Severity Of Hepatic Fibrosis Research Articles

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non-alcoholic steatohepatitis (NASH).

Ceramide is a central molecule of sphingolipid metabolism and is involved in the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). It has already been reported that the inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme in the sphingolipid biosynthetic pathway, has an inhibitory effect on hepatic lipidosis, but its effect on severe hepatic fibrosis is not clear. In this study, we examined whether a SPT inhibitor could suppress the activation of hepatic stellate cells (HSC) and ameliorate the progression of NASH. Effects on sphingolipid metabolism and HSC activation marker genes by NA808, a SPT inhibitor, were evaluated in an immortalized HSC cell line (E14C12). NA808 decreased sphingolipid synthesis and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 mRNA in HSC. We identified a novel oral SPT inhibitor, CH5169356, which is a prodrug of NA808. CH5169356 was administered in the Ath+HF model, a NASH mouse model with liver fibrosis induced by atherogenic and high-fat content diets. CH5169356 showed a significant decrease in the expression of α-SMA and collagen 1A1 mRNA in the liver and an inhibition of liver fibrosis progression. CH5169356 was also evaluated in a Stelic animal model (STAM), a NASH mouse model induced through a different mechanism than that of the Ath+HF model, and showed a significant anti-fibrotic effect. In conclusion, CH5169356 could inhibit the progression of hepatic fibrosis in the pathogenesis of NASH by suppressing HSC activation, suggesting that CH5169356 would be a potential oral NASH therapeutic agent.

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease.

FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2-null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown. The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients. One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain. This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.

The Influence of Metabolic Factors in Patients with Chronic Viral Hepatitis C Who Received Oral Antiviral Treatment.

Hepatic diseases pose a significant public health concern. Regardless of the severity of hepatic fibrosis, treatment is recommended for all chronic hepatitis C virus (HCV) subjects. However, fibrosis and steatosis assessment remains crucial for evaluating the prognosis, progression, and hepatic disease monitoring, particularly following the treatment with direct-acting antivirals (DAAs). The aim of our study was to evaluate the impact of metabolic factors and the extent of hepatic fibrosis and fat accumulation in chronic HCV infection subjects. Additionally, another objective was to investigate modifications regarding fibrosis and steatosis three months after a successful sustained viral response (SVR). A total of 100 patients with compensated cirrhosis and chronic hepatitis C (CHC) were included in our study. These patients received treatment with DAA and underwent Fibromax assessment before and three months post SVR. After DAA treatment, a significant decrease was observed in the degree of hepatic fibrosis and hepatic steatosis. This regression was evident three months following the achievement of SVR. Chronic viral hepatitis C may trigger risk factors for metabolic syndromes, such as obesity and type 2 diabetes mellitus. Conclusions: It is crucial to monitor metabolic factors and take timely measures to prevent or treat metabolic syndrome in patients with chronic viral hepatitis C.

High Prevalence of Severe Hepatic Fibrosis in Type 2 Diabetic Outpatients Screened for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a highly frequent condition in patients with type 2 diabetes (T2D), but the identification of subjects at higher risk of developing the more severe forms remains elusive in clinical practice. The aim of this study was to evaluate the occurrence and severity of liver fibrosis and its predictive factors in T2D outpatients without a known history of chronic liver disease by using recommended non-invasive methods. Consecutive T2D outpatients underwent a set of measurements of clinical and laboratory parameters, FIB-4 score (Fibrosis-4 index), and liver stiffness with controlled attenuation-parameter (CAP) performed by transient elastography (FibroScan) after excluding previous causes of liver disease. Among the 205 T2D outpatients enrolled in the study (median age: 64 years, diabetes duration: 11 years, HbA1c: 7.4%, and BMI: 29.6 kg/m2), 54% had high ALT and/or AST levels, 15.6% had liver stiffness value > 10.1 kPa (severe fibrosis), 55.1% had CAP values > 290 dB/m (severe steatosis), and FIB-4 score was >2 in 11.2% of subjects (>2.67 in 15 subjects). Moreover, 49 (23.9%) T2D patients had clinically meaningful liver harm, with either a FIB-4 score > 2 and/or FibroScan > 10.1 kPa. At regression analysis, BMI, HbA1c, creatinine, and triglycerides values were independent predictors of liver fibrosis. Liver fibrosis is a frequent finding in T2D outpatients without a known history of liver disease, especially in those with obesity, hypertriglyceridemia, worse glycemic control, and high creatinine levels.

