RESUMEN
BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.
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Antibacterianos , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Antibacterianos/efectos adversos , Alelos , Cadenas HLA-DRB1/genética , Estudio de Asociación del Genoma Completo , Combinación Amoxicilina-Clavulanato de Potasio , Hígado , Factores de Riesgo , Antígenos HLA-A/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Aminopeptidasas/genéticaRESUMEN
BACKGROUND & AIMS: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. METHODS: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. RESULTS: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. CONCLUSIONS: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. LAY SUMMARY: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Difilina , Biopsia , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Humanos , Factores de RiesgoRESUMEN
Drug-induced liver injury (DILI) due to medications and herbal and dietary supplements (HDSs) is a major cause of acute liver injury leading to liver transplantation (LT). This study used United Network for Organ Sharing LT data to analyze severe HDS-induced acute liver injury in the United States. By convention, patients with acute DILI are listed as "Acute Hepatic Necrosis" (AHN) under the subheading "AHN: Drug Other Specify." All patients waitlisted from 1994 to 2020 were divided into 3 subgroups: "HDS DILI," "Non-HDS DILI," and "AHN: unknown drug." Analyses were performed to identify epidemiologic differences between patients with HDS DILI and non-HDS DILI. A subanalysis was performed for transplanted patients, including longitudinal changes. Of 1875 patients waitlisted for LT, 736 (39.2%) underwent LT. The proportion of Asian patients in the HDS DILI group was significantly higher compared with that in the non-HDS DILI group (17.4% versus 3.8%; P < 0.001). Excluding acetaminophen cases, the proportion of Black patients in the HDS DILI versus non-HDS group was significantly lower (8.7% versus 25.3%; P < 0.001). Waitlisted patients with HDS DILI were significantly older (median age, 38 years for HDS DILI versus 31 years for non-HDS DILI; P = 0.03). Lastly, the number of patients requiring LT due to HDS DILI increased significantly over time with more than 70% of cases occurring in the last 10 years (2010-2020) compared with the prior 15 years (1994-2009; Ptrend = 0.001). Ethnicity may help in identifying the cause of severe acute DILI, a growing problem as more patients experiment with HDS.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Trasplante de Hígado , Adulto , Pueblo Asiatico , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/cirugía , Suplementos Dietéticos/efectos adversos , Humanos , Trasplante de Hígado/efectos adversos , Estados Unidos/epidemiologíaRESUMEN
Oxaliplatin is an alkylating agent given with fluorouracil and leucovorin as a mainstay adjuvant chemotherapy for stage III colorectal cancer (CRC). Liver injury from oxaliplatin ranges from mild liver enzyme increases in 42% to 57% of patients in clinical trials1 to rare severe injury leading to acute liver failure.2 Chronic injury from endothelial cell damage and architectural distortion may manifest years later with nodular regenerative hyperplasia (NRH), portal sclerosis, and noncirrhotic portal hypertension (NCPH).2,3 Chronic subclinical injury occurs in up to 78% of patients.3 Diagnosis may be confounded by nonalcoholic fatty liver disease (NAFLD), and long-term outcomes from chronic injury are unclear.
