Chronic Drug-induced Liver Injury Research Articles

Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury

BackgroundCurrently, research on biopsy-proven acute drug-induced liver injury (DILI) remains limited. This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation in patients with acute DILI. MethodsAn ambispective cohort study was conducted on biopsy-proven acute DILI patients admitted to our hospital from 2012 to 2018. Using the Scheuer scoring system, patients were categorized into G0-2 or G3-4 groups and followed up for 12 months after first admission. Clinical characteristics and outcomes were retrieved from medical records. ResultsThe median age of the 157 enrolled patients (65.6% female) was 40.4 (interquartile range (IQR), 31.9–49.1) years. The median latency and length of hospitalization were 30.0 (IQR, 5.0–60.0) and 18.0 (IQR, 12.0–26.0) days. The proportions of patients in the G0-2 and G3-4 groups were 54.8% and 45.2%, respectively. Logistic regression analysis revealed that females (odds ratio (OR): 2.623, 95% confidence interval (CI): 1.169–5.887, p ​= ​0.019), higher body mass index (OR: 1.168, 95% CI: 1.029–1.325, p ​= ​0.016), higher total bilirubin (OR: 1.004, 95% CI: 1.000–1.007, p ​= ​0.047), and lower prothrombin activity (OR: 0.976, 95% CI: 0,957–0.995, p ​= ​0.013) were associated with significant hepatic inflammation. The predominance of the hepatocellular injury pattern (60.5%) at admission transformed into a predominance of the cholestatic pattern (60.5%) at discharge. During follow-up, 23 patients (14.6%) developed chronic DILI, with nine patients (5.7%) progressing to cirrhosis. Moreover, 15 female patients (9.6%) developed autoimmunity (3cases in the G0-2 group vs 12 cases in the G3-4 group, p ​< ​0.05). ConclusionsAcute DILI patients with high-risk factors were more likely to develop significant hepatic inflammation, and females with significant inflammation were at a higher risk of developing autoimmunity during follow-up.

An analysis on clinical characteristics and prognosis-related risk factors in patients with drug-induced liver injury

Objective: To explore the drugs and clinical characteristics causing drug-induced liver injury (DILI) in recent years, as well as identify drug-induced liver failure, and chronic DILI risk factors, in order to better manage them timely. Methods: A retrospective investigation and analysis was conducted on 224 cases diagnosed with DILI and followed up for at least six months between January 2018 and December 2020. Univariate and multivariate logistic regression analyses were used to identify risk factors for drug-induced liver failure and chronic DILI. Results: Traditional Chinese medicine (accounting for 62.5%), herbal medicine (accounting for 84.3% of traditional Chinese medicine), and some Chinese patent medicines were the main causes of DILI found in this study. Severe and chronic DILI was associated with cholestatic type. Preexisting gallbladder disease, initial total bilirubin, initial prothrombin time, and initial antinuclear antibody titer were independent risk factors for DILI. Prolonged time interval between alkaline phosphatase (ALP) and alanine aminotransferase (ALT) falling from the peak to half of the peak (T(0.5ALP) and T(0.5ALT)) was an independent risk factor for chronic DILI [area under the receiver operating characteristic curve (AUC) = 0.787, 95%CI: 0.697~0.878, P < 0.001], with cutoff values of 12.5d and 9.5d, respectively. Conclusion: Traditional Chinese medicine is the main contributing cause of DILI. The occurrence risk of severe DILI is related to preexisting gallbladder disease, initial total bilirubin, prothrombin time, and antinuclear antibodies. T(0.5ALP) and T(0.5ALT) can be used as indicators to predict chronic DILI.

An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

An analysis on the clinical features and risk factors associated with the prognosis of patients with drug-induced liver injury

Aim: This is a Chinese population-based study aimed to determine the causes and clinical features of drug-induced liver injury (DILI) from traditional Chinese medicines (TCMs) and current Western medicines (WMs) and identify the risk factors of drug-induced liver failure (DILF) and chronic DILI for early recognition and better management. Methods: The medical records of patients who were diagnosed with DILI for at least six-month follow-up between January 2018 to December 2020 were reviewed and investigated. The risk factors of DILF and chronic DILI were identified by univariate and multivariate logistic regression analysis. Results: TCMs (47.5%) including herbal medicine (83.0% in TCM-induced DILI) and some Chinese patent drugs were the leading cause of DILI in the present study. Cholestatic type was more associated with severe and chronic DILI. Pre-existing gallbladder disease, initial total bilirubin (TBIL), initial prothrombin time (PT), initial antinuclear antibodies (ANA), and clinical classification are independent risk factors for DILF. Prolonged T0.5AST and T0.5GGT were independent risk factors for chronic DILI [area under the curve (AUC) = 0.812, 95% confidence interval (CI): 0.748–0.876, P &lt; 0.001] with cut-off values of 8.5 days and 29.5 days, respectively. Conclusions: TCMs especially herbal medicine were the leading causes of DILI, and the risk of developing severe DILI was associated with pre-existing gallbladder disease, clinical classification, initial TBIL, PT, and ANA. T0.5AST and T0.5GGT might serve as indicators for chronicity.

Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury

Drug-induced liver injury (DILI) is a leading cause of death from acute liver failure (ALF). Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase (ALP) levels is associated with a 10% or greater chance of progression to transplant or liver-related death. This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury. We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022. Our primary outcome was to compare acute outcomes including ALF, liver-related death, and liver transplant between patients experiencing hepatocellular, cholestatic, and mixed patterns of DILI. Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Overall, 12 studies comprising 4290 patients were included. Patients with cholestatic DILI demonstrated similar rates of ALF (OR: 0.80, 95% CI: 0.46–1.40, p = 0.429) and liver-related death (OR: 0.92, 95% CI: 0.50–1.69, p = 0.792) compared to patients with hepatocellular DILI. Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI (OR: 2.53, 95% CI: 1.34–4.79, p = 0.004). Hy's law conceives severe DILI as an exclusive consequence of hepatocellular pattern of injury. Our results demonstrate that cholestatic injury can be associated with similarly poor rates of ALF and liver-related fatality, as well as higher rates of chronic DILI.

THU-398 - Clinical characteristics of chronic drug-induced liver injury in mainland China: a multicenter retrospective cross-sectional study

THU-398 - Clinical characteristics of chronic drug-induced liver injury in mainland China: a multicenter retrospective cross-sectional study

Epidemiology and Management of Drug-induced Liver Injury: Importance of the Updated RUCAM.

Drug-induced liver injury (DILI) is a major cause of acute liver injury, liver failure, and liver transplantation worldwide. In recent years, immune checkpoint inhibitors have become widely used. This has led to an increase in DILI, for which pathophysiology and management methods differ significantly from the past. As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase, information about a DILI is becoming more valuable. DILI is classified into two types according to its etiology: intrinsic DILI, in which the drug or its metabolites cause liver damage that is dose-dependent and predictable; and idiosyncratic DILI, in which liver damage is also dose-independent but unpredictable. In addition, depending on the course of the disease, chronic DILI or drug-induced autoimmune hepatitis may be present. The number of DILI cases caused by antimicrobial agents is decreasing, whereas that caused by drugs for malignant tumors and health foods is increasing. The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI. Liver injury is a type of immune-related adverse event. The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular, but mixed type and bile stasis have also been reported. Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury. Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration; however, mycophenolate mofetil may be considered if the disease is refractory to steroids.

Significance of histological assessment in drug-induced liver injury

Liver histological assessment is of great clinical significance for the diagnosis, classification, and prognosis prediction of drug-induced liver injury (DILI). Liver histological evaluation can effectively supplement RUCAM. The clinical phenotypes of DILI are complex and diverse, including acute, chronic and severe hepatic injury. DILI has multiple insult-targets, including hepatocytes, cholangiocytes, and vascular endothelial cells and others. The pathological damage patterns are similar to many types of non-DILI liver diseases, therefore making differential diagnosis difficult. New anti-tumor drugs such as immune checkpoints inhibitors and targeted therapy are widely used in clinical antineoplastic practice, thus the growing incidence of related liver injury occurs. Liver histological examination can effectively assess the pathological phenotypes and severity of DILI, so as to guide treatment. In uncommon conditions such as special types of DILI (such as hepatic vascular disease), DILI with other competitive etiology overlapping, chronic DILI, and DILI induced liver failure, liver histological assessment can provide strong support for identifying the cause, rational treatment, and prognosis. Currently, the histological evaluation system for drug-induced liver injury seems to be a lack of consensus, and the diagnosis of DILI is short of highly specific and sensitive serological markers. All in all, liver histological assessment plays a crucial role in the diagnosis and differential diagnosis of DILI.

