Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, anti-neoplastic drugs), and signal and assessment of DILI in clinical trials.
Humans ; Chemical and Drug Induced Liver Injury/therapy* ; Drug-Related Side Effects and Adverse Reactions ; Liver Failure, Acute ; Dietary Supplements/adverse effects* ; Risk Factors

Objective To investigate the effects of YAP on the occurrence and progression of acute liver failure by regulating the ferroptosis pathway and its underlying mechanism. Methods A total of 20 8-week-old C57BL/6 mice were randomly divided into four groups: a control group, an acute liver failure model group, a YAP agonist XMU-MP-1 treatment group and a YAP inhibitor verteporfin treatment group, five mice for each group. HE staining was used to observe the pathological changes of hepatic inflammation and necrosis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by liver biochemistry. Iron (Fe), malondialdehyde (MDA), glutathione (GSH) determination kits were used to measure their levels in liver tissues of each group. The changes of hepatocyte mitochondrial in each group were observed by electron microscopy. Real time PCR and Western blot analysis were used to detect the mRNA and protein expressions of YAP, glutathione peroxidase 4 (GPX4) and 5-lipoxygenase (5-LOX). Results Compared with the control group, mice in the acute liver failure model group and the YAP inhibitor verteporfin treatment group showed severe liver tissue congestion with inflammatory cell infiltration and structural damage to hepatic lobules. Liver injury was alleviated in the XMU-MP-1 treatment group. With the occurrence of liver failure, plasma ALT and AST levels significantly increased, and liver function was improved in XMU-MP-1 treatment group. Electron microscopy showed that mitochondria in hepatocytes of mice with liver failure became smaller and bilayer membrane density increased, while mitochondria changes in the XMU-MP-1 group were alleviated. In addition, the acute liver failure model group showed an increase in Fe and MDA contents, decreased protein expressions of GPX4, and enhanced expression of 5-LOX, suggesting that ferroptosis was involved in acute liver failure in C57BL/6 mice. Ferroptosis was inhibited by activation of YAP. Conclusion Activation of YAP may ameliorate liver injury by inhibiting ferroptosis.
Animals ; Mice ; Ferroptosis ; Glutathione ; Liver Failure ; Liver Failure, Acute/drug therapy* ; Mice, Inbred C57BL ; Verteporfin ; YAP-Signaling Proteins/metabolism*

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe²⁺, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe²⁺, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Liver Failure, Acute/drug therapy* ; Isothiocyanates/pharmacology* ; Glutathione ; Histone Deacetylase 6

OBJECTIVE: To evaluate the protective effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) against acute kidney injury induced by acute liver failure and unravel the underlying mechanism, so as to provide insights into the clinical therapy of acute kidney injury. METHODS: Twenty-four male C57BL/6J mice at ages of 6 to 8 weeks were randomly divided into the normal control group, rSj-Cys control group, lipopolysaccharide (LPS)/D-galactosamine (D-GaIN) model group and LPS/D-GaIN + rSj-Cys treatment group, of 6 mice each group. Mice in the LPS/D-GaIN group and LPS/D-GaIN + rSj-Cys group were intraperitoneally injected with LPS (10 μg/kg) and D-GaIN (700 mg/kg), and mice in the LPS/D-GaIN + rSj-Cys group were additionally administered with rSj-Cys (1.25 mg/kg) by intraperitoneal injection 30 min post-modeling, while mice in the rSj-Cys group were intraperitoneally injected with rSj-Cys (1.25 mg/kg), and mice in the normal control group were injected with the normal volume of PBS. All mice were sacrificed 6 h post-modeling, and mouse serum and kidney samples were collected. Serum creatinine (Cr) and urea nitrogen (BUN) levels were measured, and the pathological changes of mouse kidney specimens were examined using hematoxylin-eosin (HE) staining. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were detected using enzyme-linked immunosorbent assay (ELISA), and the expression of inflammatory factors and pyroptosis-related proteins was quantified in mouse kidney specimens using immunohistochemistry. In addition, the expression of pyroptosis-related proteins and nuclear factor-kappa B (NF-κB) signaling pathway-associated proteins was determined in mouse kidney specimens using Western blotting assay. RESULTS: HE staining showed no remarkable abnormality in the mouse kidney structure in the normal control group and the rSj-Cys control group, and renal tubular injury was found in LPS/D-GaIN group, while the renal tubular injury was alleviated in LPS/D-GaIN+rSj-Cys treatment group. There were significant differences in serum levels of Cr (F = 46.33, P < 0.001), BUN (F = 128.60, P < 0.001), TNF-α (F = 102.00, P < 0.001) and IL-6 (F = 202.10, P < 0.001) among the four groups, and lower serum Cr [(85.35 ± 32.05) μmol/L], BUN [(11.90 ± 2.76) mmol/L], TNF-α [(158.27 ± 15.83) pg/mL] and IL-6 levels [(56.72 ± 4.37) pg/mL] were detected in the in LPS/D-GaIN + rSj-Cys group than in the LPS/D-GaIN group (all P values < 0.01). Immunohistochemical staining detected significant differences in TNF-α (F = 24.16, P < 0.001) and IL-10 (F = 15.07, P < 0.01) expression among the four groups, and lower TNF-α [(106.50 ± 16.57)%] and higher IL-10 expression [(91.83 ± 5.23)%] was detected in the LPS/D-GaIN + rSj-Cys group than in the LPS/D-GaIN group (both P values < 0.01). Western blotting and immunohistochemistry detected significant differences in the protein expression of pyroptosis-related proteins NOD-like receptor thermal protein domain associated protein 3 (NLRP3) (F = 24.57 and 30.72, both P values < 0.001), IL-1β (F = 19.24 and 22.59, both P values < 0.001) and IL-18 (F = 16.60 and 19.30, both P values < 0.001) in kidney samples among the four groups, and lower NLRP3, IL-1β and IL-18 expression was quantified in the LPS/D-GaIN + rSj-Cys treatment group than in the LPS/D-GaIN group (P values < 0.05). In addition, there were significant differences in the protein expression of NF-κB signaling pathway-associated proteins p-NF-κB p-P65/NF-κB p65 (F = 71.88, P < 0.001), Toll-like receptor (TLR)-4 (F = 45.49, P < 0.001) and p-IκB/IκB (F = 60.87, P < 0.001) in mouse kidney samples among the four groups, and lower expression of three NF-κB signaling pathway-associated proteins was determined in the LPS/D-GaIN + rSj-Cys treatment group than in the LPS/D-GaIN group (all P values < 0.01). CONCLUSIONS rSj-Cys may present a protective effect against acute kidney injury caused by acute liver failure through inhibiting inflammation and pyroptosis and downregulating the NF-κB signaling pathway.
Mice ; Male ; Animals ; Interleukin-10 ; Tumor Necrosis Factor-alpha/genetics* ; NF-kappa B/therapeutic use* ; Interleukin-18/therapeutic use* ; Schistosoma japonicum/metabolism* ; Interleukin-6/therapeutic use* ; Lipopolysaccharides/therapeutic use* ; NLR Family, Pyrin Domain-Containing 3 Protein ; Mice, Inbred C57BL ; Acute Kidney Injury/drug therapy* ; Liver Failure, Acute ; Cystatins/therapeutic use*

Hepatitis type E virus (HEV) is one of the main causes of acute hepatitis globally and has thus gained attention as a public health issue. The diverse clinical manifestations of hepatitis type E are typically acute and self-limiting with mild symptoms, but populations with underlying liver disease or immunocompromised patients can have severe and chronic symptoms. Severity and chronicity can arise and manifest as fulminant hepatitis, chronic hepatitis, or even hepatic failure. HEV infection-induced hepatic failure (acute-on-chronic liver failure), based on the different backgrounds of chronic liver disease, is a clinical phenotype of severe HEV infection that requires attention. In addition, HEV infection can exhibit extrahepatic clinical manifestations of multi-system and organ involvement like neurological diseases (Guillain-Barré syndrome), renal diseases (membranous/membranous proliferative glomerulonephritis, cryoglobulinemia), and blood diseases (thrombocytopenia). At home or abroad, there are no antiviral drugs approved, particularly for HE treatment. Since most acute HE can resolve spontaneously, no special treatment is required clinically. However, in patients with severe or chronic HE, ribavirin (RBV) monotherapy and/or pegylated interferon-combination therapy have achieved certain antiviral effects. Combined small-molecule drugs and RBV have been attempted to treat HEV, but high-level evidence-based treatment is still lacking. Thus, new, highly effective anti-HEV drugs are clinical priorities to address these concerns. Severe and chronic HEV infections' clinical phenotype, early detection, mechanism, intervention, and outcome need additional study.
Humans ; Antiviral Agents/therapeutic use* ; Ribavirin/therapeutic use* ; Hepatitis, Chronic/drug therapy* ; Hepatitis E virus ; Liver Diseases/drug therapy* ; Liver Failure/drug therapy*