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Neoplasias Colorrectales , Hipertensión Portal , Enfermedad del Hígado Graso no Alcohólico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Hígado , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Oxaliplatino/efectos adversosRESUMEN
PURPOSE OF REVIEW: With its high variability in both presentation and severity, drug-induced liver injury (DILI) is a complex condition increasingly confronting all providers. DILI has an even more muddled presentation among the geriatric population due to age-related changes in liver physiology and biochemistry as well as polypharmacy common in the geriatric population. RECENT FINDINGS: Most cases of DILI are idiosyncratic and unpredictable. DILI, especially related to herbal and dietary supplement (HDS) use, is increasingly recognized as a leading cause of acute liver failure and need for liver transplantation. Unfortunately, liver transplantation is a limited option for the elderly, a population that exhibits significant HDS use. One recent study suggests that early use of N-acetylcysteine may be useful in preventing progression to acute liver failure in non-acetaminophen DILI. In the future, a personalized medicine approach using genomic signatures may be feasible to prevent DILI. This review serves to raise recognition of the unique aspects of DILI in the geriatric population to promote rapid diagnosis and early intervention to prevent progression to liver failure and death. For now, DILI remains a diagnosis of exclusion, and care providers for the elderly must focus on obtaining a thorough history that includes HDS use and intervening early in suspected DILI cases.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Factores de Edad , Anciano , Envejecimiento/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Humanos , Hígado/fisiología , Hígado/fisiopatología , Polifarmacia , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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Negro o Afroamericano/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Hispánicos o Latinos/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Población Blanca/genética , Adulto , Amoxicilina/efectos adversos , Antibacterianos/efectos adversos , Estudios de Casos y Controles , Ácido Clavulánico/efectos adversos , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Antígeno HLA-A2/genética , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
INTRODUCTION: PBC registries in the UK focus on data from secondary care without clear coordinated contribution from primary care. The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) receives data from > 500 primary care practices (PCPs). Notably, the Lancet commissioning group is extracting data from the RCGP RSC database to shape UK policy on liver disease. AIMS: To create a novel ontology to facilitate PBC case finding from primary care provider (PCP) records. METHODS: RCGP RSC data were collected from participating PCPs in the county of Surrey, UK. PBC diagnostic criteria of the AASLD and EASL guidelines were used to develop 725 data codes to facilitate patient record searches. A scoring system built into the ontology allowed categorization of cases as PBC definite, PBC probable, and PBC unlikely. RESULTS: A total of 218,099 records were searched from participating PCPs. Of these, there were 58 PBC definite, 2317 PBC probable, and 215,724 PBC unlikely patients. There were 32 PBC definite patients who did not match to our regional PBC database and were henceforth included as new-found cases. Two of these cases were not labeled as PBC by the PCP. From the PBC unlikely group, 7/215,724 (0.003%) patients were labeled as PBC in secondary care records; however, none of them were coded as having PBC by their PCPs. CONCLUSIONS: Utilization of the UK National RCGP RSC database supported by novel ontology score has successfully helped us identify (i) new cases of PBC not known to local/regional secondary care providers and (ii) de novo PBC cases. There are many PBC probable cases whose data merit further careful evaluation.
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Colangitis/epidemiología , Atención Primaria de Salud , Atención Secundaria de Salud , Áreas de Influencia de Salud , Colangitis/terapia , Estudios de Factibilidad , Humanos , Sistema de Registros , Reino Unido/epidemiologíaRESUMEN
Bile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug-induced liver injury with histologically proven bile duct loss. All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary-supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50%-75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. CONCLUSION: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. (Hepatology 2017;65:1267-1277).
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Enfermedades de los Conductos Biliares/inducido químicamente , Conductos Biliares/efectos de los fármacos , Conductos Biliares/patología , Suplementos Dietéticos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedades de los Conductos Biliares/epidemiología , Enfermedades de los Conductos Biliares/patología , Biopsia con Aguja , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Distribución de Chi-Cuadrado , Estudios de Cohortes , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Inmunohistoquímica , Incidencia , Masculino , Persona de Mediana Edad , Preparaciones Farmacéuticas/administración & dosificación , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores Sexuales , Estadísticas no Paramétricas , Estados UnidosRESUMEN
BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. METHODS: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. RESULTS: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. CONCLUSION: HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. LAY SUMMARY: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.
