Drug-related Liver Injury Research Articles

Clinical Characteristics and Outcomes of Patients With Antithyroid Drug-Related Liver Injury.

Antithyroid drugs (ATDs) are the cornerstone of hyperthyroidism management. Hepatotoxicity due to ATDs can range from mild transaminase elevation to liver transplantation requirement and mortality. The primary objective of the systematic review was to assess the clinical characteristics and outcomes of patients with drug induced liver injury (DILI) due to ATDs. We conducted a systematic review of PUBMED, SCOPUS, and EMBASE on characteristics and outcomes of adults (>18 years) with DILI due to ATDs. We defined DILI as bilirubin ≥2.5 mg/dL or international normalized ratio >1.5 with any rise in alanine aminotransferase (ALT), aminotransferase (AST), or alkaline phosphatase (ALP), or an elevation of ALT or AST >5 times or ALP >2 times the upper limit of normal without jaundice/coagulopathy. The review included 100 articles describing 271 patients; 148 (70.8%) were female (N = 209). Mean age was 42.9 ± 17.2 years. Graves' disease was the most common indication for ATDs. Carbimazole/methimazole (CBM/MMI) was the most common offending agent (55.7%). DILI pattern was hepatocellular in 41.8%, cholestatic in 41.3%, and mixed in 16.9%. Outcomes included death in 11.8%, liver transplantation in 6.4%, partial improvement in 2.2%, and complete resolution in 79.6% with a median time (IQR) to resolution of 45 (20-90) days. Patients in the propylthiouracil (PTU) group had higher initial bilirubin, initial AST, initial ALT, peak ALT, peak AST, severe and fatal DILI, liver transplantation, and mortality than CBM/MMI. Rechallenge of antithyroid medication was infrequently reported (n = 16) but was successful in 75%. DILI due to ATDs can present with different patterns and should prompt immediate drug discontinuation. Referral to a hepatologist should be considered if severe as transplantation is sometimes required. PTU-induced DILI may have worse outcomes than CBM/MMI.

Gut Microbiota and Drug-Related Liver Injury: Challenges and Perspectives

Drug-related liver injury (DILI) is increasing in the incidence of liver injury due to nonviral liver disease and has become a health problem that should not be underestimated. As a hot research topic in recent years, gut microbiota have been studied in various tumors, cardiovascular metabolic diseases, and human immunity. However, there is still a lack of research related to gut microbiota and DILI. It is known that they can influence each other through the regulation of the “gut-liver axis,” and the relationship between them and the possible mechanisms of action are still at the research stage. Human leukocyte antigen (HLA) gene polymorphisms are closely related to the development of DILI, and the gene can also affect changes in the composition of gut microbes. In this paper, we review the possible relationships and mechanisms between DILI and gut microbiota in order to provide new research directions for the prevention and treatment of DILI in the future. In the future, untargeted therapies using antibiotics, probiotics, or FMT will be replaced by personalised and precision medicine approaches, such as bioengineered bacterial strains or drugs that modulate specific bacterial enzymes and metabolic pathways.

Early diagnostic value of liver stiffness measurement in hepatic sinusoidal obstruction syndrome induced by hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT)-sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a clinical syndrome characterized by symptoms, such as right upper quadrant pain, jaundice, fluid retention, and hepatomegaly, and is caused by pre-treatment-related hepatotoxicity during the early stages after HSCT. Clinical diagnosis of HSCT-SOS is based on the revised Seattle or Baltimore standards. The revised standard by the European Society for Bone Marrow Transplantation in 2016 has good practicability and can be used in combination with these two standards. Eight studies have shown the value of liver stiffness measurement (LSM) in the early diagnosis of HSCT-SOS. Four studies investigated LSM specificity and sensitivity for the early diagnosis of HSCT-SOS. LSM can distinguish SOS from other post-HSCT complications, enabling a clear differential diagnosis. It has been shown that median LSM of patients with SOS is significantly higher than that of patients with other treatment-related liver complications (e.g., acute cholecystitis, cholangitis, antifungal drug-related liver injury, liver graft-versus-host disease, isolated liver biochemical changes, and fulminant Epstein Barr virus related hepatitis reactivation). Therefore, the above data confirmed the utility of LSM and strongly suggested that LSM improves the positive predictive value of the SOS diagnostic clinical score after allogeneic HSCT. Early diagnosis of SOS is beneficial in preventing severe HSCT complications.

