Recreational Drugs and the Risk of Hepatocellular Carcinoma

Hepatocellular carcinoma represents an important contributor to the global cancer-related burden, and liver cirrhosis is the main risk factor for its development. Conventional or illegal drug consumption is a potential but infrequent cause of cirrhosis. However, the causal relationship between recreational drugs and the risk of developing liver cancer has not been studied in detail thus far. The aim of this review is to synthesize the available published evidence on legal and illegal recreational drug use and the risk of hepatocellular carcinoma and other liver tumors. Expanding our knowledge about the contributions of these substances to the appearance of liver cancers is important for combatting this preventable cause of cancer. Abstract Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis’ potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. (...)This research was supported by grants from Instituto de Salud Carlos III, cofounded by the Fondo Europeo de Desarrollo Regional—FEDER (contract numbers: FIS 21_01248; PI18/00901; UMA18-FEDERJA-193). CIBEREHD is funded by the Instituto de Salud Carlos III (ISCIII). All authors are members of the COST ACTION “CA-17112”, Prospective European Drug-Induced Liver Injury Network, supported by COST (European Cooperation in Science and Technology), www.cost.eu. JMPB holds a Rio Hortega contract from ISCIII. ASZ holds a Jaume Bosch Training Action 2022 from CIBEREHD (ISCIII)

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries

Background & aims: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly re-ported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. Methods: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Results: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p= .001). DILI cases with autoimmune features had significantly longer time to onset (p< .001) and resolution time (p= .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. Conclusions: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.Instituto de Salud Carlos III; Fondo Europeo de Desarrollo Regional— FEDER, Grant/Award Number: UMA18- FEDERJA-193, PI18/00901, PI19/00883 and PI21/01248; Consejería de Salud y Familia de la Junta de Andalucía, Grant/Award Number: P18-RT- 3364 and PI- 0310- 2018; Agencia Española del Medicamento; Sara Borrell, Grant/Award Number: CD20/00083; Rio Hortega, Grant/Award Number: CM21/00074; Garantía Juvenil, Grant/Award Number: SNGJ5Y6-09; Junta de Andalucía and European Social Fund; European Cooperation in Science and Technology; Universidad de Málaga/CBUA Funding for open access charge: Universidad de Málga / CBU

Modeling drug-induced liver injury: current status and future prospects.

Idiosyncratic drug-induced liver injury (iDILI) is a challenging and unpredictable multifactorial condition. At present, validated preclinical models for the prediction of the hepatotoxic potential of a given drug are scarce. This review intends to sum up the current knowledge about in vitro (including hepatocyte 2D cultures, cocultures with non-parenchymal cells, 3D configurations and non-typical closer to reality in vitro models), in vivo (covering models for immunological and oxidative stress features, humanized mouse-based and non-rodent models) and in silico approaches for iDILI modeling, highlighting the recent advances in each topic. The future strategy for iDILI modeling should be patient-centered. Future animal and cell-based models, with more predictive value, will be easier to design by using a more translational approach based on mechanisms demonstrated in humans. Genetic and epigenetic information gathered from iDILI patients, together with data from in vitro and in vivo studies, could be used to develop sophisticated predictive in silico models to find compounds with iDILI potential. Collecting genetic, metabolic, and biomarker data from patient cohorts might be another option to create a 'fingerprint' characteristic of people at risk, allowing for the development of new, mechanistic strategies to enhance iDILI in vitro evaluation

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes