Development Of Liver Injury Research Articles

Serum ECM1 is a promising biomarker for staging and monitoring fibrosis in patients with chronic hepatitis B.

It is critical to assess the extent and progression of liver fibrosis for patients to receive suitable treatments, but its diagnostic methods remain unmet. Extracellular matrix protein 1 (ECM1) has previously been reported to be a key factor in the induction and progression of liver fibrosis. However, little is known about the use of ECM1 as a biomarker to evaluate fibrosis. In a CCl4-induced mouse model of liver fibrosis, the present study demonstrated that ECM1 decreased with gradually increasing fibrosis. Using biopsy as a reference, the serum ECM1 levels decreased with increasing fibrosis stage in 247 patients with liver fibrosis, but there were no significant changes between fibrosis stage 2 and stage 0-1. To improve the performance of ECM1, age, platelet count, and ECM1 concentration were combined to calculate an EPA (ECM1-platelet-age) score (ranging from 0 to 10). The areas under the receiver operating characteristic curve of the EPA scores for the detection of F⩾2, F⩾3, and F4 were 0.6801, 0.7377, and 0.8083, respectively, which showed a comparable or significantly greater diagnostic performance for assessing fibrosis than that of the AST/ALT ratio, APRI score, or FIB-4 score. In HBV patients following antiviral treatment, the dynamics of the EPA score depended on the status of liver fibrosis development. The accuracy of the EPA score in predicting fibrosis regression and progression was 66.00% and 71.43%, respectively, while that of the LSM, another useful method for monitoring hepatic fibrosis changes during treatment, was only 52.00% and 7.14%, respectively. Compared with healthy controls, there were lower levels of serum ECM1 in HBV patients and individuals with HCV infection, MAFLD, ALD, PBC, and DILI. These findings suggested that individuals with reduced ECM1 levels may have a risk of developing liver injury, and further examinations or medical care are needed. In conclusion, the ECM1-containing EPA score is a valuable noninvasive test for staging fibrosis and predicting the progression of liver fibrosis. Additionally, ECM1 alone is an indicator for distinguishing patients with liver injury from healthy controls.

Assessment of the Role of Keratin 18 and High Mobility Group Box 1 Biomarkers for Early Prediction of Drugs and Chemicals Induced Hepatotoxicity A Prospective Study in the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH)

Abstract Background Drug-induced hepatotoxicity represents a major clinical problem worldwide. Hepatotoxicity may be caused by drugs, chemicals used in laboratories and industries or natural products and rodenticides such as metal phosphides. Early identification of hepatotoxicity would facilitate patient- individualized treatment strategies. New biomarkers (HMGB1and K18) used to identify subsequent acute liver injury (ALI) in patients on admission to the hospital. Objectives This study aims to assess the role of keratin 18 and high mobility group box 1 biomarkers in early prediction of drugs and chemicals induced hepatotoxicity for better outcome and to compare these new liver biomarkers with the currently used parameters (ALT & AST) in the early prediction of drugs and chemicals induced hepatotoxicity. Methods This prospective study was conducted on 50 adult patients of both sex presented to the PCC- ASUH with acute intoxication of hepatotoxic drugs or chemicals. For all patients, we measured high mobility group box-1 (HMGB1), keratin-18 (K18), AST and ALT on admission then patients were followed- up for development of liver injury . Subjects were classified into group I (control group), group II (no liver affection) and group III (with liver affection). Receiver operator characteristic (ROC) curve was used to compare sensitivity and specificity to report liver injury versus alanine transaminase (ALT) and aspartate transaminase (AST). Results This study showed that HMGB1 and K18 were much more elevated in patients who developed liver injury in the first hospital presentation when ALT and AST were within normal ranges with a highly significant difference between the hepatotoxic and non-hepatotoxic group. ROC analysis showed that HMGB1 and K18 were more sensitive than ALT and AST and more specific than AST in predicting ALI. Conclusion Elevations in plasma HMGB1, and K18 identified subsequent ALI development in patients on admission to the hospital, soon after drug and chemical overdose, and in patients with ALT and AST in the normal range.