P520: PHASE 1/2 STUDY OF SEL24/MEN1703, A FIRST-IN-CLASS DUAL PIM/FLT3 KINASE INHIBITOR, IN PATIENTS WITH IDH1/2-MUTATED ACUTE MYELOID LEUKEMIA: THE DIAMOND-01 TRIAL.

Background: Mutations in the FLT3 tyrosine kinase are the most frequent mutations that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, first-in-class, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3 of 8 IDHm patients responded. Aims: Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 patients with R/R IDHm AML. Methods: Patients with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety, and adverse events (AEs) were graded according to NCI CTCAE v4.03. The secondary endpoint was antileukemic activity including overall response rate (ORR). Results: As of 10 January 2022, 14 patients were enrolled in the IDHm cohort. Median age was 68 years (range 37–79). Four patients had AML secondary to myelodysplastic syndrome and 7 patients had intermediate cytogenetic risk. Median number of prior lines of treatment was 2 (range 1–3). Seven patients had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3-ITD were detected in 2 patients. Median duration of treatment was 2 cycles (range 1–8). Safety data (N=12) showed that serious treatment-emergent AEs (TEAEs; reported in ≥5% patients) were pneumonia (33%), skin infection, and clostridial gastroenteritis (8% each). These events were all unrelated to study drug. Drug-related TEAEs were liver injury and hyponatremia (8% each). The drug-related liver injury occurred in a patient who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10% patients) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 patients who completed ≥1 treatment cycle and had ≥1 postbaseline assessment or clear disease progression, ORR was 28.6%; 1 patient achieved a complete response with incomplete blood count recovery (CRi) at cycle 3 and underwent hematopoietic stem cell transplant, 1 patient had a partial response at cycle 4 (confirmed at cycle 7 and still on treatment), 4 had disease progression, and 1 discontinued for an AE (not drug related). Among the 7 remaining patients, 3 discontinued before completion of cycle 1 without progression or response, while 4 patients were ongoing and have not yet had any postbaseline assessment. Summary/Conclusion: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first-in-class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in patients with R/R IDHm AML. Updated results will be presented at the congress.

Phase 1/2 study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in patients with IDH1/2-mutated acute myeloid leukemia: The DIAMOND-01 trial.

7024 Background: Mutations in the FLT3 tyrosine kinase are the most frequent ones that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3/8 IDHm patients (pts) responded. Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 pts with R/R IDHm AML. Methods: Pts with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety; adverse events (AEs) were graded according to NCI-CTCAE v4.03. The secondary endpoint was anti-leukemic activity including overall response rates (ORR). Results: As of 10 Jan 2022, 14 pts were enrolled in the IDHm cohort. Median age was 68 years (range 37-79). Four pts had AML secondary to myelodysplastic syndrome and 7 pts had intermediate cytogenetic risk. The median number of prior lines was 2 (range 1-3). Seven pts had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3/ITD were detected in 2 pts. Median duration of treatment was 2 cycles (range 1-8). Safety data (N = 12) showed that serious treatment-emergent AEs (TEAEs; ≥5%) were pneumonia (33%), and skin infection and gastroenteritis clostridial (8% each). These were all unrelated to study drug. Drug-related TEAEs were liver injury, overdose, and hyponatremia (8% each). The drug-related liver injury occurred in a pt who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10%) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 pts who completed ≥1 treatment cycle and had ≥1 post-baseline assessment or clear disease progression, ORR was 28.6%; 1 pt achieved CRi at cycle (C) 3 and underwent hematopoietic stem cell transplant, 1 pt had PR at C4 (confirmed at C7 and still on treatment), 4 had disease progression, 1 discontinued for AE not drug-related. Among the 7 remaining pts, 3 discontinued before completion of C1 without progression or response, while 4 pts were ongoing and have not yet had any post-baseline assessment. Conclusions: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first in class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in pts with R/R IDHm AML. Updated results will be presented at the congress. Clinical trial information: NCT03008187.

