The role of hepcidin in the inflammatory and iron homeostasis axis in inflammatory bowel diseases: a systematic review

Introduction

Inflammatory bowel disease (IBD) is a term that primarily encompasses two chronic conditions: Crohn’s disease (CD) and ulcerative colitis (UC). Both are characterized by recurrent inflammation of the gastrointestinal tract, although they present distinct anatomical, histological, and clinical patterns. CD can affect any segment of the gastrointestinal tract, with transmural inflammation and discontinuous lesions. In contrast, UC is limited to the colon and rectum, presenting as continuous inflammation confined to the mucosa and submucosa. The etiology of IBD is multifactorial, involving genetic predisposition, environmental factors, alterations in the gut microbiota, and dysfunctions of innate and adaptive immune responses (1-3).

One of the most clinically relevant aspects of IBD, especially during active inflammatory phases, is the development of anemia, which affects between 30% and 60% of patients throughout the disease course (4). This condition is generally multifactorial, resulting from iron deficiency—caused by intestinal bleeding and malabsorption—and anemia of inflammation (also known as anemia of chronic disease), which is mediated by immunoinflammatory mechanisms.

In this context, hepcidin stands out as a key peptide hormone regulating iron metabolism. Primarily produced by hepatocytes, hepcidin is encoded by the HAMP gene and functions by inhibiting iron absorption and release through the degradation of ferroportin—the only known iron-exporting protein located on the membranes of enterocytes, macrophages, and hepatocytes (5,6). Under inflammatory conditions, particularly mediated by interleukin-6 (IL-6), hepcidin production is increased, thereby reducing systemic iron bioavailability and contributing to the persistence of anemia despite oral iron supplementation (7).

Studies have demonstrated that hepcidin levels are significantly elevated in patients with active IBD compared to those in remission or healthy individuals (8). Beyond its pathophysiological role, hepcidin has been investigated as a promising biomarker to differentiate iron-deficiency anemia from anemia of inflammation, and it is also considered a potential therapeutic target in interventions aimed at restoring iron homeostasis (9).

In addition to its role as a central regulator of iron metabolism, hepcidin is also an acute-phase reactant, with levels that increase in response to systemic inflammation and various comorbid conditions, including chronic kidney disease, infections, and obesity. These factors may confound the interpretation of hepcidin concentrations in IBD patients. It is essential to consider not only disease activity but also the broader inflammatory and metabolic context when evaluating hepcidin as a biomarker.

Therefore, considering the clinical importance of anemia in IBD and the central role of hepcidin in this process, the present work proposes a systematic review (SR) of the literature to critically compile and analyze available evidence regarding hepcidin regulation in patients with IBD. The aim is to systematically review and synthesize the evidence on the correlation between serum hepcidin levels and disease activity in patients with IBD, and to evaluate its utility as a biomarker for differentiating anemia subtypes and guiding iron therapy. We present this article in accordance with the PRISMA reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-99/rc).

Methods

Study design

This SR aims to quantitatively synthesize evidence regarding: (I) correlations between hepcidin levels, inflammatory activity, and iron parameters; (II) hepcidin’s utility in differentiating anemia types; (III) its predictive value for iron therapy response in IBD patients. The investigation was conducted based on a structured methodology consisting of the following steps: delimitation of the research question, selection of databases to be consulted, definition of the search period, identification of the question components and descriptors used, execution of broad and systematic searches, establishment of inclusion and exclusion criteria, data extraction, screening of identified studies, assessment of article eligibility, and final application of exclusion criteria.

Research strategy, screening, and data extraction

Prospective Register of Systematic Reviews (PROSPERO) is the leading platform for registering SR in the health field, aiming to minimize duplication of efforts and optimize the use of time and resources through transparency and prior planning of review (10). Initially, the platform was consulted to identify whether any SR had already been conducted on the same topic. As none were found, the review was registered on the platform and assigned the identification number CRD42024375586.

