLI had a higher risk of all-cataract surgery. This association was maintained even after limiting the analyses to senile-cataract surgery.

The effect of folate deficiency and different doses of folic acid supplementation on liver diseases

Abstract Liver has multiple functions such as detoxification, metabolism, synthesis and storage. Folate is a water-soluble vitamin B9, which participates in one-carbon transfer reactions, maintains methylation capacity, and improves oxidative stress. Folic acid is a synthetic form commonly used as a dietary supplement. The liver is the main organ for storing and metabolizing folate/folic acid, and the role of folate/folic acid in liver diseases has been widely studied. Deficiency of folate results in methylation capacity dysfunction and can induce liver disorders. However, adverse effects of excessive use of folic acid on the liver have also been reported. This review aims to explore the mechanism of folate/folic acid in different liver diseases, promote further research on folate/folic acid, and contribute to its rational clinical application.

Abstract A068: Evaluate the performance of FibraChek™ for non-invasive detection of hepatic fibrosis and hepatocellular carcinoma

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD), fibrosis, and cirrhosis are risk factors for hepatocellular carcinoma (HCC). Blood-based assays to date have limited accuracy for detecting MASLD and cirrhosis, and thus have not been widely adopted in the clinical setting. The identification and validation of a multiplex molecular signature associated with liver disease may address this unmet need. This prospective single-center US study evaluated the performance of the non-invasive Liver FibraChek Dx serum assay for detecting MASLD. The study algorithm analyzes weighted values of five serum biomarkers (AST, ALT, taurocholic acid, L-tyrosine, and platelet count) plus age to derive a risk score. Samples comprised 14 MASLD cases, 19 HCC cases, and 12 healthy controls. Liver status was confirmed by tissue biopsy. Wilcoxon rank sum tests determined the association between the risk score and confirmed liver histology. Diagnostic performance was assessed using ROC curves. The probability of identifying MASLD and/or HCC by Liver FibraChek Dx, in conjunction with other patient parameters, was demonstrated by an AUROC of 0.890 (95% CI: 0.776-1.000), with 93.9% sensitivity, 75.0% specificity, 91.1% positive predictive value, 81.8% negative predictive value, and 88.9% accuracy. Risk scores associated with the biomarker panel enabled accurate discrimination of liver disease from healthy controls. The non-invasive multiplex Liver FibraChek Dx test can effectively and accurately detect and classify hepatic fibrosis risk in peripheral blood samples and may have utility in diagnosing and monitoring liver pathogenesis. Citation Format: Fernando Siguencia, Michitaka Matsuda, Vijay Pandyarajan, Sunao Tanaka, Steven M Smith, Ekihiro Seki, Charles J Rosser, Hideki Furuya. Evaluate the performance of FibraChek™ for non-invasive detection of hepatic fibrosis and hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A068.

Identification of risk factors associated with metabolic dysfunction-associated steatotic liver disease in psoriatic patients

Introduction. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common cause of chronic liver disease. Patients suffering from psoriasis are at an increased risk of developing MASLD. Psoriasis and MASLD share a pro-inflammatory cytokine milieu, however it is still unclear whether these conditions are related through shared metainflammatory processes or shared comorbidities such as obesity, diabetes, insulin resistance and metabolic syndrome. The aim of our study was to better characterise the anthropometric and metabolic profile of psoriatic patients with MASLD. Methods. We conducted a prospective, single centre, cross-sectional study between June 2014 and August 2017. Recruitment was restricted to adult patients with psoriasis. Blood analysis, liver ultrasonography and a fibroscan were performed. Blood investigations, baseline anthropometric measurements and components of fatty liver disease (hepatic ultrasound, fibroscan) were assessed. Results. 100 patients were recruited. Of which, 43% (65.1% men, n=28) were diagnosed with MASLD. The mean body mass index (BMI) was significantly higher in MASLD than in non-MASLD (27.7kg/m2 vs 30.1kg/m2, p=<0.001). The mean waist circumference in MASLD patients was significantly higher than in non-MASLD patients (105.6cm vs 97.2cm, p=0.005). There was no significant difference between the mean age of both patient groups (50.4 vs 47.3 years, p=0.26). Psoriatic arthritis was more prevalent in MASLD than in the non-MASLD group (14.3% vs 1.8%, p=0.004). Biochemical analysis revealed significantly higher C-peptide level in patients with MASLD compared with patients without MASLD (2.5 vs 1.6ng/ml, p=0.036). Moreover, MASLD patients were found to have a lower HDL level and higher glycemia, triglyceridemia, cholesterol and LDL levels than non-MASLD patients. 16.3% of patients with MASLD had fibrosis stage ranging from F2 to F4 based on liver stiffness measurement compared with only 10.6% of patients without MASLD. Discussion. We identified parameters which were more prevalent in patients with psoriasis having MASLD, specifically a high BMI, elevated triglycerides levels, decreased HDL levels and an elevate level of C-peptide. Patients with psoriasis and MASLD were more likely to suffer from co-morbid psoriatic arthritis, despite having similar psoriasis disease severity as measured by PASI. Conclusion. This study highlights the importance of screening patients with psoriasis for MASLD to prevent the progression to liver fibrosis.

