Cause Of Cirrhosis Research Articles

A rare case of Flood syndrome in emergency department: A case report and review of recent reported cases

Introduction:Flood syndrome is a rare and potentially fatal complication of liver cirrhosis with gross ascites.Case presentation:We present a case of Flood syndrome in a gentleman with alcoholic cirrhosis and ascites who had sudden spontaneous rupture of umbilical hernia, resulting in sudden gush of ascitic fluid from the hernia. The wound was cleaned and covered in sterile dressing and was admitted for further management. His umbilical hernia wound was closed at bedside by General Surgery team and he underwent ultrasound‐guided ascitic drain insertion by Interventional Radiology. His stay was complicated by bacterial peritonitis which was treated with intravenous antibiotic. Patient eventually recovered and was discharged well.Discussion:Flood syndrome has high complication and mortality rate. Recent reported cases were reviewed, focusing on the causes of cirrhosis, complications of Flood syndrome, treatments provided and the outcomes.Conclusion:There is currently no standard guideline for the management of Flood syndrome which falls in the grey area between medical and surgical management. Proper medical management with early surgical consultation is important to reduce the morbidity and mortality for these patients.

Diagnostic Validity of Leucocyte Esterase Dipstick Tests for Spontaneous Bacterial Peritonitis in Patients with Cirrhosis

Background: One of the worst sequelae of cirrhosis and ascites is spontaneous bacterial peritonitis (SBP). Early detection and treatment of SBP are therefore essential for survival because this complication is linked to a high death risk if antibiotics are not administered promptly. Leukocyte esterase dipstick testing can identify the SBP quickly. Objective: To evaluate the diagnostic accuracy of leucocyte esterase dipstick test for the detection of spontaneous bacterial peritonitis taking ascitic fluid neutrophil count as gold standard. Study Design: Cross Sectional Study Settings: Department of Gastroenterology, Lady Reading Hospital, Peshawar Study Duration: This study was conducted from 1st July 2021 till 30th June 2022 Materials and Methods: Two samples (10cc each) of ascitic fluid aspirate were obtained from patients with cirrhosis on admission to the hospital, presenting with ascites, fever and abdominal pain. Bedside leucocyte esterase dipstick test was performed on one sample and the other was sent to hospital laboratory for ascitic fluid analysis for neutrophil count. The results of both modalities were compared diagnostic accuracy which was recorded in terms of sensitivity, specificity, positive predictive value and negative predictive. Results: Mean age of the patients was 46.68 ± 10.239 years. A total of 170 patients were enrolled. Age of the patients ranged from 18 to 75 years. Male patients were 113 (66.5%) while 57 patients (33.5%) were female. Hepatitis C was the leading cause of cirrhosis observed in 89 patients (52.4%). The sensitivity, specificity, positive and negative predictive value of leucocyte esterase dipstick test observed were 89.7%, 96.2%, 87.5% and 96.9% respectively. Conclusion: Leucocyte esterase dipstick test is a convenient, inexpensive and rapid diagnostic modality for SBP with better diagnostic accuracy. Keywords: Spontaneous Bacterial Peritonitis, Leucocyte Esterase Dipstick test, Diagnostic Accuracy.

Midodrine versus Albumin to Prevent Paracentesis Induced Circulatory Dysfunction in Acute on Chronic Liver Failure Patients in the Outpatient Clinic–a Randomized Controlled Trial

Paracentesis-induced circulatory disturbance (PICD) occurs in 12-20% of patients receiving human albumin for large-volume paracentesis, and can occur at lower than five liter paracentesis in acute-on-chronic liver failure (ACLF). Albumin infusions are associated with higher costs and more prolonged daycare admissions. The aim of the study was to determine if oral midodrine-hydrochloride can prevent PICD in these patients by increasing the mean arterial pressure (MAP). This open-labeled randomized controlled trial included ACLF patients undergoing paracentesis between 3 and 5L, who were randomized to receive either 20% human albumin or midodrine hydrochloride 7.5mg thrice daily for three days, 2h before paracentesis. MAP was recorded daily. The primary outcome was the plasma renin activity (PRA) on day six, and a 50% increase from baseline was considered PICD. 183 consecutive patients of ACLF were screened, and 50 patients were randomized to either arms. Alcohol was the most common underlying cause of cirrhosis. On day 6, PRA was non-significantly (P=0.056) higher in the midodrine group. The absolute change of PRA between the two groups was not significant (P= 0.093). Four (16%) patients in the albumin group and five (20%) in the midodrine group developed PICD. MAP increase was not different between the albumin and midodrine arms (P= 0.851). Midodrine was found to be more cost-effective. Three days of oral midodrine is as effective as a human-albumin infusion in preventing PICD in ACLF patients undergoing paracentesis lesser than that done in large volume paracentesis.

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages.

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD. To examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11-/- mice. Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.

Effectiveness of Proton Pump Inhibitor Therapy in the Prevention of Bleeding After Prophylactic Endoscopic Variceal Band Ligation.

Background Endoscopic variceal ligation (EVL) is a surgical intervention that can work well to curb variceal bleeding in people with liver cirrhosis. However, it could make ulcer bleeding worse and be fatal in some cases. The widespread use of proton pump inhibitors (PPI) in cirrhotic individuals with variceal bleeding is empirical rather than based on scientific data. According to many studies, PPIs reduce the size of post-EVL ulcers. This study aimed to see if PPI use could reduce rebleeding after endoscopy therapy in cirrhotic patients with variceal bleeding. Methodology A retrospective cross-sectional study was conducted at a tertiary care hospital from August 2019 to September 2021. Cirrhotic patients with bleeding gastroesophageal varices(GEVs) who had undergone EVL at the same hospital were enrolled in the study. Medical records were organized, and the sample was divided into two groups based on whether or not PPI was given. Both PPI and non-PPI patients had their endoscopic findings, initial hemostasis outcomes, rebleeding rates, bleeding-related mortality rates, and treatment-related comorbidities compared. Results A total of 46 patients were selected for the study and divided into two groups (PPI group n=28 and non-PPI group n=18). The majority of the patients were males. The PPI group had a mean age of 58.6 ±7.8 years, whereas the non-PPI group had a mean age of 53.6 ±4.4 years. Hepatitis B virus (HBV) infection was the most prevalent cause of cirrhosis in both groups. After endoscopic treatment, three patients (16%) in the non-PPI group suffered a variceal hemorrhage. Bleeding-related fatalities and the time it took for the bleeding to stop varied significantly between the two groups. History of variceal bleeding (relative risk (RR)=1.45; 95% confidence interval (CI), 1.60-7.67; p=0.02), presence of gastric varices (RR=2.23; 95% CI, 2.56-9.832; p=0.035), and not administering PPIs (RR =7.542; 95% CI, 3.98-29.13; p=0.008) were linked with rebleeding. The presence of red concurrent esophageal varices (RR=6.37; 95% CI, 0.562-15.342; p=0.002) and failure to provide PPIs (RR=2.3; 95% CI, 1.621-25.64; p=0.04) were linked with post-EVL bleeding in a multivariate analysis. Conclusions Proton pump inhibitors reducethe occurrence of early bleeding and adverse events after EVL in cirrhotic patients. Not prescribing PPIs and the presence of GEVs were substantially related to a higher risk of bleeding during preventative EVL. Not initiating PPI medication immediately was the sole predictor of bleeding complications in patients who had undergone EVL without gastric varix treatment. To lower the risk of post-EVL ulcer bleeding, we recommend PPI use in patients undergoing EVL.

Identification of the Interaction between Minichromosome Maintenance Proteins and the Core Protein of Hepatitis B Virus.

Chronic HBV infection is a major cause of cirrhosis and hepatocellular carcinoma. Finding host factors involved in the viral life cycle and elucidating their mechanisms is essential for developing innovative strategies for treating HBV. The HBV core protein has pleiotropic roles in HBV replication; thus, finding the interactions between the core protein and host factors is important in clarifying the mechanism of viral infection and proliferation. Recent studies have revealed that core proteins are involved in cccDNA formation, transcriptional regulation, and RNA metabolism, in addition to their primary functions of capsid formation and pgRNA packaging. Here, we report the interaction of the core protein with MCMs, which have an essential role in host DNA replication. The knockdown of MCM2 led to increased viral replication during infection, suggesting that MCM2 serves as a restriction factor for HBV proliferation. This study opens the possibility of elucidating the relationship between core proteins and host factors and their function in viral proliferation.

