Drug-induced Liver Injury Onset Research Articles

Comparison of the prognostic models for mortality in idiosyncratic drug-induced liver injury.

Several models have been proposed to predict acute liver failure/death in patients with drug-induced liver injury (DILI), but the predictive performances of them have not been systematically compared. We aim to compare the current models for their predictive potency of mortality at DILI onset. DILI patients hospitalized at both Beijing Friendship Hospital and the Fifth Medical Center of PLA General Hospital were categorized into death/liver transplantation (LT) or survival without LT group. Predictive potency of 28-day, 90-day, 6-month and 12-month death/LT outcomes of Hy's Law, nHy's Law, Robles-Diaz Model, drug-induced liver toxicity (DrILTox ALF) Score, Model for End-stage Liver Disease (MELD) Score, and Ghabril Model was compared by Delong method. A total of 6.3% (83/1314) patients died or received LT within 12months after DILI onset. The area under receiver operating characteristic of Hy's Law, nHy's Law, and Robles-Diaz Model was all lower than 0.750 for the prediction of within 12months' mortality. DrILTox ALF Score, MELD Score and Ghabril Model showed better predictive potency of 28-day [0.896 (0.878-0.912), 0.934 (0.919-0.947), 0.935 (0.921-0.948), respectively], 90-day [0.883 (0.864-0.899), 0.951 (0.938-0.962), 0.952 (0.939-0.963), respectively], 6-month [0.820 (0.799-0.841), 0.905 (0.888-0.921) and 0.908 (0.891-0.923), respectively] and 12-month [0.801 (0.779-0.823), 0.882 (0.863-0.899) and 0.885 (0.866-0.902), respectively] mortality. Despite the difference of clinical characteristics and implicated-drug categories between China and industrialized countries, we demonstrate that MELD Score and Ghabril Model have the best predictive performance in the prediction of mortality within 12months after DILI onset.

Alanine Aminotransferase and Bilirubin Dynamic Evolution Pattern as a Novel Model for the Prediction of Acute Liver Failure in Drug-Induced Liver Injury.

Aims: To develop, optimize, and validate a novel model using alanine aminotransferase (ALT) and total bilirubin (TB) dynamic evolution patterns in predicting acute liver failure (ALF) in drug-induced liver injury (DILI) patients. Methods: The demographics, clinical data, liver biopsy, and outcomes of DILI patients were collected from two hospitals. According to the dynamic evolution of ALT and TB after DILI onset, the enrolled patients were divided into ALT-mono-peak, TB-mono-peak, double-overlap-peak, and double-separate-peak (DSP) patterns and compared. Logistic regression was used to develop this predictive model in both discovery and validation cohorts. Results: The proportion of ALF was significantly higher in patients with the DSP pattern than in the ALT-mono-peak pattern and DOP pattern (10.0 vs. 0.0% vs. 1.8%,p < 0.05). The area under receiver operating characteristic curve (AUROC) of the DSP pattern model was 0.720 (95% CI: 0.682–0.756) in the discovery cohort and 0.828 (95% CI: 0.788–0.864) in the validation cohort in predicting ALF, being further improved by combining with international normalized ratio (INR) and alkaline phosphatase (ALP) (AUROC in the discovery cohort: 0.899; validation cohort: 0.958). Histopathologically, patients with the DSP pattern exhibited a predominantly cholestatic hepatitis pattern (75.0%, p < 0.05) with a higher degree of necrosis (29.2%, p = 0.084). Conclusion: DILI patients with the DSP pattern are more likely to progress to ALF. The predictive potency of the model for ALF can be improved by incorporating INR and ALP. This novel model allows for better identification of high-risk DILI patients, enabling timely measures to be instituted for better outcome.

Liver Injury with Nintedanib: A Pharmacovigilance-Pharmacokinetic Appraisal.

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration’s Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15–7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis.

From the Editor’s Desk...

From the Editor’s Desk...

Value of liver biopsy in the diagnosis of drug-induced liver injury

The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Drug-Induced Liver Injury Due To Losartan.

Drug-induced liver injury (DILI) is a challenging diagnosis since a wide variety of medicines can cause adverse reactions. Losartan is an angiotensin II receptor antagonist (ARA-II) approved for the treatment of arterial hypertension. The most common adverse effects are fatigue, anaemia, weakness and cough. An increase in transaminases has been reported with less frequency (<2% of cases). Although the mechanism is not fully understood, DILI onset is usually within 1–8 weeks of therapy, and hepatic enzymology usually normalizes 2–4 months after drug suspension. The authors present the case of a 66-year-old male patient with a medical history of arterial hypertension and a prior hospitalization (4 years previously) for drug-induced hepatitis, which, at the time, was attributed to a dietary supplement. Four years later, because of new onset of hypertension, losartan was reintroduced. After 3 weeks, the patient was admitted to the emergency department with complaints of acute abdominal pain associated with asthenia, nausea and increased abdominal volume that had first developed 8 days previously. After exclusion of other causes, DILI associated with losartan was assumed. This is a very rare adverse effect since only seven cases have been described in the literature.LEARNING POINTSToxic hepatitis due to losartan is very rare, despite widespread use of the drug.A high index of suspicion for drug-induced liver injury (DILI) should be maintained while other diagnoses are carefully excluded.Monitoring the use of the offending drug is crucial, since DILI recurrence is associated with worse prognosis.

