A Case of Drug-induced Liver Injury Considered Steroid-resistant and Histologically Diagnosed with Vanishing Bile Duct Syndrome.

Vanishing bile duct syndrome (VBDS) is characterized by bile duct degeneration and necrosis, which result in bile duct loss and bile stasis. A 70-year-old man had malaise after receiving celecoxib. Laboratory tests revealed elevated hepatobiliary enzymes. His condition worsened without response to medical treatment, and he was transferred to our hospital. A liver biopsy revealed severe bile duct injury and mild cholestasis. He was diagnosed with celecoxib-induced VBDS and underwent bilirubin adsorption therapy. However, his condition continued to deteriorate, and he died. An autopsy showed that liver regeneration was poor, and bile duct loss was exacerbated. The pathological autopsy findings were consistent with VBDS.

Drug-Induced Liver Injury Used in the Treatment of Inflammatory Bowel Disease.

Therapeutic options for the management of inflammatory bowel disease [IBD] have been expanding in recent decades. New biological and small molecule therapies have been incorporated into the pharmacological arsenal, allowing a more personalized management, and seeking increasingly strict remission goals. However, the fear of developing adverse events represents one of the most important limitations in deciding its use by patients and by a multidisciplinary team. Despite the risk of hepatotoxicity of thiopurines and methotrexate, these drugs are still used either as monotherapy or as combined therapy with anti-tumour necrosis factor [anti-TNF] biological agents. Although drug-induced liver injury [DILI] appears to be less frequent with anti-TNF agents, newer biologics and small molecules, liver tests should be considered in the follow-up of these patients, especially regarding future combined therapy of biologics or of these drugs with small molecules. The objective of this review is to show data on the risk of developing DILI in patients with IBD who are undergoing treatment with traditional therapy or new drugs, whether biological or small molecules.

Pharmacoeconomic Evaluation of Magnesium Isoglycyrrhizinate Preventing Liver Damage Induced by Chemo- therapeutic Drugs for Gastric Cancer / 中国药房

OBJECTIVE：To ev aluate pha rmacoeconomics of magnesium isoglycyrrhizinate preventing liver damage induced by chemotherapeutic drugs for gastric cancer ，and to provide reference for rational use of liver-protecting drugs. METHODS ：Totally 200 inpatient medical records were collected from our hospital retrospectively during Jan. 2018-Feb. 2020，and then divided into group A （prophylactic use of magnesium isoglycolate ，50 cases），group B （prophylactic use of magnesium isoglycolate combined with TCM prescriptions ，50 cases），group C （prophylactic use of polyene phosphatidylcholine ，50 cases） and group D （non-prophylactic use of liver-protection drugs ，50 cases）. The effects （total response rate ）of four plans preventing liver damage were evaluated. Pharmacoeconomic evaluation was analyzed by cost-minimization analysis and cost-effectiveness method ， sensitivity analysis was carried out at the same time . RESULTS ：Total response rates of group A ，B，C and D were 94.00％， 96.00％，82.00％ and 72.00％. The total response rates of group A and B had no statistical significance （P＞0.05），but were significantly higher than those of group C and D （P＜0.05）；total response rate of group C was significantly higher than that of group D （P＜0.05）. The costs of groups A ，B，C and D were 1 936.70，2 086.96，1 800.91，2 975.42 yuan. The cost-minimization analysis was used to compare the therapeutic plan of group A and B ，and plan of group A was more economical. The cost-effectiveness method was used to compare therapeutic plan between group C and D ，and the plan of group C was more economical. The cost-effectiveness method was used to compare therapeutic plan between group A and C ，and the cost-effectiveness ratio of 2 groups were 2 060.32 and 2 196.2 3，incremental cost-effectiveness ratio was 1 131.58，and the plan of group A was more economical. Above conclusion were supported by the results of sensitivity analysis. CONCLUSIONS ：The cost-effectiveness of magnesium isoglycyrrhizinate preventing liver damage induced by chemotherapeutic drugs for gastric cancer is better than magnesium isoglycyrrhizinate combined with TCM prescription ， polyene phosphatidylcholine and non-prophylactic use of liver-protecting drugs ，showing economical advantage.

