The non-linear association between serum iron and severe impairment of activities of daily living in ischemic stroke patients

Abstract

Objectives:

This study aims to explore the dose–response relationship and threshold effect of serum iron levels on severe impairment of activities of daily living (ADL) in ischemic stroke patients.

Methods:

This cross-sectional study included 2,035 ischemic stroke patients admitted to Shanghai East Hospital from 2020 to 2022. Serum iron levels were measured upon admission, and ADL was evaluated using the Barthel Index. Restricted cubic spline regression, multivariate logistic models, and subgroup analysis were employed to analyze the dose–response relationship.

Results:

A non-linear relationship (p = 0.005) was observed between serum iron and severe ADL impairment, with an inflection point at 17.5 μmol/L. Below this threshold, each 1 μmol/L increase in serum iron was associated with 9% lower odds of severe ADL impairment (OR = 0.91, 95% CI: 0.876–0.946). No significant association was observed above 17.5 μmol/L (p > 0.05). Subgroup analyses revealed no significant interactions in any subgroup.

Conclusion:

The study found a non-linear relationship between serum iron and severe ADL impairment after ischemic stroke, with an inflection point at about 17.5 μmol/L. Future prospective studies are necessary to clarify this association.

Introduction

Stroke ranks as the second leading cause of death worldwide and is a major contributor to disability, with its prevalence increasing, especially in developing nations (1–4). According to the China Stroke Surveillance Report 2021, an estimated 17.8 million adults in China had a stroke in 2020, with 2.2 million leading to disability (5). The majority of strokes are ischemic, resulting from arterial blockage (6). Stroke-related long-term disability is primarily the result of impaired motor function (7, 8). Survivors of stroke frequently experience challenges with daily activities such as bathing and dressing, along with a lower quality of life and diminished participation in community activities (9–11).

Iron is a crucial trace element involved in numerous cellular processes, including oxygen transport, energy metabolism, and antioxidant defense (12). Disruptions in iron metabolism, whether due to deficiency or overload, can lead to adverse health effects, especially in older adults (13). Emerging evidence links iron metabolism to cognitive function, dementia risk, and the progression of neurodegenerative diseases (14, 15), which could indirectly impact the development of activities of daily living (ADL). Several studies have investigated the relationship between iron levels and functional outcomes following ischemic stroke (16). For example, one study suggested that iron stores, measured by serum ferritin levels, may influence prognosis in patients with acute stroke (17). This indicates that iron status may have an indirect effect on ADL by influencing functional recovery after stroke.

In summary, although there is evidence linking iron status, cognitive function, neurodegenerative diseases, and functional outcomes after ischemic stroke, no studies have directly examined the relationship between serum iron levels and ADL post-stroke. This study aims to investigate the dose–response relationship and the threshold effect of serum iron levels on severe ADL impairment in ischemic stroke patients.

Materials and methods

Study design and population

We designed a cross-sectional study of stroke patients admitted to Shanghai East Hospital between January 2020 and August 2022, which was conducted. The study included patients aged 18 years or older, with ischemic stroke diagnoses confirmed within 24 h of admission by cranial CT or MRI. Patients lacking an admission Barthel Index score or without recorded serum iron levels were excluded from the study. The patient selection process is illustrated in Figure 1. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and received approval from the Ethics Committee of Shanghai East Hospital (No. 2024055). As a retrospective study using anonymized data, informed consent was not necessary. All methods and procedures adhered to the ethical standards set by the World Medical Association’s Declaration of Helsinki on Human Experimentation.

Figure 1

General data collection

Overall, data collection depends on a combination of prior literature reports and clinical experience (18–20). Demographic and lifestyle data, including height, weight, gender, and age, were collected during the initial hospital admission and entered into the electronic medical records. Height and weight were measured according to World Health Organization standards, and body mass index (BMI) was calculated as weight (kg) divided by height squared (m²). Smoking and drinking status were categorized as “yes or no, in the current or past.” Hypertension was diagnosed either by documented history or by blood pressure readings ≥140/90 mmHg on at least two occasions in the hospital. Additional medical history, including diabetes, coronary artery disease, and a history of stroke, was also obtained from the records.

The severity of stroke at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS) (21, 22). The TOAST criteria classified ischemic strokes into five subtypes: small-vessel occlusion, large-artery atherosclerosis, cardio embolism, stroke of other known causes, and stroke of undetermined etiology (23). Additionally, ALT, CRP, and ferritin levels were measured using an automated analyzer by the enzymatic rate method, immunoturbidimetric method, and chemiluminescent method, respectively. Serum iron levels were measured using a Roche analyzer by the colorimetric method within 24 h of the stroke onset. All blood indicators were measured in the morning following an overnight fast.

