European Journal of Cardiovascular Medicine

Anemia, defined by a reduction in hemoglobin concentration or red blood cell mass, is a globally prevalent condition and one of the most common comorbidities encountered in the inpatient setting [1]. Its presence in hospitalized patients is not an incidental finding but an independent risk factor associated with a wide range of adverse outcomes, including prolonged hospital stays, increased risk of readmission, functional decline, and higher mortality rates [2, 3]. The pathophysiology of anemia in hospitalized individuals is often multifactorial, stemming from nutritional deficiencies, iatrogenic blood loss, and the inflammatory stress of acute or chronic illness.

Among the various etiologies, iron deficiency anemia (IDA) and anemia of chronic disease (ACD), also known as anemia of inflammation, represent the two most common forms [4]. IDA is characterized by an absolute depletion of iron stores, impairing heme synthesis and erythropoiesis. It is typically caused by chronic blood loss, inadequate dietary intake, or malabsorption [5]. In contrast, ACD develops in the context of chronic inflammatory, infectious, or neoplastic diseases. The central pathogenic mechanism involves the inflammatory cytokine-mediated upregulation of hepcidin, a peptide hormone that blocks intestinal iron absorption and sequesters iron within the reticuloendothelial system, leading to a state of functional iron deficiency despite adequate body stores [6, 7].

Differentiating between IDA and ACD is a common diagnostic challenge, yet it is clinically paramount as their management strategies diverge significantly. IDA is treated with iron supplementation, whereas the primary management for ACD involves treating the underlying inflammatory condition, with iron therapy being ineffective and potentially harmful in some cases [8]. While previous studies have established the high prevalence of anemia in specific patient populations, such as those with heart failure, chronic kidney disease, or cancer [9, 10], there is a comparative lack of comprehensive data on the relative prevalence and outcomes of ACD versus IDA in a heterogeneous, general adult inpatient population.

Recent research has focused on the prognostic significance of anemia as a whole, but few studies have performed a direct, head-to-head comparison of clinical outcomes specifically between patients with ACD and those with IDA. This represents a critical knowledge gap, as understanding these differences can improve risk stratification, guide therapeutic decisions, and inform healthcare resource allocation. Anemia in the context of chronic inflammation may serve as a more potent marker of disease severity and physiological stress than anemia from absolute iron deficiency alone.

Therefore, this study aimed to address this gap by (1) determining the prevalence of ACD and IDA among anemic patients admitted to a tertiary care hospital and (2) comparing key clinical outcomes, including hospital length of stay, 30-day readmission, and in-hospital mortality, between these two distinct anemic subtypes. We hypothesized that ACD would be more prevalent than IDA and would be associated with worse clinical outcomes, reflecting the prognostic weight of the underlying inflammatory disease.

Study Population: We utilized the electronic health record (EHR) database to identify all adult patients (≥18 years) admitted to non-obstetrical medical and surgical wards. An initial cohort was identified using International Classification of Diseases, Tenth Revision (ICD-10) codes for anemia (D50-D64) or a laboratory finding of anemia, defined according to World Health Organization (WHO) criteria as a hemoglobin (Hb) level <13 g/dL for men and <12 g/dL for women on admission.

Inclusion and Exclusion Criteria: Patients were included in the final analysis if they met the criteria for anemia and had a complete set of laboratory data available within the first 48 hours of admission, including serum ferritin, serum iron, total iron-binding capacity (TIBC), and C-reactive protein (CRP). Transferrin saturation (TSAT) was calculated as (serum iron / TIBC) × 100.

Exclusion criteria were: (1) known hematologic malignancy (e.g., leukemia, lymphoma, myeloma); (2) active, overt bleeding at the time of admission; (3) receipt of a red blood cell transfusion within 30 days prior to admission; (4) end-stage renal disease (eGFR <15 mL/min/1.73m²) or receiving chronic dialysis; (5) pregnancy; and (6) incomplete laboratory data for classification.

Data Collection and Definitions: Data were extracted from the EHR by a trained data abstractor. Collected variables included patient demographics (age, sex), admission and discharge dates, comorbidities, and laboratory values. The Charlson Comorbidity Index (CCI) was calculated to quantify the burden of chronic disease.

Patients were classified into two primary groups based on their laboratory profiles:

1. Iron Deficiency Anemia (IDA): Defined as Hb below the WHO threshold and either a serum ferritin <30 ng/mL, or a serum ferritin of 30–100 ng/mL with a TSAT <20%.
2. Anemia of Chronic Disease (ACD): Defined as Hb below the WHO threshold, a serum ferritin >100 ng/mL, a TSAT <20%, and evidence of inflammation (CRP >5 mg/L).

Patients who did not fit these strict criteria (e.g., those with potential mixed IDA/ACD features, vitamin B12/folate deficiency, or normal iron studies) were categorized as "Other/Unclassified" and excluded from the comparative analysis between the IDA and ACD groups.

Clinical Outcomes: The primary clinical outcomes of interest were:

1. Hospital Length of Stay (LOS): Calculated in days from admission to discharge.
2. 30-Day All-Cause Readmission: Defined as any unplanned hospital admission within 30 days of discharge from the index hospitalization.
3. In-Hospital Mortality: Defined as death occurring at any point during the index hospitalization.

Statistical Analysis: All statistical analyses were performed using SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY). Descriptive statistics were used to summarize the data. Continuous variables were presented as mean ± standard deviation (SD) and compared between groups using the independent samples t-test. Categorical variables were presented as counts and percentages (n, %) and compared using the Chi-square test or Fisher’s exact test, as appropriate. A two-tailed p-value of <0.05 was considered statistically significant for all analyses.

Patient Selection and Prevalence of Anemia Subtypes: During the study period, a total of 1,580 unique patients with anemia on admission were identified. After applying the exclusion criteria, 898 patients were excluded, primarily due to incomplete laboratory data (n=450) or the presence of confounding conditions like end-stage renal disease or hematologic malignancy (n=245). A final cohort of 682 patients with complete data was established. Of these, 482 patients met the specific laboratory criteria for classification into IDA, ACD, or were considered for comparative analysis.

Within this cohort of 482 patients, 221 (45.8%) were classified as having ACD, and 145 (30.1%) were classified as having IDA. The remaining 116 patients (24.1%) had laboratory profiles suggestive of mixed etiologies or other causes of anemia and were thus excluded from the direct comparative analysis between the IDA and ACD groups.

Baseline Demographics and Comorbidities: The baseline characteristics of the IDA and ACD groups are presented in Table 1. Patients in the ACD group were significantly older than those in the IDA group (mean age 68.4 ± 12.1 vs. 55.2 ± 15.8 years; p<0.001). The ACD group also had a significantly higher burden of comorbidities, as reflected by a higher mean Charlson Comorbidity Index (4.8 ± 1.9 vs. 2.5 ± 1.5; p<0.001). While there was no significant difference in sex distribution, conditions such as congestive heart failure and chronic pulmonary disease were more prevalent in the ACD group.

Table 1. Baseline Demographics and Comorbidities of Patients with IDA and ACD

IDA: Iron Deficiency Anemia; ACD: Anemia of Chronic Disease; SD: Standard Deviation.

Hematological and Inflammatory Parameters: Table 2 summarizes the key laboratory findings for both groups. As per the diagnostic criteria, hemoglobin levels were low in both groups but were slightly lower in the IDA group, though this difference was not statistically significant. The groups differed significantly in their iron and inflammatory markers. The IDA group had markedly lower mean serum ferritin (18.5 ± 8.2 ng/mL) and higher TIBC, whereas the ACD group exhibited significantly higher mean serum ferritin (345.6 ± 180.1 ng/mL) and a markedly elevated mean CRP level (85.2 ± 55.4 mg/L), confirming the inflammatory nature of their anemia.

Table 2. Hematological and Inflammatory Parameters

MCV: Mean Corpuscular Volume; TIBC: Total Iron-Binding Capacity; TSAT: Transferrin Saturation.

Clinical Outcomes: The primary clinical outcomes are detailed in Table 3. The ACD group experienced significantly worse outcomes across all three measured domains compared to the IDA group. The mean hospital length of stay was approximately two days longer for patients with ACD (8.2 ± 4.5 days vs. 6.1 ± 3.3 days, p<0.001). The 30-day all-cause readmission rate was also significantly higher in the ACD group (24.9% vs. 15.2%, p=0.028). Finally, in-hospital mortality was more than double in the ACD group compared to the IDA group (8.1% vs. 3.4%, p=0.045).

