Inflammation Blood Index Linked to Iron Deficiency in Adult Celiac Disease

Three numbers that hospitals already compute from every routine blood count may quietly reveal which adults with celiac disease are running low on iron stores. In a retrospective cross-sectional study of 120 adults followed at a tertiary gastroenterology center in Istanbul between January 2020 and October 2023, researchers found that patients with ferritin deficiency had significantly higher values of the systemic immune-inflammation index (SII), the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) than patients with normal ferritin levels. All three associations survived the Holm correction for multiple comparisons, and the link between higher SII and ferritin deficiency persisted after multivariable adjustment, with an adjusted odds ratio of 2.12 per doubling of SII (95% CI, 1.31–3.58; p = 0.002). The findings, published in Frontiers in Medicine, suggest that systemic inflammatory activity and micronutrient status are intertwined in treated adult celiac disease, particularly with respect to iron.

Celiac disease is a chronic, immune-mediated enteropathy that develops in genetically susceptible individuals after exposure to dietary gluten. The immune assault flattens the villi of the small intestine, deepens the crypts, and floods the mucosa with intraepithelial lymphocytes, producing a structural injury that impairs the absorption of several micronutrients. In adults the disease often presents with nonspecific symptoms, biochemical abnormalities, or isolated anemia, and micronutrient deficiencies may persist despite diagnosis and dietary treatment. Because chronic inflammation can disturb iron homeostasis through hepcidin-mediated pathways, while persistent deficiencies may in turn sustain low-grade inflammatory activity, the interaction between systemic inflammation and nutritional status is complex and not yet fully clarified.

The indices at the center of the study are derived from complete blood count parameters that are measured routinely in every patient. The SII integrates neutrophil, lymphocyte, and platelet counts into a single composite parameter calculated as platelet count multiplied by neutrophil count divided by lymphocyte count, and it was selected as the primary inflammatory index because it captures three peripheral blood cell populations rather than two. The NLR and PLR, which are based on two-cell ratios, were included as established comparator indices. All three have attracted growing interest as measures of systemic immune-inflammatory activity in chronic inflammatory and autoimmune disorders, but data on SII in celiac disease, particularly in relation to nutritional parameters, remain limited.

The researchers evaluated the indices according to ferritin, transferrin saturation, vitamin B12, folate, and vitamin D status. Ferritin and transferrin saturation were chosen to assess iron status because they provide complementary information on iron stores and functional iron availability, particularly in the presence of chronic inflammation. Vitamin B12 and folate were included because deficiencies may result from impaired intestinal absorption and are associated with hematological and neurological complications, whereas vitamin D was evaluated because of its established role in bone metabolism and immune regulation. Deficiencies were defined using the hospital laboratory’s reference ranges: ferritin below 15 ng/mL, transferrin saturation below 20%, vitamin B12 below 200 pg/mL, folate below 4 ng/mL, and 25-hydroxyvitamin D below 20 ng/mL.

The cohort was predominantly female, with 79 of the 120 patients (65.8%) being women, and the mean age was 35.3 years. The median disease duration was 9 years, and 90% of patients were documented as adherent to a gluten-free diet. Anemia, defined by World Health Organization criteria, was present in 20.8% of patients. Micronutrient deficiency rates were striking: 32.5% of patients with available ferritin measurements had ferritin levels below 15 ng/mL, 54.8% had transferrin saturation below 20%, 12.2% had vitamin B12 deficiency, 22.1% had folate deficiency, and 68% had vitamin D deficiency. Patients receiving active iron, vitamin B12, or folate replacement therapy at the time of laboratory assessment were excluded to minimize confounding.

The most consistent associations were observed for iron status. Patients with ferritin deficiency had higher SII, NLR, and PLR values, and all three differences remained statistically significant after Holm correction (SII: Holm-adjusted p = 0.025; NLR: p = 0.049; PLR: p = 0.007). Spearman correlation analysis demonstrated a modest inverse correlation between serum ferritin levels and SII (ρ = −0.23, p = 0.013), indicating that higher SII values tended to be associated with lower ferritin concentrations. In contrast, patients with low transferrin saturation showed higher SII and NLR values in unadjusted analyses, but these associations did not remain significant after correction for multiple comparisons.

