Drug-induced Liver Injury Group Research Articles

The etiology and differential diagnosis of "autoimmune hepatitis-like liver disease" in children: a single-center retrospective study.

Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance. All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups. A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p < 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, n = 3) and smooth muscle antibodies (SMA, n = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (p < 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (p < 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p < 0.05). Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Clinicopathological features of Sjogren's syndrome complicated with liver injury

Objective: To study the clinicopathological features of Sjogren's syndrome (SS) with liver injury and to improve the understanding of this disease. Methods: Forty-nine patients with SS complicated with liver injury were collected from Beijing Ditan Hospital, Capital Medical University from October 2008 to January 2022. All patients underwent ultrasound-guided liver biopsy, and all specimens were stained with HE. The histopathologic characteristics were observed and the pathologic indexes were graded. Immunohistochemical stains for CK7, CK19, CD38, MUM1 and CD10 were performed by EnVision method; and special histochemical stains for reticulin, Masson's trichrome, Rhodanine, Prussian blue, periodic acid Schiff (PAS) and D-PAS stains were conducted. Results: The age of patients ranged from 31 to 66 years, including 3 males and 46 females. SS combined with drug-induced liver injury was the most common (22 cases, 44.9%), followed by autoimmune liver disease (13 cases, 26.5%, including primary biliary cholangitis in eight cases, autoimmune hepatitis in 3 cases, and PBC-AIH overlap syndrome in 2 cases), non-alcoholic fatty liver disease (NAFLD, 9 cases, 18.4%) and other lesions (5 cases, 10.2%; including 3 cases of nonspecific liver inflammation, 1 case of liver amyloidosis, and 1 case of porto-sinusoidal vascular disease). Among them, 28 cases (57.1%) were associated with obvious interlobular bile duct injury, mainly in SS combined with PBC group and drug-induced liver injury group. Twenty-three cases (46.9%) were associated with hepatocyte steatosis of varying degrees. In SS with autoimmune liver disease group, ISHAK score, degree of fibrosis bile duct injury, bile duct remodeling, lymphocyte infiltration of portal area, and plasma cell infiltration, MUM1 and CD38 expression; serum ALP and GGT, IgM; elevated globulin; positive AMA, proportion of AMA-M2 positive and IgM positive were all significantly higher than those in other groups(all P<0.05). Serum ALT, direct bilirubin and SSA positive ratio in SS combined with drug liver group were significantly higher than those in other groups(all P<0.05). The serum total cholesterol level in SS combined with PBC group (P=0.006) and NALFD group (P=0.011) were significantly higher than those in other groups (P<0.05). Conclusions: The pathologic manifestations of SS patients with liver injury are varied. The inflammatory lesions of SS patients with autoimmune liver disease are the most serious, and the inflammatory lesions of SS patients with non-alcoholic fatty liver disease and non-specific inflammation are mild. Comprehensive analysis of liver histopathologic changes and laboratory findings is helpful for the diagnosis of SS complicated with different types of liver injury.

Evaluation of the Clinical Characteristics of Dry Eye Secondary to Different Types of Liver Diseases.

This study compares the clinical characteristics of dry eye secondary to primary biliary cholangitis (PBC), drug-induced liver injury (DILI), and viral hepatitis B(HBV) to evaluate the ocular surface damage caused by different types of liver diseases. Thirty healthy people were included as control group. Sixty patients with dry eye secondary to different types of liver disease were included, including 19 cases of PBC, 18 cases of DILI, and 23 cases of HBV. All patients were evaluated by the SPEED questionnaire, corneal fluorescein staining (CFS), noninvasive tear breakup time (NIBUT), Schirmer I test (SIt), tear meniscus height test (TMH), the area of meibomian glands dropout (MG dropout), partial blinking rate (PBR), lipid layer thickness (LLT), meibum expressibility, and meibum quality. There are statistical differences in ophthalmic examination results between different types of liver diseases and normal people (P < 0.05). Compared with DILI and HBV groups, the CFS score of PBC group score was higher (P < 0.05), the PBR was higher (P < 0.05), and the SIt was lower (P < 0.01). The TMH of PBC and DILI groups were significantly lower than the HBV group, and the difference was statistically significant (P < 0.05). Compared with the PBC group, the LLT of the DILI group decreased (P < 0.01). The area of meibomian glands dropout of the three groups had mild-to-moderate defects, but there was no significant statistical difference between groups (P > 0.05).The Meibum quality score in the DILI group was significantly higher than the HBV group (P < 0.05). The PBC group was more prone to aqueous-deficient dry eye. The DILI group was more prone to obstructive meibomian gland dysfunction (MGD).The HBV group was more prone to nonobstructive MGD. The symptoms of dry eye in the PBC group are mild-to-moderate discomfort, but the degree of corneal damage is higher, indicating that the corneal sensitivity is reduced, which may be related to the high rate of partial blinking.

