Drug induced liver injury (DILI) is the most common cause of acute liver failure and 5-10% of patients hospitalized for jaundice are diagnosed with DILI. For a diagnosis of DILI to be made, there should be exclusion of other etiologies of liver injury and the use of a precipitator drug, latency of symptoms, and resolution of liver injury once the offending drug is identified and discontinued. In our case report, we present a patient with idiosyncratic hepatocellular pattern DILI after two doses of ocrelizumab for treatment of multiple sclerosis. Ocrelizumab was given 16 and 27 days prior to the onset of icterus, jaundice, and fatigue, in a patient without the evidence of prior exposure to hepatitis B virus. At presentation labs revealed severe acute hepatocellular liver injury with R factor of 30.42, marked hyperbilirubinemia, and transient hypoalbuminemia. No evidence of latent or active hepatitis B infection was detected. Drug dechallenge led to return of liver chemistries to near-normal levels 31 days after the onset of her symptoms. This case indicates DILI diagnosis associated with the use of ocrelizumab, and warrants careful monitoring of liver functions in patients even in the absence of hepatitis B.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

The aim of this study was to investigate in-vitro antioxidant properties and in-vivo protective effects of different concentrations of Hypericum triquetrifolium Turra. (HT) seed methanol extracts against acute hepatotoxicity, myelotoxicity and hematotoxicity in rats exposed to overdose of cyclophosphamide (CP). HT seed methanol extracts were tested in view of its in-vitro antioxidant activities as total phenolic contents and DPPH free radical-scavenging activity. To investigate in-vivo protective effects of HT seed methanol extracts on rat tissues; tested animals were divided into nine groups. Three groups only were treated with HT extracts (25, 50 and 100 mg/kg HT) for 6 days. Three groups were pre-treated with the extract of HT (25, 50 and 100 mg/kg HT) for 6 days and on the last day they were injected with single dose of CP (150-mg/kg body weight). Two groups were used as control groups and one group was only treated with CP (150 mg/kg) on the 6th day. The toxic effects of CP and protective effects of HT extracts on the nucleated cells which were produced by bone marrow and serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), oxidative stress index (OSI) levels were investigated biochemically. Additionally, liver tissue samples were examined histopathologically. Our results show that HT seed methanol extract has high total phenolic content and antioxidant activity. Over dose CP administration caused hepatotoxicity, myelotoxicity and hematotoxicity on rat. Whereas, 25, 50 and 100 mg/kg HT plus CP administered groups showed significant protective effects on nucleated cells. And 25, 50, 100 mg/kg HT plus CP treated groups showed an important decrease on serum ALT, ALP, LDH and OSI levels when compared with CP treated group. Our results showed that the administration of different HT doses with high doses of CP significantly reduced hepatotoxicity, myelotoxicity and hematoxicity on rats.

Drugs are known to cause substantial liver injury, with hepatotoxicity ranging from asymptomatic increase of liver enzymes to hepatic failure. HIV/AIDS patients, with compromised immune systems, are especially vulnerable to opportunistic infections such as tuberculosis (TB). Patients with co-infection frequently get combined antiretroviral (ART) and antitubercular (ATD) regimens, which can cause hepatotoxicity. Hepatotoxicity has been linked to commonly administered antiretroviral drug regimens as well as first-line antitubercular agents such isoniazid, rifampin, and pyrazinamide, which are required for the treatment of both drug-sensitive and drug-resistant tuberculosis. As a result, there is an urgent need to investigate treatments based from traditional herbs known for their hepatoprotective abilities against ART and ATD-induced liver injury. Many researchers have investigated the effectiveness of medicinal plants in treating chemically caused hepatotoxicity. Medicinal plants are high in phytochemicals and secondary metabolites, both of which have a variety of medicinal benefits. Currently, there is a lack of specific therapeutic regimens to address this adverse effect, and management often relies on symptomatic treatment or therapy withdrawal. Traditional medicinal plants may have the potential to restore normal liver function, enzyme activity, and cellular structure in response to ART and ATD-induced hepatotoxicity. This review aims to examine the scientific evidence supporting the use of medicinal plants as hepatoprotective agents against liver damage induced by ART and ATDs.

Severe acute respiratory syndrome coronavirus 2 infects many people, but many infected individuals do not develop symptoms. COVID-19 is an inflammatory disease that affects a portion of individuals infected with the virus, and it is associated with liver injury and other complications leading to hospitalization, critical illness, and death. Remdesivir is an antiviral agent used for treatment of hospitalized patients with COVID-19 to improve time to recovery, reduce duration of mechanical ventilation, decrease the need for supplemental oxygen, and decrease the risk of mortality. Remdesivir-associated hepatotoxicity has been observed as increased transaminases more than 5 times the upper limit of normal in hospitalized patients with COVID-19 but causality has not been proven. It is generally difficult to distinguish between remdesivir-associated hepatotoxicity and COVID-19-induced hepatotoxicity. The purpose of this review is to evaluate the evidence for remdesivir-associated hepatotoxicity. Current evidence suggests that elevated liver enzymes in hospitalized COVID-19 patients are more likely to be due to the infection than remdesivir and that a 5-day course of remdesivir seems to be safe in regards to hepatotoxicity.

Sulfated polysaccharides from seaweed are highly active natural substances having valuable applications. In the present paper, attempts have been made to discuss the physicochemical and structural features of polysaccharides isolated from red marine alga Alsidium corallinum (ACPs) and its protective effect in hepatic impairments induced by tebuconazole (TBZ) in rats. Structural features were determined using High performance liquid chromatography, Fourier transformed infrared, and solid state ¹H and ¹³C-Nuclear magnetic resonance analysis. ACPs are found to be hetero-sulfated-anionic polysaccharides that contained carbohydrates, sulfate groups and uronic acids. In vitro biological activities suggested the effective antioxidant and antimicrobial capacities of ACPs. For antioxidant testing in vivo, the biochemical analysis and plasma profiles displayed that oral administration of ACPs could mitigate blood lipid indicators, including total cholesterol, triglyceride, low and high density lipoprotein cholesterol, bilirubin, liver function indexes involving alanine aminotransferase and aspartate aminotransferase, showed that ACPs possessed obvious antioxidant activities. Besides, the intervention of ACPs potentially inhibited lipid peroxidation, protein oxidation, key enzymes of lipid metabolism (<0.001) and increased levels and antioxidant status (<0.05). Histomorphological observation confirmed that ACPs intervention could partially repair liver injuries caused by TBZ. The computational results showed that A. corallinum monosaccharides bound 1JIJ, 1HD2 and 1WL4 receptors with acceptable affinities, which together with deep embedding and molecular interactions support the antioxidant, antimicrobial and hypolipidemic outlined effects in the in vitro and in vivo findings. In view of their prominent antioxidant effects, ACPs stand for promising candidates in liver diseases and need be considered in pharmaceutical applications.

Methotrexate (MTX) is a potent drug for the treatment of various diseases globally amidst being a chemotherapeutic and immunosuppressant agent. However, hepatotoxicity induced by MTX could be life-threatening if left untreated. Folate supplementation is concurrently applied to reduce the adverse effects of MTX, albeit efficacy compromise. Therefore, there is the need to understand the process for the prevention and treatment strategies for MTX induced hepatotoxicity (MIH). In recent times, preliminary preclinical and clinical findings indicate the potential of natural phytobioactive compounds for MIH prevention and treatment. This mini review therefore summarizes proposed mechanisms of MIH and recent advances in the prevention and treatment prospects of natural phytobioactive compounds on MIH.

Zidovudine (AZT) has significantly reduced the mortality and morbidity rates among AIDS patients, but it has been associated with hepatotoxicity. AZT treatment has been linked to disrupted lipid and glucose metabolism, and the enhancement of pro-inflammatory chemokines and other mediators, which can lead to liver steatosis. In contrast, the administration of adenosine (ADO) has proven to be an effective hepatoprotector against both acute and chronic liver damage. Therefore, present study was aimed to investigate the harmful effects of chronic AZT administration and the beneficial effects of the co-administered ADO. Chronic oral AZT administration did not induce hyperglycemia or dyslipidemia, but serum liver marker enzyme activities were increased, as well as evidence of liver steatosis and inflammation. These findings were associated with low insulin and glucagon levels, elevated serum levels of pro-inflammatory cytokines and disruptions in cell redox states in these animals. ADO co-administration attenuated the deleterious effects induced by AZT: blocking the production of inflammatory molecules, increasing serum insulin and glucagon levels, and restoring liver cellular redox state. Then, blood insulin levels seemed to be greatly influenced by the cellular redox state, which was altered by AZT administration. This alteration is likely to be connected to mitochondrial integrity and metabolism.

Cisplatin (CDDP), an important chemotherapeutic agent, could result in potential hepatotoxicity, but the precious molecular mechanisms remain unclear. In this study, the protective effect of ellagic acid (EA) on CDDP exposure-induced hepatotoxicity and underlying molecular mechanisms were investigated using a mouse model. Mice were randomly divided into control, CDDP model, EA100 (i.e., EA 100 mg/kg/day), and CDDP plus EA 25, 50, and 100 mg/kg/day. Mice in all CDDP-treated groups were intraperitoneally injected with CDDP 20 mg/kg/day for 2 days. In all EA co-treatments, mice were orally administrated with EA for 7 days. Our results found that, compared to the control group, CDDP treatment resulted in liver dysfunction, oxidative stress, and hepatocyte necrosis, which are effectively revised by EA supplementation in a dose-dependent manner. Meanwhile, EA supplementation inhibited CDDP-induced the elevation of caspases-9 and -3 activities in the liver tissues of mice. Furthermore, EA supplementation significantly downregulated CDDP exposure-induced the increases of NF-κB, IL-1β, TNF-α, and IL-6 proteins and mRNAs, while further upregulated the expression of Nrf2, and HO-1 proteins and mRNAs. Taken together, our results reveal that EA supplementation could ameliorate CCDP-induced liver injury in mice via the opposite regulation of Nrf2/HO-1 and NF-kB pathways.