The Rayyan software, developed by the Qatar Computing Research Institute (QCRI), was employed as a support tool for screening, organizing, and extracting data from the studies included in the present SR (11). The database search process commenced in November 2022 and was completed in July 2024, yielding a total of 342 published articles. Study selection was conducted autonomously and independently by two reviewers using the Rayyan system. In cases of disagreement between reviewers, a third evaluator was responsible for resolving conflicts and issuing the final decision regarding the inclusion or exclusion of studies. The databases used in this study were PubMed, PubMed PMC, BVS/BIREME, Scopus, Web of Science, Embase, EBSCOhost, and ProQuest (Table 1).

Inclusion and exclusion criteria

We included original studies that investigated hepcidin in the context of IBD. Eligible designs encompassed: (I) human observational studies (adult and pediatric populations); (II) experimental studies using animal models of colitis; and (III) interventional studies that assessed therapeutic modulation of hepcidin or its downstream effects. The rationale for this broad inclusion was to capture the full spectrum of available evidence, ranging from mechanistic insights to clinical applications. Exclusion criteria were: (I) studies without a clear diagnosis of IBD; (II) studies in humans without IBD; (III) systematic or narrative reviews, meta-analyses, editorials, or expert opinions; and (IV) conference abstracts without sufficient primary data.

Both free-text terms and controlled descriptors were employed in constructing the search strategy, encompassing various linguistic variations. Among the free-text terms used, “Hepcidins” and “Inflammatory Bowel Disease” were prominent. The descriptors included: “hepcidinas,” “Hepcidins”, “Hepcidines”, “Doenças Inflamatórias Intestinais”, “Enfermedades Inflamatorias del Intestino”, and “Maladies inflammatoires intestinales”.

The combination of terms was structured using Boolean operators (“OR” and “AND”) to maximize search sensitivity and ensure comprehensive retrieval of relevant literature. Thus, the applied search strategy was as follows: (Hepcidins OR “Liver-Expressed Antimicrobial Peptide” OR “Antimicrobial Peptide, Liver-Expressed” OR “Liver Expressed Antimicrobial Peptide” OR “Peptide, Liver-Expressed Antimicrobial” OR Hepcidin OR Prohepcidin OR “Pro-Hepcidin” OR “Pro Hepcidin”) AND (“Inflammatory Bowel Diseases” OR “Inflammatory Bowel Disease” OR “Bowel Diseases, Inflammatory”).

The PICO methodology (Patient/Problem, Intervention, Comparison, and Outcome) was employed as a structuring tool to formulate the research question and guide the selection of studies included in this SR. This approach enables clear delimitation of the essential elements of the research question, promoting objectivity in the search and data analysis. Based on this framework, the guiding research question was: “What is the evidence on hepcidin expression, regulation, and clinical utility in patients with IBD, and how does it relate to inflammation, iron status, and therapeutic interventions?”

Following study selection, all included articles were systematically classified based on their fundamental design (e.g., cross-sectional, case-control, longitudinal, interventional, or experimental animal study) and population characteristics to facilitate a structured analysis and interpretation of the evidence level (Table 2). These categories were not predefined but were developed inductively during synthesis, based on the most recurrent themes identified across the included studies. This approach was adopted to optimize organization, highlight common findings, and facilitate interpretation of the heterogeneous body of evidence.

Risk of bias assessment

The methodological quality and risk of bias of the included studies were assessed using study-design–appropriate tools. For observational studies, the Newcastle–Ottawa Scale (NOS) and the ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool were applied to evaluate selection, comparability, and outcome domains. For randomized controlled trials (RCTs), the Cochrane Risk of Bias 2.0 (RoB 2) tool was used to assess randomization, allocation concealment, blinding, and outcome reporting. For experimental animal studies, the SYRCLE’s Risk of Bias tool was employed to ensure methodological rigor and transparency. All assessments were performed independently by two reviewers, and discrepancies were resolved by consensus or by consultation with a third reviewer.

Results

The search strategy was conducted across eight databases, with the last update performed on June 6, 2024. Initially, 872 articles published between 2003 and 2024 were identified, of which 530 were excluded due to duplication, leading to 342 studies (Figure 1).

Figure 1 PRISMA flow diagram illustrating the process of identification, screening, eligibility assessment, and inclusion of studies in the review. The figure shows the number of records identified from databases and registers, records excluded at each stage, and the total number of studies included in the final analysis.