A case report of drug-induced liver injury after tigecycline administration: histopathological evidence and a probable causality grading as assessed by the updated RUCAM diagnostic scale

BackgroundThere have been no reports of tigecycline-associated drug-related liver injury (DILI) identified by histopathological assistance and causal assessment method. We reported the histopathological manifestations for the first time and described tigecycline-associated liver injury’s pattern, severity, duration, and outcome.Case presentationA 68-year-old male with post-liver transplantation was given high-dose tigecycline intravenously (loading dose 200 mg, followed by 100 mg every 12 h) combined with polymyxin B (50,000 units by aerosol inhalation every 12 h) for hospital-acquired pneumonia caused by carbapenem-resistant Klebsiella pneumoniae. At the same time, tacrolimus was discontinued. Liver function was initially normal but started to decline on day 4 of tigecycline. Reducing the dose of tigecycline and resuming tacrolimus could not reverse the deterioration. Therefore, a liver puncture biopsy was performed for further diagnosis, with histopathological findings being cytotoxic injury. The updated RUCAM scale was used to evaluate the causal relationship between tigecycline and liver injury, with the result of 7 points indicating a “probable” causality grading. Methylprednisolone was initiated to treat DILI that was determined to be Grade 1 cholestatic injury. Total bilirubin and transaminase levels returned to normal on day 4 and 11 after tigecycline withdrawal, respectively. Monthly outpatient follow-up showed that the patient’s liver function stayed normal.ConclusionsThis case possessed a significant reference value for differential diagnosis and treatment prognosis of tigecycline-associated DILI. With early diagnosis and timely management, the tigecycline-associated DILI of this patient was successfully reversed.

Oral Fluoroquinolone Use and the Risk of Acute Liver Injury: A Nationwide Cohort Study.

BackgroundAntibiotics are considered to be among the most frequent causes of drug-related acute liver injury (ALI). Although many ALIs have mild and reversible clinical outcomes, there is substantial risk of severe reactions leading to acute liver failure, need for liver transplant, and death. Recent studies have raised concerns of hepatotoxic potential related to the use of fluoroquinolones.MethodsThis study examined the risk of ALI associated with oral fluoroquinolone treatment compared with amoxicillin (419 930 courses, propensity score matched 1:1). The information on drug use was collected from a national, registry-based cohort derived from all Swedish adults aged 40–85 years.ResultsDuring a follow-up period of 60 days, users of oral fluoroquinolones had a >2-fold risk of ALI compared to users of amoxicillin (hazard ratio, 2.32 [95% confidence interval {CI}, 1.01–5.35). The adjusted absolute risk difference for use of fluoroquinolones as compared to amoxicillin was 4.94 (95% CI, .04–16.3) per 1 million episodes.ConclusionsIn this propensity score–matched study, fluoroquinolone treatment was associated with an increased risk of ALI in the first 2 months after starting treatment.

Patients with cirrhosis during the COVID-19 pandemic: Current evidence and future perspectives.

The outbreak of coronavirus disease-2019 (COVID-19) has resulted in a global public health emergency. Patients with cirrhosis were deemed more susceptible to viral infection because of their dysregulated immune response. Similar to the general population, cirrhotic patients exhibit various degrees of COVID-19-related liver injury, which could be attributed to direct virus cytotoxicity, systemic immune system activation, drug-related liver injury, reactivation of pre-existing liver disease, and hypoxic hepatitis. The clinical symptoms in patients with cirrhosis and COVID-19 were similar to those in the general population with COVID-19, with a lower proportion of patients with gastrointestinal symptoms. Although respiratory failure is the predominant cause of mortality in cirrhotic patients with COVID-19, a significant proportion of them lack initial respiratory symptoms. Most evidence has shown that cirrhotic patients have relatively higher rates of morbidity and mortality associated with COVID-19. Advanced cirrhosis was also proposed as an independent factor affecting a poor prognosis and the need to consider COVID-19 palliative care. General measures implemented to prevent the transmission of the virus are also essential for cirrhotic patients, and they should also receive standard cirrhosis care with minimal interruptions. The efficacy of the available COVID-19 vaccines in cirrhotic patients still needs investigation.

Liraglutide-Induced Hepatotoxicity

A 52-year-old woman with a BMI of 31.2 kg/m2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug’s mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.