Activities of daily living (ADLs) refer to the fundamental tasks necessary for self-care and maintaining personal well-being, including personal care, mobility, and eating. The Barthel Index (BI) is a widely recognized tool for evaluating a patient’s ability to carry out basic ADLs. First introduced in 1965 by Dorothea Barthel and Florence Mahoney in the United States, the index assesses 10 functional areas, including feeding, bathing, dressing, toileting, mobility, walking, stair climbing, and bowel and bladder control (24, 25). The total BI score ranges from 0 to 100, with higher scores reflecting greater independence in daily activities. The Barthel Index is extensively applied in assessing functional status across various medical conditions, particularly in studies on stroke, spinal cord injury, dementia, and Parkinson’s disease (26–29). In China, several studies have also employed the BI to evaluate ADL capacity in stroke patients (2). This study assessed the BI score of patients on the first day of admission.

A Barthel Index score below 40 indicates that a patient lacks independence in mobility, self-feeding, personal grooming, and sphincter control (30). Patients are unable to perform daily tasks independently and require assistance from others to complete them. This level of dependence is classified as severe impairment in activities of daily living.

Statistical analysis

Descriptive analyses were performed for each patient. Categorical variables were presented as frequencies (percentages), while continuous variables were reported as medians (interquartile ranges) or means ± standard deviations, depending on their distribution. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between serum iron levels and severe ADL impairment among ischemic stroke patients. Multiple imputation was used to handle missing data. In Model 1, adjustments were made for age, sex, BMI, and smoking and drinking status. Model 2 included additional adjustments for hypertension, diabetes, coronary heart disease, history of stroke, TOAST classification, and NIHSS score. Model 3 incorporated all variables from Model 2, with further adjustments for Alanine Aminotransferase (ALT), C-Reactive Protein (CRP), and ferritin.

Due to missing data, multiple imputation was performed across the entire study population, and multivariable regression analysis was conducted on the imputed datasets. To assess the robustness of our findings, a sensitivity analysis was performed using a BI score of less than 60 as the cutoff for defining ADL dependence. Since the study did not include a prior statistical power analysis, the sample size was determined based solely on the available data. Additionally, in the sensitivity analysis, the E-value method was used to assess the potential impact of unmeasured confounding on the results.

After adjusting for the variables in Model 3 across the entire study population, we used restricted cubic spline (RCS) regression to examine the nonlinear relationship between serum iron levels and severe ADL impairment, as well as to assess the dose–response association between serum iron and ADL impairment. To investigate the threshold effect of serum iron on severe ADL impairment following ischemic stroke, we applied a smoothed binary logistic regression model. Additionally, likelihood ratio tests and bootstrap regression methods were used to identify significant inflection points in this relationship.

In addition, we examined several variables that could influence the relationship between serum iron levels and severe ADL impairment following ischemic stroke. The variables analyzed included: sex; age (<60 years vs. ≥60 years); body mass index (BMI) categories (<25, 25–29.9, and ≥30 kg/m²); smoking and drinking status (yes or no); hypertension (yes or no); and diabetes (yes or no). Multivariate logistic regression was used to assess subgroup heterogeneity, and the likelihood ratio test was employed to explore interactions between subgroups and serum iron levels.

All analyses were performed using R version 4.3.1 (http://www.R-project.org, The R Foundation) and Free Statistics version 1.8. A descriptive study was conducted for each participant, and a two-tailed p-value of <0.05 was considered statistically significant.

Results

Study population

The study initially enrolled 3,365 patients with ischemic stroke. However, 73 patients were excluded due to missing data on activities of daily living (ADL), and an additional 1,257 patients were excluded because of incomplete serum iron level data. As a result, this cross-sectional study included a total of 2,035 ischemic stroke patients from Shanghai East Hospital, with data collected between 2020 and 2022. Figure 1 provides a detailed overview of the selection process, outlining both inclusion and exclusion criteria.

Baseline characteristics

Table 1 summarizes the baseline characteristics of the subjects, grouped by quartiles of serum iron. The mean age of the patients was 69.3 ± 11.7 years, with 1,326 (65.2%) being male. Patients with higher serum iron levels were younger, predominantly male, and had a slightly higher BMI. They also have higher BI scores. These patients were more likely to have a history of hypertension. According to the TOAST classification, they were more frequently classified under large-artery atherosclerosis and small-vessel occlusion. In Supplementary Table S1 and Supplementary Table S2, we compare the baseline characteristics of the included and excluded patients, clearly presenting the information regarding missing data in this study.

