Risk Of Liver Injury Research Articles

Management of hepatitis B virus reactivation due to treatment of COVID-19.

The world has made significant progress in developing novel treatments for COVID-19 since the pandemic began. Some treatments target the patient’s dysregulated inflammatory response during COVID-19 infection and may cause hepatitis B reactivation (HBVr) in patients with current or past hepatitis B virus (HBV) infection. This review summarizes the risk and management of HBVr due to different treatments of COVID-19 in patients who have current or past HBV infection. Abnormal liver function tests are common during COVID-19 infection. Current evidence suggests that current or past HBV infection is not associated with an increased risk of liver injury and severe disease in COVID-19 patients. Among patients who received high-dose corticosteroids, various immunosuppressive monoclonal antibodies and inhibitors of Janus kinase, the risk of HBVr exists, especially among those without antiviral prophylaxis. Data, however, remain scarce regarding the specific use of immunosuppressive therapies in COVID-19 patients with HBV infection. Some results are mainly extrapolated from patients receiving the same agents in other diseases. HBVr is a potentially life-threatening event following profound immunosuppression by COVID-19 therapies. Future studies should explore the use of immunosuppressive therapies in COVID-19 patients with HBV infection and the impact of antiviral prophylaxis on the risk of HBVr.

Is there a role for preoperative liver reducing diet in hepatectomy? A systematic review.

Preoperative very low-calorie diets (VLCDs) have been shown to reduce liver volume, reduce the risk of liver injury and improve safety during bariatric surgery. Hepatic steatosis (HS) has been associated with poorer outcomes in liver resection. VLCD can be used to improve HS. We aim to explore if preoperative VLCD could improve outcomes for patients with HS undergoing liver resection. We performed a systematic review of MEDLINE, EMBASE, PubMed and Cochrane databases. Studies were included if they were full-text articles investigating the effect of a preoperative dietary intervention in patients undergoing liver resection on intra-operative and post-operative outcomes. The last search was performed on 11 Jun 2020. Evidence quality was assessed by "GRADE". A narrative review was undertaken. Five studies were found: one RCT and four cohort studies including 133 patients in intervention groups and 181 controls. Three used diet-only strategies and two diet and exercise strategies with varying time courses and monitoring. The quality of evidence assessed by GRADE was "high" for the RCT and "low" for the four cohort studies. Steatosis objectively improved in three studies, with evidence of reduced liver volume and increased attenuation on imaging in one. All studies showed a reduction in body weight and body mass index (BMI). Intra-operative blood loss was decreased following a diet-only intervention in two studies, and liver mobility improved in one. No difference was found in morbidity, mortality or hospital length of stay between intervention and control groups. There is evidence of poorer outcomes in liver resection patients with existing HS. There is an expected role for a preoperative VLCD to optimise these patients for surgery. Existing publications support this, but diet interventions and outcome measures are inconsistent, and patient numbers are small. There is scope for a well-designed, multi-centre randomised trial to investigate this further.

Interaction between the HIF-1α gene rs1957757 polymorphism and CpG island methylation in the promoter region is associated with the risk of anti-tuberculosis drug-induced liver injury in humans: A case-control study.

HIF-1α gene polymorphisms, including rs11549465, rs11549467, rs1957757 and rs10873142, cause liver cell damage or pulmonary disease. The aim of this study was to analyse the association between the polymorphisms of the loci of the HIF-1α gene and its CpG island methylation in the promoter region with the risk of anti-tuberculosis drug-induced liver injury (ADLI). 286 patients with tuberculosis (TB) and ADLI (case group) and 286 patients with TB but without liver injury (control group) were matched one-to-one, among the 1728 TB patients recruited from July 2019 to July 2020. Genotyping of the four loci of the HIF-1α gene was confirmed using PCR-RFLP technology. Methylation of the HIF-1α gene was measured using the MSP method. The comparison of risk factors, HIF-1α genotype and methylation status between the case group and the control group was all achieved through univariate and multivariate conditional logistic regression. Univariate analysis showed that the frequency of rs1957757 mutation genotype and CpG island methylation was significantly higher in the case group than in the control group (P<0.001, all). In contrast, there was no statistical difference in the frequency of mutated genotypes at the other three loci between the two groups (p=0.21, p=0.12 and p=0.55, respectively). Further, multivariate analysis showed that CpG islands were methylated, the mutation genotype of the rs1957757 locus was independently associated with the high risk of ADLI, and the adjusted OR (95%CI) reached 1.92 (1.32-2.63) and 2.01 (1.32-2.83), respectively. Furthermore, taking the rs1957757 locus wild genotype and CpG islands without methylation as the reference group, the mutation genotype and CpG island methylation increased the risk of ADLI, and the probability of ADLI could reach 4.73 times that of the reference group. This is the first demonstration of the association of HIF-1α gene polymorphism and CpG island methylation with ADLI risk stratification. The interaction between CpG islands methylated in the promoter region of the HIF-1α gene and its rs1957757 locus mutant genotype was associated with a higher risk of ADLI.

