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1.
Eur J Endocrinol ; 184(4): 513-520, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524005

RESUMO

Context: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal. Objective: The incidence of liver injury in a transgender population using gender-affirming hormone therapy. Design: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020. Methods: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST. Results: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals). Conclusion: The incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Disforia de Gênero/tratamento farmacológico , Hormônios Esteroides Gonadais/efeitos adversos , Hormônios Esteroides Gonadais/uso terapêutico , Fígado/enzimologia , Pessoas Transgênero , Adulto , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/uso terapêutico , Bélgica/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Estudos de Coortes , Estradiol/efeitos adversos , Estradiol/uso terapêutico , Feminino , Humanos , Itália/epidemiologia , Masculino , Países Baixos/epidemiologia , Noruega/epidemiologia , Estudos Prospectivos , Testosterona/efeitos adversos , Testosterona/uso terapêutico
2.
Ecotoxicol Environ Saf ; 208: 111719, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396050

RESUMO

Long-term exposure to high levels of arsenic has been documented to induce skin and liver damage, affecting hundreds of millions of people. While arsenic-induced skin and liver damage and trace element alterations have been studied, their correlations and risks have not been explained. Based on the above premise, this study included a total of 172 subjects from a coal-burning arsenic poisoning area. The levels of 18 trace elements in hair and six liver function indices in serum were detected, and the associations between and risks of trace elements related to skin and liver damage were analyzed. Finally, the receiver operating characteristic (ROC) curve and areas under the curve (AUC) were used to analyze the diagnostic values of certain trace elements for arsenic-induced skin and liver damage. The results found that a decrease in Se was a risk factor for arsenic-induced skin and liver damage (OR = 8.33 and 1.92, respectively). Furthermore, increases in Al and V were risk factors for arsenic-induced skin damage (OR = 1.05) and liver damage (OR = 13.16), respectively. In addition, the results found that Se and Al possessed certain diagnostic values for arsenic-induced skin damage (AUC = 0.93, 0.80), that Se possessed a diagnostic value for liver damage (AUC = 0.93), and that the combination of Se and Al increased the diagnostic value for skin damage (AUC = 0.96). This study provides an important research basis for further understanding the reasons for arsenic-induced skin and liver damage, for screening and identifying candidate diagnostic biomarkers, and for improving prevention and control strategies for arsenism.


Assuntos
Intoxicação por Arsênico/etiologia , Arsênico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Carvão Mineral/efeitos adversos , Dermatopatias/induzido quimicamente , Oligoelementos/análise , Adulto , Intoxicação por Arsênico/diagnóstico , Biomarcadores/análise , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , China/epidemiologia , Feminino , Cabelo/química , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Dermatopatias/diagnóstico
3.
Anticancer Res ; 41(1): 437-444, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419841

RESUMO

BACKGROUND/AIM: Intraarterial Technetium-99m-Macroaggregated Albumin (99mTc-MAA) administration is an established method to predict particle distribution prior to radioembolization. This study aimed to analyse the impact of intraarterial administration of 99mTc-MAA on changes in liver-specific laboratory parameters and to assess whether such changes are associated with post-radioembolization hepatotoxicity. PATIENTS AND METHODS: A total of 202 patients treated with radioembolization received prior mapping angiography with 99mTc-MAA administration. All patients underwent clinical and laboratory examinations, including liver-specific parameters at certain times before and after mapping angiography/99mTc-MAA administration, as well as before radioembolization and during follow-up. RESULTS: Bilirubin increased temporarily after 99mTc-MAA administration (p<0.001), but was not clinically relevant, and returned close to the initial value before radioembolization. These changes showed no association with subsequent postradioembolic hepatotoxicity or shortened overall survival. CONCLUSION: 99mTc-MAA administration results in a significant, however, not clinically relevant transient increase in bilirubin levels, which does not provide a predictive value for subsequent radioembolization outcome or postradioembolic hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Embolização Terapêutica/efeitos adversos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/efeitos adversos , Agregado de Albumina Marcado com Tecnécio Tc 99m/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia por Tomografia Computadorizada , Gerenciamento Clínico , Embolização Terapêutica/métodos , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Prognóstico , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Agregado de Albumina Marcado com Tecnécio Tc 99m/administração & dosagem , Resultado do Tratamento
4.
Medicine (Baltimore) ; 100(2): e24045, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466156