Non-invasive testing in metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease, affecting up to 30% of the global population. MASLD is strongly associated with metabolic risk factors such as obesity and type 2 diabetes, and can progress to advanced stages including cirrhosis and hepatocellular carcinoma. Early diagnosis and accurate staging of fibrosis are critical in managing the disease and preventing complications. While liver biopsy has long been considered the gold standard for assessing fibrosis, it is invasive and carries associated risks. In response, non-invasive tests (NITs) have emerged as essential alternatives for the diagnosis and monitoring of MASLD. Key methods include blood-based biomarkers such as the Fibrosis-4 (FIB-4) score, NAFLD Fibrosis Score (NFS), and Enhanced Liver Fibrosis (ELF) test, as well as imaging modalities like vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE). These tests provide safer, more accessible methods for identifying liver fibrosis and guiding clinical management. They are integral in assessing disease severity, guiding treatment decisions, and monitoring disease progression, particularly in light of emerging therapies. NITs have become increasingly recommended by clinical guidelines as they reduce the need for invasive procedures like liver biopsy, improving patient care and outcomes. In conclusion, non-invasive testing plays a crucial role in the effective management of MASLD, offering reliable alternatives for diagnosis and monitoring while minimizing risks associated with traditional invasive methods.

Laparoscopic access is the modern standard for extended liver resection

Objective. To evaluate the safety and early results of laparoscopic extended liver resection in case of focal liver pathology by retrospective comparison with the relevant parameters of a similar open intervention. Materials and methods. The study involved 162 patients who were divided into two groups: Group 1 – 50 patients who underwent laparoscopic extended liver resection, and Group 2 – 112 patients who underwent open extended liver resection. The groups were compared by age structure, sex, body mass index, type of pathology (benign/malignant), as well as by characteristics of surgical intervention and postoperative period. Statistical analysis included a t–test for independent samples, Pearson's chi–square test, and other appropriate methods with the calculation of the confidence level p (parametric criterion). The difference in indicators was considered statistically significant at p < 0.05. Results. Laparoscopic osshire for liver resection was longer (p = 0.0012), but was associated with a lower level of pain according to the visual analog scale (p = 0.02) and fewer bed days to discharge (p = 0.0007) than a similar open intervention. There was no statistically significant difference between the groups in terms of age structure, body mass index, number of liver tumors, blood loss, complication rate, and degree of ischemic liver damage. Conclusions. Laparoscopic extended liver resection is a less invasive method than open liver resection, and patients recover faster after it, although its duration is longer. At the same time, laparoscopic and open intervention had a similar incidence of complications, which indicates acceptable safety and high clinical efficacy of the laparoscopic approach in the treatment of patients with liver disease.