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Antibacterianos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Antígeno HLA-B35/genética , Minociclina/efectos adversos , Adolescente , Adulto , Alelos , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended. AIMS: The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate. METHODS: All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed. RESULTS: Among 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37-61) years, and latency to onset was short (5-8 weeks) in 4 patients but more prolonged (18-56 weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA-A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2. CONCLUSIONS: Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Fenofibrato/efectos adversos , Hipolipemiantes/efectos adversos , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Antígenos HLA-A/genética , Humanos , Hígado/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with hepatitis C virus (HCV) with or without human immunodeficiency virus (HIV) achieve high sustained virological response (SVR) rates on sofosbuvir (SOF)-containing regimens in clinical trials. Real world data on patients coinfected with HCV and HIV treated with SOF-based regimens are lacking. METHODS: This observational cohort study included HIV/HCV-coinfected adults with genotype 1 HCV who initiated treatment with a SOF-containing regimen between December 2013 and December 2014 (n = 89) at the Mount Sinai Hospital or the Brooklyn Hospital Center. The primary outcome was SVR at 12 weeks after the end of treatment. The secondary outcomes were risk factors for treatment failure, serious adverse events, and side effects. A post hoc per protocol analysis of SVR was performed on patients who completed treatment and follow-up. RESULTS: In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV), and 52% (16/31) for SOF/RBV. The SVR rates of SMV/SOF/RBV and SMV/SOF did not differ significantly in this small study (P = .15). However the SVR rate of SMV/SOF/RBV was higher than that of SOF/RBV (P < .01). In a per protocol analysis, SMV/SOF/RBV had a higher SVR rate than SOF/RBV: 100% (16/16) vs 57% (16/28) (P < .01). The most commonly reported adverse effects were rash, pruritus, fatigue, and insomnia. One patient who had decompensated cirrhosis prior to treatment initiation died after receiving SMV/SOF. CONCLUSIONS: SMV/SOF ± RBV is an effective option with minimal adverse effects for most HIV-positive patients with genotype 1 HCV. SMV should be used with caution in patients with decompensated cirrhosis.
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Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Sofosbuvir/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Femenino , Infecciones por VIH/epidemiología , VIH-1 , Hepacivirus , Hepatitis C/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Factores de Riesgo , Simeprevir/administración & dosificación , Simeprevir/efectos adversos , Simeprevir/uso terapéutico , Sofosbuvir/administración & dosificación , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Carga ViralRESUMEN
UNLABELLED: In registration trials, triple therapy with telaprevir (TVR), pegylated interferon (Peg-IFN), and ribavirin (RBV) achieved sustained virological response (SVR) rates between 64% and 75%, but the clinical effectiveness and economic burdens of this treatment in real-world practice remain to be determined. Records of 147 patients who initiated TVR-based triple therapy at the Mount Sinai Medical Center (May-December 2011) were reviewed. Direct medical costs for pretreatment, on-treatment, and posttreatment care were calculated using data from Medicare reimbursement databases, RED Book, and the Healthcare Cost and Utilization Project database. Costs are presented in 2012 U.S. dollars. SVR (undetectable hepatitis C virus [HCV] RNA 24 weeks after the end of treatment) was determined on an intention-to-treat basis. Cost per SVR was calculated by dividing the median cost by the SVR rate. Median age of the 147 patients was 56 years (interquartile range [IQR] = 51-61), 68% were male, 19% were black, 11% had human immunodeficiency virus/HCV coinfection, 36% had advanced fibrosis/cirrhosis (FIB-4 scores ≥3.25), and 44% achieved an SVR. The total cost of care was $11.56 million. Median cost of care was $83,721 per patient (IQR = $66,652-$98,102). The median cost per SVR was $189,338 (IQR = $150,735-$221,860). Total costs were TVR (61%), IFN (24%), RBV (4%), adverse event management (8%), professional fees (2%), and laboratory tests (1%). CONCLUSIONS: TVR and Peg-IFN accounted for 85% of costs. Pharmaceutical prices and the low (44%) SVR rate, in this real-world study, were major contributors to the high cost per SVR.
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Antivirales/uso terapéutico , Costos de la Atención en Salud/estadística & datos numéricos , Hepatitis C/tratamiento farmacológico , Hepatitis C/economía , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Antivirales/farmacología , Costo de Enfermedad , Quimioterapia Combinada , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Humanos , Interferón-alfa/farmacología , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Polietilenglicoles/farmacología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Ribavirina/farmacología , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
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Cromosomas Humanos Par 13 , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 7 , Epistasis Genética , Sitios Genéticos , Cirrosis Hepática Biliar/genética , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Cirrosis Hepática Biliar/inmunología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases.
