Cause Of Drug-induced Liver Injury Research Articles

GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug-induced liver injury.

Antituberculosis (anti-TB) drugs are the most common cause of drug-induced liver injury (DILI). There are numerous studies revealing the associations between the polymorphisms of pharmacogenes and the risk of anti-TB DILI (ATDILI). In the present study, relevant studies regarding the pharmacogenes associated with ATDILI were systematically searched in PubMed and Scopus. A total of 24 genes associated with ATDILI were reported on and the top five reported genes in terms of frequency were revealed to be N-acetyltransferase 2, cytochrome P450 family 2 subfamily E member 1, glutathione S-transferases [glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1)] and solute carrier organic anion transporter family member 1B1. As ATDILI may be the result of direct and indirect interactions, the encoded proteins were further analysed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to observe the protein-protein interactions and the associations amongst these proteins. The results suggested that only GSTT1 and GSTM1 were central proteins associated with all the other analysed proteins. Therefore, the association between GSTT1 or GSTM1 and the risk of developing ATDILI were further analysed. The results revealed that a GSTM1 deletion genotype was significantly associated with risk of ATDILI [odds ratio (OR), 1.28; 95% confidence interval (CI), 1.08-1.51; P=0.004], whereas the GSTT1 deletion genotype and GSTM1/GSTT1 dual-deletion genotype were not significantly associated with risk of ATDILI. Subgroup analysis based on ethnicity was performed and the results demonstrated a significant association between GSTM1 and ATDILI in South Asian individuals (OR, 1.48; 95% CI, 1.12-1.95; P=0.005), which has not been reported previously, to the best of our knowledge. In conclusion, GSTM1 was associated with ATDILI in South Asian individuals.

Systematic review: ibuprofen-induced liver injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a leading cause of drug-induced liver injury (DILI) across the world. Ibuprofen is one of the most commonly used and safest NSAIDs, nevertheless reports on ibuprofen-induced hepatotoxicity are available. To analyse previously published information on ibuprofen-induced liver injury for a better characterisation of its phenotypic expression. A systematic search was performed and information on ibuprofen-induced liver injury included in case series and case reports, in terms of demographic, clinical, biochemical and outcome data, was analysed. Twenty-two idiosyncratic ibuprofen hepatotoxicity cases were identified in the literature, suggesting a very low prevalence of this type of DILI. These patients had a mean age of 31years and 55% were females. Mean cumulative dose of ibuprofen and time to onset were 30g and 12days, respectively. Hepatocellular injury was the most frequently involved liver injury pattern. Six cases developed vanishing bile duct syndrome. Full recovery occurred in 11 patients after a mean time of 14 weeks, whereas five cases evolved to acute liver failure leading to death/liver transplantation. When assessing potential hepatotoxicity cases, physicians should keep in mind that ibuprofen has been associated with hepatotoxicity in the literature. Ibuprofen-associated DILI presents commonly as hepatocellular damage after a short latency period. Published reports on ibuprofen hepatotoxicity leading to liver failure resulting in liver transplantation or death are available. However, due to the apparent low absolute risk of ibuprofen-induced liver complications, ibuprofen can be regarded as an efficacious and safe NSAID.

Drug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study

Antiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI. We attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital. We carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI. Five out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification. A significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.

A case of teriflunomide-induced hepatic injury: assessing causality using available rules

Teriflunomide, a pyrimidine synthesis inhibitor approved for treatment for the relapsing form of multiple sclerosis, has been deemed reasonably safe though hepatic toxicity is a rare serious adverse event. We report an uncommon case of a 48-year-old man who developed severe hepatotoxicity within a short time after initiation of teriflunomide treatment with resolution of signs and symptoms after drug discontinuation and concomitant treatment with cholestyramine. In this case, we provide a general framework regarding the assignment of causation in potential causes of drug-induced liver injury. The patient met the case definition of Hy’s law and his hepatotoxicity was assessed as causally related to teriflunomide using the Roussel Uclaf Causality Assessment Method (RUCAM).