OBJECTIVES: Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure in China, with a high mortality. Early rapid reduction of HBV-DNA load can improve the survival rate of HBV-ACLF patients. At present, the commonly used drugs are nucleoside (acid) analogues, such as entecavir (ETV), tenofovir, and so on. The newly listed tenofovir alafenamide fumarate (TAF) has attracted great attention of clinicians because of its stronger antiviral effect, higher transaminase normalization rate, better bone and kidney safety, and zero drug resistance. However, there are few clinical research data on the efficacy and safety of TAF in the treatment of Chinese HBV-ACLF patients, and there is a lack of pharmacoeconomic evaluation. This study aims to compare the efficacy, safety, and cost-effectiveness between TAF and ETV in patients with HBV-ACLF. METHODS: The data were collected from 196 HBV-ACLF patients (80 patients in the TAF group and 116 patients in the ETV group) who were hospitalized in Xiangya Hospital, Central South University from May 2020 to March 2021. Biochemistry and virology were detected before and after treatment (at baseline, Week 2, 4, and 12). Clinical features, disease prognosis, and cost-effectiveness were compared between the 2 groups. According to the baseline, HBV-ACLF patients were divided into 4 stages including pre-liver failure stage, early stage, medium stage, and end stage. And the liver transplantation rate and mortality was also compared. Pharmacoeconomic evaluation was taken using cost-effectiveness analysis and cost minimization analysis．. RESULTS: After 4 weeks of treatment, there were no significant differences in the efficacy (liver function, viral load) between the 2 groups (all P>0.05). The TAF group showed lower creatinine [(80.35±18.77) μmol/L vs (105.59±82.32) μmol/L, P<0.05] and higher estimated glomerular filtration rate (eGFR) levels [(95.65±23.21) mL/(min·1.73 m²) vs (82.68±26.32) mL/(min·1.73 m²), P<0.05] than the ETV group. After 12 weeks of treatment, the analysis of overall the liver transplantation rate and mortality between the 2 groups showed similar conclusion. However, the TAF group had a lower the liver transplantation rate and mortality than the ETV group in patients with pre-liver failure (0vs13.89%, P<0.05). No evident distinction was found in the liver transplantation rate and mortality during the early, medium, or end stages of liver failure (13.04% vs 17.65%, 37.50% vs 37.04%, and 54.55% vs 68.42%, respectively). Ratio of cost to effectiveness in the ETV group was higher than that in the TAF group. CONCLUSIONS TAF is not more efficient than ETV group in improving liver function and reducing viral load for HBV-ACLF patients and they also show similar safety. However, TAF has a greater advantage over ETV not only in preserving renal function, but also in reducing the liver transplantation rate and mortality in patients with pre-liver failure. TAF can provide economic benefit to patients with HBV-ACLF.
Acute-On-Chronic Liver Failure/drug therapy* ; Alanine/therapeutic use* ; Antiviral Agents/therapeutic use* ; Guanine/analogs & derivatives* ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Humans ; Tenofovir/analogs & derivatives* ; Treatment Outcome

On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of "traditional Chinese medicine (TCM) regulating liver regeneration." A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of "TCM regulating liver regeneration" (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P < 0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.
Drugs, Chinese Herbal/therapeutic use* ; Hepatitis B/drug therapy* ; Humans ; Liver Failure ; Liver Regeneration ; Medicine, Chinese Traditional ; Retrospective Studies