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Hepatopatías/fisiopatología , Hígado/metabolismo , Modelos Biológicos , Transducción de Señal/fisiología , Receptores Toll-Like/metabolismo , Humanos , Ligandos , Hígado/citología , Hepatopatías/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: Adding telaprevir to pegylated-interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment. We identified variables associated with severe anaemia during telaprevir-based triple therapy. METHODS: An observational study was performed on 142 HCV-infected patients between June 2011 and March 2012. All subjects completed 12 weeks of telaprevir-based triple therapy or discontinued early because of anaemia. Severe anaemia was defined by a haemoglobin≤8.9 g/dl; advanced fibrosis was determined by Fib-4≥3.25. RESULTS: The 47 (33%) patients who developed severe anaemia were similar to those who did not in sex, race, and prior response to dual therapy, but they were more likely to have diabetes (23.4% vs. 6.3%, P<0.01), advanced fibrosis (46.8% vs. 29.5%, P=0.04) and a history of anaemia during previous dual therapy (29.7% vs. 11.4%, P=0.02). Patients developing severe anaemia were older (59 vs. 56 years, P=0.02), had lower baseline platelet counts (134 vs. 163×10(9) /L, P=0.04), haemoglobin (14.0 vs. 15.0 g/dl, P<0.01), estimated glomerular filtration rate (79 vs. 90 ml/min/1.73 m2, P=0.03) and a higher median ribavirin/weight ratio (14.9 vs. 13.2 mg/kg, P<0.01). In multivariable logistic regression, presence of diabetes (OR=5.61, 95% CI: 1.59-19.72), Fib-4≥3.25 (OR=3.09, 95% CI: 1.28-7.46), higher ribavirin/weight ratio (OR=1.31 per mg/kg, 95% CI: 1.13-1.52) and lower baseline haemoglobin (OR=0.57 per g/dl, 95% CI, 0.41-0.80) were independently associated with developing severe anaemia. CONCLUSIONS: Severe anaemia occurred in one-third of patients receiving telaprevir-based triple therapy. Risk was greater in patients with diabetes, advanced liver fibrosis, higher ribavirin/weight ratio and lower baseline haemoglobin.
Asunto(s)
Anemia/etiología , Diabetes Mellitus Tipo 2/epidemiología , Hepatitis C/tratamiento farmacológico , Cirrosis Hepática/epidemiología , Oligopéptidos/efectos adversos , Humanos , Interferón-alfa/uso terapéutico , Modelos Logísticos , Análisis Multivariante , Oportunidad Relativa , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that ß-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Complicaciones del Embarazo , Humanos , Femenino , Embarazo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Adulto , Complicaciones del Embarazo/tratamiento farmacológico , Estados Unidos/epidemiología , Adulto Joven , Isoniazida/efectos adversos , Bloqueadores de los Canales de Calcio/efectos adversos , Periodo Posparto , Metildopa/efectos adversos , Antagonistas Adrenérgicos beta/efectos adversos , Antituberculosos/efectos adversosRESUMEN
BACKGROUND: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. METHODS: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. RESULTS: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). CONCLUSION: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.