Increased TG to HDL-C ratio is associated with severity of drug-induced liver injury

We investigated the relationship between dyslipidemia and drug-induced liver injury (DILI), especially the level of triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) in severe DILI. In this single-centered retrospective study, of 326 patients with DILI, 221 patients were analyzed. Control groups include medication using group and acute hepatitis B group. The relationship between dyslipidemia and DILI was estimated. Demographic and clinical features were analyzed. Dyslipidemia and TG/HDL-C ratios were compared between DILI and control groups, DILI mild group and severe group. The area under the receiver-operating characteristic curve (AUC) was used to evaluate the credibility of the relationship and to find cut-off points. Dyslipidemia is related to DILI when compared with medication using control group (AOR 4.60; 95% CI 2.81–7.54; P < 0.01) and compared with acute hepatitis B group (AOR 2.12; 95% CI 1.37–3.29; P < 0.01). Dyslipidemia is associated with the severity of DILI (AOR 25.78; 95% CI 7.63–87.1; P < 0.01). TG/HDL-C ratio is higher in DILI group than that of medication using control group, also higher in severe DILI group than that of mild DILI group. AUCs for TG/HDL-C ratio to indicate the severity of DILI was 0.89 (P < 0.05), the cut-off point was 2.35. Dyslipidemia and TG/HDL-C ratio were related to DILI occurrence. Severe liver injury in DILI was associated with dyslipidemia and elevated TG/HDL-C ratio.

Plasma Sphingoid Base Profiles of Patients Diagnosed with Intrinsic or Idiosyncratic Drug-induced Liver Injury.

Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects. DILI patients, whether intrinsic or idiosyncratic cases, had no alterations in total sphingoid base levels and profile composition compared to controls, whereby cardiovascular disease (CVD) was a confounding factor. Upon exclusion of CVD individuals, elevation of 1-deoxysphingosine (1-deoxySO) in the DILI group emerged. Notably, 1-deoxySO values did not correlate with ALT values. While 1-deoxySO was elevated in all DILI cases, only intrinsic DILI cases concomitantly displayed reduction of select shorter chain sphingoid bases. Significant perturbation of the sphingolipid metabolism observed in this small exploratory clinical study is discussed and put into context, in the consideration that sphingolipids might contribute to the onset and progression of DILI, and that circulating sphingoid bases may function as mechanistic markers to study DILI pathophysiology.

Correlation between serum cytokines and clinicopathological features in patients with drug-induced liver injury.

Objectives: Changes in serum levels of cytokines have been proposed as possible biological markers of tissue damage, including drug-induced liver injury (DILI). Here, we aimed to screen cytokine markers that have guiding significance for the degree of inflammation of DILI. Patients and methods: 54 patients with DILI were retrospectively analyzed as the experimental group, and 14 healthy subjects were randomly selected as the control group. A total of 20 cytokines were detected by using a cytokine protein antibody chip, and differentially expressed proteins were screened. Results: There were significant differences in serum cytokines between DILI patients and healthy controls. Compared with the control group, the DILI group expressed 11 differential proteins. IL-8, TNF RII, TNFα, TNF RI, MIP-1β, MIP-1α, and IL-1β were differentially expressed in DILI patients with different degrees of inflammation from G1 to G4. MIG, IL-12p40, and IL-10 were differentially expressed in the higher degree of inflammation groups (G2, G3, and G4 groups). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was differentially expressed in the group with the highest inflammation degree (G4 group). Chemokine C-C motif ligand 1 (I-309) was only differentially expressed in the lowest inflammation group (G1 group). Conclusion: The changes and differential expression of specific cytokine levels were helpful for evaluating different degrees of inflammation of DILI.