Splenic Arterial Pulsatility Index to Predict Hepatic Fibrosis in Hemodialysis Patients with Chronic Hepatitis C Virus Infection.

The clinical utility of the splenic arterial pulsatility index (SAPI), a duplex Doppler ultrasonographic index, to predict the stage of hepatic fibrosis in hemodialysis patients with chronic hepatitis C virus (HCV) infection remains elusive. We conducted a retrospective, cross-sectional study to include 296 hemodialysis patients with HCV who underwent SAPI assessment and liver stiffness measurements (LSMs). The levels of SAPI were significantly associated with LSMs (Pearson correlation coefficient: 0.413, p < 0.001) and different stages of hepatic fibrosis as determined using LSMs (Spearman's rank correlation coefficient: 0.529, p < 0.001). The areas under receiver operating characteristics (AUROCs) of SAPI to predict the severity of hepatic fibrosis were 0.730 (95% CI: 0.671-0.789) for ≥F1, 0.782 (95% CI: 0.730-0.834) for ≥F2, 0.838 (95% CI: 0.781-0.894) for ≥F3, and 0.851 (95% CI: 0.771-0.931) for F4. Furthermore, the AUROCs of SAPI were comparable to those of the fibrosis index based on four parameters (FIB-4) and superior to those of the aspartate transaminase (AST)-to-platelet ratio index (APRI). The positive predictive value (PPV) for ≥F1 was 79.5% when the Youden index was set at 1.04, and the negative predictive values (NPVs) for ≥F2, ≥F3, and F4 were 79.8%, 92,6%, and 96.9%, respectively, when the maximal Youden indices were set at 1.06, 1.19, and 1.30. The diagnostic accuracies of SAPI with the maximal Youden index for a fibrosis stage of ≥F1, ≥F2, ≥F3, and F4 were 69.6%, 67.2%, 75.0%, and 85.1%, respectively. In conclusion, SAPI can serve as a good noninvasive index in predicting the severity of hepatic fibrosis in hemodialysis patients with chronic HCV infection.

Chronic administration of triclosan leads to liver fibrosis through hepcidin-ferroportin axis-mediated iron overload

Triclosan (TCS) has been manufactured as an antibacterial compound for half a century. Currently, it is widely used in various personal care products; however, its potential adverse effects raise a lot of attention. Here, we create a long-term oral administration mouse model and identify the corresponding hepatotoxicity of TCS. We discover that daily intragastric administration of 10 mg/kg TCS to mice for 12 weeks results in severe hepatic fibrosis. Further study displays that hepatic iron increased 18%, 23% and 29% upon oral TCS treatment for 4, 8 and 12 weeks, respectively. Accompanied by hepatic iron variation, splenic and duodenal iron are increased, which indicates systemic iron disorder. Not only excessive iron accumulated in the liver, abnormal hepatic malondialdehyde, prostaglandin synthase 2 and glutathione peroxidase 4 are pointed to ferroptosis. Additional study uncovers that hepcidin expression increases 7%, 10%, 4% in serum and 2.4-, 4.8-, and 2.3-fold on transcriptional levels upon TCS exposure for 4, 8 and 12 weeks, individually. Taken together, the mice in the TCS-treated group show disordered systemic iron homeostasis via the upregulated hepatic hepcidin-ferroportin axis. Meanwhile, both hepatic iron overload (systemic level) and hepatocyte ferroptosis (cellular level) are accused of TCS-induced liver fibrosis. Ferriprox®, an iron scavenger, significantly ameliorates TCS-induced liver fibrosis. In summary, this study confirms the impact of TCS on liver fibrosis; a critical signal pathway is also displayed. The significance of the current study is to prompt us to reevaluate the “pros and cons” of TCS applications.

