Drug-Induced Liver Injury Network Research Articles

Drug-Induced Liver Injury: Highlights of the Recent Literature.

Drug-induced liver injury (DILI), herbal-induced liver injury, and herbal and dietary supplement (HDS)-induced liver injury are an important aspect of drug safety. Knowledge regarding responsible drugs, mechanisms, risk factors, and the diagnostic tools to detect liver injury have continued to grow in the past year. This review highlights what we considered the most significant publications from among more than 1800 articles relating to liver injury from medications, herbal products, and dietary supplements in 2017 and 2018. The US Drug-Induced Liver Injury Network (DILIN) prospective study highlighted several areas of ongoing study, including the potential utility of human leukocyte antigens and microRNAs as DILI risk factors and new data on racial differences, the role of alcohol consumption, factors associated with prognosis, and updates on the clinical signatures of autoimmune DILI, thiopurines, and HDS agents. Novel data were also generated from the Spanish and Latin American DILI registries as well as from Chinese and Korean case series. A few new agents causing DILI were added to the growing list in the past 2years, including sodium-glucose co-transporter-2 inhibitors, as were new aspects of chemotherapy-associated liver injury. A number of cases reported previously described hepatotoxins confirmed via the Roussel Uclaf Causality Assessment Method (RUCAM; e.g., norethisterone, methylprednisolone, glatiramer acetate) and/or the DILIN method (e.g., celecoxib, dimethyl fumarate). Additionally, much work centered on elucidating the pathophysiology of DILI, including the importance of bile salt export pumps and immune-mediated mechanisms. Finally, it must be noted that, while hundreds of new studies described DILI in 2017-2018, the quality of such reports must always be addressed. Björnsson reminds us to remain very critical of the data when addressing the future utility of a study, which is why it is so important to adhere to a standardized method such as RUCAM when determining DILI causality. While drug-induced hepatotoxicity remains a diagnosis of exclusion, the diverse array of publications that appeared in 2017 and 2018 provided important advances in our understanding of DILI, paving the way for our improved ability to make a more definitive diagnosis and risk assessment.

Critically Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network Criteria.

Background: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, effect of weight-based fluconazole dosing on liver injury is unknown. Furthermore, no studies have systematically applied the Drug-Induced Liver Injury Network (DILIN) Criteria to identify patients who may have drug-induced liver injury in an intensive care unit (ICU) setting. Objective: This study evaluated how often patients met DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Methods: This dual-center, retrospective cohort study was performed in hospitalized critically ill fluconazole recipients. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after discontinuation using DILIN criteria. The primary objective was to evaluate the number of patients meeting DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Secondary objectives were to evaluate incidence of patients meeting DILIN criteria in patients with renal dysfunction, cirrhosis, septic shock, or those receiving a loading dose. Results: Of 248 patients included, 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. In patients receiving <6 mg/kg of fluconazole, 55% (110/199) met DILIN criteria versus 46.9% (23/49) in the ⩾6 mg/kg cohort (P = .20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. Weight-based fluconazole dose and creatinine clearance <50 mL/min were not independent risk factors for meeting DILIN criteria. However, 77.3% of patients with cirrhosis met DILIN criteria (OR 4.84 [95% confidence interval, CI, 2.61-9.28]) and 76.3% with septic shock met DILIN criteria (OR 4.56 [95% CI, 2.44-8.88]). Conclusion: Weight-based fluconazole dosing did not affect the number of critically ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically ill patients.

The influence of drug properties and host factors on delayed onset of symptoms in drug-induced liver injury.

Most patients with drug-induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two-tier regression-based model was used to assess host/drug interactions affecting the probability of delayed onset. Antibacterial and anti-inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4-32.2, P=0.0003), daily dose ≥1000mg (OR: 2.77, 95% CI: 1.3-6.1, P=0.0063) and the absence of pre-existing conditions in a patient (OR: 2.55, 95% CI: 1.3-4.9, P=0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N=131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre-existing cardiac diseases. This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.

The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine

Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01. Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform. All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03. Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians. A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.

