Elevated Alanine Aminotransferase Levels Research Articles

Assessing the Impact of Annona muricata Aqueous Extract on Liver Enzymes in Wister Rats Exposed to Paracetamol Over Dose

Aims: This study examines the effect of the aqueous leaf extract of Annona Muricata on liver enzymes in wister rats using the spectrophotometric method. Methodology: 20 Wister rats were divided into groups A, B, C, and D, of 5 rats each, housed, fed, and the experimental groups administered treatments orally in distilled water (10 ml/kg) by means of orogastric cannula for 14 days. 500g of the plant powder was submerged for 72 hours 1500ml of distilled water. The sample was taken with a rotating evaporator, an electrical evaporator extraction apparatus. With water heated to 45°C, the solvent was removed. Before use, a paste-like sample was made and kept in a refrigerator at 4 degrees Celsius. The animals in group A were used as the control. The animals in group B were given feeds + 20mg of paracetamol, and the animals in group C were administered 100mg of paracetamol + silymarin. In comparison, the ones in group D were given 150mg of paracetamol + Annona muricata extracts. The animals were then sacrificed 48 hours following the final dose. A blood sample was collected, allowed to coagulate, and then the serum was separated, while the liver was excised and utilized for biochemical analyses. Results: The alanine aminotransferase activities (ul) recorded 9.0±2.71, 14.67±1.5, 13.50±0.58, 15.75±2.50 for animals in groups A, B, C, and D respectively with corresponding activities of aspartate aminotransferase (ul) of 7.25±0.50, 27.33±4.04, 20.00±2.71, 17.25±1.71. Results revealed a significant difference (p<0.05) in the activities of ALT and AST of all the treated groups. Thus, the aqueous leaf extract of Annona muricata could be hepato-protective. The silymarin could also be hepatoprotective, but it is less effective than Annona muricata. The untreated group, B, showed elevated levels of alanine aminotransferase and aspartate aminotransferase, confirming paracetamol's hepatotoxic activity. Conclusion: The ethanol leaf extract of Annona muricata decreased the activities of liver enzymes in male wister rats, suggesting its hepato-protective tendency. It also does not encourage body weight loss.

Correlation of alanine aminotransferase levels and a histological diagnosis of steatohepatitis with ultrasound-diagnosed metabolic-associated fatty liver disease in patients from a centre in Nigeria

BackgroundMetabolic-associated fatty liver disease (MAFLD) is defined as the occurrence of hepatic fat accumulation in patients with negligible alcohol consumption or any other cause of hepatic steatosis. This study aimed to correlate the ultrasound-based diagnosis of MAFLD with the histological diagnosis of nonalcoholic steatohepatitis (NASH) and alanine aminotransferase (ALT) levels in patients with MAFLD.MethodsThis was a hospital-based cross-sectional study of 71 patients with MAFLD diagnosed by ultrasound. Percutaneous liver biopsy was performed for histological evidence of NASH in all patients, regardless of liver function test (LFT) values, provided that they had no contraindications. Liver histology was graded using the NASH Clinical Research Network MAFLD Activity Score. The data obtained were entered into SPSS version 21 and analysed using descriptive and inferential statistics. The significance level was set at < 0.05.ResultsA total of 71 patients (26 males and 45 females) with MAFLD were included. Thirty-nine (76.5%) patients with MAFLD and normal ALT levels had NASH, while 14 (82.4%) had elevated ALT levels. There was no statistically significant difference in the histological grade of NASH between patients with normal and elevated ALT levels. A weak correlation was found between the severity of steatosis on ultrasound scan and NASH incidence (p = 0.026). The sensitivity and specificity of ALT levels for predicting NASH according to the area under the receiver operating characteristics (AUROC 0.590) at an ALT cut-off value of 27.5 IU/L were 55.8% and 64.7%, respectively.ConclusionNASH can occur in patients with MAFLD, irrespective of alanine transaminase (ALT) levels, and ultrasound grading of the severity of steatosis cannot accurately predict NASH. Liver biopsy remains the investigation of choice.

Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats

Abstract This research aimed to explore the protective and therapeutic properties of safranal in mitigating inflammation and oxidative stress induced by elevated acetaminophen (APAP) doses in a rat model. The protective and therapeutic effects of safranal were determined by histopathologically and examining some biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), glutathione, glutathione peroxidase, catalase, malondialdehyde, interleukin-6, tumor necrosis factor-α, and interleukin-1β. Male Wistar–Albino rats were subject to random allocation, forming five groups, each comprising seven rats (n = 7) in the study. Group 1 was the control group. APAP was administered in Group 2 to induce hepatotoxicity. Rats in Groups 3, 4, and 5 received intraperitoneal injections of safranal at doses of 0.025, 0.05, and 0.1 mL/kg/day for 14 days, respectively. On the 15th day, to induce APAP-induced hepatotoxicity, four groups (Groups 2, 3, 4, and 5) acquired a single intraperitoneal injection of 600 mg/kg APAP. The presence of APAP-induced hepatotoxic effect was proven by elevated AST and ALT levels, which are typical biomarkers of liver function in addition to the demonstration of histopathological changes. The findings suggest that pre-treatment with safranal may offer a protective effect against hepatotoxicity by attenuating oxidative stress and the inflammatory response.

Hepatotoxic effects of Stevia rebaudiana leaf extract and commercial stevia on rats: a comparative study

The popularity of stevia is high, especially among diabetics and those looking to reduce their calorie-intake. The aim of this study was to compare the effects of a commercially-available stevia and of a Stevia rebaudiana leaf extract on the liver function and histology of rats. After preparing the Stevia rebaudiana leaf extract, 60 healthy adult male rats were randomly separated into three groups: untreated control, commercial stevia treatment (25 mg/kg), and Stevia rebaudiana leaf extract treatment (25 mg/kg). Our results show that after 60 days of treatment (oral administration), a significant elevation of the alanine aminotransferase (ALT) levels was observed in the commercial stevia-treated group, suggesting potential effects on liver function. The Stevia rebaudiana leaf extract-treated group also exhibited increased ALT levels. Moreover, the aspartate aminotransferase (AST) levels were found significantly increased in both of these treatment groups (when compared to the control group). Alkaline phosphatase levels were not found altered between groups. Histological-examinations, in spite of the elevated ALT and AST levels, exhibited no abnor¬malities in the liver. Although stevia is generally regarded as safe, this study underlines the importance of considering the type and form of stevia when evaluating its effects on liver health. Further study is warranted so as to elucidate the specific components and mechanisms responsible for the observed variations in liver enzymes, and to confirm the overall safety of stevia products.

Mesenteric panniculitis associated with non-alcoholic fatty liver disease: a case series

Mesenteric panniculitis (MP) is a benign inflammatory condition of the abdominal mesentery which presents with a wide variety of symptoms. It is diagnosed non-invasively through computed tomography (CT) scan, whereas biopsy is still considered the gold standard. Steroids are the first line of treatment. Here, we report four cases who presented with abdominal pain. These patients were overweight and the CT scan findings were suggestive of mesenteric panniculitis. Three cases had concomitant non-alcoholic steatohepatitis with elevated alanine transaminase levels, dyslipidaemia, and insulin resistance. FibroScan showed moderate to severe steatosis. PNPLA3 rs738409 genotype was homozygous positive (GG) in one patient, whereas two patients were heterozygous positive (CG). This association has not been well-described so far and warrants further investigation. There may be some common predisposing factors. Key words: Mesenteric panniculitis, Non-alcoholic steatohepatitis, Dyslipidaemia, Insulin resistance.

Heparin-induced DRESS syndrome in a paediatric patient and successful anaesthetic management in cardiovascular bypass surgery: case report

BackgroundDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin.Case presentationWe report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia.ConclusionThe severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient’s needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.

Assessment of Gastrointestinal Manifestations and Predictive Factors Associated with Their Occurrence in Kawasaki Disease Patients: A Cross-Sectional Study

