Cause Of Liver Disease Research Articles

Role of Vitamin D Supplementation with Liv-52 on Inflammatory Biomarkers in Carbon Tetrachloride (Ccl4) Induced Liver Disease in Wister Rats

Introduction: Liver disease is a significant global health concern, with a wide range of etiologies and adverse effects on overall health. Among the various causes of liver disease, exposure to hepatotoxins such as carbon tetrachloride (CCl4) has been widely studied. Inflammatory processes play a crucial role in the development and progression of liver disease. Inflammatory biomarkers, serve as important indicators of liver injury and can provide insights into the underlying inflammatory response. Therefore, identifying effective interventions that can modulate these inflammatory biomarkers holds great promise for the management of liver disease. The goal of the current study was to examine the anti-inflammatory effects of vitamin D combined with Liv-52 on liver disease caused by CCl4. Materials and Methods: Male Wistar rats were given CCl4, twice a week for nine weeks, Liv-52 (1 mL/kg b.w), and vitamin D (500 IU/kg b.w) orally for nine weeks. The effects of vitamin D supplementation along with Liv-52 on inflammatory markers were estimated in the serum samples. Results: When compared to control animals, it was discovered that the hepatotoxic carrying animals had higher serum concentrations of IL-6, TGF-β and TNF-α. Supplementation of vitamin D (group III) and Liv-52 (group IV) treated rats showed significantly reduced the levels of IL-6, TGF-β and TNF-α when compared with group II animals. The supplementation with combination of vitamin D and liv-52 more significantly reduced the levels of IL-6, TGF-β and TNF-α. The comparative analysis between group III vs IV, the protective function of vitamin D in-isolation is similar to the protection by Liv-52 in-isolation, there is no marker difference between the two and both have significant protection effect. Conclusion: The results obtained indicate that the combination of vitamin D supplementation and Liv-52 exhibited beneficial effects on inflammatory biomarkers in CCl4-induced liver disease.

Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

Saroglitazar in Non-alcoholic Fatty Liver Disease From Bench to Bedside: A Comprehensive Review and Sub-group Meta-Analysis.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common causes of liver diseases globally, with a projected exponential rise.In contrast to the exponential rise in disease burden, there are limited options in the pharmacotherapeutic armamentarium against NAFLD. Saroglitazar belongs to the class of drugs known as peroxisome proliferator-activated receptor (PPAR) agonists, initially introduced for managing diabetic dyslipidemia. However, based on translational and clinical studies, it has been shown to be efficacious in NAFLD. It has been shown to modify key parameters in NAFLD, including reduction of transaminase levels, improvement in overall metabolic health, reduction of liver fat content, and improvement of liver stiffness and histology. Given the promising results, it has been made a part of society's guidelines in the therapeutic management of NAFLD. However, there remains a dearth of detailed reviews encompassing both pre-clinical and clinical data on the effectiveness of saroglitazar in NAFLD. In this review, we comprehensively review the pharmacology, pre-clinical data, and clinical studies on saroglitazar usage in NAFLD and conduct a subgroup meta-analysis of studies focussing on the impact of saroglitazar on liver stiffness changes.

FRI661 Assessing The Current State Of Screening And Managementof Non-alcoholic Fatty Liver Disease In An Academic Endocrinology Clinic