Predictive study of circulating MicroRNA as serum diagnostic marker of drug-Induced liver injury

To investigate the correlation between circulating microRNAs and liver injury indexes in drug-induced liver injury (DILI). We collected data on 72 DILI patients and 150 healthy subjects undergoing physical examination at our hospital from January 2021 to February 2022. From the diagnostic results, they were divided into a DILI group and a control group. Nano-magnetic beads were used to extract nucleic acid from serum, then qPCR was used to determine circulating microRNA levels, and the results were analyzed. Meanwhile, the serum liver function index levels before and after treatment were determined, and the correlations between circulating microRNA and these indexes were analyzed. We analyzed microRNA expression and found that miR-122-3p, miR-92a-3p, and miR-192-5p expression was consistent with a database, all of which were highly expressed in DILI. Moreover, after a period of treatment, their levels in circulation significantly decreased. ALT, ALP, GGT, AST, and TBIL also all decreased to different degrees after treatment. Multivariate analysis showed that the correlations between miR-122-3p and miR-92a-3p expression and ALT/AST index change were significant, as were the correlations between miR-192-5p expression and ALP/ALT/AST index change. This study showed that circulating microRNA expression levels in serum of DILI significantly increased and were positively correlated with the AST, ALP, and ALT expression levels. Circulating miRNA expression in serum can be used as a predictor and therapeutic index of DILI, which has high clinical value.

Microbiota diversity in nonalcoholic fatty liver disease and in drug-induced liver injury

The gut microbiota could play a significant role in the progression of nonalcoholic fatty liver disease (NAFLD); however, its relevance in drug-induced liver injury (DILI) remains unexplored. Since the two hepatic disorders may share damage pathways, we analysed the metagenomic profile of the gut microbiota in NAFLD, with or without significant liver fibrosis, and in DILI, and we identified the main associated bacterial metabolic pathways. In the NAFLD group, we found a decrease in Alistipes, Barnesiella, Eisenbergiella, Flavonifractor, Fusicatenibacter, Gemminger, Intestinimonas, Oscillibacter, Parasutterella, Saccharoferementans and Subdoligranulum abundances compared with those in both the DILI and control groups. Additionally, we detected an increase in Enterobacter, Klebsiella, Sarcina and Turicibacter abundances in NAFLD, with significant liver fibrosis, compared with those in NAFLD with no/mild liver fibrosis. The DILI group exhibited a lower microbial bacterial richness than the control group, and lower abundances of Acetobacteroides, Blautia, Caloramator, Coprococcus, Flavobacterium, Lachnospira, Natronincola, Oscillospira, Pseudobutyrivibrio, Shuttleworthia, Themicanus and Turicibacter compared with those in the NAFLD and control groups. We found seven bacterial metabolic pathways that were impaired only in DILI, most of which were associated with metabolic biosynthesis. In the NAFLD group, most of the differences in the bacterial metabolic pathways found in relation to those in the DILI and control groups were related to fatty acid and lipid biosynthesis. In conclusion, we identified a distinct bacterial profile with specific bacterial metabolic pathways for each type of liver disorder studied. These differences can provide further insight into the physiopathology and development of NAFLD and DILI.