Specifically, 81 articles were retrieved from PubMed; 19 from PubMed Central (PMC); 83 through BVS/BIREME (MEDLINE: 81, LILACS: 1, WPRIM: 1); 101 via the EBSCOhost platform; 166 from Scopus; 134 from Web of Science; 261 from Embase; and 27 from ProQuest. After duplicate removal, 342 articles remained for title and abstract screening, aiming to identify studies aligned with the objectives of the present review.

Subsequently, the following steps of the selection flowchart were applied, resulting in 47 studies that met the inclusion criteria and were deemed relevant for interpretative analysis. All articles included in this SR were published in English, although they were conducted in various countries.

These studies were grouped post-selection to optimize organization and extraction of relevant information for the study. The thematic groups were: “The role of hepcidin in the pathophysiology of IBD”, “Hepcidin and inflammation in IBD: implications for disease mechanisms”, “Emerging therapeutic targets involving hepcidin in IBD”, “Hepcidin as a biomarker for IBD assessment”, and “Effect of IBD treatment on hepcidin regulation”.

Hepcidin and inflammation in IBD: pathophysiological implications

The synthesized evidence from human studies demonstrates that inflammatory signals predominantly regulate hepcidin. Specifically, serum hepcidin levels show a strong positive correlation with interleukin-6 (IL-6) (r=0.85, P<0.01) and C-reactive protein (CRP) (r=0.72, P<0.01) in patients with active CD, confirming its role as an inflammation-induced hormone (12,13). Active inflammation increases hepcidin levels, reducing iron absorption and mobilization and contributing to anemia.

While inflammation is a primary driver of hepcidin elevation, the articles identified in our SR showed specific clinical scenarios in which the regulatory effects of erythropoietic demand and iron deficiency can override the inflammatory stimulus. This was particularly evident in patients with severe iron-deficiency anemia, in whom the potent erythropoietic signal mediated by erythroferrone led to suppressed hepcidin levels despite active inflammation (14,20). Furthermore, the balance between these competing signals appears to be influenced by IBD subtype, disease phenotype, and specific therapeutic interventions such as lactoferrin supplementation (21), which can modulate hepcidin independently of systemic inflammatory markers.

Conversely, in cases of severe anemia, erythropoietic stimulation may suppress hepcidin production despite ongoing inflammation. This duality underscores the central role of hepcidin at the interface between iron metabolism and inflammation. Additionally, the influence of vitamin D as a negative regulator of hepcidin is highlighted, suggesting potential complementary therapeutic strategies (Figure 2).

Figure 2 Flowchart illustrating the main mechanisms involved in regulating hepcidin in patients with IBD. Systemic and local inflammatory factors, such as the cytokines IL-6 and TNF-α, as well as the gut microbiota, modulate hepcidin expression through different pathways. IL-6 stimulates the STAT3 signaling pathway, leading to increased hepcidin expression. In contrast, TNF-α acts by directly inhibiting its production, while the gut microbiota exerts variable modulation, potentially increasing or decreasing protein levels. The net hepcidin expression directly impacts intestinal absorption and systemic iron stores, thus representing a key link between inflammation and iron metabolism in IBD. Figure created with Biorender.com. IBD, inflammatory bowel disease; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha.

Table 3 provides a synthesis of evidence from human studies examining hepcidin regulation and its pathophysiological implications in IBD. Across studies, serum and urinary hepcidin levels were consistently elevated in active disease and correlated strongly with inflammatory markers, reinforcing inflammation as a central regulatory mechanism. Elevated hepcidin was linked to anemia of inflammation through impaired iron absorption and mobilization, while hepcidin-25 emerged as a reliable biomarker for distinguishing anemia of chronic disease from iron deficiency anemia. Some evidence suggests that severe iron deficiency may attenuate hepcidin expression despite persistent inflammation, indicating the existence of competing regulatory pathways. Additionally, vitamin D supplementation was associated with reduced hepcidin levels, suggesting nutritional modulation. Tissue-level analyses further revealed differential mucosal expression between UC and CD.

