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Objectives: The hepatotoxicity of irinotecan has been widely implicated in the treatment of multiple solid tumours. However, there are few studies on the influencing factors of irinotecan-induced hepatotoxicity. Herein, we investigated the risk factors for irinotecan-induced liver injury among 421 patients receiving irinotecan-based regimens (IBRs)., Design: Retrospective multi-centre cross-sectional study., Setting: This study surveyed four hospitals in China., Participants: After excluding participants with missing variables, we retrospectively collected the demographic, clinical and therapeutic data of 421 patients who received IBRs in four hospitals between January 2020 and December 2021 and divided the patients into two groups: those without liver injury and those with liver injury., Results: The 421 enrolled patients were grouped (liver injury group: n=92; control group: n=329) according to their hepatic biochemical monitoring parameters. In our study, the multivariate logistic regression results showed that three to four cycles of chemotherapy (OR (95% CI): 2.179 (1.272 to 3.733); p=0.005) and liver metastasis (OR (95% CI): 1.748 (1.079 to 2.833); p=0.023) were independent risk factors for irinotecan-induced liver injury. The Cox proportional hazards model demonstrated that alcohol consumption history (OR (95% CI): 2.032 (1.183 to 3.491); p=0.010) and a cumulative dose of irinotecan ≥1000 mg (OR (95% CI): 0.362 (0.165 to 0.792); p=0.011) were significantly correlated with the onset time of irinotecan-induced liver injury., Conclusions: These findings suggest that patients with liver metastasis or who received three to four cycles of chemotherapy should undergo rigorous liver function monitoring to prevent or reduce the incidence of irinotecan-induced liver injury. Moreover, patients with a history of alcohol consumption should also be closely monitored., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. IMPORTANCE Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

Molecular mimicry is one of the main processes for producing autoantibodies during infections. Although some autoantibodies are associated with autoimmune diseases, the functions of many autoantibodies remain unknown. Previously, we reported that S16, a mouse (BALB/c) monoclonal antibody against the hemagglutinin-esterase fusion glycoprotein of influenza C virus, recognizes host proteins in some species of animals, but we could not succeed in identifying the proteins. In the present study, we found that S16 cross-reacted with acetyl-CoA acyltransferase 2 (ACAA2), which is expressed in the livers of BALB/c mice. ACAA2 was released into the serum after acetaminophen (APAP) administration, and its serum level correlated with serum alanine aminotransferase (ALT) activity. Furthermore, we observed that S16 injected into mice with APAP-induced hepatic injury prompted the formation of an immune complex between S16 and ACAA2 in the serum. The levels of serum ALT (p < 0.01) and necrotic areas in the liver (p < 0.01) were reduced in the S16-injected mice. These results suggest that S16 may have a mitigation function in response to APAP-induced hepatotoxicity. This study shows the therapeutic function of an autoantibody and suggests that an antibody against extracellular ACAA2 might be a candidate for treating APAP-induced hepatic injury.