Nomogram model for predicting risk of anti-tuberculosis drug-induced liver injury among inpatients with tuberculosis

Objective: To explore the influencing factors of anti-tuberculosis drug-induced liver injury (ATB-DILI) in hospitalized tuberculosis patients, and to establish a risk prediction model of Nomogram. Methods: A retrospective study was conducted on 5 681 tuberculosis patients admitted to Guiyang public health treatment center from January 2017 to June 2021, including 3 342 males and 2 339 females. The inpatients with ATB-DILI were selected as the case group (214 cases) and the non-ATB-DILI patients as the control group (5 427 cases). The baseline characteristics, tuberculosis condition, behavior and disease-related data of the patients were retrospectively analyzed, and the influencing factors were screened by chi-square test and multivariate logistic regression, based on which the Nomogram model was constructed and verified. The decision curve was used to evaluate the clinical application value of the model. Results: In this study, 3.8%(214/5 681) patients developed ATB-DILI. Multivariate logistic regression analysis showed that extrapulmonary tuberculosis (OR=1.876, P<0.001), malnutrition (OR=4.411, P<0.001), complicated with underlying liver disease (OR=4.961, P<0.001) and intermittent use of hepatoprotective drugs (OR=2.137, P=0.007) were independent risk factors for ATB-DILI, while whole-course use of hepatoprotective drugs (OR=0.292, P<0.001) was protective factor. The Nomogram model was constructed based on the above five related factors. The area under the receiver operating characteristic (ROC) curve was 0.749 (95%CI:0.713-0.786), the sensitivity was 0.640, and the specificity was 0.752, respectively. The Bootstrap method was used for internal repeated sampling for 1 000 times, the average absolute error was 0.003, the correction curve and the ideal curve were basically fitted, and the predicted values were in good agreement with the actual values. Hosmer-lemeshow test showed that the model had a good degree of fit (χ2=3.068, P=0.381). The decision curve showed that the Nomogram model had certain clinical practicability in the high risk threshold range (0.10-0.68). Conclusions: The Nomogram model for risk predicting ATB-DILI among inpatients with tuberculosis in this study has good predictability, consistency and clinical practicability, and can provide a basis for clinical prevention and control of ATB-DILI and individualized treatment in the process of anti-tuberculosis treatment.

Impact of Prior Drug Allergies on the Risk, Clinical Features, and Outcomes of Idiosyncratic Drug-Induced Liver Injury in Adults.

