Raúl Andrade - Academia.edu (original) (raw)
Papers by Raúl Andrade
Nature Reviews Disease Primers, Aug 22, 2019
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs... more Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.
Annals of Hepatology, Sep 1, 2021
Hepatology, 2022
Diseases (NIDDK) under grants: U24-DK065176 (Duke), U01-DK065201 (UNC), U01-54 DK065184 (Michigan... more Diseases (NIDDK) under grants: U24-DK065176 (Duke), U01-DK065201 (UNC), U01-54 DK065184 (Michigan), U01-DK065211 (Indiana), U01DK065193 (UConn), U01-DK065238 55 (UCSF/CPMC), U01-DK083023 (UTSW), U01-DK083027 (Einstein), U01-DK082992 (Mayo), 56 U01-DK083020 (USC), U01-DK100928 (Mount Sinai). Additional support is provided by CTSA 57 grants: UL1 RR025761 (Indiana), UL1TR000083 (UNC), UL1 RR024134 (UPenn), UL1 58 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and by the Intramural
Biomedicines, 2021
Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury... more Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI. Methods: We analyzed the activation profile (CD69, CD25, and HLA-DR) and natural killer group 2 member D (NKG2D) on iNKT cells, and CD4/CD8 T cells in peripheral blood mononuclear cells from NAFLD, with or without significant liver fibrosis, and DILI patients. Results: There was an increase in iNKT cells in NAFLD patients compared to DILI or control subjects. Regarding the cellular activation profile, NAFLD with significant liver fibrosis (F ≥ 2) displayed higher levels of CD69+iNKT cells compared to NAFLD with none or mild liver fibrosis (F ≤ 1) and control patients. CD69+iNKT positively correlated with insulin resistance, aspartate aminotransferase (AST) level, liver fibrosis-4 index (...
Gastroenterology, 2018
Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liv... more Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liver Injury
Journal of Clinical Medicine, 2021
Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the li... more Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Altho...
Posters, 2021
Conclusion We have identified and characterized a rare causal variant in MTTP and homozygosity fo... more Conclusion We have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.
![Research paper thumbnail of Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]](https://attachments.academia-assets.com/117324993/thumbnails/1.jpg)
](Journal of Hepatology, 2021
Archives of Toxicology, 2021
Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to ... more 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 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 2-fold 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 seven 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.
Pharmacological Research, 2021
Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is... more Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31 st , 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I 2 statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.
Clinical Pharmacology & Therapeutics, 2020
Drug‐induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs,... more Drug‐induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)‐containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti‐TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti‐TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans‐ethnic meta‐analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA‐B*52:01 was significant (meta‐analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63–4.37, P = 9.4 × 10−5). For N‐acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57–0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84–4....
Current Pharmaceutical Design, 2019
Idiosyncratic drug-induced liver injury (DILI) occasionally occurs in the setting of severe cutan... more Idiosyncratic drug-induced liver injury (DILI) occasionally occurs in the setting of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). This strengthens the proposed immunologic mechanism associated with this adverse reaction. DRESS exhibits the most common association with DILI. SCARs have a wide spectrum of heterogeneous clinical presentations and severity, and genetic predisposition has been identified. In the context of SCARs, DILI present a different clinical picture, ranging from mild injury to acute liver failure. Elucidating the role of DILI in the clinical presentation and outcome of SCARs represents a challenge due to limited information from published studies and the lack of consensus on definitions. The cholestatic and mixed pattern of liver damage typically predominates in the case of DILI associated with SCARs, which is different from D...
Nature Reviews Disease Primers, 2019
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs... more Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.
Gastroenterology, 2019
Background & Aims: We performed a nationwide, retrospective study to determine the incidence and ... more Background & Aims: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. Methods: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n=29,478) according to the Roussel Uclaf Causality Assessment Method. Results: Most cases of DILI presented with hepatocellular injury (51.39%; 95% CI, 50.76-52.03), followed by mixed injury (28.30%; 95% CI, 27.73-28.87) and cholestatic injury (20.31%; 95% CI, 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and anti-tuberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%).
Clinical Pharmacology & Therapeutics, 2019
Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including s... more Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug‐induced liver injury (CBZ‐DILI). In order to evaluate shared or phenotype‐specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta‐analysis of two genomewide association studies (GWAS) on a total of 43 well‐phenotyped Northern and Southern European CBZ‐SCAR cases and 10,701 population controls and a GWAS on 12 CBZ‐DILI cases and 8,438 ethnically matched population controls. HLA‐A*31:01 was identified as the strongest genetic predisposing factor for both CBZ‐SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ‐DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA‐A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens‐Johnson syndrome/toxic epidermal necrolysis cases, w...