Abstract Disclosure: K.M. Myers: None. C.D. Hendrickson: None. Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease and the second most common cause of liver failure leading to transplantation. NAFLD is strongly associated with factors of metabolic syndrome including diabetes mellitus (DM), with which it shares a strong bi-directional relationship. Up to 70% of patients with DM also have NAFLD, and DM is a risk factor for higher rates of NAFLD progression leading to steatohepatitis, fibrosis and cirrhosis. In September 2021, the American Gastroenterological Association published recommendations including endocrinology in the screening and management of NAFLD patients. Screening for NAFLD involves computing a FIB-4 score to risk-stratify patients into low, intermediate or high risk of having liver fibrosis. The FIB-4 score is calculated using patient age, AST, ALT and platelet count. Further management is determined by the level of risk identified, with some indeterminate-risk and all high-risk patients needing referral to hepatology clinic. Methods: Deidentified patient data was abstracted from an electronic health record registry associated with a large academic medical center. Patient qualifiers included: age over 18 years, diagnosis of type 2 DM, a prior visit within 5 years at one of two endocrinology clinic locations and having a primary care physician associated with the system. Of these patients, lab data was obtained for AST, ALT and platelet count. Additionally, the presence or absence of a prior hepatology clinic encounter was assessed. Two endocrinology clinics were analyzed, including one clinic at the main hospital campus and a second, smaller clinic located in an adjacent county. Results: Within the larger clinic, 16,398 patients met the above criteria; however, only 1797 (11.0%) had all lab components evaluated within 5 years to calculate a FIB-4 score, largely due to only 11.3% of total patients having platelet count data available. Of patients with a FIB-4 score, 342 had a score over 2.67, indicating high-risk for liver fibrosis. Of these 342 patients, 181 (53.0%) had an associated hepatology visit. Within the smaller clinic, 3844 patients met the above criteria; however, only 1055 (274%) had all lab components evaluated within 5 years to calculate a FIB-4 score, again largely due to only 30.0% of total patients having platelet count data available. Of the patients with a FIB-4 score, 148 had a score ≥ 2.67, indicating high-risk for liver fibrosis. Of these 148 patients, 47 (31.8%) had an associated encounter with hepatology. Conclusion: This study highlights a need for improved screening and risk-stratification of diabetic patients for NAFLD, including the increased awareness of screening with appropriate lab evaluation and subsequent referral to hepatology when appropriate. Presentation: Friday, June 16, 2023

ASPP2 binds to hepatitis C virus NS5A protein via an SH3 domain/PxxP motif-mediated interaction and potentiates infection.

Hepatitis C virus (HCV) infects millions of people worldwide and is a leading cause of liver disease. Despite recent advances in antiviral therapies, viral resistance can limit drug efficacy and understanding the mechanisms that confer viral escape is important. We employ an unbiased interactome analysis to discover host binding partners of the HCV non-structural protein 5A (NS5A), a key player in viral replication and assembly. We identify ASPP2, apoptosis-stimulating protein of p53, as a new host co-factor that binds NS5A via its SH3 domain. Importantly, silencing ASPP2 reduces viral replication and spread. Our study uncovers a previously unknown role for ASPP2 to potentiate HCV RNA replication.

Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women

Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P < 10−10; advanced fibrosis/hepatocellular carcinoma, P = 0.034) and in the general population (P < 10−7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR–Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.

Overall and subgroup prevalence of non-alcoholic fatty liver disease and prevalence of advanced fibrosis in the United States: An updated national estimate in National Health and Nutrition Examination Survey (NHANES) 2011-2018

Introduction and ObjectivesData on the prevalence of non-alcoholic fatty liver disease (NAFLD) in subgroups of the United States (US) population are limited. This study was conducted to estimate NAFLD prevalence overall and by subgroups, and prevalence of NAFLD with advanced fibrosis. Materials and MethodsUsing the National Health and Nutrition Examination Survey (NHANES) 2011-2018 data, a cross-sectional study was conducted. NAFLD was defined as having a US Fatty Liver Index (USFLI) ≥ 30 in the absence of other causes of liver disease, including excessive alcohol intake, chronic hepatitis B, and chronic hepatitis C. Likelihood for having advanced fibrosis was determined by the calculated NAFLD fibrosis score (NFS; high ≥ 0.676; low < −1.445) and fibrosis-4 index (FIB-4; high ≥ 2.67; low < 1.30). ResultsThe weighted national prevalence of NAFLD in US adults was 26.7% (95% confidence interval: 25.3%-28.1%). Prevalence was higher among those aged ≥ 65 years, males, Mexican Americans, with BMI ≥ 35 kg/m2 (class 2 and 3 obesity) and with type 2 diabetes (T2D). Of those meeting the USFLI criterion for NAFLD, 18.1% and 3.7% were determined as having a high probability of advanced fibrosis based on NFS ≥ 0.676 and FIB-4 ≥ 2.67 cut-off values, respectively. ConclusionsThis study supports an increased prevalence of NAFLD in specific subpopulations (aged ≥ 65 years, males, Mexican Americans, obese population, and patients with T2D). The observed difference in the prevalence of advanced fibrosis as estimated by NFS and FIB-4 highlights the challenge of choosing optimal cut-off values.

A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies.

As screening for the liver disease and risk-stratification pathways are not established in patients with type-2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost-utility of different screening strategies for MASLD in the community. Consecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score-4 (FIB-4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality-adjusted life year (QALY) gained and calculated the incremental cost-effectiveness ratio (ICER) over a lifetime horizon. Of 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB-4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB-4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost-utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB-4. Screening for MASLD in the diabetic population in primary care is cost-effective and should become part of a holistic assessment. However, traditional screening strategies, including FIB-4 and ELF, underestimate the presence of significant liver disease in this setting.

Roles of Herbals in Paracetamol Induced Hepatotoxicty

In the area of herbal medicine, this has led to a great deal of research and development. In the majority of industrialized and developing nations today, there is a rising need for herbal medicine. The most common form of liver disease varies by country and may be impacted by local factors. Infection with viruses and exposure to specific chemicals are two causes of liver diseases. Herbal medications have the potential to be an effective treatment for liver problems. An extensive review of the literature on hepatoprotective plants clearly shows that herbal medications have significant promise for the treatment of liver ailments. It is difficult to find effective treatments for common liver conditions such as cirrhosis, fatty liver, and chronic hepatitis. There aren't many therapeutic drugs that work well and rarely cause side effects. Few plants can effectively treat liver disorders, so there is a lot of interest in researching the many plant therapies that can help with liver diseases. As a result, we conclude that herbs are an important source of hepatoprotective and liver regeneration drugs. More study is needed, however, to identify, characterize, and standardize the active substances, beneficial compounds, and formulations for the treatment of liver illnesses. The availability of modern hepatoprotective medications with realistic clinical utility is still quite restricted, and the discovery of new compounds with similar potentials will undoubtedly encourage the drug discovery process.&#x0D; Keywords: Herbal Medicine, Hepatotoxicity, Hepatoprotective, Antioxidant Activities

Corrected and republished from: Metabolic associated liver disease.

Alcohol consumption (AC) and metabolic syndrome (MS) represent the first cause of liver disease, hepatocellular carcinoma and liver transplantation. The habit of consuming alcoholic beverages and the presence of MS and non-alcoholic fatty liver disease (NAFLD) often coexist in the same patient. The histoclinical boundaries between alcohol related liver disease (ALD) and NAFLD are often not well defined. The co-presence of AC and MS increases the risk of hepatic and extra-hepatic disease. The terminological evolution from NAFLD to metabolic associated fatty liver disease (MAFLD) is certainly a useful advance. However, it is known that the appearance of liver fibrosis increases oncologic and cardiovascular disease risk, which in the case of cirrhosis can be present even in the absence of steatosis and that the mechanisms of fibrogenesis can act independently of the presence of steatosis/steatohepatitis. For this reason, as already stated recently, a further terminological evolution can be hypothesized. This article was originally published with mistakes in the text. The new corrected citable version appears below.

Chronic Hepatitis B Finite Treatment: Similar and Different Concerns With New Drug Classes.

Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.