Imaging-based vascular-related biomarkers for early detection of acetaminophen-induced liver injury.

Acetaminophen (APAP) is the foremost cause of drug-induced liver injury in the Western world. Most studies of APAP hepatotoxicity have focused on the hepatocellular injury, but current hepatocyte-related biomarkers have delayed presentation time and a lack of sensitivity. APAP overdose can induce hepatic microvascular congestion, which importantly precedes the injury of hepatocytes. However, the underlying molecular mechanisms remain unclear. It is imperative to discover and validate sensitive and specific translational biomarkers of APAP-induced liver injury.Methods: In this study, we assessed APAP toxicity in sinusoidal endothelial cells and hepatocytes in mice treated with overdose APAP at different time points. The underlying mechanisms of APAP overdose induced sinusoidal endothelial cell injury were investigated by RT2 Profiler PCR arrays. The impact of APAP overdose on endothelial cell function was assessed by pseudovessel formation of endothelial cells in 2D Matrigel and in vivo hepatic vascular integrity using multiphoton microscopy. Finally, the effects of APAP overdose on oxygen levels in the liver and hepatic microcirculation were evaluated by contrast enhanced ultrasonography. Potential imaging-based vascular-related markers for early detection of APAP induced liver injury were assessed.Results: Our study confirmed that hepatic endothelial cells are an early and direct target for APAP hepatotoxicity. ICAM1-related cellular adhesion pathways played a prominent role in APAP-induced endothelial cell injury, which was further validated in primary human sinusoidal endothelial cells and human livers after APAP overdose. APAP overdose impacted pseudovessel formation of endothelial cells and in vivo hepatic vascular integrity. Use of ultrasound to detect APAP-induced liver injury demonstrated that mean transit time, an imaging-based vascular-related biomarker, was more sensitive and precise for early detection of APAP hepatotoxicity and monitoring the treatment response in comparison with a conventional blood-based biomarker.Conclusion: Imaging-based vascular-related biomarkers can identify early and mild liver injury induced by APAP overdose. With further development, such biomarkers may improve the assessment of liver injury and the efficacy of clinical decision-making, which can be extended to other microvascular dysfunction of deep organs.

Green Tea Polyphenols Protect against Acetaminophen-Induced Liver Injury by Regulating the Drug Metabolizing Enzymes and Transporters.

Green tea polyphenols (GTPs) have been shown to exhibit diverse beneficial effects against a variety of diseases. Acetaminophen (APAP) overdose is one of the most frequent causes of drug-induced liver injury. In the current study, we aimed to investigate the protective effect of GTP on APAP-induced liver injury in mice and the underlying mechanisms involved. Male C57BL/6J mice were treated orally with different doses of GTP (37.5, 75, or 150 mg/kg) 4 h after APAP overdose (400 mg/kg) and continuously given every 8 h until sacrificed at 4, 12, 20, and 48 h after the first treatment of GTP. Survival rate and histological and biochemical assessments were performed to evaluate the APAP-induced liver injury. Protein expression of multiple drug metabolizing enzymes and transporters was measured to demonstrate the possible mechanisms involved. Our results revealed that administration of different doses of GTP significantly alleviated APAP-induced liver injury by improving the survival rate, hepatocellular necrosis, and ALT/AST/GSH levels after APAP overdose (400 mg/kg). The protein expression of APAP-induced drug transporters and metabolizing enzymes was mostly induced by GTP treatment, which was followed by reduction in drug transporters at the later time points. The current study collectively demonstrated that GTP protects against APAP-induced liver injury, possibly through regulating drug metabolizing enzymes and transporters after APAP overdose.

