RESUMEN
Conventional serum markers often fail to accurately detect cholestasis accompanying many liver diseases. Although elevation in serum bile acid (BA) levels sensitively reflects impaired hepatobiliary function, other factors altering BA pool size and enterohepatic circulation can affect these levels. To develop fluorescent probes for extracorporeal noninvasive hepatobiliary function assessment by real-time monitoring methods, 1,3-dipolar cycloaddition reactions were used to conjugate near-infrared (NIR) fluorochromes with azide-functionalized BA derivatives (BAD). The resulting compounds (NIRBADs) were chromatographically (FC and PTLC) purified (>95%) and characterized by fluorimetry, 1H NMR, and HRMS using ESI ionization coupled to quadrupole TOF mass analysis. Transport studies using CHO cells stably expressing the BA carrier NTCP were performed by flow cytometry. Extracorporeal fluorescence was detected in anesthetized rats by high-resolution imaging analysis. Three NIRBADs were synthesized by conjugating alkynocyanine 718 with cholic acid (CA) at the COOH group via an ester (NIRBAD-1) or amide (NIRBAD-3) spacer, or at the 3α-position by a triazole link (NIRBAD-2). NIRBADs were efficiently taken up by cells expressing NTCP, which was inhibited by taurocholic acid (TCA). Following i.v. administration of NIRBAD-3 to rats, liver uptake and consequent release of NIR fluorescence could be extracorporeally monitored. This transient organ-specific handling contrasted with the absence of release to the intestine of alkynocyanine 718 and the lack of hepatotropism observed with other probes, such as indocyanine green. NIRBAD-3 administration did not alter serum biomarkers of hepatic and renal toxicity. NIRBADs can serve as probes to evaluate hepatobiliary function by noninvasive extracorporeal methods.
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Ácidos y Sales Biliares , Colorantes Fluorescentes , Hígado , Animales , Ácidos y Sales Biliares/química , Colorantes Fluorescentes/química , Ratas , Hígado/metabolismo , Hígado/diagnóstico por imagen , Células CHO , Cricetulus , Pruebas de Función Hepática/métodos , Masculino , Espectroscopía Infrarroja Corta/métodos , Ratas Sprague-Dawley , FluorescenciaRESUMEN
Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1â¯000â¯000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10â¯261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11â¯159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.
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Bosentán , Enfermedad Hepática Inducida por Sustancias y Drogas , Pruebas de Función Hepática , Fenilpropionatos , Piridazinas , Humanos , Fenilpropionatos/uso terapéutico , Fenilpropionatos/efectos adversos , Piridazinas/efectos adversos , Piridazinas/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Estados Unidos , Bosentán/uso terapéutico , Adulto , Etiquetado de Medicamentos/normas , United States Food and Drug Administration , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Anciano , Antagonistas de los Receptores de Endotelina/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
In this study, we aimed to explore the clinical significance of serum CK18-M65 and CK18-M30 levels in patients with chronic hepatitis B (CHB) complicated by nonalcoholic steatohepatitis (NASH) and liver fibrosis. The observation and control groups comprised 133 patients with CHB complicated by NASH and 50 healthy patients from our hospital, respectively. Liver function indices, including alanine aminotransferase, glutamic aminotransferase, γ-glutamyltransferase, total bilirubin, total protein, and total cholesterol, were determined using an automatic biochemical analyzer. Hyaluronic acid, type III procollagen, type IV collagen, laminin, and CK18-M65 and M30 levels were detected using ELISA. Serum CK18-M65 and M30 levels in patients with CHB complicated by NASH were positively correlated with the liver fibrosis stage (Pâ <â .05). While serum CK18-M65 demonstrated a low diagnostic value for liver fibrosis in the S0-1 stage, it exhibited good diagnostic value for S2-3 stage liver fibrosis. Serum CK18-M30 displayed good diagnostic value for S0-1 and S2-3 hepatic fibrosis, particularly for S2-3 hepatic fibrosis. Elevated serum CK18-M65 and CK18-M30 levels in patients with CHB complicated with NASH suggest their potential utility in evaluating the progression of liver fibrosis in this population. In particular, CK18-M30 exhibits superior diagnostic efficiency.