Case analysis of hepatotoxicity caused by vancomycin

BackgroundAlthough the correlation between liver toxicity and vancomycin is generally considered low, it has been observed that the use of vancomycin can lead to abnormal liver function indicators, such as elevated aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, and jaundice. To further understand the clinical features associated with vancomycin-induced liver toxicity and to provide clinical guidance, we conducted an analysis of the characteristics and clinical manifestations of vancomycin-induced liver injury.MethodsPatients with liver function injury who received vancomycin treatment at the Third Xiangya Hospital of Central South University and Hunan Maternal and Child Health Hospital between 2016 and 2021 were selected for retrospective analysis of their general characteristics, vancomycin course, dose, liver function index, severity of liver injury, and concomitant medications.ResultsOf the 4562 patients who received vancomycin, 17 patients were finally included, with an incidence rate of 0.37%. Of these patients, 12 were male (70.6%) and 5 were female (29.4%), ranging in age from 17 to 84 years with a mean average age of 45.41 ± 20.405 years. All patients were evaluated using Naranjo’s score, with score ≥ 3. The dosage, time, and plasma concentration of vancomycin were analyzed and it was found that nine patients (52.94%) had abnormal liver function when initially given a dose of 1 g every 12 hours. In total, 14 patients (82.35%) with liver injury were taking vancomycin in combination with two to four drugs, and severe liver injury occurred in patients taking vancomycin in combination with two drugs. The occurrence time of liver injury was 2–12 days after starting vancomycin, with a mean of 4.53 ± 2.401 days. Of these patients, 16 patients (94.1%) showed liver function abnormalities within 7 days of taking the drug, and 2 patients with grade 3–4 liver injury both showed liver function abnormalities within 3 days of taking the drug. Only 4 of the 17 patients (23.53%) had vancomycin blood concentrations within the normal range, and there was no correlation found between blood concentration and severity of liver injury. Analysis of the correlation between the severity of liver injury and vancomycin showed that none of the patients had allergies such as rash, two patients (11.76%) had jaundice, and fatigue occurred in five patients (29.41%). The remaining ten patients (58.82%) had no symptoms related to liver injury. All 17 patients had abnormal aspartate aminotransferase/alanine aminotransferase levels and 9 patients also had abnormal bilirubin levels. In 15 patients (88.24%), the severity of liver injury was grade 1, indicating mild liver injury, and no correlation was observed between the severity of liver injury and creatinine. Of the 17 patients, 1 patient received no intervention, 4 patients stopped taking vancomycin after developing liver injury, 1 patient reduced the dose, and 11 patients (64.7%) were treated with hepatic protectant.ConclusionAlthough the study concluded that the incidence of liver injury was not high, the liver toxicity of vancomycin should still be considered and liver function indicators should be monitored during the clinical use of vancomycin.

Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations

ObjectiveTo describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA’s surveillance database.MethodsHepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020.ResultsAmong DILIN’s 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause.Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes.ConclusionAmiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Functional analysis of virus-specific CD4(+)T cells and CD8(+)T cells in patients with liver injury caused by Epstein-Barr virus infection

Objective: To analyze the functional differences between virus-specific CD4(+)T cells and CD8(+)T cells in patients infected with Epstein-Barr virus (EBV) who develop liver injury and those who do not. Methods: 45 cases of EBV infections were enrolled, including 28 cases developing liver injuries and 17 that did not. Mononuclear cells from peripheral blood were isolated. CD4(+)T cells and CD8(+)T cells were purified and cultured using recombinant EBV core antigen 2 (EBNA2) for 96 h with stimulation. The CCK-8 method was used to detect cell proliferation. Flow cytometry was used to detect the proportion of CD4(+)T cells and CD8(+)T cells. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of CD4(+)T cells secreting cytokines and CD8(+)T cells secreting molecular toxicity. Real-time quantitative PCR was used to detect the mRNA levels of transcription factors and molecular toxicity in CD4(+)T cell subsets. Flow cytometry was used to detect the immune checkpoints at molecular levels in CD8(+)T cells. The inter-group comparison was performed using a t-test or Mann-Whitney test. Results: There was no statistically significant difference (P > 0.05) in the proliferation proportion of peripheral blood mononuclear cells, CD4(+)T cells, and CD8(+)T cells after stimulation with recombinant EBNA2 between the EBV-infected non-liver injury group and the infected liver injury group (P > 0.05). There was no statistically significant difference in the proportion of CD4(+)T cells secreting related cytokines and the mRNA levels of transcription factors after stimulation with recombinant EBNA2 between the EBV-infected non-liver injury group and the infected liver injury group (P > 0.05).The levels of perforin secreted by CD8(+)T cells and granzyme B after stimulation with recombinant EBNA2 were higher in the EBV infection-induced liver injury group than those in the non-liver injury group [(75.51±23.33) pg/ml vs. (58.99±18.39) pg/ml, P = 0.017] [(117.8±44.55) pg/ml vs. (90.22±34.21) pg/ml, P = 0.034]. The mRNA levels of Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand in CD8(+)T cells in the liver injury group caused by EBV infection were approximately 1.5 and 1.2 times higher than those in the non-liver injury group, respectively, and the difference was statistically significant (P < 0.001), but there was no statistically significant difference in the proportional expression of programmed cell death-1 and cytotoxic T lymphocyte-associated antigen-4 in CD8(+)T cells between the EBV-infected non-liver injury group and infected liver injury group (P > 0.05) Conclusion: Patients with liver injury caused by EBV infection have strong virus-specific CD8(+) T cell toxic effects, which may mediate EBV-induced liver injury.

Ampicillin-Sulbactam-Induced Liver Injury in a Pediatric Patient

Drug-induced liver injury (DILI) is a rare adverse drug reaction (ADR) in pediatric patients and limited reports exist examining ampicillin-sulbactam-induced liver injury. This report summarizes a 12-year-old male who received ampicillin-sulbactam and subsequently developed liver injury characterized by elevated serum aminotransferases and bilirubin. Ampicillin-sulbactam was subsequently discontinued and the patient’s liver function tests (LFTs) rapidly improved. This report describes the rare adverse reaction of ampicillin-sulbactam-induced liver injury.

Development and Validation of a Clinical Risk Score to Predict Immune-mediated Liver Injury Caused by Sintilimab: Assessed for Causality Using Updated RUCAM.

Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event. The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors. Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids. This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.

A clinical study of targeted immunotherapy combined with hepatic arterial chemoembolization in the treatment of liver injury associated with primary liver cancer

Objective: To investigate the conditions of occurrence and factors influencing liver injury caused by molecular targeted drugs and immune checkpoint inhibitors combined with hepatic arterial chemoembolization (TACE) in the treatment of primary liver cancer. Methods: 105 cases of primary liver cancer admitted to the Third Hospital of Hebei Medical University from January 2020 to June 2023 were selected. Patients liver biochemical indicators conditional changes before and after treatment with targeted drugs+TACE and targeted drugs+immune checkpoint inhibitors (ICIs)+TACE were analyzed. Liver injuries above grade 2 and its independent risk factors to predict and evaluate model accuracy were established. Independent samples t-test, analysis of variance, and rank sum test were used for comparison of measurement data between groups. Count data were compared with a χ(2) test between groups. Results: A total of 50 (47.62%) of the 105 cases developed liver injury during the treatment course, with 26 (52%) cases of first-grade liver injury, 16 (32%) cases of second-grade liver injury, 8 (16%) cases of third-grade liver injury, and none of fourth-grade liver injury. There was no statistically significant difference in the incidence of liver injury between the two groups of patients (χ(2)=1.299, P = 0.637). Multivariate logistic regression analysis showed that total bilirubin, prealbumin, and prothrombin activity were independent risk factors for the occurrence of liver injury. The total bilirubin-prealbumin-prothrombin activity (TAP) model was established. TAP diagnosis of grade 2 or higher liver injury had an area under the receiver characteristic curve of 0.935, sensitivity of 84.35%, and specificity of 92.31% at a cut-off value of 1.24, and significantly better diagnostic performance than albumin-bilirubin (ALBI) grade. Conclusion: The occurrence of severe liver injury is minimal and well tolerated in the targeted drug + TACE treatment group and targeted drug + ICIs + TACE treatment group. The TAP model can be used as a new method to assess the risk of liver injury above grade 2 in patients treated with targeted immunotherapy combined with TACE.

Trends in teicoplanin loading dose implementation from 2010 to 2019 and evaluation of safety and efficacy factors: a retrospective cohort study based on a Japanese administrative claims database

BackgroundThe loading dose of teicoplanin (TEIC) is recommended for implementation. However, there is significant discrepancy between the dose settings in the package insert and, in the guidelines, and the actual status of loading doses in Japan is unclear. Furthermore, TEIC causes liver injury as side effect. Although the risk of developing liver injury has not been reported to be increased following a loading dose based on the guidelines, there is a lack of reports in large populations. Therefore, we evaluated the trend in the loading dose and factors affecting the efficacy and safety of TEIC administration.MethodsA Japanese administrative claims database was used in this study. Trends in loading doses were evaluated in target populations administered TEIC between 2010 and 2019. Patient characteristics were adjusted by propensity score matching based on the guideline group (total dose of 3 days > 1,600 mg) and non-guideline group (≤ 1,600 mg) of the loading dose. Finally, univariable and multivariable conditional logistic regression analysis was performed to evaluate factors affecting 30-day mortality and liver injury.ResultsA total of 10,030 patients were selected based on these criteria. The proportion of loading doses based on the recommended guidelines showed an increase over time, regardless of the implementation of therapeutic drug monitoring (TDM), but especially so in cases where TDM was implemented, the loading doses were administered in accordance with the recommendations of the guidelines. Conditional logistic regression analysis showed a relationship between drug management and guidance fees (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.36‒0.55), a reimbursement indicating pharmacist intervention, and a reduction in 30-day mortality. In addition, loading doses based on the recommended guidelines had no influence on liver injury, and other factors were not significantly associated with increased incidence of liver injury.ConclusionThus, this study implies the benefits of pharmacological management as indicated by drug management and guidance fee and supports the implementation of loading doses based on the guideline on TEIC administration.

Chronic non-bacterial osteomyelitis with autoimmune hepatitis: a case report and literature review

Objective: To summarize the clinical characteristics and treatments of chronic non-bacterial osteomyelitis with autoimmune hepatitis in children. Methods: A child who had chronic non-bacterial osteomyelitis with autoimmune hepatitis was admitted to the Department of Gastroenterology of the Children's Hospital Capital Institute of Pediatrics at April 2022. The clinical data was retrospectively analyzed. Using the keywords of "chronic non-bacterial osteomyelitis""autoimmune hepatitis" in Chinese and English, the literature from database establishment to December 2022 in CNKI, Wanfang, China Biomedical Literature Database and Pubmed was searched. Combined with this case, the clinical characteristics and treatment of chronic non-bacterial osteomyelitis combined with autoimmune hepatitis were analyzed. Results: A 5 years and 3 months girl was admitted to the Department of Gastroenterology of Children's Hospital, Capital Institute of Pediatrics for "transaminase elevated for 1 year and swelling of right maxillofacial area for half a year". The physical examinations at admission found a 4.0 cm × 4.0 cm swelling area with tenderness before the right ear, abdominal distention with visible abdominal wall vein, firm and enlarged liver (10.0 cm below the xiphoid and 4.5 cm below the right ribs), and splenomegaly (Line Ⅰ 10.0 cm, Line Ⅱ 11.5 cm, and Line Ⅲ 25.0 cm). There was no redness, swelling or restriction of the limbs. Laboratory examination found abnormal liver function with alanine aminotransferase 118 U/L, aspartate aminotransferase 227 U/L, γ-glutamyltransferase 360 U/L, and positive direct anti-human globulin test; immunology test found immunoglobulin G 41.60 g/L and a homogeneous type of antinuclear antibody of 1∶1 000; the autoimmune hepatitis antibody test found a positive anti-smooth muscle antibody (1∶100). Liver biopsy showed moderate interfacial inflammation and the patient was diagnosed with autoimmune hepatitis (International Autoimmune Hepatitis Group 19). The imaging findings showed extensive involvement of the bilateral mandible, while the right side was severe. There were expansile bone changes, thinning of the bone cortex, and significant swelling of the surrounding soft tissue in the mandibular body, mandibular angle, and mandibular ramus. After treatment of glucocorticoid, the swelling of the right maxillofacial region disappeared and the transaminase returned to normal. Only one case was reported before in English and none in Chinese. The two cases were both girls whose main clinical features were joint pain and swelling. The previous case started with pain in both knee joints, and developed liver injury during treatment while this case had liver injury as the initial clinical presentation. Besides, the affected sites and degrees of arthritis in the 2 cases were different. After glucocorticoid treatment, the clinical symptoms were alleviated, and transaminases returned to normal. Conclusions: Chronic non bacterial osteomyelitis may involve the liver and manifest as autoimmune hepatitis. Glucocorticoids therapy is effective.

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience.

Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato-cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06-189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1-312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5-132): all alive at 19, 18 and 3 years post-LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early-onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

Risk evaluation of carbapenem-induced liver injury based on machine learning analysis

IntroductionInformation regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of liver injury. Thus, we aimed to compare the rate of liver injury between MEPM and DRPM and construct a flowchart that can be used to predict carbapenem-induced liver injury. MethodsWe investigated patients treated with MEPM (n = 310) or DRPM (n = 320) and confirmed liver injury as the primary outcome. We used a chi-square automatic interaction detection algorithm to construct DT models. The dependent variable was set as liver injury from a carbapenem (MEPM or DRPM), and factors including alanine aminotransferase (ALT), albumin-bilirubin (ALBI) score, and concomitant use of acetaminophen were used as explanatory variables. ResultsThe rates of liver injury were 22.9% (71/310) and 17.5% (56/320) in the MEPM and DRPM groups, respectively; no significant differences in the rate were observed (95% confidence interval: 0.710–1.017). Although the DT model of MEPM could not be constructed, DT analysis showed that the incidence of introducing DRPM in patients with ALT >22 IU/L and ALBI scores > −1.87 might be high-risk. ConclusionsThe risk of developing liver injury did not differ significantly between the MEPM and DRPM groups. Since ALT and ALBI score are evaluated in clinical settings, this DT model is convenient and potentially useful for medical staff in assessing liver injury before DRPM administration.

Outcomes of COVID-19 among patients with liver disease

Coronavirus disease 2019 (COVID-19) is primarily a respiratory disease with multi-organ involvement, including impaired liver function. It has been noticed that a significant proportion of COVID-19 patients have liver dysfunction, especially those with a more severe disease course. The coronavirus causes direct damage to the liver using the angiotensin-converting enzyme 2, a cell-surface receptor for cellular entry, that is expressed in the liver. According to previous research, liver enzyme abnormalities were observed in a considerable proportion of COVID-19 patients, and elevated liver transaminases were found in about 20% of these patients, alkaline phosphatase in 6.1%, and gamma-glutamyl transferase in 21.1%. COVID-19 might trigger a deterioration of liver function in patients with pre-existing chronic liver diseases (CLDs) and also in those without previous liver disorders. The majority of COVID-19 patients who develop liver injury are men, the elderly, and those with a higher body mass index. Compared to the general population, COVID-19 is associated with significant morbidity and mortality in patients with liver disease (cirrhosis and liver transplantation recipients). However, some studies indicate that CLDs have a lesser role in determining patient progression towards higher disease severity.

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Thiopurine Hepatotoxicity in Crohn's Disease.

Patients with Crohn's disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD. In this prospective cohort analysis, CD patients at a single center were recruited 6/2017-5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF >5.5%. Statistical analysis was performed using a Cox-proportional hazards model. Of the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2-7.3, P = .018) independent of age, body mass index, hypertension, and type 2 diabetes. Steatosis severity by PDFF positively correlated with peak alanine aminotransferase (ALT) at follow-up. Kaplan-Meier analysis demonstrated poorer complication-free survival (log-rank 13.1, P < .001). NAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy.

Risk of Abemaciclib-induced Liver Injury in Hormone Receptor-positive, HER2-negative Metastatic Breast Cancer: A Retrospective Analysis.

The efficacy of endocrine therapy combined with abemaciclib for hormone receptor-positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI. This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI. Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005]. Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted.