Epidemiological analysis of liver injury related to bone diseases

A total of 1 392 reports on liver injury associated adverse drug reaction(LI-ADR) related to bone diseases were retrospectively analyzed based on national ADR monitoring system [18.75% of the patients used traditional Chinese medicine(TCM) alone and 68.68% used Western medicine alone]. This kind of cases accounted for 2.5% of all drug-related liver injury adverse reactions, ranking top ten of all drug categories. The number of reported cases and the proportion of serious cases showed an increasing trend from 2012 to 2016. The average age of the patients was(54.2±15.8) years old, and there was little difference in overall gender(male-female 1.04∶1). However, the number of female patients with rheumatoid arthritis was significantly higher than that of male patients(male-female 1∶2.6), while the number of male patients with gout was significantly higher than that of female patients(male-female 7.16∶1). The overall prognosis was good, with the recovery and improvement rate of 85.27%. The time from medication to liver injury varied due to different medicines. The median time to liver injury was 27 days in TCM alone group, later than 11 days in Western me-dicine alone group(P<0.05). Drugs for bone diseases have been one of the important categories for clinical drug-induced liver injury, and the number of reported cases on liver injury caused by drugs for bone diseases is increasing, so we should pay close attention to the safe and rational use of them. The LI-ADRs of male and female were different due to their different diseases, and the latency of adverse reactions in TCM group was generally longer than that in Western medicine group. In clinical medication, liver function should be monitored according to different diseases and characteristics of drugs to prevent the risk of liver injury.

Liver Injury in Critically Ill and Non-critically Ill COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Background: Liver injury commonly occurs in patients with COVID-19. There is limited data describing the course of liver injury occurrence in patients with different disease severity, and the causes and risk factors are unknown. We aim to investigate the incidence, characteristics, risk factors, and clinical outcomes of liver injury in patients with COVID-19.Methods: This retrospective observational study was conducted in three hospitals (Zhejiang, China). From January 19, 2020 to February 20, 2020, patients confirmed with COVID-19 (≥18 years) and without liver injury were enrolled and divided into non-critically ill and critically ill groups. The incidence and characteristics of liver injury were compared between the two groups. Demographics, clinical characteristics, treatments, and treatment outcomes between patients with or without liver injury were compared within each group. The multivariable logistic regression model was used to explore the risk factors for liver injury.Results: The mean age of 131 enrolled patients was 51.2 years (standard deviation [SD]: 16.1 years), and 70 (53.4%) patients were male. A total of 76 patients developed liver injury (mild, 40.5%; moderate, 15.3%; severe, 2.3%) with a median occurrence time of 10.0 days. Critically ill patients had higher and earlier occurrence (81.5 vs. 51.9%, 12.0 vs. 5.0 days; p < 0.001), greater injury severity (p < 0.001), and slower recovery (50.0 vs. 61.1%) of liver function than non-critically ill patients. Multivariable regression showed that the number of concomitant medications (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.05–1.21) and the combination treatment of lopinavir/ritonavir and arbidol (OR: 3.58, 95% CI: 1.44–9.52) were risk factors for liver injury in non-critically ill patients. The metabolism of arbidol can be significantly inhibited by lopinavir/ritonavir in vitro (p < 0.005), which may be the underlying cause of drug-related liver injury. Liver injury was related to increased length of hospital stay (mean difference [MD]: 3.2, 95% CI: 1.3–5.2) and viral shedding duration (MD: 3.0, 95% CI: 1.0–4.9).Conclusions: Critically ill patients with COVID-19 suffered earlier occurrence, greater injury severity, and slower recovery from liver injury than non-critically ill patients. Drug factors were related to liver injury in non-critically ill patients. Liver injury was related to prolonged hospital stay and viral shedding duration in patients with COVID-19.Clinical Trial Registration: World Health Organization International Clinical Trials Registry Platform, ChiCTR2000030593. Registered March 8, 2020.

Etiological evaluation of the elevated transaminases in children

Objective: We aimed to determine the etiology of hypertransaminasemia in children, demonstrate the differences according to the age and evaluate course of transaminases.Method: We retrospectively analyzed the medical records of children who presented with elevated transaminase levels for at least 2 months, aged between 3 months and 18 years, for demographic features, laboratory, radiologic and histopathological findings.Results: Among total 292 children, 194 (66.4%) were male and 98 (33.6%) were female. The mean age was 6.5±5.4 years. The 45.9% of the children had no complaints at presentation. Majority of the patients had mildly elevated transaminases (81.6%). The most common etiology was non-alcoholic fatty liver disease (NAFLD) (25.7%). The NAFLD was more prevelant in patients older than 5 years-old (p<0.001). The second cause was infectious diseases (97.8% were viral infections) and more prevelant in patients younger than 2 years-old (p=0.043). In 34.1 % of the children, no overt cause of hypertransaminasemia was identified. The patients with unidentified etiology were significantly younger, but had higher mean aspartate aminotransferase (AST) levels than the patients in whom the etiology was identified (p= <0.0001, p=0.008 respectively). The normalization of transaminases was seen in 40.4% of the patients at mean 5.4±4.4 months. The shortest normalization time was observed in drug related liver injury (DILI) among all other etiologies (p=0.015). Conclusions: The most common cause of hypertransaminasemia in childhood were NAFLD and viral infections, which varies by age. A stepwise approachment to hypertransaminasemia leads to early diagnosis.

