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Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs. Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events. During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031-1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816-3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439-5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150-4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1.051-7.521) were independently associated with the development of hepatotoxicity. The baseline CD4 cell counts and use of NVP were associated with increased risk of skin rashes, while hepatotoxicity was independently associated with HCV or hepatitis B virus coinfection, and development of skin rashes in antiretroviral-naïve HIV-positive Taiwanese patients within 4 weeks of initiation of nNRTI-containing regimens.

Introduction Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p < 0.001. Conclusion Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Background Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. Objective The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine. Method A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n  = 7605) or placebo ( n  = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts. Results Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. Conclusion Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored.

This research investigated the hepatoprotective effects of esomeprazole (ESOM) and canagliflozin (CANA) against methotrexate-induced liver toxicity, focusing on AMPK modulation and its regulation of MAPK/JNK/ERK, JAK1/STAT3, and PI3K/Akt pathways. Fifty male Wistar rats were divided into five groups: control, MTX, and three pretreatment groups receiving ESOM (30 mg/kg), CANA (30 mg/kg), or their combination. ESOM and CANA were administered for 8 days before and 1 day after a single MTX injection (20 mg/kg, intraperitoneally) on day 9 to induce hepatotoxicity. Liver injury, oxidative stress, inflammation, and apoptosis were assessed using biochemical, histopathological, immunohistochemical, qRT-PCR, and western blot analyses. Data were analyzed by one-way analysis of variance (ANOVA) and Tukey’s post hoc test, with significance at p  < 0.05. Results were presented as mean ± standard error (SE). Rats that received MTX showed significant liver damage, marked by elevated ALT, AST, MDA, MPO, iNOS, TNF-α, IL-6, and IL-1β levels ( p  < 0.01) and decreased antioxidant enzymes (HO-1, Nrf2, and GSH). Immunohistochemistry revealed increased NF-kB p65 and caspase-9 expression ( p  < 0.01), correlating with histopathological changes. Pretreatment with ESOM and CANA reduced liver enzyme levels, improved histology, restored antioxidant balance, and inhibited inflammatory pathways via p38MAPK/NF-kB p65 and JAK1/STAT3 ( p  < 0.01). Moreover, ESOM and CANA preserved PI3K/Akt activity and prevented caspase-dependent apoptosis ( p  < 0.01). Additionally, the combination treatment showed synergistic hepatoprotective effects, demonstrated by significant improvements in all measured parameters. These findings suggested that ESOM and CANA had significant potential as therapeutic agents for alleviating MTX-induced hepatotoxicity and warranted further investigation in future research.

Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.

Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)—a bioactive polyphenolic compound—in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers.

Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl 4 induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-β induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl 4 induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl 4 in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.

Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2 −/− mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.

Purpose To review the current literature on suspected green tea-related hepatic reactions and to describe two new cases reported within the framework of the Italian surveillance system of natural health products. Results A literature search of publication between 1999 and October 2008 retrieved 34 cases of hepatitis. Histological examination of the liver revealed inflammatory reactions, cholestasis, occasional steatosis, and necrosis. A positive dechallenge was reported in 29 cases. There was one reported death. A positive rechallenge occurred in seven cases (20%). In the two new cases, the causality assessment was judged as “possible” according to the RUCAM score. Conclusions Our analysis of the published case reports suggests a causal association between green tea and liver damage. The hepatotoxicity is probably due to (-)-epigallocatechin gallate or its metabolites which, under particular conditions related to the patient’s metabolism, can induce oxidative stress in the liver. In a few cases, toxicity related to concomitant medications could also be involved.