Drug-induced Liver Injury Patients Research Articles

Characteristics of Drug-Induced Liver Injury in Northeast China: Disease Spectrum and Drug Types.

The aim of this study was to determine the disease spectrum and drug types causing drug-induced liver injury (DILI) in northeast China, so that the affected population can be reminded of the need to increase their post-medication monitoring. A total of 470 DILI patients hospitalized at Shengjing Hospital between 2013 and 2016 were involved in this retrospective study. There were significant differences in the disease spectrum of the different age groups (P < 0.001) and genders (P = 0.009). Drugs used to treat osteopathies, dermatitis and infections, as well as health care supplements, each accounted for > 10% of all drugs that caused DILI. The percentage of DILIs related to Chinese herbal medicines (CHMs) gradually increased with patient age (P = 0.002). The percentage of males taking health supplements or CHMs was significantly lower compared with females. Total bilirubin (β = 0.01, OR = 1.01, P < 0.001) and INR (β = 0.74, OR = 2.11, P < 0.001) were found to be independent predictors of liver damage. The main type of drug that causes DILI in northeast China is a CHM. There are differences in the disease spectrum found in DILI patients of different ages and gender. Making appropriate changes in the drug-taking habits of high-risk groups and the drugs used to treat high-risk underlying diseases, as well as increasing patient monitoring, may help to reduce the incidence of DILIs.

Research on drug-induced liver injury in association with co-infections and anti-tuberculosis drugs

This study uses data mining techniques to find out the risk factors for the tuberculosis (TB) patients with drug-induced liver injury (DILI). The Taiwan National Health Insurance Database is used for collection of domestic TB cases during 2004-2011 to study these TB patients and their drug prescribing patterns in order to build a model to predict the risk of drug-drug interaction between hepatitis B and C, acquired immune deficiency syndrome (AIDS) and TB. The results out of the total 188,032 TB patients have shown that 77,574 have taken anti-TB drugs. Afterwards, DILI occurred in 0.7% of the cases. Besides, for those DILI patients associated with TB and hepatitis B or C, this study reveals that DILI is associated with the use of ethambutol and rifampin. It is suggested that TB patients associated with hepatitis C should pay attention to their uses of rifampicin, and TB patients (especially males) associated with hepatitis B should pay attention to the ethambutol's impact on DILI. Moreover, our results also showed that having both AIDS and TB shows no significant effect on DILI.

Research on drug-induced liver injury in association with co-infections and anti-tuberculosis drugs

This study uses data mining techniques to find out the risk factors for the tuberculosis (TB) patients with drug-induced liver injury (DILI). The Taiwan National Health Insurance Database is used for collection of domestic TB cases during 2004-2011 to study these TB patients and their drug prescribing patterns in order to build a model to predict the risk of drug-drug interaction between hepatitis B and C, acquired immune deficiency syndrome (AIDS) and TB. The results out of the total 188,032 TB patients have shown that 77,574 have taken anti-TB drugs. Afterwards, DILI occurred in 0.7% of the cases. Besides, for those DILI patients associated with TB and hepatitis B or C, this study reveals that DILI is associated with the use of ethambutol and rifampin. It is suggested that TB patients associated with hepatitis C should pay attention to their uses of rifampicin, and TB patients (especially males) associated with hepatitis B should pay attention to the ethambutol's impact on DILI. Moreover, our results also showed that having both AIDS and TB shows no significant effect on DILI.

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.

Clinicopathological features of Bu Gu Zhi-induced liver injury, a long-term follow-up cohort study.

Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI. Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed. Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N=23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3months with recovery in 37 patients within 6months. No patients died or required transplantation. BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6months, and none developed end-stage liver disease or died.

Fructus Psoraleae-Induced Severe Liver Injury and Treatment With Two Artificial Liver Support Systems: A Case Series Study.

To describe the clinical features and outcomes of patients with suspected Fructus Psoraleae (FP)-induced severe liver injury who underwent treatment with two artificial liver support systems (ALSSs). The cases of 12 patients with severe liver injury by FP were enrolled. We evaluated the tolerability of, and changes in biochemical parameters after treatment with plasma exchange combined with hemofiltration and double plasma molecular absorption system, and 6-month follow-up information were collected. The median age of the 12 patients was 60 years and nine (75%) patients were females. All patients had jaundice as the initial symptom. Two ALSS types were used to treat the patients. The group that underwent plasma exchange combined with hemofiltration showed remarkable improvements in ALT, AST, total bilirubin (TB), GGT and international normalized ratio levels (AST, TB, international normalized ratio, P < 0.01; ALT, GGT, P < 0.05), and the levels of AST, ALP, TB, and total bile acid decreased significantly in the double plasma molecular absorption system group after treatment (TB, P < 0.01; AST, ALP, total bile acid P < 0.05). During 6 months of follow-up, two patients died, two became chronic, and eight recovered to normal. FP can cause clinically severe liver injury, characterized by gastrointestinal symptoms and jaundice, which can lead to death or become chronic. Both ALSSs were safe and well tolerated in drug-induced liver injury patients. After ALSS treatment, the levels of biochemical indicators of liver function improved significantly, indicating that ALSS might be beneficial for patients with severe drug-induced liver injury.

CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization.

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

Serum metabolome and targeted bile acid profiling reveals potential novel biomarkers for drug-induced liver injury.

This study aims to determine the non-invasive, reliable and sensitive biochemical parameters for the diagnosis of drug-induced liver injury (DILI).Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) and selected reaction monitoring (SRM) were used to profile the serum metabolome and quantify 15 targeted bile acid metabolites, respectively, in samples obtained from 38 DILI patients and 30 healthy controls.A comparison of the resulting serum metabolome profiles of the study participants revealed significant differences between DILI patients and healthy controls. Specifically, serum palmitic acid, taurochenodeoxycholic acid, glycocholic acid (GCA), and tauroursodeoxycholic acid (TUDCA) levels were significantly higher, and serum lysophosphatidylethanolamine levels were significantly lower in DILI patients vs healthy controls (P < .001). Furthermore, the SRM assay of bile acids revealed that the increase in GCA, taurocholic acid (TCA), TUDCA, glycochenodeoxycholic acid (GCDCA), glycochenodeoxycholic sulfate (GCDCS), and taurodeoxycholic acid (TDCA) corresponded to a higher degree of liver damage. These results also indicate that serum concentrations of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA) were significantly lower in patients with severe DILI, when compared to healthy controls, and that this decrease was closely correlated to the severity of liver damage.Taken together, these results demonstrate that bile acids could serve as potential biomarkers for the early diagnosis and severity of DILI.

A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients.

Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.

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.

Metabolomics and Cytokine Analysis for Identification of Severe Drug-Induced Liver Injury.

To evaluate the levels of metabolites and cytokines in the serum of patients with severe and non-severe idiosyncratic drug-induced liver injury (DILI) and to identify biomarkers of DILI severity. Gas chromatography-mass spectrometry (GC-MS) and ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) based metabolomic approaches were used to evaluate the metabolome of serum samples from 29 DILI patients of severity grade 3 (non-severe), 27 of severity grade 4 (severe), and 36 healthy control (HC). The levels of total keratin-18 (K18), fragment K18, and 27 cytokines were determined by enzyme-linked immunosorbent assay. The alkaline phosphatase activity ( p = 0.021) and international normalized ratio (INR) ( p < 0.001) differed significantly between the severe and non-severe groups. The severe group had a higher serum fragment K18 level than the non-severe group. A multivariate analysis showed good separation between all pairs of the HC, non-severe, and severe groups. According to the orthogonal partial least-squares-discriminant analysis (OPLS-DA) model, 14 metabolites were selected by GC-MS and 17 by UPLC-MS. Among these metabolites, the levels of 16 were increased and of 15 were decreased in the severe group. A pathway analysis revealed major changes in the primary bile acid biosynthesis and alpha-linolenic acid metabolic pathways. The levels of PDGF-bb, IP-10, IL-1Rα, MIP-1β, and TNF-α differed significantly between the severe and non-severe groups, and the levels of most of the metabolites were negatively correlated with those of these cytokines. An OPLS-DA model that included the detected metabolites and cytokines revealed clear separation of the severe and non-severe groups. We identified 31 metabolites and 5 cytokines related to the severity of idiosyncratic DILI. The primary bile acid biosynthesis and alpha-linolenic acid metabolism pathways were also related to the severity of DILI. A model that incorporated the metabolites and cytokines showed clear separation between patients with severe and non-severe DILI, suggesting that these biomarkers have potential as indicators of DILI severity.