Prior drug allergies are common and may increase susceptibility to adverse medication effects. The aim of this study was to compare the frequency, clinical features, and outcomes of DILI among patients with and without a history of prior drug allergy. The EMR at a large liver referral center was searched for all DILI encounters using ICD-10T-codes for drug poisoning/toxicity and K-71 codes for toxic liver injury between 10/1/2015 and 9/30/2019. Clinically significant liver injury was identified using predefined laboratory criteria, and cases were adjudicated using a 5-point expert opinion scale: 1/2/3 = probable DILI and 4/5 = non-DILI. Drug allergy was defined as a history of anaphylaxis, hives, rash, or pruritus after drug exposure. Among 766,930 patient encounters, 127 unique patients met inclusion criteria with 72 (56.7%) cases adjudicated as probable DILI and 55 (43.3%) as non-DILI. In the probable DILI group, the most frequent suspect drug classes were: antimicrobials (41.9%), herbal and dietary supplements (9.5%), and antineoplastics (8.1%). Twenty-three of the 72 DILI patients (31.9%) had a history of drug allergy before the DILI episode compared to 16 (29.1%) of the 55 non-DILI cases (p = 0.89). However, none of the allergy drugs and suspect DILI drugs were the same although many were in the same drug class. DILI patients with a prior drug allergy were more likely to be female (73.9% vs. 44.9%, p = 0.04) and have lower serum bilirubin (4.0 vs. 7.8, p = 0.08) and INR (1.1 vs. 1.6, p = 0.043) levels at presentation. The likelihood of death or liver transplantation among probable DILI cases with prior drug allergy was lower than those without prior drug allergy (0% vs. 8.2%, p = 0.35). The suspect drug was subsequently documented in the "Drug Allergy" section of the EMR in only 23 (31.9%) of the 72 probable DILI patients, and these patients were more likely to present with a rash (7% vs. 2%, p = 0.006) and higher serum bilirubin levels (10.5 vs. 4.7, p = 0.008) compared to those in whom the suspect drug was not listed as "drug allergy." A prior drug allergy history was not associated with a greater likelihood of developing DILI compared to other causes of acute liver injury. However, the probable DILI patients with a history of prior drug allergy tended to have less severe liver injury and clinical outcomes. The low rate of suspect drug documentation in the "Drug Allergy" section of EMR after a DILI episode is of concern and could lead to avoidable harm from inadvertent suspect drug re-challenge.

Health Effects of Dietary Oxidized Milk Administration in Offspring Mice during Pregnancy and Lactation with Metabolomic Strategies.

Milk is an important source of nutrients during pregnancy. Previous studies have consistently shown that oxidation in milk and dairy products can induce oxidative stress, inflammation, and fibrosis in the liver and kidney. However, the mechanism underlying these effects remains largely unexplored. This study aimed to investigate the effects of oxidized milk on fecal metabolism and liver and kidney function of offspring mice. Oxidative modification of milk was performed using H2O2-Cu or heating, causing varying degrees of oxidative damage. Kunming female mice were fed with a H2O2-Cu, heat, or normal control diet until their offspring were 3 weeks old. Feces were collected for the metabolomics study based on mass spectrometry. Forty-two potentially significant metabolic biomarkers were screened, and each group's relative intensity was compared. The results showed that oxidized milk mainly regulated isoleucine metabolism, proline metabolism, and tricarboxylic acid cycle. In addition, the histopathological analysis showed accumulation of protein and lipid oxidation products in the liver and kidney tissues after intake of oxidized milk, which induced oxidative stress, increased the levels of inflammatory factors, and significantly increased the expression of genes and proteins involved in inflammatory pathways. The above results suggest that intake of oxidized milk during gestation may increase the risk of liver and kidney injury in male offspring by interfering with amino acid and energy metabolism, highlighting the potential health risks of oxidized milk in humans.

Evaluating Membrane Electrical Properties of SMMC7721 Cells with TiO₂ NPs Applications to Cytotoxicity by Dielectric Spectroscopy.

Titanium dioxide nanoparticles (TiO₂ NPs) represent one of the most frequently applied nanomaterials in numerous areas of daily life. Recent studies show that TiO₂ exposure increases the occupational risk of liver injury and inflammation, and even liver cancer to the workers of factories handling these NPs. However, the potential risks and biophysical effects of TiO₂ on hepatic cells need extensive evaluation. To this end, we explored the electrophysiological changes in the human liver cancer cell line SMMC7721 following exposure to TiO₂ NPs. TiO₂ NPs decreased the first (Δε1) and second dielectric relaxation intensity (Δε₂) of the SMMC7721 cells by 6.62% and 0.86% respectively, and significantly increased the first characteristic frequency (fc1, 4.82%) and the first Cole-Cole parameter (β1, 1.24%). The double spherical-shell model showed that TiO₂ NPs significantly lowered the permittivity of unit-membrane and capacitance, as well as the conductivity of extracellular fluid, cytoplasm, and nuclear contents compared to the untreated control. Conclusively, this study revealed that TiO₂ NPs induce cytotoxic effects by disrupting the permeability and electrical conductivity of unit membranes. Further, we report that dielectric spectrum combined with model parameter analysis can evaluate the bioelectrical effects of TiO₂ NPs on human liver cancer cells.