The impact of drug-eluting bead (vs. conventional) transarterial chemoembolization on hepatic fibrosis in treating intermediate or advanced hepatocellular carcinoma

ABSTRACT Objective Limited studies have reported the impact of drug-eluting bead transarterial chemoembolization (DEB-TACE) on hepatic fibrosis in hepatocellular carcinoma (HCC). This study evaluated multiple hepatic fibrosis indicators, aiming to comprehensively compare the influence of DEB-TACE and conventional transarterial chemoembolization (cTACE) on hepatic fibrosis in treating HCC patients. Methods Intermediate/advanced HCC patients (N = 121) were divided into the DEB-TACE group (n = 62) and the cTACE group (n = 59) based on their chosen treatment. Serum hyaluronic acid (HA), pro-collagen type-III (PC-III), collagen type-IV (IV-C), and laminin (LN) were detected; aminotransferase to platelet ratio index (APRI) and fibrosis index based on the four factors (FIB-4) were calculated; liver stiffness measurement (LSM) was assessed by real-time shear wave elastography. Results HA, PC-III, IV-C, and LN at 1 month after the second TACE and at 12 months after the first TACE were all decreased in DEB-TACE group compared with cTACE group (all P < .050). Then, APRI, FIB-4, and LSM were further assessed, which also showed a decreasing trend at aforementioned timepoints in DEB-TACE group compared with cTACE group (all P < .050). Additionally, the multivariate logistic regression analysis revealed that DEB-TACE (vs. cTACE) was independently associated with reduced occurrence of severe hepatic fibrosis at 12 months (OR = 0.215, 95%CI: 0.058–0.802, P = .022). Concerning the liver function indexes, alanine aminotransferase, aspartate aminotransferase, and total bilirubin after treatment were not different between the two groups (all P > .050). Conclusion DEB-TACE displays attenuated hepatic fibrosis progression and noninferior tolerance compared to cTACE in treating intermediate- or advanced-stage HCC patients.

Low-Dose Administration of Cannabigerol Attenuates Inflammation and Fibrosis Associated with Methionine/Choline Deficient Diet-Induced NASH Model via Modulation of Cannabinoid Receptor

8-week-old C57BL/6 male mice were fed with methionine/choline deficient (MCD) diet or control (CTR) diets for five weeks. At the beginning of week 4, mice were divided into three sub-groups and injected with either a vehicle, a low or high dose of CBG for two weeks. Overall health of the mice, Hepatic steatosis, fibrosis, and inflammation were evaluated. Increased liver-to-body weight ratio was observed in mice fed with MCD diet, while a low dose of CBG treatment rescued the liver-to-body weight ratio. Hepatic ballooning and leukocyte infiltration were decreased in MCD mice with a low dose of CBG treatment, whereas the CBG treatment did not change the hepatic steatosis. The high dose CBG administration increased inflammation and fibrosis. Similarly, the expression of cannabinoid receptor (CB)1 and CB2 showed decreased expression with the low CBG dose but not with the high CBG dose intervention in the MCD group and were co-localized with mast cells. Additionally, the decreased mast cells were accompanied by decreased expression of transforming growth factor (TGF)-β1. Collectively, the low dose of CBG alleviated hepatic fibrosis and inflammation in MCD-induced NASH, however, the high dose of CBG treatment showed enhanced liver damage when compared to MCD only group. These results will provide pre-clinical data to guide future intervention studies in humans addressing the potential uses of CBG for inflammatory liver pathologies, as well as open the door for further investigation into systemic inflammatory pathologies.

Severe COVID-19 May Impact Hepatic Fibrosis /Hepatic Stellate Cells Activation as Indicated by a Pathway and Population Genetic Study.

Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present severe illness. We hypothesised that shared genomic characteristics, distinct from the rest of Europe, could be a contributor factor to a poor prognosis in these two populations. To identify pathways related to COVID-19 severity, we shortlisted 437 candidate genes associated with host viral intake and immune evasion from SARS-like viruses. From these, 21 were associated specifically with clinically aggressive COVID-19. To determine the potential mechanism of viral infections, we performed signalling pathway analysis with either the full list (n = 437) or the subset group (n = 21) of genes. Four pathways were significantly associated with the full gene list (Caveolar-mediated Endocytosis and the MSP-RON Signalling) or with the aggressive gene list (Hepatic Fibrosis/Hepatic Stellate Cell (HSC) Activation and the Communication between Innate and Adaptive Immune Cells). Single nucleotide polymorphisms (SNPs) from the ±1 Mb window of all genes related to these four pathways were retrieved from the dbSNP database. We then performed Principal Component analysis for these SNPs in individuals from the 1000 Genomes of European ancestry. Only the Hepatic Fibrosis/HSC Activation pathway showed population-specific segregation. The Spanish and Italian populations clustered together and away from the rest of the European ancestries, with the first segregating further from the rest. Additional in silico analysis identified potential genetic markers and clinically actionable therapeutic targets in this pathway, that may explain the severe disease.