RESUMEN
BACKGROUND: Enhanced cell expression of MAdCAM-1 is critical in tissue recruitment of lymphocytes in response to stimuli expressing the α4ß7 integrin. MAdCAM-1 is well characterized in gut mucosa with emerging evidence of hepatic expression. AIMS: (i) Compare quantitative/semi-quantitatively MAdCAM-1 expression in relation to early and advanced liver diseases (ii) Define the fine structure of vascular plexuses/lymphatics in the portal tract on which MAdCAM-1 is expressed. METHODS: Using alkaline phosphatase anti-alkaline phosphatase methodology on paraffin embedded tissue sections (n=28) from cirrhotic individuals who underwent orthotopic liver transplant, we evaluated MAdCAM-1 expression and compared with pre-cirrhotic, fulminant hepatitis B, and non-cirrhotic portal hypertension tissue sections. The positive controls included normal colon tissue with negative controls without primary antibody and isotype-matched purified IgG. We developed a real time PCR to quantify levels of MAdCAM-1 mRNA in our samples. RESULTS: MAdCAM-1 was expressed in 27/28 of the cirrhotic sections, localized primarily to septal areas within (i) endothelium of the peribiliary vascular plexus (PBP) (ii) lymphoid aggregates, with absence from normal, non-cirrhotic portal hypertension and pre-cirrhotic livers. There was significant upregulation of MAdCAM-1 mRNA in cirrhosis (p<0.011), consistent with immunohistochemical analysis. CONCLUSIONS: MAdCAM-1 is up-regulated in cirrhosis with expression on PBP and lymphoid aggregates. MAdCAM-1 is likely to contribute to the localization and recruitment of α4ß7 lymphocytes during the pathogenesis of cirrhosis. MAdCAM-1 could be a useful marker of advanced liver disease. Further studies with respect to the expression of MAdCAM-1 in the presence of reversible and non-reversible stages of liver disease may be of merit.
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Inmunoglobulinas/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Mucoproteínas/metabolismo , Adulto , Moléculas de Adhesión Celular , Colon/metabolismo , Endotelio Linfático/metabolismo , Femenino , Humanos , Inmunohistoquímica , Hígado/irrigación sanguínea , Tejido Linfoide/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
Regulation and downstream effects of mitochondrial protein S-glutathionylation in response to oxidative stress are poorly understood. The study aim was to determine whether anti-oxidants such as catalase and estradiol alter mitochondrial protein S-glutathionylation and in turn affect apoptosis following ultraviolet B (UV-B) light irradiation. HeLa cells were transduced with increasing amounts of adenovirus encoding catalase (Ad-Cat) and ß-galactosidase (Ad-Lac Z) or pre-incubated with estradiol before induction of apoptosis by UV-B light exposure. Inhibition of mitochondrial protein S-glutathionylation was assessed using autoantibodies specific for the non-S-glutathionylated form of PDC-E2. The percentage of apoptotic cells following UV-B irradiation were not significantly different between mock cells (cells with no virus infection) and Ad-Cat and Ad-Lac Z infected cells at all viral doses (all p > 0.050). Autoantibody staining of non-S-glutathionylated PDC-E2 in apoptotic cells was three times greater in only Ad-Cat infected cells compared to only Ad-Lac Z infected cells (81.3 ± 16.7 vs 26 ± 7.2 %, respectively, p = 0.030). Similarly estradiol treatment (33 and 100 nM) also significantly increased PDC-E2 staining in apoptotic cells compared to non-treated cells (both p < 0.010). The percentage of apoptotic cells was not significantly different with any of the estradiol concentrations (all p > 0.100). The observed procaspase 12 cleavage following UV-B irradiation suggests that a mitochondrial-independent apoptotic pathway was activated. In conclusion, following an apoptotic stimulus, estradiol may inhibit mitochondrial protein S-glutathionylation without inhibiting apoptosis. This effect may play a role in ninefold greater prevalence of autoantibodies against PDC-E2 in women with primary biliary cirrhosis.
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Antioxidantes/fisiología , Catalasa/fisiología , Estradiol/fisiología , Glutatión/metabolismo , Proteínas Mitocondriales/metabolismo , Antioxidantes/farmacología , Apoptosis , Catalasa/metabolismo , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/metabolismo , Estradiol/farmacología , Humanos , Estrés OxidativoRESUMEN
BACKGROUND: Kratom is a botanical product used as an opium substitute with abuse potential. METHODS: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. RESULTS: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. CONCLUSION: Kratom can cause severe liver injury with jaundice.