Drug-induced Liver Injury: Pathology Patterns and Common Culprits.

12049 Background: The risk and impact of drug-induced liver injury (DILI) due to ICI treatment on newly diagnosed cancer patients have not been fully investigated. This study aims to assess the incidence and impact of ICI related DILI on overall survival. Methods: We included patients with newly diagnosed cancer treated with ICIs between 01/2012 and 12/2020 at the Ohio State University Comprehensive Cancer Center. DILI was defined using ICD-9 and ICD-10 codes for abnormal results of liver function, acute hepatitis, drug-induced liver injury, or toxic liver disease. History of Liver Disease (HLD) before ICI infusion was defined using ICD-9 and ICD-10 codes for any liver disease, including primary and secondary liver malignant neoplasms. To examine the causal effects of ICI-related DILI, patients who developed hepatocellular carcinoma or metastatic liver disease were excluded. Kaplan Meier method was used to estimate DILI risk post-ICI infusion in patients with and without HLD. Crude and Adjusted Cox proportional models were used to examine the association between DILI, modeled as time-dependent, and overall survival. Results: A total of 2,816 patients were included in the study, with a median age of 62 years, 58% male, and 90% white non-Hispanics. An estimated 11% of patients developed DILI during follow-up. The median (interquartile range) follow-up time from ICI infusion to DILI was 8.7 (3.0–20.1) months. The overall risk of DILI was 25.3%, which was significantly higher in patients with HLD than in those without HLD (17.8% vs. 30.8%, Log-Rank P <0.001). The median (interquartile range) survival time was 10.4 (3.7–22.7) months. During follow-up, a total of 1390 (49.4%) patients died. DILI was significantly associated with a higher risk of all-cause mortality in all regression models. The crude risk of all-cause mortality was 40% higher in patients with DILI than in those without DILI [HR: 1.40; 95% CI: 1.15–1.70]. In the fully adjusted models, DILI was associated with a 63% higher risk of all-cause mortality [adjusted HR: 1.63; 95% CI: 1.34–1.99]. DILI's effects on the overall survival risk remained significant when we further adjusted for HLD status [HR: 1.57; 95% CI: 1.29–1.93]. Conclusions: The findings from this retrospective cohort study highlight the significant risk and detrimental impact of DILI on overall survival in patients treated with ICIs. Notably, the incidence of DILI was significantly higher among patients with HLD, underscoring the elevated vulnerability of this subgroup. Furthermore, DILI was a significant predictor of increased all-cause mortality regardless of HLD status. These results underscore the need for vigilant monitoring and management of liver function in patients receiving ICIs, particularly in those with pre-existing liver conditions, to mitigate the risk of DILI and improve survival outcomes.

Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.

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.

Drug-Induced Liver Injury: Icelandic Lessons

Drug induced liver injury and its relationship to autoimmune hepatitis

Approach to the patient with acute severe autoimmune hepatitis.

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development

Liver Injury Associated With Drugs and Complementary and Alternative Medicines in India

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 late event onset of a fraction of idiosyncratic drug-induced liver injury (DILI) cases and the link observed by genome-wide association studies (GWASs) of certain human leucocyte antigen (HLA) alleles with DILI due to specific drugs support the crucial role of the immune system (both innate and adaptive) in the pathogenesis of DILI. Recent advances in both flow and mass cytometry have allowed the profiling of all major immune cell types in a given sample. Therefore, determining the lymphocyte populations in samples from patients with DILI would facilitate the development of specific biomarkers for DILI diagnosis and prognosis. To date, a few studies have explored the immune landscape in DILI. In a recent study of leukocyte immunophenotyping using flow cytometry from the Spanish DILI Registry, an important role of adaptive immune response in DILI is suggested. DILI patients had significantly higher levels of T helper 1 (Th1) cells and activated helper and cytotoxic T cells than healthy controls. Furthermore, the increased expression of negative immune checkpoints and ligands in DILI patients could reflect a restoration of the immune homeostasis. Differences in the profile of cytokines in DILI patients from the Drug-Induced Liver Injury Network (DILIN) also suggest an involvement of both innate and adaptive immune systems in DILI development and prognosis. Moreover, several studies based on immunophenotyping of liver infiltrates showed a distinctive pattern of cellular infiltrates in patients with immune checkpoint inhibitors (ICIs)-DILI, with lower levels of plasma cells, CD20+ B cells and CD4+ T cells than in autoimmune hepatitis (AIH) patients. These pioneering studies highlight the importance of immunophenotyping for the mechanistic understanding of DILI. In this review, available data on immunophenotyping in DILI are gathered, and the potential clinical applications of cutting-edge, novel immunophenotyping techniques are discussed.