Journal of Hepatology, 2019
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver diso... more Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Clinical Pharmacology & Therapeutics, 2019
Nature Reviews Disease Primers, Aug 22, 2019
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs... more Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.
Annals of Hepatology, Sep 1, 2021
Hepatology, 2022
Diseases (NIDDK) under grants: U24-DK065176 (Duke), U01-DK065201 (UNC), U01-54 DK065184 (Michigan... more Diseases (NIDDK) under grants: U24-DK065176 (Duke), U01-DK065201 (UNC), U01-54 DK065184 (Michigan), U01-DK065211 (Indiana), U01DK065193 (UConn), U01-DK065238 55 (UCSF/CPMC), U01-DK083023 (UTSW), U01-DK083027 (Einstein), U01-DK082992 (Mayo), 56 U01-DK083020 (USC), U01-DK100928 (Mount Sinai). Additional support is provided by CTSA 57 grants: UL1 RR025761 (Indiana), UL1TR000083 (UNC), UL1 RR024134 (UPenn), UL1 58 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and by the Intramural
Biomedicines, 2021
Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury... more Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI. Methods: We analyzed the activation profile (CD69, CD25, and HLA-DR) and natural killer group 2 member D (NKG2D) on iNKT cells, and CD4/CD8 T cells in peripheral blood mononuclear cells from NAFLD, with or without significant liver fibrosis, and DILI patients. Results: There was an increase in iNKT cells in NAFLD patients compared to DILI or control subjects. Regarding the cellular activation profile, NAFLD with significant liver fibrosis (F ≥ 2) displayed higher levels of CD69+iNKT cells compared to NAFLD with none or mild liver fibrosis (F ≤ 1) and control patients. CD69+iNKT positively correlated with insulin resistance, aspartate aminotransferase (AST) level, liver fibrosis-4 index (...
Gastroenterology, 2018
Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liv... more Identification of a PTPN22 Missense Variant As a General Genetic Risk Factor for Drug-Induced Liver Injury
Journal of Clinical Medicine, 2021
Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the li... more Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Altho...
Posters, 2021
Conclusion We have identified and characterized a rare causal variant in MTTP and homozygosity fo... more Conclusion We have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.
Journal of Hepatology, 2021
Archives of Toxicology, 2021
Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to ... more 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 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 2-fold 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 seven 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.
Pharmacological Research, 2021
Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is... more Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31 st , 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I 2 statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.
Clinical Pharmacology & Therapeutics, 2020
Drug‐induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs,... more Drug‐induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)‐containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti‐TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti‐TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans‐ethnic meta‐analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA‐B*52:01 was significant (meta‐analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63–4.37, P = 9.4 × 10−5). For N‐acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57–0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84–4....
Current Pharmaceutical Design, 2019
Idiosyncratic drug-induced liver injury (DILI) occasionally occurs in the setting of severe cutan... more Idiosyncratic drug-induced liver injury (DILI) occasionally occurs in the setting of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). This strengthens the proposed immunologic mechanism associated with this adverse reaction. DRESS exhibits the most common association with DILI. SCARs have a wide spectrum of heterogeneous clinical presentations and severity, and genetic predisposition has been identified. In the context of SCARs, DILI present a different clinical picture, ranging from mild injury to acute liver failure. Elucidating the role of DILI in the clinical presentation and outcome of SCARs represents a challenge due to limited information from published studies and the lack of consensus on definitions. The cholestatic and mixed pattern of liver damage typically predominates in the case of DILI associated with SCARs, which is different from D...
Nature Reviews Disease Primers, 2019
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs... more Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.
Gastroenterology, 2019
Background & Aims: We performed a nationwide, retrospective study to determine the incidence and ... more Background & Aims: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. Methods: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n=29,478) according to the Roussel Uclaf Causality Assessment Method. Results: Most cases of DILI presented with hepatocellular injury (51.39%; 95% CI, 50.76-52.03), followed by mixed injury (28.30%; 95% CI, 27.73-28.87) and cholestatic injury (20.31%; 95% CI, 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and anti-tuberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%).
Clinical Pharmacology & Therapeutics, 2019
Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including s... more Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug‐induced liver injury (CBZ‐DILI). In order to evaluate shared or phenotype‐specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta‐analysis of two genomewide association studies (GWAS) on a total of 43 well‐phenotyped Northern and Southern European CBZ‐SCAR cases and 10,701 population controls and a GWAS on 12 CBZ‐DILI cases and 8,438 ethnically matched population controls. HLA‐A*31:01 was identified as the strongest genetic predisposing factor for both CBZ‐SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ‐DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA‐A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens‐Johnson syndrome/toxic epidermal necrolysis cases, w...
Journal of Hepatology, 2019
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver diso... more Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Clinical Pharmacology & Therapeutics, 2019