Background & Aims: Aryl hydrocarbon receptor (AhR) is a liver-enriched xenobiotic receptor that plays important role in detoxification response in liver. This study aimed to investigate how AhR signaling may impact the pathogenesis of alcohol-related liver disease (ALD)., Methods: Chronic alcohol feeding animal studies were conducted with mouse models of hepatocyte-specific AhR knockout (AhR Δhep ) and NAD(P)H quinone dehydrogenase 1 (NQO1) overexpression, and dietary supplementation of the AhR ligand indole-3-carbinol. Cell studies were conducted to define the causal role of AhR and NQO1 in regulation of redox balance and apoptosis., Results: Chronic alcohol consumption induced AhR activation and nuclear enrichment of NQO1 in hepatocytes of both alcoholic hepatitis patients and ALD mice. AhR deficiency exacerbated alcohol-induced liver injury, along with reduction of NQO1. Consistently, in vitro studies demonstrated that NQO1 expression was dependent on AhR. However, alcohol-induced NQO1 nuclear translocation was triggered by decreased cellular oxidized nicotinamide adenine dinucleotide (NAD + )-to-NADH ratio, rather than by AhR activation. Furthermore, both in vitro and in vivo overexpression NQO1 prevented alcohol-induced hepatic NAD + depletion, thereby enhancing activities of NAD + -dependent enzymes and reversing alcohol-induced liver injury. In addition, therapeutic targeting of AhR in the liver with dietary indole-3-carbinol supplementation efficiently reversed alcoholic liver injury by AhR-NQO1 signaling activation., Conclusions: This study demonstrated that AhR activation is a protective response to counteract alcohol-induced hepatic NAD + depletion through induction of NQO1, and targeting the hepatic AhR-NQO1 pathway may serve as a novel therapeutic approach for ALD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Sustained c-Jun N-terminal kinase (JNK) activation plays a major role in drug-induced liver injury (DILI). Stress-responsive microRNA-31 (miR-31) has been implicated in regulating different cellular damage, and JNK activation could induce miR-31 expression. However, the regulatory role of miR-31 in DILI has not been studied previously. We aimed to investigate whether miR-31 could ameliorate DILI and ascertain potential molecular mechanism., Methods: miR-31 gene knockout (31-KO) and wild-type C57BL/6J mice were used to construct an acetaminophen (APAP)-induced DILI model. Primary mouse hepatocytes, as well as alpha mouse liver 12 (AML-12) cell lines, were used for in vitro experiments. Argonaute 2-associated RNA immunoprecipitation combined with high-throughput sequencing were performed to identify specific targets of miR-31., Results: 31-KO mice showed a higher mortality rate, liver transaminase levels, and hepatic necrosis compared with those in wild-type mice after APAP-induced hepatotoxicity. The protective role of miR-31 on hepatocytes has been analyzed via constructing bone marrow chimeric mice. Mechanistically, we found that hepatic JNK phosphorylation increased significantly in 31-KO mice. This caused mitochondrial phosphorylated Src (p-Src) inactivation and more reactive oxygen species production, which directly amplifies hepatocyte necrotic cell death, while administration of JNK-specific inhibitor SP600125 could abrogate the differences. Moreover, bioinformatics analysis of RNA immunoprecipitation combined with high-throughput sequencing identified that guanosine triphosphatase, cell division cycle protein 42 (Cdc42), the upstream molecule of JNK signaling, was the specific target of miR-31 and could form a miR-31/Cdc42/phosphorylated mixed-lineage kinase 3 (p-MLK3) negative feedback loop to restrict JNK overactivation. Clinically, both miR-31 and phosphorylated JNK (p-JNK) were highly increased in liver tissues of DILI patients with different etiologies., Conclusions: miR-31 can down-regulate Cdc42 to restrict overactivation of reactive oxygen species/JNK/mitochondria necrotic death loop in hepatocytes of APAP-induced DILI, which might provide a new therapeutic target for alleviating JNK overactivation-based liver injury., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We present a case of a 49-year-old woman diagnosed with aquaporin-4 antibody-positive transverse myelitis, who developed a significant transaminitis 2 months after commencing mycophenolate mofetil (MMF) as a steroid-sparing agent. No other risk factors were identified, a blood liver panel was negative and liver biopsy showed features compatible with drug-induced liver injury (DILI). MMF was stopped with a corresponding normalisation of serum alanine aminotransferase over the next 2 months. This case highlights MMF as a rare cause of DILI and provides justification for monitoring of liver biochemistry on therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls ( p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.