RESUMO

RATIONALE: Drug-induced liver injury (DILI) has a relatively low incidence, whereas the incidence of herb-induced liver injury (HILI) is still under investigation. As a special type of DILI, the diagnosis of drug-induced autoimmune-like hepatitis presents a persistent challenge, because this condition has partial characteristics of both DILI and autoimmune hepatitis (AIH), such as a certain history of medication use and histology that similar is to AIH. Thus, the differential diagnosis between DILI and AIH can be confusing. PATIENT CONCERNS: A 67-year-old woman taking xiang-tian-guo for 6 months was admitted to our hospital with a complaint of experiencing jaundice for 2 weeks. DIAGNOSIS: A liver biopsy exhibited interface inflammation, foam cells, and "rosette" -like hepatocytes. She was diagnosed with herb-induced liver injury (hepatocellular and acute), a RUCAM score of 7 (probable), a severity for grade 4 liver injury, and accompanied autoimmune-like changes. INTERVENTIONS: The patient was instructed to cease the administration of suspicious drugs. The patient also received liver protection and albumin transfusion. OUTCOMES: After 25 days of hospitalization, the patients aminotransferase levels returned to normal. No recurrence was observed after the administration of the treatments and a close follow-up. LESSONS: We must to be vigilant about the safety of xiang-tian-guo as a herbal medicine. When faced with the difficulty of distinguishing between AIH and DILI, long-term follow-up observations for recurrence can aid clinicians in making a judgment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Meliaceae/efeitos adversos , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Hepatite Autoimune/diagnóstico , Humanos , Testes de Função Hepática
5.
Biomed Pharmacother ; 134: 111150, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33395599

RESUMO

Risk factors related to the development of acetaminophen (APAP)-induced adverse reactions and liver injury remain uncertain. Sleep disorders have been linked to some health outcomes. This study examined the associations of sleep disorders with APAP-induced adverse reactions or liver injury and the possible mechanisms. From NIS database, adverse reactions, liver injury and sleep disorders were identified. Factors associated with the risk of the total adverse effects or liver injury were examined with logistic regression. From Gene Expression Omnibus database, datasets GSE111828, containing transcriptome data based on RNA-seq analysis from liver samples extracted from mice post APAP administration, and GSE92913, containing transcriptome data based on microarray analysis from liver samples extracted from mice with sleep deprivation, were analyzed. A total of 4372754 patients without and 91314 patients with sleep disorders were eligible for analyses. Both before and after propensity score matching, APAP-induced adverse reactions were higher in patients with sleep disorders than in patients without. In multivariate regression, sleep disorders were associated with higher odds of APAP-induced adverse reactions (adjusted OR [aOR] 2.005, 95 % CI 1.343-2.995) and liver injury (aOR 2.788, 95 % CI 1.310-5.932). Genes that were enriched in bile secretion and retinol metabolism and PPAR signaling pathways were basically down-regulated in livers of mice after APAP administration and livers of mice with sleep deprivation. This study shows that sleep disorders may be novel independent risk factors for APAP-associated adverse reactions and liver injury and provides bioinformation linking sleep disorders to increased risk of APAP-induced liver injury.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transtornos do Sono-Vigília/complicações , Adulto , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/genética , Estudos Transversais , Bases de Dados Genéticas , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pacientes Internados , Masculino , Camundongos , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Transdução de Sinais , Sono , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/fisiopatologia , Transcriptoma
6.
BMJ Case Rep ; 14(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462036

RESUMO

Terbinafine is a commonly used antifungal medication. Its side effects, while widely known, are rarely described and can be missed by the medical community. We present a 55-year-old woman who visited her primary care physician with onychomycosis. She started treatment with terbinafine, and 1 week later developed a rash in the left flank that extended to the chest, back, and upper part of lower extremities. Laboratory results showed elevated liver enzymes. A treatment with steroids did not improve the rash and she was admitted to our institution. She was started with intravenous dexamethasone, topical hydrocortisone and triamcinolone. Seven days later the liver enzymes normalised, and the rash resolved on the chest and back. Our patient had concurrent acute generalised exanthematous pustulosis and hepatitis that together has been very rarely associated with terbinafine.