Стан нейронально-астроцитарного апарату гіпокампу на тлі тривалого введення ізоніазиду та рифампіцину за умов корекції мікрофлори товстого кишечника

The purpose of the study was to determine the morphometric and ultrastructural features of neurons and glial cells, as well as the levels of glial fibrillar acid protein in the hippocampus of rats under long-term administration of isoniazid and rifampicin during experimental therapy with a combination of pro/prebiotics. Materials and methods. The studies were conducted on three groups of white Wistar male rats with drug-induced hepatitis, reproduced by intragastric administration of isoniazid and rifampicin for 28 days. In the last 14 days of the intragastric experiment, rats of the research group were administered probiotic and prebiotic. The content of cytosolic glial fibrillar acid protein in the hippocampus was determined by competitive enzyme-linked immunosorbent assay. Semi-thin sections of CA1 sections of the rat hippocampus were analyzed using the Image J. analysis program. The ultrastructural characteristics were studied using a PEM-100-01 transmission electron microscope (Selmi, Ukraine). Results and discussion. Long-term administration of isoniazid and rifampicin was associated with changes in the content of the cytosolic fraction of glial fibrillar acid protein obtained from the hippocampus. These changes were characterized by a tendency to increase the level of this protein by 17.8% (p=0.2) compared with intact animals. In contrast to the group of animals reproduced in the experiment drug-induced liver injury, in the experimental group, the level of glial fibrillar acid protein was significantly lower by 25.0% compared to the drug-induced liver injury group (p &lt;0.05). Morphological analysis revealed a decrease in neuronal density in rats with drug-induced liver injury compared with intact control. At the same time, the specific number of degeneratively altered neurons in comparison with intact control in the group of drug-induced liver injury animals increased by 8.57 times. The number of degeneratively altered neurons in the group receiving yogurt / lactulose was 55.87 ± 4.23%, which was significantly higher than intact control rats, but was 19.4% (p &lt;0.05) lower levels in rats with MIUP. Electron microscopic examination of rat hippocampal neuroglia was based on the study of changes in the astrocytic and oligodendroglial components. Changes in rat hippocampal neuroglia under experimental conditions were mainly related to the astrocytic link. Astrocytes were characterized by significantly lower cytoplasmic edema and adaptive-compensatory changes in the cell. Conclusion. Course administration of pro/prebiotics reduces the severity of manifestations of neurodegeneration, improves the state of astroglia in the hippocampus, and reduces the cytoplasmic levels of glial acidic fibrillar protein in animals with drug-induced liver injury

Analysis of Clinical Characteristics and Chronic Factors of Drug-induced Liver Injury in Chronic Hepatitis B Infection: A Retrospective Study

Background: This study investigated clinical characteristics and chronic factors of drug-induced liver injury (DILI) among patients with chronic hepatitis B virus (HBV) infection. Methods: DILI patients were enrolled and divided into a DILI group and an HBV+DILI group. Laboratory indicators were recorded and analyzed. Multivariate logistic regression and the receiver operating characteristic (ROC) curve were used to determine risk factors and the predictive value for chronic DILI. Results: Of all the 114 patients, 87 were in the DILI group and 27 were in the HBV+DILI group. Baseline total bilirubin (TBIL), direct bilirubin (DBIL), and incidence of chronicity were significantly higher in the HBV+DILI group than in the DILI group (P = 0.017, P = 0.037, P = 0.045, respectively). However, platelet (PLT) and prothrombin activity (PTA) were significantly lower in the HBV+DILI group than in the DILI group (P = 0.022, P = 0.013, respectively). HBV infection, baseline aspartate aminotransferase (AST) &gt; 200 U/L, and TBIL &gt; 34.2 μmol/L were predictors of chronic DILI (OR = 4.481 [95% CI, 1.298 - 15.470], P = 0.018; OR = 8.478 [95% CI, 2.079 - 34.566], P = 0.003; OR = 7.358 [95% CI, 2.215 - 24.446], P = 0.001). The area under ROC curve (AUC) of joint diagnosis for chronic DILI was 0.814 (95% CI, 0.704 - 0.925, P &lt; 0.001), which was significantly higher than that of single parameter prediction. Also, the sensitivity, specificity, positive predictive value, and negative predictive value of joint diagnosis were 81.0%, 73.1%, 40.5%, and 94.4%, respectively. Conclusions: HBV infection aggravated liver injury. HBV infection, baseline AST &gt; 200 U/L, and TBIL &gt; 34.2 μmol/L were predictors of chronic DILI, and their joint diagnosis could be used to predict chronic DILI effectively.