A 33-year-old male presenting with subacute abdominal pain was found to have hyperbilirubinaemia, hypokalaemia and hyponatraemia. This was in the setting of transitioning between deferasirox iron chelator formulations, from dispersible tablets to film-coated tablets for ongoing treatment of chronic iron overload secondary to transfusion requirement for beta-thalassemia major. A liver biopsy demonstrated acute cholestasis with patchy confluent hepatocellular necrosis and mild to moderate microvesicular steatosis. Based on the histological, biochemical and clinical findings, the diagnosis of hepatotoxicity and Fanconi-like syndrome was made. The patient improved clinically and biochemically with cessation of the deferasirox film-coated tablets and supportive management. To our knowledge, this is the first case report of hepatotoxicity and Fanconi-like syndrome occurring due to deferasirox film-coated tablets with previous tolerance of dispersible deferasirox tablets. It is important to raise clinical awareness of this potentially severe complication., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The immense resources required and the ethical concerns for animal-based toxicological studies have driven the development of in vitro and in silico approaches. Recently, we validated our approach in which the expression of a set of genes is uniquely associated with an organ-injury phenotype (injury module), by using thioacetamide, a known liver toxicant. Here, we sought to explore whether RNA-seq data obtained from human cells (in vitro) treated with thioacetamide-S-oxide (a toxic intermediate metabolite) would correlate across species with the injury responses found in rat cells (in vitro) after exposure to this metabolite as well as in rats exposed to thioacetamide (in vivo). We treated two human cell types with thioacetamide-S-oxide (primary hepatocytes with 0 (vehicle), 0.125 (low dose), or 0.25 (high dose) mM, and renal tubular epithelial cells with 0 (vehicle), 0.25 (low dose), or 1.00 (high dose) mM) and collected RNA-seq data 9 or 24 h after treatment. We found that the liver-injury modules significantly altered in human hepatocytes 24 h after high-dose treatment involved cellular infiltration and bile duct proliferation, which are linked to fibrosis. For high-dose treatments, our modular approach predicted the rat in vivo and in vitro results from human in vitro RNA-seq data with Pearson correlation coefficients of 0.60 and 0.63, respectively, which was not observed for individual genes or KEGG pathways.

Vitamin D deficiency has been reported in alcoholics. This study is aimed at evaluating the effects of vitamin D deficiency on chronic alcohol-induced liver injury in mice. Mice were fed with modified Lieber-DeCarli liquid diets for 6 weeks to establish an animal model of chronic alcohol-induced liver injury. In the VDD+EtOH group, mice were fed with modified diets, in which vitamin D was depleted. Vitamin D deficiency aggravated alcohol-induced liver injury. Furthermore, vitamin D deficiency aggravated hepatocyte apoptosis during alcohol-induced liver injury. Although it has a little effect on hepatic TG content, vitamin D deficiency promoted alcohol-induced hepatic GSH depletion and lipid peroxidation. Further analysis showed that vitamin D deficiency further increased alcohol-induced upregulation of hepatic inducible nitric oxide synthase ( inos ), two NADPH oxidase subunits p47phox and gp91phox , and heme oxygenase- (HO-) 1. By contrast, vitamin D deficiency attenuated alcohol-induced upregulation of hepatic antioxidant enzyme genes, such as superoxide dismutase ( sod ) 1 and gshpx . In addition, vitamin D deficiency significantly elevated alcohol-induced upregulation of hepatic proinflammatory cytokines and chemokines. Taken together, these results suggest that vitamin D deficiency aggravates hepatic oxidative stress and inflammation during chronic alcohol-induced liver injury., Competing Interests: The authors have declared that no financial conflicts of interest and no competing interests exist., (Copyright © 2020 Chun-Qiu Hu et al.)

Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver injury remain unclear. To determine the role of adipose autophagy and mechanistic target of rapamycin (mTOR) in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (KO), adipocyte-specific mTOR KO, adipocyte-specific Raptor KO, and adipocyte-specific tuberous sclerosis complex 1 KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type mice were challenged with chronic-plus-binge alcohol mouse model. Chronic-plus-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in wild-type mice. Adipocyte-specific Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither adipocyte-specific mTOR nor adipocyte-specific tuberous sclerosis complex 1 KO mice exhibited similar detrimental effects. Adipocyte-specific Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 and adiponectin and were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Crizotinib has been approved for patients with advanced lung adenocarcinoma harboring rearrangements of the c-ROS-1 (ROS1) and anaplastic lymphoma kinase (ALK) genes. We report a patient with ROS1-rearranged lung adenocarcinoma who developed a crizotinib-induced mixed/cholestatic type of liver injury. The patient discontinued crizotinib after 34 days due to liver toxicity. Twenty-four days later, when transaminases and C reactive protein (CRP) were normalized, crizotinib was resumed using an oral desensitization method. The patient was successfully treated for manageable recurrence of liver injury and has been able to continue the treatment.

The use of new oral anticoagulants such as apixaban is increasing. We present the case of an 85-year-old patient who was diagnosed with mixed profile toxic hepatitis due to apixaban use. An etiological study was negative, except for anti-smooth muscle antibodies, and a liver biopsy ruled out autoimmune hepatitis. The patient was assigned a score of 7 on the CIOMS/RUCAM scale, indicating a probable causality. The liver injury improved after the withdrawal of apixaban. A previous meta-analysis reported that the risk of hepatotoxicity does not increase with the use of apixaban, nor were any cases reported in registry studies. Nonetheless, more than 120 possible cases currently appear in the European pharmacovigilance database (EudraVigilance). We suggest that apixaban should be considered as a possible cause of liver injury.

Traditional Chinese medicine (TCM) herbs are commonly regarded to be safe with minimal toxicities in Chinese communities. Cancer patients who are receiving Western oncology therapy often concurrently take TCM herbs for anticancer and symptom relief purposes. We performed a literature review for current evidence on TCM herb-induced liver injury from an oncological perspective. A literature search on PubMed was performed to identify publications regarding TCM herbs and concoctions with hepatoprotective or hepatotoxic properties. Lists of commonly used herbs and their causality levels were compiled. In view of the wide range of evidence available, cases assessed by the well-established RUCAM (Roussel Uclaf Causality Assessment Method) algorithm were categorized as the highest level of evidence. More than one case of TCM herb-induced liver injury was confirmed by RUCAM in the following herbs and concoctions: Lu Cha ( Camellia sinensis ), Bai Xian Pi ( Dictamnus dasycarpus ), Tu San Qi ( Gynura segetum ), Jin Bu Huan ( Lycopodium serratum ), He Shou Wu ( Polygoni multiflora ), Ge Gen ( Pueraria lobata ), Dan Lu Tong Du tablet, Shou Wu Pian, Xiao Chai Hu Tang, Xiao Yin pill, and Yang Xue Sheng Fa capsule. Finally, TCM with anticancer or symptom relief uses were discussed in detail with regard to their hepatotoxic or hepatoprotective properties.

Background & Aims: Liver fibrosis, hepatocellular necrosis, inflammation, and proliferation of liver progenitor cells are features of chronic liver injury. Mouse models have been used to study the end-stage pathophysiology of chronic liver injury. However, little is known about differences in the mechanisms of liver injury among different mouse models because of our inability to visualize the progression of liver injury in vivo in mice. We developed a method to visualize bile transport and blood-bile barrier (BBlB) integrity in live mice., Methods: C57BL/6 mice were fed a choline-deficient, ethionine-supplemented (CDE) diet or a diet containing 0.1% 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) for up to 4 weeks to induce chronic liver injury. We used quantitative liver intravital microscopy (qLIM) for real-time assessment of bile transport and BBlB integrity in the intact livers of the live mice fed the CDE, DDC, or chow (control) diets. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, real-time polymerase chain reaction, and immunoblots., Results: Mice with liver injury induced by a CDE or a DDC diet had breaches in the BBlB and impaired bile secretion, observed by qLIM compared with control mice. Impaired bile secretion was associated with reduced expression of several tight-junction proteins (claudins 3, 5, and 7) and bile transporters (NTCP, OATP1, BSEP, ABCG5, and ABCG8). A prolonged (2-week) CDE, but not DDC, diet led to re-expression of tight junction proteins and bile transporters, concomitant with the reestablishment of BBlB integrity and bile secretion., Conclusions: We used qLIM to study chronic liver injury, induced by a choline-deficient or DDC diet, in mice. Progression of chronic liver injury was accompanied by loss of bile transporters and tight junction proteins., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Taurolidine has been used for peritonitis, oncological and catheter-lock treatment because of its anti-inflammatory properties. It has been suggested that taurolidine has no severe side-effects, but after long-term use morphological and functional changes of the liver were reported. The aim of this study was to investigate the effect of short-term use of taurolidine on the liver., Methods: In HepaRG cell cultures and on a novel liver biochip dose-dependent effects of taurolidine treatment on hepatocyte adherence and cell viability was investigated. Furthermore, liver enzymes and interleukin- (IL-) 6 were measured in supernatants. Male rats were treated with low- or high-dose taurolidine, respectively, and compared to controls with physiological saline solution administration regarding blood serum parameters and histology., Results: In HepaRG cell cultures, hepatocyte adherence was significantly decreased, cell death and cleaved caspase-3 were significantly increased after administration of taurolidine in a dose-dependent manner. High-dose application of taurolidine led to elevated liver enzymes and IL-6 secretion in hepatic organoid. After 24 h a significant increase of serum GLDH and ASAT was observed in rats treated with high-dose taurolidine treatment., Conclusions: Our results suggest that taurolidine caused liver injury after short-term use in in vitro and in vivo models probably due to direct toxic effects on hepatocytes. Therefore, the taurolidine dose should be titrated in further investigations regarding liver injury and inflammation.