Assuntos
Pustulose Exantematosa Aguda Generalizada/diagnóstico , Pustulose Exantematosa Aguda Generalizada/etiologia , Antifúngicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Terbinafina/efeitos adversos , Pustulose Exantematosa Aguda Generalizada/terapia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Onicomicose/tratamento farmacológico
7.
Medicine (Baltimore) ; 99(41): e22259, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031266

RESUMO

Drug-induced liver injury (DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely.We enrolled 458 consecutive hospitalized DILI patients from January 1, 2012 to December 31, 2018, using Roussel-Uclaf Causality Assessment Method (RUCAM), Maria & Victorino scale (M&V), and Digestive Disease Week-Japan criterion (DDW-J) combined with refined pathological scoring system respectively to perform the evaluation.A total of 458 DILI patients were enrolled, the area under receiver operating characteristics (AUROC) of the 3 clinical diagnostic criteria were 0.730 (95% confidence interval [CI]: 0.667-0.793), 0.793 (95% CI: 0.740-0.847), and 0.764 (95% CI: 0.702-0.826) respectively. Three hundred two DILI patients' liver biopsies were included: steatosis in 204 cases (67.5%), cholestasis in 151 cases (50%), cell apoptosis in 139 cases (46%), eosinophil granulocyte infiltration in 131 cases (43.4%), central and/or portal phlebitis in 103 cases (34.1%), iron deposition in 90 cases (29.8%), and pigmented macrophages in 92 cases (30.5%). The AUROC of refined pathological scale combined with 3 criteria were 0.843 (95% CI: 0.747-0.914), 0.907 (95% CI: 0.822-0.960), and 0.881 (95% CI: 0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894 (95% CI: 0.787-0.959), 0.960 (95% CI: 0.857-0.994), and 0.940 (95% CI: 0.847-0.985); in cholestatic type, the AUROCs were 0.750 (95% CI: 0.466-0.931), 0.500 (95% CI: 0.239-0.761), and 0.500 (95% CI: 0.239-0.761); in mixed type, the AUROCs were 0.786 (95% CI: 0.524-0.943), 0.869 (95% CI: 0.619-0.981), and 0.762 (95% CI: 0.498 to -0.930).Combined with pathological scale can significantly improve the accuracy of clinical diagnostic criteria, no matter in alone or combined condition, M&V might be more accurate in diagnosing DILI from suspected patients.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biomarcadores/sangue , Biópsia por Agulha , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
8.
Bull Cancer ; 107(10): 1056-1068, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-32951849

RESUMO

Pharmacological immune checkpoint inhibitors (ICI) restore the anti-tumor properties of T-lymphocytes, but unfortunately can engender auto-immune-like disorders. Those, frequent and of variable severity, sometimes target the liver parenchyma. Liver toxicity of ICI firstly leads to alteration of liver function tests (ALFT) with a risk of clinical decompensation. The appearance of ALFT should lead the clinician to exclude a non-immunological injury or a tumoral invasion of the liver parenchyma. In case of high grade ALFT, liver biopsy is necessary for diagnosis purpose. In ICI-induced hepatoxicity, histology examination shows most frequently a lobular acute hepatitis associated with lymphocytic infiltrates, but with different features than those encountered in primary auto-immune hepatitis. The management of ICI-related ALFT depends of their severity. Discontinuation of ICI is recommended for ALFT≥grade 2, and corticosteroid therapy for ALFT≥grade 3, or grade 2 without any improvement after ICI discontinuation. Addition of mycophenolate may be indicated whether corticosteroid inefficiency. Reintroduction of ICI is inadvisable for the most severe toxicities. The management of ALFT occurring on underlying chronic hepatopathy has not got consensual guidelines so far, but they should take account of the basal grade of ALFT and their worsening level under ICI therapy. The situation becomes more complex with associations between ICI and anti-angiogenic agents or cytotoxic chemotherapies where each of the drugs can be hepatotoxic. Thus, liver biopsy is primordial to figure out the mechanism of liver toxicity.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Humanos , Incidência
9.
BMC Geriatr ; 20(1): 346, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928134

RESUMO

BACKGROUND: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI. METHODS: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes. RESULTS: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively. CONCLUSION: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Clínicos Gerais , Fígado/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
10.
J Toxicol Sci ; 45(9): 515-537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879252