Serum Mac-2 Binding Protein Glycosylation Isomer to Predict the Severity of Hepatic Fibrosis in Patients with Hepatitis C Virus Infection.

Large-scale studies to assess the utility of the Mac-2 binding protein glycosylation isomer (M2BPGi) in predicting hepatic fibrosis in patients with hepatitis C virus (HCV) infection are limited. Serum M2BPGi level determination was performed in 1460 patients with HCV who received liver stiffness measurement (LSM) using transient elastography (TE). The correlation of LSM and grade of hepatic fibrosis as staged by TE with M2BPGi was assessed. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic power of M2BPGi for fibrosis stages of ≥F2, ≥F3, and F4. The selected M2BPGi cutoff values were chosen based on the maximal Youden index, a positive likelihood ratio (LR) ≥ 10, and a negative LR ≤ 0.1. Serum M2BPGi level was highly correlated with LSM (Pearson correlation coefficient: 0.567, p &lt; 0.001) and hepatic fibrosis stage (Spearman's rank correlation coefficient: 0.772, p &lt; 0.001). The areas under ROC curves (AUROCs) of M2BPGi for ≥F2, ≥F3, and F4 were 0.865 (95% confidence interval [CI]: 0.846-0.884), 0.937 (95 % CI: 0.922-0.952), and 0.962 (95% CI: 0.951-0.972). The maximal Youden indices for ≥F2, ≥F3, and F4 were 1.72, 2.65, and 3.93. By selecting M2BPGi cutoff values with a positive LR ≥ 10 and a negative LR ≤ 0.1, clinicians were able to correctly discriminate F2, F3, and F4 in 69.1%, 77.8%, and 90.1% of patients. In conclusion, serum M2BPGi is a good diagnostic tool to predict the severity of hepatic fibrosis in patients with HCV infection.

Clinical Spectrum of Nonalcoholic Fatty Liver Disease in Patients with Chronic Obstructive Pulmonary Disease.

The purpose of this study was to determine the prevalence of nonalcoholic fatty liver disease in a group of chronic obstructive pulmonary disease patients. This study comprised 48 stable chronic obstructive pulmonary disease patients who were diagnosed and categorized using the Global Initiative for Chronic Obstructive Lung Disease 2017 criteria. The prevalence of nonalcoholic fatty liver disease in chronic obstructive pulmonary disease patients was determined using noninvasive biomarkers and imaging methods. Steatosis was detected using magnetic resonance mDIXON-Quant sequence imaging, while fibrosis was detected using the acoustic radiation force impulse and FIB-4 index. A total of 58.3% of the patients investigated had a fat level of 5%, and nearly a quarter of them had a fat content of 10% or more, and 45.8% of the patients studied had severe hepatic fibrosis. The Fibrosis-4 (FIB-4) index revealed advanced fibrosis in 18.75% of them. No statistically significant association was found between chronic obstructive pulmonary disease groups of studied patients and the presence of steatosis and fibrosis (≥F2) using acoustic radiation force impulse. The presence of fibrosis, however, was statistically significant linked with chronic obstructive pulmonary disease groups of examined patients using the FIB-4 index. γ-Glutamyl transferase and alkaline phosphatase levels were greater in Global Initiative for Chronic Obstructive Lung Disease 3/4 and C/D groups. Nonalcoholic fatty liver disease is a common comorbidity in chronic obstructive pulmonary disease and should be included in the list of chronic obstructive pulmonary disease comorbidities.

