RESUMEN

OBJECTIVES: Magnetic resonance venography (MRV) is underutilized in the evaluation of thrombus properties prior to endovascular treatment but may improve procedural outcomes. We therefore investigated the clinical impact of using a dedicated MRV scoring system to assess thrombus characteristics prior to endovascular intervention for iliofemoral deep vein thrombosis (DVT). METHODS: This is a post hoc analysis of data from the CAVA trial ( Clinicaltrials.gov :NCT00970619). MRV studies of patients receiving ultrasound-accelerated catheter-directed thrombolysis (CDT) for iliofemoral DVT were reviewed. Thrombus age-related imaging characteristics were scored and translated into an overall score (acute, subacute, or old). MRV scores were compared to patient-reported complaints. MRV-scored groups were compared for CDT duration and success rate. RESULTS: Fifty-six patients (29 men; age 50.8 ± 16.4 years) were included. Using MRV, 27 thrombi were classified acute, 17 subacute, and 12 old. Based on patient-reported complaints, 11 (91.7%) of these old thrombi would have been categorized acute or subacute, and one (3.7%) of the acute thrombi as old. Average duration of CDT to > 90% restored patency differed significantly between groups (p < 0.0001): average duration was 23 h for acute thromboses (range: 19-25), 43 h for subacute (range: 41-62), and 85 h for old thromboses (range: 74-96). CDT was almost eleven times more successful in thromboses characterized as acute and subacute compared to old thromboses (OR: 10.7; 95% CI 2.1-55.5). CONCLUSION: A dedicated MRV scoring system can safely discriminate between acute, subacute, and old thromboses. MRV-based selection is predictive of procedural duration and success rate and can help avoid unnecessary complications. KEY POINTS: • Thrombus age, characterized by MRV as acute, subacute, and old, can predict CDT duration and probability of success. • Accurate pre-interventional MRV-based thrombus aging has the potential to facilitate identification of eligible patients and may thus prevent CDT-related complications.

Asunto(s)

Terapia Trombolítica , Trombosis de la Vena , Adulto , Anciano , Catéteres , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Flebografía , Terapia Trombolítica/métodos , Resultado del Tratamiento , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/tratamiento farmacológico

RESUMEN

Background The CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) trial did not show a reduction of post-thrombotic syndrome (PTS) after additional ultrasound-accelerated catheter-directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1-year follow-up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long-term follow-up. Methods and Results Patients aged 18 to 85 years with a first-time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow-up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow-up of 39.0 months (interquartile range, 23.3-63.8), 120 patients (79.8%) participated in the final follow-up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of -14.2% (95% CI, -32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19-0.84 [P=0.01]) with an absolute difference between groups of -22.2% (95% CI, -39.8% to -2.8%). No new major bleedings occurred following the 12-month follow-up. Conclusions The impact of additional ultrasound-accelerated catheter-directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.

Asunto(s)

Catéteres , Síndrome Postrombótico/prevención & control , Terapia Asistida por Computador/métodos , Terapia Trombolítica/métodos , Ultrasonografía/métodos , Trombosis de la Vena/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Vena Femoral , Estudios de Seguimiento , Humanos , Vena Ilíaca , Masculino , Persona de Mediana Edad , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento , Trombosis de la Vena/diagnóstico , Adulto Joven

Asunto(s)