Toxicidad hepática causada por medicamentos: revisión estructurada / Structured Literature Review of Hepatic Toxicity Caused by Medicines

Resumen Objetivos: elaborar un listado actualizado de medicamentos causantes de hepatotoxicidad e identificar, de acuerdo con la evidencia científica, los medicamentos con mayor probabilidad de causar hepatotoxicidad. Método: se realizó una búsqueda en PubMed/Medline utilizando términos Mesh: "liver disease" y "drug-induced liver injury". La búsqueda se filtró por: reportes de casos, revisiones, ensayos clínicos, metaanálisis y cartas, hasta diciembre de 2015, en inglés, español y francés. Se incluyeron artículos con evidencia de hepatotoxicidad causada por medicamentos y referencias relevantes; fueron excluidos artículos sin relación con los objetivos de la búsqueda, relacionados con hepatotoxicidad por agentes diferentes, concernientes a otras causas de enfermedad hepática o relacionados con ensayos predictivos o células madre. Algunos aspectos de los medicamentos hepatotóxicos fueron: aparición de hepatotoxicidad, tipo de lesión, mecanismos de hepatotoxicidad, factores de riesgo y manifestaciones clínicas. Para valorar la probabilidad de aparición de hepatotoxicidad y del tipo de lesión se establecieron 3 categorías: definida, probable y posible. Resultados: se identificaron 610 artículos de los cuales se eligieron 402, se excluyeron 208 artículos. Se elaboró un listado con 181 medicamentos y 17 formas farmacéuticas combinadas o regímenes terapéuticos con probabilidad de causar hepatotoxicidad; de estos, 6 medicamentos tuvieron probabilidad definida (metotrexato, minociclina, vancomicina, everolimus, isoniazida y tamoxifeno). Conclusiones: se identificaron más de 180 medicamentos hepatotóxicos, 6 tienen una probabilidad definida, mientras que para la mayoría es posible. La consolidación de la información demostró que diversas categorías de medicamentos tienen mayor probabilidad de ser causantes de hepatotoxicidad.

Abstract Objectives: The aim of this study was to prepare an updated list of drugs that cause hepatotoxicity and identify drugs most likely to cause hepatotoxicity according to scientific evidence. Method: A search of PubMed/Medline was conducted using the MeSH terms: "Liver disease" and "Drug-induced Liver Injury". The search was filtered by case reports, reviews, clinical trials, metaanalyses and letters until December 2015. The search was limited to articles in English, Spanish and French. Articles with evidence of hepatotoxicity caused by medications and relevant references were included. Articles not related to the objectives of the search were excluded. These include articles related to hepatotoxicity due to other agents, articles about other causes of liver disease and/or articles related to predictive tests or stem cells. Some aspects of hepatotoxic drugs were appearance of hepatotoxicity, type of injury, mechanisms of hepatotoxicity, risk factors and clinical manifestations. Three categories, definite, probable and possible, were established to assess probability of hepatotoxicity and type of lesion. Results: Six hundred ten articles were identified, 402 articles were chosen, and 208 articles were excluded. A list was prepared with 181 drugs and 17 combined pharmaceutical forms or therapeutic regimens likely to cause hepatotoxicity. Of these, methotrexate, minocycline, vancomycin, everolimus, isoniazid, and tamoxifen were categorized as definite probabilities. Conclusions: More than 180 hepatotoxic drugs were identified, six were categorized as definite probabilities, and most were categorized as possibilities. The consolidation of information shows that diverse categories of drugs are likely to cause liver toxicity.

Clinical Observation and Economic Evaluation of 3 Kinds of Drugs Preventing Chemotherapy-induced Liv-er Damage in Patients with Gastrointestinal Tumors / 中国药房

