Abstract Insufficient iron levels cause oral signs of iron insufficiency. Iron is necessary for several biological activities, including oral tissue health. Low iron levels might alter oral tissues, causing particular symptoms. The aim of this study to detect the oral manifestations of iron deficiency anemia as well as to investigate the link between the severity of these manifestations and the degree of the iron deficiency. The study includes 100 patients with iron deficiency anemia at an Azadi Teaching Hospital, in Duhok City, North of Iraq, and 98 healthy persons. A full history was obtained, and complete blood count and serum ferritin were recorded.

In terms of gender distribution, a clear dominance of females was observed, as they represented 94% of the total cases compared to only 6% for males. Regarding the severity of anemia, most patients had moderate to mild degrees, while severe anemia cases represented a smaller percentage (12%). The comparison between patients and healthy people showed highly significant statistical differences in all pathological changes of the oral mucosa. Complete absence of pathological changes was more common in healthy controls (85%) than in patients (34%). Some pathological changes were closely associated with iron deficiency anemia, such as atrophic glossitis and angular cheilitis.

This study concludes by highlighting the strong correlation between iron deficiency anemia (IDA) and oral mucosal lesions, and the most common oral manifestations are present in patients with severe iron deficiency anemia.

Keywords: Anemia, Blood disorders, Iron, Oral manifestations, Severity

Citation:  Adwar, H. S., Ahmed, S. A. and Hamad, F.H. 2025. Association of oral manifestations with iron deficiency anemia: A case-control study. Natural and Life Sciences Communications. 24(1): e2025006.

INTRODUCTION

Iron is an essential element required for the synthesis of hemoglobin and the transport of oxygen to the body's cells. A deficiency in iron can lead to iron deficiency anemia (from the Greek: an = without, haima = blood) (Rama and Anuradha, 2020). It is estimated that 90% of all types of anemia in the world are due to iron deficiency (Cappellini et al., 2020). In general, (IDA) occurs as a result of blood loss and/or prolonged deficiency in dietary iron intake, especially in periods of greater demand, such as children and adolescents, who have a rapid growth rate, and in women in periods of pregnancy and lactation (Bathla and Arora, 2022; Kumar et al., 2022). According to Mantadakis et al. and Kranjčec et al., iron deficiency, despite being one of the most prevalent deficiencies in the world, is a problem that persists in both developed and developing countries (Kranjčec et al., 2023; Mantadakis et al., 2020).

Assessment of the oral cavity can reveal several clues regarding the patient's systemic changes (Ciesielska et al., 2021). Oral tissues have an intimate relationship with the rest of the body, whether through the bloodstream or the lymphatic system (Jerônimo et al., 2022). During the examination of the oral cavity, due to the fact that it is part of the gastrointestinal system, it is possible to identify the signs and symptoms of systemic diseases resulting from mucocutaneous diseases, immunological disorders, hormonal changes, hematological disorders, systemic infections as well as nutritional problems (Genco and Sanz, 2020; Venkatasalu et al., 2020; Amirzade-Iranaq and Boojar; 2021; Amorim dos Santos et al., 2021; Kapila, 2021).

Systemic diseases, in many cases, can manifest themselves in their initial stage or during their evolution in the oral cavity (Capodiferro et al., 2021). Therefore, its diagnosis and its understanding and interrelationship can lead to a more assertive and targeted treatment of iron deficiency anemia disease in question (Lee, 2020; Al-Naseem et al., 2021; Auerbach, 2023). Therefore, taking into account that the mouth can be the primary site of contamination and the route of transmission of various diseases, it is important that health professionals have complete knowledge of these changes, in order to carry out specialized therapeutic management for each patient (Han et al., 2021; Saboor et al., 2021; Ayejoto et al., 2024).

Oral manifestations of the (IDA) may include fissured tongue (FT), atrophic glossitis(AG), angular cheilits (AG), paleness of lips, recurrent aphthous ulcer (RAS), Thus, this work is justified by the need to expand the dissemination of the oral lesions that may result from the iron deficiency anemia, it is essential that doctors pay attention to their patients complains|, For this ,it is inevitable to carry out a clinical examination, in order to detect oral manifestations and correlate them with iron deficiency anemia problems and, consequently, obtain a better diagnosis ( Hariri, 2023; Lo et al., 2023; Ali and Taha, 2024;Talib and Taha, 2024). This study aims to study the oral manifestations iron deficiency and their severity depending on the degree of iron deficiency.

