Publications by authors named "Raul Andrade"

199 Publications

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions.

J Clin Med 2021 Nov 15;10(22). Epub 2021 Nov 15.

Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Malaga, Spain.

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. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10225317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618381PMC
November 2021

A 2-Step Strategy Combining FIB-4 With Transient Elastography and Ultrasound Predicted Liver Cancer After HCV Cure.

Am J Gastroenterol 2021 Sep 9. Epub 2021 Sep 9.

Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Spain.

Introduction: Despite the direct-acting antiviral therapy has dramatically decreased the likelihood of having liver-related complications and extrahepatic outcomes, the risk of developing hepatocellular carcinoma (HCC) is not totally eliminated after sustained virological response (SVR). We aimed to develop an easy-to-apply strategy to be adopted in clinical practice for accurately classifying the HCC risk in hepatitis C virus patients after SVR.

Methods: Prospective and multicenter study enrolling hepatitis C virus patients with advanced fibrosis (transient elastography [TE] > 10 kPa) or cirrhosis by ultrasound showing SVR. They were followed up until HCC, liver transplantation, death, or until October 2020, which occurred first, with a minimum follow-up period of 6 months after SVR (follow-up: 49 [interquartile range 28-59] months).

Results: Patients with cirrhosis by ultrasound represented 58% (611/1,054) of the overall cohort. During the study, HCC occurrence was 5.3% (56/1,054). Multivariate analyses revealed that Fibrosis-4 (FIB-4) > 3.25 (hazard ratio [HR] 2.26 [1.08-4.73]; P = 0.030), TE (HR 1.02 [1.00-1.04]; P = 0.045) and cirrhosis by ultrasound (HR 3.15 [1.36-7.27]; P = 0.007) predicted HCC occurrence. Baseline HCC screening criteria (TE > 10 kPa or cirrhosis) identified patients at higher risk of HCC occurrence in presence of FIB-4 > 3.25 (8.8%; 44/498) vs FIB-4 < 3.25 (2.4%; 12/506), while those with only FIB > 3.25 had no HCC (0%; 0/50) (logRank 22.129; P = 0.0001). A combination of baseline FIB-4 > 3.25 and HCC screening criteria had an annual incidence >1.5 cases per 100 person-years, while the rest of the groups remained <1 case. Patients who maintained post-treatment FIB-4 > 3.25 and HCC screening criteria remained at the highest risk of HCC occurrence (13.7% [21/153] vs 4.9% [9/184]; logRank 7.396, P = 0.007).

Discussion: We demonstrated that a two-step strategy combining FIB-4, TE, and ultrasound could help stratify HCC incidence risk after SVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000001503DOI Listing
September 2021

Long-term sequelae of drug-induced liver injury.

J Hepatol 2021 Oct 22. Epub 2021 Oct 22.

Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Electronic address:

Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.10.011DOI Listing
October 2021

Lymphocyte Profile and Immune Checkpoint Expression in Drug-Induced Liver Injury: An Immunophenotyping Study.

Clin Pharmacol Ther 2021 12 3;110(6):1604-1612. Epub 2021 Oct 3.

Servicio de Farmacología Clínica and UGC Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

The identification of specific HLA risk alleles in drug-induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA-4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helper T-cell (P < 0.0001), activated cytotoxic T-cells (P = 0.0003), Th1 (P = 0.0358), intracellular CTLA-4 level in helper T-cells (P = 0.0192), and PD-L1 presenting monocytes (P = 0.0452) than HLC. These levels approached those of HLC over time. No significant differences were found between DILI and VH. However, DILI presented higher level of activated helper T-cells and CTLA-4 than NAFLD and lower PD-L1 level than AIH. Our findings suggest that an adaptive immune response is involved in DILI in which activated CD4+ and CD8+ play an important role. Increased expression of negative immune checkpoints is likely the effect of peripheral tolerance regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2423DOI Listing
December 2021

Safety of treating acute liver injury and failure.

Expert Opin Drug Saf 2021 Jul 22:1-13. Epub 2021 Jul 22.

Servicio De Aparato Digestivo, Instituto De Investigación Biomédica De Málaga-IBIMA. Hospital Universitario Virgen De La Victoria, Universidad De Málaga, Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas CIBERehd, Málaga, Spain.

Introduction: Acute liver injury and progression to acute liver failure can be life-threatening conditions that require prompt careful clinical assessment and therapeutic management.

Areas Covered: The aim of this article is to review the safety and side effect profile of pharmacological therapies used in the treatment of acute liver injury with specific focus on hepatic toxicity. We performed an extensive literature search with the terms 'acute liver injury,' 'acute liver failure,' 'therapy,' 'safety,' 'adverse reactions' and 'drug induced liver injury.' A thorough discussion of the main drugs and devices used in patients with acute liver injury and acute liver failure, its safety profile and the management of complications associated to therapy of these conditions is presented.

Expert Opinion: Several pharmacological approaches are used in acute liver injury and acute liver failure in an empirical basis. Whilst steroids are frequently tried in serious drug-induced liver injury there is concern on a potential harmful effect of these agents because of the higher mortality in patients receiving the drug; hence, statistical approaches such as propensity score matching might help resolve this clinical dilemma. Likewise, properly designed clinical trials using old and new drugs for subjects with serious drug-induced liver injury are clearly needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14740338.2021.1955854DOI Listing
July 2021

Advanced preclinical models for evaluation of drug-induced liver injury - consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET].

J Hepatol 2021 10 24;75(4):935-959. Epub 2021 Jun 24.

Center for Regenerative Medicine, Institute for Regenerative and Repair, The University of Edinburgh, Edinburgh, UK, EH16 4UU; School of Engineering, Institute for Bioengineering, The University of Edinburgh, Faraday Building, Colin Maclaurin Road, EH9 3 DW, Scotland, UK; Institute of Biological Chemistry, Biophysics and Bioengineering (IB3), School of Engineering and Physical Sciences (EPS), Heriot-Watt University, Edinburgh EH12 2AS, Scotland, UK. Electronic address:

Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.06.021DOI Listing
October 2021

Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study.

Am J Gastroenterol 2021 11;116(11):2250-2257

Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital Universitari Sagrat Cor, Barcelona, Spain.

Introduction: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments.

Methods: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation.

Results: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events.

Discussion: Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000001343DOI Listing
November 2021

Non-pharmacologic direct cost of a simplified strategy with glecaprevir/pibrentasvir for 8 weeks in naïve non-cirrhotic patients with hepatitis C implemented in clinical practice. The Just SIMPLE Study.

Gastroenterol Hepatol 2021 Jun 12. Epub 2021 Jun 12.

Service of Digestive Diseases, Hospital Universitario La Paz, Madrid, Spain.

Background And Objective: The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain.

Patients And Methods: Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naïve subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018.

Results: The GLE/PIB effectiveness was 100% (CI95%: 96.2-100%) in the mITT population and 94.1% (CI95%: 87.5-97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35±103.60€ compared to 1689.42€ and 2007.89€ of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95€ and 1689.42€ of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources.

Conclusions: 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gastrohep.2021.05.015DOI Listing
June 2021

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models.

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22094557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123708PMC
April 2021

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.

Liver Int 2021 09 7;41(9):2076-2086. Epub 2021 May 7.

Digestive Department, Hospital Universitario San Cecilio, Granada, Spain.

Background And Aim: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD).

Methods: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years).

Results: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these.

Conclusions: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14898DOI Listing
September 2021

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

J Hepatol 2021 08 18;75(2):333-341. Epub 2021 May 18.

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA. Electronic address:

Background & Aims: 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.

Methods: 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.

Results: 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 by the model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner.

Conclusion: 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.

Lay Summary: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.03.021DOI Listing
August 2021

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice.

Antioxidants (Basel) 2021 Mar 5;10(3). Epub 2021 Mar 5.

Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts-neoantigens-that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10030390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000729PMC
March 2021

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

Arch Toxicol 2021 04 24;95(4):1475-1487. Epub 2021 Mar 24.

Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain. CIBERehd, Madrid, Spain.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-021-03000-8DOI Listing
April 2021

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Drug Saf 2021 Jun 16;44(6):619-634. Epub 2021 Mar 16.

Otsuka Pharmaceutical Development and Commercialization, Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-021-01051-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184702PMC
June 2021

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach.

Arch Toxicol 2021 05 5;95(5):1793-1803. Epub 2021 Mar 5.

UGC Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga - IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-021-03013-3DOI Listing
May 2021

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

J Hepatol 2021 07 1;75(1):86-97. Epub 2021 Feb 1.

UGC Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.01.029DOI Listing
July 2021

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

Clin Gastroenterol Hepatol 2021 Jan 9. Epub 2021 Jan 9.

UGC de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red: Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2021.01.011DOI Listing
January 2021

Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials.