RESUMO

The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activities of transaminases are altered not only in the liver but also in other organs by modification of gluconeogenesis by nutritional or hormonal factors and this phenomenon leads to alteration of transaminase activity in the blood. Drugs, which are considered to directly or secondarily modify gluconeogenesis through lowering blood glucose levels or activating lipid metabolism, such as α-glucosidase inhibitors and fibrates, slightly increase transaminase activities in the blood but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). This type of elevations can be called pharmacology-related elevation. The pharmacology-related elevation of transaminase activities sometimes makes it difficult to assess precisely the potential hepatotoxicity of new investigational drugs. Considering the characteristic of transaminases, concomitant use of new biomarkers more specific to hepatic injury is needed in the assessment of DILI both in non-clinical and clinical studies. In this review, we will discuss the specificity of transaminases to DILI and future perspectives for transaminases in the estimation of risk of DILI.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gluconeogênese , Glicólise , Humanos , Fígado/metabolismo , Valor Preditivo dos Testes , Risco , Sensibilidade e Especificidade
11.
J Gastrointestin Liver Dis ; 29(3): 473-475, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32919428
12.
Hepatol Int ; 14(5): 881-883, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32725454
14.
Drug Discov Ther ; 14(3): 135-138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669522

RESUMO

Drug-induced liver injury (DILI) due to anti-tubercular treatment (ATT) leads to increased morbidity and mortality in patients with tuberculosis (TB). The aim of this study was to find the impact of malnutrition on the development of DILI. This was a prospective cohort study (September 2017 to August 2019) in which all newly diagnosed in-patients with tuberculosis above the age of 18 years were included. Those patients with a body mass index (BMI) of < 18.5 kg/m2 were considered malnourished. The patients were monitored for the development of DILI. Liver function tests were done at the baseline (before initiation of ATT), on the third day and at discharge in all the patients. Chi-square tests and conditional multiple logistic analysis was performed to identify risk factors associated with DILI. Out of the 319 subjects who were enrolled, a total of 138 patents chose to follow up at our hospital. A total of 14 patients (10%) developed DILI. The median time to onset of DILI was found to be ten days. Extra-pulmonary TB, low BMI and high baseline liver enzyme levels had a significant association with the development of DILI (p < 0.05). Low serum albumin had increased odds ratio but wasn't statistically significant. Malnutrition is an important risk factor for TB-DILI.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Centros de Atenção Terciária/tendências , Adulto , Doença Hepática Induzida por Substâncias e Drogas/sangue , Estudos de Coortes , Feminino , Humanos , Índia/epidemiologia , Masculino , Desnutrição/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Tuberculose/sangue , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia
15.
United European Gastroenterol J ; 8(7): 814-819, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32588791

RESUMO

BACKGROUND: Reports of liver injury in patients with novel coronavirus disease 2019 (COVID-19) are emerging from China and the USA. A wide variety of liver function test abnormalities and few cases of severe liver failure have been reported. No data on the hepatic phenotype from Europe are available at current. METHODS: We report a case series of 44 consecutive patients hospitalized for COVID-19 in Germany. RESULTS: At the time of admission, aspartate aminotransferase greater than the upper limit of normal was present in 70%, while alanine aminotransferase was elevated in 15.8%. Markers of cholestatic liver injury were altered only in a minority of patients. During hospitalization, 31% and 22% experienced increasing aspartate aminotransferase and alanine aminotransferase, respectively, when transaminases were normal at admission. Severe liver injury defined by 3×> upper limit of normal was observed in 9.1% over a mean time of 10.5 days. Importantly, patients exhibited cytotoxicity including lactate dehydrogenase and creatinine kinase elevations, but no signs of relevant liver function impairment. CONCLUSION: In summary, in a case series of hospitalized patients in Germany, cytotoxicity in the absence of severe liver dysfunction at admission and only few cases suggestive of severe liver injury during hospital were observed.


Assuntos
Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Infecções por Coronavirus/complicações , Falência Hepática Aguda/epidemiologia , Pneumonia Viral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/virologia , Testes de Função Hepática/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Adulto Jovem
16.
Toxicology ; 441: 152493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479839