Mitochondria are the central hubs for cellular bioenergetics and are crucial to cell survival. It is well accepted that compromised mitochondrial function is linked with hepatocytes injury and contribute to progression of liver diseases. Despite the therapeutic potential of mesenchymal stem cells (MSCs) transplantation on hepatic disorders have been extensively investigated, the effects of MSCs on mitochondrial function in liver injury models remain unknown. Here we investigated the effects of treatment with umbilical cord (UC) MSC in a rat model of D-galactose (D-Gal) induced liver injury, characterized by organ damage, oxidative stress and mitochondrial dysfunction. Our results showed that UC-MSCs treatment significantly alleviated histological lesion and attenuated the elevation of liver biochemical markers, demonstrating its protective effects on D-Gal induced hepatic disorders. Mitochondria isolated from the liver of D-Gal models exhibited decreased antioxidant capacity as well as compromised bioenergetics functions, as shown by a loss of mitochondrial membrane potential, elevation of reactive oxygen species (ROS) production, reduction of mitochondrial respiration complexes and ATP decrement. Treatment of rats with UC-MSCs remarkably blunted these changes and rescued mitochondrial efficiency. Mechanistically, we found that the protective potential of UC-MSCs administration was mediated by nuclear factor-E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway, but not FOXO3a pathway. In conclusion, the attenuating effects of UC-MSCs on hepatic damage partially rely on normalizing mitochondrial function and preventing a state of energetic deficit via activation of Nrf2/HO-1 pathway.

Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation.

Background/aim: The aim of this study was to investigate the effect of bone-marrow mesenchymal stem cells (BMSCs) on repair of liver damage in a carbon tetrachloride (CCl4)-induced mouse model of chronic liver damage., Materials and Methods: Green fluorescent protein (GFP)-expressing BMSCs, isolated from GFP transgenic mice, were transplanted into mice with chronic liver damage induced by CCl4 The GFP-expressing BMSCs in livers were detected by fluorescence microscopy. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured for assessment of liver function. Liver histopathology was performed to assess liver damage. mRNA and protein expression of liver-associated markers albumin (Alb) and alpha-fetoprotein (Afp) were detected to confirm the hepatic differentiation of BMSCs in the liver. Immunostaining for the expression of interleukin-10 (IL-10) and matrix metallopeptidase-9 (MMP-99), and enzyme-linked immunosorbent assay for the secretion of type III collagen and lamininin was carried out., Results: After BMSC transplantation, GFP-expressing BMSCs were detected in the peri-portal and injured areas of the CCL4-injured liver. mRNA and protein expressions of Alb and Afp were significantly increased in BMSC-transplanted liver. Mice treated with BMSCs displayed reduced serum levels of ALT and AST, and CCl4-induced histopathological changes in livers were repaired. BMSC transplantation increased the production of IL-10 and inhibited the expression of MMP-9, as well as the secretion of type III collagen and lamininin., Conclusion: BMSCs transplanted into mice can migrate into damaged liver, differentiate into hepatocytes and promote recovery from chemically-induced liver damage. Promotion of IL-10 and inhibition of MMP-9 by transplanted BMSCs may be involved in the anti-inflammatory and anti-fibrotic action of BMSCs., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Several serum markers are used to assess hepatocyte damage, but they have limitations related to etiology specificity and prognostication. Identification of novel hepatocyte-specific biomarkers could provide important prognostic information and better pathogenesis classification. We tested the hypothesis that hepatocyte-selective biomarkers are released after subjecting isolated mouse hepatocytes to Fas-ligand-mediated apoptosis. Proteomic analysis of hepatocyte culture medium identified the mitochondrial matrix protein carbamoyl phosphate synthetase-1 (CPS1) among the most readily detected proteins that are released by apoptotic hepatocytes. CPS1 was also detected in mouse serum upon acute challenge with Fas-ligand or acetaminophen and in hepatocytes upon hypoosmotic stress, independent of hepatocyte caspase activation. Furthermore, CPS1 was observed in sera of mice chronically fed the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mouse CPS1 detectability was similar in serum and plasma, and its half-life was 126 ± 9 min. Immune staining showed that CPS1 localized to mouse hepatocytes but not ductal cells. Analysis of a few serum samples from patients with acute liver failure (ALF) due to acetaminophen, Wilson disease, or ischemia showed readily detectable CPS1 that was not observed in several patients with chronic viral hepatitis or in control donors. Notably, CPS1 rapidly decreased to undetectable levels in sera of patients with acetaminophen-related ALF who ultimately recovered, while alanine aminotransferase levels remained elevated. Therefore, CPS1 becomes readily detectable upon hepatocyte apoptotic and necrotic death in culture or in vivo. Its abundance and short serum half-life, compared with alanine aminotransferase, suggest that it may be a useful prognostic biomarker in human and mouse liver injury., (Copyright © 2014 the American Physiological Society.)