Liver Transplantation for Acute Liver Injury in Asians Is More Likely Due to Herbal and Dietary Supplements.

Drug-induced liver injury (DILI) due to medications and herbal and dietary supplements (HDSs) is a major cause of acute liver injury leading to liver transplantation (LT). This study used United Network for Organ Sharing LT data to analyze severe HDS-induced acute liver injury in the United States. By convention, patients with acute DILI are listed as "Acute Hepatic Necrosis" (AHN) under the subheading "AHN: Drug Other Specify." All patients waitlisted from 1994 to 2020 were divided into 3 subgroups: "HDS DILI," "Non-HDS DILI," and "AHN: unknown drug." Analyses were performed to identify epidemiologic differences between patients with HDS DILI and non-HDS DILI. A subanalysis was performed for transplanted patients, including longitudinal changes. Of 1875 patients waitlisted for LT, 736 (39.2%) underwent LT. The proportion of Asian patients in the HDS DILI group was significantly higher compared with that in the non-HDS DILI group (17.4% versus 3.8%; P<0.001). Excluding acetaminophen cases, the proportion of Black patients in the HDS DILI versus non-HDS group was significantly lower (8.7% versus 25.3%; P<0.001). Waitlisted patients with HDS DILI were significantly older (median age, 38 years for HDS DILI versus 31 years for non-HDS DILI; P=0.03). Lastly, the number of patients requiring LT due to HDS DILI increased significantly over time with more than 70% of cases occurring in the last 10years (2010-2020) compared with the prior 15years (1994-2009; Ptrend =0.001). Ethnicity may help in identifying the cause of severe acute DILI, a growing problem as more patients experiment with HDS.

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P < 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top five drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top four drugs (ROR values > 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P < 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs.

The Diagnosis of Drug-induced Liver Injury: Current Diagnostic Ability and Future Challenges of the Digestive Disease Week-Japan 2004 Scale 15 Years after Its Proposal.

Objective This study examined whether or not the Digestive Disease Week-Japan (DDW-J) 2004 scale proposed over 15 years ago can be applied to current cases of drug-induced liver injury (DILI). Methods The new patients group included 125 patients from 2012 to 2019 and was divided into 2 subgroups: 96 patients in the new DILI group and 29 patients in the new non-DILI group. Similarly, the old patients group included 105 patients from 1997 to 2002 and was divided into 2 subgroups: 59 patients in the old DILI group and 46 patients in the old non-DILI group. Patients were assessed by the DDW-J 2004 scale; those with a score ≥3 were defined as having DILI. Results The total score of the new DILI group was significantly lower than that of the old DILI group [6 (1-11) vs. 6 (3-9), p=0.004]. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were 94.8%, 65.6%, 90.1%, and 79.2%, respectively, in the new patients group and 100%, 91.4%, 93.7%, and 100%, respectively, in the old patients group. The specificity and NPV of the new patients group were significantly lower than those of the old patients group. Conclusion The DDW-J 2004 scale maintains a stable diagnostic ability for DILI, regardless of differences in eras and verification methods. However, differential diagnoses can affect the scoring, and new types of DILI, such as immune-related adverse events, must be addressed. Therefore, upgrading the scale should be considered.

The association of transporter ABCC2 (MRP2) genetic variation and drug-induced hyperbilirubinemia.