Modification of alprazolam-induced liver injury by bone marrow-derived mesenchymal stem cells and the role of miRNA-192

The group of drugs known as Benzodiazepines (BDZs) are among the most widely prescribed CNS-depressant drugs. Alprazolam (Alp) is a member of the BDZs family, commonly prescribed as an antipsychotic and anxiolytic agent. Induction of oxidative stress, impairment of cognitive functions and psychomotor skills, conformational alterations in hemoglobin structure and elevation of liver enzymes are among the side effects reported on the use of alprazolam. Several studies have found that alprazolam could favor hepatotoxicity, whereas other studies contradicted those findings. Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been studied as a novel approach for treatment of liver diseases. The current study was designed to assess the biochemical, histopathological and molecular liver alterations in response to oral administration of alprazolam at a dose of 0.3 mg/kg/day for 4 weeks in adult male albino rats and to evaluate the therapeutic effect of BM-MSCs on the alprazolam- induced alterations. Forty adult male albino rats (Sprague Dawley strain; 170-200 g mean body weight) were used. Liver enzymes were measured, isolation and preparation of BM- MSCs were done, and immunohistochemical staining for alpha smooth muscle actin and FGF2 were assessed. Moreover, histological and ultrastructural liver tissue examination and PCR detection of SOD, TNF-α and mirNA-192 were investigated. Animals exposed to alprazolam developed liver injury characterized by significant increase in TNF-α and significant decrease in SOD and miRNA- 192 expression. Histological findings provided supportive evidence for the biochemical and molecular analyses. Treatment with stem cells caused a significant alleviation of the alprazolam- induced findings. In conclusion, alprazolam was found to induce liver injury and oxidative stress, which were ameliorated by BM-MSCs administration.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

Identifying Drug-Induced Liver Injury Associated With Inflammation-Drug and Drug-Drug Interactions in Pharmacologic Treatments for COVID-19 by Bioinformatics and System Biology Analyses: The Role of Pregnane X Receptor.

Of the patients infected with coronavirus disease 2019 (COVID-19), approximately 14–53% developed liver injury resulting in poor outcomes. Drug-induced liver injury (DILI) is the primary cause of liver injury in COVID-19 patients. In this study, we elucidated liver injury mechanism induced by drugs of pharmacologic treatments against SARS-CoV-2 (DPTS) using bioinformatics and systems biology. Totally, 1209 genes directly related to 216 DPTS (DPTSGs) were genes encoding pharmacokinetics and therapeutic targets of DPTS and enriched in the pathways related to drug metabolism of CYP450s, pregnane X receptor (PXR), and COVID-19 adverse outcome. A network, constructed by 110 candidate targets which were the shared part of DPTSGs and 445 DILI targets, identified 49 key targets and four Molecular Complex Detection clusters. Enrichment results revealed that the 4 clusters were related to inflammatory responses, CYP450s regulated by PXR, NRF2-regualted oxidative stress, and HLA-related adaptive immunity respectively. In cluster 1, IL6, IL1B, TNF, and CCL2 of the top ten key targets were enriched in COVID-19 adverse outcomes pathway, indicating the exacerbation of COVID-19 inflammation on DILI. PXR-CYP3A4 expression of cluster 2 caused DILI through inflammation-drug interaction and drug-drug interactions among pharmaco-immunomodulatory agents, including tocilizumab, glucocorticoids (dexamethasone, methylprednisolone, and hydrocortisone), and ritonavir. NRF2 of cluster 3 and HLA targets of cluster four promoted DILI, being related to ritonavir/glucocorticoids and clavulanate/vancomycin. This study showed the pivotal role of PXR associated with inflammation-drug and drug-drug interactions on DILI and highlighted the cautious clinical decision-making for pharmacotherapy to avoid DILI in the treatment of COVID-19 patients.

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all patients with DILI had a RUCAM score ≥ 6. Eight clinical variables and variants in six candidate genes were assessed. A logistic multivariate regression analysis identified four risk factors for AT-DILI: age ≥ 55 years (OR:3.67; 95% CI:1.82–7.41; p < 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23–5.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25–4.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02–4.17; p = 0.044). The statistical model explains 24.9% of the susceptibility to AT-DILI, with an 8.9 times difference between patients in the highest and in the lowest quartiles of risk scores. This study sustains the complex architecture of AT-DILI. Prospective studies should evaluate the benefit of NAT2 and ABCB11 genotyping in AT personalization, particularly in patients over 55 years.