Pharmacol Res 2021 02 24;164:105404. Epub 2020 Dec 24.

Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain; Platform for Clinical Research and Clinical Trials IBIMA, Plataforma ISCiii de Investigación Clínica, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Electronic address:

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, 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2020.105404DOI Listing
February 2021

Genetic risk factors in the development of idiosyncratic drug-induced liver injury.

Expert Opin Drug Metab Toxicol 2021 Feb 14;17(2):153-169. Epub 2020 Dec 14.

Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga, Spain.

: Idiosyncratic drug-induced liver injury (DILI) is a challenging condition with widespread implications. The underlying mechanism of DILI is not yet fully elucidated, but genetic predispositions are believed to contribute to DILI susceptibility. The identification of genetic risk factors has been a goal in DILI research for more than two decades. : Here we provide an overview of genetic studies in DILI performed to date and outline polymorphisms identified to have a potential role in DILI development. This review covers both earlier candidate gene studies and more recent genome-wide association studies. The clinical applications of these findings are also discussed. : Various polymorphisms have been identified as associated with DILI susceptibility, but all of these have not been confirmed in independent studies or contradictive findings are available. Genome-wide significant associations between distinct HLA risk alleles and DILI due to specific causative agents strengthen the hypothesis that DILI is partially immune-mediated. These HLA alleles generally have low positive predictive value and are therefore not useful in preemptive tests to reduce DILI incidences, but can aid DILI diagnosis and clinical decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2021.1854726DOI Listing
February 2021

Clinical Characteristics and Outcome of Drug-Induced Liver Injury in the Older Patients: From the Young-Old to the Oldest-Old.

Clin Pharmacol Ther 2021 04 6;109(4):1147-1158. Epub 2020 Dec 6.

Biomedical Research Network Center for Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute, Madrid, Spain.

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: "young" (< 65 years); "young-old" (65-74 years); "middle-old" (75-84 years); and "oldest-old" (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non-liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2108DOI Listing
April 2021

Association between vitamin D and cardioprotection in adult patients.

Rev Assoc Med Bras (1992) 2020 Oct;66(10):1444-1448

Médico e Professor do Centro Universitário CESMAC, Maceió, AL, Brasil.

Objective: To conduct a review of articles which have evaluated the relationship between vitamin D and cardioprotection in adult.

Methods: A literature search was performed in the Pubmed and Scielo databases. The results were extracted from primary and secondary sources and will be presented in the form of a bibliographic review.

Results: Twenty-three articles were identified from the electronic search that reported on physiological mechanisms relating the vitamin D axis and the cardiovascular system through receptors. Of the ten studies that evaluated the therapeutic effect of vitamin D in cardiovascular diseases, none reported significant results.

Conclusion: The articles assessed in this review did not demonstrate a cardioprotective effect of vitamin D, despite the epidemiological correlation of vitamin D deficiency with a higher prevalence of cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1806-9282.66.10.1444DOI Listing
October 2020

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

Drug Saf 2021 02 3;44(2):133-165. Epub 2020 Nov 3.

Indiana University School of Medicine, Indianapolis, IN, USA.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-020-01014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847464PMC
February 2021

Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens.

Clin Pharmacol Ther 2021 04 5;109(4):1125-1135. Epub 2020 Dec 5.

NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, UK.

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 ). 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 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2100DOI Listing
April 2021

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

Liver Int 2021 07 16;41(7):1523-1531. Epub 2020 Nov 16.

Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14713DOI Listing
July 2021

Discriminant indexes to simplify the differential diagnosis between iron deficiency anemia and thalassemia minor in individuals with microcytic anemia.

Rev Assoc Med Bras (1992) 2020 Sep;66(9):1277-1282

Doutor em Ciências da Saúde. Professor adjunto da disciplina Bases da Técnica Cirúrgica e Anestésica da Universidade Federal de Alagoas, Maceio, AL, Brasil.

Introduction: Microcytic anemias are very common in clinical practice, with iron deficiency anemia (IDA) and thalassemia minor (TT) being the most prevalent. Diagnostic confirmation of these clinical entities requires tests involving iron metabolism profile, hemoglobin electrophoresis, and molecular analysis. In this context, several discriminant indices have been proposed to simplify the differential diagnosis between IDA and TM.

Objective: The aim of this paper was to demonstrate the clinical relevance of the use of discriminant indices in individuals with microcytic anemia to simplify the differential diagnosis between iron deficiency anemia and minor thalassemia.