MATERIAL AND METHODS

Materials

This study was carried out from 2023 to 2024, one hundred cases was collected from hematology center in Azadi Teaching Hospital in Duhok City, and the age and gender matched ninety-eight controls group was collected from Khanzad Training Center, The research was approved by the Research Protocol Ethics Committee, Kurdistan Higher Council of Medical Specialties and an informed consent was recorded.

Target population

In this study, Inclusion criteria were selection of all persons with (IDA) and the study population included both men and women. exclusion criteria were patient on drug therapy that may have oral mucosal manifestations or patients with malignancy or recent surgery were be excluded.

To ensure the accuracy of the association between iron deficiency anemia (IDA) and oral manifestations, the study carefully considered and excluded other potential causes of oral ulcers. Patients on drug therapy that could cause oral mucosal lesions or those with a history of malignancy or recent surgery were excluded from the study. Additionally, thorough medical histories were obtained from all participants, including details about previous diagnoses of systemic conditions such as Behcet's syndrome, oral lichen planus, or other autoimmune disorders. Candida infections were assessed and ruled out through clinical examination. Moreover, trauma-induced ulcers were excluded based on the absence of reported physical injury to the oral cavity. Finally, patients with known vitamin deficiencies (e.g., vitamin B12 or folate deficiency) that could also contribute to ulcer formation were excluded by evaluating their nutritional and medical history. This rigorous approach allowed the study to specifically focus on the correlation between IDA and the observed oral lesions.

Data collection included Medical charts contain patient's identification (address, age, parents' names, city, date of birth, and skin color), medical history (medication taken with duration), physical examination, hematologic conditions, drinking alcohol and a description of general medical status of the patient. and oral examination of patients and healthy groups was done by using disposable mirror, gloves, light torch to detect the oral lesions such as 'AG, AC, paleness of lips, RAS, burning sensation of the oral mucosa, geographic tongue, candida infection, and taste disturbance ".

Blood analysis

The complete blood count and Serum Ferritin, mean blood levels of hemoglobin, Ferritin concentrations, and the sevirity of IDA (mild, moderate, sever) were measured by the routine test in Azadi Teaching Hospital in Duhok city.

Statistical analysis

Comparisons of between 100 iron deficiency anemia patients and 98 age- and gender-randomized healthy controls were carried out by student t-test. The differences in frequency of disease severity between 100 iron deficiency anemia patients were compared by Chi-square test. Additionally, the differences in frequency of each oral manifestation between 100 iron deficiency anemia patients and were also compared by Chi-square test. The results were performed to be significant, high significant and very high significant, if P < 0.05, 0.01 and 0.001, respectively unless indicated otherwise.

RESULTS

Comparative analysis of oral mucosal lesions, gender, and age

Table 1 shows a thorough breakdown of the distribution of Oral Mucosal Lesions (OML), gender, and age in (IDA) patients and healthy controls.

In terms of gender, the majority of IDA patients were female (94%, N=94), with men constituting a lesser fraction (6%, N=6). In contrast, the healthy control group had a more even distribution of males (33.7%, N=33) and females (66.3%, N=65). The gender distribution of IDA patients differed significantly from that of controls (P < 0.001).

In terms of oral lesions, IDA patients had a higher prevalence (66%, N=66) than healthy controls (12.2%, N=12). In contrast, a higher proportion of healthy controls (87.8%, N=86) reported no oral lesions than IDA patients (34%, N=34). The difference in oral lesion prevalence between groups was statistically significant (P < 0.001).

The distribution by age group revealed that IDA patients were primarily in the 19-40 years category (83%, N=83), followed by the 41-70 years category
(13%, N=13), and a smaller proportion in the 1-18 years category (4%, N=4). Healthy controls, in contrast, had a higher proportion in the 19-40 years category (89.8%, N=88), followed by the 41-70 years category (10.2%, N=10), and no persons in the 1-18 years category. The age difference between IDA patients and controls was statistically significant (P < 0.001).

Table 1. Distribution of oral mucosal lesions, gender, and age in patients with iron deficiency anemia and healthy controls.