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Biomarcadores , Hepatitis B Crónica , Queratina-18 , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Hepatitis B Crónica/sangre , Hepatitis B Crónica/complicaciones , Masculino , Femenino , Queratina-18/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Fragmentos de Péptidos/sangre , Pruebas de Función Hepática/métodos , Estudios de Casos y Controles , Relevancia ClínicaRESUMEN
INTRODUCTION: The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been reported to decrease proinflammatory cytokine production and may have a potential role in treating NASH. We aimed to evaluate the efficacy and safety of misoprostol in treating patients with NASH. METHODS: In this phase 2, double-blind, randomised, placebo-controlled trial, patients with NASH were randomly assigned in a 1:1 ratio to receive 200 µg of misoprostol or placebo thrice daily for 2 months. The primary endpoint was an improvement in liver function tests (LFTs), interleukin-6 (IL-6) and endotoxin levels. The secondary endpoint was improvement in insulin resistance, dyslipidaemia, hepatic fibrosis and hepatic steatosis. RESULTS: A total of 50 patients underwent randomisation, of whom 44 (88%) were males. The age range was 25-64 years (mean±SE of mean (SEM) 38.1±1.4). 19 (38%) patients had concomitant type 2 diabetes mellitus. 32 (64%) patients were either overweight or obese. At the end of 2 months' treatment, a reduction in total leucocyte count (TLC) (p=0.005), alanine aminotransferase (ALT) (p<0.001), aspartate aminotransferase (AST) (p=0.002) and controlled attenuation parameter (CAP) (p=0.003) was observed in the misoprostol group, whereas placebo ensued a decline in ALT (p<0.001), AST (p=0.018), gamma-glutamyl transferase (GGT) (p=0.003), CAP (p=0.010) and triglycerides (p=0.048). There was no diminution in insulin resistance, hepatic fibrosis (elastography) and dyslipidaemia in both groups. However, misoprostol resulted in a significant reduction in CAP as compared with the placebo group (p=0.039). Moreover, in the misoprostol group, pretreatment and post-treatment IL-6 and endotoxin levels remained stable, while in the placebo group, an increase in the IL-6 levels was noted (p=0.049). Six (12%) patients had at least one adverse event in the misoprostol group, as did five (10%) in the placebo group. The most common adverse event in the misoprostol group was diarrhoea. No life-threatening events or treatment-related deaths occurred in each group. CONCLUSION: Improvement in the biochemical profile was seen in both misoprostol and placebo groups without any statistically significant difference. However, there was more improvement in steatosis, as depicted by CAP, in the misoprostol group and worsening of IL-6 levels in the placebo group. TRIAL REGISTRATION NUMBER: NCT05804305.
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Resistencia a la Insulina , Interleucina-6 , Misoprostol , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Femenino , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Persona de Mediana Edad , Método Doble Ciego , Adulto , Misoprostol/administración & dosificación , Misoprostol/uso terapéutico , Misoprostol/efectos adversos , Interleucina-6/sangre , Resultado del Tratamiento , Resistencia a la Insulina/fisiología , Cirrosis Hepática/tratamiento farmacológico , Pruebas de Función Hepática/métodos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismoRESUMEN
BACKGROUND: The liver function reserve has a significant impact on the therapeutic effects of anti-programmed cell death-1 (PD-1) for hepatocellular carcinoma (HCC). This study aimed to comprehensively evaluate the ability of liver-function-based indicators to predict prognosis and construct a novel prognostic score for HCC patients with anti-PD-1 immunotherapy. METHODS: Between July 2018 and January 2020, patients diagnosed with HCC who received anti-PD-1 treatment were screened for inclusion in the study. The valuable prognostic liver-function-based indicators were selected using Cox proportional hazards regression analysis to build a novel liver-function-indicators-based signature (LFIS). Concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and Kaplan-Meier survival curves were utilized to access the predictive performance of LFIS. RESULTS: A total of 434 HCC patients who received anti-PD-1 treatment were included in the study. The LFIS, based on alkaline phosphatase-to-albumin ratio index, Child-Pugh score, platelet-albumin score, aspartate aminotransferase-to-lymphocyte ratio index, and gamma-glutamyl transpeptidase-to-lymphocyte ratio index, was constructed and identified as an independent risk factor for patient survival. The C-index of LFIS for overall survival (OS) was 0.692, which was higher than the other single liver-function-based indicator. The AUC of LFIS at 6-, 12-, 18-, and 24-month were 0.74, 0.714, 0.747, and 0.865 for OS, respectively. Patients in the higher-risk LFIS group were associated with both worse OS and PFS. An online and easy-to-use calculator was further constructed for better application of the LFIS signature. CONCLUSION: The LFIS score had an excellent prognosis prediction ability superior to every single liver-function-based indicator for anti-PD-1 treatment in HCC patients. It is a reliable, easy-to-use tool to stratify risk for OS and PFS in HCC patients who received anti-PD-1 treatment.