The Impact of Patient Age and Corticosteroids in Patients With Sulfonamide Hepatotoxicity.

Sulfonamides are widely used to treat and prevent various bacterial and opportunistic infections. The aim of this study was to describe the clinical presentation and outcomes of a large cohort of patients with sulfonamide hepatotoxicity. Between 2004 and 2020, 105 patients with hepatotoxicity attributed to trimethoprim/sulfamethoxazole (TMP-SMZ) (n = 93) or other sulfonamides (n = 12) were enrolled. Available liver biopsies were reviewed by a single hepatopathologist. Among the 93 TMP-SMZ cases, 52% were female, 7.5% younger than 20 years, and the median time to drug-induced liver injury (DILI) onset was 22 days (range: 3-157). Younger patients were significantly more likely to have rash, fever, eosinophilia, and a hepatocellular injury pattern at onset that persisted at the peak of liver injury compared with older patients ( P < 0.05). The 18 (19%) TMP-SMZ patients treated with corticosteroids had more severe liver injury and a higher mortality but a trend toward more rapid normalization of their laboratory abnormalities compared with untreated patients. During follow-up, 6.2% of the TMP-SMZ patients died or underwent liver transplantation. Chronic DILI developed in 20% and was associated with cholestatic injury at onset and higher peak total bilirubin levels. Sulfonamide hepatotoxicity is characterized by a short drug latency with frequent hypersensitivity features at onset. Subject age is an important determinant of the laboratory profile at presentation, and patients with cholestasis and higher total bilirubin levels were at increased risk of developing chronic DILI. Corticosteroids may benefit a subgroup of patients with severe injury, but further studies are needed.

Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro

Low-dose methotrexate (MTX) is a standard therapy for rheumatoid arthritis due to its low cost and efficacy. Despite these benefits, MTX has been reported to cause chronic drug-induced liver injury, namely liver fibrosis. The hallmark of liver fibrosis is excessive scarring of liver tissue, triggered by hepatocellular injury and subsequent activation of hepatic stellate cells (HSCs). However, little is known about the precise mechanisms through which MTX causes hepatocellular damage and activates HSCs. Here, we investigated the mechanisms leading to hepatocyte injury in HepaRG and used immortalized stellate cells (hTERT-HSC) to elucidate the mechanisms leading to HSC activation by exposing mono- and co-cultures of HepaRG and hTERT-HSC to MTX. The results showed that at least two mechanisms are involved in MTX-induced toxicity in HepaRG: (i) oxidative stress through depletion of glutathione (GSH) and (ii) impairment of cellular respiration in a GSH-independent manner. Furthermore, we measured increased levels of endoplasmic reticulum (ER) stress in activated HSC following MTX treatment. In conclusion, we established a human-relevant in vitro model to gain mechanistical insights into MTX-induced hepatotoxicity, linked oxidative stress in HepaRG to a GSH-dependent and -independent pathway, and hypothesize that not only oxidative stress in hepatocytes but also ER stress in HSCs contribute to MTX-induced activation of HSCs.

A high relapse risk of chronic drug-induced liver injury is correlated with a greater severity of liver fibrosis