Note: *There is significant difference between groups (P value <0.005)

Table 2 examines the relationship between the frequency of (OML) and (IDA), using a chi-squared test to determine statistical significance. The table divides OML into several kinds and shows the associated numbers (N) and percentages (%) for both the sick and healthy control groups. The distribution of OML among patients with IDA is as follows: "No lesion" (N=34, 26.4%), "AG" (N=23, 17.8%), "AC" (N=5, 3.9%), "RAU" (N=13, 10.1%), "FT" (N=33, 25.6%), "P" (N=15, 11.6%), "CI" (N=1, 0.8%), and "BS" (N=5, 3.9%).

In contrast, the healthy control group has significantly fewer incidences of "No lesion" (N=86, 87%), "RAU" (N=3, 3%), "FT" (N=9, 9%), and "BS" (N=1, 1%). IDA patients and healthy controls have significantly different frequencies of OML across all categories (P < 0.001)

Table 2. Correlation between frequencies of oral mucosal lesions and iron deficiency anemia.

Note: *There is significant difference between groups (P value <0.005)

Relationship between anemia severity and hemoglobin, serum iron, and ferritin levels

In Table 3, The greatest mean hemoglobin level is found in mild anemia (10.1322 g/dl), followed by moderate anemia (7.8600 g/dl) and severe anemia (5.1317 g/dl). Severe Anemia has the highest level of variability (Std. Deviation = 1.00074).

Serum iron levels follow this pattern, with the lowest mean (17.3975) for severe anemia and the highest mean (40.1273) for mild anemia. The most variable condition is mild anemia (standard deviation = 5.37162). Ferritin levels, which show the amount of iron stored, drastically drop with anemia severity: the greatest mean is found in mild anemia (11.2185), followed by moderate anemia (5.5228), and severe anemia (2.1042). The clinical significance of these discrepancies is highlighted by statistical significance (P < 0.001).

Table 3. Comparison of hemoglobin, serum iron, and ferritin levels across anemia severity.

Note: *significant difference between groups (P value < 0.05)

Prevalence and clinical significance of oral mucosal lesions across anemia severity levels

no lesion, there were 19.38% of patients had no oral lesions in the Mild Anemia, compared to 6.98% in Moderate Anemia and none in Severe Anemia.

The AG rises dramatically from Mild (1.55%) to Moderate (13.95%), and it remains significant in Severe Anemia (2.33%). indicating a strong link between anemia severity and AG. This growing incidence with deteriorating anemia implies AG's potential value as a biomarker of iron insufficiency in clinical assessments.

The AC exclusively in Severe Anemia (3.1%), with no cases detected in Mild or Moderate Anemia groups, it shows a clear trend, indicating its potential as a marker for severe iron shortage.

RAU increases across anemia severity categories, from 3.88% in Mild Anemia to 10.08% overall, with a significant correlation (P = 0.0016). This gradual increase shows a link between anemia severity and the development of RAU.

FT group increases considerably from Mild (6.98%) to Moderate Anemia (14.73%) and reduces in Severe Anemia (3.88%), indicating a significant overall correlation (P = 0.008).

P is absent in Mild Anemia, present in 2.33% of Moderate Anemia, and rises to 9.3% in Severe Anemia, indicating a significant connection (P = 0.0004). This highlights its association with severe forms of anemia. Pallor has a strong correlation with severe anemia, highlighting its practical use as a visible clinical diagnostic of progressive iron shortage that aids in clinical assessments.

BS is present in Mild (1.55%) and Moderate Anemia (2.33%), but not in Severe Anemia, with no significant association between the categories (P = 0.2465).

CI is uncommon (0.78%) in Severe Anemia, with no cases found in Mild or Moderate Anemia groups. The chi-squared test (P = 0.3678) found no significant correlation between severity categories.

Table 4. Prevalence of oral mucosal lesions across different severity categories of anemia and statistical associations.

Note: *Significant difference between groups (P value < 0.05)

Distribution of anemia severity by gender and age

In table 5, the analysis categorizes data by gender (Male, Female) and age intervals (1-18 years, 19-40 years, 41-70 years), examining how anemia severity, classified into Mild (9 - 11 g/dl), Moderate (7 - 9.9 g/dl), and Severe (< 7 g/dl) categories, varies across demographic groups. Each cell in the table represents counts of individuals within these categories based on gender and age group, with totals provided for quick assessment of distribution, indicating no significant association (NS) between gender and anemia severity across age intervals.