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Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Pruebas de Función Hepática/métodos , Estudios Retrospectivos , Tasa de Supervivencia , Hígado/patología , Inmunoterapia/métodos , Biomarcadores de Tumor , AdultoRESUMEN
OBJECTIVES: Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS: Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS: Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION: Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
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Quelantes , Quimioterapia Combinada , Degeneración Hepatolenticular , Penicilamina , Recurrencia , Humanos , Degeneración Hepatolenticular/tratamiento farmacológico , Penicilamina/uso terapéutico , Penicilamina/administración & dosificación , Femenino , Masculino , Estudios Prospectivos , Adolescente , Niño , Quelantes/uso terapéutico , Quelantes/administración & dosificación , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Zinc/administración & dosificación , Zinc/uso terapéutico , Pruebas de Función Hepática/métodos , Cobre/sangre , Privación de TratamientoRESUMEN
BACKGROUND: The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min. AIMS: Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests. METHODS: This study combined the data from two prospectively conducted US studies: HALT-C and SHUNT-V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD). RESULTS: DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500). CONCLUSIONS: DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs.
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Várices Esofágicas y Gástricas , Pruebas de Función Hepática , Índice de Severidad de la Enfermedad , Humanos , Várices Esofágicas y Gástricas/fisiopatología , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Pruebas de Función Hepática/métodos , Adulto , Estudios Prospectivos , Anciano , Endoscopía del Sistema Digestivo/métodos , Factores de Riesgo , Hígado/fisiopatología , Hígado/irrigación sanguíneaRESUMEN
HepQuant tests quantify liver function from clearance of deuterium- and 13C-labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child-Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child-Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty-one subjects with hepatic impairment (8 Child-Pugh A, 7 Child-Pugh B, and 6 Child-Pugh C), and 10 age- and sex-matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal-systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24-13C]-cholate and oral administration of [2,2,4,4-2H]cholate. Ampreloxetine plasma exposure (AUC0-inf) was similar to controls in Child-Pugh A, increased 1.7-fold in subjects with Child-Pugh B, and 2.5-fold in subjects with Child-Pugh C and correlated with both Child-Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC0-inf) in subjects with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC0-inf) compared to Child-Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child-Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple-to-administer, oral-only DuO version of the HepQuant test could enhance clinical utility.
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Hepatopatías , Morfolinas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hepatopatías/metabolismo , Anciano , Administración Oral , Morfolinas/farmacocinética , Morfolinas/administración & dosificación , Adulto , Pruebas de Función Hepática/métodos , Índice de Severidad de la Enfermedad , Isótopos de Carbono , Deuterio , Hígado/metabolismo , Alcohol Feniletílico/análogos & derivadosRESUMEN
INTRODUCTION: On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. OBJECTIVE: The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. METHODS: The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. RESULTS: The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. CONCLUSION: For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.
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Bilirrubina , Enfermedad Hepática Inducida por Sustancias y Drogas , Pruebas de Función Hepática , Humanos , Bilirrubina/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Pruebas de Función Hepática/métodos , Ensayos Clínicos como Asunto , Transaminasas/sangreRESUMEN
PURPOSE: This study compared the predictive performance of the relative enhancement index (REI) derived from gadoxetic acid (GA)-enhanced MRI with that of the functional liver imaging score (FLIS) in estimating liver function among patients with chronic liver disease (CLD) or liver cirrhosis (LC) by validating them with the albumin-bilirubin (ALBI) grade. MATERIALS AND METHODS: We retrospectively examined 166 patients (79 women, 87 men; 57.4 years) who were diagnosed with LC or CLD and underwent GA-enhanced MRI between August 2020 and September 2023. The enhancement ratio (ER) is calculated using the formula: ER = [hepatobiliary phase liver signal (SI HBP20)-precontrast liver signal (SI pre)]/SI pre. The REI is calculated using the formula: REI = Liver Volume (LV) × ER. FLIS was assigned from the sum of three HBP image features, each scored between 0 and 2: liver parenchymal enhancement, biliary contrast excretion, and portal vein sign. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff values of ER, REI, and FLIS in differentiating between ALBI grades. The area under the curve (AUC), accuracy, sensitivity, and specificity were calculated for REI and FLIS to distinguish the ALBI grades. Spearman's rank correlation was used to evaluate the ER, REI, and FLIS correlations between the ALBI grades. To evaluate inter-reader reliability for LV, ER, REI, and FLIS, intraclass correlation coefficient (ICC) was used. RESULTS: ROC curve analysis showed that the optimal cutoff value of REI for predicting ALBI Grade 1 was 899-905 for readers 1 and 2 and 461-477 for ALBI Grade 3, respectively. REI performed best in predicting ALBI Grade 1, achieving an accuracy range of 94%-92.2%, sensitivity of 94.9%-94.1%, and specificity of 91.7%-87.5% for readers 1 and 2, respectively. All parameters showed high accuracy in distinguishing ALBI Grade 3 from other grades. However, REI outperformed the others, showing an accuracy range of 98.8%-97.6%, sensitivity of 94.4%-94.4%, and specificity of 99.3%-98% for readers 1 and 2, respectively. REI showed the best and very strong correlation with ALBI for both readers. CONCLUSION: REI showed a very strong correlation with the ALBI grades for assessing liver function. It outperformed FLIS in predicting the ALBI grades, indicating its potential as a radiologic tool comparable to or better than FLIS in predicting liver function, especially given its dependence on liver volume.