Fibro-scan Based Score and Novel Noninvasive Serum Marker, FGF-21, to Assess Liver Fibrosis in Morbidly Obese Patients with Nonalcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of liver disease in the Western world, affecting up to 20-30% of the general adult population. It is a growing public health problem, because of the increasing prevalence of the pathologies that contribute to its development such as obesity and inflammation status. Aim of the Work This prospective cohort study aims to develop and validate noninvasive scoring system for assessment liver fibrosis in morbidly obese patients with NAFLD. Subjects and Methods This is a Prospective cohort study, was carried out on 50 morbidly obese patients selected from endocrinology department, AIN SHAMS UNIVERSITY, through a period of six months. Results The main results of the study revealed that: There were 32(64.0%) male and 18(36.0%) female with mean age 40.48 (± 12.16) SD. There were 14(28.0%) between (20 -30), 11(22.0%) between (30-40), 9(18.0%) between (40-50) and 16(32.0%) ≥50. Mean Weight (Kg) was 106.6 (± 13.31) SD with range (82.50 – 145.5), mean Height (Cm) was 171.7 (± 6.25) SD with range (158.0 – 185.0), mean BMI (Kg/m2) was 36.17 (± 4.15) SD with range (29.30 – 43.40), mean Waist circumference 113.1 (± 8.64) SD with range (92.0 – 129.0). There were 37(74.0%) with Comorbidity. 10(20.0%) have DM, 11(22.0%) have HTN, 11(22.0%) have CDK and 5(10.0%) have COPD. mean Hb was 12.24 with range (11.0 – 13.50), mean Plts was 193.2 with range (151.0 – 250.0), mean WBCs with range (4.70 – 8.20), mean AST was 85.20 with range (21.0 – 210.0), mean ALT was 86.64 with range (15.0 – 212.0), mean Cholesterol was 181.4 with range (122.0 – 248.0), mean Triglycerides was 156.3 with range (12.0 – 294.0), mean LDL was 119.1 with range (61.0 – 193.0), mean HDL was 61.32 with range (23.0 – 96.0), mean GGT (U/l) was 18.22 with range (7.0 – 33.0), mean HBA1C was 5.72 with range (4.70 – 9.30), mean Fasting blood sugar was 101.8 with range (81.0 – 155.0) and mean Uric acid was 6.23 with range (4.0 – 10.10). Regarding ultrasound outcome there were 33(66.0%) have Gallbladder wall blurring, 34(68.0%) have Portal vein wall blurring, 42(84.0%) have Hepatic vein blurring and 50 (100.0%) have fatty liver. Regarding fibrosis grade there were 12(24.0%) F1, 17(34.0%) F2, 18(36.0%) F3 and 3(6.0%) F4. Conclusion That the combination of Fibroscan and, APRI, FGF-21 and FIB-4 methods provides a valuable approach for assessing liver fibrosis in NAFLD patients. This can eliminate the need for liver biopsy in patients without clear indication. In addition, several recent studies have also validated the used of non-invasive markers in the diagnosis of NAFLD. The establishment of a national program for the recognition of NAFLD is therefore essential to reduce the risk of liver disease progression.

The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are the leading causes of chronic liver disease worldwide. NAFLD and ALD share pathophysiological, histological and genetic features and bothalcohol and metabolic dysfunction coexist as aetiological factors in many patientswith hepatic steatosis. A diagnosis of NAFLD requires the exclusion of significant alcohol consumption and other causes of liver disease. However, data suggest that significant alcohol consumption is often under-reported in patients classified as having NAFLD and that alcohol and metabolic factors interact to exacerbate the progression of liver disease. In this Review, we analyse existing data on the interaction between alcohol consumption and metabolic syndrome as well as the overlapping features and differences in the pathogenesis of ALD and NAFLD. We also discuss the clinical implications of the coexistence of alcohol consumption, of any degree, in patients with evidence of metabolic derangement as well as the use of alcohol biomarkers to detect alcohol intake. Finally, we summarize the evolvingnomenclature of fatty liver disease and describe a recent proposal to classify patients at the intersection of NAFLD and ALD. We propose that, regardless of the presumed aetiology, patients with fatty liver disease should be evaluated for both metabolic syndrome and alcohol consumption to enable better prognostication and a personalized medicine approach.

