Disrupted coupling between ferritin and iron absorption in enteropathy-related anemia: Evidence for a dual-pathway model

Abstract

BACKGROUND

Serum ferritin is widely used as a biomarker of iron deficiency; however, its diagnostic value in patients with enteropathy remains uncertain, particularly in the absence of overt bleeding or systemic inflammation. As both a storage protein and an acute-phase reactant, ferritin may not accurately reflect functional iron availability in the presence of small-bowel mucosal pathology. Enteropathies affecting absorptive enterocytes can impair intestinal iron uptake through structural and regulatory mechanisms that are not captured by conventional biomarkers alone. Video capsule endoscopy offers a non-invasive approach to assessing mucosal integrity, yet its relationship with biochemical indices of iron absorption remains poorly explored.

AIM

To evaluate relationships among serum ferritin, intestinal iron absorption, and enteropathy-related mucosal changes in unexplained anemia.

METHODS

In this single-center prospective study, patients with unexplained anemia or fatigue underwent video capsule endoscopy and a 4-hour oral iron absorption test (ΔFe), and completed the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue questionnaire. Pathway analysis based on structural equation modeling principles, together with general linear models, was used to evaluate associations among mucosal injury, iron absorption, iron biomarkers, and functional status.

RESULTS

The analysis supported a dual-pathway model, in which enteropathy independently influenced both intestinal iron absorption (ΔFe, P = 0.005) and serum ferritin levels (P = 0.002). ΔFe did not significantly predict serum ferritin levels (P = 0.619), indicating an interruption of a simple serial absorption pathway. Patients with lower ΔFe demonstrated a trend toward lower FACIT-Fatigue scores, indicating worse fatigue; however, this difference did not reach statistical significance. FACIT-Fatigue scores showed a weak but significant correlation with serum ferritin (r = 0.310, P = 0.021) but not with short-term iron absorption (ΔFe, P = 0.412).

CONCLUSION

Enteropathy independently impairs iron absorption and alters ferritin levels through dissociated pathways. Combined use of capsule endoscopy and oral iron absorption testing may improve diagnostic evaluation of unexplained anemia.

Key Words: Iron deficiency; Enteropathy; Ferritin; Capsule endoscopy; Iron absorption; Fatigue; Functional Assessment of Chronic Illness Therapy; Pathway modeling

Core Tip: Iron deficiency anemia without overt gastrointestinal bleeding remains a diagnostic challenge, particularly in patients with suspected small-bowel disease. In this study, we integrated video capsule endoscopy findings with an oral iron absorption test, serum iron biomarkers, and fatigue scores. Our results demonstrate that enteropathy independently impairs intestinal iron absorption and alters ferritin levels, yet without a direct association between these two processes. This dissociation suggests that ferritin alone may not accurately reflect functional iron deficiency in enteropathy and highlights the importance of assessing small-bowel mucosal integrity in patients with unexplained anemia or fatigue.

INTRODUCTION

Iron deficiency anemia (IDA) is among the most common hematological conditions encountered in both primary and specialized care. While its diagnosis is generally straightforward - based on decreased hemoglobin, low serum ferritin, and microcytic indices - there remains a subset of patients in whom the etiology of anemia is uncertain, and in whom traditional biomarkers provide inconsistent or insufficient information regarding the relationship between iron absorption and iron stores[1,2].

In such cases, gastrointestinal causes of iron malabsorption, particularly related to small-bowel mucosal pathology, may remain undiagnosed. Enteropathies such as celiac disease, mucosal inflammation, or nonspecific mucosal injury can compromise iron uptake by disrupting the structure and function of absorptive enterocytes. However, in the absence of overt bleeding or definitive histopathological findings, subtle mucosal changes may be missed by conventional diagnostic approaches. Video capsule endoscopy (VCE) has emerged as a valuable non-invasive tool for assessing small-bowel mucosal integrity in these patients[3]; however, its correlation with biochemical indices of iron absorption remains poorly explored.