Methods: A bibliographic and cross-sectional search was performed in the PubMed, SciELO and LILACS databases, using the following descriptors: iron deficiency anemia, thalassemia minor, and differential diagnosis.

Results: More than 40 mathematical indices based on erythrocyte parameters have been proposed in the hematological literature in individuals with microcytosis. Green & King indexes (IGK), Ehsani index, and erythrocyte count (RBC) had excellent performances, especially when their efficacy was observed in adults and children.

Conclusions: Confirmatory tests for differential diagnosis between IDA and TM require time-consuming and costly methods. Despite the excellent performances of IGK, Ehsani index, and RBC, none of them presented sufficient sensitivity and specificity to establish a diagnosis. However, they can provide a powerful additional tool for diagnostic simplification between IDA and TM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1806-9282.66.9.1277DOI Listing
September 2020

Management of chronic liver disease-associated severe thrombocytopenia in Spain: a view from the experts.

Rev Esp Enferm Dig 2020 Oct;112(10):778-783

CEO and Partner, Omakase Consulting, España.

Background: chronic liver disease (CLD) patients often present thrombocytopenia (TCP) and when severe, it may prevent them from undergoing necessary invasive procedures due to an increased bleeding risk. The lack of scientific evidence makes it impossible to determine key aspects of the current management and associated healthcare burden of these patients in Spain.

Purpose: to gain insight into the current situation of patients with CLD-associated severe TCP undergoing invasive procedures in Spain, based on the experience of clinical experts.

Methods: national Delphi study involving 32 medical experts.

Results: the estimated prevalence of CLD-associated severe TCP is approximately 5,967, with an annual incidence of 1,148 new patients. Patients undergo a median of 1 (0-3) invasive procedures/year. Platelet transfusions (PTs) are the standard option to raise platelet counts and are associated with significant burden. The achievement of target platelet levels (≥ 50 x 109/l) after a transfusion is not routinely measured. The lack of effectiveness and short life span of transfused platelets can lead to procedure cancellations and bleeding events, which potentially affect patient outcomes. Adverse events occur in 1-25 % of patients, including mild (febrile and allergic reactions) and severe events (e.g., transfusion-related acute lung injury). Between 5-15 % of patients are unfit to receive PTs and approximately 3 % are treated off-label with thrombopoietin receptor agonists.

Conclusions: this study provides a snapshot of the current situation in Spain, highlighting that the current management is poorly standardized and suboptimal in some cases. The results suggest the benefit of developing a consensus document to address some of these shortcomings and to advance in the search for alternatives to PTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17235/reed.2020.6895/2020DOI Listing
October 2020

The effectiveness of percutaneous injections of ozonotherapy in low back pain.

Rev Assoc Med Bras (1992) 2020 Aug;66(8):1146-1151

. Universidade Federal de Alagoas (Ufal), Maceió, AL, Brasil.

Introduction: Lumbar pain is one of the main reasons for medical consultation, causing the disruption of daily routines due to its disabling nature, thus resulting in social and personal damage. Among the complementary treatments, ozonotherapy offers analgesia to most patients, with reports of complications. However, great questions about its clinical effectiveness have not been answered yet, and there have been reports of serious complications.

Objective: To describe the use of ozonotherapy in the treatment of lumbar pain, focusing on its favorable and unfavorable effects, and its analog profile.

Methods: A cross-sectional bibliographic research was performed with scientific articles obtained from the Pubmed, LILACS and Scopus database, using the following descriptors: "Ozone", "Therapy", "Lumbar pain", "complication", "Disk herniation", "Guideline", "Protocol", "Standards", "Criteria".

Results: The researched literature corroborates that, in clinical practice, there is safety in the use of oxygen-ozone therapy through percutaneous injections for the treatment of lumbar pain, especially when compared to surgeries and use of medicines, provided that strict criteria are followed.

Conclusion: The procedure is effective and has a favorable analgesic profile. However, it is necessary to produce a medical guideline that will help in its strict and systematic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1806-9282.66.8.1146DOI Listing
August 2020

Drug induced liver injury: an update.

Arch Toxicol 2020 10 27;94(10):3381-3407. Epub 2020 Aug 27.

Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.

Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-020-02885-1DOI Listing
October 2020

Drug-induced liver injury in older people.

Lancet Gastroenterol Hepatol 2020 09;5(9):862-874

Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain.

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(20)30006-6DOI Listing
September 2020
-->