Aurantio-obtusin induces hepatotoxicity through activation of NLRP3 inflammasome signaling.

Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1ß, IL-1ß and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.

Hepatic oxidative damage and Nrf2 pathway protein changes in rats following long-term manganese exposure.

This study investigated hepatic oxidative damage in rats following long-term manganese (Mn) exposure and clarified the underlying mechanisms. Forty-eight rats (SPF, male) were randomly assigned to receive low (10 mg/kg, n = 16) or high doses of Mn (50 mg/kg, n = 16) or sterilized distilled water (control group, n = 16). Rats were euthanized after 12 months, and liver Mn levels and histopathological changes were determined. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA), glutathione peroxidase (GSH-PX), nuclear factor E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinine oxidoreductase-1 (NQO1) levels were also determined. The Mn concentration and relative liver weights were significantly higher in the high-dose Mn group than in the control and low-dose Mn exposure groups. Low-dose Mn exposure resulted in mild expansion of hepatic sinuses and intact nuclei, whereas high-dose exposure led to pathological alterations in hepatocytes. High-dose Mn treatment significantly increased AST, ALT, and MDA activities and decreased GSH-PX activity. Additionally, liver Nrf2, HO-1, and NQO1 protein expression were markedly reduced by Mn exposure. Under the study conditions, long-term low-dose Mn exposure resulted in slight pathological changes in liver structure, but high-dose Mn exposure affected both liver structure and function, which might be related to the inhibition of Nrf2 expression, suppression of the transcription of its underlying antioxidant genes, and down regulation of the corresponding proteins. Consequently, the antioxidant capacity in the rat liver was weakened.

Efficacy of Coccinia grandis against monosodium glutamate induced hepato-cardiac anomalies by inhibiting NF-kB and caspase 3 mediated signalling in rat model.

Since prehistoric times Coccinia grandis has been used as traditional medicine for various diseases including diabetes, dyslipidemia, metabolic and digestive disorders. Although the rationality of efficacy as natural antioxidants with different bioactive compounds in Coccinia grandis against monosodium glutamate (MSG) induced hepato-cardiac damage remains to be disclosed. Six different solvent extracts of the leaves of Coccinia grandis were chosen to evaluate in vitro antioxidant and free radical (FR)-scavenging activity. Due to high antioxidant content and FR-scavenging property of ethanol extract of Coccinia grandis leaves (EECGL) and presence of different bioactive compounds in EECGL was further tested to evaluate in vivo hepato-protective and cardio-protective efficacy against MSG-induced anomalies. MSG-induced dyslipidemia, increased cell toxicity markers altered functional status and histopathological peculiarities of target organs were blunted by EECGL. Additionally, MSG incited increase level of interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-1ß which activates nuclear factor kappa-B (NF-kB) guided inflammation via down regulation of IL-10; impaired redox-homeostasis subsequently promoted inflammation associated oxidative stress (OS) and increased vascular endothelial growth factor (VEGF) which provoked microvascular proliferation related cellular damage. On the contrary, increased lipid peroxidation and nitric oxide promotes reduced cell viability, deoxyribonucleic acid damage and apoptosis via activation of caspase 3. EECGL significantly reduced MSG-induced inflammation mediated OS and apoptosis via inhibition of pro-inflammatory factors and pro-apoptotic mediators to protect liver and heart. Therefore, it can be suggested that EECGL contributed competent scientific information to validate the demands for its use to treat MSG-induced hepato-cardiac OS mediated inflammation and apoptosis from natural origin.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Hepatoprotective effect of forsythiaside a against acetaminophen-induced liver injury in zebrafish: Coupling network pharmacology with biochemical pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine and possesses various pharmacological activities, including anti-inflammation, anti-oxidant and liver protection. AIM OF THE STUDY: Although acetaminophen (APAP) has been frequently used for its antipyretic and analgesic effects, it leads to liver injury at an overdose or long-term medication. Forsythiaside A (FA), the principal active component of Forsythiae Fructus, exerts prominent antioxidant, anti-inflammatory and hepatoprotective effects. However, the protective property and underlying mechanism of FA against APAP challenge have not yet been elucidated. Therefore, we aimed to explore the hepatoprotective effect and action mechanism of FA against APAP-induced liver injury in zebrafish. MATERIALS AND METHODS: In this study, liver-specific transgenic zebrafish larvae (lfabp: EGFP) were used to investigate the protective effect of FA against overdose APAP exposure. The liver phenotype, morphological and biochemical assessments were carried out to evaluate the hepatoprotective effect of FA. Network pharmacology and molecular docking study were conducted to analyze the potential targets of FA in the treatment of APAP-induced liver injury. Finally, the mechanism of action was verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: The liver phenotype, morphological and biochemical assessments indicated that FA could mitigate APAP-triggered liver injury. Network pharmacology and molecular docking analysis indicated that the protective effect of FA might be related to the regulation of targets tumor necrosis factor (TNF), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and phosphatidylinositol 3-kinase (PI3K). PCR results confirmed that FA could reverse the progressive alterations of genes involving in extracellular matrix remolding and PI3K/AKT-mediated apoptosis signaling pathway. CONCLUSIONS: Our results indicated that FA could mitigate APAP-induced liver injury through modulating the remolding of extracellular matrix and PI3K/AKT-mediated apoptosis.