Aim: To investigate the effects of diammonium glycyrrhizinate (Gly) on portal hypertension (PHT) in isolated portal perfused rat liver (IPPRL) with carbon tetrachloride (CCl₄)-induced chronic hepatitis., Methods: PHT model was replicated with CCl₄ in rats for 84 d. Model was identified by measuring the ascetic amounts, hepatic function, portal pressure in vivo, splenic index, and pathological alterations. Inducible nitric oxide synthase (iNOS) in liver was assessed by immunohistochemistry. IPPRLs were performed at d₀, d₂₈, d₅₆, and d₈₄. After phenylephrine-induced constriction, Gly was geometrically used to reduce PHT. Gly action was expressed as median effective concentration (EC₅₀) and area under the curve (AUC). Underlying mechanism was exploited by linear correlation between AUC values of Gly and existed iNOS in portal triads., Results: PHT model was confirmed with ascites, splenomegaly, serum biomarkers of hepatic injury, and elevated portal pressure. Pathological findings had shown normal hepatic structure at d₀, degenerations at d₂₈, fibrosis at d₅₆, cirrhosis at d₈₄ in PHT rats. Pseudo lobule ratios decreased and collagen ratios increased progressively along with PHT development. Gly does dose-dependently reduce PHT in IPPRLs with CCl₄-induced chronic hepatitis. Gly potencies were increased gradually along with PHT development, characterized with its EC₅₀ at 2.80 × 10⁻¹⁰, 3.03 × 10⁻¹¹, 3.77 × 10⁻¹¹ and 4.65×10⁻¹¹ mol/L at d₀, d₂₈, d₅₆ and d₈₄, respectively. Existed iNOS was located at hepatocyte at d₀, stellate cells at d₂₈, stellate cells and macrophages at d₅₆, and macrophages in portal triads at d₈₄. Macrophages infiltrated more into portal triads and expressed more iNOS along with PHT development. AUC values of Gly were positively correlated with existed iNOS levels in portal triads., Conclusion: Gly reduces indirectly PHT in IPPRL with CCl₄-induced chronic hepatitis. The underlying mechanisms may relate to rescue NO bioavailability from macrophage-derived peroxynitrite in portal triads.

Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8⁻/⁻ and krt18⁻/⁻ mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8⁻/⁻ and krt18⁻/⁻ compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18⁻/⁻ mice already at an early stage of intoxication in contrast to krt8⁻/⁻ mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8⁻/⁻, krt18⁻/⁻ and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18⁻/⁻ and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8⁻/⁻ mice, steatosis was less, ballooning, and MDBs were absent. krt18⁻/⁻ mice developed MDBs whereas krt8⁻/⁻ mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8⁻/⁻ and krt18⁻/⁻ mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8⁻/⁻ and krt18⁻/⁻ mice on different genetic backgrounds were investigated.

Tuberculosis is a major health burden worldwide. In Nepal, it is a significant cause of morbidity and mortality. Although better drugs are available for managing tuberculosis, treatment failure is one of the common problems encountered. Among the various causes which can cause treatment interruption, drug induced hepatotoxicity is a common cause. Isoniazid and Pyrazinamide are the common drugs causing hepatotoxicity. Upon occurrence of hepatotoxicity, the hepatotoxic drugs should be stopped and reintroduced as per the available guidelines. The healthcare professional should also counsel the patients for recognizing the early symptoms due to hepatotoxicity which could prevent morbidity.