The Impact of Sira Vedha (Phlebotomy) at the Right Elbow Joint in the Treatment of Non-Alcoholic Fatty Liver Disease - A Research Report

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) affects 9%–53% of the Indian population. No Indian studies have examined Sira Vedha (phlebotomy) for NAFLD, although it has been studied for other conditions. Sushruta recommended Sira Vedha at the right elbow joint for liver diseases, but clinical evidence for its efficacy in NAFLD is lacking. This clinical trial aimed to generate evidence for Sira Vedha in NAFLD patients. One hundred eleven patients with Grade I/II NAFLD were randomly assigned to either a control group (diet and exercise) or an intervention group (Sira Vedha, diet, and exercise). Blood samples were collected for lipid profile and liver function tests before and after treatment. Results showed significant improvements in SGOT, SGPT, cholesterol, HDL, and triglyceride levels in the intervention group compared to the control group, supporting the efficacy of Sira Vedha in NAFLD treatment. This study highlights the need for clinical evidence to confirm traditional Ayurvedic practices.

Accuracy of International Guidelines in Identifying Normal Liver Histology in Chinese Patients With HBeAg‐Positive Chronic HBV Infection

ABSTRACTWe evaluated the diagnostic accuracy of various international guideline criteria for identifying HBeAg‐positive chronic HBV infection patients with no significant liver disease. A total of 1108 HBeAg‐positive CHB patients were retrospectively enrolled. The guidelines assessed included those from the European Association for the Study of the Liver (EASL) 2017, the American Association for the Study of the Liver Disease (AASLD) 2018, the Asian Pacific Association for the Study of the Liver (APASL) 2015 and the Chinese Society of Hepatology (CSH) 2022. The CSH criteria demonstrated a higher proportion of patients with G0‐1 and S0‐1 (82.9%) compared to the EASL (75.9%), AASLD (75.3%) and APASL groups (58.8%). Additionally, the CSH criteria exhibited a significantly higher predictive value (AUC 0.782, 95% CI 0.754–0.809) than the EASL (AUC 0.765, 95% CI 0.737–0.793), AASLD (AUC 0.749, 95% CI 0.720–0.778) and APASL (AUC 0.720, 95% CI 0.690–0.750) criteria for identifying G0‐1 and S0‐1. Adding quantitative HBsAg levels (> 104 IU/mL) to the EASL, AASLD and APASL criteria improved diagnostic performance. Consequently, the CSH guideline thresholds showed higher accuracy in identifying Chinese HBeAg‐positive patients with no significant liver disease compared to EASL, AASLD and APASL criteria, emphasising the importance of considering quantitative HBsAg in the evaluation of HBeAg‐positive chronic HBV infection.

Favorable inhibitory effect of clodronate on hepatic steatosis in short bowel syndrome model rats

Abstract Purpose This study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS). Methods The rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20 mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60 mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed. Results Hepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups. Conclusion The high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS.

Molecular Insights into The Replication and Pathogenesis of Hepatitis C Virus

Hepatitis C virus (HCV) is a major infectious disease problem worldwide, resulting in serious liver disease, including cirrhosis and hepatocellular carcinoma. This review article acts as a general overview of molecular aspects of HCV replication and pathogenesis emphasizing the virus structure and genome, entry mechanisms, the replication cycle, and HCV interactions with the host immune system. It also examines the progression of disease causing HCV infections and the clinical symptoms. Antiviral treatments have improved patient outcomes, but they remain far from an effective vaccine, because viral diversity, lack of access to health care, remain. Research in the future should look to increase healthcare accessibility, to understand long term outcomes after treatment, and to develop the vaccine. Solution to these challenges will enable us to diminish the worldwide burden of HCV and better patient health results.

HPB SO20 - Evaluating the Impact of Enhanced Recovery After Surgery Protocols Post Hepatectomy in Patients with Chronic Liver Disease: A Meta-Analysis