Background: Kawasaki disease is an idiopathic febrile systemic vasculitis, recognized as the leading cause of acquired heart disease in pediatric patients. Gastrointestinal manifestations can lead to delayed treatment, underscoring the importance of identifying and predicting factors associated with these manifestations to enable timely intervention. Objectives: The primary objective of this study was to identify the aforementioned factors. Methods: This retrospective study collected demographic information, medical history, physical examination findings, and laboratory results of 359 children suspected of having Kawasaki disease and referred to Mofid Children’s Hospital between 2013 and 2022. The study assessed the frequency of gastrointestinal manifestations and their association with physical examination findings and laboratory data. Results: A total of 359 patients were included in the study, comprising 153 males and 206 females. The mean age of participants was 2.8 ± 2.6 years. Abdominal pain was the most common clinical manifestation, reported in 39% of patients. Elevated levels of aspartate aminotransferase (AST) were observed in 38.1% of patients, while 30.2% showed elevated alanine aminotransferase (ALT) levels, and 10.5% exhibited direct hyperbilirubinemia. Patients with elevated ALT and AST levels had a higher incidence of abdominal pain, nausea/vomiting, and anorexia. Moreover, patients with positive findings of red blood cell (RBC) and white blood cell (WBC) in their stool examination had a higher incidence of fever and abdominal pain. Conclusions: Based on our statistical analysis, elevated AST and ALT levels, hyperbilirubinemia, and positive stool findings of RBC and WBC appear to be predictive factors for gastrointestinal manifestations in Kawasaki disease.

Growth performance, physiological response, and tissue microarchitecture of the carp Labeo rohita challenged with AFB1 are improved by supplementing with turmeric

Aim of study: To examine the impact of dietary supplementation with turmeric (TM) (Curcuma longa) on growth, haematological, biochemical parameters, and histoarchitecture in rohu (Labeo rohita) challenged with aflatoxin B1 (AFB1).&#x0D; Area of study: Ludhiana, Punjab, India.&#x0D; Material and methods: A completely randomized design involved the utilization of 225 fingerlings distributed across five treatments with three replicates each. Diets were allocated as follows: T1 denoted the negative control diet, T2 comprised AF100, while T3, T4, and T5 were formulated with AF25TM, AF50TM, and AF100TM, respectively.&#x0D; Main results: The results indicated a negative correlation between AFB1 dosage in feed and fish growth, with higher doses resulting in decreased growth. Significant changes were observed in haematological parameters, including reductions in total erythrocyte count, total leukocyte count, haemoglobin, and packed cell volume, alongside alterations in biochemical parameters, such as decreases in total protein, albumin, and globulin levels, and an increase in glucose levels and albumin/globulin ratio. Additionally, elevated levels of aspartate aminotransferase, alanine aminotransferase, catalase and superoxide dismutase were noted in T2 and T5 compared to other treatments. AFB1 exposure also led to damage in the microarchitecture of the brain, kidney, and liver tissues, although inclusion of TM at 25 ppb AFB1 showed signs of recovery.&#x0D; Research highlights: The changes observed were dose-dependent, and supplementation of TM showed increased resistance against AFB1 and the greatest improvement in T3. Therefore, a diet containing 5 g TM kg-1 would lower AFB1 contamination of 25 ppb compared to 50 and 100 ppb. In conclusion, supplementing TM in fish feeds can help regulating the AFB1, which in turn can improve sustenance-based output.

Impact of hepatic inflammation and fibrosis on the recurrence and long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after hepatectomy

BackgroundUnderlying liver disease is correlated with hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV) infection. However, the impact of hepatic inflammation and fibrosis on the patients’ prognoses remains unclear.MethodsThe clinicopathological data of 638 HBV-infected patients with early-stage HCC between 2017 and 2019 were prospectively collected. Hepatic inflammation and fibrosis were evaluated by experienced pathologists using the Scheuer score system. Survival analysis was analyzed using the Kaplan–Meier analysis.ResultsApplication of the Scheuer scoring system revealed that 50 (7.9%), 274 (42.9%), and 314 (49.2%) patients had minor, intermediate, and severe hepatic inflammation, respectively, and 125 (15.6%), 150 (23.5%), and 363 (56.9%) patients had minor fibrosis, advanced fibrosis, and cirrhosis, respectively. Patients with severe hepatitis tended to have a higher rate of HBeAg positivity, higher HBV-DNA load, elevated alanine aminotransferase (ALT) levels, and a lower proportion of capsule invasion (all Pp < 0.05). There were no significant differences in the recurrence-free and overall survival among the three groups (P = 0.52 and P = 0.66, respectively). Patients with advanced fibrosis or cirrhosis had a higher proportion of HBeAg positivity and thrombocytopenia, higher FIB-4, and larger tumor size compared to those with minor fibrosis (all P < 0.05). Patients with minor, advanced fibrosis, and cirrhosis had similar prognoses after hepatectomy (P = 0.48 and P = 0.70). The multivariate analysis results indicated that neither hepatic inflammation nor fibrosis was an independent predictor associated with prognosis.ConclusionsFor HBV-related HCC patients receiving antiviral therapy, hepatic inflammation and fibrosis had little impact on the post-hepatectomy prognosis.