Drug-Induced Liver Injury in Children

Drug-induced liver injury (DILI) is relatively rare among children but can cause substantial morbidity and mortality. Here, we summarize the literature on pediatric DILI including a focus on commonly used classes of drugs. The incidence of pediatric DILI remains poorly defined. Antimicrobials and antiepileptic medications are the most commonly reported causes of pediatric idiosyncratic DILI in the US DILI network (DILIN) experience. DILI among children being treated for cancer appears to be underreported, and recent literature clearly implicates newer classes of agents such as tumor necrosis factor-α inhibitors as potentially hepatotoxic. Many drugs trigger signature patterns of DILI; autoimmune hepatitis secondary to minocycline is an example. DILI should be suspected whenever a child presents with evidence of liver injury. Familiarity with established patterns of DILI secondary to specific agents can facilitate recognition of cases. Active reporting of cases by clinicians to registries such as US DILIN remains critical to a continuing understanding of the causes and risk factors of DILI among children.

Sclerosing Cholangitis–Like Changes on Magnetic Resonance Cholangiography in Patients With Drug Induced Liver Injury

Drug-induced liver injury can lead to changes of the biliary tree that resemble sclerosing cholangitis. These changes can be seen on magnetic resonance cholangiopancreatography. Idiosyncratic drug-induced liver injury (DILI) has a variable presentation including cholestatic liver injury,1 in which case magnetic resonance imaging (MRI) is often performed to exclude pancreaticobiliary causes of obstruction. Sclerosing cholangitis (SC)-like changes on imaging have been described anecdotally with DILI.2,3 A recent study of 25 consecutive, unselected DILI patients found that 10% had SC-like changes on magnetic resonance cholangiopancreatography (MRCP).4 The aim of the current study was to identify the clinical features of patients enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) prospective study who had SC-like changes on MRCP.

Heavy Consumption of Alcohol is Not Associated With Worse Outcomes in Patients With Idiosyncratic Drug-induced Liver Injury Compared to Non-Drinkers

The relationship between alcohol consumption and idiosyncratic drug-induced liver injury (DILI) is not well understood. We investigated the relationship between heavy consumption of alcohol and characteristics and outcomes of patients with DILI enrolled in the Drug-induced Liver Injury Network (DILIN) prospective study. We collected data from 1198 individuals with definite, highly likely, or probable DILI enrolled in the DILIN study from September 2004 through April 2016. At enrollment, all participants were asked about alcohol consumption; those with any alcohol consumption during previous 12 months were asked to complete the Skinner questionnaire to assess drinking history. Heavy consumption of alcohol was defined as more than 3 drinks, on average, per day by men or more than 2 drinks, on average, per day by women. Of the 601 persons who reported consuming at least 1 alcoholic drink in the preceding 12 months, 348 completed the Skinner questionnaire and 80 reported heavy consumption of alcohol. Heavy drinkers were younger (average age, 42 years) than non-drinkers (average age, 49 years) and a higher proportion were men (63% of heavy drinkers vs 35% of nondrinkers) (P< .01 for each comparison). Anabolic steroids were the most common cause of DILI among heavy drinkers (in 13% vs 2% in non-drinkers) (P < .001). Heavy drinkers had significantly higher peak serum levels of alanine aminotransferase (1323 U/L) than non-drinkers (754 U/L) (P = .02) and higher levels of bilirubin (16.1 mg/dL vs 12.7 mg/dL in non-drinkers) (P = .03) but there was no significant difference in liver-related death or liver transplantation between heavy drinkers (occurred in 10%) vs non-drinkers (occurred in 6%) (P = .18). In an analysis of data from the DILIN, we found anabolic steroids to be the most common cause of DILI in individuals who are heavy consumers of alcohol. Compared to non-drinkers, DILI was not associated with a greater proportion of liver-related deaths or liver transplantation in heavy drinkers.

Identification and Characterization of Fenofibrate-Induced Liver Injury.

Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended. The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate. All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed. Among 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37-61) years, and latency to onset was short (5-8weeks) in 4 patients but more prolonged (18-56weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA-A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2. Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.

