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Antimicrobial peptides, disease severity and exacerbations in bronchiectasis.
Sibila, O, Perea, L, Cantó, E, Shoemark, A, Cassidy, D, Smith, AH, Suarez-Cuartin, G, Rodrigo-Troyano, A, Keir, HR, Oriano, M, et al
Thorax. 2019;(9):835-842
Abstract
RATIONALE Recently a frequent exacerbator phenotype has been described in bronchiectasis, but the underlying biological mechanisms are unknown. Antimicrobial peptides (AMPs) are important in host defence against microbes but can be proinflammatory in chronic lung disease. OBJECTIVES To determine pulmonary and systemic levels of AMP and their relationship with disease severity and future risk of exacerbations in bronchiectasis. METHODS A total of 135 adults with bronchiectasis were prospectively enrolled at three European centres. Levels of cathelicidin LL-37, lactoferrin, lysozyme and secretory leucocyte protease inhibitor (SLPI) in serum and sputum were determined at baseline by ELISA. Patients were followed up for 12 months. We examined the ability of sputum AMP to predict future exacerbation risk. MEASUREMENTS AND MAIN RESULTS AMP levels were higher in sputum than in serum, suggesting local AMP release. Patients with more severe disease at baseline had dysregulation of airway AMP. Higher LL-37 and lower SLPI levels were associated with Bronchiectasis Severity Index, lower FEV1 (forced expiratory volume in 1 s) and Pseudomonas aeruginosa infection. Low SLPI levels were also associated with the exacerbation frequency at baseline. During follow-up, higher LL-37 and lower SLPI levels were associated with a shorter time to the next exacerbation, whereas LL-37 alone predicted exacerbation frequency over the next 12 months. CONCLUSIONS Patients with bronchiectasis showed dysregulated sputum AMP levels, characterised by elevated LL-37 and reduced SLPI levels in the frequent exacerbator phenotype. Elevated LL-37 and reduced SLPI levels are associated with Pseudomonas aeruginosa infection and can predict future risk of exacerbations in bronchiectasis.
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Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia.
Bregman, DB, Morris, D, Koch, TA, He, A, Goodnough, LT
American journal of hematology. 2013;(2):97-101
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Abstract
Levels of hepcidin, a major regulator of iron homeostasis, may identify patients with iron deficiency anemia (IDA) who will not respond to oral iron therapy. In this study, IDA patients underwent a 14-day trial (run-in) course of ferrous sulfate therapy. Nonresponders (Hgb increase <1 g/dL with 67% compliance rate) were randomized to IV ferric carboxymaltose (FCM; two injections of 750 mg) or further oral iron for 14 days. Screening hepcidin levels were 38.4 versus 11.3 ng/mL, P = 0.0002 in nonresponders versus responders to a trial of oral iron. Hepcidin of > 20 ng/mL, showed sensitivity of 41.3%, specificity of 84.4%, and positive predictive value of 81.6% for predicting nonresponsiveness to oral iron. PPVs for ferritin> 30 ng/mL or transferrin saturation (TSAT)>15% were 59.2 and 55%, respectively. Negative predictive values for hepcidin, ferritin, and TSAT were 46.3, 22.7, and 19.7, respectively. FCM versus oral iron showed Hgb increases of ≥ 1 gm/dL in 65.3% versus 20.8% (P < 0.0001) and Hgb increases of 1.7 ± 1.3 versus 0.6 ± 0.9 g/dL (P = 0.0025), respectively. We conclude that hepcidin predicts nonresponsiveness to oral iron in patients with IDA and is superior to TSAT or ferritin for this purpose. Nonresponse to oral iron therapy does not rule out IDA, since two-thirds of patients subsequently responded to intravenous iron.
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Hepcidin-25 in chronic hemodialysis patients is related to residual kidney function and not to treatment with erythropoiesis stimulating agents.
van der Weerd, NC, Grooteman, MP, Bots, ML, van den Dorpel, MA, den Hoedt, CH, Mazairac, AH, Nubé, MJ, Penne, EL, Gaillard, CA, Wetzels, JF, et al
PloS one. 2012;(7):e39783
Abstract
Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.
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Serum levels of the hepcidin-20 isoform in a large general population: the Val Borbera study.
Campostrini, N, Traglia, M, Martinelli, N, Corbella, M, Cocca, M, Manna, D, Castagna, A, Masciullo, C, Silvestri, L, Olivieri, O, et al
Journal of proteomics. 2012;(5):28-35
Abstract
Hepcidin, a 25 amino-acid liver hormone, has recently emerged as the key regulator of iron homeostasis. Proteomic studies in limited number of subjects have shown that biological fluids can also contain truncated isoforms, whose role remains to be elucidated. We report, for the first time, data about serum levels of the hepcidin-20 isoform (hep-20) in a general population, taking advantage of the Val Borbera (VB) study where hepcidin-25 (hep-25) was measured by SELDI-TOF-MS. Detectable amount of hep-20 were found in sera from 854 out of 1577 subjects (54.2%), and its levels were about 14% of hep-25 levels. A small fraction of subjects (n=30, 1.9%) had detectable hep-20 but undetectable hep-25. In multivariate regression models, significant predictors of hep-20 were hep-25 and age in males, and hep-25, age, serum ferritin and body mass index in females. Of note, the hep-25:hep-20 ratio was not constant in the VB population, but increased progressively with increasing ferritin levels. This is not consistent with the simplistic view of hep-20 as a mere catabolic byproduct of hep-25. Although a possible active regulation of hep-20 production needs further confirmation, our results may also have implications for immunoassays for serum hepcidin based on antibodies lacking specificity for hep-25. This article is part of a Special Issue entitled: Integrated omics.