After adjusting for confounding factors, multivariate analysis revealed that for every 5 μmol/L increase in serum iron levels, there was 18% lower odds of severe ADL impairment following ischemic stroke. When serum iron levels were examined by quartiles, a negative association with severe ADL impairment was observed after accounting for relevant variables. Compared to patients with lower serum iron levels (<10.3 μmol/L), the adjusted odds ratios (OR) for severe ADL impairment in the second quartile (Q2: 10.3–13.9 μmol/L), third quartile (Q3: 13.9–18.0 μmol/L), and fourth quartile (Q4: >18.0 μmol/L) were 0.68 (95% confidence interval [CI]: 0.47–1), 0.43 (95% CI: 0.28 ~ 0.66), and 0.54 (95% CI: 0.35–0.83), respectively (Table 2).

In Figure 2, the relationship between serum iron levels and severe ADL impairment after stroke showed a nonlinear association (p = 0.005). The analysis identified an inflection point at approximately 17.5 μmol/L. In the threshold analysis, the odds ratio (OR) for severe ADL impairment among stroke patients with serum iron levels below 17.5 μmol/L was 0.91 (95% confidence interval [CI]: 0.876–0.946). Notably, when serum iron levels reached or exceeded 17.5 μmol/L, the association between serum iron and severe ADL impairment was no longer evident (Table 3).

Figure 2

Subgroup analyses

Figure 3 presents the results of the subgroup analyses. Serum iron levels were significantly associated with impaired ability to perform activities of daily living in several subgroups, including males (OR, 0.95; 95% CI, 0.92–0.98), individuals aged over 65 years (OR, 0.96; 95% CI, 0.93–0.99), those with a BMI less than 25 kg/m² (OR, 0.95; 95% CI, 0.92–0.98), smokers (OR, 0.94; 95% CI, 0.90–0.98), drinkers (OR, 0.88; 95% CI, 0.81–0.95), non-drinkers (OR, 0.97; 95% CI, 0.94–0.99), individuals with hypertension (OR, 0.95; 95% CI, 0.93–0.98), those with diabetes (OR, 0.95; 95% CI, 0.91–0.99), and individuals without diabetes (OR, 0.96; 95% CI, 0.92–0.99). No significant associations were observed in females under 65, individuals with BMI between 25–29.9 kg/m² or ≥30 kg/m², or among non-smokers and individuals without hypertension. Subgroup analyses based on sex, age, BMI, smoking, drinking, hypertension, and diabetes revealed no significant interactions (all p-values for interaction > 0.05).

Figure 3

Sensitivity analysis

To address missing data, we applied multiple imputation across the entire study population. After adjusting for potential confounders, multivariate analysis showed that a 5 μmol/L increase in serum iron was associated with 26% lower odds of ADL impairment following stroke. Compared to individuals with lower serum iron levels (<11.1 μmol/L), the adjusted odds ratios (ORs) for severe ADL impairment in the second quartile (Q2: 11.1–14.2 μmol/L), third quartile (Q3: 14.2–17.3 μmol/L), and fourth quartile (Q4: >17.3 μmol/L) were 0.65 (95% confidence interval [CI]: 0.49–0.88), 0.45 (95% CI: 0.32–0.63), and 0.47 (95% CI: 0.33–0.68), respectively (Supplementary Table S3). Sensitivity analysis using a Barthel Index (BI) score of less than 60 as the cutoff for ADL dependence revealed a stronger and more consistent association between serum iron levels and ADL impairment after ischemic stroke (Supplementary Table S4). In this analysis, each 5-μmol/L increase in serum iron was associated with lower odds of severe ADL disability (OR = 0.82, 95% CI: 0.72–0.94), with an E-value of 1.74. In the categorical analysis, the E-values for Q2, Q3, and Q4 versus Q1 were 2.30, 4.08, and 3.11, respectively. Detailed results are provided in Supplementary Table S5.

Discussion

Serum iron is a vital trace element involved in oxygen transport, cellular respiration, and antioxidant defense. Iron deficiency (ID) occurs when iron levels are insufficient to meet physiological needs (31) and has been linked to decreased physical performance and quality of life in adults, as well as cognitive decline in older individuals (32, 33). In this cross-sectional study of patients with ischemic stroke, we found a non-linear association between serum iron levels and severe ADL impairment in activities of daily living, with an inflection point at 17.5 μmol/L. No significant interactions were observed across subgroups divided by sex, age, BMI, smoking, alcohol consumption, hypertension, or diabetes. Sensitivity analyses supported the robustness of the findings.