Clinicopathological features of drug-induced liver injury or primary biliary cholangitis with vanishing bile duct syndrome

Objective To investigate the clinical features of patients with drug-induced liver injury ( DILI) and vanishing bile duct syndrome ( VBDS) and patients with primary biliary cholangitis ( PBC) and VBDS. Methods A retrospective analysis was performed for the clinical data of 42 DILI patients and 43 PBC patients who visited Shijiazhuang Fifth Hospital from January 2003 to January 2018 were diagnosed with VBDS by liver biopsy, including general information, clinical symptoms and signs, and serological markers, and pathomorphological features were observed. The Mann-Whitney U rank sum test was used for comparison between two groups; the chi-square test was used for comparison of categorical data between groups. Results Most of the patients in the two groups were female patients aged 40-50 years. The D-VBDS group had a significantly higher incidence rate of yellow staining of skin and sclera than the P-VBDS group ( X2=5. 683, P = 0. 017) . Comparison of the peak values of liver biochemical indices showed that compared with the P-VBDS group, the D-VBDS group had significantly higher total bilirubin ( Z =-2. 020, P = 0. 043) and direct bilirubin ( Z =-2. 910, P = 0. 004) . According to the results of pathomorphological analysis and morphological scores of the portal area, the P-VBDS group had significantly higher morphological scores of portal inflammation, fibrosis, and granuloma than the D-VBDS group ( Z =-3. 136, -2. 710, and-2. 913, P =0. 002, 0. 007, and 0. 005) . The morphological scores of the hepatic lobules showed that compared with the P-VBDS group, the D-VBDS group had significantly higher morphological scores of intralobular inflammation, bile thrombus in bile capillary, and activated phagocytes ( Z =-3. 255, -2. 455, and-4. 398, P = 0. 001, 0. 014, and

Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan.

In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30days and 79% of DILI cases occurred within 90days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.

The diagnostic role of miR-122 in drug-induced liver injury: A systematic review and meta-analysis.

Background:Drug-induced liver injury (DILI) is a potentially severe adverse drug reaction especially in susceptible patients. But there are no sensitive or specific parameters to detecting DILI. The specific expression of miR-122 in the liver has been a hotspot in the evaluation of hepatic toxicity due to its high stability and sensitivity.Methods:We performed a systematic literature review through July 31, 2017 to identify studies which evolved DILI patients testing miR-122 without limiting a certain drug. According to the PRISMA statement, a meta-analysis: the diagnostic role of miR-122 in DILI was made. QUADAS-2 quality evaluation table was used to evaluate the quality of the documentary evidence, PRISMA flowchart and quality evaluation table were drawn with RevMan, use Stata to calculate the sensitivity and specificity of miR-122 in diagnosing DILI, ROC curve and Deeks funnel plot were also drawn by STATA.Results:Eleven studies involved 194 DILI patients and 251 controls, all were tested miR-122 (fold change). Sensitivity of miR-122 in diagnosing DILI was [0.85 (95% CI, 0.75–0.91), I2 = 53.46%] and specificity was [0.93 (95% CI, 0.86–0.97), I2 = 65.10%], the area under ROC curve was 0.95 (95% CI, 0.93–0.97). While in acetaminophen (APAP)-induced liver injury, the sensitivity was [0.82 (95%CI, 0.67–0.91), I2 = 65.77%] specificity was [0.96 (95%CI, 0.88–0.99), I2 = 31.46%], AUROC was 0.97 (95% CI, 0.95–0.98).Conclusions:In this systematic review and meta-analysis, we found miR-122 have a high specificity in DILI, and a modest positive diagnostic effects. On the basis of the limited evidence, further research is needed to evaluate the long-term observation and more clinical data to testify miR-122 in diagnosing DILI.