Table 5. Association between gender and anemia severity in different age intervals.

Note: NS: Non significant association between groups.

DISCUSSION

This study makes several key points in comparison with existing literature regarding the association between oral changes and iron deficiency anemia.

The current study showed a large disparity between genders, with women representing 94% of all cases compared to 6% of men. This significant difference suggests that women are more likely to develop iron deficiency anemia, perhaps due to biological or behavioral factors.

The incidences of iron deficiency anemia have been increasing in the population in Middle East (Aleem et al., 2020; Al-Jawaldeh et al., 2021; Owaidah et al., 2020). Notably with the results of this study, the incidence rate in females has nearly increased by 40-fold in ages ranged of 19-40 year when a compared to that seen with ranges of 1-18 years. This finding is comparable to that in a previous report from the AlFaris et al., (2021), Shaheen et al., (2022) and Arbaeen and Iqbal, (2022), where an increase in the new cases of iron deficiency anemia was approved over the last fifteen years among adult women (AlFaris et al., 2021; Arbaeen and Iqbal, 2022; Shaheen et al., 2022).

Low levels of iron in the body cause a reduction in the synthesis of healthy red blood cells, which is the hallmark of a lack of iron anemia. Although blood and general overall wellness are the main signs of anemia caused by iron deficiency, it can also present as a variety of mouth diseases.

Moderate anemia was the most common grade, followed by mild anemia, while only of cases presented with severe anemia.

Among all studied sample, fissured tongue and atrophic glossitis, which were the most frequent oral signs and symptoms, demonstrated the highest prevalence with moderate iron deficiency anemia. On the other hand, pallor shows the highest prevalence with severe iron deficiency anemia, while burning sensation of oral mucosa and recurrent aphthous ulcers were not detected with this life-threatening disease. Mild iron deficiency anemia appeared with women earlier than seen with men as agreed with other studies conducted by Abuaisha et al., (2020), Cappellini et al., (2020), and Stoffel et al., (2020) (Abuaisha et al., 2020; Cappellini et al., 2020; Stoffel et al., 2020).

Overall, the significant associations between iron deficiency anemia and various oral manifestations, as shown in this study, are consistent with previous research. The importance of regular dental checkups and effective management strategies for these oral diseases in IDA patients to improve their overall health cannot be overstated.

The lower frequency of oral lesions in severe anemia may be due to the body’s physiological adaptations to prolonged iron deficiency, where the immune response and inflammation in non-vital areas like the oral mucosa are diminished, resulting in fewer visible symptoms. In contrast, moderate anemia might present with more pronounced lesions as the body is still actively responding to the iron deficiency. The higher frequency of oral lesions in females can be attributed to hormonal fluctuations during menstruation, pregnancy, and menopause, which affect oral health, and the overall higher prevalence of iron deficiency anemia in women due to factors like menstruation and nutritional disparities. These combined factors make women more prone to anemia-related oral manifestations.

Limitations

The current study has several limitations. Healthy persons aged 18 years or younger are required to undergo medical examination. A cross-section of the various cities and people from various castes were not included in the selection of patients. The differences between urban and rural populations were also not included in the study populations. This missed information will be covered in our further studies.

CONCLUSION

This study highlights the significance of the oral cavity as a reflection of systemic health, with early manifestations of various diseases, including iron deficiency anemia. The comprehensive understanding of the oral manifestations associated with iron deficiency anemia gained from our study makes it an essential resource for healthcare professionals, aiding in the prompt diagnosis and treatment of this condition. Ultimately, early intervention and management of iron deficiency anemia can help prevent severe complications and enhance the overall health outcomes of affected individuals.

ACKNOWLEDGEMENTS

The authors thank the Faculty of dentistry, Kurdistan higher council of medical specialties, Erbil- KRG-Iraq for providing instruments.

AUTHOR CONTRIBUTIONS

Hiba shokry Adwar: contributed to conceptualizing, validation, writing original draft, supervision, and project administration, also contributed to the methodology, formal analysis, resources, original draft, review, editing, and visualization. Shahen Ali Ahmed and Farman Hamadameen Hamad: contributed to the methodology, formal analysis, resources, original draft, review, editing, and visualization.

CONFLICT OF INTEREST

The authors declare that they hold no competing interests.

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