Ameliorating Effects of Solanum anomalum Thonn. Ex. Schumach Fruit Extracts on Paracetamol-induced Kidney Injuries and Haemato-biochemical Indices in Rats

Paracetamol (acetaminophen) is a widely used non-opioid analgesic and antipyretic drug that is safe at therapeutic doses but toxic to the liver and kidneys in overdose. Although the risk of paracetamol-induced liver injury is much higher than in the kidneys, incidents of kidney damage by paracetamol should not be ignored, given the enormous cost of treating kidney diseases, particularly in resource-challenged developing nations. In an onerous quest for a cheaper and readily available antidote, this study examined the effect of Solanum anomalum fruit extract on paracetamol-induced kidney injuries and haemato-biochemical indices in rats. Twenty-five mature albino rats of both sexes were used, divided into five groups of five rats per group. Group 1 (normal control) rats were given distilled water (10ml/kg) for 8 days, group 2 (negative control) given distilled water (10 ml/kg) for 8 days, group 3 (positive control) given 100 mg/kg Silymarin for 8 days, group 4 given 452 mg/kg of S. anomalum fruit extract for 8 days, and group 5 given 678 mg/kg of S. anomalum fruit extract for 8 days. Thereafter, 2.0 g/kg of paracetamol was administered to groups 2-5 orally on the 8th day. Rats in group 2 showed significant increases in urea, creatinine, sodium ion, total WBCs, decrease in PCV, Hb concentration and RBCs. Administration of Solanum anomalum fruit extract significantly reversed most of these biomarkers. Histopathology of the kidneys also points to the mitigating effect of Solanum anomalum fruit against paracetamol-induced nephrotoxicity.

Combination of molecular docking and liver transcription sequencing analysis for the evaluation of salt-processed psoraleae fructus-induced hepatotoxicity in ovariectomized mice

Ethnopharmacological relevanceSalt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effect of SPF in the treatment of osteoporosis; however, the exact mechanism underlying this phenomenon is unclear.Aim of the study: To evaluate SPF-induced hepatotoxicity in an ovariectomized murine model of estrogen deficiency and examine the mechanisms underlying this process. Materials and methodsTo explore the molecular mechanism of SPF-induced cholestatic liver injury, different concentrations of SPF (5 and 10 g/kg) were intragastrically administered to ovariectomized and non-ovariectomized female ICR mice for 30 days. ResultsSPF-treated mice showed noticeably swollen hepatocytes, dilated bile ducts, and elevated levels of serum biochemical markers. Compared to ovariectomized mice, these changes were more prominent in non-ovariectomized mice. According to the sequence data, a total of 6689 mRNAs were identified. Compared with the control group, 1814 differentially expressed mRNAs were identified in the group treated with high SPF doses (SPHD), including 939 upregulated and 875 downregulated mRNAs. Molecular docking and Western blot experiments showed that liver injury was closely related to the estrogen levels. Compared with the negative control group, the expression levels of FXR, Mrp2, CYP7a1, BSEP, SULT1E1, HNF4a, and Nrf2 decreased in the estradiol-treated (E2), low-dose SPF-treated (SPLD), and SPHD groups. Interestingly, the expression levels of FXR, CYP7a1, SULT1E1, and HNF4α were significantly higher in the ovariectomized groups than in the non-ovariectomized groups (#P < 0.05; ###P < 0.001). ConclusionsOverall, this study demonstrates that SPF downregulates key enzymes involved in cholesterol and bile acid biosyntheses, posing a risk for cholestatic liver injury. SPF also regulates the FXR-SULT1E signaling pathway via HNF4α, which is an important causative factor of cholestasis. Moreover, the severity of liver damage was significantly lower in the ovariectomized groups than in the non-ovariectomized group. These results suggest that the estrogen level is the most critical factor determining liver injury.

Involvement of the CYP1A1 inhibition-mediated activation of aryl hydrocarbon receptor in drug-induced hepatotoxicity.