OBJECTIVE:To observe the preventive effects and safety of 3 kinds of drugs on chemotherapy-induced liver dam-age in patients with gastrointestinal tumors,and to evaluate economics. METHODS:A total of 128 patients with gastrointestinal malignant tumor and systemic chemotherapy indication selected from our hospital during 2014-2015 were divided into group A(42 cases),B(46 cases)and C(40 cases)according to random number table. Since the first day of chemotherapy,group A,B and C were given Reduced glutathione for injection(1.2 g),Magnesium isoglycyrrhizinate injection(100 mg)and Polyene phosphati-dylcholine injection(465 mg)for preventing chemotherapy-induced liver damage respectively,for 7 d. The preventive effects and ADR occurrence were observed in 3 groups,and the economic analysis was conducted. RESULTS:Total response rates of group A,B and C were 90.48%,97.83% and 87.50%,and that of group B was significantly higher than other 2 groups,with statistical significance(P<0.05). But there was no statistical significance between group A and C(P>0.05). The costs of group A,B and C were 1 465.86,1 518.94,1 554.04 yuan,and cost-minimization analysis was adopted to evaluate the plans of group A and C. The plan of group A was more economical. Cost-effectiveness analysis was used to evaluate the plans of group A and B,cost-effectiveness ratio of group A and B were 1 620.09 and 1 552.63;incremental cost-effectiveness ratio was 722.18, and the plan of group B was more economical. The above conclusion was supported by the results of sensitivity analysis. Three patients in group B suffered from transient elevated blood pressure and then recovered 2-3 d after drug withdrawal. CONCLU-SIONS:The preventive effects and economics of Magnesium isoglycyrrhizinate injection is better than Reduced glutathione for injection and Polyene phosphatidylcholine injection for chemotherapy-induced liver damage in patients with gastrointestinal tu-mors. The blood pressure of patients should be monitored closely during application. Reduced glutathione for injection is more suitable for patients with primary hypertensive disease.

Clinical Observation and Economic Evaluation of 3 Kinds of Drugs Preventing Chemotherapy-induced Liv-er Damage in Patients with Gastrointestinal Tumors / 中国药房

OBJECTIVE:To observe the preventive effects and safety of 3 kinds of drugs on chemotherapy-induced liver dam-age in patients with gastrointestinal tumors,and to evaluate economics. METHODS:A total of 128 patients with gastrointestinal malignant tumor and systemic chemotherapy indication selected from our hospital during 2014-2015 were divided into group A(42 cases),B(46 cases)and C(40 cases)according to random number table. Since the first day of chemotherapy,group A,B and C were given Reduced glutathione for injection(1.2 g),Magnesium isoglycyrrhizinate injection(100 mg)and Polyene phosphati-dylcholine injection(465 mg)for preventing chemotherapy-induced liver damage respectively,for 7 d. The preventive effects and ADR occurrence were observed in 3 groups,and the economic analysis was conducted. RESULTS:Total response rates of group A,B and C were 90.48%,97.83% and 87.50%,and that of group B was significantly higher than other 2 groups,with statistical significance(P<0.05). But there was no statistical significance between group A and C(P>0.05). The costs of group A,B and C were 1 465.86,1 518.94,1 554.04 yuan,and cost-minimization analysis was adopted to evaluate the plans of group A and C. The plan of group A was more economical. Cost-effectiveness analysis was used to evaluate the plans of group A and B,cost-effectiveness ratio of group A and B were 1 620.09 and 1 552.63;incremental cost-effectiveness ratio was 722.18, and the plan of group B was more economical. The above conclusion was supported by the results of sensitivity analysis. Three patients in group B suffered from transient elevated blood pressure and then recovered 2-3 d after drug withdrawal. CONCLU-SIONS:The preventive effects and economics of Magnesium isoglycyrrhizinate injection is better than Reduced glutathione for injection and Polyene phosphatidylcholine injection for chemotherapy-induced liver damage in patients with gastrointestinal tu-mors. The blood pressure of patients should be monitored closely during application. Reduced glutathione for injection is more suitable for patients with primary hypertensive disease.

Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

AIMS: To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI). METHODS: Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. RESULTS: In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration < 20 mg l(-1) and a normal ALT/AST on initial presentation or when RSPI was first suspected, but both of these values were only available for 79 (40%) cases. CONCLUSIONS: Severe liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases.

CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure.

BACKGROUND & AIMS: Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. METHODS: We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. RESULTS: Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. CONCLUSIONS: Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury.

Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity.

Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co-formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today.