To construct a risk prediction model for relapse of chronic drug-induced liver injury (DILI) and explore the correlation between DILI relapse risk and liver fibrosis. We retrospectively collected the clinical data of 1138 patients with chronic DILI hospitalized from January, 2017 to January, 2022, including 154 patients with and 984 without DILI relapse. Based on the results of univariable and multivariable logistic regression analyses, a risk prediction model for DILI relapse was constructed, evaluated for its discrimination and calibration using AUC value and Hosmer-Lemeshow test, and verified with a 200 times 5, 10 and 20 folds cross validation method. Spearman correlation analysis was used to evaluate the correlation between the new model and liver fibrosis, and its diagnostic efficiency for liver fibrosis was assessed by comparison with APRI and FIB-4 using ROC curve. The proportions of patients with S0, S1, S2, S3 and S4 liver fibrosis were 1.9%, 13.1%, 42.2%, 27.9% and 14.9% in the relapse group, respectively, as compared with 8.9%, 43.5%, 26.1%, 17.1% and 4.4% in the non-relapse group, respectively, showing severer liver fibrosis in patients with than those without DILI relapse. Multivariable logistic regression analysis identified LSM≥13.7 kPa (OR=4.35, 95%CI: 2.61-7.25, P < 0.001), CHE < 2500 U/L (OR=5.17, 95%CI: 2.13-12.53, P < 0.001), CHE of 2500-5000 U/L (OR=4.07, 95%CI: 2.75-6.01, P < 0.001), and AST > 2×ULN (OR=2.29, 95%CI: 1.38-3.80, P=0.001) as risk factors for relapse of chronic DILI. The ACLS model constructed based on these non-invasive indicators had an AUC value of 0.803 (95%CI: 0.78-0.83). The results of Hosmer-Lemeshow goodness of fit test (χ2=7.73, P=0.46) and the cross validation tests (average AUC of 0.803) all showed a good stability of the model. Spearman correlation analysis showed that ACLS score was positively correlated with the severity of liver fibrosis (rho=0.530, P < 0.001). At the optimal cut-off value of 3 points for diagnosing moderate liver fibrosis, the ACLS model had an AUC value of 0.78 (with specificity of 72.7% and sensitivity of 73.3%), demonstrating a better efficacy than that of APRI and FIB-4 (P < 0.001). At the cut-off value of 6 for severe liver fibrosis, the diagnostic efficacy of the model (AUC=0.83; specificity 75.7%, sensitivity 72.7%) was still better than that of APRI (P < 0.001) but comparable with that of FIB-4 (P=0.38). The patients at high risks of chronic DILI relapse have severer liver fibrosis and should be followed up regularly for timely aggressive treatment.

Spectrum of drug-induced liver injury in a tertiary hospital in southern India.

Background Anti-tuberculosis drugs are thought to account for about 50% of drugs that cause liver injury in India. We show that the spectrum of drugs is much wider than previously reported. Methods We evaluated all patients with unexplained acute liver injury presenting during 2006-2016 using a structured proforma for drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method was used to assess causality. Results DILI was found in 143 of 2534 patients with acute liver injury. Nineteen patients had probable ayurvedic DILI. The other common causes of DILI were statins (16 patients) and anti-tuberculosis drugs (11 patients). Eight patients had DILI post-liver transplant. Fluconazole was the most common cause of post-liver transplant DILI. Chronic DILI (abnormal liver function test after 12 months of stopping the suspected drug) was found in 2 patients. Conclusion In otherwise unexplained acute liver injury, DILI due to ayurvedic drugs should be sought. DILI should be considered in post-liver transplant patients. Patients with DILI should be monitored for at least 12 months to exclude progression to chronic DILI.

S1202 Drug-Induced Liver Injury (DILI) Ascribed to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in the USA: An Update With Genetic Correlations From the U.S. Drug-Induced Liver Injury Network (DILIN)