Clinical and patient-reported outcome profile of patients with hepatitis B viral infection from the Global Liver Registry™.

Chronic hepatitis B (CHB) infection is one of the most common causes of cirrhosis and liver cancer worldwide. Our aim was to assess clinical and patient-reported outcome (PRO) profile of CHB patients from different regions of the world using the Global Liver Registry. The CHB patients seen in real-world practices are being enrolled in the Global Liver Registry. Clinical and PRO (FACIT-F, CLDQ, WPAI) data were collected and compared to baseline data from CHB controls from clinical trials. The study included 1818 HBV subjects (48 ± 13 years, 58% male, 14% advanced fibrosis, 7% cirrhosis) from 15 countries in 6/7 Global Burden of Disease super-regions. The rates of advanced fibrosis varied (3-24%). The lowest PRO scores across multiple domains were in HBV subjects from the Middle East/North Africa (MENA), the highest - Southeast/East and South Asia. Subjects with advanced fibrosis had PRO impairment in 3 CLDQ domains, Activity of WPAI (p < 0.05). HBV subjects with superimposed fatty liver had more PRO impairments. In multivariate analysis adjusted for location, predictors of PRO impairment in CHB included female sex, advanced fibrosis, and non-hepatic comorbidities (p < 0.05). In comparison to Global Liver Registry patients, 242 controls from clinical trials had better PRO scores (Abdominal, Emotional, and Systemic scores of CLDQ, all domains of WPAI) (p < 0.05). In multivariate analysis with adjustment for location and clinicodemographic parameters, the associations of PROs with the enrollment setting (real-life Global Liver Registry vs. clinical trials) were no longer significant (all p > 0.10). The clinico-demographic portrait of CHB patients varies across regions of the world and enrollment settings. Advanced fibrosis and non-hepatic comorbidities are independently associated with PRO impairment in CHB patients.

Prognostic role of platelet lymphocyte ratio (PLR) among patients with hepatocellular carcinoma undergoing liver transplantation

Abstract Background Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, but it is so aggressive that is the third most common cause of cancer related death. We aim to study the role of PLR in prognosis of HCC and to see if it can be a predictor of overall survival and disease free survival among HCC patients that received liver transplantation in our centre. Patients and Methods This is a single centre retrospective analysis of prospectively collected data. The study was carried out in liver transplant institute of Inonu University, Malatya, Turkey. Consecutive patients that received liver transplantation for HCC and survive for at least 90 days post transplantation were included in the study. Data was collected regarding age, gender, presence or absence of cirrhosis, cause of cirrhosis, number of nodules, maximum size of the tumour, preoperative PLR, pre-transplant GGT, type of transplant, presence or absence of microvascular invasion, overall survival and disease free survival. The study was censored on June 2022. Data was analyzed using SPSS version 25. Results Platelet lymphocyte ratio was found to be significantly associated with some poor prognostic factors of HCC in our patients. We found that PLR is significantly associated with maximum tumour diameter (MTD) and total tumor diameter (TTD) with p= &lt;0.0001 and 0.0016 respectively. Univariate analysis revealed that PLR is a predictor of worse DFS or OS but when subjected to multivariate analysis, we found that PLR is not an independent predictor of OS and DFS. Conclusion Platelet lymphocyte ratio is associated with poor prognostics feature of hepatocellular carcinoma.