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Medios de Contraste , Gadolinio DTPA , Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Pruebas de Función Hepática/métodos , Bilirrubina/sangre , Anciano , Hígado/diagnóstico por imagen , Valor Predictivo de las Pruebas , Hepatopatías/diagnóstico por imagen , Adulto , Cirrosis Hepática/diagnóstico por imagen , Aumento de la Imagen/métodos , Albúmina Sérica , Reproducibilidad de los ResultadosRESUMEN
Data on alanine aminotransferase (ALT) measurement practices and diagnoses associated with increased values are limited. We evaluated these issues by collecting ALT measurements from 1- to 16-year-old patients investigated in 1992-2018 in a tertiary center. Diagnoses were gathered in 2008-2018. Altogether 145,092 measurements from 28,118 children were taken 42% undergoing repeated testing. Testing increased from 21/1000 to 81/1000 children and the prevalence of elevated values fluctuated between 18% and 26%. An increase was seen especially in emergency care and departments of rheumatology, gastroenterology, hemato-oncology, and psychiatry. Common acute causes associated with elevated ALT were infections (45%), hemato-oncologic conditions (17%), and external reasons (13%), whereas autoimmune diseases (28%), psychiatric conditions (14%), and metabolic-dysfunction associated steatotic liver disease (10%) were common chronic causes. In conclusion, ALT testing increased 3.9-fold while the proportion of increased values remained stable, indicating that increased testing was justified. However, in some departments the testing efficiency was low.
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Alanina Transaminasa , Humanos , Alanina Transaminasa/sangre , Adolescente , Niño , Masculino , Femenino , Preescolar , Lactante , Estudios Retrospectivos , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Hepatopatías/sangre , Hepatopatías/diagnóstico , Pautas de la Práctica en Medicina/estadística & datos numéricosRESUMEN
BACKGROUND: Identification of abdominal injury (AI) in children with concern for physical abuse is important, as it can provide important medical and forensic information. Current recommendations are to obtain screening liver function tests (LFTs) in all children with suspected physical abuse and an abdominal computed tomography (CT) when the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is >80 IU/L. This threshold to obtain an abdominal CT is lower than general trauma guidelines, which use a cutoff of AST >200 IU/L or ALT >125 IU/L. METHODS: This was a retrospective review of children aged 0 to 60 months at a single pediatric tertiary care center who were evaluated for physical abuse and had AST or ALT >80 IU/L. Subjects were then stratified into two groups: midrange (AST ≤200 IU/L and ALT ≤125 IU/L) and high-range (AST >200 IU/L and/or ALT >125 IU/L) LFTs. RESULTS: Abdominal CTs were performed in 55% (131 of 237) of subjects, 38% (50 of 131) with midrange LFTs and 62% (81 of 131) with high-range LFTs. Abdominal injury was identified in 19.8% (26 of 131) of subjects. Subjects with AI were older than those without AI (mean [SD] age, 18.7 [12.5] vs. 11.6 [12.2] months; p = 0.009). The highest yield of abdominal CTs positive for AI was in the group with high-range LFTs with signs or symptoms of AI at 52.0% (13 of 25; 95% confidence interval, 31.3-72.2%). The negative predictive value of having midrange LFTs and no signs or symptoms of AI was 100% (95% confidence interval, 97.0-100%). CONCLUSION: Our data suggest that abdominal CT may not be necessary in children being evaluated for physical abuse who have AST ≤200 IU/L and ALT ≤125 IU/L and do not have signs or symptoms of AI. This could limit the number of abdominal CTs performed. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level IV.