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner.

Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus-pituitary-adrenal axis overactivity.

Abstract CT142: Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML)

Abstract Background: The novel small-molecule inhibitor and degrader, BPI-23314, targeting of the bromodomain and extra-terminal domain (BET) family proteins, BPI-23314, has been showndemonstrated promising preclinical efficacy in hematologic malignancies. This Phase 1 study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of BPI-23314 monotherapy in patients with relapsed or refractory acute myeloid leukemia (R/R AML). Methods: This ongoing phase 1 study of BPI-23314 enrolled adult patients with R/R AML. Dose escalation was conducted using a standard 3+3 design, followed by additional expansion cohorts to further assess safety and preliminary efficacy. BPI-23314 tablets were administered orally once daily (QD) or twice daily (BID) in consecutive 21-day cycles. The key endpoints included determining the recommended Phase 2 dose (RP2D), safety, pharmacokinetics, and preliminary efficacy. Results: As of July 31, 2022, a total of 22 patients diagnosed with R/R AML were treated with BPI-23314 at seven different dose levels, ranging from 5 to 60 mg QD or 40 to 50 mg BID. The median age of the patients was 48 years (range: 19-68 years), and the median treatment duration was 6 weeks (range: 2-9 weeks). The median number of prior therapy lines was 3 (range: 1-4), with 15 (68.2%) being refractory to last line of therapy. Due to the high incidence of grade≥3 anemia, thrombocytopenia, and neutropenia among the patients at baseline, most treatment-emergent adverse events (TEAE) of hematologic toxicities were mainly correlated with disease progression. Only one patient experienced grade 3 treatment-related adverse events (TRAE) comprising anemia (4.5%) and neutropenia (4.5%). Non-hematologic TRAEs were predominantly of grade 1-2. The most common TRAEs (≥10%) were gastrointestinal reactions (10/22, 45.5%), hypertriglyceridemia (6/22, 27.3%), hyperbilirubinemia (4/22, 18.2%), elevated alanine aminotransferase levels (3/22, 13.6%), and increased gamma-glutamyl transferase levels (3/22, 13.6%). Gastrointestinal reactions characterized by nausea and/or diarrhea were the most commonly reported toxicities. The most common TEAEs associated with disease progression were infection and bleeding. No dose-limiting toxicity or treatment-related deaths were reported during the study period, and the maximum tolerated dose was not reached. Among the evaluable responses in all dose levels for R/R AML patients (n=21), one patient achieved complete response (CR) at a dosage of 40 mg BID while three patients maintained stable disease (SD) across various dosages, including QD at 60 mg and BID at both 40 mg and 50 mg. Furthermore, BPI-23314 demonstrated moderate elimination kinetics, with a plasma half-life ranging from 8.6 to 23.3 hours, while exhibiting dose-proportional exposure. Conclusion: BPI-23314 monotherapy exhibited preliminary clinical efficacy with manageable adverse events in patients with R/R AML. The study is ongoing. The satisfactory pharmacokinetic attribute and outstanding safety profile of BPI-23314 provide compelling rationales for further exploration of its therapeutic potential. Citation Format: Mingyuan Sun, Xiangyu Jin, Jing Guo, Xiaoyun Liu, Yan Xu, Hong Lan, Jiabing Wang, Jiangnan Zhen, Jing Yang, Lieming Ding, Junyuan Qi. Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT142.

Prevalence and Associated Factors of Liver Enzyme Abnormalities Among Bangladeshi Women: A Cross-Sectional Study.