Liver Injury after Autologous Hematopoietic Stem Cell Transplant: DILI and SOS

Introduction: Autologous Hematopoietic Stem Cell Transplant (AHCT) is an integral part of the treatment for many hematological and immunological diseases. However, the AHCT is associated with several complications, including liver diseases, such as sinusoidal obstruction syndrome (SOS), viral hepatitis, and sepsis-associated cholestasis. Drug-induced liver injury (DILI) is one of the most common and serious adverse drug side effects. This issue is particularly important in the context of high dose chemotherapy but it is still understudied. This study aims to determine the incidence of SOS and DILI among patients who underwent the autologous stem cell transplant.Methods: A retrospective cohort study was conducted among all patients who had undergone an autologous stem cell transplant at the hospital of Universidade Federal da Bahia (UFBA), Brazil, from July 2010 to July 2017. Daily weight and clinical and laboratory data ̶ aminotransferases, alkaline phosphatase (ALP), gamaGT (GGT), and total bilirubin (TB) levels ̶ were collected from beginning of the conditioning regimen to D+21 post-transplant. SOS diagnosis was based on modified Seattle Criteria (2 of 3 of the following items during the first 21 days post-transplant: TB ≥ 2mg/dl, hepatomegaly or upper right quadrant abdominal pain, and weight gain above 2% of pre-transplant weight). SOS severity was based on EBMT criteria. The International Serious Adverse Events Consortium 2011 criteria was used for DILI diagnosis, considering any of the following: (1) hepatocellular DILI: ALT ≥ 5 x upper limit normal (ULN); (2) cholestatic DILI: ALP ≥ 2 x ULN, especially in patients with elevated GGT, and without bone-disease-related ALP elevation; (3) mixed DILI: ALT ≥ 3 x ULN and total bilirubin (TB) ≥ 2 x ULN. All patients with SOS were excluded for the DILI diagnosis. All statistics were calculated using SPSS v 20.0 (SPSS Inc). Descriptive analysis and chi-square were applied, and the alpha error was 5%. The study protocol was approved by the institutional review board.Results: One hundred and seventy-five patients were included in the study. The mean age was 44.2 ± 15.4 years old, and 56.6% of patients (n= 99) were male. The main transplant indications were the following: multiple myeloma (55.4%, n= 97), lymphoma (36.0%, n= 63), acute myeloid leukemia (3.4%, n= 6), and germ cell tumor (3.4%, n= 6). Most patients presented aminotransferases (73.1%, n= 128) or ALP (44.0%, n= 77) elevations, but DILI incidence was 12% (n= 21). Hepatic, cholestatic, and mixed DILI were found in 3 (1.7%), 15 (8.6%), and 3 (1.7%) patients respectively. Five of six patients who developed hepatocellular or mixed DILI were exposed to etoposide (p=0.006). Cholestatic DILI occurred in 12 melphalan-based and 3 busulfan-based patients. The prophylactic use of ursodeoxycholic acid (UDCA) was associated with lower incidence of DILI (incidence among UDCA users: 1/43; incidence among non-users of UDCA: 20/132; p= 0,028). Mortality among DILI patients was 12% (n=2).SOS incidence was 6.9% (n= 12); 4 (33.3%) patients with mild, 4 (33.3%) with moderate, 2 (16.7%) with severe, and 2 (16.7%) with severe SOS. A higher incidence of SOS was found among recipients who was transplanted for germ cell tumors (p= 0.004); those previously submitted to abdominal irradiation (p= 0.068) and iron overload (p= 0.068); only one patient died from this syndrome. Almost all (83.3%; n=5) patients submitted to AHCT for germ cell tumors (using carboplatin + etoposide as conditioning regimen) developed liver injury (3 patients developed SOS and 2 developed DILI).Conclusion: Liver injury associated with the autologous hematopoietic stem cell transplant, represented mainly by DILI and SOS, had a high incidence (18.9%) among the subjects in the study and was associated with an elevated mortality rate. Drug induced liver injury has been underestimated and deserves further studies. DisclosuresNo relevant conflicts of interest to declare.

Glycosyltransferase GLT25D2 Acts as a Negative Regulator of Autophagy to Promote Acetaminophen-Induced Hepatotoxicity

Background: Acetaminophen (N-acetyl-para-aminophenol, APAP) overdose induces mitochondria damage and subsequent necrosis in hepatocytes, thereby causing liver injury. However, the glycosylation of proteins in APAP-induced hepatotoxicity remains enigmatic. Here, we have assessed the contribution of the collagen galactosyltransferase GLT25D2 gene to the development of APAP-induced hepatotoxicity. Methods: GLT25D2 knockout and C57 wild-type mice were treated with APAP overdose, followed by histological and biochemical evaluation of liver injury and autophagy. The mechanism of GLT25D2 action against APAP-induced hepatotoxicity was also explored in primary cultured hepatocytes. The serum and liver biopsy samples from drug-induced liver injury patients were further analyzed. Results: The GLT25D2 expression was significantly elevated in the early stage of liver injury in mice exposed to APAP, and knockout of GLT25D2 ameliorated the hepatocellular damage. Interestingly, knockout of GLT25D2 decreased the levels of proinflammatory cytokines (TNF-α, IL-6) and chemokines (CXCL-1, CXCL-10 and MIG), however, increased the levels of anti-inflammatory cytokines (IL-10, IL-22). Mechanistic investigations elucidated that (1) knockout of GLT25D2 enhanced autophagy, promoted autophagy flux in vitro, but blocked autophagy flux in vivo; (2) inhibition of autophagy by Atg 7 knockdown abrogated liver protection by GLT25D2 knockout; and (3) autophagy induced by GLT25D2 knockout seemed to be selective for damaged mitochondria in APAP-induced hepatotoxicity. Moreover, the expression of GLT25D2 was significantly downregulated in the serum and liver of patients with a drug-induced liver failure. Conclusions: The increased GLT25D2 expression suppressed autophagy to promote the occurrence and development of APAP-induced hepatotoxicity. Funding: This work was supported by grants from the National Natural Science Foundation of China (81770611, 81270532), the Natural Science Foundation of Beijing (7162085), Applied Research for the Clinical Characteristics of Capital (Z161100000516113), the High-level Technical Personnel Training Plan of the Beijing Health System (2013-3-075 and 2015-3-099), National Science and Technology Key Project on “Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment” (2017ZX10203201-005, 2017ZX10202203-006-001, 2017ZX10302201-004-002, 2017ZX10201201). Declaration of Interest: None. Ethical Approval: This study met the ethical guidelines of the 1975 Declaration of Helsinki, and the study protocol was approved by the Medical Ethics Committee of Beijing YouAn Hospital. Informed consent was obtained from all patients.