Ferritin, the most commonly used marker of iron status, is limited by its dual role as both a storage protein and an acute-phase reactant[1,4]. Systemic inflammation may elevate ferritin levels independently of actual iron stores, thereby masking true iron deficiency. Furthermore, ferritin may not adequately reflect short-term alterations in intestinal iron absorption, particularly in the presence of small-bowel mucosal dysfunction. Alternative approaches - such as direct absorption testing (e.g., Δ serum iron response following an oral iron challenge) and patient-reported outcome measures, including fatigue scores - may better capture clinically relevant iron deficiency in this context[5,6].

In clinical practice, this limitation may complicate the diagnostic evaluation of patients with unexplained anemia or persistent fatigue, particularly when conventional iron biomarkers appear only mildly abnormal. In such cases, reliance on serum ferritin alone may underestimate disturbances in intestinal iron handling associated with small-bowel mucosal pathology.

Most previous studies have evaluated iron deficiency using single biochemical markers or individual clinical parameters. In contrast, the present study integrates multiple complementary dimensions, including VCE to assess mucosal integrity, an oral iron absorption test (OIAT) to evaluate intestinal iron uptake, patient-reported fatigue scores, and pathway-based statistical modeling. This multidimensional approach aims to better characterize the complex interactions between mucosal injury, iron absorption, iron biomarkers, and clinical symptoms in patients with unexplained anemia or fatigue. The dynamic interplay between mucosal integrity, iron absorption, and systemic iron availability remains incompletely elucidated[7].

We hypothesized that enteropathy exerts a dual effect on iron metabolism - impairing intestinal iron absorption and reducing systemic iron stores - and that ferritin alone may not reliably reflect these disturbances. This study aimed to evaluate the relationships between mucosal changes observed on VCE, intestinal iron absorption capacity, and established clinical biomarkers of IDA, using both statistical modeling and patient-centred functional outcome measures.

MATERIALS AND METHODS

Study design and data source

The original data were collected during a five-year period beginning in November 2014. The dataset included VCE findings for the assessment of enteropathy, as well as laboratory tests and an OIAT. The primary objective of the original study was to evaluate intestinal iron absorption capacity in patients with suspected enteropathy using a single-dose oral iron challenge. That investigation primarily focused on anemia of unknown origin. In the present analysis, however, the focus shifts toward developing a statistical model aimed at characterizing iron absorption disturbances across different forms of enteropathy. Accordingly, the previously collected dataset was reanalyzed to address this expanded and integrative research objective.

Study population

For the original study, 76 adult participants of both sexes (aged ≥ 18 years) were recruited. Of these, patients with complete biomarker datasets and adequate responses to the OIAT were selected for statistical modeling. Inclusion criteria were as follows: (1) Completion of VCE; (2) Performance of an OIAT; (3) Completion of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue questionnaire; availability of complete laboratory parameters; (4) No iron supplementation within 8 weeks prior to testing; and (5) Provision of written informed consent. Exclusion criteria included: (1) Active gastrointestinal bleeding; (2) Pregnancy or lactation; (3) Renal impairment (estimated glomerular filtration rate < 60 mL/minute/1.73 m²); (4) Known malignancy; and (5) Incomplete VCE data.

Capsule endoscopy and mucosal assessment

All VCE procedures were performed using the OMOM capsule endoscopy system (Chongqing Jinshan Science & Technology Group, Chongqing, China) according to the manufacturer’s instructions. Patients fasted for at least 12 hours prior to the procedure and underwent standard bowel preparation with 2 L of polyethylene glycol solution administered the evening before the examination. The capsule was swallowed in the upright position with approximately 200 mL of water, after which normal ambulation was permitted. Following completion of the examination, image data were retrieved and analyzed using the dedicated OMOM software workstation.