Looking to the Future of Drug-Induced Liver Injury: An Interview With Paul B Watkins

Paul Watkins talks to Francesca Lake, Head of Open Access Publishing: Paul is The Howard Q Ferguson Professor in the Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill (UNC, NC, USA), and an expert in drug safety and drug-induced liver injury (DILI). Since its formation in 2009, he has been the director of the University of North Carolina Institute for Drug Safety Science. He is also Director of the DILI-sim Initiative and Chairman of the Board of Directors for the spin-off company, DILIsym Services, Inc. He is chair of the steering and genetics committees for the US Drug-Induced Liver Injury Network supported by the NIH and has been the recipient of a number of awards.

High Prevalence of Ibuprofen Drug-Induced Liver Injury in Spanish and Latin-American Registries

High Prevalence of Ibuprofen Drug-Induced Liver Injury in Spanish and Latin-American Registries

The Incidence of Drug- and Herbal and Dietary Supplement-Induced Liver Injury: Preliminary Findings from Gastroenterologist-Based Surveillance in the Population of the State of Delaware.

The population-based incidence rate of drug-induced liver injury (DILI) in the USA is not known. The Drug-Induced Liver Injury Network (DILIN) accrues cases of hepatotoxicity due to medications and herbal and dietary supplements (HDS) from limited geographical areas. The current analysis was an ancillary study of DILIN aimed at determining the annual incidence of DILI in the USA on a population basis, through surveillance in the state of Delaware. At the outset of the study, there were 41 gastroenterologists in the state of Delaware and all agreed to participate in surveillance for DILI, which comprised active reporting of suspected cases to the DILIN. The gastroenterologists underwent training in the diagnosis of DILI and were provided with DILIN inclusion criteria. Only cases that met the DILIN laboratory inclusion criteria in 2014 were included in the incidence calculation, and these patients were invited to participate in the DILIN Prospective Study. The number of suspected cases that met inclusion criteria served as the numerator and the 2014 Delaware adult population as the denominator. During 2014, 23 patients were identified by the surveillance network, 20 of whom met DILIN laboratory inclusion criteria, leading to an incidence of 2.7 cases of DILI per 100,000 adult residents [95% confidence interval (CI) 1.5-3.9 per 100,000]. Fourteen subjects agreed to participate in the DILIN; six declined. Among enrolled cases, the mean age was 51years, 57% were women, and 71% were white. Eight cases were attributed to antibiotics (36%) and other drugs (21%) and six to HDS (43%). The pattern of injury was hepatocellular in all HDS cases, but only 50% of conventional drug cases (p=0.05), which more commonly presented with eosinophilia (p=0.47) and higher alkaline phosphatase levels (p=0.05). Half of patients were jaundiced, none developed liver failure, and all recovered without the need for transplantation. Prospective, gastroenterologist-based surveillance for suspected DILI in Delaware yielded an incidence of 2.7 cases per 100,000 adults in 2014; this is the first prospective estimate of DILI for the USA. Because surveillance was limited to subspecialists, the actual incidence of DILI is likely to be higher. These findings provide a benchmark statistic for the epidemiology of DILI in the United States, to be refined with expansion of the surveillance period.

Causality assessment for liver injury attributable to dietary supplements.