Abstract Background Defined criteria for the resectability of liver disease continue to be refined. In the era of enhanced recovery after surgery (ERAS), data regarding its safety and efficacy in specific patient populations is required. Patients with liver cirrhosis are particularly vulnerable, owing to both operative and peri-operative risk. However, the application of ERAS in cirrhotic patients undergoing hepatectomy is absent from the most recent ERAS Society Group recommendations from 2022. We present a meta-analysis assessing outcomes after liver resection in patients with cirrhosis following an ERAS protocol compared to standard post-operative care. Method A systematic literature search was performed using PubMed, Embase and Web of Science. Studies were included if comparing ERAS protocols versus standard post-operative care in patients undergoing liver resection in which more than 50% of the patient population had cirrhosis at time of surgery. The primary outcome analysed was overall complication rates with secondary outcomes of post-operative mortality, estimated blood loss, operation time, post-operative incidence of liver failure, readmission and reoperation rates. Statistical analysis was performed using Review Manager by the Cochrane Collaboration. Results 930 records were screened for eligibility. Five articles were eligible for inclusion(ERAS n = 425 vs control group n = 423 patients). Cirrhotic patients enrolled in an ERAS program post-hepatectomy had a significantly reduced risk of overall complications (OR 0.45, 95% CI 0.33, 0.61, p<0.00001) and a shorter hospital stay when compared to standard post-operative care by 1.8 days (mean difference -1.83, 95% CI -2.22, -1.45, p<0.00001). No significant differences were noted in post-operative mortality, estimated blood loss, operation time, post-operative incidence of liver failure, readmission or reoperation rates between the ERAS group and control. Conclusion Application of an ERAS protocol for patients undergoing liver resection is safe and feasible in cirrhotic patients. ERAS protocols were successful in significantly reducing overall complication rates and length of inpatient hospital stay, and did not negatively impact secondary post-operative outcomes or mortality. ERAS protocols should be reflected in future guidelines, specifically for cirrhotic patients undergoing hepatectomy, and additional research on the utility of ERAS in higher risk patients is encouraged.

Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy response

The conceptual evolution of non-alcoholic fatty liver disease (NAFLD) to what, since 2023, is called metabolic dysfunction-associated steatotic liver disease (MASLD) not only represents a change in the classification and definition of the disease but also reflects a broader understanding of this heterogeneous condition, which still with many aspects to refine. Although the definition of NAFLD can be interchanged to a high percentage with the new MASLD concept in different aspects, MASLD has been proposed as a relevant factor that influences the response to new immunotherapeutic treatments in the management of MASLD-related hepatocellular carcinoma (HCC), compared to HCC of other etiologies. This indicates that the etiology of HCC plays a relevant role in the prognosis, highlighting the urgency of evaluating treatment regimens for this subgroup of patients in upcoming clinical trials. A better understanding of the pathophysiology of MASLD generates strategies that not only aid in its management but also provide strategies to directly intervene in the carcinogenesis of HCC.

Microvesicle-Shuttled microRNA-130b Activates the Hepatic Inflammation by Inhibiting Glucocorticoid-Receptor-Mediated Immunosuppression in High-Fat Diet-Induced Obese Mice

Metabolism-disorder-induced liver diseases have become increasingly prevalent worldwide and are clinically linked to obesity and type 2 diabetes. In addition, a large number of previous literature studies have indicated that plasma miR-130b is a promising biomarker for the early diagnosis and treatment of obesity. However, whether miRNA-130b that was positively correlated with obesity resulted in hepatic inflammation needs to be further studied. Therefore, the study aims to determine the effect of microvesicle-shuttled miRNA-130b (miR-130b-MV) on the hepatic inflammation and its potential mechanism in high-fat diet-induced obese mice. Three-week-old C57BL/6 mice were fed a high-fat diet for eight weeks. Then, the obese mice received tail vein injections of MV-packaged scrambled control microRNA (miR-SC-MV) or miR-130b-MV every other day for 10 days. Compared with the control group, the miR-130b-MV injection significantly reduced the body weight while increasing the ratio of liver wet weight to total body weight. In addition, the miR-130b-MV injection significantly activated the hepatic inflammation by increasing the expression of proinflammatory genes, although the plasma concentrations of IL-6 and TNF-α were only slightly increased. Furthermore, the miR-130b-MV injection significantly increased the hepatic miR-130b expression while significantly suppressing the protein expression and phosphorylation of GR, a potential target of miR-130b. Moreover, the miR-130b overexpression results in a decrease in the expression of endogenous GR protein and a decrease in the activity of the luciferase reporter of GR 3′-UTR. In addition, the miR-130b-MV injection significantly upregulated NF-kB (p50) in both the cytoplasm and nucleus, showing enhanced proinflammation response. The above results demonstrated that miR-130b-MV activated the hepatic inflammation by inhibiting GR-mediated immunosuppression in high-fat diet-induced obese mice, suggesting a novel mechanism underlying the obesity-induced hepatic inflammation, and the inhibition of miR-130b may serve as a new molecular therapeutic target for the prevention and treatment of hepatic inflammation.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer’s disease