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury.

Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.

Hepatotoxicity of nutmeg: A pilot study based on metabolomics.

Incidences of abuse and poisoning have been reported for nutmeg, a household spice made from grinding the seed of Myristica fragrans, owing to its hallucinogenic properties. However, there have been no reports on nutmeg hepatotoxicity in relation to dose and duration of exposure. To investigate the hepatotoxicity of different nutmeg exposure durations and doses, male mice were administered daily with normal saline, 1.0 g/kg nutmeg, or 4.0 g/kg nutmeg by intragastrical gavage for either 7 or 14 days (for a total of six treatment groups, n = 6). Body weight of each mouse was monitored daily. Histological analysis of liver tissues was performed using hematoxylin and eosin (H&E) staining to investigate the morphological changes in hepatocytes. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined using enzyme-linked immunosorbent assay (ELISA) to investigate liver function. Metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed between treatment groups for identifying differential metabolites. Mice in the nutmeg exposure groups exhibited slow growth trends, hepatocyte damage, and significantly elevated serum AST and ALT levels associated with nutmeg dose and exposure duration. Metabolomics and KEGG enrichment pathway analyses also revealed differential levels of some metabolites related to liver function upon nutmeg exposure. Therefore, the present study reasonably speculates that nutmeg exposure may cause liver damage and affect liver function depending on the dose and duration.

Functional Food XingJiuTang Attenuates Alcohol-Induced Liver Injury by Regulating SIRT1/Nrf-2 Signaling Pathway.

Lipid accumulation, inflammatory responses and oxidative stress have been implicated in the pathology of alcohol-induced liver injury (ALI). In this work, we evaluated the effects of the functional food XingJiuTang (XJT) on ALI and explored the underlying mechanism. We used alcohol-stimulated human normal hepatocytes L02 for in vitro experiments, while for in vivo experiments, 55 % alcohol was intragastrically administrated to C57BL/6 mice at 16 mL/kg with pre-administration of bifendate and XJT. Liver histology and function, along with the inflammatory cytokines, oxidative mediators and SIRT1/Nrf-2 pathway were evaluated. The results showed that XJT treatment significantly alleviated ALI, ameliorated lipid peroxidation, improved the liver function impaired by alcohol and inhibited the hepatocytes apoptosis in vitro and in vivo. In addition, XJT treatment modulated the activation of the SIRT1/Nrf-2 signaling pathway and suppressed the overexpression of NOX4. Overall, the functional food XJT effectively protects against experimental ALI via activating the SIRT1/Nrf-2 pathway.

Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

New molecular and biochemical insights of doxorubicin-induced hepatotoxicity.

Chemotherapeutic antibiotic doxorubicin belongs to the anthracycline class, slaughters not only the cancer cells but also non-cancerous cells even in the non-targeted organs thereby resulting in the toxicity. The liver is primarily involved in the process of detoxification and this mini-review we focused mainly to investigate the molecular mechanisms heading hepatotoxicity caused due to doxorubicin administration. The alterations in the doxorubicin treated liver tissue include vacuolation of hepatocytes, degeneration of hepatocyte cords, bile duct hyperplasia and focal necrosis. About the literature conducted, hepatotoxicity caused by doxorubicin has been explained by estimating the levels of liver serum biomarkers, ROS production, antioxidant enzymes, lipid peroxidation, and mitochondrial dysfunction. The liver serum biomarkers such as ALT and AST, elated levels of free radicals inducing oxidative stress characterized by a surge in Nrf-2, FOXO-1 and HO-1 genes and diminution of anti-oxidant activity characterized by a decline in SOD, GPx, and CAT genes. The augmented levels of SGOT, SGPT, LDH, creatine kinase, direct and total bilirubin levels also reveal the toxicity in the hepatic tissue due to doxorubicin treatment. The molecular insight of hepatotoxicity is mainly due to the production of ROS, ameliorated oxidative stress and inflammation, deteriorated mitochondrial production and functioning, and enhanced apoptosis. Certain substances such as extracts from medicinal plants, natural products, and chemical substances have been shown to produce an alleviating effect against the doxorubicin-induced hepatotoxicity are also discussed.

What have we learned from animal models of idiosyncratic, drug-induced liver injury?

INTRODUCTION: Idiosyncratic, drug-induced liver injury (IDILI) continues to plague patients and restrict the use of drugs that are pharmacologically effective. Mechanisms of IDILI are incompletely understood, and a better understanding would reduce speculation and could help to identify safer drug candidates preclinically. Animal models have the potential to enhance knowledge of mechanisms of IDILI. AREAS COVERED: Numerous hypotheses have emerged to explain IDILI pathogenesis, many of which center on the roles of the innate and/or adaptive immune systems. Animal models based on these hypotheses are reviewed in the context of their contributions to understanding of IDILI and their limitations. EXPERT OPINION: Animal models of IDILI based on an activated adaptive immune system have to date failed to reproduce major liver injury that is of most concern clinically. The only models that have so far resulted in pronounced liver injury are based on the multiple determinant hypothesis or the inflammatory stress hypothesis. The liver pathogenesis in IDILI animal models involves various leukocytes and immune mediators such as cytokines. Insights from animal models are changing the way we view IDILI pathogenesis and are leading to better approaches to preclinical prediction of IDILI potential of new drug candidates.

Dimethylacetamide-induced toxic hepatitis in spandex workers: clinical presentation and treatment outcomes.

BACKGROUND: Dimethylacetamide (DMAc) exposure has been associated with toxic hepatitis, and no clinical treatment has been reported. AIM: To investigate the clinical manifestations of DMAc-induced symptoms and how to rescue the functional loss due to occupational exposure. DESIGN: Clinical observations of 60 spandex factory workers with the exposure to DMAc from January, 2017-19. METHODS: Chinese drugs (reduced glutathione, polyene phosphatidylcholine, glycyrrhizin compound, Hugan tablets and ornithine aspartate) were used to evaluate the therapeutic improvements in DMAc-exposed patients. RESULTS: Our data found that 58.3% patients had no distinct clinical symptoms, but 41.7% patients felt fatigue, and 21.7% patients suffered abdominal discomfort and appetite loss, and 8.3% patients had yellow skin and sclera. The ultrasonic and CT imaging revealed that some patients have fatty livers, intrahepatic calcifications, hepatomegaly, gallbladder wall edema and abdominal effusions. Biochemical analysis showed that the alanine aminotransferase (ALT) (P < 0.001), aspartate aminotransferase (AST) (P < 0.001), lactate dehydrogenase (LDH) (P < 0.001) and bilirubin (P < 0.01) statistically decreased after the drug treatment, but alkaline phosphatase (P >0.05) and glutamyl transpeptidase (P> 0.05) did not decrease. Twenty-nine out of the thirty-one patients' abnormal blood ammonia recovered. The risk factor of ALT on hospitalization time was significantly related (P < 0.01). CONCLUSIONS: The drugs above are sufficient to rescue functional loss in DMAc-induced toxic hepatitis, in part via the regulations of ALT, AST, LDH, bilirubin and ammonia. Workers with the exposure to DMAc should receive specific drugs to maintain the health and prevent functional loss in the long term.

Hepatotoxicity assessment of Rhizoma Paridis in adult zebrafish through proteomes and metabolome.

Rhizoma Paridis hepatotoxicity is a risk factor limiting its extensive use in clinic, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. The adult zebrafish were exposed to Rhizoma Paridis at a sub-lethal concentration. The alterations in protein expression profiles and metabolite levels in the adult zebrafish liver, a popular model for toxicity assessment, exposed to the Rhizoma Paridis were observed. The result showed that Rhizoma Paridis exposure treatment caused an obvious toxic effect on the zebrafish liver, resulting in a significant change of the liver organization structure and various biochemical parameters. The hepatotoxicity of adult zebrafish liver induced by Rhizoma Paridis was mainly associated with lipid metabolism and energy metabolism disorder. Furthermore, oxidative stress injury, inflammation, and endoplasmic reticulum stress might also be involved in the hepatotoxicity. Our study facilitated the understanding of molecular signatures of toxic effects of Rhizoma Paridis causing liver injury to move away from the risk assessment based on in vivo animal experiments.

Drug-Induced Liver Injury Resources and Reporting for the Clinician.

Although many risk factors for developing drug-induced liver injury (DILI) have been identified and more than 1000 medications and herbal and dietary supplements are known to cause liver dysfunction, idiosyncratic drug reactions remain unpredictable and erratic. Varying effects of individual drugs on the event cascade and patient genetic polymorphisms lead to different clinical presentations. Mechanisms and causality scales have been developed to guide the clinician in diagnosis, and several databases and registries are available for reference and reporting. We identify and summarize the resources available to clinicians to help diagnose, manage, and report DILI and to identify hepatotoxic drugs.

High-content analysis boosts identification of the initial cause of triptolide-induced hepatotoxicity.

Triptolide (TP) has been widely used in China for more than 40 years as an immunosuppressive agent. Recently, serious concerns have been raised over TP-induced liver injury, though the real hepatotoxic mechanism is still unclear, particularly in terms of the initial cause. To our knowledge, this study is the first to screen systematically the mechanism of TP-induced toxicity through a global cytotoxicity profile high-content analysis using three independent cytotoxic assay panels with multiple endpoints of cytotoxicity, including cell loss, mitochondrial membrane potential, nuclear membrane permeability, manganese superoxide dismutase, phosphorylated gamma-H2AX, light chain 3B, lysosome, reactive oxygen species and glutathione. We assessed nine parameters and four stress response pathway models by labeling nuclear factor erythroid 2-related factor 2, activating transcription factor 6, hypoxia inducible factor 1α and nuclear factor κB and found that all testing parameters except glutathione and manganese superoxide dismutase showed concentration- and time-dependent changes, as well as increased cell loss after TP treatment. Considering that RNA polymerase II is the molecular target of TP, we quantified transcription from inducible genes, bromodeoxyuridine incorporation, and expression from transiently transfected green fluorescence protein plasmids in HepG2 cells. The results show that inhibition of global transcription by TP took place at earlier times and at lower concentrations than those observed for cell death. Therefore, global transcriptional suppression and the cell dysfunction it drives play a central role in TP-induced hepatotoxicity. This provides valuable information for the safe use of TP in the clinic.

Gadoxetic Acid-Enhanced Hepatobiliary-Phase Magnetic Resonance Imaging for Pyrrolizidine Alkaloid-Induced Hepatic Sinusoidal Obstruction Syndrome and Association with Liver Function.

Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by pyrrolizidine alkaloids(PAs)-containing herbals. In this study, the aim of our study was to investigate the imaging features of PAs-induced HSOS on gadoxetic acid-enhanced magnetic resonance imaging (MRI), susceptibility-weighted imaging(SWI) and T2* weighted imaging (T2* WI). We analyzed medical records and MR images of 28 PAs-induced HSOS patients enrolled from Feb, 2013, to Apr, 2017. Abnormal liver function was observed in most of the PAs-induced HSOS patients. Heterogeneity of liver parenchyma in hepatobillary phase (HBP) of gadoxetic acid-enhanced MR scan was observed in 100% of the PAs-induced HSOS patients. Distributional patterns of heterogeneous hypointensity were multifocal distribution (mild) in 4 patients (14.29%), multifocal distribution (severe) in 15 cases (53.57%), and diffuse distribution in 9 patients (32.14%). Hypointense in SWI and T2*WI was observed in the patients of PAs-induced HSOS, and the distribution of hypointense in SWI and T2*WI was similar to that of portal-venous phase of MR scan. The severity of heterogeneous hypointensity scored by volume fraction in hepatobillary phase of gadoxetic acid-enhanced MRI was positively correlated with PT and INR, the severity of hypointensity in HBP was a risk factor of death events. In conclusion: Heterogenous hypointensity of liver parenchyma was an imaging sign of hepatobillary phase in gadoxetic acid-enhanced MRI; thus, it will provide evidences for the diagnosis of PA-induced HSOS.

Hepatoprotective potential of Ferula communis extract for carbon tetrachloride induced hepatotoxicity and oxidative damage in rats.

We investigated the hepatoprotective potential of Ferula communis extract for CCI4 induced liver damage. We used six groups of rats: group 1, untreated control; group 2, CCl4 treated (hepatotoxic); group 3, treated with 150 mg/kg F. communis; group 4, treated with 300 mg/kg F. communis; group 5, treated with CCl4 + 150 mg/kg F. communis; and group 6, treated with CCl4 + 300 mg/kg F. communis. Liver damage was produced by injection of 1 ml/kg CCI4 twice/week. Extracts of F. communis, 150 and 300 mg/kg/day, were administered for 8 weeks. The effects of F. communis were assessed by measuring aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT) and total bilirubin (T-BIL) levels, and the activities of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the liver. The histology and immunohistochemistry of liver tissue were evaluated using hematoxylin and eosin staining, and caspase 3 and 8-OHdG immunostaining. F. communis extract produced significant reductions in elevated levels of ALT, AST, GGT and T-BIL and increased levels of GPx and SOD in rats treated with CCl4. F. communis extract decreased CCl4 induced 8-OHdG formation and caspase 3 activation significantly in hepatocytes, especially at the 150 mg/kg dose. Our findings demonstrate the potential efficacy of F. communis for attenuating CCl4 induced hepatotoxicity and oxidative damage.

Drug-Induced Liver Injury Caused by Kratom Use as an Alternative Pain Treatment Amid an Ongoing Opioid Epidemic.

Kratom ( Mitragyna speciosa) is a prevalent medicinal plant used mainly for the stimulant and analgesic properties provided through multiple alkaloid compounds. Over the past decade, use of kratom has increased despite the limited knowledge of toxicities and adverse side effects. With the current opioid epidemic, both patients and providers are seeking alternative methods to treat both addiction and pain control, and kratom as an alternative means of treatment has increasingly entered the mainstream. In this article, we present the clinical course of a 47-year-old male who developed fatigue, pruritus, and abnormal liver tests (with a mixed hepatocellular/cholestatic pattern) approximately 21 days after beginning kratom. After extensive evaluation including a negligible alcohol history, negative hepatitis serologies, and inconclusive imaging, the patient was diagnosed with drug-induced liver injury (DILI) caused by kratom. Nine months after his liver tests returned to normal, he took kratom again, and after a latency of 2 days, he developed fatigue, pruritus, and loss of appetite along with abnormal liver tests (with the same biochemical profile as previously), consistent with a positive rechallenge. We believe, through the use of the Roussel-Uclaf Causality Assessment Method and expert opinion, that this is a highly likely or definite example of kratom-induced DILI. With the gaining popularity of this drug, it appears that DILI may be an important complication of kratom for providers to recognize.