The hepatobiliary system is one of the most common sites of extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The progression of IBD can lead to a primary hepatobiliary manifestation and can occur secondary to multiple drugs or accompanying viral infections. Primary sclerosing cholangitis is the representative hepatobiliary manifestation of IBD, particularly in ulcerative colitis. Although most agents used in the treatment of IBD are potentially hepatotoxic, the risk of serious hepatitis or liver failure is low. The prevalence of HBV and HCV in IBD is similar to the general population, but the clinical concern is HBV reactivation associated with immunosuppressive therapy. Patients undergoing cytotoxic chemotherapy or immunosuppressive therapy with a moderate to high risk of HBV reactivation require prophylactic antiviral therapy. On the other hand, HCV has little risk of reactivation. Patients with IBD are more likely to have nonalcoholic fatty liver disease than the general population and tend to occur at younger ages. IBD and cholelithiasis are closely related, especially in Crohn's disease.
Cholangitis, Sclerosing ; Cholelithiasis ; Colitis, Ulcerative ; Crohn Disease ; Drug Therapy ; Drug-Induced Liver Injury ; Hand ; Hepatitis ; Hepatitis Viruses ; Humans ; Inflammatory Bowel Diseases ; Liver Failure ; Non-alcoholic Fatty Liver Disease ; Prevalence

The hepatobiliary system is one of the most common sites of extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The progression of IBD can lead to a primary hepatobiliary manifestation and can occur secondary to multiple drugs or accompanying viral infections. Primary sclerosing cholangitis is the representative hepatobiliary manifestation of IBD, particularly in ulcerative colitis. Although most agents used in the treatment of IBD are potentially hepatotoxic, the risk of serious hepatitis or liver failure is low. The prevalence of HBV and HCV in IBD is similar to the general population, but the clinical concern is HBV reactivation associated with immunosuppressive therapy. Patients undergoing cytotoxic chemotherapy or immunosuppressive therapy with a moderate to high risk of HBV reactivation require prophylactic antiviral therapy. On the other hand, HCV has little risk of reactivation. Patients with IBD are more likely to have nonalcoholic fatty liver disease than the general population and tend to occur at younger ages. IBD and cholelithiasis are closely related, especially in Crohn's disease.
Cholangitis, Sclerosing ; Cholelithiasis ; Colitis, Ulcerative ; Crohn Disease ; Drug Therapy ; Drug-Induced Liver Injury ; Hand ; Hepatitis ; Hepatitis Viruses ; Humans ; Inflammatory Bowel Diseases ; Liver Failure ; Non-alcoholic Fatty Liver Disease ; Prevalence

BACKGROUND/AIMS: Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to investigate the prognosis predictors and the role of second-line cytotoxic systemic chemotherapy (CSC) in patients with advanced HCC after sorafenib discontinuation in the pre-regorafenib era. METHODS: From 2007 to 2015 in the pre-regorafenib era, the medical records of 166 HCC patients, who had permanently discontinued sorafenib, were retrospectively reviewed. For further analysis of survival factors after sorafenib treatment failure, we compared the survival of patients who had maintained liver function after second-line treatment with the best supportive care (BSC) group and selective BSC (SBSC) group. RESULTS: After discontinuation of sorafenib, median overall survival (OS) was 2.8 (1.9–3.7) months. The OS in patients who discontinued sorafenib due to adverse effect, progression, and poor clinical condition were 5.5 (2.4–8.6), 5.5 (2.2–8.9), and 0.9 (0.5–1.3) months, respectively (P<0.001). The independent predictive factors of survival after sorafenib failure were serum level of bilirubin and albumin, α-fetoprotein, discontinuation cause, and second-line CSC. In comparison with survival between second-line CSC and BSC group, the CSC group showed better survival outcome compared to the BSC group (10.6 vs. 1.6 months, P<0.001) and SBSC group (10.6 vs. 4.2 months, P=0.023). CONCLUSIONS: The survival after sorafenib failure in patients who discontinued sorafenib due to progression and adverse effects was significantly better than in those who discontinued treatment due to clinical deterioration. In the pre-regorafenib era, patients who received second-line CSC showed better survival than those who received only supportive care after sorafenib failure.
Bilirubin ; Carcinoma, Hepatocellular ; Drug Therapy ; Humans ; Liver ; Medical Records ; Prognosis ; Retrospective Studies ; Treatment Failure