Etiology and Pattern of Drug Induced Liver Injury in a Tertiary Care Hospital of Nepal

Drug induced liver injury (DILI) is one of the common cause of liver toxicity. Most of the drugs used today are hepatotoxic. DILI accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. It is the single most common adverse drug reaction leading to a halt in the development of new medication by pharmaceutical company, failure of new drug to obtain regulatory approval, and withdrawal or restriction of existing drug from the market. The aim of this study is to evaluate common causes and patterns of DILI in our setting. Twenty-seven patients were enrolled in the study. Ant tubercular drugs were most common cause of DILI, accounting for 48.2%. Other common causes of DILI were paracetamol (14.8%) and NSAID’s (11.1%). The most common pattern of liver injury seen was mixed pattern which was present in63%, followed by cholestatic and hepatocellular pattern. Hence, we should be very careful while prescribing these frequently used drugs.

Curcumin and Selenium Prevent Lipopolysaccharide/Diclofenac-Induced Liver Injury by Suppressing Inflammation and Oxidative Stress.

Diclofenac (DCL), an anti-inflammatory drug used to reduce pain and inflammation, ranks in the top causes of drug-induced liver injury. The inflammatory stress induced by inflammagens is implicated in DCL-induced liver injury. Curcumin (CUR) and selenium (Se) possess anti-inflammatory effects; therefore, this study evaluated their protective potential against lipopolysaccharide (LPS)/DCL-induced liver injury. Rats received CUR and/or Se for 7 days followed by a single intravenous administration of LPS 2 h before a single injection of DCL and two other doses of CUR and/or Se 2 and 8 h after DCL. Administration of nontoxic doses of LPS and DCL resulted in liver damage evidenced by the significantly elevated liver function markers in serum. LPS/DCL-induced liver injury was confirmed by histological alterations, increased lipid peroxidation and nitric oxide, and diminished glutathione and superoxide dismutase. CUR and/or Se prevented liver injury, histological alterations, and oxidative stress and boosted antioxidant defenses in LPS/DCL-induced rats. In addition, CUR and/or Se reduced serum C-reactive protein, liver pro-inflammatory cytokines, and the expression of TLR4, NF-κB, JNK, and p38, and upregulated heme oxygenase-1 (HO-1). In conclusion, CUR and/or Se mitigated LPS/DCL-induced liver injury in rats by suppressing TLR4 signaling, inflammation, and oxidative stress and boosting HO-1 and other antioxidants. Therefore, CUR and Se can hinder the progression and severity of liver injury during acute inflammatory episodes.

Auriculatone Sulfate Effectively Protects Mice Against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) overdose is very common worldwide and has been widely recognized as the leading cause of drug-induced liver injury in the Western world. In our previous investigation, auriculatone, a natural product firstly obtained from Aster auriculatus, has demonstrated a potent protective effect against APAP-induced hepatotoxicity in HL-7702 cells. However, the poor water solubility and low bioavailability restrict its application. Auriculatone sulfate (AS) is a sulfated derivative of auriculatone with highly improved water-solubility. Hepatoprotective effects against APAP-induced liver injury (AILI) showed that intragastric pretreatment with AS at 50 mg/kg almost completely prevented mice against APAP-induced increases of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and ATPase. Histological results showed that AS could protect the liver tissue damage. In addition, AS pretreatment not only significantly retained hepatic malondialdehyde and the activities of glutathione, superoxide dismutase, and glutathione peroxidase at normal levels, but also markedly suppressed the increase of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels in mouse liver caused by overdose APAP. Immunohistochemical analysis showed that AS obviously attenuated the expression of CD45 and HNE in liver tissue. Further mechanisms of action investigation showed that inhibition of cytochrome P450 3A11 (CYP 3A11) and CYP2E1 enzymatic activities (but not that of CYP1A2) was responsible for APAP bioactivation. In conclusion, AS showed a hepatoprotective effect against AILI through alleviating oxidative stress and inflammation and inhibiting CYP-mediated APAP bioactivation. It may be an effective hepatoprotective agent for AILI and other forms of human liver disease.