Predicting Antituberculosis Drug-Induced Liver Injury Using an Interpretable Machine Learning Method: Model Development and Validation Study.

BackgroundTuberculosis (TB) is a pandemic, being one of the top 10 causes of death and the main cause of death from a single source of infection. Drug-induced liver injury (DILI) is the most common and serious side effect during the treatment of TB.ObjectiveWe aim to predict the status of liver injury in patients with TB at the clinical treatment stage.MethodsWe designed an interpretable prediction model based on the XGBoost algorithm and identified the most robust and meaningful predictors of the risk of TB-DILI on the basis of clinical data extracted from the Hospital Information System of Shenzhen Nanshan Center for Chronic Disease Control from 2014 to 2019.ResultsIn total, 757 patients were included, and 287 (38%) had developed TB-DILI. Based on values of relative importance and area under the receiver operating characteristic curve, machine learning tools selected patients’ most recent alanine transaminase levels, average rate of change of patients’ last 2 measures of alanine transaminase levels, cumulative dose of pyrazinamide, and cumulative dose of ethambutol as the best predictors for assessing the risk of TB-DILI. In the validation data set, the model had a precision of 90%, recall of 74%, classification accuracy of 76%, and balanced error rate of 77% in predicting cases of TB-DILI. The area under the receiver operating characteristic curve score upon 10-fold cross-validation was 0.912 (95% CI 0.890-0.935). In addition, the model provided warnings of high risk for patients in advance of DILI onset for a median of 15 (IQR 7.3-27.5) days.ConclusionsOur model shows high accuracy and interpretability in predicting cases of TB-DILI, which can provide useful information to clinicians to adjust the medication regimen and avoid more serious liver injury in patients.

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Although most drug-induced liver injury (DILI) cases resolve after the offending medication is discontinued, time to recovery varies among patients, with 6 -12% developing a chronic disease. Herein, we investigated clinical factors and drug properties as potential risk determinants that influence the time course for DILI recovery and developed a model to predict its trajectory. We applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated using 257 cases from the Spanish DILI Registry and 191 cases from the LiverTox database. Higher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by 6 months was 0.46 (95% CI 0.26-0.61) for the high-risk group and 0.93 (95% CI 0.58-0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified bythe model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner. The trajectory of biochemical recovery from DILI is predicted by the extent of drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when a significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow-up. In this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in 2 independent cohorts. Our findings offer important insights into the factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those for whom a delayed recovery is predicted.

A High Serum Level of Taurocholic Acid Is Correlated With the Severity and Resolution of Drug-induced Liver Injury

Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 (ABCB11) gene and expression of its product, ABCB11 (also called BSEP). We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n=100; healthy controls) and patients with chronic hepatitis B (n=105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP was analyzed by immunohistochemistry in liver biopsy specimens. Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71-0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids. In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids.

Risk factors for acute liver failure among inpatients with anti-tuberculosis drug-induced liver injury.

ObjectiveTo analyze the clinical and laboratory features and determine the predictors of acute liver failure (ALF) among inpatients with anti-tuberculosis (TB) drug-induced liver injury (DILI).MethodPatients diagnosed with anti-TB DILI from 2010 to 2016 at The First Affiliated Hospital of Zhejiang University were retrospectively included in this study. Demographic and clinical data were collected by reviewing electronic medical records.ResultsAmong 155 inpatients with anti-TB DILI, 55 (35.48%) developed ALF, with an overall mortality of 9.68%. The median time to DILI onset was significantly longer in the ALF compared with the non-ALF group (51 versus 24 days). Eighty-three patients (53.55%) developed DILI (53.55%) within the first month of anti-TB treatment, and 60% of ALF cases occurred within 2 months. Multivariable models for ALF incorporating aspartate aminotransferase, total bilirubin, platelets, white blood cell count, and pre-existing hepatitis yielded a concordance (C-statistic) of 98.93%.ConclusionsThe results of this study suggest that approximately half of all cases of DILI occur within the first month, while 60% of ALF cases occur within 2 months. Elevated total bilirubin, aspartate aminotransferase, white blood cell count, pre-existing hepatitis, and low platelet count are independent risk factors for the development of anti-TB drug-induced ALF.

The diagnosis and management of idiosyncratic drug-induced liver injury.

