Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification.

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 - 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 - 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. METHODS: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. RESULTS: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. CONCLUSIONS: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry.

BACKGROUND & AIMS: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. METHODS: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. RESULTS: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). CONCLUSIONS: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. LAY SUMMARY: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.

Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. METHODS: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n = 144), HEV antigen (Ag) and anti-HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in eight patients. RESULTS: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age was 61 years. Underlying hepatic diseases (OR = 23.4, P < .001) and AST peak >20 fold upper limit of normal (OR = 10.9, P = .002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). CONCLUSIONS: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.

Serious liver injury induced by Nimesulide: an international collaborative study.

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and Latin American DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a twofold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤ 15 days in 12 patients (21%) and one patient developed ALF within 7 days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.

Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports.

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review. Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re-challenge and chronic damage. This study underscores the challenge in causality assessment when multi-ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA.

Assessment of Serious Acute and Chronic Idiosyncratic Drug-Induced Liver Injury in Clinical Practice.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF) in developed countries. The extremely variable phenotype of DILI, both in presentation and in severity, is one of the distinctive characteristics of the disease and one of the major challenges that hepatologists face when assessing hepatotoxicity cases. A new Hy's law that more accurately predicts the risk of ALF related to DILI has been proposed and validated. Other prognostic scoring algorithms for the early identification of DILI patients who may go on to develop ALF have been developed as it is of most clinical relevance to stratify patients for closer monitoring. Recent data indicate that acute DILI often presents a more prolonged resolution or evolves into chronicity at a higher frequency than other forms of acute liver injury. Risk factors for chronicity, specific phenotypes, and histological features are discussed in this study. Biomarkers to predict DILI outcome are in need.

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

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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 ≥1000 mg (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. CONCLUSIONS: 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.

Hepatic Damage by Natural Remedies.

The rising burden of herbal and dietary supplement hepatotoxicity (HILI) is a growing concern in Western countries. The estimated incidence of HILI in well-designed prospective studies ranges from less than 1 to 3 individuals per 100,000 inhabitants/year. Herbal hepatotoxicity has a particular signature encompassing female predominance, hepatocellular type of damage with markedly elevated transaminases on presentation, more common unintentional rechallenge, and a greater risk of death/liver transplantation. Herbal hepatotoxicity recognition is particularly challenging for hepatologists because of the often hidden herbal consumption, difficulties in identifying the causative herbal component, and the possibility of contamination, adulteration, and misidentification, which preclude a proper adjudication and lead to inaccurate reporting of cases in scientific journals. Collaborative efforts to retrieve detailed phenotypic data and biological samples of patients with HILI would facilitate genomic and other molecular approaches for a better understanding of host risk factors and, hopefully, for biomarker identification.

Herbal and Dietary Supplement-Induced Liver Injuries in the Spanish DILI Registry.

BACKGROUND & AIMS: There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry. METHODS: We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement-associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid-containing products. RESULTS: Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement-induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37-fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement-induced liver injury progressed to acute liver failure in 6% of patients, compared with none of the cases of anabolic androgenic steroid-induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement-induced liver injury vs none of the patients with anabolic androgenic steroid-induced injury and 6% of patients with liver injury from conventional drugs. CONCLUSION: In an analysis of cases of herbal and dietary supplement-induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement-induced liver injury is more severe than other types of DILI and re-exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage.

Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: the influence of human leucocyte antigen alleles.

OBJECTIVES: Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients. METHODS: High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls. RESULTS: Compared with controls, HLA-B*08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc)=1.0E-11], C*07:01 (46 vs. 24%, P=6.4E-04/Pc=0.012), DRB1*03:01 (58 vs. 21.5%, P=5.0E-09/Pc=1.0E-07) and DQB1*02:01 (56 vs. 22%, P=6.8E-08/Pc=9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P=0.02/Pc=0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P=0.02/Pc=0.5; 13.8 vs. 4.7%, P=0.04/Pc=0.5). CONCLUSION: The presence of HLA alleles B*08:01, C*07:01, DRB1*03:01, DQB1*02:01 and possibly A*01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.

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

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases.

BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. METHODS: Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.

Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

The value of serum aspartate aminotransferase and gamma-glutamyl transpetidase as biomarkers in hepatotoxicity.

BACKGROUND & AIMS: The current definition of the pattern of liver injury in hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal at DILI onset. We aimed to explore the validity of using aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) as biomarkers of hepatocelullar and cholestatic damage, respectively, when calculating the R value. METHODS: Clinical, laboratory and histological data from 588 DILI episodes included in the Spanish DILI Registry were analyzed. Linear regression analysis was performed to establish the most appropriate cut-off points for hepatocellular and cholestatic patterns when calculating R with AST and GGT. RESULTS: The overall agreement between ALT/ALP and AST/ALP was 76%, with 96%, 61% and 41% agreement in the hepatocellular (R ≥ 5), cholestatic (R ≤ 2) and mixed groups respectively (P < 0.001). Classified by the causative drug, the agreement was higher (87-95%) among drug classes that mainly present with hepatocellular damage and lower (48-58%) for those in which cholestatic-mixed injury predominate (P < 0.001)). The overall agreement between ALT/ALP and ALT/GGT was weak (59%), except for in hepatocellular cases that showed a good agreement (94%) (P = 0.001). Pattern of injury according to liver histology demonstrated 65%, 68% and 47% agreement for ALT/ALP, AST/ALP and ALT/GGT ratios respectively. CONCLUSIONS: AST can reliably replace ALT when calculating pattern of liver injury in DILI, while GGT can only substitute ALP when the R value scores as hepatocellular. The biochemical signature of causative drugs does influence the validity of the ratios with AST or GGT.

[Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela]. / Reporte de casos de lesión hepática inducida por medicamentos en un centro hospitalario de referencia del estado Zulia, Venezuela.

Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.