2228 A Rare Report of Pantoprazole-Induced Acute Hepatocellular and Cholestatic Hepatitis

INTRODUCTION: Pantoprazole is a widely used proton pump inhibitor that is used to treat variety of acid related disorders. It is well tolerated with excellent safety profile. Mild transient elevations in serum aminotransferase can be seen with pantoprazole use that resolves without dose modification. Pantoprazole induced clinically apparent liver injury on the other hand is exceedingly rare. CASE DESCRIPTION/METHODS: A 47-year-old woman with no prior liver disease was referred to the hospital for acute hepatitis. She started pantoprazole 2 months prior to admission for gastritis. Patient had nausea, fatigue, abdominal pain, jaundice and dark urine 2 weeks after starting pantoprazole and stopped it a week prior to hospital admission. She denied alcohol use. Her current medications were levothyroxine, enalapril/hydrochlorothiazide and aspirin and no use of herbal supplements. Physical exam was notable for conjunctival icterus. Baseline liver enzymes were normal. Labs on admission were: AST 681 U/L (< 32 U/L), ALT 2100 U/L (< 36 U/L), total bilirubin 12.3 mg/dL (0.2-1.2 mg/dL), direct bilirubin 8.3 mg/dL (< 0.5 mg/dL), alkaline phosphatase 96 U/L (45-117 U/L) and INR 1.9 (0.8-1.2). Urine drug screen was negative for acetaminophen toxicity. Imaging excluded biliary obstruction and hepatic venous thrombosis. Laboratory investigations for viral and autoimmune hepatitis, wilson’s disease and hemochromatosis were negative. Liver biopsy (Figure 1) reported portal areas with edema and a minimal amount of inflammation composed of mixed lymphocytes, occasional eosinophils and neutrophils. The lobular parenchyma showed cholestasis with lymphocytic and neutrophilic inflammation. Patient noted improvement of symptoms with supportive care (Table 1). Two months after stopping pantoprazole, liver enzymes were normal. DISCUSSION: DILI (drug-induced liver injury) is a significant cause of acute hepatitis. To our knowledge, only 7 case reports of pantoprazole induced liver injury have been published. The timing of starting pantoprazole prior to acute hepatitis, negative serologies, and normalized liver enzymes after stopping suggests pantoprazole as the cause of DILI. Based on its pharmacokinetics, timeline and pattern of insult, an idiosyncratic reaction has been suggested as the mechanism for hepatotoxicity. We have described a rare case of acute mixed (hepatocellular and cholestatic) liver injury from pantoprazole use suggesting its consideration in the differential diagnosis of DILI.

Amoxicillin-clavulanate-induced Granulomatous Hepatitis: Case Report and Review of the Literature.

Amoxicillin-clavulanate (AC) is a common cause of drug-induced liver injury, either cholestatic or mixed with hepatitis pattern. Rarely, AC causes granulomatous hepatitis. We report a new case of AC-induced granulomatous hepatitis documented by liver biopsy, with complete resolution of any histological sequelae on a follow-up liver biopsy after AC was withdrawn.

Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration.

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury–acetaminophen (APAP)–in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury–the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.

Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality.

Drug-induced liver injury (DILI) is rare; however, it is one of the important causes of acute liver failure which results in significant morbidity or mortality. Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months or until normalization of liver tests. Causality assessment was done by applying the Roussel Uclaf Causality Assessment Method model. We collected data from 82 individuals diagnosed with DILI at our hospital from 2014 through 2015 (41 men; median age, 38 years). The most commonly implicated drugs were antitubercular therapy (ATT) (49%), antiepileptic drugs (12%), complementary and alternative medicine (CAM) in 10%, antiretroviral drugs (9%) and non-steroidal anti-inflammatory drugs (6%). 8 out of 13 deaths were liver related. Also, liver related mortality was significantly higher for ATT DILI (17.5%) vs. those without (2.4%) (P = 0.02). There was no significant difference in overall as well as liver related mortality in hepatocellular, cholestatic or mixed pattern of injury. Laboratory parameters at one week after discontinuation of drug predicted mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephalopathy, MELD (Model for end stage liver disease) score and alkaline phosphatase at one week, independently predicted mortality. DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence of jaundice, encephalopathy, MELD score and alkaline phosphatase at one week are independent predictors of mortality.