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. In this study, the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in liver were investigated. Rats were fed the diets with (0.54 %) or without EGCG supplementation for four weeks and were then intraperitoneally injected with acetaminophen (1g/kg). Results showed EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by increasing the Bax/Bcl2 ratio in liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen-glutathione and acetaminophen-protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in liver after acetaminophen treatment. Our results indicate that EGCG may lower oxidative stress and reduce the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in liver and thus lower hepatotoxicity

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. Noteworthy, only few cases of severe hepatotoxicity have been described in literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. On the basis of these data, coumarin-induced hepatotoxicity seems to be restricted to a small subset of patients, probably due to the expression of specific alleles of CYP450 isoform not yet well characterized. In summary, more research is needed in order to identify patients at risk of developing hepatotoxicity following coumarin treatment, in order to improve the risk/benefit ratio of the product and allow more patients to benefit from its therapeutic properties.

Context: Persea Americana is reported to have medicinal value. Calcium Carbide (CaC2), a fruit-ripening agent, has been shown to be toxic to body organs. Objective: To determine the effect of avocado seed extract (ASE) on CaC2-induced hepatotoxicity in rats. Methodology: Four experimental groups, each of 5 adult wistar rats were fed respectively with normal diets (group A); 250mg/kg ASE (group B); 100mg/kg CaC2 (group C); combination of 100mg/kg CaC2 and 250mg/kg ASE – group D. Changes in the rats’ behaviours, body weights, and liver function were assessed over 21 days. Data were analyzed using SPSS. The cumulated rat weights, rat liver weights and serum liver enzyme levels for groups B, C, and D rats were compared to group A. Results: Abnormal behavior was most observed in group C rats. Rats in group A showed a significant increase in weight before and three weeks following administration of feeds while rats in groups B, C, and D showed significant decrease in weight – more marked in group C rats. Only the mean liver weights of rats in group C showed significant decrease compared to that in group A, p = 0.001. Similarly, only the cumulated liver enzyme levels of rats in group C demonstrated significant increase when compared to group A rats - indicating hepatotoxicity. Conclusion In this study, hepatotoxicity occurred in CaC2-administered rats. However, the combination of CaC2 and ASE showed no liver toxicity indicating a mitigating effect of ASE to CaC2-induced hepatotoxicity.

Drug induced liver injury (DILI) remains one of the challenges in the safety profile of both authorized drugs and candidate drugs and predicting hepatotoxicity from the chemical structure of a substance remains a challenge worth pursuing, being also coherent with the current tendency for replacing non-clinical tests with in vitro or in silico alternatives. In 2016 a group of researchers from FDA published an improved annotated list of drugs with respect to their DILI risk, constituting “the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans”, DILIrank. This paper is one of the few attempting to predict liver toxicity using the DILIrank dataset. Molecular descriptors were computed with the Dragon 7.0 software, and a variety of feature selection and machine learning algorithms were implemented in the R computing environment. Nested (double) cross-validation was used to externally validate the models selected. A number of 78 models with reasonable performance have been selected and stacked through several approaches, including the building of multiple meta-models. The performance of the stacked models was slightly superior to other models published. The models were applied in a virtual screening exercise on over 100,000 compounds from the ZINC database and about 20% of them were predicted to be non-hepatotoxic.

The objective of the this study was to reduce the benzo[a]pyrene-induced hepatotoxicity method in herbal medicine products and to give proof that neferine, daidzein, genistein possess antihepa-totoxic effects. B[a]P which classified as a group 1 carcinogen and metabolized to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) causes mutagenic DNA addition products. The reduc-tion of BPDE-DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) was derived by benzo[a]pyrene (B[a]P). In HepG2 cells, B[a]P exhibited toxicity and substance treatment of the cells with B[a]P with neferine in lotus and daidzein, genistein in soybean reduced the BPDE-DNA ad-ducts level. The level of B[a]P-metabolites in the substance treatment of the cells was presented that BPDE levels were reduced by neferine in lotus and daidzein, genisten in soybean. These results suggest that neferine in lotus and daidzein, genistein in soybean prevent B[a]P-induced hepato-toxicity for BPDE-DNA adduct formation.