Table 3. Comparison of Clinical Outcomes between IDA and ACD Groups

This study provides a direct comparison of the prevalence and clinical outcomes associated with anemia of chronic disease and iron deficiency anemia in a heterogeneous cohort of hospitalized adult patients. Our principal findings are twofold: first, ACD was substantially more prevalent than pure IDA in this setting; and second, the presence of ACD was associated with significantly worse clinical outcomes, including longer hospitalizations, higher rates of 30-day readmission, and increased in-hospital mortality.

The higher prevalence of ACD (45.8%) compared to IDA (30.1%) in our cohort is consistent with literature suggesting that inflammation-driven anemia is a dominant etiology in hospitalized populations [7, 11]. The inpatient environment concentrates individuals with acute and chronic inflammatory conditions, such as severe infections, autoimmune diseases, and malignancies, all of which are potent drivers of hepcidin production and the development of ACD [12]. Our finding that ACD patients were older and had a greater burden of comorbidities, as measured by the Charlson Comorbidity Index, reinforces the concept that ACD is intrinsically linked to underlying systemic illness.

The most critical finding of our study is the strong association between ACD and adverse clinical outcomes. The two-day longer mean LOS for ACD patients translates into a substantial burden on healthcare resources. This extended stay is likely not caused by the anemia per se, but rather reflects the severity and complexity of the underlying inflammatory diseases that cause ACD [9]. In this context, ACD serves as a powerful prognostic marker, signaling a state of heightened and sustained inflammation that complicates recovery and prolongs the need for inpatient care. In contrast, IDA, while clinically significant, may often stem from more manageable conditions like gastrointestinal bleeding or nutritional deficiencies, which may resolve more quickly with targeted intervention [5].

The elevated rates of 30-day readmission and in-hospital mortality in the ACD group further underscore its prognostic weight. This finding aligns with studies that have linked elevated inflammatory markers, such as CRP and IL-6, to poor outcomes across various diseases [13]. Hepcidin itself, the key mediator of ACD, has been proposed as a biomarker for disease severity and mortality in critically ill patients [14]. Therefore, the hematologic profile of ACD—characterized by high ferritin and low TSAT in the presence of inflammation—is a window into a dysfunctional iron metabolism driven by a systemic disease process that is independently associated with poor prognosis.

The clinical implications of these findings are significant. First, they emphasize the necessity of accurate and timely differentiation between ACD and IDA in anemic inpatients. Misdiagnosing ACD as IDA and prescribing iron supplementation may be futile, as the hepcidin block prevents iron utilization, and in some cases, excess iron could theoretically worsen inflammation or infection [8]. Second, the diagnosis of ACD should prompt clinicians to focus aggressively on identifying and managing the underlying inflammatory driver. The anemia is a signal of a more severe systemic problem, and its resolution is contingent upon controlling the primary disease.

This study has several strengths, including a relatively large and diverse sample of hospitalized patients, the use of strict, guideline-consistent laboratory criteria for defining anemia subtypes, and the analysis of multiple, patient-centered clinical outcomes. However, several limitations must be acknowledged. Its retrospective, single-center design may limit the generalizability of our findings. We did not perform a multivariate analysis to adjust for the confounding effects of age and comorbidities, and thus we cannot definitively attribute the worse outcomes to ACD independently of these factors. Causality cannot be inferred from this cross-sectional analysis. Furthermore, the exclusion of patients with mixed-etiology anemia, while necessary for a clean comparison, means our findings do not apply to this complex and common subgroup. Future research should include prospective, multi-center studies that utilize advanced biomarkers like soluble transferrin receptor and hepcidin to improve diagnostic accuracy and employ regression models to isolate the independent prognostic impact of ACD [15].

In conclusion, this study demonstrates that anemia of chronic disease is more prevalent than iron deficiency anemia among a general population of hospitalized patients. More importantly, ACD is associated with a significantly greater risk of adverse clinical outcomes, including prolonged length of stay, higher 30-day readmission rates, and increased in-hospital mortality. These findings highlight that ACD is not a benign condition but rather a key indicator of severe underlying systemic inflammation and a marker of poor prognosis. Clinicians should prioritize the accurate diagnosis of anemia subtypes to guide appropriate management, focusing on treating the underlying inflammatory disorder in patients with ACD to potentially improve their clinical trajectory.

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