Development of a Computer-Assisted Adverse Drug Events Alarm and Assessment System for Hospital Inpatients in China.

Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China. Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert. Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%. An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions.

Development of a Computer-Assisted Adverse Drug Events Alarm and Assessment System for Hospital Inpatients in China

Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China. Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert. Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%. An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions.

Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial

BackgroundThere is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. MethodsIn this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). FindingsBetween Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)].After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort. InterpretationThis study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort. Funding SourceAMED.

From the Cover: Characterization of Isoniazid-Specific T-Cell Clones in Patients with anti-Tuberculosis Drug-Related Liver and Skin Injury.

Isoniazid, rifampicin, pyrazinamide, and ethambutol are commonly used for the treatment of tuberculosis. Drug exposure is occasionally associated with liver and/or skin injury. The aim of this study was to determine whether drug-specific T-cells are detectable in patients with adverse reactions and if so characterize the nature of the T-cell response. Peripheral blood mononuclear cells (PBMC) from 6 patients with anti-tuberculosis drug-related adverse reactions (4 liver, 2 skin) were used to detect drug-responsive T-lymphocytes. Positive lymphocyte transformation test and/or ELIspot results were observed with all 6 patients. Over 3400 T-cell clones were generated from isoniazid, rifampicin, pyrazinamide, or ethambutol-treated PBMC. CD4+ clones from all 3 patients were activated to proliferate and secrete cytotoxic mediators (granzyme B, perforin, FasL) and effector (IFN-γ, Il-13) and regulatory (Il-10) cytokines with isoniazid, but not rifampicin, pyrazinamide, or ethambutol. Il-17 was not detected, while only 1 clone secreted Il-22. Isoniazid-responsive clones were not activated with other anti-tuberculosis drugs or isonicotinic acid albumin adducts. Activation of the clones with isoniazid was MHC class II-restricted and dependent on antigen-presenting cells. Most clones were activated rapidly even in the presence of the enzyme inhibitor 1-aminobenzotriazole. However, a time-dependent pathway of activation involving auto-oxidation of isoniazid was also observed. The discovery of isoniazid-specific CD4+ T-cell clones in patients with liver and skin injury suggests that the adaptive immune system is involved in the pathogenesis of both forms of iatrogenic disease.

Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage.

Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients.

Protocolo diagnóstico de la colestasis intrahepática

IntroductionIntrahepatic cholestasis is characterized by impairment in the synthesis or secretion of biliary components into bile ducts. AetiopathogenesisIntrahepatic cholestasis in the adult can be primary (primary biliary cholangitis) or acquired (sepsis, total parenteral nutrition, drug-related liver injury…). In infants a number of inherited disorders are responsible for the dysfunction of transmembrane proteins in the hepatocyte that cause systemic accumulation of bile components. DiagnosisThe clinical manifestations of intrahepatic cholestasis are similar despite the etiology of cholestasis and comprise pruritus, fatigue, malnutrition and hypercholesterolemia. The diagnosis is based on a combination of biliary imaging, liver histology and autoimmunity testing.

Isoniazid‐specific T‐cell Responses in patients with anti‐tuberculosis drug related liver injury

Background A combination of isoniazid (INH), rifampicin, pyrazinamide and/or ethambutol (anti-tuberculosis drugs, ATDs) is commonly used for the treatment of tuberculosis. A significant clinical problem is that drug treatment is associated with mild elevations of liver enzymes that occasionally develop into severe liver injury. The culprit drug(s) and mechanistic basis of the reaction has not been defined. Thus, the aims of this study were to (1) explore whether drug-responsive T-lymphocytes were detectable in patients with ATD-related liver injury, (2) identify the drug(s) that activate T-cells and (3) characterize the nature of the T-cell response.

Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management.

Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.