Carbonic anhydrase 14 protects the liver against the cytotoxicity of bile acids in a biliary bicarbonate umbrella-related manner

AimsThe “biliary bicarbonate umbrella” is considered a critical protective mechanism of cholangiocytes against bile acid cytotoxicity. Defects in its function are closely related to various chronic cholangiopathies. Carbonic anhydrase 14 (CAR14) is an important element of normal bicarbonate homeostasis and is highly expressed in liver tissues. This study aimed to explore the effects and mechanism of CAR14 on bile acid cytotoxicity in the liver. Main methodsIn vitro, alterations in the whole transcriptome after Car14 gene silencing were assessed by RNA sequencing, and the expression changes in key factors in the “biliary bicarbonate umbrella” were verified by qRT-PCR and western blotting. In vivo, 7 days after bile duct ligation in Car14 gene knockout and wild-type mice, their serum liver function indicators, liver histopathology, hepatic bile acid composition, and whole hepatic proteomic changes were investigated. Key findingsIn vitro, the transcriptional alterations induced by Car14 silencing were mainly related to transmembrane transport, including ion exchangers and ion channels that are vital in the “biliary bicarbonate umbrella” such as AE2 and CFTR. In vivo, Car14 knockout induced more severe liver dysfunction, hepatic fibrosis and bile duct lesions, and resulted in increased hepatic bile acid levels and altered bile acid compositions in BDL mice. In response, the uptake and synthesis of bile acids in the liver of Car14 knockout mice were suppressed. SignificanceOur data revealed that CAR14 protects the liver against bile acid toxicity, which might provide a theoretical basis for clinical strategies to prevent or treat bile duct diseases.

S1186 Mild Thrombocytopenia as a Predictor of Surgical Outcomes Following Cholecystectomy: A Tool for Perioperative Assessment in Patients With Non-Alcoholic Fatty Liver Disease?

Introduction: As evidenced by its inclusion in estimations of liver fibrosis, thrombocytopenia is a well-defined abnormality in chronic hepatic disease. Studies show that platelet counts fewer than 160 x 109/L are an independent marker for severity of hepatic fibrosis. Non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disorder in Western countries making characterization of morbidity increasingly important. There is a paucity of information available to characterize perioperative risk for patients with NAFLD. We used a threshold of 150 x 109 as a surrogate for NAFLD in patients undergoing laparoscopic cholecystectomy to study its effect on perioperative complications and mortality. Methods: We queried the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for cholecystectomies occurring from 2005 through 2018. Demographic differences between patients with and without thrombocytopenia were evaluated using the t-test or the chi-square test, whereas differences in outcome risk was evaluated using log-binomial regression models. Results: We identified 437,630 patients who underwent cholecystectomy, of whom 6.9% had thrombocytopenia. Patients with thrombocytopenia were more often male, older, with chronic disease. As shown in Table and Figure, patients with thrombocytopenia had higher 30-day mortality rates risk ratio (RR) 5.3 (95% CI: 4.8-5.9) and higher complication rates RR 2.4 (95% CI: 2.3-2.5). The most frequent complications included respiratory, need for transfusion, and renal. Conclusion: Peri-operatively, patients with mild thrombocytopenia undergoing cholecystectomy had higher mortality rates and complications compared to patients with normal platelet counts, and this effect continued as thrombocytopenia became more pronounced. Other etiologies of mild thrombocytopenia could not be excluded; however, aside from cancer (a small proportion) these are unlikely to affect clinical outcomes. Currently, most society guidelines including the AASLD practice guidance do not recommend NAFLD screening in the general population even among high-risk patients with diabetes or obesity. Thrombocytopenia might be a promising, cost-effective tool for NAFLD screening especially if used in high-risk populations (male gender, hypertension or diabetes, with or without high BMI). Furthermore, our study suggests that platelet counts may have utility in predicting peri-operative outcomes in this population.Figure 1.: Estimated rate of 30-day Mortality (left) and having any complication (right; infection, cardiac, respiratory, thrombotic, transfusion, renal, and/or unplanned return to the OR) across observed pre-operative platelet counts. Shaded areas represent 95% confidence intervals. The solid vertical line defines thrombocytopenia threshold at 150 x 109/L. The dashed vertical lines identify the 1st and 99th percentile of pre-operative platelet counts (92 and 480, respectively) indicating that <1% of the pre-operative platelet counts were below 92 or above 480. Table 1. - Unadjusted outcomes Thrombocytopenia p No Yes Ratio (95% CI) Sample Size 407,380 30,250 - - 30-day Mortality 0.3 1.7 5.3 (4.8-5.9) <.001 Complication 5.2 12.4 2.4 (2.3-2.5) <.001 Cardiac 0.2 0.9 3.7 (3.2-4.3) <.001 Respiratory 0.5 2.2 4.1 (3.8-4.5) <.001 Thrombotic 0.0 0.0 - - Transfusion 0.2 1.2 5.7 (5.0-6.4) <.001 Renal 0.2 1.0 4.2 (3.7-4.8) <.001 Return to OR 1.2 2.2 1.9 (1.8-2.1) <.001 Prolonged Hospitalization 0.1 0.3 2.7 (2.1-3.5) <.001 Unplanned Readmission 55.0 72.9 1.3 (1.2-1.5) <.001 Length of Stay Same-day Discharge Yes 43.4 21.5 0.5 (0.5-0.5) <.001 No (days) 3.8 5.5 1.5 (1.4-1.5) <.001 Note. Data presented as estimated percent or days. Thrombocytopenia defined as pre-operative platelet count less than 150 x 109/L. The ratios for 30-day Mortality through Unplanned Readmission are risk ratios. For all ratios, a ratio greater than 1 indicates greater unadjusted outcome for patients with thrombocytopenia.