COVID-19 , SARS-CoV-2 , Humanos , Huésped Inmunocomprometido , Reinfección

RESUMEN

BACKGROUND: The CAVA trial did not show the anticipated risk reduction for postthrombotic syndrome (PTS) after thrombus removal via additional ultrasound-accelerated catheter-directed thrombolysis (UACDT) in patients with acute iliofemoral deep vein thrombosis (IFDVT). Difficulties in achieving an effective degree of recanalization through thrombolysis may have influenced outcomes. We therefore assessed whether successful UACDT (restored patency ≥ 90%) did reduce the development of PTS. METHODS: This CAVA trial post hoc analysis compared the proportion of PTS at 1-year follow-up between patients with successful UACDT and patients that received standard treatment only. In addition, clinical impact as well as determinants of successful thrombolysis were explored. RESULTS: UACDT was initiated in 77 (50.7%) patients and considered successful in 41 (53.2%, interrater agreement κ = 0.7, 95% confidence interval 0.47-0.83). PTS developed in 15/41 (36.6%) patients in the successful UACDT group versus 33/75 (44.0%) controls (p = 0.44). In this comparison, successful UACDT was associated with lower Venous Clinical Severity Score (3.50 ± 2.57 vs. 4.82 ± 2.74, p = 0.02) and higher EuroQOL-5D (EQ-5D) scores (40.2 ± 36.4 vs. 23.4 ± 34.4, p = 0.01). Compared with unsuccessful UACDT, successful UACDT was associated with a shorter symptom duration at inclusion (p = 0.05), and higher rates of performed adjunctive procedures (p < 0.001) and stent placement (p < 0.001). CONCLUSION: Successful UACDT was not associated with a reduced proportion of PTS 1 year after acute IFDVT compared with patients receiving standard treatment alone. There was, however, a significant reduction in symptom severity and improvement of generic quality of life according to the EQ-5D. Better patient selection and optimization of treatment protocols are needed to assess the full potential of UACDT for the prevention of PTS. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT00970619.

Asunto(s)

Fibrinolíticos/uso terapéutico , Síndrome Postrombótico/prevención & control , Terapia Trombolítica/métodos , Ultrasonografía Intervencional , Trombosis de la Vena/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cateterismo , Femenino , Vena Femoral , Fibrinolíticos/administración & dosificación , Fibrinolíticos/efectos adversos , Estudios de Seguimiento , Humanos , Vena Ilíaca , Masculino , Persona de Mediana Edad , Síndrome Postrombótico/epidemiología , Síndrome Postrombótico/etiología , Método Simple Ciego , Stents , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/instrumentación , Grado de Desobstrucción Vascular , Trombosis de la Vena/complicaciones , Adulto Joven

RESUMEN

BACKGROUND: Early thrombus removal might prevent post-thrombotic syndrome by preserving venous function and restoring flow. Previous trials comparing additional catheter-directed thrombolysis to standard treatment showed conflicting outcomes. We aimed to assess the benefit of additional ultrasound-accelerated catheter-directed thrombolysis for the prevention of post-thrombotic syndrome compared with standard therapy in patients with iliofemoral deep-vein thrombosis. METHODS: We did a multicentre, randomised, single-blind, allocation-concealed, parallel group, superiority trial in 15 hospitals in the Netherlands. Patients aged 18-85 years with a first-time acute iliofemoral deep-vein thrombosis and symptoms for no more than 14 days were randomly assigned (1:1) to either standard treatment with additional ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. Randomisation was done with a web-based automatic programme and a random varying block size (2-12), stratified by age and centre. Standard treatment included anticoagulant therapy, compression therapy (knee-high elastic compression stockings; 30-40 mmHg), and early ambulation. Additional ultrasound-accelerated catheter-directed thrombolysis was done with urokinase with a starting bolus of 250 000 international units (IU) in 10 mL NaCl followed by a continuous dose of 100 000 IU/h for a maximum of 96 h through the Ekos Endowave-system. Adjunctive percutaneous transluminal angioplasty, thrombosuction, or stenting was performed at the discretion of the physician who performed the intervention. The primary outcome was the proportion of patients with post-thrombotic syndrome at 12 months diagnosed according to the original Villalta criteria-a Villalta-score of at least 5 on two consecutive occasions at least 3 months apart or the occurrence of venous ulceration-and was assessed in a modified intention-to-treat population of all randomly assigned patients who passed screening and started treatment. The safety analysis was assessed in the same modified intention-to-treat population. This study is complete and is registered at ClinicalTrials.gov, NCT00970619. FINDINGS: Between May 28, 2010, and Sept 18, 2017, 184 patients were randomly assigned to either additional ultrasound-accelerated catheter-directed thrombolysis (n=91) or standard treatment alone (n=93). Exclusion because of screening failure or early withdrawal of informed consent resulted in 77 patients in the intervention group and 75 in the standard treatment group starting allocated treatment. Median follow-up was 12·0 months (IQR 6·0-12·0). 12-month post-thrombotic syndrome occurred in 22 (29%) patients allocated to additional treatment versus 26 (35%) patients receiving standard treatment alone (odds ratio 0·75 [95% CI 0·38 to 1·50]; p=0·42). Major bleeding occurred in four (5%) patients in the intervention group, with associated neuropraxia or the peroneal nerve in one patient, and no events in the standard treatment group. No serious adverse events occurred. None of the four deaths (one [1%] in the intervention group vs three [4%] in the standard treatment group) were treatment related. INTERPRETATION: This study showed that additional ultrasound-accelerated catheter-directed thrombolysis does not change the risk of post-thrombotic syndrome 1 year after acute iliofemoral deep-vein thrombosis compared with standard therapy alone. Although this trial is inconclusive, the outcome suggests the possibility of a moderate beneficial effect with additional ultrasound-accelerated catheter-directed thrombolysis. Further research is therefore warranted to better understand this outcome in the context of previous trials, preferably by combining the available evidence in an individual patient data meta-analysis. FUNDING: The Netherlands Organisation for Health Research and Development (ZonMw), Maastricht University Medical Centre, BTG-Interventional Medicine.

Asunto(s)

Anticoagulantes/administración & dosificación , Cateterismo Periférico , Síndrome Postrombótico/prevención & control , Terapia Trombolítica/métodos , Trombosis de la Vena/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Método Simple Ciego , Medias de Compresión , Adulto Joven

RESUMEN

PURPOSE: Supportive care for cancer patients may benefit from improving treatment decisions and optimal use of the family physicians' and specialists' strengths. To improve shared decision-making (SDM) and facilitate continuity of primary care during treatment, a cancer care path including a "time out consultation" (TOC) in primary care before treatment decision, was implemented. This study assesses the uptake of a TOC and the added value for SDM. METHODS: For patients with metastatic lung or gastro-intestinal cancer, a TOC was introduced in their care path in a southern region of The Netherlands, from April until October 2016. Uptake of a TOC was measured to reflect on facilitation of continuity of primary care. The added value for SDM and overall experiences were evaluated with questionnaires and semi-structured interviews among patients, family physicians, and specialists. RESULTS: Of the 40 patients who were offered a TOC, 31 (78%) had a TOC. Almost all patients, family physicians, and specialists expressed that they experienced added value for SDM. This includes a stimulating effect on reflection on choice (expressed by 83% of patients) and improved preparation for treatment decision (75% of patients). Overall added value of a TOC for SDM, only evaluated among family physicians and specialists, was experienced by 71% and 86% of these physicians, respectively. CONCLUSION AND IMPLICATIONS FOR CANCER SURVIVORS: The first experiences with a TOC in primary care before cancer treatment decision suggest that it may help to keep the GP "in the loop" after a cancer diagnosis and that it may contribute to the SDM process, according to patients, family physicians, and specialists.

Asunto(s)

Toma de Decisiones/ética , Neoplasias/terapia , Derivación y Consulta/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Atención Primaria de Salud , Encuestas y Cuestionarios , Sobrevivientes

RESUMEN

OBJECTIVE: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts. METHODS: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. RESULTS: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle. CONCLUSION: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neutrófilos/efectos de los fármacos , Taxoides/uso terapéutico , Adulto , Anciano , Antineoplásicos , Recuento de Células Sanguíneas/métodos , Ensayos Clínicos Fase III como Asunto , Docetaxel , Femenino , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

BACKGROUND: We conducted a population-based study to investigate long-term survival in patients diagnosed with a (suspected) pancreatic adenocarcinoma. METHODS: All patients diagnosed with a pancreatic adenocarcinoma or with a pathologically unverified tumour of the pancreas between 1993 and 2008 in the South of the Netherlands were selected from the Netherlands Cancer Registry (NCR). Medical charts of patients who were alive five years or longer since diagnosis were reviewed. RESULTS: A total of 2 564 patients were included, of whom 1 365 had a pancreatic adenocarcinoma and 1 199 had a pathologically unverified pancreatic tumour. Five-year survival of patients with pathologically verified adenocarcinomas was 1.7% (24 of 1 365 patients). Twenty-one-one of these 24 long-term survivors were among the 207 cases that underwent surgical resection as initial treatment; five-year survival after resection thus being 10.1%. Half of the long-term survivors who underwent surgical resection still eventually died of recurrent disease. Five-year survival among patients with clinically suspected but microscopically unverified pancreatic tumours was 1.3% (16 of 1 199 patients). In 15 of these 16 long-term survivors the initial clinical diagnosis was revised: 14 had benign disease and one a premalignant tumour. CONCLUSIONS: Long-term survival among patients with pancreatic adenocarcinoma is extremely rare. As long-term survival in clinically suspected but pathologically unverified cancer is very unlikely, repeated fine needle aspiration or, preferably, histological biopsy is recommended in order to establish an alternative diagnosis in patients who survive longer than expected (more than 6-12 months).

Asunto(s)

Adenocarcinoma/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Pancreáticas/mortalidad , Sobrevivientes/estadística & datos numéricos , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Países Bajos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pronóstico , Tasa de Supervivencia

Asunto(s)

Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/mortalidad , Neoplasias Gástricas/patología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/terapia

RESUMEN

PURPOSE: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis. METHODS: Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented. RESULTS: The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented. CONCLUSION: We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.

Asunto(s)

Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Costos de los Medicamentos , Neutropenia Febril/prevención & control , Factor Estimulante de Colonias de Granulocitos/economía , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/economía , Análisis Costo-Beneficio , Esquema de Medicación , Neutropenia Febril/inducido químicamente , Neutropenia Febril/economía , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Persona de Mediana Edad , Modelos Económicos , Países Bajos , Polietilenglicoles , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéutico , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

PURPOSE: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. PATIENTS AND METHODS: In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. RESULTS: After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). CONCLUSION: In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neutropenia Febril/prevención & control , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Esquema de Medicación , Terminación Anticipada de los Ensayos Clínicos , Neutropenia Febril/inducido químicamente , Neutropenia Febril/epidemiología , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Incidencia , Persona de Mediana Edad , Análisis Multivariante , Países Bajos/epidemiología , Polietilenglicoles , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND/AIMS: In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. METHODS: Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). RESULTS: The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. CONCLUSIONS: This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

Asunto(s)

Ferritinas/sangre , Hemocromatosis/sangre , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/genética , Proteínas de la Membrana/genética , Modelos Genéticos , Adulto , Anciano , Índice de Masa Corporal , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Genotipo , Proteína de la Hemocromatosis , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Países Bajos , Factores de Riesgo , Índice de Severidad de la Enfermedad

RESUMEN

HFE C282Y-homozygosity has been associated with low hepcidin expression, leading to increased ferritin levels. However, serum hepcidin protein levels have not been documented in humans. In the current study, we compared serum hepcidin levels of newly diagnosed HFE C282Y-homozygotes with (N = 15) and without (N = 7) elevated serum ferritin levels to levels of 40 controls (20 heterozygotes and 20 wild types). In addition, hepcidin levels of four C282Y homozygotes were investigated during the course of all phlebotomy treatment phases. Serum hepcidin levels were lower in HFE C282Y-homozygotes (median; 25th-75th percentile: 1.88; 0.78-2.77 nmol/l) compared to controls (2.74; 1.45-5.39). Hepcidin/ferritin ratios were also lower in homozygotes. Homozygotes with an elevated serum ferritin had a higher serum hepcidin but a lower hepcidin/ferritin ratio than those with normal ferritin (2.28; 1.62-3.23 nmol/l hepcidin vs. 0.80; 0.60-1.29 and 3.63; 2.72-7.59 pmol hepcidin/microg ferritin vs. 13.2; 5.15-14.2). Serum hepcidin decreased during the depletion phase of phlebotomy and remained low during maintenance. This study showed that serum hepcidin is innately low in HFE-related haemochromatosis. Elevated ferritin levels were associated with increased hepcidin levels while erythropoiesis lead to lower hepcidin levels. During depletion, therefore, hepcidin levels are decreased, which may exacerbate intestinal iron absorption.

Asunto(s)

Péptidos Catiónicos Antimicrobianos/sangre , Hemocromatosis/sangre , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Adulto , Anciano , Eritropoyesis , Femenino , Ferritinas/sangre , Hemocromatosis/genética , Hemocromatosis/cirugía , Proteína de la Hemocromatosis , Hepcidinas , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Flebotomía

RESUMEN

UNLABELLED: Non-transferrin-bound iron (NTBI) is implicated in lipid peroxidation but the relation with oxidative modification of low-density lipoprotein (LDL) is not known. We assessed variables reflecting in vitro and in vivo LDL oxidation in two age- and sex-matched groups (n=23) of hereditary hemochromatosis heterozygotes (C282Y), characterized by a clear difference in mean serum NTBI (1.55+/-0.57 micromol/L vs 3.70+/-0.96 micromol/L). Plasma level of oxidized LDL (absolute and relative to plasma apolipoprotein B), and IgG and IgM antibodies to oxidized LDL, markers of in vivo LDL oxidation, did not differ between the groups with low and high serum NTBI. Mean lag-phase of in vitro LDL oxidation was also not significantly different between both study groups. CONCLUSION: these findings do not support the hypothesis that NTBI promotes oxidative modification of plasma LDL.

Asunto(s)

Hemocromatosis/sangre , Hemocromatosis/genética , Heterocigoto , Hierro/sangre , Peroxidación de Lípido , Lipoproteínas LDL/sangre , Adulto , Femenino , Humanos , Masculino , Oxidación-Reducción , Unión Proteica , Transferrina/análisis

RESUMEN

Non-transferrin-bound iron (NTBI) appears in the circulation of patients with iron overload. Various methods to measure NTBI were comparatively assessed as part of an international interlaboratory study. Six laboratories participated in the study, using methods based on iron mobilization and detection with iron chelators or on reactivity with bleomycin. Serum samples of 12 patients with hereditary (n=11) and secondary (n=1) hemochromatosis were measured during a 3-day analysis using 4 determinations per sample per day, making a total of 144 measurements per laboratory. Bland-Altman plots for repeated measurements are presented. The methods differed widely in mean serum NTBI level (range 0.12-4.32mumol/L), between-sample variation (SD range 0.20-2.13mumol/L and CV range 49.3-391.3%), and within-sample variation (SD range 0.02-0.45mumol/L and CV range 4.4-193.2%). The results obtained with methods based on chelators correlated significantly (R(2) range 0.86-0.99). On the other hand, NTBI values obtained by the various methods related differently from those of serum transferrin saturation (TS) when expressed in terms of both regression coefficients and NTBI levels at TS of 50%. Recent studies underscore the clinical relevance of NTBI in the management of iron-overloaded patients. However, before measurement of NTBI can be introduced into clinical practice, there is a need for more reproducible protocols as well as information on which method best represents the pathophysiological phenomenon and is most pertinent for diagnostic and therapeutic purposes.

Asunto(s)

Hemocromatosis/diagnóstico , Hierro/sangre , Bleomicina/química , Análisis Químico de la Sangre/normas , Quelantes/química , Humanos , Isoformas de Proteínas/sangre , Transferrina/análisis