Acute Drug-induced Liver Injury Research Articles

Drug-induced acute liver injury signal identified

Drug-induced acute liver injury signal identified

Signal Detection of Potentially Drug-Induced Acute Liver Injury in Children Using a Multi-Country Healthcare Database Network

Data mining in spontaneous reporting databases has shown that drug-induced liver injury is infrequently reported in children. Our objectives were to (i) identify drugs potentially associated with acute liver injury (ALI) in children and adolescents using electronic healthcare record (EHR) data; and (ii) to evaluate the significance and novelty of these associations. We identified potential cases of ALI during exposure to any prescribed/dispensed drug for individuals <18 years old from the EU-ADR network, which includes seven databases from three countries, covering the years 1996-2010. Several new methods for signal detection were applied to identify all statistically significant associations between drugs and ALI. A drug was considered statistically significantly associated with ALI, using all other time as a reference category, if the 95% CI lower band of the relative risk was >1 and in the presence of at least three exposed cases of ALI. Potentially new signals were distinguished from already known associations concerning ALI (whether in adults and/or in the paediatric population) through manual review of published literature and drug product labels. The study population comprised 4,838,146 individuals aged <18 years, who contributed an overall 25,575,132 person-years of follow-up. Within this population, we identified 1,015 potential cases of ALI. Overall, 20 positive drug-ALI associations were detected. The associations between ALI and domperidone, flunisolide and human insulin were considered as potentially new signals. Citalopram and cetirizine have been previously described as hepatotoxic in adults but not in children, while all remaining associations were already known in both adults and children. Data mining of multiple EHR databases for signal detection confirmed known associations between ALI and several drugs, and identified some potentially new signals in children that require further investigation through formal epidemiologic studies. This study shows that EHRs may complement traditional spontaneous reporting systems for signal detection and strengthening.

Bicalutamide-induced hepatotoxicity: A rare adverse effect

Patient: Male, 81Final Diagnosis: Prostate cancerSymptoms: Anorexia • dark urine • joundice • letargyMedication: CasodexClinical Procedure: —Specialty: OncologyObjective:Adverse events of drug therapyBackground:Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature.Case Report:An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days.Conclusions:While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. ConclusionsAcute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

Clinical analysis of 230 cases of drug-induced liver injury

Objective To review the clinical features of acute drug-induced liver injury. Methods The clinical data of 230 patients with acute drug-induced liver injury admitted to Beijing Ditan Hospital from October 2005 to May 2011 were retrospectively analyzed. Results In 230 patients, more than 60% had symptoms of fatigue, anorexia, jaundice and liver damage presenting LT, AST, ALP and TBIL changes. The hepatocellular injury type accounted for 80.4% (185/230), cholestatic type accounted 11.7% (27/230) and mixed type accounted for 7.8% (18/230). Chinese herbal medicine or Chinese patent medicine was the most common cause of drug-induced liver injury (55.2%), followed by anti-TB drugs (9.6%) and other anti-bacterial drugs (5.2%). There were 218 cases (94.7%) with favorable prognosis and 12 cases (5.3%) with poor prognosis, including 4 aggravating cases discharged against medical advance and 8 deaths. Conclusion The lack of gold standard for the diagnosis of drug-induced liver injury may easily lead to misdiagnosis. Chinese Traditional medicine, anti-TB drugs and other anti-microbial drugs are main causes of drug-induced liver injury. Early detection and timely treatment are important for the management of drug-induced liver injury. Key words: Retrospective studies; Drug-induced liver injury; Clinical features

Are We Closer to Finding Biomarkers for Identifying Acute Drug-Induced Liver Injury?

Over recent years, there has been a considerable effort to identify and develop new biomarkers of acute drug-induced liver injury (DILI). It is clear that the development and qualification of sensitive and specific hepatic biomarkers that permit quantitative assessment of the translation between preclinical and clinical studies is urgently required. The potential for novel biomarkers to provide enhanced understanding of the fundamental mechanisms that result in clinical DILI is becoming increasingly recognized. Furthermore, there is a great need for mechanistic biomarkers that can bridge between preclinical models and the clinical situation of DILI. These will therefore enable us to understand the human relevance of predictive models of acute DILI and the interpretation of data generated from such models. Such biomarkers would not only accelerate the pace of drug development but also provide a point-of-care test to enable patient and/or DILI-specific treatment stratification once a new drug is licensed. Currently, the number of putative biomarkers that hold some clinical utility is low, mainly because less attention has been placed on the science of drug safety compared with drug efficacy [1].

Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate

Herbal and dietary supplements are widely used as measures to improve and preserve health and well-being. Among the bestselling preparations are dietary supplement containing glucosamine and chondroitine sulfate taken to improve symptoms of osteoarthritis. We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate. Response to steroids was favorable and resulted in complete remission of the patient. Diagnostic work-up of the case revealed no other possible cause of liver injury, and causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) resulted in a possible causal relationship between intake of glucosamine and chondroitine sulfate and the adverse hepatic reaction. The present case recalls that products containing glucosamine and chondroitine sulfate can occasionally cause acute liver injury mimicking autoimmune hepatitis, and reminds of the potential dangers of compounds with poor efficacy and ill-defined safety records.