Introduction: NSAIDs are widely used throughout the world, mainly for management of chronic inflammatory and painful conditions. NSAIDs rarely cause idiosyncratic, non-dose dependent liver injury. Recent evidence from the US DILIN, as well as elsewhere, implicates host immune responses as central to pathogenesis of such idiosyncratic DILI. Previously, we reported the US DILIN experience with NSAID DILI for 2004-2013.1 Aim: To update our clinical experience and report on HLA and other genetic factors recently described as important in idiosyncratic DILI. Methods: The US DILIN, begun in 2004; is comprised of clinical sites [currently 7 in number], a data coordinating center, and the NIDDK. We enroll subjects with suspected DILI and follow them for at least 6 months.2 We adjudicate causality both with RUCAM, and RECAM3 and by a Delphic approach4 and grade severity from mild to fatal or requiring liver transplant.5 Between Sep 2004 and Mar 2022, we enrolled 2,626 subjects and adjudicated causality at 6 months in 2,498. Following adjudication, we identified 55 [41 (75%) women] as definitely [ >95%], highly likely [75-95%], or probably [51-74% likely] due to NSAIDs. Results: Diclofenac was the causative drug in 29/55 [53%] of cases, followed by celecoxib [7], ibuprofen [5], etodolac and meloxicam [4 each]. Median latency was 51 d. With the notable exceptions of meloxicam and oxaprozin [n=2], the type of liver injury was hepatocellular with median R 15-25. 4 subjects died within 6 mo of onset, and 2 others [1 each due to diclofenac and celecoxib] required liver transplants. 7 had chronic DILI at 6+ mo. HLA DRB1*03:01 was more frequent in those with NSAID DILI than in matched controls, and 6/10 had the ancestral AI extended haplotype. The likelihood of carrying the DRB1*04:03 allele increased with causality score confidence and with more severe DILI [p =0.006]. Conclusion: NSAID DILI is relatively rare in the US. The most common cause is diclofenac, which, if prescribed, should carry with it special warnings of risk and close observation, as in the package insert. The increased frequencies of HLA DRB1*03:01, an HLA type known to be associated with SLE and other auto-immune disorders, and the extended ancestral AI haplotype, suggests that immune-mediated responses are of central importance in pathogenesis.

S3229 A Case of Cholestatic Drug-Induced Liver Injury After Ashwagandha Root Supplementation

Introduction: Ashwagandha root is an ancient Indian Ayurvedic herbal medicine sometimes referred to as “Indian Winter cherry” or “Indian Ginseng,” that is growing in popularity for its purported benefits of weight loss, muscle building and stamina benefits, and cognition promoting effects. In vitro studies suggest possible benefits of ashwagandha to include muscle growth, exercise stamina, weight loss, hepatocellular carcinoma targeting, and others, but no large scale studies have been done to test for safety or adverse effects. Rare case reports of drug induced liver injury (DILI) related to ashwagandha have been documented. Case Description/Methods: 19-year-old male presented to our hospital with severe pruritus and new onset jaundice after starting Ashwagandha. Two weeks after starting he developed progressive pruritus without any noted rash. Five days after the onset of pruritis he noted jaundice with nausea and dark urine, no abdominal pain. Initial labs showed a total bilirubin 7.6, AP 149, ALT 144 and AST 74. He had imaging including MRI and CT scan which were unremarkable. He was discharged with prn hydroxyzine for itching and told his DILI would resolve with time. A month since discontinuing the ashwagandha supplements his pruritus and jaundice worsened and he arrived to our hospital for evaluation. He was treated with cholestyramine, ursodiol and antihistamines. His bilirubin ultimately nadired at 30. Was also started on low dose naltrexone, and discharged. Returned for short hospital stay with severe pruritis. His t. bili remained similar compared to prior at 29, with normal INR. He was started on low dose rifampin given persistent pruritus, with mild improvement, and ultimately discharged with close follow-up. Discussion: Ashwagandha root is a rare cause of cholestatic liver injury. The Drug Induced Liver Injury Network (DILIN) were able to identify five incidences of drug induced liver injury related to ashwagandha. The clinical course of our patient closely matches the six total cases described in the literature so far. Latency period of 2 weeks to the development of jaundice. He then had a prolonged course of cholestatic liver injury after discontinuing supplements that lasted several months. Ashwagandha-containing herbal medications can result in severe cholestatic liver injury, without the development of chronic DILI or progression to acute liver failure. This case report further re-enforces the importance of careful monitoring and awareness of our patients’ supplemental health products. Table 1. - Bilirubin and symptoms trend Days since Symptom onset 6 days 36 days 42 days 44 days 46 days 49 days 52 days 56 days 67 days Total Bilirubin Level 7.6 25 30 29 31.3 21.2 18 16.6 - Symptoms Jaundice/pruritis Worsening jaundice/pruritis/pale stools Persistent pruritis AMS vs. panic attack, persistent pruritis Mild improvement pruritis - Pruritis improving - Pruritis resolved, visible jaundice improving