Hepatotoxicity is one of the most common toxicities observed in non-clinical safety studies of drug candidates, and it is important to understand the hepatotoxicity mechanism to assess the risk of drug-induced liver injury in humans. In this study, we investigated the mechanism of hepatotoxicity caused by 2-[2-Methyl-1-(oxan-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole (DSP-0640), a drug candidate that showed hepatotoxicity characterized by centrilobular hypertrophy and vacuolation of hepatocytes in a 4-week oral repeated-dose toxicity study in male rats. In the liver of rats treated with DSP-0640, the expression of aryl hydrocarbon receptor (AHR) target genes, including Cyp1a1, was upregulated. In in vitro reporter assays, however, DSP-0640 showed only minimal AHR-activating potency. Therefore, we investigated the possibility that DSP-0640 indirectly activated AHR by inhibiting the CYP1 enzyme-dependent clearance of endogenous AHR agonists. In in vitro assays, DSP-0640 showed inhibitory effects on both rat and human CYP1A1 and enhanced rat and human AHR-mediated reporter gene expression induced by 6-formylindolo[3,2-b]carbazole, a well-known endogenous AHR agonist. The possible involvement of CYP1A1 inhibition in AHR activation was also demonstrated with other hepatotoxic compounds tacrine and albendazole. These results suggest that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity caused by DSP-0640 and that DSP-0640 might induce hepatotoxicity in humans as well. We propose that CYP1A1 inhibition-mediated AHR activation is a novel mechanism for drug-induced hepatotoxicity.

Liver Injury and Dysfunction Associated with COVID-19: a Review Article.

The coronavirus disease 2019 (COVID-19) pandemic has had a negative impact on health, the economy, and social life throughout the world. COVID-19 pathology mainly involves the lungs. However, other organs can also be involved, including the liver, resulting in liver injury, elevated liver enzymes and reduced albumin levels. Involvement of the liver may increase the possibility of a misdiagnosis due to atypical presentations. This re-view article aimed to highlight the impact of COVID-19 on the liver, focusing on liver injury and its effect on severity and prognosis. The author reviewed all published and in-press articles about COVID-19-associated liver injury using four electronic databases. A total of 55 articles were included in this review after removing duplicate records and establishing the necessary relevance. This review summarizes the recent studies focusing on how SARS-CoV-2 infection affects liver histology, liver enzymes, and albumin levels. COVID-19 is associated with varying degrees of liver injury, most notably increased levels of aspartate transaminase and alanine transaminase. Patients with severe COVID-19 are more likely to develop liver injury, elevation in the liver enzymes, and reduction in the albumin levels. In addition, COVID-19 patients with pre-existing liver injury are predisposed to develop more severe disease and have a poorer prognosis and higher mortality. Portal inflammation and focal hepatic necrosis are the most common histopathological characteristics observed among COVID-19-associated liver injury patients. The mechanisms of liver injury in COVID-19 are thought to arise from systemic inflammatory responses, hypoxia-reperfusion dysfunction, drug-induced liver injury, and/or a direct effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinicians need to be alert when dealing with COVID-19 patients who have chronic liver disease, particularly when prescribing medications to avoid the risk of drug-induced liver injury. Monitoring liver enzymes and albumin levels during COVD-19 illness is essential, as it predicts disease severity and prognosis.

THE OVERWEIGHT AND OBESITY ROLE IN THE OCCURRENCE OF CHEMOTHERAPY-INDUCED HEPATOTOXIC REACTIONS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA.

The aim: To investigate the frequency of development and nature of cytostatic-induced hepatotoxic reactions in patients with acute myeloid leukemia (AML) with overweight and obesity during remission induction сhemotherapy (CT). Materials and methods: We examined 25 patients with newly diagnosed acute leukemia (AL), of which 56% (14/25) were men, 44% (11/25) were women. Depending on the body mass index (BMI), patients were divided into groups: I (n=10) - patients with AML and BMI of 18.5-24.9 kg/m2; IІ (n=15) - patients with AML and BMI ≥25.0 kg/m2. The biochemical blood analysis was evaluated twice: before and on the 56th day of CT, which included alanine-, aspartate-aminotransferases, gamma-glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), total protein and total bilirubin. Results: In patients with AML and normal BMI, CT conduction increased the risk of GGT (RR=3.00; 95% CI=1.14-7.91; p<0.05) and ALP activity impairment (RR=2.67; 95% CI=0.98-7.22; p>0.05). The presence of overweight and obesity in patients with AML of group II led to significant risk of increase the GGT (RR=3.00; 95% CI=1.46-6.14; p<0.05) and ALP activity (RR=4.00; 95% CI=1.41-11.35; p<0.05) during CT. GGT and ALP activity in the blood serum of group II patients after CT exceeded the baseline data in 2.4 times (p<0.0001) and 1.6 times (p=0.0007), respectively. Conclusions: The remission induction CT of AML is accompanied by the risk of cytostatic-induced liver injury. The presence of overweight, obesity and primary disorders of biochemical liver tests due to the oncohematological disease influence are the risk factors for hepatotoxic reactions development during CT.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Niemann-Pick病C型患者にアセトアミノフェンを使用する際の肝障害リスクに関する基礎的検討