Efficacy and Safety of Magnesium Isoglycyrrhizinate Injection versus 4 Common Medicines in the Treatment of Drug-induced Liver Damage:A Systematic Review / 中国药房

OBJECTIVE:To systematically review the efficacy and safety of Magnesium isoglycyrrhizinate injection versus 4 comnon medicines in the treatment of drug-induced liver damage,and to provide evidence-based reference for clinic treatment. METHODS:Retrieved from PubMed,EMBase,Cochrane Library,CBM,CJFD,Wanfang Database and VIP Database,random-ized controlled trials (RCT) about Magnesium isoglycyrrhizinate injection versus other medicines in the treatment of drug-induced liver damage were enrolled. Meta-analysis was performed by using Rev Man 5.3 software after literature selection,data extract and quality assessment. RESULTS:A total of 13 RCTs were included,involving 1 093 patients. Results of Meta-analysis showed clini-cal effective in magnesium isoglycyrrhizinate group was significantly higher than tiopronin group[RD=0.29,95%CI(0.17,0.42), P<0.001] and diammonium glycyrrhizinate group [RD=0.07,95%CI(0.01,0.12),P=0.02],compared with glutathione group and compound ammonium glycyrrhetate group,there were no significant differences ;incidence of adverse reactions in magnesium iso-glycyrrhizinate group was significantly lower than diammonium glycyrrhizinate group [RD=-0.07,95%CI(-0.11,-0.03),P<0.001] and compound ammonium glycyrrhetate group[RD=-0.21,95%CI(-0.38,-0.04),P=0.02],compared with triopro-nin group and glutathione group,there were no significant differences among 3 groups. CONCLUSIONS:Magnesium isoglycyrrhiz-inate injection has better efficacy and safety than other 4 commons hepatoprotective medicines in the treatment of drug-induced liver damage. Due to the limit of methodological quality,more large-scale and long-term follow-up studies with strict designed are need-ed for the further verification of the conclusion.

Valproic acid derivatives signal for apoptosis and repair in vitro.

PURPOSE: To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication. METHODS: Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2h and for 24h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA. RESULTS: VCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time. SIGNIFICANCE: HepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.

Effects of Different Anti-rejection Regimens on Liver Function in Renal Transplant Recipients / 药物流行病学杂志

Objective:To study the effects of cyclosporine A coadministrated with azathioprine,mycophenolate, mizorihine,rapamycin and/or prednisone on liver function in renal transplant recipients.Method:The drug history records of 600 renal transplant recipients in 1995 to 2005 were retrospectively investigated.Biochemical indexes before and after the treatment with cyclosporine A coadministrated with other immunosuppressants were analyzed.Result:The liver damage was found in 109 cases(18.2%)among 600 cases.The blood concentrations of cyclosporine A in the group with abnormal liver functions were significantly higher than those in the group with normal liver functions(P

Protection of Herbal Medicines to Tonify Qi and Strengthen the Spleen on Antituberculotic Liver Damage / 中医杂志

Objective To explore the protective effect of herbal medicine to tonify qi and strengthen the spleen on liver damage induced by antituberculotic according to the TCM theory "reinforce the earth to reduce the wood".Methods The 100 tuberculosis patients randomized into two groups,50 in each,all took antituberculosis drugs with the liver-protecting medicine,Tiopronin,and the herbal medicines to nourish qi and strengthen the spleen were administered to those in the treatment group.Incidence of liver damage and the changes of liver function including serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and total bilirubin(TBiL) were observed for four weeks.Results In the treatment group,the incidence of liver damage was significantly lower than that in the control group(P

Timely Monitoring Drug-induced Liver Damage by Using Hospital Centralized Management System for Monitoring ADR / 中国药房

OBJECTIVE:To establish a way to monitor drug-induced liver damage by using hospital centralized management system for monitoring ADR.METHODS:Using self-designed computer program,the data of inpatients with abnormal ALT,AST and TBIL,admitted in the period from Dec. 2001 to Feb. 2002,were extracted from hospital HIS system of databa_se,and ADR and irrational drug-use were retrospectively analysed.RESULTS:There were 50 ADR incidents concerned with 30 kinds of drug and 11 cases receiving irrational medication concerned 10 kinds of drug.CONCLUSION:By this way,we can timely get the information of drug-induced liver damage and set up a new way for developing centralized ADR monitoring in hospital.