FRI-092-Metamizole as a leading cause of drug-induced liver injury

FRI-092-Metamizole as a leading cause of drug-induced liver injury

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China

We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n= 29,478) according to the Roussel Uclaf Causality Assessment Method. Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher thanthat reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

Lack of multidrug resistance-associated protein 4 (Mrp4) alters the kinetics of acetaminophen toxicity.

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver injury in humans and a common chemical model to investigate genetic determinants of susceptibility to drug-induced liver injury (DILI). Previous studies performed in our laboratory identified the efflux transporter multidrug resistance-associated protein 4 (Mrp4) as an inducible gene in the liver following toxic APAP exposure in both humans and rodents. In mice, blockade of hepatic Mrp4 induction following APAP administration increases susceptibility towards APAP hepatotoxicity. Collectively, these findings suggest that Mrp4 plays an important role in tolerance to APAP-induced liver injury. To further study the role of Mrp4 in APAP-induced hepatotoxicity, we treated 10–12 weeks old male wild type (WT, C57BL/6J) and Mrp4 knockout (Mrp4−/−) mice with APAP (400 mg/Kg in saline, i.p.) or vehicle. Liver injury endpoints and hepatic gene expression were analyzed at 12, 24 and 48 h post-APAP injections. Unexpectedly, the kinetics of histologically measured liver damage and plasma ALT revealed that Mrp4−/ mice had decreased ALT levels and hepatic necrosis compared to WT mice only at 12 h. Notably, hepatic non-protein sulfhydryl (NPSH) levels were increased in the APAP treated Mrp4−/− mice at intervals less than 24 h, consistent with the capability of Mrp4 to export glutathione. Further gene expression analysis revealed that hepatic drug metabolism genes were downregulated in Mrp4−/− mice at earlier time points post-APAP administration. However, despite significant decreases in endpoints of liver injury detected at an early time point after APAP treatment, these changes were not sustained at later time points as Mrp4−/− mice ultimately had hepatic toxicity at levels comparable to WT mice. In conclusion, our data indicate that lack of Mrp4 by itself in mice does not alter susceptibility to APAP toxicity.

Ginsenoside Rb1, A Major Saponin from Panax ginseng, Exerts Protective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice.

Acute liver injury (ALI) induced by acetaminophen (APAP) is the main cause of drug-induced liver injury. Previous reports indicated liver failure could be alleviated by saponins (ginsenosides) from Panax ginseng against APAP-induced inflammatory responses in vivo. However, validation towards ginsenoside Rb1 as a major and marker saponin may protect liver from APAP-induced ALI and its mechanisms are poorly elucidated. In this study, the protective effects and the latent mechanisms of Rb1 action against APAP-induced hepatotoxicity were investigated. Rb1 was administered orally with 10mg/kg and 20mg/kg daily for 1 week before a single injection of APAP (250mg/kg, i.p.) 1h after the last treatment of Rb1. Serum alanine/aspartate aminotransferases (ALT/AST), liver glutathione (GSH) depletion, as well as the inflammatory cytokines, such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were analyzed to indicate the underlying protective effects of Rb1 against APAP-induced hepatotoxicity with significant inflammatory responses. Histological examination further proved Rb1's protective effects. Importantly, Rb1 mitigated the changes in the phosphorylation of MAPK and PI3K/Akt, as well as its downstream factor NF-B. In conclusion, experimental data clearly demonstrated that Rb1 exhibited a remarkable liver protective effect against APAP-induced ALI, partly through regulating MAPK and PI3K/Akt signaling pathways-mediated inflammatory responses.