Mucosal integrity was independently evaluated by two experienced endoscopists according to standardized visual criteria[8,9]. Enteropathy was defined as the presence of mucosal abnormalities detected on VCE, including villous atrophy, scalloping, mucosal flattening, mucosal erythema, erosions, or ulcerations. For the purposes of the present analysis, enteropathy was treated as a binary variable (presence vs absence of mucosal abnormalities). When present, mucosal lesions were descriptively categorized according to their predominant visual pattern (erythematous changes, erosions/ulcerations, or segmental mucosal injury). In cases of discrepancy between the two reviewers, a consensus interpretation was reached through discussion.

Laboratory parameters and iron absorption test

All blood tests, including serum iron, ferritin, transferrin saturation, mean corpuscular volume, and mean corpuscular hemoglobin, were performed in a single accredited clinical laboratory. To ensure that ferritin levels accurately reflected body iron stores, participants with elevated C-reactive protein levels (> 10 mg/L) were excluded from the study, thereby minimizing the confounding effect of systemic inflammation on iron status assessment. The OIAT involved the administration of 100 mg of elemental iron (as ferrous gluconate hydrate) under fasting conditions. Serum iron concentrations were measured at baseline and 4 hours after ingestion; the difference (ΔFe) was used as a measure absorption capacity, following previously described protocols[10,11]. All OIAT assays were performed in the same accredited clinical laboratory using standardized automated methods, thereby minimizing analytical variability.

Functional status assessment

Fatigue was assessed using the FACIT-Fatigue scale, a validated instrument for evaluating fatigue-related quality of life in chronic illness[12]. The scale ranges from 0 to 52, with lower scores indicating more severe fatigue. The questionnaire was self-administered on the same day as VCE and OIAT.

Statistical analysis

The primary independent variable was enteropathy status. The dependent variables for hematological status were two composite scores - red blood cell (RBC) quality and RBC quantity - derived from principal component analysis of key RBC indices. principal component analysis with varimax rotation revealed a clear two-component structure: Component 1 (RBC quality) was primarily loaded by mean corpuscular hemoglobin, mean corpuscular volume, and hemoglobin, (reflecting cell size and hemoglobinization), while component 2 (RBC quantity) was primarily loaded by RBC count and hematocrit. Key process variables included short-term intestinal iron absorption (ΔFe), serum ferritin (ferritin), and serum iron concentration (iron). Due to sample size limitations that precluded convergence of a full structural equation model, a stepwise path analysis based on a series of linear regression models was employed. This approach allowed for a robust evaluation of three competing causal hypotheses regarding the relationships between enteropathy, iron absorption, iron biomarkers, and hematological outcomes. All statistical analyses were performed using jamovi (version 2.5). A two-sided alpha level of 0.05 was used to determine statistical significance[13,14]. The following path models were tested: (1) Dual-pathway model: This model proposed that enteropathy independently influences both iron absorption and ferritin levels, represented as: Enteropathy → ΔFe→ ferritin → erythrocyte status (components 1 and 2); (2) Serial mediation via serum iron model: This model specified the causal chain: Enteropathy → ΔFe→ serum iron → ferritin → Erythrocyte_Status (components 1 and 2); and (3) Serial mediation via ferritin model: This model tested the alternative causal sequence: Enteropathy → ferritin → serum iron → erythrocyte status (components 1 and 2).

Ethics approval

The original study protocol was approved by the Riga East University Hospital Support Foundation Medical and Biomedical Research Ethics Committee (protocol No. 10-A/14) and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent prior to participation. This secondary analysis was exempt from additional ethical approval, as it was conducted using fully anonymized data.

RESULTS

Patient characteristics

Of the original cohort of 76 participants, 53 were included in the analysis. The exclusion of 23 participants was attributable to several predefined criteria: Two patients had a confirmed diagnosis of celiac disease; several declined further participation; and the majority were excluded due to incomplete or invalid completion of the questionnaire protocols. The mean age of the analyzed cohort was 42.3 ± 11.5 years, comprising 45 females (84.9%) and 8 males (15.1%). The median hemoglobin level was 116 g/L (interquartile range: 102-124 g/L), and the mean serum ferritin concentration was 18.7 ± 10.2 μg/L. Most patients were referred because of unexplained fatigue, mild anemia, or clinical suspicion of occult iron deficiency. Among patients classified as having enteropathy, the most frequently observed mucosal pattern consisted of segmental erythematous changes of the small-bowel mucosa. Less frequently observed findings included erosive lesions and congestive mucosal abnormalities detected on VCE. Baseline characteristics of the study population are presented in Table 1.