Noninvasive Diagnosis of Hepatic Fibrosis in Hemodialysis Patients with Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is a major health problem in hemodialysis patients, which leads to significant morbidity and mortality through progressive hepatic fibrosis or cirrhosis. Percutaneous liver biopsy is the gold standard to stage hepatic fibrosis. However, it is an invasive procedure with postbiopsy complications. Because uremia may significantly increase the risk of fatal and nonfatal bleeding events, the use of noninvasive means to assess the severity of hepatic fibrosis is particularly appealing to hemodialysis patients. To date, researchers have evaluated the performance of various biochemical, serological, and radiological indices for hepatic fibrosis in hemodialysis patients with HCV infection. In this review, we will summarize the progress of noninvasive indices for assessing hepatic fibrosis and propose a pragmatic recommendation to diagnose the stage of hepatic fibrosis with a noninvasive index, in hemodialysis patients with HCV infection.

Factors associated with the development of extrahepatic malignancy in patients with nonalcoholic fatty liver disease: a single-center longitudinal study.

The aim of the present study was to determine incident cases of extrahepatic malignancy in patients with nonalcoholic fatty liver disease (NAFLD) and to identify whether the factors are associated with cancer development. Between 15 January 2001 and 14 March 2021, a total of 1365 patients had been diagnosed with NAFLD were enrolled in the study. The median follow-up period was 59.5 months. The mean age was 50.9 ± 10.9 years. The female gender was predominant (57%). During the follow-up period, 62 extrahepatic malignancies and 11 hepatocellular carcinomas were identified. Of all extrahepatic malignancies, 51 were solid organ malignancies and 11 were hematological malignancies. Female breast cancer was the most frequent (25.8%), followed by thyroid cancer (19.4%), lymphoma (12.9%), and lung cancer (9.7%). In univariate and multivariable analyses, after adjusting for age and sex, the presence of diabetes and high initial baseline gamma glutamyl transpeptidase (GGT) levels were significantly associated with the development of extrahepatic malignancies [hazard ratio (HR) = 1.82, 95% confidence interval (CI): 1.04-3.20, P = 0.036] and HR = 1.96, 95% CI: 1.14-3.38, P = 0.015, respectively). In 424 biopsy-proven NAFLD patients, the development of extrahepatic cancer was significantly associated with the severity of hepatic fibrosis (HR = 3.31, 95% CI: 1.36-8.07; P = 0.008). Extrahepatic malignancies are frequently seen in patients with NAFLD. Diabetes mellitus, high baseline GGT levels, and significant hepatic fibrosis are associated with the development of extrahepatic cancer in patients with NAFLD.

Iron metabolism mediates the relationship between Vitamin C and hepatic steatosis and fibrosis in NAFLD.