Watch a video presentation of this article Watch the interview with the author Dietary supplements (DS) have been used by Americans with remarkable consistency over the past several decades. Data from the National Health and Nutrition Examination Survey 2003 to 2006 revealed that approximately 50% of all Americans and 70% of adults aged ≥71 years used DS during the reporting period.1 DS are nonprescribed products intended to supplement the diet. They include vitamins, minerals, amino acids, and other botanicals.2 Although the use of DS remains ubiquitous, their true impact, whether beneficial or deleterious, has been difficult to define. The potential for liver injury from DS is irrefutable; however, the accuracy of diagnosis of attributable liver injury is confounded by limitations in causality assessment. The incidence of drug-induced liver injury (DILI) caused by DS remains unknown. Population-based studies have attempted to address this issue. In 2013, a study based on the Icelandic population revealed an incidence of DILI of 19.1 per 100,000 inhabitants per year; DS was the second most common cause for DILI.3 The first US population-based estimate revealed an incidence rate of 2.7 DILI cases per 100,000 adults.4 This estimate was determined by a 2014 prospective surveillance program for DILI conducted through gastroenterologists practicing in the state of Delaware. Notably, Delaware has a demographic composition closely mirroring that of the overall US population. Given the limitation to subspecialists, the true incidence of DILI is likely higher. Supplements was the second most common cause for injury, corroborating findings from the Drug Induced Liver Injury Network (DILIN).5 Although there appears to be an association between DS and DILI, their ill effects are not limited solely to the liver. An estimated 23,000 emergency department visits in the United States each year are attributed to adverse events related to DS.6 Adverse events ranged from cardiac symptoms to pill-induced dysphagia, with weight-loss products implicated in more than half of adverse events among patients 20 to 34 years of age. DILI can be a difficult diagnosis to establish because it is largely a diagnosis of exclusion. However, assessment tools have been developed in an effort to evaluate objectively the likelihood that liver injury is due to a drug. These tools have also been applied to the assessment of liver injury caused by DS. The Roussel Uclaf Causality Assessment Model (RUCAM) is commonly used in research and serves as a validated causality algorithm (Table 1).7, 8 However, this approach is not without its limitations for DS, because it was originally developed for assessing injury caused by medications. In the United States, structured expert opinion has been widely regarded as the gold standard for assessing causality and arguably may be superior to the RUCAM when applied to DS. Specifically, three of the seven RUCAM domains can be confounded by nuances unique to DS. First, the RUCAM has a limited period of ascertainment of 90 days. It is possible that a culprit DS could have been consumed for a much longer period, but changed composition, thus leading to a more toxic ingredient or mixture. Second, the risk factors for liver injury caused by DS may be different from those for drugs. For example, the patterns of use or associated behaviors surrounding use of DS may contribute to toxicity. Third, previous information on hepatotoxicity may be limited. Thus, there may be limited recognition of a product's capacity for injury or a specific injury pattern. In addition, the RUCAM does not take into account the possibility that DS adulteration, contamination, or mislabeling could account for injury. In Hong Kong, a toxicology analysis of 26 weight-loss products that were associated with adverse events (liver failure requiring transplant in one patient) was performed.9 The majority of products (15) were adulterated with analogues of sibutramine and fenfluramine. Although a causal association between the unlabeled ingredients and injury is not firm, their presence and known toxic potential raise valid concern.10 The association between DILI and DS has now long been recognized. However, there are shortcomings to the RUCAM that confound the accuracy of causality assessment and in making the association more confident. Implicating a DS depends on determining the potential toxicity of individual ingredients, or combinations thereof. Therefore, further efforts must be made to develop an assessment approach that can include chemical analysis of products, followed by validation of its hepatotoxic potential.

Development of a modified lymphocyte transformation test for diagnosing drug-induced liver injury associated with an adaptive immune response

Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH.

Drug-induced liver injury: Do we know everything?

Interest in drug-induced liver injury (DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of LiverTox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.

Azathioprine and 6-Mercaptopurine-induced Liver Injury: Clinical Features and Outcomes.

The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.

Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance.

Drug induced liver injury (DILI) is challenging because of the lack of biomarkers to predict mortality. Our aim was to describe miRNA changes in sera of subjects with acute idiosyncratic DILI and determine if levels of miRNAs were associated with 6month mortality. Clinical data and sera were collected from subjects enrolled in the Drug Induced Liver Injury Network prospective study. miRNAs were isolated from serum obtained from 78 subjects within 2weeks of acute DILI and followed up for 6months or longer. miRNAs were compared to 40 normal controls and 6month survivors vs non-survivors. The mean age of the DILI cohort was 48years, and 55% were female. Eleven (14.1%) subjects died, 10 within 6months of DILI onset, 5 (45%) liver related. Lower levels of miRNAs-122, -4463 and -4270 were associated with death within 6months (P<.05). None of the subjects with miRNA-122 greater than the median value died within 6months for a sensitivity of 100% and specificity of 57%. In subjects with a serum albumin <2.8g/dL and miR-122<7.89 RFU the sensitivity, specificity, positive and negative predictive values for death within 6months were 100%, 57%, 38% and 100% respectively. Serum miRNA-122 combined with albumin accurately identified subjects who died within 6months of drug induced liver injury. If confirmed prospectively, miRNA-122 and albumin may be useful in identifying patients at high risk for mortality or liver transplantation.