Introduction: The diagnosis of drug induced liver injury (DILI) is difficult as it is largely a clinical diagnosis of exclusion. To aid in diagnostic decision making, we reviewed cases enrolled in DILIN with an initial diagnosis of DILI that were ultimately adjudicated as unlikely with alternative etiologies accounting for the abnormal liver tests. Methods: The DILIN is an ongoing NIH observational trial in which hepatologists enrolled patients from 2004 to the present with a high suspicion of DILI. Cases were adjudicated by a panel of experts through a structured process and scored from 1 (definite DILI) to 5 (unlikely DILI). Cases that were scored at least probable DILI (1-3) were compared to unlikely DILI (5). Unlikely cases were further reviewed for salient features and trends over time. Results: From 9/04 to 12/21, 1916 cases were adjudicated; 134 (7%) were unlikely DILI. There were no demographic features to distinguish at least probable cases from unlikely cases. Unlikely cases more often had renal disease (18% vs 9%, p=0.005), HIV (7% vs 2% p< 0.001), hepatitis C (HCV) (12% vs 3% p< 0.001), and hepatitis B (5% vs 1 % p< 0.001). Unlikely DILI vs. true DILI was higher for brief latency between drug use and liver injury (< 1 week 9% vs 5%) or very long latency ( >24 weeks 28% vs 16%) p=0.002 overall. The most common alternative diagnoses for unlikely cases were autoimmune hepatitis (AIH) (20%) and HCV (20%) (Table). Among white patients, carriage frequency of two copies of HLA-DQA1*03:01 was greater among those with AIH (13%) compared to DILI (3%) and population controls (1%). Patients with unlikely DILI had greater all-cause (16% vs 7%, p< 0.001) and liver related mortality (10% vs 3%, p< 0.001). Unlikely DILI cases died within six months at a higher rate (14% vs 6%, p=0.004). Transplant rates, hospitalization, and duration of illness were similar. Conclusion: DILI is difficult to diagnose, even among experienced hepatologists. Demographic factors are not helpful in the initial diagnosis. Very short or very long latency between suspect drug and initial liver injury decreases likelihood of true DILI. HCV PCR testing is critical in presumed DILI. Genetic testing in white patients with AIH vs. DILI may be useful. Longitudinal follow up of patients with DILI is essential to refine the diagnosis, treat an alternative disease, and potentially absolve a medication presumed to have caused DILI. Table 1. - Alternative Diagnoses in 134 Unlikely DILI cases Diagnosis N % Comments Autoimmune hepatitis 27 20.1 The most common incorrectly implicated class of medications were antibiotics (9/27) followed by HDS products (8/27). Nearly all had a liver biopsy, but findings were neither diagnostic for DILI nor classic for AIH. Other common themes included 1) prevalent systemic immune mediated disease (systemic lupus erythematous, hypothyroidism, inflammatory bowel disease, etc.) in 8/27 cases; 2) negative or relatively low antinuclear antibody titers (< 1:80) which increased on follow up; 3) a response to steroids in 14/27 with six of these having a flare in enzymes after immunosuppression titration or withdrawal. Hepatitis C 27 20.1 Of the 24 that were acute cases, 17 were enrolled prior to 2011 and none since 2017. Most of these cases had negative HCV antibodies and were discovered to have a positive HCV viral load later in their clinical course. Three patients had prevalent detectable HCV virus which later cleared spontaneously on follow up. Gallstones/BiliaryDisease 18 13.4 Eight cases with biliary tract malignancy.Three cases with primary sclerosing cholangitis. Normal imaging in some patients who acutely passed a stone.No differences in the presence of stones (3.3% vs. 6.7% p=0.32), or ductal dilation (3.3% vs. 2.5% p=0.89) between unlikely DILI and probable and higher DILI cases. Hepatitis E 11 8.2 Diagnosis often delayed as test is a send-out in most centers. Sepsis 7 5.2 Frequently in Intensive Care Unit on multiple drugs and hypotensive. Other ( >20 diverse etiologies) 44 32.8 Etiologies included alcohol, myopathy, Epstein Barr virus, cytomegalovirus, nonalcoholic steatohepatitis, metastatic cancer, and granulomatous liver disease.