AbstractAlzheimer’s disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients’ quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA’s imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer’s disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Complete inhibition of liver acetyl-CoA carboxylase activity is required to exacerbate liver tumorigenesis in mice treated with diethylnitrosamine

Abstract Background The metabolic pathway of de novo lipogenesis (DNL) is upregulated in fatty liver disease and liver cancer. Inhibitors of DNL are in development for the treatment of these disorders; however, our previous study showed that blocking DNL unexpectedly exacerbated liver tumorigenesis when liver acetyl-CoA carboxylase (ACC) 1 and 2 enzymes were deleted in mice treated with diethylnitrosamine (DEN) and fed high fat diet. Herein, we used 3 new approaches including ACC1 vs. ACC2 isotype-selective inhibition, delaying ACC inhibition until after carcinogen treatment, and feeding mice normal chow diet to better understand the impact of ACC inhibition on liver tumorigenesis. Methods Six genotypes of female C57BL/6J mice with floxed ACC1 and/or ACC2 alleles were injected with DEN at 2 weeks of age followed by liver-specific knockout of ACC genes at 9 weeks. Mice were fed a normal chow diet and evaluated at 52 weeks for liver tumours. Results Compared to the wildtype control group, no genotype decreased tumour multiplicity or burden; however, mice completely lacking liver ACC1 and ACC2 had > 5-fold increases in liver tumour multiplicity and burden. Conclusion ACC inhibition exacerbated DEN-induced liver tumorigenesis only when both ACC isotypes were completely inhibited. The pro-tumour phenotype of ACC inhibition was strongly reproducible irrespective of chow or high fat feeding, and irrespective of ACC inhibition prior to or after DEN treatment. Retaining partial ACC activity at either isotype prevented tumour exacerbation in mice at risk for developing liver tumours.

HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via non-canonical phosphorylation

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. Approach and Results: Herein, we identified Cyclin-dependent kinase like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis and diabetes. Mechanism-wise, CDKL3 directly phosphorylates FoxO1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of HNF4α. HNF4α is inhibited during MASLD, which led to diminished CDKL3 expression. The CDKL3-mediated crosstalk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.

HPB SO64 - Outcomes of liver resection for hepatocellular cancer with or without liver functional assessment using Tc 99m Mebrofenate SPECT-CT, portal pressures: A comparative study

Abstract Background Presence of background liver disease increases the post operative morbidity and mortality among patients undergoing liver resection for hepatocellular carcinoma (HCC). These patients need evaluation of background liver function and portal hypertension, in addition to the conventional risk assessment. The current study aims to look at the outcomes of liver resections performed for HCC cases comparing cohorts with conventional risk assessment (CA) and those with functional assessment (FA) of background liver. Method A retrospective study including all liver resections for HCC cases performed in our tertiary care hepatobiliary unit between 2013 and 2022 (10 years) was conducted. A pathway for liver functional assessment using Tc 99m Mebrofenate SPECT-CT, and portal pressures (cut-off values of 2.79/min/m2 and 10mmHg, respectively) was included in the departmental protocol in December 2018. Data on demographics, underlying degree of liver cirrhosis, types of liver resection and post-operative outcomes including post-hepatectomy liver failure (PHLF) were collected and reported using descriptive statistics. Results 200 liver resections, performed for HCC between 2013 and 2022, were divided into a conventional (126 patients) and functional (74 patients) assessment groups. Median age (68 years) was similar. Background liver cirrhosis was present in 27 (21%) vs 19 (26%) cases, and major resections were performed in 47 (37%) and 10 (13%) cases in the CA and FA groups respectively. In the CA group, 90-day mortality was 7% (compared to FA group (1%) (p=0.26). None of the patients in FA group was found to have PHLF whereas 3 patients each had PHLF grade B and C in the conventional group. Conclusion Formal functional assessment of the background liver by evaluating the function of future liver remnant and presence of portal hypertension helps in selection of patients for appropriate surgical treatment options and improve the post-operative outcomes.