We retrospectively examined the summaries of all admission records of patients from 1979 to 1999 in our department, and selected for further study all liver injuries suspected of being related to Kampo medicines. Among 2,496 summaries, 30 summaries described liver disorders suspected of being related to Kampo medicines. Whether there was a causal relationship between the use of Kampo medication and the occurrence of liver injury was assessed according to the criteria described by Haller and Benowitz (2000), independently of the results of the lymphocyte transformation test (LTT). Among 30 events, we concluded that 9 were definitely unrelated, and 6 were probably unrelated to the use of Kampo medicines. Nine events (0.36% of 2,496 patient admissions and 0.06% of 14,616 outpatients) were considered possibly related, and only 6 events (0.24% of 2,496 patient admissions and 0.04% of 14,616 outpatients) were judged to be definitely or probably related to Kampo medicines. Low-grade eosinophilia was observed in a few patients of these "related" groups, and no fever or rash was observed in these "related" groups. Other clinical features, including type of liver injury, duration of Kampo medicine-use, recovery period and laboratory data, were not different from liver injuries associated with western drugs. Most patients in the definitely "unrelated" group were positive in the LTT for the suspect Kampo medicine, suggesting that the LTT may be unreliable for the diagnosis of Kampo-medicine-induced liver injury. From 1979 to 1999, our use of Kampo medicines to treat patients resulted in a low rate of liver injury and no fatalities.

Objective: The benefits of 5-year tamoxifen administration for patients with estrogen receptor-positive breast cancer undoubtedly outweigh the risk of any adverse effects. Massive hepatic steatosis is an example of its side effects. Here we show risk factors for the development of massive hepatic steatosis and describe a representative clinical course of these patients treated with fibrates for the first time., Methods: Computed tomography (CT) numbers of the liver and spleen were measured and correlated to body mass index (BMI) and pregnanetriol/pregnanediol ratio in urine (P3/P2 ratio)., Patients: We enrolled 56 premenopausal women treated with breast conservation treatment. They received oral tamoxifen (40 mg/day for 2 to 3 years) as adjuvant endocrine therapy with systemic chemotherapy., Results: Serum estradiol level in 48 of 56 patients treated with tamoxifen was less than 10 pg/ml. The ratio of hepatic CT number to splenic CT number<0.9 was related to increased BMI (>23.6 kg/sqm) and reduced P/P2 ratio (<1). Fibrates are potent enough to improve hepatic steatosis in tamoxifen-induced hepatic steatosis., Conclusion: P3/P2 ratio<1 was related to sufficient blockade of estrogen receptor proven by the development of massive hepatic steatosis. Therefore, we propose that tamoxifen is not a mere antagonist of estrogen, but it may also suppress estrogen synthesis when estrogen receptor is blocked sufficiently. The undetectable level of serum estrogen in tamoxifen-treated premenopausal women may partially explain why tamoxifen was so effective in estrogen receptor-positive early breast cancer.

To evaluate the occurrence of hepatotoxicity in patients during antiretroviral therapy (ART) that contains protease inhibitors and the role of hepatitis viruses in its development, we performed a retrospective study including 1325 HIV-infected patients treated with ART for at least 6 months. Presence or absence of hepatitis viruses, alanine aminotransferase (ALT), total bilirubin, CD4 cell count, and plasma HIV RNA levels were evaluated. Hepatotoxicity developed in a few study subjects without coinfection, whereas it was significantly higher in coinfected patients. Univariate logistic regression analysis showed that viral hepatitis coinfections are independent risk factors for hepatotoxicity. After 6 months of treatment, ritonavir was associated with higher rates of severe hepatotoxicity in the coinfected group; in fact, ritonavir seems to be the most strongly hepatotoxic agent among coinfected patients. After 12 months of therapy, hepatotoxicity occurred more frequently in patients with hepatitis C virus who did not respond to antiretroviral therapy (ART), whereas patients who did respond to ART showed decreased ALT levels. Hepatotoxicity is not exclusively an effect of drug toxicity, and the presence of hepatitis coinfection is an independent risk factor. Moreover, chronic hepatotoxicity mainly occurs in patients who did not respond to therapy. Conversely, patients who did respond to ART seemed to show improvement of chronic liver infection.