LIVER TRANSPLANTATION AND DEATH WITHIN 4 MONTHS OF SUSPECTED DRUG-INDUCED LIVER INJURY (DILI) FROM AMOXICILLIN

Introduction Antibiotic prescription is not without risk. We present a case of suspected Drug induced liver injury (DILI) secondary to amoxicillin. Case Description An 18-year-old African American male presents from an outside hospital for acute liver failure. Initially, he reports developing “yellow eyes” on day 5 of taking amoxicillin, which was prescribed by his primary care provider for sore throat and a positive rapid strep test. He is an athlete with no significant medical history or antibiotic use prior to this encounter. He does not drink alcohol, smoke or do illicit drugs. Extensive workup following the AASLD (American Association for Study of Liver Diseases) guidelines was unremarkable for biliary, autoimmune, infectious, genetic, obstructive, veno-occlusive, alcohol or salicylic acid-induced causes. Laboratory tests show a hepatocellular pattern without significant peripheral eosinophilia (AEC 110). The patient receives a liver transplant but has a hospital course complicated by bacteremia and multi-organ failure resulting in death. Discussion There is yet to be a reliable method to predict, diagnose, and risk assess DILI. The two most common causes of DILI are acetaminophen and amoxicillin-clavulanic acid. Amoxicillin alone is less likely to cause DILI, although it may, and it can be associated with a mixed hepatocellular/cholestatic picture. The chronologic association between initiation of antibiotic and the onset of liver injury is pertinent. Immediate hypersensitivity reactions are IgE mediated and can occur within 1 hour after last drug administration. Delayed reactions are often T lymphocyte specific and can occur more than 1 hour after the last drug administration.

Pazopanib-Induced Liver Injury: A Near TKO From a TKI

A 56 year old man with Renal Cell Carcinoma on Pazopanib was admitted with right upper quadrant (RUQ) abdominal pain and fatigue. He had no significant alcohol use. Vitals were normal, exam revealed scleral icterus, jaundice, and mild RUQ tenderness. Labs were notable for Total bilirubin 4.1 mg/dL, AST 770 U/L, ALT 909 U/L, and ALP 681 U/L. Viral markers for Hepatitis A, B, C, E and Cytomegalovirus (CMV) and autoimmune panel were negative. Serum ceruloplasmin level was 30mg/dl, ferritin 2365ng/ml, and transferrin saturation 65%. Ultrasound with liver doppler was unremarkable. Liver biopsy revealed severe lobular inflammation and portal expansion by lymphocytes, with admixed plasma cells and eosinophils. Stains for fibrosis, iron deposition, and alpha-1 antitrypsin globules were negative. IHC staining was negative for CMV and HSV antigens. He was diagnosed with drug-induced liver injury (DILI) from Pazopanib and started on ursodiol with tapering course of oral prednisone. Liver enzymes gradually improved and completely resolved by week 10.Pazopanib, a Tyrosine Kinase Inhibitor (TKI), is approved for the treatment of Renal Cell Carcinoma (RCC) and Soft Tissue Sarcomas (STS). It targets VEGF receptor and other kinases involved in tumor angiogenesis. The mechanism of TKI induced liver injury remains unclear. Mitochondrial toxicity, inhibition of glycolysis, and apoptosis has been proposed to be the mechanisms of hepatotoxicity. In our case, patient had a score of 7 on the Naranjo probability scale for adverse drug reaction, indicating that Pazopanib is the probable cause of DILI. Although hepatotoxicity with Pazopanib has been reported, only a single case report with accompanying biopsy has been reported in the literature. Both patients in the report had normal baseline liver function tests and significant AST and ALT elevation by week 6 after initiation. Liver biopsies in these patients revealed similar features. With increasing use of TKI agents in oncotherapy, one must be aware of the potential adverse effect of DILI from newer agents such as Pazopanib. The onset of DILI from Pazopanib ranges from 4-12 weeks after initiation. Majority of patients recover completely on drug discontinuation with normalization of liver function and enzymes as seen in our patient, however occasional fatalities have been reported. Thus monitoring liver enzymes on TKI therapies is imperative for early recognition of Pazopanib induced DILI and prompt discontinuation of the drug.

The changing epidemiology of liver diseases in the Asia-Pacific region.

This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.