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

Real Time Identification of Drug-Induced Liver Injury (DILI) through Daily Screening of ALT Results: A Prospective Pilot Cohort Study

ObjectiveIdentification of drug-induced liver disease (DILI) is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening.DesignWe prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN) and notified the designated hepatologists, who then went to the patients' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium).ResultsDuring the 24-week period of the standard strategy, 12 (0.04%) patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498%) [odds ratio vs. standard = 12.1 (95% CI, 3.9–32.3); P<0.0001] were identified with possible DILI, and 5 were included in the protocol.ConclusionA simple strategy based on the daily analysis of cases with ALT >3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy.This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70.

Serum microRNA biomarkers for drug-induced liver injury.

New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation with existing biomarkers of liver injury and patient outcomes in acetaminophen toxicity, mechanisms of cellular microRNA release, and their potential advantages over current clinical biomarkers of DILI.

Herbal hepatoxicity from Chinese skullcap: A case report

The use of herbal supplements has increased considerably over the last decade. We report a case of an elderly woman who began taking Move Free Advanced for arthritis, which in addition to glucosamine and chondroitin, contained two herbal ingredients, Chinese skullcap and Black Catechu. Our patient presented with significant cholestasis and hepatitis which significantly improved after discontinuation of the supplement. Since neither the patient nor the treating physician recognized this supplement as a potential hepatotoxin, she resumed taking the supplement and again suffered from considerable hepatotoxicity. Liver biopsy at that time was consistent with acute drug induced liver injury. She, once again, recovered after discontinuation of the supplement. Review of the literature confirms that Chinese skullcap has been implicated as a possible hepatotoxic agent which was demonstrated in this case.

Clinical metabolomics using 1 H NMR spectral data in acute drug-induced liver injury

Clinical metabolomics using 1 H NMR spectral data in acute drug-induced liver injury

Predicting and preventing acute drug-induced liver injury: what's new in 2010?

Importance of the field: The field of drug-induced liver injury (DILI) continues to expand in terms of global registries and with new agents added every year. Given the need to improve on our current methods of preclinical testing and monitoring for DILI during both clinical trials and in the post-approval setting, there is increasing research aimed at better understanding why injury occurs and who is most susceptible. To this end, the active pursuit of biomarkers that will predict injury prior to its occurrence and genetic testing that can identify individuals at risk of DILI continue to be at the forefront.Areas covered in this review: While alanine aminotransferase (ALT) testing remains the workhorse of biochemical monitoring, it only detects hepatic injury after it has occurred and, therefore, is not a true predictor. The utility and shortcomings of ALT and other liver tests are reviewed along with a synopsis of several other candidate biomarkers that are being studied. In addition, we review the recent data supporting testing for genetic predisposition to DILI and how identifying clinical risk factors may translate into better means for preventing DILI.What the reader will gain: We update the basis on which age and gender are considered risk factors for DILI, and review the latest reports detailing the association of several candidate genes and the development of DILI in a susceptible patient. Human leukocyte antigen-B*5701 is closely linked to the hypersensitivity reaction seen with abacavir, and such screening has been successfully incorporated into HIV treatment around the globe and offers the promise that testing for other genetic markers will soon become a routine part of clinical practice. At present, candidate genes conferring specific susceptibility to DILI have been identified for a relatively few agents (e.g., flucloxacillin, amoxicillin–clavulanate, ximelagatran and isoniazid), but many more are under study. Preventing DILI often comes down to avoiding the use of potentially hepatotoxic drugs in certain situations, and we review the clinical scenarios in which this is most relevant.Take home message: Given the number and range of studies aimed at identifying predictors of DILI, the focus of this review is to summarize what we consider to be the most relevant new information published on the topics of clinical and genetic factors that predispose to DILI, the use of biomarkers as predictors of acute DILI, along with advances in prevention strategies.

Clinical significance of liver function and autoantibodies in patients with acute or chronic drug-induced liver injury

To investigate the clinical significance of liver function and autoantibodies in patients with acute or chronic drug-induced liver injury. 51 patients with drug-induced liver injury were divided into acute drug induced liver injury group and chronic drug induced liver injury group, liver function and autoantibodies were compared between these two groups. There was no significant difference (P more than 0.05) in alanine aminotransferase [(412.1+/-387.5) U/L and (376.0+/-319.7) U/L], aspartate aminotransferase [(352.5+/-457.9) U/L and (198.8+/-142.7) U/L], total bilirubin [(109.7+/-104.80)micromol/L and(102.4+/-135.7)micromol/L], direct bilirubin [(66.4+/-73.3)micromol/L and (61.2+/-72.1)micromol/L], alkaline phosphatase [(133.4+/-50.1) U/L and (147.4+/-97.3) U/L], gamma-glutamyltransferase [(139.9+/-134.1) U/L and (180.6+/-227.9) U/L], and albumin [(41.3+/-4.9) g/L and (39.8+/-5.3)g/L] between these two groups, however, the level of globulin [(25.1+/-5.3) g/L and (28.6+/-5.1) g/L] was significantly different between these two groups (P less than 0.05). The titers of Anti-nuclear antibody (ANA) and smooth muscle antibody (SMA) were less than or equal to 1:320 in patients with acute drug induced liver injury. The titers of ANA, antimitochondrial antibody (AMA), and SMA were more than or equal to 1:320 in most of the patients with chronic drug induced liver injury. Liver function has no value in the diagnosis of acute or chronic drug induced liver injury. High titer autoantibodies are found in patients with chronic drug induced liver injury.