S-08-4: SELENIUM LEVELS AND FUNCTIONAL STATE OF LIVER IN PATIENTS WITH HYPERTENSION AND NONALCOHOLIC FATTY LIVER DISEASE

Introduction: Hypertension (HTN) is significant medical problem due to high levels of morbidity and mortality worldwide. Nonalcoholic fatty liver disease (NAFLD) is chronic disease, with gradual progression and is one of main causes of cirrhosis and hepatocellular carcinoma. Researches show controversies in Selenium levels in NAFLD patients. According to data, lower Selenium levels can increase risks of development of hypertension, while its increase can promote protective effect. Research in this area is actual due to insufficient data on Selenium metabolism in patients with HTN and NAFLD comorbidity, especially depending on liver damage grade. Aim: was to investigate levels of Selenium in patients with hypertension and NAFLD depending on functional state of liver. Materials and methods: We examined 100 patients. Main group: 49 hypertensive NAFLD patients (33 (67.3%) females and 16 (32.7%) males). Comparison group: 51 non-hypertensive NAFLD patients (30 (58.8%) females and 21 (41.2%) males).Control group: 20 relatively healthy individuals (11 (55.0%) females and 9 (45.0%) males). Median age in main group was 51.0 [45.0–56.0] years; comparison group: 52.0 [47.0–54.0] years (p = 0.564); control group: 51.0 [45.0–55.5] years. In the main group hypertension 1 stage was diagnosed in 14 (28.6%) patients, 2 stage: in 35 (71.4%) patients; 1 and 2 grade was diagnosed respectively in 16 (32.7%) and 33 patients (67.3%). In the main group steatosis was found in 27 (55.1%) patients; steatohepatitis: in 22 (44.9%) patients; in comparison group 30 (58.8%) and 21 (41.2%) patients respectively (p = 0.707). Selenium levels were assessed using Humal Selenium ELISA kit. Ultrasound of liver was performed according standard procedure using Samsung (Medison) SonoAce X8. Statistical calculations were made using IBM SPSS 25.0. Results: Median systolic and diastolic blood pressure in main group was 150.0 [145.0–158.0] mm Hg. and 90.0 [85.0–90.0] mm Hg. In comparison group:125.0 [115.0–130.0] and 80.0 [70.0–80.0] mm Hg. Respectively Selenium levels were significantly (p &lt; 0.001) increased in patients of comparison group: 67.2 [61.5–77.4] mkg/l vs. 43.5 [39.9–49.1] mkg/l in main group. In control group its levels were 108.0 [96.9–118.8] mkg/l, which was significantly (p &lt; 0.001) higher than in other groups. Analysis of Selenium levels depending on liver damage grade did not show significant differences. However patients with hypertension and steatohepatitis had higher Selenium levels than patients with steatohepatitis, while non-hypertensive patients had reversed trend (table 1) Conclusions: Hypertension is main trigger of decrease in Selenium levels in patients with comorbid NAFLD, which can be connected with its increased metabolism due to providing antihypertensive homeostasis and protection of vascular endothelium via antioxidant mechanisms.

Spleen stiffness determined by spleen-dedicated device accurately predicted esophageal varices in cirrhosis patients

Background: The advantages of spleen stiffness in prediction of high-risk varices (HRV) in cirrhosis patients have been confirmed. Recently, a new device utilizing a 100 Hz probe dedicated to spleen stiffness measurement (SSM) was developed. Objectives: To validate the clinical applicability of SSM@100 Hz in predicting HRV by comparing it with other non-invasive tests (NITs). Design: A prospective cohort study. Methods: A total of 171 cirrhosis patients who underwent esophagogastroduodenoscopy (EGD) examination were included in this study. SSM using a 100 Hz probe and liver stiffness measurement using a 50 Hz probe were performed. Additionally, 22 healthy controls underwent spleen stiffness evaluation using the 100 Hz probe. Results: The failure rates of spleen stiffness examination in patients with cirrhosis and in healthy controls were 2.9% and 4.5%, respectively. The means of SSM values were 56.4 ± 21.6 and 13.8 ± 6.7 kPa in cirrhosis and controls. SSM increased proportionally with the severity of esophageal varices. The area under receiver operating characteristic (ROC) for spleen stiffness in predicting HRV was 0.881 (95% confidence interval 0.829–0.934), with a cutoff value of 43.4 kPa. The accuracy, false negative rate and EGD spare rate were 86.5%, 2.5% and 24.3%, respectively. For HRV prediction, SSM was comparable to expanded Baveno VI and VII and superior to other NITs. As to viral versus non-viral cirrhosis and compensated versus decompensated cirrhosis, the cut-off and performance of SSM were different. Conclusion: SSM@100 Hz demonstrates high accuracy in predicting HRV with a low missed HRV rate. Our findings suggest that SSM@100 Hz can be used independently due to its simplicity and effectiveness. However, further studies are needed to determine appropriate cutoff values based on the cause of cirrhosis and liver function. Trail Registration: ChiCTR2300070270.