Prevalence of Nonalcoholic Fatty Liver Disease in Hypothyroid Subjects: A Cross-sectional Comparative Study

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. NAFLD has become the leading cause of liver disease globally. Hypothyroidism is a major factor in the development of NAFLD. Thus, the current investigation aimed to estimate the prevalence of NAFLD in individuals with hypothyroidism. Materials and Methods: This cross-sectional comparative study was conducted on 142 patients who qualified for the eligibility criteria. Proper history, examination, anthropometric measurements, and biochemical parameters were estimated. The collected data were entered in Excel and analyzed using the Statistical Package for Social Science 25 version developed by IBM (International Business Machine), IBM is a USA based company and the Student’s t-test and the Chi-square test were applied. Results: In this study, 12.6% of the treated subjects had fatty liver and 59.15% of the untreated subjects had fatty liver. From these untreated cases, fatty liver was found in 17.6% of subclinical hypothyroid subjects and 41.5% of overt hypothyroid subjects. There was a significant association between thyroid status and fatty liver (χ2 = 68.046, P &lt; 0.001). Conclusions: We have found that NAFLD is more prevalent in untreated hypothyroid subjects. The severity of NAFLD is more in patients with overt hypothyroidism. Early treatment with thyroxine can prevent the progression of the fatty liver and grave consequences such as nonalcoholic steatohepatitis and cirrhosis.

Growth hormone and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent cause of liver disease and metabolic comorbidities. Obesity is strongly associated with NAFLD and is also a state of relative deficiency of growth hormone (GH). Evidence supports a role of reduced GH and insulin-like growth factor-1 (IGF-1) in NAFLD pathogenesis. Physiological actions of GH in the liver include suppression of de novo lipogenesis (DNL) and promotion of lipid beta-oxidation, and GH also appears to have anti-inflammatory actions. Physiologic actions of IGF-1 include suppression of inflammatory and fibrogenic pathways important in the evolution from steatosis to steatohepatitis and fibrosis. Rodent models of impaired hepatic GH signaling show the development of steatosis, sometimes accompanied by inflammation, hepatocellular damage, and fibrosis, and these changes are ameliorated by treatment with GH and/or IGF-1. In humans, individuals with GH deficiency and GH resistance demonstrate an increased prevalence of NAFLD compared to controls, with improvement in hepatic lipid, steatohepatitis, and fibrosis following GH replacement. As a corollary, individuals with GH excess demonstrate lower hepatic lipid compared to controls along with increased hepatic lipid following treatment to normalize GH levels. Clinical trials demonstrate that augmentation of GH reduces hepatic lipid content in individuals with NAFLD and may also ameliorate steatohepatitis and fibrosis. Taken together, evidence supports an important role for perturbations in the GH/IGF-1 axis as one of the pathogenic mechanisms of NAFLD and suggests that further study is needed to assess whether augmentation of GH and/or IGF-1 may be a safe and effective therapeutic strategy for NAFLD.

Hepatitis C and Nonalcoholic Steatohepatitis in the 21st Century: Impact on Liver Disease and Liver Transplantation

Hepatitis C infection is a leading etiology of hepatic dysfunction and a major indication for liver transplantation due to the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease (NAFLD) and, specifically, its subtype nonalcoholic steatohepatitis (NASH) is a rising cause of liver disease. It is predicted to surpass hepatitis C as a leading indication for transplant. The introduction of direct-acting antivirals (DAAs) decreased the prevalence of chronic hepatitis C infections, but the obesity epidemic and metabolic syndrome have increased the prevalence of NASH. Weight loss and dietary modifications are recommended NASH therapies, but unlike for hepatitis C, federally approved agents are lacking and currently under investigation. Clinical trials face many barriers in NASH treatment because of the difficulty of diagnosis and a lack of standardized and accurate clinical and histologic responses. Mortality and morbidity in NASH are heightened because of the presence of multiple comorbidities including cardiovascular disease, diabetes, and renal dysfunction. A liver transplant may be indicated, but a thorough screening of candidates, including a comprehensive cardiovascular assessment, is essential to ensuring successful outcomes pre- and post-transplant. Therapeutic agents for NASH are warranted before it becomes a significant and leading cause of morbidity and mortality worldwide.