Table 1 Characteristics of the study population, n (%)/mean ± SD.

Parameter	Anemia		P value	Effect size
	Non-anemic group	Anemic group
Gender			0.683	N/A
Male	4 (17.4)	4 (13.3)
Female	19 (82.6)	26 (86.7)
Age	37.5 ± 15.8	39.3 ± 11.8	0.634	N/A
RBC	4.57 ± 0.47	4.46 ± 0.40	0.377	N/A
HB	13.03 ± 1.52	10.28 ± 1.15	< 0.001	2.01
MCV	87.06 ± 6.54	77.10 ± 6.44	< 0.001	1.54
MCH	28.67 ± 2.75	23.71 ± 2.93	< 0.001	1.74
Hematocrit	39.80 ± 3.91	33.99 ± 3.16	< 0.001	1.66
Iron	13.23 ± 6.80	5.21 ± 3.90	< 0.001	1.50
Ferritin	12.19 ± 8.90	5.51 ± 3.92	< 0.001	1.02
FACIT-F total	32.96 ± 9.48	29.30 ± 13.49	0.274	N/A
FACIT-F groups			0.078	N/A
1	2 (8.7)	7 (23.3)
2	5 (21.7)	10 (33.3)
3	10 (43.5)	4 (13.3)
4	6 (26.1)	9 (30.0)

Anemia was defined according to World Health Organization criteria: Male < 130 g/L, women < 120 g/L. Functional Assessment of Chronic Illness Therapy groups were categorized as follows: 1 = severe fatigue (0-20), 2 = moderate fatigue (21-30), 3 = mild fatigue (31-40), 4 = minimal or no fatigue (41-52), according to previously published Functional Assessment of Chronic Illness Therapy-Fatigue scoring guidelines. N/A: Not applicable; RBC: Red blood cells; HB: Hemoglobin; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; FACIT-F: Functional Assessment of Chronic Illness Therapy Fatigue scale.

Iron absorption and ferritin levels

After the OIAT, ΔFe demonstrated marked interindividual variability, with changes in serum iron concentration ranging from < 2 μmol/L (severely impaired absorption) to > 10 μmol/L (preserved absorption). The mean ΔFe across the cohort was 5.4 ± 3.1 μmol/L.

Fatigue and functional status (FACIT)

The mean FACIT-Fatigue score was 32.8 ± 9.7. Patients with poor iron absorption (ΔFe < 5 μmol/L) exhibited numerically lower FACIT-Fatigue scores, indicating worse fatigue; however, this difference did not reach statistical significance (P = 0.080). Correlation analysis revealed a weak but statistically significant correlation between ferritin and FACIT (r = 0.310, n = 53, P = 0.021). In contrast, no significant correlation was observed between ΔFe and FACIT (P = 0.412).

Pathway analysis

The analysis revealed that the data most strongly supported the dual-pathway model, whereas the serial mediation models were not consistently supported. The detailed results for each model are presented in Table 2.

Table 2 Summary of stepwise regression analyses for pathways linking enteropathy to erythrocyte status.