Hyperbilirubinemia is a predictor of severe drug-induced liver injury (DILI). Hepatobiliary ATP-binding cassette (ABC) transporters play an important role in the transportation of many drugs and bilirubin; however, little is known about these transporters and the risk of DILI. The aim of this study was to explore associations between genetic variations in important ABC transporters and susceptibility to DILI, with a particular focus on hyperbilirubinemia. A total of 200 patients with DILI and 200 healthy controls were enrolled as the training dataset. Another 106 patients with DILI were recruited as the validation dataset. They were genotyped for ABCB11 (BSEP) rs2287622, ABCB1 (MDR1) rs1128503, rs1045642, ABCB4 (MDR3) rs2230028, ABCC2 (MRP2) rs1885301, rs717620, rs2273697, rs3740066 and rs8187710 using polymerase chain reaction-based TaqMan genotyping assays. There were no statistical differences in any of the nine ABC transporter single nucleotide polymorphisms between the DILI and control groups. However, in the DILI group, the patients with hyperbilirubinemia had a higher frequency of the ABCC2 rs717620 C/T and T/T genotypes than those without hyperbilirubinemia (44.2% vs 20.2%, p = 0.001). After adjusting for other confounding factors, the ABCC2 rs717620 T variant was still associated with an increased risk of hyperbilirubinemia (adjusted odds ratio [OR]: 3.83, 95% confidence interval [CI]: 1.73-8.48, p = 0.001). This association was confirmed by the validation dataset (adjusted OR: 3.92, 95% CI: 1.42-10.81, p = 0.015). We also found that the mortality group had higher frequencies of the ABCC2 (MRP2) rs717620 C/T and T/T genotypes than the survival group (50.0% vs 27.9%, p = 0.048). Carriage of the ABCC2 (MRP2) rs717620 T variant may increase the risk of hyperbilirubinemia and mortality in patients with DILI. Screening for this variant may help to prevent and mitigate drug-induced hyperbilirubinemia.

High Serum Estradiol Reduces Acute Hepatotoxicity Risk Induced by Epirubicin Plus Cyclophosphamide Chemotherapy in Premenopausal Women with Breast Cancer.

Aim: We evaluated whether acute drug-induced liver injury (DILI) caused by adjuvant chemotherapy with epirubicin plus cyclophosphamide for early breast cancer was associated with estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods: Reproductive hormone test results of breast cancer patients were collected in the first chemotherapy cycle. E2, LH, and FSH levels were loge-transformed to normally distributed variables and were assessed using Student’s t-test to determine significant differences between the case and control groups. Hormone levels were classified according to the interquartile range and analyzed by logistic regression to determine their association with DILI caused by chemotherapy. Results: Among the 915 enrolled patients (DILI group: 204; control group: 711), menopausal status, along with serum E2, LH, and FSH levels, did not substantially differ between case and control groups. However, in the premenopause subgroup (n = 483), we found a significant difference in the E2 level between the case and control groups (p = 0.001). After adjusting for age and body mass index, premenopausal patients with 152–2,813 pg/mL E2 showed a lower risk of chemotherapy-induced DILI than patients with ≤20 pg/mL E2 (odds ratio: 0.394; 95% confidence interval: 0.207–0.748). The linear trend χ2 test revealed that E2 levels in premenopausal patients with breast cancer were inversely associated with the development of DILI. Conclusion: High serum E2 levels are associated with a reduced DILI risk in premenopausal patients with breast cancer undergoing epirubicin plus cyclophosphamide adjuvant chemotherapy.

Clinical features of liver injury induced by anti-tuberculosis drugs and related risk factors