In Vitro Models for Studying Chronic Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a major clinical problem in terms of patient morbidity and mortality, cost to healthcare systems and failure of the development of new drugs. The need for consistent safety strategies capable of identifying a potential toxicity risk early in the drug discovery pipeline is key. Human DILI is poorly predicted in animals, probably due to the well-known interspecies differences in drug metabolism, pharmacokinetics, and toxicity targets. For this reason, distinct cellular models from primary human hepatocytes or hepatoma cell lines cultured as 2D monolayers to emerging 3D culture systems or the use of multi-cellular systems have been proposed for hepatotoxicity studies. In order to mimic long-term hepatotoxicity in vitro, cell models, which maintain hepatic phenotype for a suitably long period, should be used. On the other hand, repeated-dose administration is a more relevant scenario for therapeutics, providing information not only about toxicity, but also about cumulative effects and/or delayed responses. In this review, we evaluate the existing cell models for DILI prediction focusing on chronic hepatotoxicity, highlighting how better characterization and mechanistic studies could lead to advance DILI prediction.

The progression of chronicity and autoimmune hepatitis in recurrent drug-induced liver injury

Background and aimsRecurrent drug-induced liver injury (DILI) is not well documented. We retrospectively analysed the characteristics of patients who had a history of two separate DILI episodes due to different drugs. MethodsWe collected data from 57 patients with recurrent DILI from 9582 confirmed DILI cases. Demographic, laboratory, and clinical data from both episodes were collected and analysed to determine the relationship between recurrent DILI, chronic DILI, and autoimmune hepatitis (AIH). ResultsThe incidence rate of recurrent DILI in our cohort was 0.59%. Most of the 57 patients with recurrent DILI were female (73.68%). The latency period of the initial episode was 30 days, whereas that of the second episode was 13 days (P = 0.003). The pattern of liver injury was not significantly different between episodes (P = 0.52). Laboratory indicators, such as alanine aminotransferase, aspartate transaminase, alkaline phosphatase, and total bilirubin, were significantly lower in the second episode than in the initial episode (P < 0.05). The incidence of chronic DILI was 43.86% during the initial episode and increased to 63.16% during the second episode. After the initial episode, 15 patients developed AIH during the second episode. ConclusionsThe latency period of recurrent DILI was gradually shortened. The clinical indices of liver injury tended to be less elevated during the second episode. Female post-menopausal patients with abnormal serum immunoglobulin G levels may be predisposed to AIH. The second DILI episode was more likely to have features of AIH.

Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury.

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction–related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism. Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan. Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI–associated fibrosis. Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p=0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Gynura segetum-induced liver injury leading to acute liver failure: a case report and literature review

BackgroundGynura segetum (GS) is widely used in medical care and in community settings in China as the herbal remedy. It is widely thought to have antiphlogistic properties and pain relief in traditional Chinese medicine. It has been reported that GS can cause chronic drug-induced liver injury (DILI), manifested as hepatic sinusoid obstruction syndrome (HOSO). But case reports of acute DILI developing acute liver failure (ALF) due to GS are extremely rare.Case presentationWe report a case of a 63-year-old female patient with hepatolithiasis for more than 6 years. There were no deterioration of liver function and no history of viral liver disease, autoimmune liver disease, blood transfusion or surgical allergy before operation. ALF and grade II liver encephalopathy occurred after partial hepatectomy. To follow up the medical history, the patient has been taking GS (Tusanqi) for a year and a half. The causality assessment was done by the updated Roussel Uclaf Causality Assessment Method, and the possibility of DILI caused by GS as highly probable for the score was 6 points. Excluding other causes, a diagnosis of DILI-associated ALF was established. After symptomatic support and artificial liver support system (ALSS) treatment, the clinical symptoms and signs of the patients were significantly improved. After discharge, the liver function of the patients returned to normal.ConclusionsBased on this rare case of severe liver injury, we recommend that timely prevention, identification, and appropriate management of DILI is essential for patients with a history of taking GS and other hepatotoxic drugs, and careful monitoring of liver function for patients with DILI could avoid ALF as far as possible.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p<0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.