Pathway tested	F-statistic	P value	R2	Outcome
Dual-pathway model
Enteropathy → iron absorption	F(4, 48) = 4.23	0.005	0.26	Supported
Enteropathy → ferritin stores	F(4, 48) = 5.09	0.002	0.30	Supported
Iron absorption → ferritin stores	F(1, 50) = 0.25	0.619	0.01	Not supported
Ferritin stores → RBC quality	F(1, 51) = 14.70	< 0.001	0.22	Supported
Ferritin stores → RBC quantity	F(1, 51) = 0.62	0.434	0.01	Not supported
Serial via serum iron model
Iron absorption → serum iron	F(1, 50) = 1.79	0.186	0.04	Not supported
Serial via ferritin model
Serum iron → RBC quality	F(1, 51) = 32.3	< 0.001	0.39	Supported
Serum iron → RBC quantity	F(1, 51) = 2.52	0.118	0.05	Not supported

The results indicate that simple serial mediation models (serial via serum iron model and serial via ferritin model) were not supported, owing to disruptions in key links of the proposed causal pathways. In contrast, the data most strongly support a dual-pathway model (dual-pathway model) in which enteropathy independently influences both intestinal iron absorption and serum ferritin levels. RBC: Red blood cell.

Dual-pathway model: The initial analysis supported a model with two independent pathways originating from enteropathy. The effect of enteropathy on ΔFe was statistically significant [F(4, 48) = 4.23 (P = 0.005)], as was the direct effect of enteropathy on ferritin [F(4, 48) = 5.09 (P = 0.002)]. However, the path between ΔFe and ferritin was not statistically significant [F(1, 50) = 0.25 (P = 0.619)], thereby excluding simple mediation through iron absorption. Finally, ferritin was a strong predictor of RBC quality (P < 0.001) but not of RBC quantity (P = 0.434).

Serial mediation via serum iron model: This model, which tested the causal chain enteropathy → ΔFe → serum iron → ferritin, was not supported by the data. The association between short-term iron absorption (ΔFe) and serum iron (iron) was not statistically significant [F(1, 50) = 1.79, P = 0.186]. Consequently, the mediation pathway was interrupted at this step, despite a strong subsequent association between serum iron and ferritin (P < 0.001).

Serial mediation via ferritin model: This alternative model, which tested the causal sequence enteropathy → ferritin → iron → Erythrocyte_Status, was also not fully supported by the data. Although the association between ferritin and serum iron was significant (P < 0.001), and serum iron significantly predicted RBC quality (P < 0.001), its effect on RBC quantity was not significant (P = 0.118). These findings indicate that serum iron does not function as a complete mediator for all dimensions of erythrocyte status.

Post-hoc power analysis

To evaluate the statistical reliability of the findings given the sample size (n = 53), a post-hoc power analysis was performed. For the primary hematological outcomes, the study demonstrated high statistical power; for instance, the comparison of serum ferritin levels between patients with and without anemia (effect size d = 1.02) yielded a power of 95%. Regarding the path analysis, the models examining the direct effects of enteropathy on intestinal iron absorption and ferritin achieved statistical power of 88% and 92%, respectively. These values exceed the conventional 80% threshold, indicating that the study was sufficiently powered to detect the identified structural relationships.

DISCUSSION

This study investigated the mechanisms of impaired iron handling in patients with suspected enteropathy using a combination of VCE, serum biomarkers, fatigue scores, and pathway analysis. Our results support a dual-pathway model, in which enteropathy independently influences both short-term intestinal iron absorption (ΔFe) and systemic iron stores, as reflected by ferritin, without a direct mechanistic link between these two processes. These findings suggest that iron metabolism in enteropathy is not governed by a simple linear malabsorption pathway, but rather by multiple, partially independent physiological regulatory mechanisms.

