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(Chest. 2002;121:48-54.)
© 2002 American College of Chest Physicians

Iron Deficiency in Cystic Fibrosis*

Relationship to Lung Disease Severity and Chronic Pseudomonas aeruginosa Infection

David W. Reid, MD; Nicholas J. Withers, MD; Libby Francis, RN; John W. Wilson, MD, FCCP and Thomas C. Kotsimbos, MD

* From the Cystic Fibrosis Service, Department of Respiratory Medicine, Monash University Medical School, Alfred Hospital, Prahran, Melbourne, VIC, Australia.

Correspondence to: David W. Reid, MD, Cystic Fibrosis Service, Department of Respiratory Medicine, Monash University Medical School, Alfred Hospital, Commercial Rd, Prahran, Melbourne, VIC, Australia 3181; e-mail: d.reid{at}alfred.org.au


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Iron deficiency (ID) is common in patients with cystic fibrosis (CF) and may be related to GI factors and chronic inflammation. Pseudomonas aeruginosa (PA) infection is predominantly responsible for chronic lung suppuration in patients with CF, but its survival is critically dependent on the availability of extracellular iron, which it obtains via highly efficient mechanisms.

Objective: To determine whether ID in CF patients is directly related to the severity of suppurative lung disease.

Design: We determined the iron status of 30 randomly selected adult CF patients (13 women) and assessed the relationship to lung disease severity and GI factors by determining their daily sputum volume, FEV1 percent predicted, C-reactive protein (CRP) level, erythrocyte sedimentation rate, and degree of pancreatic supplementation. Additionally, we measured the sputum concentrations of iron and ferritin in a randomly selected subgroup of 13 of the 30 subjects.

Setting: Adult CF Service in a tertiary-care center.

Results: Seventy-four percent of subjects experienced ID (ie, serum iron levels <= 12 µmol/L and/or transferrin saturation levels <= 16%). There was no relationship found with the degree of pancreatic supplementation. The daily sputum volume was strongly associated with low serum iron levels, transferrin saturation, ferritin/CRP ratio, and FEV1 percent predicted (p < 0.05). Serum iron levels and transferrin saturation were negatively related to CRP (r = -0.8 and r = -0.7, respectively; p < 0.01) and erythrocyte sedimentation rate (r = -0.5 and r = -0.4, respectively; p < 0.05). FEV1 percent predicted was positively related to serum iron level (r = 0.5; p < 0.01), transferrin saturation (r = 0.4; p < 0.05), and ferritin/CRP ratio (r = 0.7; p < 0.05). Sputum iron concentration (median, 63 µmol/L; range, 17 to 134 µmol/L) and ferritin concentration (median, 5,038 µg/L; range, 894 to 6,982 µg/L) exceeded plasma levels and negatively correlated with FEV1 percent predicted (r = -0.6 and r = -0.5, respectively; p <= 0.05).

Conclusion: In our CF patients, ID was directly related to the increased severity of suppurative lung disease but not to the degree of pancreatic insufficiency. Iron loss into the airway may contribute to ID and may facilitate PA infection.

Key Words: cystic fibrosis • iron deficiency • Pseudomonas aeruginosa


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Iron deficiency (ID) in patients with cystic fibrosis (CF) has been well-described, although its clinical significance is uncertain. The prevalence of ID increases from approximately 33% of pediatric cases to > 60% in the adult population, and it is normally attributed to a combination of chronic inflammation, GI factors, and poor dietary intake.1 2 3 4 5 6

Lung disease in patients with CF is characterized by colonization of the airway by Pseudomonas aeruginosa (PA) at an early age, and the development of chronic suppuration is related to the ability of this organism to proliferate despite a florid host immune response and aggressive antibiotic treatment. An indirect relationship between lung disease severity and the degree of malnutrition and ID in patients with CF has been identified,2 but whether this simply relates to the frequent association of severe lung disease with pancreatic insufficiency is unclear. However, it is possible that malabsorption of dietary antioxidants and systemic ID per se may contribute to lung destruction by impairing antioxidant and immune defense systems within the airway of the CF patient.7 8

A direct causal effect of PA infection and ID has not been established. However, the ability of PA to obtain extracellular iron from host tissues for growth and enhancement of virulence by the secretion of iron-binding granules, called siderophores, suggests that this organism could play a direct role in depleting the body of iron stores.9 If the loss of iron into the airway does occur as a consequence of PA infection, then the volume of purulent sputum expectorated daily and its potential iron content could significantly contribute to ID in CF patients. Indeed, evidence to support this potential mechanism of iron loss comes from two studies10 11 that have confirmed that the sputum and BAL fluid of CF subjects contains increased amounts of iron.

In this study, to test our hypothesis that ID in CF may be directly related to the severity of suppurative lung disease and PA infection, we measured serum indexes of iron status and determined their relationship to daily sputum volume, FEV1 percent predicted, and several biochemical markers of inflammation in 30 stable adult CF patients with moderately severe disease who were chronically infected with PA. Additionally, we determined the concentrations of total iron and ferritin in sputum from a randomly selected subgroup of 13 of the 30 CF patients. To assess the potential contribution of GI factors, we also determined the relationship between iron status and the degree of pancreatic supplementation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Thirty randomly selected adult patients (median age, 27 years; age range, 21 to 36 years; 13 women) who attended the Alfred Cystic Fibrosis Service outpatient clinic were recruited. All patients were stable, a term that was defined as no recent (ie, <= 4 weeks) worsening in symptoms or fall in lung function (median FEV1, 38% predicted; FEV1 range, 16 to 102% predicted). A history of macroscopic hemoptysis within the preceding 4 weeks or of massive or recurrent hemoptysis at any time in the past excluded that patient from this analysis. All subjects were infected with PA, which was confirmed by a routine microbiological culture. Patients were asked to recall the approximate volume of sputum expectorated daily over the preceding 2 weeks, and their daily usage and type of pancreatic enzyme supplementation was recorded. Venesection then was performed to determine serum iron and ferritin concentrations, transferrin saturation, and full blood count. Additionally, C-reactive protein (CRP) concentration and erythrocyte sedimentation rate were determined. Functional ID was considered to be present when transferrin saturation was < 16% and/or serum iron concentration was < 12 µmol/L, levels at which erythropoiesis becomes impaired.12 The acute-phase reactant nature of ferritin was corrected for by calculating the ferritin/CRP ratio. All hematologic and biochemical indexes were measured routinely by the hospital pathology service. FEV1 was measured by a heated pneumotachograph (Masterlab; Jaeger; Würzburg, Germany) and was expressed as the percent predicted for age, sex, and height (Table 1) .


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  		Table 1.. Characteristics of Patient Population, Serum and Sputum Indices, and Systemic Markers of Inflammation*

 
Microbiological Diagnosis
Sputum was sent for routine culture in the Department of Microbiology at our institution.

Sputum Processing
Spontaneously expectorated sputum was analyzed. Sputum samples were refrigerated (<= 4°C) and were processed within 2 h of expectoration. Sputum that was free of saliva was selected from the raw sample to avoid salivary cellular or solute contamination. The weight of sputum was measured, a volume of dithiothreitol 0.1% (Sputalysin; Calbiochem; San Diego, CA) equal to four times the weight of sputum was added, and the sample was mixed thoroughly prior to placing it in a water bath at 38°C for 30 min to lyse the mucus. The sample was removed at 10-min intervals for further mixing and, when it had been adequately homogenized, was centrifuged at 2,200 revolutions per minute for 10 min. The supernatant was decanted and stored in 1-mL aliquots at -80°C for further analysis.

Sputum Total Iron and Ferritin Assays
The total iron content of the cell-free, unconcentrated sputum supernatant was determined using a routine colorimetric assay (747 analyzer; Boehringer-Engelheim/Hitachi, Indianapolis, IN). The ferritin concentration was determined by fluorescence immunoassay using an analyzer (AXSYM; Abbott Laboratories; Abbott Park, IL).

Statistical Analysis
The data are expressed as medians and ranges, assuming a nonparametric distribution unless otherwise stated. Differences between categoric groups were assessed with the Mann-Whitney U test for nonparametric data. To determine the relationships between biochemical and physiologic variables, Spearman’s rank correlation was used. A two-tailed p value of < 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Seventy-four percent of the CF subjects studied experienced ID (ie, serum iron < 12 µmol/L and/or transferrin saturation < 16%). There was a trend toward a worse iron status in female patients (ID: women, 83%; men, 68%), although this did not reach statistical significance (p = 0.2). The degree of ID was unrelated to pancreatic supplementation. Iron status as determined by serum iron, transferrin saturation, and ferritin level corrected for CRP (ie, ferritin/CRP ratio) was strongly associated with the volume of daily sputum expectorated (p < 0.01). Additionally, FEV1 percent predicted was strongly related to the daily sputum volume (p < 0.01) and was positively correlated with serum iron concentration (r = 0.5; p < 0.01), transferrin saturation (r = 0.4; p < 0.05), ferritin/CRP ratio (r = 0.7; p < 0.05), and body mass index (BMI) [r = 0.6; p < 0.01]. The total sputum concentrations of iron (median, 63 µmol/L; range, 17 to 134 µmol/L) and ferritin (median, 5,038 µg/L; range, 894 to 6,982 µg/L) exceeded those found in normal serum, and both were significantly related to the FEV1 percent predicted (r = -0.6 and r = -0.5, respectively; p < 0.05). There was a significant relationship between sputum total iron and ferritin content (r = 0.5; p < 0.05). There was a significant negative relationship between FEV1 percent predicted and CRP (r = -0.7; p < 0.01) and a trend toward a negative relationship with erythrocyte sedimentation rate (r = -0.3; p = 0.09). Both serum iron concentration and transferrin saturation were positively related to BMI (r = 0.6; p < 0.01). There was no relationship between sputum iron indexes and systemic markers of iron status or inflammation (Table 1 and Figs 1 2 3 ).



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  		Figure 1.. Top left: comparison of FEV1 percent predicted values, depending on the daily sputum volume. The wide bars represent the 25th and 75th percentiles, the whisker bars show the fifth and 95th percentiles, and the center crossbar shows the median. * p < 0.05 (group 1 vs groups 2 and 3). Top right: comparison of serum iron results depending on the daily sputum volume. * p = 0.05 (group 1 vs group 2); ** p = 0.02 (group 1 vs group 3). Bottom left: comparison of the serum ferritin/CRP ratio depending on the daily sputum volume. * p < 0.05 (group 1 vs group 2); ** p < 0.001 (group 1 vs group 3). Bottom right: comparison of serum transferrin saturation depending on the daily sputum volume. * p = 0.08 (group 1 vs group 2); ** p < 0.05 (group 1 vs group 3). Sputum volume: 1 = <= 1/3 cup; 2 = 1/3 to 2/3 cup; 3 = >= 2/3 cup.

 


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  		Figure 2.. Top: relationship between FEV1 percent predicted and serum iron concentration. FEV1 percent predicted correlated significantly with serum iron concentration (r = 0.5; p < 0.01). Middle: relationship between FEV1 percent predicted and serum transferrin saturation. FEV1 percent predicted correlated significantly with serum transferring saturation (r = 0.4; p < 0.05). Bottom: relationship between FEV1 percent predicted and ferritin/CRP ratio, which had a significant correlation (r = 0.7; p < 0.05).

 


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  		Figure 3.. Top: relationship between FEV1 percent predicted and sputum iron concentration, which correlated significantly (r = -0.6; p < 0.05). Bottom: relationship between FEV1 %predicted and sputum ferritin concentration, which correlated significantly (r = -0.5; p = 0.05).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have confirmed the high prevalence of ID in CF patients and have demonstrated that ID is directly related to the severity of the underlying suppurative lung disease. Importantly, we also have found that ID is not related to pancreatic supplementation, although we have not excluded the potential role of other GI factors. Furthermore, we have demonstrated that sputum from stable adult CF patients with moderately severe lung disease contains high concentrations of iron and ferritin and have shown that a significant negative relationship exists between sputum iron and ferritin content and lung function in CF patients.

ID in patients with CF is common and has been attributed to a combination of factors, including chronic inflammation,3 malabsorption of iron secondary to pancreatic supplementation,5 13 GI blood loss as a consequence of gastroesophageal reflux or portal hypertension,4 6 and poor dietary intake. However, evidence concerning ID in CF patients is conflicting, especially with respect to GI absorption of iron and the role of pancreatic insufficiency and supplementation. Early studies found a surprising lack of ID anemia in children with CF when compared to other GI disorders characterized by steatorrhea, which were, in contrast, usually associated with ID.13 Postmortem studies14 of children with CF that were performed prior to the era of pancreatic replacement found evidence of considerable hemosiderosis of the liver, spleen, and bone marrow, suggesting that iron uptake and deposition were increased in CF patients. Other studies have demonstrated that this apparent increase in iron uptake can be inhibited by pancreatic enzymes,15 and pancreatic supplementation has been shown to significantly impair iron absorption in CF patients and healthy control subjects.5 However, more recent data demonstrate that iron absorption in CF patients is unrelated either to pancreatic insufficiency or replacement and that it increases only in response to depleted bone marrow stores, further adding to the uncertainty regarding iron homeostasis in CF.16 Additionally, the potential relationship between ID and the severity of suppurative lung disease has not previously been confirmed in CF patients.2 6 17

PA has evolved an efficient mechanism for obtaining ferric iron from its environment by secreting proteases and iron-chelating siderophores that are capable of cleaving ferric iron from binding proteins such as ferritin, lactoferrin, and transferrin.18 The end products of proteolysis and PA siderophores are detectable within the sputum of CF patients, and this ability to acquire iron from host tissues accompanied by the overwhelming burden of infection in the airway of the CF patient suggests that PA may play a significant role in the pathogenesis of ID in CF patients, particularly as disease severity progresses.19 Our findings of increased total iron and ferritin content of CF sputum support this hypothesis, and it is possible to approximate the annual loss of iron in the sputum using the following equation if one knows the atomic weight of iron (55.9) and assumes a median iron content of 63 µmol/L and an average daily sputum volume of 200 mL:

This represents a significant (and probably underestimated) loss of iron (that is, swallowed but not absorbed iron) given that normal menstruation, which is the most common cause of ID in the western world, has been estimated to account for approximately 800 mg iron loss per year.20 Although we were unable to demonstrate a significant correlation between an isolated sputum iron concentration and systemic or hematologic indexes of ID, this is not surprising as iron loss probably varies considerably over time depending on the patient’s clinical status, burden of infection, and volume of sputum. Additionally, ID remains multifactorial in CF patients, and its severity also will depend on the magnitude of GI losses and the adequacy of dietary intake and supplementation. One potential criticism of our findings and their interpretation is that the iron and ferritin content of sputum merely represents recurrent episodes of occult hemorrhage or continuous extravasation of RBCs as a consequence of airway inflammation. We believe that these potential explanations are unlikely for several reasons. First, the results of BAL performed in stable CF subjects suggest that RBCs normally comprise < 1% of recovered cells and are, therefore, an uncommon finding in the absence of clinically apparent pulmonary hemorrhage.21 Additionally, RBCs contain almost negligible amounts of ferritin (ie, < 10-19 g/L), and to account for the concentrations of ferritin detected in our study would require a hemorrhage of at least 100 L if this were the only source of loss (ie, 100 L x [5 x 1012 RBCs/L blood] x [10-19 RBC ferritin content µg/L] = 500 x 10 -6g/L). Furthermore, although vascular leakage may be responsible for some of the iron and ferritin detected, plasma exudation is unlikely to be a significant contributor because the concentrations of ferritin and iron within sputum greatly exceeded those of normal plasma (ie, 15 to 300 x 10-6 g/L and 11 to 31 µmol/L, respectively).

Chronic PA infection and the cycle of acute exacerbations that ultimately results in organ destruction and failure also may contribute to ID in CF patients indirectly by stimulating a florid systemic inflammatory response. Detectable circulating cytokines such as tumor necrosis factor-{alpha} and interleukin-8, which are released in response to bacterial infection, can reduce the systemic availability of iron by diverting it away from hemoglobin synthesis, and they also contribute to the anorexia and cachexia of chronic disease.22 23 Increased levels of these circulating inflammatory mediators have been demonstrated in CF patients, and data suggest that production is up-regulated during exacerbations and during the terminal phases of the disease.24 25 Additionally, tumor necrosis factor-{alpha} up-regulates cellular ferritin messenger RNA synthesis, and increased tissue iron deposition within the lung could potentially provide a reservoir of iron for PA acquisition.26

In summary, ID is very common in the adult CF population and is directly related to the severity of suppurative lung disease. Contrary to previous belief, ID is not related to pancreatic supplementation and does not appear to confer any demonstrable benefit to the host by limiting the burden of PA infection.27 PA probably contributes both directly and indirectly to ID and anemia in CF patients, first by actively acquiring iron from the host airway and, second, by stimulating the production of circulating cytokines, which can both divert iron away from hemoglobin synthesis and promote local iron storage as intracellular ferritin. The presence of ID may be a surrogate marker of more severe disease, and further studies need to be undertaken to investigate the significance of ID in the early stage of the disease and to relate its presence to subsequent outcome. Finally, our knowledge concerning the role of PA infection in the evolution of CF lung disease and systemic morbidity continues to expand, and aggressive therapeutic interventions, including the use of iron-binding agents early in the course of the disease might lessen the impact of PA infection and improve outcome.


   Footnotes
 
Abbreviations: BMI = body mass index; CF = cystic fibrosis; CRP = C-reactive protein; ID = iron deficiency; PA = Pseudomonas aeruginosa

Received for publication February 13, 2001. Accepted for publication June 27, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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