Deficiência de Lipase Ácida Lisossômica (LAL): Análise Enzimática em Papel-filtro como Ferramenta Diagnóstica em Paciente com Diagnóstico Prévio de Doença de Niemann-Pick tipo C

Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disorder involved in cholesterol ester metabolism. It is a poorly understood genetic cause of cirrhosis, dyslipidemia and premature atherosclerotic disease in children and adults. As the manifestations of LAL-D may resemble those observed in other more common diseases, delayed diagnosis is not uncommon. Wolman disease is an early-onset LAL-D phenotype that is usually fatal in the first year of life, but the most common form of the disease may occur at all ages. Recently, enzyme replacement therapy (ERT) for LAL-D has become available. Case report: A 12- year-old male patient was referred for hepatomegaly. Initially diagnosed as having Niemann-Pick type C disease (NPC), it did not present confirmatory mutations of this disease. Later, with enzymatic dosage of lysosomal acid lipase on filter paper, the diagnosis was redirected to LAL-D (with confirmation in enzymatic dosage in leukocytes and fibroblasts). Discussion: Although LAL-D is considered a rare and uncommon cause of liver disease, recent studies point to a higher prevalence of this disease. Early diagnosis is essential, since specific treatment for this disease is already available. About half of patients with LAL-D die before age 21 in the absence of adequate treatment

Complications and mortality in cirrhotic children awaiting liver allografts: a single-center report from Iran

Liver transplantation (LT) is the treatment of choice for end-stage liver disease in children, but donor shortage is still a central problem in this age group. Objective. To evaluate the rate of complications and mortality in cirrhotic children awaiting transplantation. Patients and methods. We analyzed medical records of 113 children under 18 years of age who were listed for LT, but the organ was unavailable between 2013 and 2018. The outcome was assessed from their records or follow-up data. Results. Among the children (mean age: 3.79 years; 50.4% boys and 49.6% girls) awaiting LT, the common causes of cirrhosis were biliary atresia (38.9%) and progressive familial intrahepatic cholestasis (17.7%). While awaiting transplantation, 82 (72.6%) children died. The most common complications were encephalopathy (34.5%), esophageal bleeding (26.5%), infections (23.0%), and spontaneous bacterial peritonitis (13.3%). The mean duration of hospital admission was 2.72 ± 3.10 days. Conclusion. About two-thirds of children listed for LT developed complications, and about three-quarters died without any LT. It seems that split liver transplantation and the introduction of a live-related transplant program in our center will provide many benefits to pediatric patients. Key words: liver transplantation, mortality, cirrhosis, pediatrics, children

Deficiência de Lipase Ácida Lisossômica (LAL): análise enzimática em papel-filtro como ferramenta diagnóstica em paciente com diagnóstico prévio de doença de Niemann-Pick tipo C

INTRODUCTION: Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disorder involved in cholesterol ester metabolism. It is a poorly understood genetic cause of cirrhosis, dyslipidemia and premature atherosclerotic disease in children and adults. As the manifestations of LAL-D may resemble those observed in other more common diseases, delayed diagnosis is not uncommon. Wolman disease is an early-onset LAL-D phenotype that is usually fatal in the first year of life, but the most common form of the disease may occur at all ages. Recently, enzyme replacement therapy (ERT) for LAL-D has become available. CASE REPORT: A 12-year-old male patient was referred for hepatomegaly. Initially diagnosed as having Niemann-Pick type C disease (NPC), it did not present confirmatory mutations of this disease. Later, with enzymatic dosage of lysosomal acid lipase on filter paper, the diagnosis was redirected to LAL-D (with confirmation in enzymatic dosage in leukocytes and fibroblasts). DISCUSSION: Although LAL-D is considered a rare and uncommon cause of liver disease, recent studies point to a higher prevalence of this disease. Early diagnosis is essential, since specific treatment for this disease is already available. About half of patients with LAL-D die before age 21 in the absence of adequate treatment.

Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s Disease

Wilson's disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson's disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurologic symptoms. In this study, we showed the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of Wilson's disease. We investigated the neutrophil response in atp7b-/- zebrafish by live imaging, movement tracking, and transcriptional analysis in sorted cells. Experiments were conducted to validate liver neutrophil heterogeneity in Atp7b-/- mice. Invitro experiments were performed in ATP7B-knockout human hepatocellular carcinomas G2 cells and isolated bone marrow neutrophils to reveal the mechanism of neutrophil heterogeneity. Recruitment of neutrophils into the liver is observed in atp7b-/- zebrafish. Pharmacologic stimulation of neutrophils aggravates liver and behavior defects in atp7b-/- zebrafish. Transcriptional analysis in sorted liver neutrophils from atp7b-/- zebrafish reveals a distinct transcriptional profile characteristic of N2 neutrophils. Furthermore, liver N2 neutrophils also were observed in ATP7B-knockout mice, and pharmacologically targeted transforming growth factor β1, DNA methyltransferase, or signal transducer and activator of transcription 3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-knockout mice. Epigenetic silencing of Socs3 expression by transforming growth factor β1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils. Our findings provide a novel prospect that pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson's disease.

Perception, attitude, and beliefs of Saudi population concerning nonalcoholic fatty liver disease and role of diet in Riyadh region

Objective: This study was designed to evaluate the perception, attitude, and beliefs of Saudi population towards nonalcoholic fatty liver disease (NAFLD). Methods: In this cross-sectional observational study, an online questionnaire was used that was distributed via social media platforms. Details of participants regarding sex, marital status, place of residence, socioeconomic status were obtained. Further, the association of knowledge with age, sex, and level of education was also measured. Results: In total, 397 participants were recruited. Among them, only 40 (10.08%) were diagnosed with NAFLD, and 27 (6.80%) had heard about NAFLD from their physicians; however, 315 (79.35%) individuals were aware regarding cirrhosis. Hepatitis B and C was considered the primary cause of cirrhosis, as perceived by 187 (47.10%) participants, while 131 (33%) participants associated it with alcohol consumption. Approximately 20% participants perceived that NAFLD transferred from generation to generation via genes. Overall, 282 (71.03%) participants agreed that dietary habits could affect disease control patterns, whereas 33% associated it with diabetes. Conclusion: There was a knowledge gap concerning NAFLD, even though patients acknowledged that lifestyle modifications are the primary therapy for the disease. The two factors that consistently aided and hindered lifestyle changes were the availability of social support and competing medical comorbidities.

Herpetrione, a New Type of PPARα Ligand as a Therapeutic Strategy Against Nonalcoholic Steatohepatitis.

Non-alcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), is a leading cause of cirrhosis and liver cancer worldwide; nevertheless, there are no Food and Drug Administration-approved drugs for treating NASH until now. Peroxisome proliferator-activated receptor alpha (PPARα) is an interesting therapeutic target for treating metabolic disorders in the clinic, including NASH. Herpetrione, a natural lignan compound isolated from Tibetan medicine Herpetospermum caudigerum, exerts various hepatoprotective effects, but its efficacy and molecular mechanism in treating NASH have not yet been elucidated. Here, we discovered that herpetrione lessened lipid accumulation and inflammation in hepatocytes stimulated with oleic acid and lipopolysaccharide, and effectively alleviated NASH caused by a high-fat diet or methionine-choline-deficient diet by regulating glucolipid metabolism, insulin resistance, and inflammation. Mechanistically, RNA-sequencing analyses further showed that herpetrione activated PPAR signaling, which was validated by protein expression. Furthermore, the analysis of molecular interactions illustrated that herpetrione bound directly to the PPARα protein, with binding sites extending to the Arm III domain. PPARα deficiency also abrogated the protective effects of herpetrione against NASH, suggesting that herpetrione protects against hepatic steatosis and inflammation by activation of PPARα signaling, thereby alleviating NASH. Our findings shed light on the efficacy of a natural product for treating NASH, as well as the broader prospects for NASH treatment by targeting PPARα.

Ivermectin Attenuates CCl4-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease

Nonalcoholic steatohepatitis (NASH), a leading cause of cirrhosis, strongly associates with the metabolic syndrome, an insulin-resistant proinflammatory state that disrupts energy balance and promotes progressive liver degeneration. We aimed to define the role of Smoothened (Smo), an obligatory component of the Hedgehog signaling pathway, in controlling hepatocyte metabolic homeostasis and, thereby, susceptibility to NASH. We conditionally deleted Smo in hepatocytes of healthy chow-fed mice and performed metabolic phenotyping, coupled with single-cell RNA sequencing (RNA-seq), to characterize the role of hepatocyte Smo in regulating basal hepatic and systemic metabolic homeostasis. Liver RNA-seq datasets from 2 large human cohorts were also analyzed to define the relationship between Smo and NASH susceptibility in people. Hepatocyte Smo deletion inhibited the Hedgehog pathway and promoted fatty liver, hyperinsulinemia, and insulin resistance. We identified a plausible mechanism whereby inactivation of Smo stimulated the mTORC1-SREBP1c signaling axis, which promoted lipogenesis while inhibiting the hepatic insulin cascade. Transcriptomics of bulk and single Smo-deficient hepatocytes supported suppression of insulin signaling and also revealed molecular abnormalities associated with oxidative stress and mitochondrial dysfunction. Analysis of human bulk RNA-seq data revealed that Smo expression was (1) highest in healthy livers, (2) lower in livers with NASH than in those with simple steatosis, (3) negatively correlated with markers of insulin resistance and liver injury, and (4) declined progressively as fibrosis severity worsened. The Hedgehog pathway controls insulin sensitivity and energy homeostasis in adult livers. Loss of hepatocyte Hedgehog activity induces hepatic and systemic metabolic stress and enhances susceptibility to NASH by promoting hepatic lipoxicity and insulin resistance.

638. Utility of Recombinant Hepatitis B Vaccine in Pre-liver Transplant Candidates

Abstract Background A recombinant, adjuvanted Hepatitis B (HBV) vaccine (HepB-CpG) was approved by the FDA in 2017. Initial FDA data showed greater immunogenicity than comparable recombinant HBV vaccines. Moreover, it requires only two doses over four weeks instead of three doses over six months, so there is a time advantage to HepB-CpG, which is advantageous in pre-liver transplant candidates, given their limited time before transplantation. The efficacy in this population is unknown, so we explored its efficacy This study aims to explore the efficacy of HepB-CpG in pre-liver transplant candidates, as there is currently no data on this subject. Methods This study was a retrospective review of pre-liver transplant candidates greater than 18 years old at Memorial Hermann Hospital in Houston, TX, who received at least two doses of HepB-CpG. Patients were identified from our pre-liver transplant database. Patient characteristics were collected at the time of the first dose. Vaccine efficacy was measured by anti-Hepatitis B surface antibody titers (≥10mIU/mL) at least four weeks after completion of the series. Patients who received only one dose or did not have any post-vaccine titers were excluded from the analysis. Results A total of 78 potential eligible patients were identified. After exclusion due to various reasons, a total of 27 patients were eligible for our study. Data are summarized in Table 1. Briefly, our patients were Hispanic dominant (59.3%). The median MELD score was 18, and a significant number of patients (48.1%) had underlying malignancy. The cause of cirrhosis was mainly due to alcoholic and non-alcoholic steatohepatitis (NASH). Only 13 patients (48.1%) showed seroconversion after their second dose of HepB-CpG. Moreover, of the five patients receiving immunosuppressive drugs, only one patient (20%) responded to the vaccine. Characteristics of Pre-Liver Transplant Candidates Who Had Serological Evaluation after Two Doses of Recombinant Adjuvanted Hepatitis B Vaccine. Conclusion Despite administration of HepB-CpG, less than 50% of pre-liver transplant candidates showed seroconversion. Furthermore, only one cirrhotic patient on immunosuppressive drugs responded to the vaccine. Our results illustrate the need for a better strategy to improve immunogenicity among this patient population. Larger studies are warranted to confirm the findings. Disclosures Victor I. Machicao, M.D., Gilead Inc: Advisor/Consultant.

The role of bile acid metabolism in the occurrence and development of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become one of the important causes of cirrhosis and liver cancer, resulting in a huge medical burden worldwide. Currently, effective non-invasive diagnostic indicators and drugs for NAFLD are still lacking. With the development of metabolomics technology, the changes in metabolites during the development of NAFLD have been gradually revealed. Bile acid (BA) is the main endpoint of cholesterol metabolism in the body. In addition, it also acts as a signaling factor to regulate metabolism and inflammation in the body through the farnesyl X receptor and G protein-coupled BA receptor. Studies have shown that BA metabolism is associated with the development of NAFLD, but a large number of animal and clinical studies are still needed. BA homeostasis is maintained through multiple negative feedback loops and the enterohepatic circulation of BA. Recently, treatment of NAFLD by interfering with BA synthesis and metabolism has become a new research direction. Here, we review the changes in BA metabolism and its regulatory mechanisms during the development of NAFLD and describe the potential of studies exploring novel non-invasive diagnostic indicators and therapeutic targets for NAFLD based on BA metabolism.