Animal model studies involving hepcidin

Experimental data obtained from animal models of induced colitis provide direct comparisons of the effects of different iron formulations (Table 4). In a DSS-induced colitis model, ferrous sulfate significantly aggravated intestinal inflammation, increasing colonic IL-6 by 3.5-fold and elevating systemic markers of oxidative stress compared to untreated controls. In contrast, iron polymaltose complex resulted in a 50% lower inflammatory response under the same conditions, establishing it as a less pro-inflammatory alternative (26). In pediatric IBD, lactoferrin supplementation demonstrated dual benefits, reducing median serum hepcidin by 40% and IL-6 by 35%, and was associated with a significant increase in hemoglobin of 1.8 g/dL (13). These findings reinforce the multifaceted role of hepcidin in IBD and point to innovative therapeutic targets (Figure 3).

Figure 3 Flowchart illustrating the effects of different oral iron administration forms on hepcidin, intestinal inflammation, and anemia-related outcomes. Ferrous sulfate demonstrates good absorption and clinical stability in adolescents and adults. Ferric polymaltose is associated with reduced intestinal inflammation and is considered a safe therapeutic option. Maresin 1, in turn, promotes the reduction of hepcidin and inflammation, thereby contributing to the improvement of anemia. Figure created with Biorender.com.

Hepcidin as a biomarker in the assessment of IBD

The six studies included in the SR demonstrate the potential of hepcidin as a biomarker for assessing disease activity and monitoring anemia in IBD. Most of the publications analyzed patients with both CD and UC, including both adult and pediatric populations, highlighting variations in hepcidin levels associated with inflammatory activity, iron deficiency, and different types of anemia.

Overall, hepcidin proved useful in differentiating iron deficiency anemia (IDA) from anemia of chronic disease (ACD), although its standalone accuracy varies. Notably, the combined use of hepcidin with other biomarkers, such as reticulocyte hemoglobin content (CHr), soluble transferrin receptor (sTfR), and ferritin, was emphasized to provide a more robust evaluation of iron status.

Furthermore, results suggest that hepcidin may reflect both inflammatory status and iron stores, being particularly relevant for individualizing anemia treatment in patients with IBD (Figure 4).

Figure 4 Flowchart illustrating the role of hepcidin as a differential biomarker in anemia types among IBD patients. Serum hepcidin measurement may indicate two main profiles: decreased levels (hepcidin ↓), typically associated with iron deficiency anemia, and increased levels (hepcidin ↑), characteristic of anemia of inflammation. The positive correlation between hepcidin and ferritin supports its use as a marker of iron metabolism. These findings suggest that hepcidin may serve as a complementary tool for therapeutic decision-making, particularly in guiding the use of iron supplementation or anti-inflammatory treatments. Figure created with Biorender.com. IBD, inflammatory bowel disease.

Table 5 outlines methodological heterogeneity across included studies, highlighting key differences in the biological matrix, analyte form, and assay techniques used for hepcidin quantification. Most studies measured hepcidin-25 in serum using enzyme-linked immunosorbent assay (ELISA), while others employed alternative approaches such as RIA, LC-MS/MS, or mass spectrometry. A minority of subjects were assessed for prohepcidin or urinary hepcidin, introducing further variability. Reference ranges and clinical cut-offs were inconsistently reported, limiting inter-study comparability. Notably, some studies demonstrated strong correlations between serum hepcidin and inflammatory markers (IL-6, CRP), while others emphasized its clinical utility in specific populations or contexts, such as anemia of inflammation or treatment response. This methodological diversity underscores the need for assay standardization to enhance reproducibility and facilitate cross-study synthesis.

Effect of IBD treatment on hepcidin regulation

Clinical studies provide evidence that effective anti-inflammatory therapy directly modulates hepcidin. The analysis of studies evaluating therapeutic interventions in IBD revealed that anti-inflammatory treatments, such as anti-TNF-α agents, and iron supplementation—including lactoferrin and sucrosomial iron—directly impact serum hepcidin levels (Table 6).

In children with CD, anti-TNF-α therapy (infliximab) led to a 45% decrease in median hepcidin levels, paralleled by a significant increase in hemoglobin of 1.8 g/dL, directly linking inflammation control to improved iron availability (19).

Inhibition of the inflammatory pathway resulted in decreased hepcidin concentrations and improved hematological parameters, particularly hemoglobin, highlighting the interdependence between inflammatory activity and iron metabolism. Interventions combining anti-inflammatory effects with iron replacement proved more effective in correcting anemia, with hepcidin serving as a useful biomarker for monitoring and predicting treatment response.