Vitamin B12 deficiency was associated with higher SII and NLR values in unadjusted analyses, but neither association survived the Holm correction. Exploratory analyses using Firth penalized logistic regression and treating vitamin B12 as a continuous outcome nevertheless suggested a possible relationship, with an adjusted odds ratio of 1.97 per doubling of SII (95% CI, 1.05–3.92; p = 0.033). Given the small number of vitamin B12-deficient patients, only 13 or 14 depending on the analysis, the researchers considered this finding exploratory rather than confirmatory. No associations were detected between the inflammation indices and folate or vitamin D deficiency after correction for multiple comparisons, with all Holm-adjusted p values reaching 1.000.

The biological interpretation is nuanced. Ferritin reflects body iron stores but may also be influenced by inflammatory activity, whereas transferrin saturation more directly reflects circulating iron availability. Higher SII in patients with low ferritin levels may therefore not solely reflect iron depletion itself but rather the persistent inflammatory milieu accompanying active celiac disease. Conversely, iron deficiency itself may influence neutrophil, lymphocyte, and platelet counts, thereby contributing to changes in composite indices such as SII. The observed association is likely to reflect the combined effects of persistent mucosal inflammation and hematological alterations related to iron deficiency rather than a single underlying mechanism. Factors unrelated to systemic inflammation, including menstrual blood loss, dietary iron intake, and occult gastrointestinal bleeding, may also influence ferritin concentrations.

The absence of associations with vitamin D and folate is not entirely unexpected, as the determinants of these micronutrients extend beyond intestinal absorption and inflammatory activity. Vitamin D status is influenced by sunlight exposure, dietary intake, supplementation, and seasonal variation, while folate levels may be affected by nutritional habits and replacement therapy. The circulating concentrations of these micronutrients are therefore determined by a broader range of factors than systemic inflammatory activity alone. The findings suggest that not all micronutrient abnormalities in celiac disease are equally associated with systemic inflammatory indices, with the most consistent associations observed for reduced iron stores.

The researchers emphasize that the present findings should be interpreted as evidence of association rather than clinical utility. The study was not designed to evaluate the diagnostic performance of SII or its incremental value over conventional hematological parameters such as hemoglobin, mean corpuscular volume, and red cell distribution width, and no formal comparisons of discriminatory performance among SII, NLR, and PLR were performed. The retrospective, single-center design limits causal inference and generalizability, information on serological activity and histopathological severity was not consistently available, and the cross-sectional nature precludes assessment of temporal relationships. Because the majority of patients were adherent to a gluten-free diet and under long-term follow-up, the observed inflammatory indices reflect the inflammatory status during treated follow-up rather than at the time of initial diagnosis. Larger prospective cohorts are needed to confirm these associations and to determine whether inflammation-based indices derived from routine blood counts can eventually serve a clinical role in monitoring micronutrient status in adults with celiac disease.

Subject of Research: Systemic inflammation indices, particularly SII, are associated with reduced iron stores in adults with celiac disease.

Article Title: Association of systemic inflammation indices with micronutrient status in adult patients with celiac disease

Article References: Candan, S., Katı, O., Eşkazan, T., Bakkaloğlu, O. K., Hatemi, İ., Dobrucalı, A. M., & Canbakan, B. (2026). Association of systemic inflammation indices with micronutrient status in adult patients with celiac disease. Frontiers in Medicine, 13, Article 1898592. https://doi.org/10.3389/fmed.2026.1898592

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1898592

Keywords: celiac disease, systemic immune-inflammation index, iron deficiency, ferritin, vitamin B12, micronutrient status, inflammation indices, gastroenterology, Association, systemic, inflammation, indices