Vitamin C (Vit C) and iron metabolism are closely related to metabolic disorders. However, the relation between iron storage protein ferritin and Vit C has not been elucidated. We aimed to investigate the crosstalk between Vit C and ferritin and its implications on non-alcoholic fatty liver disease (NAFLD). Clinical information of 3,614 subjects was obtained from the NHANES Public Data 2017–2018. FibroScan data, which estimates liver steatosis and fibrosis and Vit C, were selected to assess factors influencing NAFLD in this cross-sectional study. Ferritin and Vit C among different categories of liver steatosis and fibrosis were assessed by CAP and E value. Logistic regression and RCS models were used to analyze the correlations. In vitro study in hepG2 were conducted to validate the regulations. Ferritin increased while Vit C decreased with more severe hepatic steatosis and hepatic fibrosis (all P < 0.001). Logistic regression models indicated that increased serum ferritin was a risk factor for NAFLD while increased Vit C was a protective factor for NAFLD and hepatic fibrosis after adjusting the continuous and categorical variables. Vitamin C was negatively associated with ferritin. Further mediation analysis identified that ferritin mediates the impact of Vit C on NAFLD (P < 0.05) and cirrhosis (P < 0.001). The experiments on cellular level suggested Vit C alleviated PA/OA induced steatosis and maintains iron homeostasis through inhibiting PA/OA induced upregulation of iron bound protein ferritin and labile iron pool (LIP) induction in hepG2 cells. In conclusion, Vit C was a protective factor, whereas ferritin was a risk factor for hepatic steatosis and fibrosis. Vitamin C alleviated NAFLD and maintained iron homeostasis via ferritin suppression and LIP induction.

Assessment of Visceral Fat Volume and Its Correlation with the Severity of Hepatic Fibrosis in Patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease. The spectrum of NAFLD includes simple steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. Our study aimed to calculate visceral fat volume at the L3-L4 vertebral level and its association with hepatic fibrosis assessed by transient elastography. All patients above 18 years undergoing computed tomography (CT) abdomen in the Department of Radiodiagnosis of Medical College Thiruvananthapuram during the study period with NAFLD were included. Transient elastography was done. Patients were categorized to advanced fibrosis (&gt;10 kPa) and without advanced fibrosis (&lt;10 kPa). The area under the receiver operating characteristic (AUROC) curve was plotted. Sixty-four patients comprised 36 males and 28 females. Thirty-one (46%) were having advanced fibrosis (transient elastography&gt;10 kPa) and 34 (54%) patients were without advanced fibrosis. About 0.733 was the AUROC for visceral fat in predicting advanced fibrosis. The cutoff was 167.5cm3 (sensitivity was 77.4% and specificity was 51.5% in predicting advanced fibrosis). About 0.733 was the AUROC for visceral fat in predicting advanced fibrosis. The cutoff was 167.5cm3 (sensitivity was 77.4% and specificity was 51.5% in predicting advanced fibrosis).

Myrrhone inhibits the progression of hepatic fibrosis by regulating the abnormal activation of hepatic stellate cells.

We focus on exploring the antihepatic fibrosis effect of Myrrhone (Myr), a compound extracted from myrrh, and its effective target. Mouse hepatic stellate cells (HSCs) were cultured in vitro and activated by transforming growth factor-β induction. After Myr intervention, cell viability was assessed by theCell Counting Kit-8 assay. The α-smooth muscle actin(α-SMA) and Collagen I levels were measured by immunofluorescence, and the expressions of tumor necrosis factor-α, interleukin-6, andmatrix metalloproteinase-9were examined by enzyme-linked immunosorbent assay, and the p-Smad3 protein level in HSCs was determined by Western Blot. Small molecule-protein docking and pull-down experiments were conducted to validate the binding capacity between Nard and Smad3. In animal experiments, a mouse model of hepatic fibrosis was established with carbon tetrachloride. Myr was administered by gavage daily to determine the serum alanine aminotransferase and aspartate transaminase levels. The severity of hepatic fibrosis was evaluated by Masson staining, the α-SMA and Collagen I expressions were measured by immunohistochemistry, and the histopathological changes were examined by Sirius red and hematoxylin and eosin staining. Myr suppressed the abnormal activation of HSCs, inhibited the cell viability, downregulated the α-SMA and Collagen I, and inhibited the p-Smad3 expression. After silencing Smad3, the effect of Myr was inhibited. Molecular docking and pull-down experiments revealed the presence of a targeted binding relationship between Myr and Smad3. In mouse experiments, Myr could inhibit hepatic fibrosis. This study discovers that Myr can affect the phosphorylation of Smad3, and inhibit the activation of HSCs and the progression of hepatic fibrosis.