Iron is essential for oxygen transport, mitochondrial energy production, antioxidant defense, DNA repair, neurotransmitter synthesis, and maintaining muscle function (7, 31). Disruptions in iron metabolism can affect neurological recovery after stroke. ID can impair mitochondrial function, antioxidant capacity, neurotransmitter production, and myelination, which can reduce neural plasticity and limit post-stroke repair. It may also lead to cognitive decline and muscle weakness (21, 34, 35). These biological mechanisms may explain the inverse association observed between serum iron and severe ADL impairment in our study, particularly as serum iron levels gradually increase. Conversely, iron overload leads to oxidative stress, endothelial dysfunction, blood–brain barrier disruption, and inflammatory responses involving cytokines such as IL-6 and TNF-α, thereby exacerbating ischemic injury (36–38). Excess iron may also increase blood viscosity, alter platelet function, and promote thrombogenesis (39, 40), all of which have been linked to ischemic stroke. Notably, no iron overload phenomenon was observed in this study, as we did not see an increase in severe ADL limitations following an increase in serum iron. This further validates the biological rationale behind the non-linear association. Once iron transporters and cellular uptake mechanisms reach saturation, excess iron does not enhance metabolic or neurodegenerative pathways beyond baseline requirements.

Growing evidence highlights the significance of iron metabolism in determining stroke outcomes. Elevated serum iron levels have been observed in patients with acute hemorrhagic stroke and may worsen neuronal injury through oxidative stress (41). Conversely, ID has been associated with poor functional recovery in acute stroke and increased long-term all-cause mortality among stroke survivors (35). Mendelian randomization studies suggest that although iron status may initially seem protective against large artery stroke or coronary heart disease, these associations become nonsignificant after adjusting for cardiovascular risk factors, indicating that iron status may be a modifiable factor for cardioembolic stroke (42). Similarly, relationships between ferritin levels and cardiovascular events disappear after multivariable adjustment (43). Recent multicenter cohort data further suggest that ID is an independent predictor of adverse 90-day functional outcomes in acute ischemic stroke (18).

The main strength of this study lies in its innovative examination of the association between serum iron levels and severe ADL impairment following ischemic stroke, including an analysis of the dose–response relationship.

However, several significant limitations must be acknowledged. First, serum iron levels were collected in the morning after an overnight fast to minimize diurnal variation; however, serum iron has a short half-life (44) and is acutely influenced by inflammation and disease severity. Although we adjusted for CRP and ferritin in multivariate models, residual confounding cannot be fully ruled out. We did not systematically measure transferrin saturation or hepcidin, preventing a comprehensive assessment of iron metabolism. Future studies should incorporate multiple iron metabolism indicators measured serially to characterize iron homeostasis better.

Second, despite regression modeling and sensitivity analyses, unmeasured confounding cannot be entirely discounted. Essential factors, such as anemia status, nutritional indices, renal function, stroke volume, large vessel occlusion, and reperfusion therapy, were not fully captured. E-value calculations suggested that substantial unmeasured confounding would be required to explain the observed associations fully; however, residual confounding remains a possibility.

Third, 37% of patients were excluded due to missing serum iron data, which may introduce selection bias. We performed multiple imputation and sensitivity analyses to assess the robustness of our results. Additionally, pre-admission functional status could not be ascertained, making it challenging to distinguish baseline impairment from stroke-related ADL disability. A history of prior stroke was included as a proxy, but may not fully capture pre-existing limitations. Future studies should prospectively collect baseline functional status data to isolate stroke-attributable ADL impairment better.

Fourth, and most critically, the cross-sectional design fundamentally precludes establishing causality between serum iron levels and severe ADL impairment. Our findings reflect associations only and cannot determine whether low serum iron contributes to poor outcomes or is merely a consequence of stroke severity and inflammation.

To establish causality, future prospective or intervention studies are needed to examine whether interventions targeting iron homeostasis can improve functional recovery, while controlling for confounders such as inflammation, anemia, nutritional status, and stroke severity.

Conclusion

Our study found a non-linear relationship between serum iron levels and severe ADL impairment in ischemic stroke patients, with an inflection point at approximately 17.5 μmol/L. Given the cross-sectional design and limited available information, these findings should be interpreted with caution.

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