A key insight from this analysis was the absence of a significant association between ΔFe and ferritin, despite both being independently influenced by mucosal changes. This finding implies that serum ferritin may fail to reflect acute alterations in intestinal iron absorption, particularly in the presence of small-bowel mucosal injury. Clinically, this may explain why patients with suspected enteropathy present with fatigue or functional iron deficiency despite ferritin values that appear only mildly reduced or even within the conventional reference range. Importantly, systemic inflammation was minimized in this cohort, as C-reactive protein levels were assessed in all participants and individuals with elevated inflammatory markers were excluded. Fatigue in this population is likely multifactorial and may be influenced not only by iron metabolism but also by hemoglobin levels and the overall severity of anemia. From a physiological perspective, this observation is consistent with the concept of the intestinal mucosal block - a regulatory phenomenon in which enterocytes downregulate iron uptake following luminal iron exposure, thereby protecting against iron overload and oxidative stress. Moreover, ferritin concentrations may remain misleadingly normal or elevated in chronic inflammatory states, effectively masking true iron deficiency, as described by Camaschella[15]. The most recent European consensus on malabsorption further supports this concept, emphasizing that iron deficiency should not be excluded solely on the basis of serum ferritin values within the conventional reference range, particularly in patients with chronic gastrointestinal disease or suspected enteropathy. In addition, the consensus highlights that small-intestinal mucosal pathology represents a frequent and underdiagnosed cause of iron deficiency, even in the absence of overt malabsorption symptoms[16]. Our findings also support the concept that small-bowel mucosal integrity plays a central role in systemic iron homeostasis, linking local intestinal pathology with systemic manifestations such as functional iron deficiency and fatigue.

In the context of capsule endoscopy, the functional significance of mucosal abnormalities may be more clinically relevant than the precise quantification of lesion burden, as small-bowel mucosal dysfunction can occur even with relatively subtle or segmental changes. Therefore, the presence of mucosal abnormalities, rather than their exact anatomical extent, was considered the most robust indicator of enteropathy in this study.

Recent computational modeling has confirmed that this mucosal block is primarily driven by intracellular ferritin sequestration and iron-regulatory protein-mediated gene regulation, rather than by alterations in DMT1 expression or trafficking[17]. This mechanistic framework may explain why ferritin behaves independently of ΔFe: It reflects long-term iron storage and inflammation-related signaling, rather than real-time intestinal transport capacity. Furthermore, our general linear model analysis demonstrated that ferritin was a strong predictor of erythrocyte morphology (RBC quality, P < 0.001), but not of RBC quantity, indicating that functional iron availability does not necessarily translate into proportional changes in erythrocyte mass, particularly in subclinical forms of enteropathy.

An additional important observation of this study is that ferritin was more strongly associated with indicators of erythrocyte quality than with absolute erythrocyte quantity. This finding suggests that in early or subclinical enteropathy-related iron deficiency, alterations in iron availability may initially impair maturation and hemoglobinization before leading to overt reductions in hemoglobin levels or erythrocyte mass. This is consistent with the physiological hierarchy of iron utilization, whereby iron is preferentially allocated to erythropoietic precursors to maintain hemoglobin content, even when total circulating erythroid mass is partially preserved.

Our sample size was relatively limited and should therefore be acknowledged as a constraint when interpreting the pathway-based analyses. The proposed dual-pathway model should accordingly be interpreted as an exploratory framework requiring validation in larger cohorts, independent cohorts. Another limitation of the study is the predominance of female participants (84.9%), which reflects the clinical epidemiology of iron deficiency but limits the ability to evaluate potential sex-specific differences in iron metabolism. Future studies with larger and more balanced cohorts will be needed to determine whether sex modifies the observed relationships between enteropathy, ferritin levels, and iron absorption. This imbalance may also limit the generalizability of the findings to male patients. The selected variables and paths in our framework were based on established physiological interactions between enterocyte iron transporters and systemic iron storage, providing a theoretical foundation that supports the observed associations despite the exploratory nature of the model. This constraint, however, reflects the stringent inclusion criteria, as only patients undergoing capsule endoscopy for non-bleeding, non-inflammatory bowel disease iron deficiency were included, thereby excluding major alternative causes of anemia. The use of capsule endoscopy - although not providing histological confirmation - remains the standard non-invasive modality for assessing small-bowel pathology in patients with IDA without overt bleeding, in accordance with current clinical guidelines[16-20]. Histological assessment was not feasible due to anatomical inaccessibility and clinical considerations. Nevertheless, histological correlation might have provided additional insight into the underlying mucosal pathology and mechanisms affecting iron absorption. Therefore, the interpretation of mucosal abnormalities in this study was based solely on endoscopic appearance, which may not fully reflect the underlying histopathological processes.

