What is hepcidin telling us about the natural history of cystic fibrosis

An expanding body of evidence suggests that iron homeostasis is abnormal in cystic fibrosis (CF). Concentrations of iron in the sputum and bronchoalveolar lavage (BAL) fluid of healthy unaffected persons are <16 μmol/l [1,2] and 0.13 μmol/l [3], respectively, whereas that of CF sputum generally exceeds 30 μmol/l and can be as high as 200 μmol/l [1,2]. Using an in-vitro co-culture model of polarized human bronchial epithelial cells and Pseudomonas aeruginosa (Pa), Moreau-Marquis et al. [4] first observed that F508del-CFTR increased the iron content of airway surface liquid, a phenomenon that promoted Pa biofilm growth. Thus, the genetic defect found in most CF patients [5] plausibly contributes to the persistence of this and other pathogens by increasing the availability of a typically scarce micronutrient. Among CF adults, those who have more iron in their sputum not only have higher circulating interleukin-6 (IL-6) levels but also have lower blood iron stores, or relative hypoferremia [6]. IL-6 drives hepatic production of the small peptide hormone, hepcidin-25, which potently induces hypoferremia [7]. I am intrigued by the observations of Uijterschout et al. [8] that serum hepcidin-25 levels were generally low in children with CF but were higher among those who recently experienced a pulmonary exacerbation than those who displayed stable health. These data in the pediatric CF population, coupled with those presented by Gifford et al. in CF adults [9], highlight the central regulatory role of hepcidin-25 in iron handling, particularly as the inflammatory milieu waxes and wanes in these patients with persistent microbial infection. Both groups studied biomarkers linking hepcidin-25 to systemic inflammation, thus providing objective evidence for the presence or absence of pulmonary exacerbations, symptomatic periods in the natural history of CF [10] for which definitions are still debated [11,12]. Uijterschout et al. [8] classified acute assessments as those during which children were found to have an elevated serum C-reactive protein (CRP) >10 mg/l and a history within the prior month of clinical deterioration and/or decrease in pulmonary function requiring antibiotics. In addition to having a mean serum hepcidin-25 level nearly three times higher than that of 36 stable children, the cohort of 13 acute patients had significantly worse pulmonary function and was older and more commonly infected by Pa. In 12 adults who met published criteria for pulmonary exacerbation [6], Gifford et al. [9] found that serum IL-6 and hepcidin-25 fell commensurately in response to intravenous antibiotics. Interestingly, the mean post-treatment serum hepcidin-25 concentration for these CF adults (22.7 ng/ml) exceeded that reported by Uijterschout et al. [8] for their acute (14.5 ng/ml) and stable (5.0 ng/ml) pediatric patients, applying a conversion factor for serum hepcidin of 1 nM = 2.79 μg/l. This comparison suggests that hepcidin-25 production might increase across the lifespan of CF patients, perhaps due to stimulation of the liver by IL-6 and/or other cytokines or by exposure to cryptic microbial factors. Alternatively, CF hepatocytes may lose their ability to appropriately restrict hepcidin-25 synthesis in light of hypoxemia or erythropoietic stimuli [13]. Progressive iron accumulation in the CF lung [14] might also convey an erroneous signal of iron sufficiency or even overload to the liver, which would be predicted to raise hepcidin-25 levels. Small peptides with internal disulfide bonds, including hepcidin-25 [15], have intrinsic antimicrobial properties, raising the possibility that higher serum concentrations in adults reflect an augmentation of the innate immune response to pathogens that are more abundant and/or virulent than those usually found in the pediatric CF lung. Studies designed to track the evolution of hepcidin biochemistry within the same patients stand to generate important knowledge about CF iron homeostasis. Given that hepcidin-25 induces hypoferremia by attenuating duodenal iron absorption and promoting iron sequestration in mononuclear cells [13], it is reasonable to posit that differences in the prevalence of hypoferremia between children and adults with CF (Table 1) are explained by differences in circulating hepcidin-25 levels, and by extension, differences in acute and chronic health status. Indeed, Gifford et al. [16] recently demonstrated in a longitudinal study of 22 adults with advanced disease that serum hepcidin-25 measurements were directly correlated with Akron Pulmonary Exacerbation Scores. Therefore, while context-specific variation in serum hepcidin-25 could limit its utility as diagnostic test for iron deficiency, changes that are stereotypical for a given patient may prove useful in the prediction of clinical events and/or treatment adequacy. Table 1 Heterogeneity in the biochemical definition of iron deficiency in cystic fibrosis. TSAT = transferrin saturation; sTfR = soluble transferrin receptor. From a practical standpoint, iron status is a moving target in CF. As Uijterschout et al. [8] discovered for soluble transferrin receptor (sTfR), a single blood test is unlikely to distinguish between absolute and functional iron deficiency in the CF population, especially when numerous biochemical criteria (Table 1) have been used to describe these entities. Nonetheless, their use of serum ferritin <12 μg/l in children <5 years of age and <15 μg/l in older children to define iron deficiency is certainly sound and consistent with earlier work [17], adding an invaluable measure of uniformity to the pediatric literature on this topic. Arbitrarily determining cutoffs for various iron-related hematologic parameters, even serum hepcidin-25, may not be the most constructive approach to understanding CF iron homeostasis. Rather, the CF community should work toward consensus about the measurement, interpretation, and use of these parameters in clinical practice.