Objective To investigate the clinical features of liver injury induced by anti-tuberculosis drugs and related risk factors. Methods A total of 129 patients who were diagnosed with liver injury induced by anti-tuberculosis drugs in Shenzhen Third People's Hospital from January 2017 to December 2018 were enrolled and divided into abnormal liver function group with 51 patients (39.53%) and drug-induced liver injury (DILI) group with 78 patients (60.47%), and among these 129 patients, 13 (10.08%) had liver failure. A retrospective analysis was performed for their laboratory markers as well as treatment and prognosis data. The chi-square test was used for comparison of categorical data between two groups; the independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. The multivariable logistic regression model was used to investigate the risk factors for DILI and liver failure. Results There were significant differences between the DILI group and the abnormal liver function group in chronic HBV co-infection (χ2=5.616, P=0.018), asymptomatic liver injury (χ2=9.451, P=0.002), liver failure (χ2=9.453, P=0.002), need to adjust anti-tuberculosis regimen (χ2=16.787, P 8 weeks (odds ratio [OR]=3.94, 95% confidence interval [CI]: 1.02-15.25, P=0.047) and asymptomatic liver injury (OR=7.64, 95% CI: 1.63-35.86, P=0.010) were independent risk factors for DILI; chronic HBV co-infection (OR=14.42, 95% CI: 2.66-78.09, P=0.002) and time to identification of liver injury > 8 weeks (OR=11.97, 95% CI: 2.03-70.50, P=0.006) were independent risk factors for liver failure, while albumin ≥35 g/L (OR=0.07, 95% CI: 0.01-0.51, P=0.010) was a protective factor. Conclusion Anti-tuberculosis drugs may induce severe liver injury, and HBV co-infection, asymptomatic liver injury, long time to identification of liver injury, and low albumin level may increase the risk of severe liver injury. Regular follow-up, liver function monitoring, appropriate nutritional support, and HBV screening are important for reducing the risk of liver injury during anti-tuberculosis therapy.

Drugs-Herbs-Dietary Supplements-induced Liver Injury: A Hidden but Emerging Clinical Problem

Background: Drug-induced liver injury (DILI) is becoming increasingly common. Additionally, there have also been worldwide increases in herbal-induced liver injury (HILI) and supplement-induced liver injury (SILI). Studies on DILI, HILI, and SILI have shown that liver injury is the result of an idiosyncratic reaction and was geographically distinct. Objective: To describe the clinical characteristics and outcomes of DILI, HILI, and SILI in a Thai population. Materials and Methods: We retrospectively included patients (both outpatients and inpatients) who were diagnosed with DILIHILI-SILI at a tertiary care university hospital setting from January 2014 to December 2019. The Roussel Uclaf Causality Assessment Method (RUCAM) score was used to assess causality in suspected cases with a cut-off score of &gt;3. R ratio was used to identify the 3 types of liver injury: hepatocellular, cholestasis, or mixed type. Results: Seventy patients were suspected to have DILI during the study period. Twenty-three patients were excluded due to incomplete data or RUCAM score &lt;3. The remaining 47 patients were included. Of these, 26 cases (55.3%) were due to herbs or supplements and 17 (36.2%) were admitted for a high degree of liver injury. Chinese traditional complementary (12.7%) and multi-herbal products (12.7%) were the common causes of HILI and SILI, respectively. Antimicrobial agents (19.1%) and analgesics (10.6%) were the common causes of conventional drug-induced liver damage. The liver injury patterns in DILI from conventional drugs were hepatocellular (R&gt;5) in 47.6% and cholestatic pattern (R&lt;2) in 33.3%, which was not significantly different (p&gt;0.05). For the HILI and SILI groups, the liver injury patterns were hepatocellular in 46.2% and cholestatic pattern in 15.4% (p = ns). The duration of exposure to diagnosis was similar between the DILI and HILI-SILI groups (3.7 vs. 5.6 months, p = 0.42). The DILI group had longer hospital stay than the HILI and SILI groups (13.5 vs. 7 days; p = 0.63). The overall mortality rate was 2.9%, with one death in each group. Conclusion: Herbal and dietary supplements played an important role in DILI and showed a trend of shorter hospital stays. Hepatocellular liver injury pattern was the most common clinical finding in patients with DILI, HILI, and SILI. Keywords: Drug-induced liver injury, DILI-HILI-SILI, Hepatitis, R pattern

Prolonged interval of total bilirubin decline is an early independent predictive factor of chronic persistent drug-induced liver injury.