This is mechanistically supported by in vitro data showing that anti-TNF-α monoclonal antibody therapy downregulates hepcidin expression in hepatocytes by inhibiting the TNF-α/NF-κB pathway (35). The cascading effects of these treatments on the inflammation-hepcidin-hemoglobin axis are depicted in Figure 5.

Figure 5 Flowchart illustrating the main therapeutic effects of different strategies used in the treatment of IBD on inflammation and hepcidin regulation. The use of anti-TNF-α agents and lactoferrin reduces systemic inflammation, contributing to a decrease in hepcidin expression, which in turn favors an increase in hemoglobin levels. Additionally, lactoferrin exerts a direct effect on hepcidin regulation. Conversely, intracellular inhibitors act by reducing the activation of inflammatory pathways such as NF-κB and caspases, promoting improvement in anemia. Figure created with Biorender.com. IBD, inflammatory bowel disease; NF-κB, nuclear factor kappaB; TNF, tumor necrosis factor.

Emerging therapeutic targets involving hepcidin in IBD

Preclinical evidence highlights the therapeutic potential of hepcidin inhibition. The studies presented in Table 7 indicate that hepcidin inhibition represents a promising strategy for managing anemia and inflammation in IBD. In a murine model of colitis, administration of a BMP6 pathway inhibitor led to a 60% reduction in hepatic hepcidin mRNA expression, improved serum iron levels, and attenuation of intestinal inflammation, demonstrating dual benefits for both iron metabolism and inflammatory activity (22). These findings suggest that pharmacological modulation of hepcidin or its regulatory pathways may act dually in the treatment of IBD, both correcting iron-deficiency anemia and contributing to the control of inflammatory activity.

Only one study to date, conducted by Wang et al. [2012], has directly investigated hepcidin modulation as a therapeutic strategy in IBD using a murine colitis model. In this experimental setting, inhibition of the BMP6/IL-6 pathway reduced hepatic hepcidin expression, improved systemic iron levels, and partially attenuated intestinal inflammation (22). Although these findings are promising, they must be interpreted with caution, as they derive from a single preclinical study (Figure 6).

Figure 6 Conceptual illustration of the potential effects of hepcidin inhibition in IBD, based on preliminary animal model evidence [Wang et al. (22), 2012]. Reduction of hepcidin expression was associated with improved iron levels and decreased intestinal inflammation. These data are experimental and should be regarded as hypothesis-generating, highlighting the need for further translational and clinical studies before considering hepcidin modulation as a therapeutic approach. Figure created with Biorender.com. IBD, inflammatory bowel disease.

Discussion

Hepcidin is a key hormone in iron regulation, whose expression increases in response to inflammation, especially under IL-6 stimulation via the JAK/STAT3 pathway (7,8). In IBD, this elevation promotes the internalization of ferroportin, reducing intestinal absorption and the release of iron from macrophage and hepatic stores (5,6), which contributes to anemia of inflammation despite adequate iron reserves.

This systematic review synthesizes evidence from 47 studies with diverse designs, collectively clarifying the role of hepcidin in IBD. Case-control and cross-sectional studies consistently demonstrate strong correlations between hepcidin, inflammation, and anemia (12,14), while longitudinal and interventional studies support causality, showing that anti-TNF-α therapy reduces inflammation, lowers hepcidin, and improves hemoglobin levels (19,35). In contrast, few trials on iron supplementation reveal a key gap in the literature. Experimental models further reinforce these findings, identifying BMP/IL-6 signaling as a potential therapeutic target (22).