Niemann-Pick病C型患者にアセトアミノフェンを使用する際の肝障害リスクに関する基礎的検討

Strategy for the control of drug-induced liver injury due to investigational treatments/drugs for COVID-19.

Investigational treatments/drugs for coronavirus disease 2019 (COVID-19) have been applied, with repurposed or newly developed drugs, and their effectiveness has been evaluated. Some of these drugs may be hepatotoxic, and each monotherapy or combination therapy may increase the risk of drug-induced liver injury (DILI). We should aim to control dysregulation of liver function, as well as the progression of COVID-19, as much as possible. We discussed the potential risks of investigational treatments/drugs and promising drugs for both COVID-19 and DILI due to investigational treatments/drugs.

Patient and Caregiver Treatment Preferences in Type 2 and Non-ambulatory Type 3 Spinal Muscular Atrophy: A Discrete Choice Experiment Survey in Five European Countries.

BackgroundSpinal muscular atrophy (SMA) is a rare neuromuscular disease that affects motor neurons, resulting in progressive skeletal muscle weakness and atrophy.ObjectiveThe aim of this study was to examine treatment preferences of patients and caregivers of patients with Type 2 and non-ambulatory Type 3 SMA in the Netherlands, Belgium, Finland, Ireland and Portugal.MethodsA discrete choice experiment (DCE) survey was developed to elicit the preferences of adult patients and caregivers regarding different treatment aspects of SMA. This survey built on the design of a similar study undertaken in the UK. The DCE described choice questions in terms of attributes and levels combined using a D-efficient design. The attributes described improvements or worsening in motor and breathing function. The mode of treatment administration (intrathecal injection, single intravenous infusion or regular oral therapy) was described. Treatment risks and side effects related to currently available treatments including risk of liver injury, fatigue, headache, nausea, diarrhoea and rash were described. Lastly, an attribute described whether a treatment had evidence of treatment effectiveness in different SMA types. Participants were recruited via patient advocacy associations to complete an online survey. A clustered conditional logit model was used to estimate treatment preferences.ResultsParticipants (n = 65) were 4.8 times and 8.1 times more likely to choose a treatment with stable or improved (vs worse) motor function, respectively. Similarly, participants were 4.3 times and 5.8 times more likely to choose stable or improved (vs worse) breathing function, respectively. Treatments with a risk of liver injury, fatigue, headache and nausea were 1.6 times less likely to be chosen than treatments with a risk of diarrhoea and rash. Treatments with demonstrated effectiveness in Type 1 SMA only were 2.3 times less likely to be chosen than those with demonstrated effectiveness in Types 1–3 SMA. Treatments administered via intrathecal injections were also 1.8 times less likely to be chosen than daily oral treatments.DiscussionStudy results show the importance of improvement as well as stabilisation of motor and breathing function to patients and caregivers, and a preference for oral treatments, treatments with demonstrated effectiveness in Types 2–3 SMA, and avoidance of liver injury risk.

BERT-Based Natural Language Processing of Drug Labeling Documents: A Case Study for Classifying Drug-Induced Liver Injury Risk.