Chronic drug-induced liver injury (DILI) with persistent abnormal liver function tests (LFTs) >6months after cessation of the insulting drugs could progress to cirrhosis. The aim of the present study was to identify the risk factors of chronic DILI for early recognition and better management. History of drug intake and results of LFTs were retrospectively retrieved for patients with a discharge diagnosis of DILI for at least 1-year follow up. The risk factors independently associated with chronic DILI were analyzed by multiple logistic regression analyses. A total of 33 of the 140 DILI patients had persistent abnormal LFTs >6months, which were considered as chronic DILI. It was found that the time intervals of alanine aminotransferase and total bilirubin decline from the peak to their half peak (T0.5ALT , T0.5TBIL ) were significantly longer in the chronic DILI group than that in the recovered group (P= 0.001 and P< 0.001). The risk factors associated with chronic DILI independently were T0.5TBIL (OR 1.315, 95% CI 1.038-1.668), longer period of insulting drug(s) intake (OR 1.018, 95% CI 1.003-1.033), mixed/cholestatic pattern (OR 97.159, 95% CI 1.866-5005.994). More importantly, receiver operating characteristic curve analysis showed that the prognostic value of T0.5TBIL for chronic DILI had a sensitivity of 60.0% at a specificity of 90.7% with the threshold of 16days. The time intervals of total bilirubin decline from its peak to half of its peak (T0.5TBIL ) was an early independent predictive factor of chronic DILI, suggesting that T0.5TBIL might serve as an indicator for chronicity.

An analysis of the serological characteristics of anti-mitochondrial M2 subtype in patients with drug-induced liver injury and primary biliary cholangitis

Objective: To analyze the serological characteristics of anti-mitochondrial antibody M2 subtype (AMA-M2) in patients with drug-induced liver injury (DILI) and primary biliary cholangitis (PBC), in order to provide reference for clinical differential diagnosis. Methods: Laboratory data of 2802 DILI cases who visited the hospital between January 2011 and December 2017 were retrospectively collected. AMA-M2 positive patients were analyzed with respect to laboratorical findings, and serum data of 120 patients with primary biliary cholangitis (PBC) at the same period was taken as a control. A chi-square test was used for group comparisons. One-way ANOVA and rank sum tests was used for ALT, AST, ALP, GGT and three groups of immunoglobulin M. Results: Among 2802 DILI patients, AMA-M2 positive rate was 5.1% (144/2 802), 77.1% (111/144) was DILI alone, 22.2% (32/144) was DILI with PBC, and 0.7% (1/144) was DILI with Sjogren's syndrome. An AMA-M2 level in DILI alone group was mostly mild and moderate than the PBC group and the DILI combined with the PBC group. There was significant difference between the two groups (P < 0.05).There was no significant difference in AMA-M2 levels between DILI group combined with PBC group and PBC group (P > 0.05). ALT and AST levels of DILI alone group and DILI combined with PBC were (585.92 ± 653.04) U/L, (501.45 ± 512.67) U/L and (373.47 ± 502.60) U/L, (335.97 ± 513.96) U/L, respectively, which were significantly higher than PBC group [(106.33 + 134.08) U/L, (112.59 + 152.20) U/L]. There were statistically significant differences between the two groups (P < 0.05).The ALP level of DILI alone group was (152.58 + 81.46) U/L, which was lower than PBC group (237.86 + 215.09). The difference was statistically significant (P < 0.05). The level of immunoglobulin M in the DILI alone group was (1.76 ± 1.16) g/L, which was lower than PBC group (4.74 ± 5.74) g/L and the DILI combined with the PBC group (3.31 ± 1.68) g/L. There was significant difference between the two groups. During follow-up, 2.7% of patients with DILI had cirrhosis, 42.3% had lower AMA-M2 titer, 14.4% had lower AMA-M2 titer, 13.5% had higher AMA-M2 titer and five cases developed PBC. Conclusion: AMA-M2 is not only positive in patients with PBC, but also low-to-medium or even high-level AMA-M2 may be detected in DILI patients. For AMA-M2-positive DILI patients, it is necessary to identify whether they are associated with PBC. Secondly, the levels of ALT, AST and ALP should be analyzed, and the patients should be on regular follow up for early and timely detection of drug-induced PBC.