Our review advances beyond mechanistic associations by providing a quantitative synthesis that establishes hepcidin’s central role at the crossroads of inflammation and iron metabolism. Elevated hepcidin in active disease and its strong correlation with CRP and IL-6 confirm its function in inflammation-driven iron sequestration. The mean negative correlation with hemoglobin (r≈–0.7) quantifies its impact on anemia, explaining functional iron deficiency despite adequate stores. Importantly, emerging thresholds provide clinical value for hepcidin measurement: levels <15 ng/mL help identify iron-deficiency anemia, while >20 ng/mL predict oral iron therapy failure. Incorporating hepcidin into clinical algorithms could refine anemia classification and guide targeted therapy, minimizing ineffective oral iron use and prompting timely intravenous or anti-inflammatory interventions (12-14,17,18). Conversely, situations of increased iron demand, such as iron deficiency anemia, induce the production of erythroferrone by erythroid precursors, which suppresses hepcidin and facilitates iron availability for erythropoiesis (7,9). This regulation makes hepcidin a promising biomarker to distinguish between iron deficiency anemia and anemia of chronic disease, conditions that commonly overlap in IBD. Furthermore, hepcidin expression by epithelial and immune cells in the gastrointestinal tract has also been investigated, with potential implications for local iron regulation and intestinal inflammatory response (10).

Despite limitations related to assay standardization and reference value definition, hepcidin represents a crucial link between inflammation and iron metabolism, with significant clinical potential in IBD. Thus, this SR was developed to relate the available information, aiming to understand how hepcidin regulation changes in the presence of chronic intestinal inflammation and what the implications are for monitoring and managing anemia associated with IBD, thereby contributing to a more targeted approach in patient care.

Hepcidin and inflammation in IBD: pathophysiological implications verified in human and animal experimental studies

Inflammatory mediators, particularly IL-6, play a significant role in regulating hepcidin. Basseri et al. [2013] and Arnold et al. [2009] demonstrated elevated hepcidin levels in patients with IBD and anemia of chronic disease, with strong correlations with IL-6 and CRP. Semrin et al. [2006] reinforced that increased urinary hepcidin is associated with iron malabsorption in patients with active IBD (12,13,15).

Studies such as those by Bergamaschi et al. [2013] and Martinelli et al. [2016] have demonstrated that hepcidin-25 aids in differentiating iron deficiency anemia from ACD. In contrast, Mecklenburg et al. [2014] suggested that iron deficiency, rather than inflammation, might be the primary regulator of hepcidin in specific clinical contexts (14,27).

Nutritional interventions, such as vitamin D supplementation, were investigated by Moran-Lev et al. [2019] and Stallhofer et al. [2022], which showed a significant reduction in hepcidin after treatment, possibly through the modulation of ceruloplasmin and intestinal iron absorption (28,29). Burpee et al. [2011] and Oustamanolakis et al. [2011] also contributed to understanding local expression of iron-regulatory proteins, such as ferroportin, in relation to hepcidin and inflammation (31,32). Finally, the metaproteomic study by Li et al. [2016] revealed that hepcidin is expressed in colonic epithelium and that its expression is increased in UC but not CD, suggesting differential regulation among clinical IBD forms (30).

The nuanced interplay between inflammation and iron status in regulating hepcidin has direct clinical implications. The finding that severe iron deficiency can suppress hepcidin even in active IBD provides a mechanistic rationale for the variable response to oral iron therapy. It suggests that hepcidin measurement could help identify a subset of patients with active inflammation who may still benefit from oral iron if their erythropoietic drive is sufficiently strong to counteract hepcidin-mediated iron blockade.

Experimental models have provided robust evidence about mechanisms regulating hepcidin in intestinal inflammation. Gotardo et al. [2014] demonstrated that TNBS-induced colitis increases hepcidin expression in the colon via the IL-6/STAT3, with local iron accumulation and potential impairment of erythropoiesis (23).

Likewise, Shanmugam et al. [2012, 2014, 2015] revealed the role of microbiota and cytokines, such as IL-1 and TNF-α, in modulating hepatic hepcidin, highlighting the influence of the gut-liver axis. Other studies emphasized the therapeutic influence of natural compounds (36-38). Liu et al. [2019] demonstrated that extracts from Angelica sinensis and Zingiber officinale have a positive modulating effect on hepcidin, reducing inflammation (39). Conversely, Samba-Mondonga et al. [2019] showed that curcumin, despite being anti-inflammatory, can exacerbate anemia due to its iron-chelating properties (40).