RESUMO

Early diagnosis of liver injuries caused by drugs or occupational exposures is necessary to enable effective treatments and prevent liver failure. Whereas histopathology remains the gold standard for assessing hepatotoxicity in animals, plasma aminotransferase levels are the primary measures for monitoring liver dysfunction in humans. In this study, using Sprague Dawley rats, we investigated whether integrated analyses of transcriptomic and metabolomic data with genome-scale metabolic models (GSMs) could identify early indicators of injury and provide new insights into the mechanisms of hepatotoxicity. We obtained concurrent measurements of gene-expression changes in the liver and kidneys, and expression changes along with metabolic profiles in the plasma and urine, from rats 5 or 10 h after exposing them to one of two classical hepatotoxicants, acetaminophen (2 g/kg) or bromobenzene (0.4 g/kg). Global multivariate analyses revealed that gene-expression changes in the liver and metabolic profiles in the plasma and urine of toxicant-treated animals differed from those of controls, even at time points much earlier than changes detected by conventional markers of liver injury. Furthermore, clustering analysis revealed that both the gene-expression changes in the liver and the metabolic profiles in the plasma induced by the two hepatotoxicants were highly correlated, indicating commonalities in the liver toxicity response. Systematic GSM-based analyses yielded metabolites associated with the mechanisms of toxicity and identified several lipid and amino acid metabolism pathways that were activated by both toxicants and those uniquely activated by each. Our findings suggest that several metabolite alterations, which are strongly associated with the mechanisms of toxicity and occur within injury-specific pathways (e.g., of bile acid and fatty acid metabolism), could be targeted and clinically assessed for their potential as early indicators of liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Acetaminofen/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/urina , Bromobenzenos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/urina , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Ratos Sprague-Dawley
17.
J Vis Exp ; (159)2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32538903

RESUMO

Drug-induced autoimmune hepatitis (DIH) is the most common hepatic drug-induced hypersensitization process observed in approximately 9 to 12% of patients with autoimmune hepatitis. The overwhelming majority of patients with DIH are women. The underlying mechanisms of these sex differences in prevalence are unclear because of the paucity of animal models that mimic human disease. Even so, underlying mechanisms are widely believed to be associated with human leukocyte antigen haplotypes and sex hormones. In contrast, using a DIH mouse model, we have uncovered that IL-4 initiated CD4+ T cells directed against an epitope of cytochrome P450 2E1 induces influx of neutrophils, macrophages and mast cells into the livers of female BALB/c mice. Using this model, we have also shown that IL-33-induced FoxP3+regulatory T cells confer protection against DIH in female and male mice. This DIH model is induced by immunizing mice with an epitope of CYP2E1 that has been covalently altered with a drug metabolite that has been associated with DIH. This epitope is recognized by patients with DIH. Our method induces robust and reproducible hepatitis and autoantibodies that can be utilized to study the pathogenesis of DIH. While in vivo studies can cause undue pain and distress in mice when done improperly, the advantage of an in vivo model is the ability to evaluate the pathogenesis of disease in a large number of mice. Additionally, biological effects of the altered liver proteins can be studied using invasive procedures. The addition of in vitro studies to the experimental design allows rapid repetition and mechanistic analysis at a cellular level. Thus, we will demonstrate our model protocol and how it can be utilized to study in vivo and in vitro mechanisms of DIH.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Hepatite Autoimune/etiologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatite Autoimune/patologia , Camundongos , Camundongos Endogâmicos BALB C
18.
Infection ; 48(5): 779-782, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32418190

RESUMO

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , RNA Viral/sangue , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Alanina/administração & dosagem , Alanina/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/imunologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/virologia , Convalescença , Infecções por Coronavirus/virologia , Estado Terminal , Darunavir/administração & dosagem , Darunavir/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Evolução Fatal , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Lopinavir/administração & dosagem , Lopinavir/efeitos adversos , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/fisiopatologia , Insuficiência de Múltiplos Órgãos/virologia , Pandemias , Pneumonia Viral/virologia , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/diagnóstico , Torsades de Pointes/fisiopatologia , Torsades de Pointes/virologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-32312690

RESUMO

Drug intake in pregnant women is common, including prescribed and over-the-counter medications, and herbal medicine and supplements. Drug-induced liver injury (DILI) has become the leading cause of acute liver failure in Western countries, and pregnancy is thought to be a risk factor, but only few anecdotal reports concerning pregnant women are found. These involved antihypertensive, antithyroid, antiretroviral, and antituberculosis medications, and antibiotics. Presentation was usually in the first 20 weeks of gestation following a latency of several weeks, because these drugs were usually prescribed before or in early pregnancy due to their fetal safety. The hepatotoxicity is usually of the idiosyncratic form, and most would resolve spontaneously although occasional liver transplantation and maternal death were reported. The scanty reports could have been related to under-reporting and missed diagnosis due to spontaneous resolution in most cases. DILI should remain one of the differential diagnoses in pregnant women with hepatitis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Complicações na Gravidez/induzido quimicamente , Antibacterianos/efeitos adversos , Antirretrovirais/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Antitireóideos/efeitos adversos , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Transplante de Fígado , Extratos Vegetais/efeitos adversos , Gravidez , Fatores de Risco , Índice de Gravidade de Doença
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