422PD - Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome

Telotristat etiprate (TE) is an oral tryptophan hydroxylase inhibitor in development for the treatment of carcinoid syndrome (CS). During the placebo-controlled, 12-week double-blind treatment (DBT) periods of 2 Phase 3 studies, TELESTAR and TELECAST, TE significantly reduced bowel movement (BM) frequency compared to placebo. Objective: To examine the safety of TE vs placebo, a combined analysis of safety data from the DBT periods of TELESTAR and TELECAST was performed. 211 patients (pts) with CS were randomly assigned (1:1:1) to placebo or TE 250 mg or 500 mg, each given 3x/day (tid). At entry, pts on stable-dose long-acting somatostatin analog (SSA) therapy had ≥4 (TELESTAR) or <4 (TELECAST) BMs/day, while pts not on SSAs had ≥4 BMs/day (TELECAST). Antidiarrheals and short-acting rescue SSAs were allowed. Treatment-emergent adverse event (TEAE), serious adverse event (SAE), and adverse event of special interest (AESI) data were pooled. AESIs related to depression, hepatic enzyme elevation, and gastrointestinal (GI) symptoms were identified by prespecified preferred terms. 71 pts on placebo and 70 pts each on TE 250 mg or 500 mg tid were analyzed. At entry, 47% of pts were female, all pts had metastatic neuroendocrine tumors with mean disease duration of 7 yrs, mean BM frequency was 5.7 (TELESTAR) and 2.5 (TELECAST) BMs/day, and mean urinary 5-hydroxyindoleacetic acid was 84 mg/day. DBT period completion rates were similar between TE (88%) and placebo (87%) pts, as were incidences of SAEs and treatment withdrawal due to TEAE. Hepatic enzyme elevations were no greater than Drug-Induced Liver Injury Network Grade 1 (mild; on a scale up to 5). Slightly higher rates of nausea, constipation, and depression were reported with TE. There were no serious AESIs related to depression. Integrated safety analyses of placebo-controlled data support the proposed use of TE for the treatment of CS in patients receiving SSA therapy.Tabled 1TE# of pts with:Placebo n = 71250 mg tid n = 70500 mg tid n = 70≥1 TEAE606263≥1 SAE12810Death311Drug withdrawal due to TEAE12159AESIs- Depression related558- Hepatic enzymes0108- Any GI303232- Nausea9916- Vomiting536- Constipation245 Open table in a new tab

Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury.

Drug-induced liver injury (DILI) has features similar to those of other liver diseases including autoimmune hepatitis (AIH). We aimed to characterize the clinical and autoimmune features of liver injury caused by nitrofurantoin, minocycline, methyldopa, or hydralazine. We analyzed data from 88 cases of DILI attributed to nitrofurantoin, minocycline, methyldopa, or hydralazine included in the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. Sera were collected from patients at baseline and follow-up examination and tested for levels of immunoglobulin G (IgG), antibodies to nuclear antigen (ANA), smooth muscle (SMA), and soluble liver antigen (SLA). An autoimmune score was derived on the basisof increases in levels of IgG, ANA, SMA, and SLA (assigned values of 0, 1+, or 2+). AIH-associated HLA-DRB1*03:01 and HLA-DRB1*04:01 allele frequencies were compared with those of the general population (controls). Of the 88 cases, 80 were women (91%), 74% had hepatocellular injury, and 25% had severeinjury. At the onset of DILI, 39% of cases had increased levels of IgG, 72% had increased levels of ANA, 60% had increased levels of SMA, and none had increases in SLA. A phenotype of autoimmunity (autoimmune score ≥2) was observed in 82% of cases attributed to nitrofurantoin and 73% of cases attributed to minocycline (73%) but only 55% of cases attributed to methyldopa and 43% of cases attributed to hydralazine (P= .16 for nitrofurantoin and minocycline vs methyldopa and hydralazine). We observed a decrease in numbers of serum samples positive for ANA (P= .01) or SMA (P < .001) and in autoimmune scores (P < .001) between DILI onset and follow-up. Similar percentages of patients with DILI had HLA-DRB1*03:01 (15%) and HLA-DRB1*04:01 (9%) as controls (12% and 9%, respectively). In analysis of data from the DILIN prospective study, we found that most cases of DILI attributed to nitrofurantoin or minocycline and about half of cases that were due to methyldopa and hydralazine have a phenotype of autoimmunity similar to AIH. These features decrease with recovery ofthe injury and are not associated with the typical HLA alleles found in patients with idiopathic AIH.

Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK(®) Weight Loss Products: Results from the DILIN Prospective Study.

Herbal and dietary supplements (HDS) have been increasingly recognized as a cause for acute liver injury (Navarro et al. Hepatology 60(4):1399-1408, 2014; Bailey et al. J Nutr 141:261-266, 2011). HDS products frequently contain numerous ingredients, and are marketed under various product names. A perusal of marketed weight loss products indicates that green tea extract (GTE) is a common ingredient in many. We aimed to describe the course and outcome of six patients who developed liver injury attributed to SLIMQUICK(®) weight loss products. Patients with suspected drug-induced liver injury were enrolled in a prospective study of the Drug-Induced Liver Injury Network (DILIN) and causality was assessed by a panel of hepatologists. During the period under study, 6 of 1091 cases of liver injury were attributed to a SLIMQUICK(®) product and were assigned causality scores of probable, highly likely, or definite. Six cases of acute liver injury attributed to SLIMQUICK(®) products were enrolled in the DILIN prospective study between 2007 and 2011. All were women aged 22 to 58years. Two had a normal body weight and four were mildly obese (body mass index 22.9-32.2kg/m(2)). All were taking SLIMQUICK(®) products for weight loss and no patient reported prior use. Laboratory tests revealed a hepatocellular pattern of injury, with initial alanine aminotransferase (ALT) levels above 1000U/L in all but one patient. Three patients were hospitalized and one underwent successful liver transplantation. No patients died of liver injury. GTE and/or its component catechins were listed among the ingredients for five of the six products. SLIMQUICK(®) products can lead to severe acute hepatocellular liver injury, which may result in transplantation. Given the frequency of GTE as a component in weight loss products, this ingredient should be studied further as a possible cause for liver injury.

Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series.

Herbal and dietary supplement (HDS) hepatotoxicity is increasingly being reported in the USA. This case series describes the presenting clinical features and outcomes of seven patients with liver injury attributed to OxyELITE Pro enrolled in the Drug-Induced Liver Injury Network (DILIN) study. The 6-month outcomes of patients with hepatotoxicity attributed to OxyELITE Pro enrolled in the DILIN prospective registry between 2004 and 2015 are presented. Six of the seven patients (86%) presented in 2013 with symptoms of hepatitis and acute hepatocellular injury. The median duration of OxyELITE Pro use was 18weeks (range 5-102weeks). Median age was 36years (range 28-62), 86% were female, and 43% were Asian. One patient had rash, none had eosinophilia, and three had antinuclear antibody reactivity. The median peak ALT was 2242U/L, alkaline phosphatase 284U/L and bilirubin 15.0mg/dL. Six patients (86%) were hospitalized, three developed acute liver failure and two underwent liver transplantation. DILIN causality scores for OxyELITE Pro were definite in 1, highly likely in 3, probable in 2, and possible in 1. Four of the five patients without liver transplant recovered completely within 6months, while one patient had mild residual ALT elevations. Seven cases of severe acute hepatocellular injury attributed to OxyELITE Pro are reported. These results reinforce the need to assess for HDS supplement use in patients presenting with unexplained acute hepatitis and point to the need for additional regulatory oversight of HDS products.