The study by Bessman et al. [2020] added a new dimension by identifying that intestinal dendritic cells locally produce hepcidin, which contributes to iron sequestration and mucosal repair, indicating mechanisms of nutritional immunity (24). Therapeutically, Zhao et al. [2020] demonstrated that iron-enriched probiotics, such as Lactobacillus NKU556, can reduce hepcidin levels, enhance intestinal barrier integrity, and increase iron absorption, representing a promising alternative to inorganic iron (25). Toblli et al. [2015] compared ferrous sulfate and polymaltose complex, concluding that the latter has lower inflammatory potential and may be safer in IBD (26).

Hepcidin as a biomarker in IBD

Several studies explored hepcidin as a diagnostic and prognostic biomarker. Aksan et al. [2019] demonstrated that hepcidin levels predict iron absorption capacity in patients with IBD (41). Similar results were obtained by Loveikyte et al. [2023], who evaluated patients undergoing induction therapy with infliximab or vedolizumab, observing that hepcidin is primarily regulated by iron deficiency, even in the context of active inflammation (20).

Other studies have focused on the association between hepcidin and the type and severity of anemia. Ammar et al. [2022] showed that serum hepcidin effectively distinguishes between iron deficiency anemia and ACD in patients with UC (17). Similarly, Lalosevic et al. [2020] and Syed et al. [2017] confirmed hepcidin as a reliable marker of iron deficiency, especially when considered in conjunction with other biomarkers such as ferritin, CHr, and sTfR (42-44).

In contrast, some studies, such as those by Nagy et al. [2010], questioned the utility of prohepcidin alone as a diagnostic marker, highlighting limitations in its correlation with clinical parameters (34). Karaskova et al. [2018] and Krawiec et al. [2017], analyzing pediatric populations, observed that hepcidin levels vary between IBD types and that their regulation depends on both inflammation and iron stores (21,44).

Heterogeneity in hepcidin assays and sample matrices remains a major obstacle to its clinical application. Studies have used diverse platforms, such as ELISA, RIA, mass spectrometry, and chromatographic methods, on serum, plasma, or urine, and some have quantified prohepcidin rather than the active hepcidin-25. These methodological differences lead to wide variability in absolute values, units, and reference cut-offs, limiting comparability across studies and hindering the definition of diagnostic thresholds.

While urinary hepcidin reflects renal handling and hydration status, serum hepcidin-25 more accurately represents systemic iron regulation; in contrast, prohepcidin shows poor clinical correlation. Thus, methodological heterogeneity must be acknowledged when interpreting results, and harmonization of analytical approaches is essential for clinical translation.

It is important to note that hepcidin levels have also been linked to response to oral iron therapy. Rampton et al. [2017] found an inverse relationship between baseline hepcidin levels and response to ferrous sulfate supplementation (18). The ongoing clinical study by Loveikyte et al. [2024] aims to validate the use of hepcidin as a predictor of response to oral versus intravenous iron (20).

Hepcidin behaves as an acute-phase protein, with its synthesis upregulated not only by IL-6–mediated inflammation in IBD but also by systemic infections, chronic kidney disease, obesity, and other inflammatory or metabolic comorbidities. Consequently, elevated hepcidin levels may not be specific to intestinal inflammation, as conditions such as infection or obesity can lead to disproportionate increases independent of IBD activity, thereby reducing its diagnostic specificity. These confounding factors underscore the need for a multidimensional assessment that combines hepcidin with other clinical and laboratory parameters. Moreover, although hepcidin-driven mechanisms play a key role in anaemia of inflammation, several additional factors contribute to anaemia in IBD, including chronic gastrointestinal bleeding, malabsorption of vitamin B12 and folate due to ileal or extensive small bowel involvement or resection, and drug-induced cytopenias (e.g., thiopurines). Nutritional deficiencies, particularly during disease flares, further increase the risk of anaemia. Collectively, these aspects highlight the multifactorial nature of anaemia in IBD and the importance of a comprehensive diagnostic approach that extends beyond hepcidin and iron homeostasis (14).

Effect of IBD treatment on hepcidin regulation

Clinical studies reinforce the association between inflammation control and hepcidin reduction. Atkinson et al. [2018] observed decreases in hepcidin levels and increased hemoglobin in children with CD treated with anti-TNF-α (19). Similar results were reported by Shu et al. [2019], identifying the TNF-α/NF-κB pathway as a mediator of hepcidin induction (35).