Acute liver injury induced by weight-loss herbal supplements.

We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

Drug-induced hepatotoxicity test using γ-glutamylcysteine synthetase knockdown rat

Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem for drug development. It is generally known that DILI is mainly caused by hepatic glutathione (GSH) depletion. The glutathione S-transferase activity of rodent is higher than that of human, which could make the prediction of DILI more difficult. Recently, we reported that an experimental rat model of GSH-depletion displayed high susceptibility to acetaminophen-induced hepatotoxicity. To deplete GSH, we used an adenovirus vector with short hairpin RNA against gamma-glutamylcysteine synthetase heavy chain subunit (AdGCSh-shRNA). In this study, we further investigated the usefulness of this rat model for determining drug-induced sensitive acute and subacute toxicity. Rats were administered diclofenac and flutamide which have been reported as idiosyncratic hepatotoxic drugs. In the acute (6 or 24h) or subacute (7 days) toxicity tests, rats were administered the drugs once or once a day for a week, respectively. Plasma biochemical markers for hepatotoxicity were measured. The 6 and 24h toxicity test of diclofenac, and the 24h and 7 days toxicity tests of flutamide showed significant ALT elevations. Additionally, the 24h toxicity test of flutamide showed a slight bilirubin elevation, and histological hepatotoxicity. The 7 days toxicity test of flutamide also demonstrated histological hepatotoxicity. In conclusion, this rat model would contribute to evaluating acute and subacute DILI in preclinical drug development.

The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice

Chronic evolution after drug-induced liver injury (DILI) has been reported. How often this leads to liver-related morbidity and mortality is unexplored. Patients who survived DILI and concomitant jaundice reported to the Swedish Adverse Drug Reaction Advisory Committee (1970-2004) were linked to the Swedish Hospital Discharge and Cause of Death Registries. Among the 712 survivors, 27 could not be retrieved but 685 patients could be linked to the registries, 392 females (57.2%) and 293 males (42.8%) median age 58 (41-74), a mean follow-up of 10 years. A total of 23/685 (3.4%) patients had been hospitalized for liver disease and 5 had liver-related mortality. Eight patients developed cirrhosis (7 decompensated, 5 died), 5 had "cryptogenic" cirrhosis in which DILI might have played a role in this development. Duration of therapy before DILI was longer in patients with liver-related morbidity/mortality (135+/-31 days vs. 53+/-3; p<0.0001). Autoimmune hepatitis developed in 5/23 (22%), all of female gender after a mean of 5.8 years. Development of clinically important liver disease after severe DILI associated with jaundice is rare after acute DILI. However decompensated "cryptogenic" cirrhosis developed in some patients with fatal outcome in which DILI might have played a role in this development.

Using controlled clinical trials to learn more about acute drug-induced liver injury

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI.

The current state of serum biomarkers of hepatotoxicity

The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione- S-transferase alpha (GSTα) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early clinical trials.

A prospective study of acute drug‐induced liver injury in patients suffering from non‐alcoholic fatty liver disease

Liver damage due to facultative hepatotoxins is scarcely foreseeable. We evaluated the prevalence of acute drug-induced liver injury (DILI) in a specific setting, assessing eventual interactions with pre-existing hepatic illnesses. The research was carried out in an Italian tertiary care hospital, by analyzing 248 patients with non-advanced liver disease, divided into two well-matched groups: 174 patients (median age 53, 94 females) with hepatitis C virus-related chronic hepatitis; and 74 (median age 55, 39 females) with non-alcoholic fatty liver disease (NAFLD). Six patients (2.4% of the whole population) belonging to the NAFLD group (chi(2)-test, P = 0.004) suffered from acute hepatoxicity related to the following drugs, that is antihypertensive, acting on platelet aggregation, antimicrobial, non-steroidal anti-inflammatory and proton pump inhibitor. The NAFLD presence was an independent risk factor in determining drug-related acute hepatitis, with an odds ratio of 3.95 (95% confidence intervals: 11.48-1.35). Central obesity was relevant in every patient with acute toxicity. Alcohol consumption and drug association did not influence the acute drug-induced liver damage. NAFLD conveys a nearly fourfold increase of DILI risk in obese middle-aged patients. NAFLD, characterized by mitochondrial dysfunction, could predispose to drug-induced hepatotoxicity that probably shares the same pathophysiological mechanism.