Background & Aims: The United States Food and Drug Administration (FDA) regulates a broad range of consumer products, which account for about 25% of the United States market. The FDA regulatory activities often involve producing and reading of a large number of documents, which is time consuming and labor intensive. To support regulatory science at FDA, we evaluated artificial intelligence (AI)-based natural language processing (NLP) of regulatory documents for text classification and compared deep learning-based models with a conventional keywords-based model. Methods: FDA drug labeling documents were used as a representative regulatory data source to classify drug-induced liver injury (DILI) risk by employing the state-of-the-art language model BERT. The resulting NLP-DILI classification model was statistically validated with both internal and external validation procedures and applied to the labeling data from the European Medicines Agency (EMA) for cross-agency application. Results: The NLP-DILI model developed using FDA labeling documents and evaluated by cross-validations in this study showed remarkable performance in DILI classification with a recall of 1 and a precision of 0.78. When cross-agency data were used to validate the model, the performance remained comparable, demonstrating that the model was portable across agencies. Results also suggested that the model was able to capture the semantic meanings of sentences in drug labeling. Conclusion: Deep learning-based NLP models performed well in DILI classification of drug labeling documents and learned the meanings of complex text in drug labeling. This proof-of-concept work demonstrated that using AI technologies to assist regulatory activities is a promising approach to modernize and advance regulatory science.

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

Patients With IBD Receiving Methotrexate Are at Higher Risk of Liver Injury Compared With Patients With Non-IBD Diseases: A Meta-Analysis and Systematic Review.

Background: Methotrexate is well-known in treating inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis (Ps), and psoriatic arthritis (PsA). Several reports have indicated a higher incidence of methotrexate (MTX)-related liver adverse events in patients with IBD. We aim to investigate the risk of liver injury in patients with IBD and those with non-IBD diseases treated with MTX.Methods: We searched PubMed, Embase, and the Cochrane Library for articles that reported liver adverse events in patients with IBD, RA, and Ps/PsA, receiving MTX therapy. Additional articles were obtained by screening the references of recent meta-analysis and reviews. Raw data from included articles were pooled to calculate the cumulative incidence of total liver injury (TLI), MTX discontinuation (MTX-D), and liver fibrosis (LF). RR (relative risk) was calculated to compare the difference between patients with IBD and those with non-IBD diseases.Results: A total of 326 articles with 128,876 patients were included. The patients with IBD had higher incidence of TLI [11.2 vs. 9.2%; relative risk (RR) = 1.22; P = 0.224] and MTX-D (2.6 vs. 1.8%; RR, 1.48; P = 0.089) than patients with non-IBD diseases. Due to the publication bias, trim-and-fill was performed. Afterwards, the patients with IBD showed significantly higher risk of TLI (11.2 vs. 3%; RR = 3.76; p < 0.001), MTX-D (3.3 vs. 0.7%; RR = 5; p < 0.001) and LF (3.1 vs. 0.1%; RR = 38.62; P = 0.001) compared with patients with non-IBD diseases.Conclusion: IBD is associated with a higher risk of MTX-related liver injury. The mechanism of MTX-induced hepatotoxicity might be different in IBD and non-IBD diseases, and needs to be verified in future research.

Genetic Variation in the Mitochondrial Glycerol-3-Phosphate Acyltransferase Is Associated With Liver Injury.

Most of the genetic basis of chronic liver disease remains undiscovered. To identify genetic loci that modulate the risk of liver injury, we performed genome-wide association studies on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome-wide significance (P<5×10-8 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol-3-phosphate acyltransferase (GPAM rs10787429) associated with increased levels of ALT (P=1.4×10-30 ), AST (P=3.6×10-10 ), ALP (P=9.5×10-30 ), and total bilirubin (P=2.9×10-12 ). This common genetic variant was also associated with an allele dose-dependent risk of alcohol-associated liver disease (odd ratio [OR]=1.34, P=2.6×10-5 ) and fatty liver disease (OR=1.18, P=5.8×10-4 ) by International Classification of Diseases, 10th Revision codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST (P=7.1×10-9 and 3.95×10-8 , respectively), as well as between GPAM rs10787429 and weekly alcohol consumption in association with ALT, AST, and alcohol-associated liver disease (P=4.0×10-2 , 1.6×10-2 , and 1.3×10-2 , respectively). Unlike previously described genetic variants that are associated with an increased risk of liver injury but confer a protective effect on circulating lipids, GPAM rs10787429 was associated with an increase in total cholesterol (P=2.0×10-17 ), LDL cholesterol (P=2.0×10-10 ), and HDL cholesterol (P=6.6×10-37 ). Single-cell RNA-sequencing data demonstrated hepatocyte-predominant expression of GPAM in cells that co-express genes related to VLDL production (P=9.4×10-103 ). Genetic variation in GPAM is associated with susceptibility to liver injury. GPAM may represent a therapeutic target in chronic liver disease.