The hepatotoxicity of drugs is the main cause of drug withdrawal from the pharmaceutical market and interruption of the development of new molecules. Biomarkers are useful in several situations. In ...case of suspected drug-induced liver injury (DILI), biomarkers can be used to confirm liver damage, its severity, prognosis, confirm drug causality, or define the type of DILI. In this review, we will first present the currently used biomarkers and candidate biomarkers for the future. The current biomarkers are certainly very helpful including with the assistance of diagnostic method such the Roussel Uclaf Causality Assessment Method, but provide a limited information for the early detection of liver injury, the role of specific drug and the prediction of DILI. Some biomarkers are promising but they are not yet available for routine use. Studies are still needed to confirm their interest, particularly in comparison to Roussel Uclaf Causality Assessment Method.
Some drugs may induce hepatotoxic lesions, such as steatosis or steatohepatitis found in Non-Alcoholic Fatty Liver Disease (NAFLD). Among these drugs there are some anti-tumoral molecules, such as ...methotrexate, 5-fluorouracil, irinotecan, tamoxifen and l-asparaginase. The hepatotoxic phenotype developed from treatment with such drugs is known as “CASH” for “Chemotherapy-induced Acute Steatohepatitis”. The mechanism of toxicity is essentially based on mitochondrial toxicity. These lesions are chronic and often reversible when the treatment is stopped. Contributing factors related to the patient, the disease or the treatment play a major role in the emergence of CASH. It is important to identify chemotherapies with steatosis or steatohepatitis as risk factors in order to improve control of the metabolic risk factors associated with the patient and to reinforce monitoring during treatment. In the particular context of neo-adjuvant chemotherapy for metastatic colorectal cancer, a short duration of chemotherapy and a few-weeks delay between chemotherapy and surgery could reduce postoperative morbidity and mortality.
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available ...herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and the association with other autoimmune diseases is well-documented. There are many therapeutic options for ...the treatment of MS. Most of the available drugs cause drug-induced liver injury (DILI) to variable extents with heterogeneous clinical and biological manifestations, including liver injury with or without signs of hypersensitivity and autoimmunity. The diagnosis of DILI may be particularly difficult because MS is frequently associated with idiopathic autoimmune hepatitis. Recent advances suggest that MS and immune-mediated DILI could be promoted by genetic factors, including HLA genotype. In addition, some of these drugs may promote hepatitis B virus reactivation. This review explores the potential hepatotoxicity of drugs used to treat MS and the criteria to distinguish DILI from idiopathic autoimmune hepatitis associated with MS. The role of susceptible genes both promoting MS and causing the hepatotoxicity of the drug used for MS treatment is also discussed.
Summary Background Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological ...response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin. Methods In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov , number NCT01965535. Findings Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89–99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91–100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue. Interpretation Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible. Funding Gilead Sciences.
AbstractNon-steroidal-anti-inflammatory drugs (NSAIDs) make a heterogenous pharmaco-therapeutic class of drugs among the most used drugs worldwide with various indications, modes of administration ...and increasing automedication. NSAIDs can cause acute liver injury with variable severity. The recent identification of genetic markers might facilitate the diagnosis and the prediction of hepatotoxicity risk.
Introduction: Uterine fibroids are benign tumors within the uterine wall affecting women. Ulipristal acetate 5 mg was first authorized in the European Union on 23 February 2012, with a post-marketing ...exposure estimated to be more than 765,000 patients so far. During the post-marketing experience, sporadic cases of liver injury and hepatic failure were reported. A detailed review of the clinical trials carried out in the development of ulipristal acetate 5 mg was undertaken to further assess the liver safety data reported during the clinical trials.
Areas covered: A detailed review of clinical data from Phase I to Phase III of patients exposed to ulipristal acetate at any investigated dose levels and for any treatment duration was conducted and the liver function test values are presented. In addition, a literature review on drug-induced liver injury is provided
Expert opinion: The experts present an evaluation of the liver safety findings observed during the clinical development and their views on the role of these findings in predicting the occurrence of drug-induced liver injury, the benefits of the treatment, the safety and the implications to the current clinical practice.
Background & Aims Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, ...anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. Methods We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28–35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. Results HD-UDCA significantly reduced mean ALT levels −28.3% from baseline after 12 months compared with −1.6% with placebo ( p <0.001). At the end of the trial, ALT levels normalized (⩽35 IU/L) in 24.5% of patients treated with HD-UDCA and in 4.8% of patients who received placebo ( p = 0.003). Both results were not accounted for by changes in weight during the trial. HD-UDCA significantly reduced the FibroTest® serum fibrosis marker ( p <0.001) compared with placebo. HD-UDCA also significantly improved markers of glycemic control and insulin resistance. There were no safety issues in this population. Conclusions Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Studies with histologic end points are warranted.
Hepatitis C virus(HCV) infection is one of the most common causes of chronic liver disease and the main indication for liver transplantation worldwide. As promising specific treatments have been ...introduced for genotype 1, clinicians and researchers are now focusing on patients infected by non-genotype 1 HCV, particularly genotype 3. Indeed, in the golden era of direct-acting antiviral drugs, genotype 3 infections are no longer considered as easy to treat and are associated with higher risk of developing severe liver injuries, such as cirrhosis and hepatocellular carcinoma. Moreover, HCV genotype 3 accounts for 40% of all HCV infections in Asia and is the most frequent genotype among HCV-positive injecting drug users in several countries. Here, we review recent data on HCV genotype 3 infection/treatment, including clinical aspects and the underlying genotype-specific molecular mechanisms.
In the last 5 years, the landscape of oncologic treatment has been deeply modified with the development and use of immune checkpoint inhibitors (ICIs) that exert their antitumoral effect by reverting ...the exhausted phenotype of tumor-infiltrating lymphocytes. This innovative therapeutic strategy has widely changed the prognosis of some advanced neoplastic diseases such as melanoma and lung cancer, providing durable remission for a significant number of patients. Unfortunately, immune-related adverse events (irAEs), especially ICI-induced hepatitis, may be very severe in some cases, impairing the prognosis of the patient. Guidelines available today on the diagnosis and management of ICI-induced hepatitis are mainly based on expert opinions and case series. This lack of large data is explained not only by the low incidence of hepatic adverse events but also by their clinical heterogeneity and variable severity. In this article, we will review the clinical, biological, and histological characteristics of ICI-induced liver injury. We will discuss the current knowledge on their pathological mechanisms and their therapeutic strategy based on immunosuppressive treatment for more severe cases. Regarding severity assessment, we will discuss the gap between the oncologist and the hepatologist's point of view, highlighting the need for multidisciplinary management. While initially developed for notably less frequent diseases than neoplastic ones, gene therapy is going to be a revolution for the treatment of diseases not responding to pharmacological therapy. Limited but growing data describe liver injury after the administration of such therapy whose exact physiopathology remains unknown. In this article, we will discuss the available data supporting the role of gene therapies in the onset of drug-induced liver injury and related mechanisms. We will describe the clinical context, the biological and histological features, and the management currently proposed.
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