Background Liver enzyme abnormalities can indicate underlying liver health issues and are influenced by various factors. This study aimed to investigate the prevalence of liver enzyme abnormalities and their associated factors among nonpregnant and nonlactating (NPNL) women in Bangladesh. Methodology A cross-sectional study was conducted among 251 NPNL Bangladeshi women. Data on demographic, socioeconomic, and health-related variables were collected. Logistic regression analysis was used to determine the association between liver enzyme abnormalities and associated factors. Results The prevalence of liver enzyme abnormalities among participants was determined, with associated factors such as age, body mass index (BMI), monthly income, and food security status examined. Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in 54 (21.5%) and 47 (18.7%) of participants, respectively, with 116 (46.2%) exhibiting an AST/ALT ratio exceeding 1.00. Food insecurity was significantly associated with a higher prevalence of elevated ALT levels (24.4% vs. 8.7%, P = 0.02), as well as low monthly income (18.8%, 14.7% vs. 36.7%, P < 0.01) and higher BMI (11% vs. 27.7% and 25.6%, P = 0.02). Similar trends were observed for AST levels. Moreover, participants with a higher BMI exhibited significantly higher rates of at least one abnormal liver function enzyme (15.9% vs. 34.9%, P = 0.01). Logistic regression analysis revealed a significant association between abnormal liver enzyme levels and certain demographic and socioeconomic factors, specifically BMI and age. Conclusions This study provides insights into the prevalence of liver enzyme abnormalities and their associated factors among NPNL Bangladeshi women. The findings underscore the importance of addressing factors such as BMI and age in mitigating liver health issues in this population. Further research and targeted interventions are warranted to address these concerns effectively.

The interplay between diabetes and non-alcoholic fatty liver disease: a cross-sectional study from Pakistan.

Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic deposition of fat in the liver, in the absence of other secondary causes of fat buildup. The relationship between NAFLD, including alanine aminotransferase (ALT), and glycated haemoglobin (HbA1c), is important for predicting the severity of disease and prognosis. This study aims to investigate the association of HbA1c in type 2 diabetes mellitus (T2DM) patients with NAFLD via measuring the ALT levels. This retrospective cross-sectional study enroled 130 patients with T2DM and NAFLD. The association between levels of HbA1c and ALT in patients of NAFLD with controlled and uncontrolled T2DM, respectively, was investigated. Stratification was done based on gender and diabetic control, using HbA1c levels as a marker of glycemic control. Serum ALT levels were also compared in both groups. The mean age of the participants was 50.2±5.7 years. The total participants were 130, of which 77 (59.3%) were females and 53 (40.7%) were males. The numbers of patients having uncontrolled T2DM (HbA1c>7%), and controlled T2DM (HbA1c <7%) were 78 (60%) and 52 (40%), respectively. Moreover, 46 (35.3%) females and 32 (24.7%) males had uncontrolled T2DM, and 31 (23.8%) females and 21 (16.2%) males had controlled T2DM. The mean ALT level for uncontrolled and controlled T2DM in female patients was found to be 24.6±3.4 and 13.5±2.4, respectively, (P <0.05). For male patients, it was found to be 54.0±4.9 and 29.1±5.4, respectively (P=0.008). There is a positive association between elevated HbA1c and ALT levels in T2DM patients with NAFLD.

Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis

BackgroundCheckpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and...

Porphyromonas gingivalis Strain W83 Infection Induces Liver Injury in Experimental Alcohol-Associated Liver Disease (ALD) in Mice

The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.

Patients with chronic hepatitis B who have persistently normal alanine aminotransferase or aged 

BackgroundThe timing of antiviral therapy for chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) or aged < 30 years is still undetermined. We aimed to elucidate the correlation between liver histology, age, and ALT level in CHB patients and analyze the histological characteristics of the liver among patients with persistently normal ALT or aged < 30 years.MethodsA retrospective analysis was conducted on 697 treatment-naive CHB patients. Liver biopsies were performed, and significant histological damage was defined as the grade of liver inflammation ≥ G2 and/or fibrosis ≥ S2 based on the Scheuer scoring system.ResultsThe liver inflammation grades and fibrosis stages correlated positively with age, ALT, AST, GGT levels and negatively with the counts of PLT (all p < 0.050) in HBeAg-positive patients. Higher ALT levels and lower PLT counts were independently associated with significant liver inflammation and fibrosis in both HBeAg-positive and HBeAg-negative patients. Furthermore, among those with persistently normal ALT levels, the incidence of significant liver inflammation and fibrosis were 66.1% and 53.7% in HBeAg-positive groups, and 63.0% and 55.5% in HBeAg-negative groups. Moreover, there was no significant difference in the prevalence of significant liver damage between patients aged < 30 years and those aged ≥ 30 years, in both HBeAg-positive (≥ G2 or ≥ S2: 63.8% vs. 75.8%, p = 0.276) and HBeAg-negative (≥ G2 or ≥ S2: 65.9% vs. 72.5%, p = 0.504) groups, among patients with persistently normal ALT levels.ConclusionsA considerable proportion of CHB patients with persistently normal ALT, including those below the age of 30 years, exhibited significant histological damage. This highlights the importance of initiating early antiviral therapy for HBV-infected individuals, even in the absence of elevated ALT levels.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range, elevated alanine aminotransferase (ALT) levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively. METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected. The incidence rate, cumulative times, and equally and unequally weighted cumulative effects of excess high-normal ALT levels (ehALT) were measured. Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD. RESULTS A total of 83.13% of participants with MAFLD had normal ALT levels. The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group. Compared with those in the low-normal ALT group, the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651 [95% confidence interval (CI): 1.199-2.273] and 1.535 (95%CI: 1.119-2.106) in the third quartile and 1.616 (95%CI: 1.162-2.246) and 1.580 (95%CI: 1.155-2.162) in the fourth quartile, respectively. CONCLUSION Most participants with MAFLD had normal ALT levels. Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

O-sialoglycoprotein Endopeptidase (OSGEP) Suppresses Hepatic Ischemia-Reperfusion Injury-Induced Ferroptosis Through Modulating the MEK/ERK Signaling Pathway.

Hepatic ischemia-reperfusion injury (HIRI) was widely accepted as a critical complication of liver resection and transplantation. A growing body of evidence suggested that O-sialoglycoprotein endopeptidase (OSGEP) was involved in cell proliferation and mitochondrial metabolism. However, whether OSGEP could mediate the pathogenesis of HIRI has still remained unclarified. This study investigated whether OSGEP could be protective against HIRI and elucidated the potential mechanisms. The OSGEP expression level was detected in cases undergoing ischemia-related hepatectomy and a stable oxygen-glucose deprivation/reoxygenation (OGD/R) condition in hepG2 cells. Additionally, it was attempted to establish a mouse model of HIRI, thus, the function and mechanism of OSGEP could be analyzed. At one day after hepatectomy, the negative association of OSGEP expression level with the elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted. Moreover, it was attempted to carry out gain- and loss-of-function analyses of OSGEP in hepG2 cells to reveal its influences on OGD/R-induced injury and relevant signaling pathways. The findings suggested that OSGEP overexpression significantly protected hepG2 cells against ferroptotic cell death, while OSGEP consumption had opposite effects. Consistent with in vitro studies, OSGEP deficiency exacerbated liver functions and ferroptoticcell death in a mouse model of HIRI. The results also revealed that OSGEP mediated the progression of HIRI by regulating the MEK/ERK signaling pathway. Rescue experiments indicated that ERK1/2 knockdown or overexpression reversed the effects of OSGEP overexpression or knockdown on hepG2 cells under OGD/R condition. Taken together, the findings demonstrated that OSGEP could contribute to alleviate HIRI by mediating the MEK-ERK signaling pathway, which may serve as a potential prognostic marker and a therapeutic target for HIRI.

Chemical characterisation of essential oil from Sambucus williamsii Hance leaves and its hepatoprotective effects

This study is the first to examine the effect of leaves of Sambucus williamsii Hance essential oil on acute liver injury. According to gas chromatography–mass spectrometry analysis, the major constituents of S. williamsii essential oil (SEO)were (S)-falcarinol (62.66%), 17-pentatriacontene (7.78%) and tetrapentacontane (8.64%). Mice were pre-treated with SEO for 6 days followed by inducing liver injury with CCl4. The results indicated that SEO protected the liver against CCl4-induced injuries. Elevated levels of alanine-aminotransferase (ALT), aspartate amino-transferase (AST), alkaline phosphatase (ALP) in serum were significantly reduced on SEO pre-treatment. SEO pre-treatment significantly inhibited the oxidative stress and inflammation. Furthermore, toll-like receptor-4 (TLR4)/nuclear factor kappa-B (NF-κB) signalling pathways were significantly modulated by SEO in the liver tissue. The findings demonstrate that the essential oil of S. williamsii has enhancing the resistance to CCl4-induced liver injury.

Toosendanin induces hepatotoxicity by restraining autophagy and lysosomal function through inhibiting STAT3/CTSC axis

Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro, and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo, suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function.