Drug-induced liver injury (DILI) is an uncommon but important cause of liver disease that can arise after exposure to a multitude of drugs and herbal and dietary supplements. The severity of idiosyncratic DILI varies from mild serum aminotransferase elevations to the development of severe liver injury that can progress to acute liver failure resulting in death or liver transplantation within days of DILI onset. Chronic liver injury that persists for more than 6months after DILI onset is also becoming increasingly recognized in up to 20% of DILI patients. Host demographic (age, gender, race), clinical and laboratory features at DILI onset have been associated with the severity and outcome of liver injury in DILI patients. In addition to cessation of the suspect drug, other medical interventions including the use of N-acetylcysteine and corticosteroids in selected patients have shown some clinical benefit, but additional prospective studies are needed. A number of promising diagnostic, prognostic and mechanistic serum and genetic biomarkers may help improve our understanding of the pathogenesis and treatment of idiosyncratic DILI.

Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a Critically Appraised Topic.

Many physicians monitor liver function tests during terbinafine therapy. To evaluate the symptoms of published cases of terbinafine-associated severe drug-induced liver injury (DILI) to assess the utility of laboratory monitoring. We based our search on the LiverTox database of the National Institutes of Health, but we also searched both PubMed and Embase. In addition, we hand searched the references of the papers we found. All reports of patients with DILI on terbinafine and with reported clinical symptoms, or absence thereof, were evaluated. Two independent reviewers (J.A. and O.N.K.) assessed articles for eligibility of inclusion, and collected and evaluated the data. Thirty-eight papers fulfilled the inclusion criteria, with reports of 69 symptomatic patients. The mean duration of terbinafine treatment until onset of symptoms was 30·2 days (range 5-84). Symptoms in order of frequency were jaundice, flu-like symptoms, dark urine and pruritus. Patients experienced symptoms for a mean and median of 14·8 and 16 days, respectively (range 0-42) until seeking medical attention. Patients who had DILI were symptomatic, usually with jaundice, abdominal pain and general malaise, but also with severe pruritus. No asymptomatic patient was identified through laboratory screening. The timeline of DILI onset varies significantly, but most cases occur between 4 and 6 weeks. There was no time point at which monitoring was meaningful, and we do not recommend monitoring of liver function tests on terbinafine; however, patients should be advised to discontinue treatment and look for medical care when symptoms of DILI occur.

Drug-induced liver injury, mortality, and liver transplantation: is it reasonable to use a global introspection causality assessment?

Drug-induced liver injury (DILI) is a challenging topic in hepatology, with high expectations on studies bringing additional data in support of disease characterization. At least since 2005 it has been documented that a majority but not all patients with DILI recover from their disease following drug cessation. Indeed, a fatality rate around 10% is expected among patients who were studied for the first 6 months. In 2017, this knowledge stimulated Hayashi et al . (1) to analyze the fatality rate of DILI patients within two years after DILI onset. With a fatality rate of 9.8%, the online study under discussion showed similar results (1) and confirmed data on the first six months from two large European registries in 2005 (2,3). These two pioneering reports were based on DILI cases from Spain (2) and Sweden (3). Both groups used Roussel Uclaf Causality Assessment Method (RUCAM) (4,5) to validly and objectively assess causality (2,3). With conclusions based on results using global introspection, the study under discussion provides data raising questions (1). These focus on causality assessment methods of DILI cases and point out other aspects of interest that merit consideration.

Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor

Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

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.

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.

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.

The long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years. Subjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit. Amongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) or an alkaline phosphatase >ULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs. 43.7 years, P=0.01) and more likely to have a cholestatic lab profile at DILI onset (54 vs. 20%, P<0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 physical summary scores at DILI onset and throughout follow-up compared with the resolvers (P<0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis. In all, 75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression.

Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition

The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1′,6-(OH)2 BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites.

Protective effect of Th22 cells and intrahepatic IL-22 in drug induced hepatocellular injury

Th22 cells regulate host immunity against pathogenic invasion, including protecting host against chronic hepatitis B; however, the relationship between drug induced liver injury (DILI) and Th22/Th17 cells is still unclear. We investigated the role of Th22 cells in DILI development. The frequencies of peripheral Th22/Th17/Th1 cells and intrahepatic IL-22/IL-17 production from DILI, non-DILI liver diseases, and healthy controls were examined. Plasma IL-22/IL-17 and the related cytokines were determined in DILI patients at week 0 (defined as the occurrence of liver injury within 7days), 4 and 24. Multivariable stepwise logistic regression was applied to explore the associations between various factors and recovery of DILI. The frequencies of Th22/Th17 cells were significantly higher in DILI onset patients than HC. Significant increase of Th22 cells and the related cytokines levels was observed in DILI with hepatocellular injury type. There was a positive correlation between intrahepatic IL-22 level and liver regeneration. Plasma IL-22 level was higher in DILI patients with improved liver function than unimproved function. Multivariable analysis showed that the odds ratio (OR) of plasma IL-22 at 4weeks was 1.054 [95% confidence interval (CI), 1.012, 1.124]. Increased peripheral and intrahepatic IL-22-secreting cells are detected in DILI. Th22 and its related cytokines might be hepato-protective, which might provide new perspective for understanding the immunopathogenesis of DILI. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.