The diagnosis and management of idiosyncratic drug-induced liver injury.

Drug-induced liver injury (DILI) is an uncommon but important cause of liver disease that can arise after exposure to a multitude of drugs and herbal and dietary supplements. The severity of idiosyncratic DILI varies from mild serum aminotransferase elevations to the development of severe liver injury that can progress to acute liver failure resulting in death or liver transplantation within days of DILI onset. Chronic liver injury that persists for more than 6months after DILI onset is also becoming increasingly recognized in up to 20% of DILI patients. Host demographic (age, gender, race), clinical and laboratory features at DILI onset have been associated with the severity and outcome of liver injury in DILI patients. In addition to cessation of the suspect drug, other medical interventions including the use of N-acetylcysteine and corticosteroids in selected patients have shown some clinical benefit, but additional prospective studies are needed. A number of promising diagnostic, prognostic and mechanistic serum and genetic biomarkers may help improve our understanding of the pathogenesis and treatment of idiosyncratic DILI.

2. Drug-induced liver injury with hypersensitivity features/drug reaction with eosinophilia and systemic symptoms (DRESS): a single center experience of 38 cases

Background and Aims: Liver involvement is the most common visceral involvement in Drug Reaction with Eosinophilia and Systemic symptoms (DRESS), which may complicate the prognosis. However, due to concomitant involvement of skin, drug induced liver injury (DILI) in them may have different picture. So this study was conducted to determine clinical characteristics, course and outcome of DRESS cases associated with liver injury. Methods: This data is collected from prospective DILI cohort from 2015 and rest of cases were collected retrospectively from the department of Gastroenterology and Dermatology, Medical college, Kozhikode, India over a period of 4 1/2 years from January 2014 till April 2018. Causality assessment was done by RUCAM scoring for DILI and by RegiSCAR for DRESS. Results: There were a total of 38 cases with DRESS and liver involvement with a mean age of 40.7 +/− 19.3 years (9–83 years) and female predominance (n = 25). Skin rash (71%) was the major symptom followed by anorexia (44.7%), fever (34.2%), vomiting (23.6%) and jaundice (15.7%). Based on R factor, 15 had hepatocellular, 17 with mixed and 6 patients had cholestatic pattern of injury. Drugs implicated were Phenytoin (31.5%), sulpha drugs (21%), carbamazepine (10.5%), valproate (7.8%), Amoxicillin-clavulanate (7.8%) and others. Stevens-Johnson syndrome was seen in 7 patients, out of which 1 patient died. When compared with the DILI cohort without DRESS (137 cases), DILI patients had significantly higher no. of severe cases (59.8% vs. 39.4%), MELD score (14.5 vs. 9.6), mean INR (1.71 vs. 1.05), albumin (3.44 g/dl vs. 3.64 g/dl), normalization of liver biochemistry (29.8 vs. 14.5 days) and mortality (13.1 vs. 2.6%). Conclusions: Although DILI has significant morbidity and mortality, patients who present with DRESS have relatively mild form of liver injury and better prognosis due to early presentation and specific treatment with steroids. The authors have none to declare.

Sclerosing Cholangitis–Like Changes on Magnetic Resonance Cholangiography in Patients With Drug Induced Liver Injury

Drug-induced liver injury can lead to changes of the biliary tree that resemble sclerosing cholangitis. These changes can be seen on magnetic resonance cholangiopancreatography. Idiosyncratic drug-induced liver injury (DILI) has a variable presentation including cholestatic liver injury,1 in which case magnetic resonance imaging (MRI) is often performed to exclude pancreaticobiliary causes of obstruction. Sclerosing cholangitis (SC)-like changes on imaging have been described anecdotally with DILI.2,3 A recent study of 25 consecutive, unselected DILI patients found that 10% had SC-like changes on magnetic resonance cholangiopancreatography (MRCP).4 The aim of the current study was to identify the clinical features of patients enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) prospective study who had SC-like changes on MRCP.

Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury.

A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes.