Clinical Significance of C-Reactive Protein Levels in Predicting Responsiveness to Iron Therapy in Patients with Inflammatory Bowel Disease and Iron Deficiency Anemia

Iron deficiency and iron deficiency anemia (IDA) are common complications in inflammatory bowel disease (IBD), IDA being a common cause of hospitalization and increased morbidity in this population [1, 2]. Poor management of anemia can significantly affect the quality of life and lead to an increase in hospitalization rates and associated medical costs [2, 3].

The two most common causes of anemia in IBD patients are absolute iron deficiency and anemia of chronic disease (ACD; also referred to as anemia of chronic inflammation) [1, 3]. Most IBD patients become iron deficient at some stages of the disease [3, 4]. Causes of iron deficiency in IBD patients include intestinal bleeding, poor absorption of iron by the diseased intestine, and/or self-imposed dietary restrictions relating to gastrointestinal symptoms. ACD is driven by the systemic immune response that accompanies inflammatory disease such as IBD [5]. Cells of the immune system release pro-inflammatory cytokines, predominantly interleukin-6 (IL-6), which in turn up-regulate the expression of hepcidin, a key regulator of iron homeostasis. Hepcidin expression results in a reduction in the uptake of iron from the duodenum and a reduction in the ability of the body to utilize sufficient iron for effective erythropoiesis—also called functional iron deficiency [5, 6].

C-reactive protein (CRP) is widely used as a routine marker of chronic or acute inflammation [7]. Normal values for CRP range between 0.20 and 6.10 mg/L [8]. In clinical practice, CRP levels ≥5 mg/L are usually considered elevated. Following an inflammatory stimulus, causing, for example, IL‐6 expression which can directly induce CRP expression in the liver, CRP levels rise rapidly to peak levels of 350–400 mg/L. CRP is routinely measured in IBD patients and forms part of the recommended diagnostic workup in patients with anemia (hemoglobin [Hb] < 12 g/dL in non-pregnant women, <13 g/dL in men) [3, 9]. A recent study in patients with IBD has shown a close correlation between CRP and hepcidin serum levels [10].

In addition to Hb and CRP measurements, the workup for IBD patients should include assessment of serum ferritin and transferrin saturation (TSAT) to accurately diagnose iron deficiency. Iron supplementation is recommended in all types of IBD-associated anemia where iron deficiency is present [2, 3, 9]. It has been proposed that chronic systemic inflammation may reduce the absorption of iron from the gut [11, 12]. In addition, gut luminal iron may induce oxidative stress [13] and increase local disease activity in IBD [3, 14]. Nevertheless, in clinical practice a course of oral iron therapy is often used as first-line treatment for anemic patients with IBD.

This study aimed to investigate the effect of baseline systemic inflammation (as assessed by CRP and IL-6) on the treatment efficacy of iron supplementation comparing tablets to intravenous injections. The correlation between the degree of inflammation and response to oral or i.v. iron therapy was retrospectively analyzed in an IBD patient population from a previously reported phase III clinical trial [15].

This is the largest study showing an impact of systemic inflammation on iron absorption in anemic IBD patients. Initial Hb response to oral iron was significantly lower in IBD patients with a high baseline CRP level (>4 mg/L), compared to those with low baseline CRP—at least for the first 2 months of treatment. Hb response to i.v. iron was mainly independent of baseline CRP. The results of this study suggest that patients with IBD and IDA, who have elevated CRP at initiation of treatment, may benefit from first-line treatment with i.v. iron to improve their IDA and obtain a more rapid response.

Our current findings are in line with the established link between inflammation and iron sequestration. In the inflammatory state, increased hepcidin levels block duodenal iron absorption [16]. Hepcidin binds to the iron exporter ferroportin located on the basolateral surface of gut enterocytes and causes its internalization and degradation. In addition, high hepcidin levels also block the release of ferritin-bound iron from cells of the reticuloendothelial system (e.g., macrophages) [6, 17]. This hepcidin block during inflammation leads to diminished amounts of free iron available for erythropoiesis [5]. Recent data suggest that there are also other pro-inflammatory pathways modulating duodenal iron absorption. In mice treated with the inflammatory cytokine TNF-α, reduced iron transport across the duodenal mucosa was shown [18, 19]. In patients with celiac disease, a correlation between iron deficiency and increased expression of ferritin in enterocytes of the duodenum was observed, indicating a link between iron absorption and local mucosal inflammation [20].

Our results are supported by the findings of three other studies. Significantly impaired oral iron absorption was reported in pediatric patients (n = 19) with active (defined by IL-6 > 5 pg/mL) versus inactive CD [11]. Serum iron levels inversely correlated with baseline CRP. As the test subjects were not anemic, only a single dose of oral iron was administered. The study lacked longer follow-up with prolonged iron administration and assessment of hematological response. Another study, a retrospective subanalysis from a phase III trial, found that a high baseline hepcidin level (>20 ng/mL) could predict reduced responsiveness to oral iron in anemic patients with chronic kidney disease (n = 240) [21]. However, the potential of hepcidin as a biomarker is limited, even though it is a more direct measure of iron sequestration than the well-established but unspecific inflammatory marker CRP. Hepcidin immunoassays may detect inactive forms as well as the biologically active form, hepcidin-25, and measurements can vary up to tenfold between different assays, making it difficult to determine reference values [22]. Other analytical methods utilizing mass spectrometry are not feasible for routine use in a hospital or outpatient setting [23]. Lastly, a recently presented investigation from our group has shown that IBD patients with ACD respond differently to oral iron treatment compared to those with IDA [12]. IBD patients with ACD had impaired oral iron absorption which correlated with disease activity and inflammatory markers but was independent of disease location and type of IBD (UC or CD).

Intravenous iron can for the most part overcome the hepcidin block [24] and is therefore advisable in IBD patients with pronounced disease activity [3, 9]. As shown in our and one other study [25], responsiveness to i.v. iron treatment appears to be independent of inflammatory status in IBD patients. Moreover, i.v. iron has been shown to be at least as effective as oral iron in randomized trials, delivering faster response rates and being better tolerated than oral iron [3, 9, 15, 26‐28].

The results of this study are indicative of a significant biological effect of systemic inflammation on iron uptake, but patient numbers were relatively small. In particular, the small number of oral iron-treated CD patients did not allow for meaningful subanalyses, although differences are likely to be more pronounced in this subpopulation due to greater systemic inflammation compared to UC patients [7]. The relevance of a single significant difference between the high- and low-CRP groups among i.v. iron-treated patients (at week 8) needs to be evaluated. It may reflect delayed release of iron from reticuloendothelial stores in active disease. We also investigated baseline IL-6 levels in our study, and some significant differences between the high- and low-IL-6 groups in terms of Hb response to oral iron could be observed. However, the predictive power of IL-6 was weak compared to CRP. The measurement of evaluated variables by local laboratories in this multicenter study may have added some additional variability into the data. Cytokines such as IL-6 are prone to degradation, and proper handling and storage of the samples are critical for the accuracy of the measurements. Published data suggest that IL-6 levels may be more relevant in CD than those in UC patients [29]. In future studies of this kind, measurement of hepcidin levels would be useful and medium-term follow-up of iron status establishes the mechanism of the effect. Of note, the efficacy data presented here are not confounded by compliance issues since adherence was monitored in the trial and was excellent (99.2 %) [15].

In conclusion, assessment of inflammatory status in terms of easily available CRP measurements could be useful in identifying patients who may initially benefit from first-line i.v. iron therapy. Based on the data from this relatively small patient group, patients with high CRP levels take longer to respond to oral iron but eventually reach similar responses at 3 months. Although the observed differences to the i.v. iron group are small, they may be important in clinical practice, where response to oral iron is often compromised by adherence problems. In the clinical trial setting, patients are selected for their willingness to participate and are more motivated to take oral iron, despite gastrointestinal side effects associated with this treatment. Overall, validation of the current findings in a larger patient sample is needed, including the investigation of potential differences in the predictive power for CD and UC patients, before clinical recommendations can be made.