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Traumatismos Abdominales , Alanina Transaminasa , Aspartato Aminotransferasas , Maltrato a los Niños , Tomografía Computarizada por Rayos X , Humanos , Estudios Retrospectivos , Alanina Transaminasa/sangre , Masculino , Femenino , Lactante , Preescolar , Tomografía Computarizada por Rayos X/métodos , Aspartato Aminotransferasas/sangre , Traumatismos Abdominales/diagnóstico por imagen , Traumatismos Abdominales/sangre , Maltrato a los Niños/diagnóstico , Pruebas de Función Hepática/métodos , Recién Nacido , Biomarcadores/sangreRESUMEN
OBJECTIVES: In this study, we aimed to investigate the causes of liver test abnormalities in newly diagnosed patients naive to anti-tumoral therapy. METHOD: This study included a total of 490 patients with ALT levels > 5X ULN on liver function tests at the initial presentation to our clinic. Data from 247 (50.4%) patients diagnosed with cancer (cohort A) and 243 (49.6%) patients without cancer (cohort B) were compared with regard to the etiology of liver test abnormalities and the risk factors. RESULTS: The most common etiological factor in cohort A was presence of liver metastasis (31.2%, n = 77). In the comparison of the two groups with regard to etiological factors; the rates of liver metastasis [31.2% vs 0%, (p < 0.001)], drug-induced liver toxicity [30/4% vs 19.8%, (p = 0.007)], pancreaticobiliary pathology [21.5% vs 14%, (p = 0.03)] and chronic viral hepatitis [14.2% vs 7.4%, (p = 0.02)] were higher in the cohort A. The rate of NAFLD was higher in the cohort B [6.9% vs 42.2% (p < 0.001). CONCLUSION: In our study, the most common cause of liver test abnormalities was the presence of liver metastasis in cohort A and NAFLD in cohort B.
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Pruebas de Función Hepática , Neoplasias Hepáticas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pruebas de Función Hepática/métodos , Neoplasias Hepáticas/secundario , Anciano , Factores de Riesgo , Adulto , Neoplasias , Estudios Retrospectivos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Alanina Transaminasa/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/diagnósticoRESUMEN
Volatile organic compounds (VOCs) present in exhaled breath can help in analysing biochemical processes in the human body. Liver diseases can be traced using VOCs as biomarkers for physiological and pathophysiological conditions. In this work, we propose non-invasive and quick breath monitoring approach for early detection and progress monitoring of liver diseases using Isoprene, Limonene, and Dimethyl sulphide (DMS) as potential biomarkers. A pilot study is performed to design a dataset that includes the biomarkers concentration analysed from the breath sample before and after study subjects performed an exercise. A machine learning approach is applied for the prediction of scores for liver function diagnosis. Four regression methods are performed to predict the clinical scores using breath biomarkers data as features set by the machine learning techniques. A significant difference was observed for isoprene concentration (p < 0.01) and for DMS concentration (p < 0.0001) between liver patients and healthy subject's breath sample. The R-square value between actual clinical score and predicted clinical score is found to be 0.78, 0.82, and 0.85 for CTP score, APRI score, and MELD score, respectively. Our results have shown a promising result with significant different breath profiles between liver patients and healthy volunteers. The use of machine learning for the prediction of scores is found very promising for use of breath biomarkers for liver function diagnosis.