Peptide YY inhibits transcription and replication of hepatitis B virus by suppressing promoter/enhancer activity.

Hepatitis B virus (HBV) infection is a noteworthy cause of liver diseases, especially cirrhosis and hepatocellular carcinomas. However, the interaction between the host and HBV has not been fully elucidated. Peptide YY (PYY) is a 36-amino-acid gastrointestinal hormone that is mainly involved in the regulation of the human digestive system. This study found that PYY expression was reduced in HBV-expressing hepatocytes and HBV patients. Overexpression of PYY could significantly inhibit HBV RNA, DNA levels, and the secretion of HBsAg. In addition, PYY inhibits HBV RNA dependent on transcription through reducing the activities of CP/Enh I/II, SP1 and SP2. Meanwhile, PYY blocks HBV replication independent on core, polymerase protein and ε structure of pregenomic RNA. These results suggest that PYY can impair HBV replication by suppressing viral promoters/enhancers in hepatocytes. Our data shed light on a novel role for PYY as anti-HBV restriction factor.

Elevated liver enzymes: A diagnostic challenge

The differential diagnosis of elevated liver enzymes is a key aspect of hepatology and a diagnostic challenge for many. Elevated liver enzymes may mostly indicate liver damage but also physiologic elevations or extrahepatic causes are possible. A rational approach to the differential diagnosis of elevated liver enzymes is necessary to avoid overdiagnosis while not missing rare causes of liver disease.

1599-P: Regulation of Mitochondrial Dynamics Ameliorates Hepatic Steatosis through TFEB Activation

Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver disease that is closely related to metabolic syndromes, obesity, and type 2diabetes. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Recently, growing evidence suggests that the TFEB plays a pivotal role in mitochondrial dynamics. In this study, we investigated that mitochondrial dynamics play the potential role and mechanisms of TFEB in the amelioration of NAFLD. FFA increased expression of mitochondrial fission proteins p-Drp1, Fis1 and decreased expression of fusion proteins OPA1, Mfn2 and inhibition of TFEB activation. Mitotracker stain significantly increased in the proportion of cells with fragmented mitochondria in FFA-treated cells. HFD-fed mice displayed histology consistent with pathological hepatic steatosis. EM analysis indicated that HFD-fed mitochondria tended to be shorter and more round than ND-fed mitochondria. Western blot analyses reveal increased expression of the fission proteins, p-Drp1, Fis1, and significantly decreased in the fusion protein, Mfn2 and OPA1 in HFD-fed group. In vivo Tfeb knockout dramatically increased hepatic fat accumulation, liver ballooning in HFD-fed mice. EM analysis showed that HFD-fed Tfeb knockout mice had more rounded and swollen mitochondria, indicating that TFEB was dependent on the regulation of mitochondrial fragmentation. In vivo Tfeb knockout reveal significantly increased expression of the fission proteins in HFD-fed group. To demonstrated the direct regulatory mechanism of mitochondrial dynamics and TFEB activation, we used siRNA DRP1 and Mdivi-1. Inhibition of Drp1 promotes mitochondrial fusion, increased expression of fusion protein and reduced fat accumulation and activated TFEB. These results suggest a role in improving hepatic steatosis through regulation of TFEB-mediated mitochondrial dynamics in NAFLD. Disclosure J.Yoo: Other Relationship; American Diabetes Association. Y.Hwang: None. Funding National Research Foundation of Korea (2022R1I1A1A01069899)