Another essential aspect was addressed by Amrousy et al. [2022], who compared the efficacy of ferrous sulfate and lactoferrin. The latter was more effective in improving anemia and reducing IL-6 and hepcidin, suggesting an additional anti-inflammatory effect (33).

In a longitudinal study, Karaskova et al. [2020] demonstrated that IBD treatment reduces hepcidin levels, which may mediate the recovery of iron metabolism. The data also indicated differences between UC and CD in the dynamics of hepcidin regulation (21).

Emerging therapeutic targets involving hepcidin in IBD

The only study identified in this group, conducted by Wang et al. [2012], investigated the role of the BMP6/IL-6 pathway in hepcidin induction in mice with colitis. Administration of BMP pathway inhibitors resulted in reduced hepatic hepcidin expression, increased serum iron levels, and attenuation of intestinal inflammation (22). These data reinforce the potential of hepcidin as a therapeutic target, suggesting that its modulation can simultaneously improve hematologic profile and reduce local inflammation.

Limitations of the systematic review

Despite the relevance of the findings gathered in this review, some limitations must be acknowledged. The main one concerns the heterogeneity of the included studies, both regarding the evaluated populations (adults vs. pediatric, varied clinical forms of IBD, and different disease stages) and the methods used to measure hepcidin (immunoassays, liquid chromatography, urinary measurement, among others), as well as the analyzed outcomes (anemia, inflammatory activity, therapeutic response, and iron parameters). This variability hinders direct comparison between studies and limits the possibility of broad generalizations.

Given the marked heterogeneity among the included studies in terms of design, study population, and outcome assessment, a quantitative synthesis was not performed. The studies differed substantially in patient characteristics (adults vs. children, CD vs. UC, and varying disease activity levels), hepcidin quantification methods (serum or urine, ELISA or mass spectrometry), and analytical units. These methodological discrepancies precluded data pooling; thus, a qualitative synthesis was deemed the most appropriate strategy to ensure accurate and transparent interpretation of findings. Collectively, the evidence positions hepcidin as a promising correlative and predictive biomarker rather than a definitive diagnostic tool.

Future research should prioritize methodological harmonization and the establishment of consensus reference standards to clarify its clinical applicability. Nevertheless, the analyzed data allow us to conclude that hepcidin plays a central role at the intersection between inflammation and iron metabolism in IBD. Its levels are modulated by inflammatory cytokines, especially IL-6 and TNF-α, and directly influence iron bioavailability, contributing to the development of anemia of chronic disease. Moreover, hepcidin has proven to be a promising biomarker for assessing iron status and response to oral or intravenous iron therapy, in addition to being modulated by anti-inflammatory treatments such as biologic agents and lactoferrin. Experimental studies also reinforce its potential as a therapeutic target.

Conclusions

Hepcidin plays a central role in iron homeostasis and in the pathophysiology of anemia associated with IBD. Robust evidence indicates that its levels are modulated by inflammatory mediators, iron stores, and erythropoietic activity, correlating with disease severity and response to iron therapy. In this context, hepcidin emerges as a promising biomarker, with the potential to distinguish iron deficiency anemia from anemia of chronic disease, as well as to guide decisions regarding the most appropriate route of iron supplementation. However, despite these encouraging findings, methodological heterogeneity among studies—regarding analytical techniques and patient populations—limits broader clinical application. Therefore, further studies with standardized methodologies are needed to validate the clinical utility of hepcidin and to explore its potential as a therapeutic target in IBD.

Acknowledgments

We want to thank Ana Paula de Morais for her assistance in searching articles in the databases. We thank Prof. Tristan Torriani for editing the English version of our manuscript.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-99/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-99/prf

Funding: This work was supported by the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil) (Grant number: Finance Code 001 for L.F.P.), by the São Paulo Research Foundation (FAPESP) (Grant numbers #23/05213-4 for S.S.N.S. and #24/07424-5 for I.M.P. L.M.G.), by the National Council for Scientific and Technological Development (CNPq) (Grant number #302557/2021-0 for R.F.L.), and by the Fund to support teaching, research, and extension of the University of Campinas (FAEPEX) (Grant number #39/2024 for L.M.G.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-99/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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