Furthermore, the present study did not specifically evaluate other factors that may influence iron metabolism, such as dietary iron intake or intestinal microbiota composition. These variables may affect both intestinal iron absorption and serum ferritin levels and should be considered in future studies investigating the complex regulation of iron homeostasis in patients with enteropathy. Despite these limitations, the study provides an integrated clinical and physiological perspective on the relationship between small-bowel mucosal abnormalities, intestinal iron absorption, and iron biomarkers in patients with otherwise unexplained anemia or fatigue. To our knowledge, this study is one of the first to integrate capsule endoscopic findings, serum iron kinetics, and fatigue scores (FACIT-Fatigue) using a regression-based path analysis informed by structural equation modeling principles to explore the absorptive consequences of small-bowel mucosal injury. While previous reports have primarily described individual biomarkers or imaging findings in isolation, the present model provides a novel systems-level perspective on iron handling in enteropathy.

The FACIT-Fatigue scale has been validated in IDA and shown to reflect changes in functional status related to treatment outcomes[21-23], supporting its inclusion in studies assessing systemic iron availability. As intended, FACIT-Fatigue scores were generally lower in patients with impaired absorption; however, in the present cohort, the scale did not demonstrate a significant correlation with ΔFe and showed only a weak association with serum ferritin. Fatigue in this clinical context is likely multifactorial. Beyond iron metabolism, hemoglobin levels and the overall severity of anemia remain critical determinants of physical endurance. Accordingly, hemoglobin levels were considered an important clinical covariate when interpreting FACIT-Fatigue scores and evaluating fatigue severity. Furthermore, the OIAT reflects an acute physiological response, whereas the FACIT-Fatigue scale captures a chronic patient-reported outcome, which may partly explain the absence of a direct correlation between ΔFe and fatigue scores. Future studies with longitudinal assessment of fatigue and iron status may help further clarify this relationship. This discrepancy may be attributable to the limited sample size or may reflect the inherent difficulty of integrating objective biochemical parameters with subjective patient-reported outcomes. Nevertheless, FACIT-Fatigue scale remains a widely applied and sensitive instrument for monitoring fatigue over time across multiple clinical contexts, extending beyond IDA[22-25].

A schematic representation of the proposed conceptual model is provided in Figure 1. In addition to the limited sample size and absence of histological confirmation, this study is further constrained by its single-center design and reflects findings from a specific clinical subset of patients. Future research should aim to validate these findings in larger, prospective multicenter cohorts. Studies integrating endoscopic findings with histological assessment of the small-bowel mucosa and molecular markers of iron metabolism - such as hepcidin and iron transport proteins - may further clarify the mechanisms underlying the proposed dual-pathway model and advance the understanding of iron handling in patients with enteropathy-related anemia.

Figure 1 Conceptual model of disrupted coupling between ferritin and iron absorption in enteropathy. The model illustrates two independent pathways through which enteropathy may affect systemic iron metabolism. Enteropathy influences intestinal iron absorption (ΔFe) and serum ferritin levels through partially independent mechanisms. Ferritin is associated with erythrocyte quality but not with erythrocyte quantity, supporting the proposed dual-pathway framework. RBC: Red blood cells.

CONCLUSION

Iron absorption in patients with enteropathy follows a complex, multi-pathway regulatory pattern. Serum ferritin alone is insufficient to characterize functional iron deficiency, and mucosal injury appears to exert its effects through both structural and regulatory mechanisms. Our findings suggest that capsule endoscopy, when combined with oral iron absorption testing and fatigue scores, may provide a more comprehensive and clinically meaningful evaluation of subclinical enteropathy and help identify patients requiring further targeted diagnostic workup.

ACKNOWLEDGEMENTS

The authors express their sincere gratitude to the clinical and laboratory staff involved in data collection and sample analysis. Special thanks to the participating patients and to the administrative team for facilitating access to capsule endoscopy and laboratory infrastructure. We are also grateful to the statistical support team for their assistance with structural equation modeling.