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Pruebas Respiratorias/métodos , Espiración/fisiología , Hepatopatías/diagnóstico , Pruebas de Función Hepática/métodos , Aprendizaje Automático , Proyectos Piloto , Compuestos Orgánicos Volátiles/análisis , Biomarcadores/análisis , Butadienos/análisis , Hemiterpenos/análisis , Limoneno/análisis , Valor Predictivo de las Pruebas , Sulfuros/análisisAsunto(s)
Atresia Biliar/cirugía , Microbioma Gastrointestinal/fisiología , Portoenterostomía Hepática/métodos , Atresia Biliar/fisiopatología , Microbioma Gastrointestinal/inmunología , Humanos , Hígado/metabolismo , Hígado/microbiología , Hígado/cirugía , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Trasplante de Hígado/métodosRESUMEN
ABSTRACT: Transient elastography or elastometry (TE) is widely used for clinically cirrhosis and liver steatosis examination. Liver fibrosis and fatty liver had been known to share some co-morbidities that may result in chronic impairment in renal function. We conducted a study to analyze the association between scores of 2 TE parameters, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), with chronic kidney disease among health checkup population.This was a retrospective, cross-sectional study. Our study explored the data of the health checkup population between January 2009 and the end of June 2018 in a regional hospital. All patients were aged more than 18 year-old. Data from a total of 1940 persons were examined in the present study. The estimated glomerular filtration rate (eGFR) was calculated by the modification of diet in renal disease (MDRD-simplify-GFR) equation. Chronic kidney disease (CKD) was defined as eGFRâ<â60âmL/min/1.73 m2.The median of CAP and LSM score was 242, 265.5, and 4.3, 4.95 in non-CKD (eGFRâ>â60) and CKD (eGFRâ<â60) group, respectively. In stepwise regression model, we adjust for LSM, CAP, inflammatory markers, serum biochemistry markers of liver function, and metabolic risks factors. The P value of LSM score, ALT, AST, respectively is .005, <.001, and <.001 in this model.The LSM score is an independent factor that could be used to predict renal function impairment according to its correlation with eGFR. This result can further infer that hepatic fibrosis may be a risk factor for CKD.
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Diagnóstico por Imagen de Elasticidad/métodos , Pruebas de Función Hepática/métodos , Hígado/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Transversales , Hígado Graso/patología , Femenino , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/patología , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/patología , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. METHODS: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. RESULTS: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. CONCLUSIONS: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS. GOV NUMBER: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.
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Ácido Quenodesoxicólico/análogos & derivados , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Adulto , Anciano , Ácido Quenodesoxicólico/administración & dosificación , Ácido Quenodesoxicólico/farmacología , Método Doble Ciego , Femenino , Humanos , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/fisiopatología , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , PlacebosRESUMEN
PURPOSE: This study aimed to evaluate the effect and individual responsiveness after 12 (12wk) and 24 weeks (24wk) of physical exercise (PE) and nutritional guidance (NG) on metabolic syndrome (MetS) criteria and hepatic parameters in overweight adolescents. METHODS: The study comprised 94 overweight adolescents, aged between 10 and 16 years old, from both sexes, allocated into groups: PE and NG (PENGG, n = 64) and control with NG (NGCG, n = 30). Variables were collected at baseline, 12wk, and 24wk. Weight, height, abdominal circumference (AC), blood pressure, and peak oxygen consumption (VO2peak), as well as insulin, triglycerides (TAG), high-density lipoprotein (HDL-c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were evaluated. HOMA-IR and QUICKI were calculated. PE session consisted of 45 min of indoor cycling, 45 min of walking, and 20 min of stretching, three times a week. The NG consisted of three collective sessions in the first 12wk. Anova, effect size, and prevalence of responders were used for statistical analysis. RESULTS: The PENGG12wk reduced anthropometric and metabolic measurements, while increased VO2peak and HDL-c. The PEG24wk promoted anthropometric, blood pressure, metabolic, and VO2peak improvements, but participants without PE returned to pre-exercise status and presented worsening AST and ALT concentrations. Frequencies of respondents in PENGG12wk versus (vs) NGCG12wk were, respectively, AC (69.1% vs 17.6%, p < 0.01), HDL-c (87.2% vs 23.5%, p < 0.01), TAG (67.3% vs 41.7%, p = 0.05) and ALT (45.5% vs 5,9%; p = 0.003). CONCLUSION: Interventions with PE were effective to reduce MetS components in 12wk and maintenance in 24wk, showing anthropometric, metabolic, and VO2peak improvements. Higher individual responses were observed in 12wk and in 24wk, important changes in overweight adolescent's therapy. LEVEL OF EVIDENCE: Level I, evidence obtained from well-designed controlled trials randomization. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: Brazilian Registry of Clinical Trials (RBR-4v6h7b) and date of registration April 4th, 2020.
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Síndrome Metabólico/clasificación , Obesidad Infantil/complicaciones , Adolescente , Análisis de Varianza , Índice de Masa Corporal , Brasil/epidemiología , Niño , Femenino , Humanos , Hígado/anomalías , Hígado/metabolismo , Hígado/fisiopatología , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Obesidad Infantil/sangre , Obesidad Infantil/epidemiología , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (â§2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score â§9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.