Diagnostic validity of serum YKL-40 as a non-invasive diagnostic marker of oesophageal varices in cirrhotic hepatitis C virus patients

BackgroundLiver cirrhosis is the last phase of chronic hepatitis C virus infection. During the compensated phase, portal pressure is still below the point where varices start to form. On the contrary, decompensated individuals have clinically significant portal hypertension. YKL-40 protein is categorized as an inflammatory protein and is related to various different variables in expressing the severity of hepatic fibrosis, including hepatic venous pressure gradient. The objective of this research was to evaluate the diagnostic validity of serum YKL-40 in cirrhotic hepatitis C virus patients as a predictive non-invasive marker for the diagnosis of oesophageal varices and to compare it to other non-invasive clinical, laboratory, and ultrasonographic parameters, as well as endoscopy with and without treatment modalities.ResultsThe present research was done on 80 participants visiting the Tropical Medicine Department at the Main University Hospital in Alexandria; they were divided into four groups, group I (n = 20) cirrhotic patients with no oesophageal varices, group II (n = 20) with small varices, group IIIa (n = 20) with large varices, and group IIIb same patients of group IIIa but after disappearance of varices by band ligation and medical treatment with carvedilol and group IV as apparently healthy control. YKL-40 in serum was evaluated using ELISA. Serum YKL-40 was statistically significantly higher in all cirrhotic patients than healthy controls (p = <0.001). Furthermore, it was statistically significantly greater in patients with small varices compared to those without varices (p = <0.001) and in large varices rather than no varices or small varices (p < 0.001) and (p < 0.001) respectively. However, there was no statistically significant difference between IIIa and IIIb (p = 0.881). In all tested groups, there was no correlation between serum YKL-40 and FIB-4 or APRI. However, only participants in group I exhibited a significant negative correlation between serum YKL-40 and AST/ALT ratio, whereas subjects in groups II and IIIa exhibited no significant correlation.ConclusionSerum YKL-40 could be used as a sensitive non-invasive predictor for diagnosis and grading of oesophageal varices but not for follow up after treatment.

The impact of body mass index on clinicopathological features of nonalcoholic fatty liver disease in Taiwan.

The aim of this study was to assess the impact of body mass index (BMI) on the clinical and histological characteristics of patients with nonalcoholic fatty liver disease (NAFLD). Patients with clinically diagnosed NAFLD who received liver biopsy were retrospectively enrolled from 2007 to 2019. For comparison, all of the patients were divided into lean body mass (<23kg/m2 ), overweight (23-24.9kg/m2 ), and obesity (BMI≧25kg/m2 ). A total of 572 patients with histologically confirmed NAFLD, including 40 (6.99%) lean body mass, 54 (9.44%) overweight, and 478 (83.57%) obese patients, were recruited. Obese NAFLD patients had significantly higher grade of steatosis (grade 3: 29.92% vs 22.22% vs 12.5%, P<0.0001) and hepatocyte ballooning (grade 2: 14.85% vs 12.96% vs 12.5%, P<0.0001) than overweight and lean NAFLD patients. The prevalence of nonalcoholic steatohepatitis (NASH) was 22.5%, 25.93%, and 36.19% in lean, overweight, and obese NAFLD patients, respectively. Obesity was significantly associated with fibrosis severity (P=0.03). The fibrosis index based on four factors (FIB-4) score can identify NAFLD patients without significant fibrosis or with cirrhosis. The areas under the receiver-operating characteristic curve of FIB-4 score to identify patients without significant fibrosis or with cirrhosis were 0.82 (95% confidence interval [CI]: 0.69-0.96) and 0.87 (95% CI: 0.76-0.99) in lean patients; 0.77 (95% CI: 0.61-0.93) and 0.81 (95% CI: 0.59-1.0) in overweight patients; and 0.77 (95% CI: 0.72-0.82) and 0.89 (95% CI: 0.85-0.92) in obese patients. The majority of NAFLD patients are obese, as defined by BMI. Obesity was significantly associated with NASH and hepatic fibrosis severity in patients with NAFLD.