2602 Background: Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. With their increasing use, it is important to track and manage potential adverse events (AEs) . One such AE of ICI therapy is immune-mediated liver injury (ILICI). We aim to review the real-world data on ILICI using FDA Adverse Event Reporting System (FAERS) database. Methods: We queried FAERS using a search-by-product strategy on 22nd January 2025 and retrieved 224889 adverse events from 2013-2024. We employed 5 ICIs in the analysis (Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, and Ipilimumab). Descriptive statistics were carried out, and disproportionality analysis was done by calculating the reportable odds ratio (ROR) with 95% confidence intervals (CI). ROR was considered significant when the lower limit of the 95% CI was &gt; 1. RORs were calculated for all hepatic events in general and Autoimmune Hepatitis (AIH), Drug-induced liver injury (DILI), Vanishing bile duct syndrome (VBDS), Primary biliary cholangitis (PBC), and Venooccluisve disease (VOD). Results: Total AEs from all included ICIs were 224889 and Hepatobiliary AEs constitute 9.2% of all AEs across all ICIs. ROR for any hepatic event is highest with Durvalumab i.e., 17.97 (16.08,20.08) in general as compared to the rest of the ICIs. AIH was seen highest with Ipilimumab with a ROR of 48.0 (43.1, 53.5); DILI with Pembrolizumab with a ROR of 5.8 (5.3, 6.4) (Overlapping CI); VBDS and PBC with Pembrolizumab with a ROR of 7.93 (4.9, 12.8) and 7.91 (4.46,14.03) respectively. Atezolizumab showed the highest ROR of 6.15 (3.6, 10.4) for VOD . (Table) Conclusions: This is the largest real-world study demonstrating specific hepatotoxic AEs with ICIs. Our results show varying patterns of hepatotoxicity with ICIs. Knowing these patterns will help us make better decisions in treating patients with ICIs. Baseline characteristics, hepatic AEs and outcomes. Baseline characteristic Pembrolizumab(n= 67603) Nivolumab(n=79283) Atezolizumab(n=28521) Durvalumab (n=13303) Ipilimumab (n= 36179) ROR for any hepatic event (95% CI) 8.24 (7.66,8.87) 7.46 (6.95, 8.01) 7.94 (7.08, 8.89) 17.97 (16.08, 20.08) 11.47 (10.54, 12.48) ROR for AIH 21.34 (18.9, 24.0) 27.3 (24.8, 30.1) 22.3 (18.7, 26.5) 22.3 (18.7, 26.5) 48.0 (43.1, 53.5) ROR for DILI 5.8 (5.3, 6.4) 3.74 (3.34, 4.19) 5.3 (4.61,6.29) 5.3 (4.61, 6.29) 5.04 (4.37, 5.82) ROR for VBDS 7.93 (4.9, 12.8) 4.37 (2.41, 7.94) 0.5 (0.03, 8.8) 1.1 (0.15, 7.86) 2.61 (0.84, 8.1) ROR for VOD 2.22 (1.2, 3.9) 3.79 (2.5, 5.6) 6.15 (3.6, 10.4) 0.44 (0.06, 3.12) 2.08 (0.9, 4.63) ROR for PBC 7.91 (4.46,14.03) 3.37 (1.5, 7.5) 0.78 (0.04, 12.5) 1.51 (0.21, 11.1) 2.46 (0.6, 9.8) Hepatic AEs included in the ROR calculation with these agents are Drug-Induced Liver Injury (DILI), Autoimmune hepatitis (AIH), Vanishing bile duct syndrome (VBDS), Veno-occlusive disease (VOD), Primary biliary cholangitis (PBC).

This Month in Gastroenterology

Drug-induced liver injury (DILI) is arare yet potentially life-threatening disease. Besides intrinsic DILI, which is mainly caused by paracetamol overdosing and which is dose-dependent and predictable, there is idiosyncratic DILI-an unpredictable and dose-independent injury of the liver caused by certain medications that only occurs in aminority of patients taking this drug. The reason why some patients react with DILI towards aspecific drug is still unknown. However, the immune system plays acentral role, which is underlined by the association of certain human leukocyte antigen (HLA) polymorphisms and DILI caused by specific drug classes. Due to the immunological processes that lead to the liver injury in DILI, there are great overlaps regarding laboratory and histological parameters between DILI and autoimmune hepatitis (AIH). Differentiating DILI and AIH can therefore be challenging, especially at the time of presentation. In addition, there are other immunologically mediated DILI phenotypes, in particular the newly defined drug-induced autoimmune-like hepatitis (DI-ALH) and liver injuries caused by checkpoint inhibitors (CPI). DI-ALH is characterized by autoimmune features and good responses towards corticosteroids, with the difference that DI-ALH mostly does not relapse after discontinuation of corticosteroids. CPI-induced liver injury has become more frequent with the rising use of those drugs and is characterized by adistinct histopathological pattern with granulomatous hepatitis and infiltration dominated by cytotoxic Tcells. Similarly, the recently recognized liver injury following vaccinations also shows an autoimmune phenotype; however, in contrast to AIH, cytotoxic Tcells seem to dominate the inflammatory infiltrates in the liver.

Causality assessment methods in drug induced liver injury: Strengths and weaknesses