Vitamin B12 and Folate Deficiencies after Allo-HSCT: Association with Gastrointestinal Chronic Graft-versus-Host Disease and Anemia

Vitamin B12 and Folate Deficiencies after Allo-HSCT: Association with Gastrointestinal Chronic Graft-versus-Host Disease and Anemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Vitamin B12 and Folate Deficiencies after Allo-HSCT: Association with Gastrointestinal Chronic Graft-versus-Host Disease and Anemia Ewa Karakulska-Prystupiuk, Aleksandra Kumorek, Agnieszka Tomaszewska, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9419543/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Allo-HSCT recipients, particularly those with gastrointestinal graft-versus-host disease (GI-GvHD), are at increased risk of vitamin B12 and folate deficiencies due to multiple factors, including mucosal injury, reduced intake and drug effects. Data on their prevalence in this population remain limited. Aims To assess the prevalence of vitamin B12 and folate deficiencies after allo-HSCT and their association with gastrointestinal chronic GvHD and post-transplant anemia. Methods This retrospective single-center study included allo-HSCT recipients transplanted between 2014 and 2023. Vitamin levels were defined using the lowest recorded values within two years post-transplant. Deficiency thresholds followed NHANES criteria. Results Among 341 allo-HSCT recipients, decreased vitamin B12 levels (<300 pg/mL) were observed in 49% of patients (17% <200 pg/mL), and folate deficiency (<3 ng/mL) in 46%. A subgroup of 68 patients with chronic GvHD was analyzed (median age 45.5 years). Gastrointestinal involvement was present in 42 patients. Median vitamin B12 levels were lower in the GI-GvHD group than in those without GI involvement (258 vs. 442 pg/mL), and deficiency was more frequent (88.6% vs. 11.4%, p < 0.001), with an inverse correlation with GI-GvHD severity (p < 0.001). Folate levels showed a similar trend without statistical significance. At 12 months post-transplant, hemoglobin concentrations were lower in the GI-GvHD group (12.2 vs. 13.25 g/dL, p = 0.006). Macrocytic anemia predominated in both groups but was not associated with vitamin deficiencies. Conclusions Vitamin B12 deficiency is common after allo-HSCT recipients and strongly associated with gastrointestinal chronic GvHD. Its lack of association with macrocytic anemia suggests that post-transplant anemia is multifactorial. Hematology allogeneic hematopoietic stem cell transplantation chronic graft-versus-host disease gastrointestinal graft-versus-host disease vitamin B12 deficiency folate deficiency post-transplant anemia Figures Figure 1 Background Vitamin B12 and folate cannot be synthesized by the human body and must be obtained from the diet. Without sufficient intake, deficiency develops. Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be particularly susceptible to vitamin deficiencies, especially in the presence of graft-versus-host disease (GvHD). GvHD is the most common non-infectious complication of allo-HSCT, resulting from donor immune response against host histocompatibility antigens [1]. It may involve multiple organs, including the gastrointestinal tract (GI-GvHD). Importantly, more than 60% of patients with acute GvHD and about one-third of those with chronic GvHD develop upper and/or lower gastrointestinal involvement, which affects sites critical for the absorption of vitamin B12 and folate [1-20]. GI-GvHD can impair vitamin absorption through mucosal injury, while GvHD-associated inflammation increases nutritional demands [1-30]. In addition, patients with GI-GvHD often avoid vitamin-rich foods for fear of worsening symptoms [13]. Other contributing factors include inadequate intake and side effects of medications commonly used (cytostatics, immunosuppressive treatment, proton pump inhibitors), which may reduce gastric acid or bile flow, impair absorption, or interfere with vitamin metabolism [1, 25-29]. Finally, small intestinal bacterial overgrowth (SIBO) may further exacerbate vitamin deficiencies in GI-GvHD recipients [18-20]. Given the essential role of vitamin B12 and folate in erythropoiesis, their deficiency may contribute to post-transplant anemia, a clinically relevant complication in allo-HSCT recipients [27, 31]. Data on vitamin B12 and folate status in allo-HSCT recipients, particularly in the context of chronic GvHD, remain scarce. In this study, we sought to determine the prevalence of vitamin B12 and folate deficiencies in adult allo-HSCT recipients, particularly those with gastrointestinal involvement of chronic GvHD, and to explore their association with post-transplant anemia. Purpose This study aimed to assess the prevalence of vitamin B12 and folate deficiencies after allo-HSCT and to investigate their association with gastrointestinal involvement of chronic GvHD and post-transplant anemia. Materials and Methods Study population This retrospective, single-center study included allo-HSCT recipients transplanted between 2014 and 2023 who were followed in outpatient care. The study was approved by the local Ethics Committee (No AKBE/7/2026). Hospital records of all allo-HSCT recipients from the preceding ten years were initially screened for vitamin B12 or folate deficiency. As these deficiencies were relatively frequent, a more detailed analysis was undertaken. From this cohort, patients with chronic GvHD were selected if complete clinical data for the first two years after transplantation were available. Allo-HSCT The type of conditioning was chosen at the responsible physician’s discretion and depended on the underlying hematological disease. GvHD prophylaxis consisted of a calcineurin inhibitor (cyclosporin or tacrolimus) combined with a short course of either methotrexate or mycophenolate mofetil. All patients with unrelated or mismatched donors received anti-T-cell globulin (2.5–5 mg/kg daily) as part of the conditioning regimen for 2–3 days prior to transplantation. Acute and chronic GvHD were diagnosed and graded based on clinical symptoms and/or biopsies according to established criteria [ 1 , 2 , 4 , 33 ]. Acute GvHD was graded using MAGIC criteria, whereas chronic GvHD severity was assessed according to the 2014 National Institutes of Health (NIH) Consensus Criteria [ 1 , 4 , 33 ]. Immunosuppressive therapy was discontinued 6–8 months after allo-HSCT in the absence of clinically significant GvHD. Vitamin Assessment Vitamin B12 and folate levels were determined during routine follow-up at least once a month during the first year after transplantation and every two months in the second year after transplantation. The lowest values recorded within the first two years post-transplantation were analyzed. The laboratory's reference ranges were 197–771 pg/mL for vitamin B12 and 3.9–26.8 ng/mL for folate. Vitamin B12 deficiency was defined as low (< 200 pg/mL), or marginal (200–300 pg/mL) according to the National Health and Nutrition Examination Survey (NHANES) [ 34 ]. Folate deficiency was defined as serum levels below 3 ng/mL [ 16 , 32 , 35 ]. Anemia and erythrocyte indices Anemia was defined using commonly applied hemoglobin thresholds (women < 12 g/dL, men < 13.5 g/dL), consistent with World Health Organization criteria. Severity was categorized into mild, moderate, and severe based on established hemoglobin thresholds (mild: ≥10 to below the lower limit of normal; moderate: 8.0–9.9 g/dL; severe: <8.0 g/dL) The reference range for MCV was 80.7–95.5 fL [ 36 ]. Statistical Analysis Statistical analyses were performed using Microsoft Excel (Microsoft 365), Jamovi (v2.3.34), and R (v4.0.3). Continuous variables were compared using the Mann–Whitney U test, categorical variables using the chi-square or Fisher’s exact test, and correlations using Spearman’s rank correlation. A two-sided p < 0.05 was considered significant. Results Vitamin status in the overall transplant population Records of 382 (177 men) allo-HSCT recipients were screened. In 41 patients, vitamin B12 and folate levels were not measured. In the remaining population of 341 patients, a total of 4,490 vitamin B12 and 5,279 folate levels were obtained. The median B12 level was 425 pg/mL, and the median folate level was 7.1 ng/mL. At least one vitamin B12 level < 300 pg/mL was found in 189 patients (49%), including 64 (17%) with levels < 200 pg/mL. At least one folate level < 3 ng/mL was identified in 175 patients (46%). Selection of the chronic GvHD patients The study population comprised 68 allo-HSCT recipients, including 35 (51.5%) men. The median age at allo-HSCT was 45.5 years (range, 18–69). Patients were transplanted from HLA-identical siblings (N = 25, 37%), matched unrelated donors (N = 30, 44%), mismatched unrelated donors (N = 9, 13%), and haploidentical related donors (N = 4, 6%). Forty patients (59%) received myeloablative conditioning (MAC), 24 (35%) reduced-intensity conditioning (RIC), and 4(6%) nonmyeloablative conditioning (NMA). More than 95% of patients received a combination of a calcineurin inhibitor and glucocorticosteroids (local or systemic); two patients additionally received methotrexate and one received ruxolitinib. Characteristics of GI-GvHD and non-GI-GvHD populations This GvHD group was stratified into GI-GvHD and non-GI-GvHD subgroups. The distribution of global cGvHD severity differed between groups due to organ involvement patterns. The GI-GvHD group comprised 42 patients (overlap syndrome, n = 7; classic chronic GvHD, n = 35), including 12 (28%) with moderate and 30 (72%) with severe global cGvHD. Gastrointestinal involvement among patients with GI-GvHD was graded as follows: grade 1 (n = 23, 33.8%), grade 2 (n = 13, 19.1%), and grade 3 (n = 6, 8.8%). Histopathological confirmation of GI-GvHD was available in 15 patients (7 classified as “likely” and 8 as “possible”). The control group included 26 patients (38.2%) with cGvHD involving organs other than the gastrointestinal tract (mild, n = 14; moderate, n = 5; severe, n = 7). Gastrointestinal colonization with multidrug-resistant bacteria was documented in 23 patients with GI-GvHD, including 6 with Clostridioides difficile ; colonization status was unavailable for 15 patients, and 4 had no evidence of colonization. Comprehensive patient characteristics for both groups are summarized in Table 1 . Table 1 Patient characteristics in the GI-GvHD and non-GI-GvHD groups Gender Number of patients in GI-GvHD group Percentage of GI-GvHD group (n = 42) Number of patients in non-GI-GvHD group Percentage of non-GI-GvHD group (n-26) Male 19 45% 16 61% Female 23 55% 10 39% Diagnosis AML 25 60% 12 47% MDS 4 9% 3 11% ALL 3 8% 4 16% AA 2 5% 3 11% MPN 4 9% 3 11% Lymphoma 4 9% 1 4% Conditioning MAC 24 57% 16 61% NMA 2 5% 2 7% RIC 16 38% 8 32% Donor MRD 14 34% 11 42% MUD 22 52% 8 31% MMUD 6 14% 3 11% haplo 0 4 16% Global severity score of cGvHD Mild 0 14 54% Moderate 12 28% 5 19% Severe 30 72% 7 27% GI tract score 0 26 100% 1 23 55% 2 13 31% 3 6 14% AML- acute myeloid leukemia, MDS- myelodysplastic syndrome, ALL- acute lymphoblastic leukemia, AA- aplastic anemia, MPN- myeloproliferative neoplasm, MAC- myeloablative conditioning, NMA- non-myeloablative conditioning, RIC- reduced intensity conditioning, MRD- matched related donor, MUD- matched unrelated donor, MMUD- mismatched unrelated donor, haplo- haploidentical donor Vitamin status in the GI-GvHD group vs non-GI-GvHD group The median vitamin concentrations in the chronic GvHD cohort were 293 pg/mL for vitamin B12 (range, 114–800) and 3.5 ng/mL for folate (range, 1.55–13.0). Median serum vitamin B12 levels were lower in the GI-GvHD group than in patients without GI involvement (258 vs. 442 pg/mL). Vitamin B12 deficiency (< 300 pg/mL) was significantly more frequent in patients with GI-GvHD than in those without GI involvement (88.6% vs. 11.4%; p < 0.001), with a large effect size (Cramer’s V = 0.56). The prevalence of vitamin B12 deficiency (< 300 pg/mL) in the GI-GvHD and non-GI-GvHD groups is presented in Fig. 1 . Median folate levels were also lower in the GI-GvHD group than in the non-GI-GvHD group (3.2 vs. 4.0 ng/mL). Folate deficiency (< 3 ng/mL) was observed in 84.6% of patients with GI-GvHD and in 15.4% of patients without GI involvement; this difference was not statistically significant (p = 0.110). Associations between vitamin status and GI-GvHD severity A moderate negative correlation was observed between GI-GvHD severity and vitamin B12 levels (Spearman’s rho = − 0.46; 95% CI, − 0.63 to − 0.24; p < 0.001). A weaker but still significant negative correlation was also found for folate levels (rho = − 0.27; 95% CI, − 0.49 to − 0.03; p = 0.024). Hematologic outcomes In all analyzed GvHD patients, the median hemoglobin concentration measured 12 months after allo-HSCT was 12.65 g/dL (range, 7.40–16.00) irrespective of sex and the median MCV was 98.50 fL (range, 83.0-116.0). Anemia, defined using sex-specific hemoglobin thresholds, was diagnosed in 30/42 (71%) patients with GI-GvHD at day 100, in 22/42 (52%) at 1 year, and in 13/42 (31%) at 2 years after allo-HSCT; it was macrocytic in 56%, 63%, and 61%, respectively. In the non-GI-GvHD group, anemia was diagnosed in 19/26 (73%) patients at day 100, in 10/26 (38%) at 1 year, and in 4/26 (15%) at 2 years after allo-HSCT; it was macrocytic in 57%, 60%, and 100%, respectively. While the majority of patients had iron overload, 4 patients with GI-GvHD had iron deficiency. The occurrence of anemia in both groups at day 100, 1 year, and 2 years after allo-HSCT, by grade and type (macrocytic vs. normocytic), is presented in Table 2 . Hemoglobin concentration assessed one year after allo-HSCT was significantly higher in the non-GI-GvHD group than in the GI-GvHD group (median, 13.25 vs. 12.2 g/dL; p = 0.006), with a moderate effect size (rank-biserial correlation = − 0.40). In sex-stratified analyses, the difference remained significant in women (13.2 vs. 12.1 g/dL; p = 0.025) but not in men. However, no correlation was found between macrocytic anemia (MCV > 100 fL) and vitamin B12 or folate deficiency. Table 2 Occurrence of anemia at day 100, 1 year, and 2 years after allo-HSCT, by grade and type (macrocytic vs. normocytic) in GI-GvHD and non-GI- GvHD groups Time point Anemia-No of patients (%) Anemia grade-n(%) Macrocytic anemia -n(%) Macrocytosis > 95fL without anemia-n(%) mild moderate severe MCV 95-105fL MCV>105fL GI-GvHD patients Day 100 30(71%) 17(57%) 10(33%) 3(10%) 15 (50%) 2(6%) 9/42(21%) 1 year 22(52%) 14(63%) 7(32%) 1(5%) 6(27%) 8(36%) 14/42(33%) 2 years 13(31%) 11 (84%) 2(16%) 0 5(38%) 3(23%) 14/42(33%) non-GI-GvHD patients Day 100 19 (73%) 10(53%) 7(37%) 2(10%) 7(37%) 4(20%) 6/26(23%) 1 year 10(38%) 9(90%) 1(10%) 0 4(40%) 2(20%) 10/26(38%) 2 years 4(15%) 4(100%) 3(75%) 1(25%) 10/26(38%) Discussion Recipients of allo-HSCT represent a growing population, and the management of late transplant-related complications is essential for improving long-term survival [ 1 , 37 ]. Among these complications, nutritional deficiencies may be particularly relevant, as effective hematopoietic recovery depends on adequate substrate availability for erythropoiesis and tissue repair. Despite their potential clinical importance and relative ease of correction, data on vitamin B12 and folate status in allo-HSCT recipients, especially in those with chronic GvHD, remain limited. In the general population, cobalamin deficiency affects approximately 10–26% of individuals, whereas folate deficiency is relatively uncommon (1–2%) [ 16 ]. In contrast, in our cohort, decreased vitamin B12 levels were observed in 49% of patients (including 17% with levels < 200 pg/mL), and low folate levels in 46%. Data in HSCT recipients are scarce; in a retrospective pediatric study conducted at 6 months post-transplant, vitamin B12 deficiency was reported in 19% and folate deficiency in 11.3% of patients [ 27 ]. However, that study excluded individuals with active gastrointestinal GvHD, limiting direct comparability with our findings. Importantly, vitamin B12 deficiency in our analysis was strongly associated with gastrointestinal involvement of chronic GvHD and correlated with its severity. Patients with GI-GvHD had significantly lower median B12 levels and a markedly higher prevalence of deficiency compared with those without gastrointestinal involvement. These findings suggest that GI involvement may represent a clinically relevant contributor to vitamin B12 deficiency in allo-HSCT recipients. Several mechanisms may underlie this association in HSCT recipients, including reduced intake due to gastrointestinal symptoms, malabsorption related to mucosal injury, alterations in the intestinal microbiome, and increased metabolic demands associated with tissue repair and depletion of body stores (e.g. liver dysfunction). These factors are likely to coexist and may be particularly pronounced in patients with GI-GvHD [ 1 – 32 ]. Complications of high-dose or prolonged corticosteroid therapy (the first-line treatment for GvHD) [ 47 ], such as muscle loss and weight gain, may also increase the demand for these vitamins. Gastrointestinal GvHD shares several clinical and functional features with inflammatory bowel diseases [ 38 – 40 ], particularly Crohn’s disease, including chronic mucosal inflammation and involvement of both the upper and lower gastrointestinal tract [ 38 , 41 – 43 ]. In this context, mechanisms such as small intestinal bacterial overgrowth (SIBO) and microbiome alterations may further impair nutrient absorption, although their role in allo-HSCT recipients remains insufficiently defined [ 3 , 18 – 20 , 46 ]. From a clinical perspective, early recognition and supplementation of vitamin deficiencies may be especially important in patients with GI involvement, in whom symptoms of deficiency may overlap with manifestations of GvHD, complicating diagnosis [ 1 , 11 ]. Moreover, the need for chronic supplementation may potentially serve as an indirect marker of the severity of inflammation and functional impairment of the small intestine. This is particularly relevant, as direct assessment of this region is often limited by patients’ clinical condition, and histological grading of GvHD correlates poorly with clinical symptoms [ 45 ]. Anemia was highly prevalent in the post-transplant population, particularly in patients with GI involvement of cGvHD, in whom it also appeared to persist longer over time. While the frequency of anemia at day 100 was comparable between groups, a divergence became evident during follow-up, with a consistently higher proportion of affected patients in the GI-GvHD group at both 1 and 2 years post-transplant. This suggests that GI involvement may be associated not only with the occurrence but also with the chronicity of anemia. This observation was further supported by hemoglobin levels, which were significantly lower in the GI-GvHD group at 12 months post-transplant. Interestingly, this difference was primarily driven by female patients, whereas no statistically significant difference was observed in males. This sex-specific discrepancy differs from previous reports [ 48 ], in which male sex has been associated with a higher susceptibility to vitamin B12 deficiency–related anemia. This inconsistency may reflect the relatively small sample size in subgroup analyses and differences in patient characteristics. Despite the high prevalence of vitamin deficiencies, particularly vitamin B12 deficiency in patients with GI involvement, no clear relationship was found between vitamin levels and macrocytic anemia. Although macrocytic anemia predominated in both groups, it did not reflect differences in vitamin status, suggesting a complex etiology. Post-transplant anemia likely reflects the interplay of multiple mechanisms [ 1 , 4 ] with potential contributions from immune-mediated, drug- induced, infection- related, or microangiopathic mechanisms, which were not evaluated in detail in the present study [ 1 ]. In particular, chronic inflammation related to GvHD, ongoing immunosuppressive therapy, and impaired bone marrow function are likely to play a major role. Almost all patients in our GvHD cohort were receiving immunosuppressive treatment, mainly calcineurin inhibitor (CNIs) which may contribute to microangiopathic haemolytic anemia. Anemia observed during ruxolitinib therapy (a second-line treatment for GVHD) [ 47 ] is thought to result from inhibition of JAK2-dependent erythropoietin signalling [ 49 ], while methotrexate may further contribute through its antifolate effects [ 28 ]. Second, the use of nadir vitamin levels in the analysis may not reflect their temporal relationship with hemoglobin or MCV values, potentially obscuring direct associations. Importantly, iron deficiency was rare in this cohort, with most patients demonstrating features of iron overload, further supporting the notion that anemia in this setting is not primarily driven by iron deficiency. Finally, so-called “functional” deficiencies may not always manifest with classical hematologic features such as macrocytosis. Notably, symptoms of B12 deficiency may occur despite normal or even elevated serum levels, particularly in patients with hepatic dysfunction (common post-HSCT), due to impaired clearance of transport proteins, oxidative stress, and reduced intracellular utilization [ 30 , 32 ]. Even moderate deficiencies may be clinically relevant and contribute to multiple post-transplant complications. Importantly, symptoms of vitamin B12 deficiency may overlap with those of GvHD-related complications and post-traumatic stress disorder (PTSD) [ 1 , 4 , 12 , 18 , 33 , 39 , 50 – 62 ]. Our study has several limitations. We assessed only serum vitamin B12 levels, and did not measure functional metabolites. At present, there is no universally accepted gold standard for diagnosing cobalamin deficiency [ 32 , 50 ]. Both methylmalonic acid (MMA) and homocysteine levels are influenced by other factors, such as impaired kidney function. In addition, vitamin B12 levels may appear low in the presence of folate deficiency. Conclusion In summary, vitamin B12 deficiency is highly prevalent in allo-HSCT recipients and strongly associated with gastrointestinal involvement of chronic GvHD. However, its lack of association with macrocytic anemia highlights the complex and multifactorial nature of post-transplant anemia. Declarations Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We thank all the patients, their families and the members of staff involved in their care Funding The authors did not receive any financial support for the submitted work. Conflicts of interest All authors declare no financial interests. Availability of data and material The data that support the findings of this study are derived from medical records and were analyzed anonymously. Code availability Not applicable. Authors’ contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ewa Karakulska-Prystupiuk, Aleksandra Kumorek. The first draft of the manuscript was written by Ewa Karakulska-Prystupiuk and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Conceptualization: Ewa Karakulska-Prystupiuk Methodology: Ewa Karakulska-Prystupiuk Formal analysis and investigation: Ewa Karakulska-Prystupiuk Writing - original draft preparation: Ewa Karakulska-Prystupiuk, Writing - review and editing: Ewa Karakulska-Prystupiuk, Aleksandra Kumorek, Agnieszka Tomaszewska, Piotr Kacprzyk, Jarosław Biliński, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak Resources: Grzegorz Władysław Basak Supervision: Agnieszka Tomaszewska, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak Ethics approval The ethical consent was approved by the Medical University of Warsaw, Bioethical Commission. (No. AKBE/7/2026). Consent to participate This retrospective study was based on anonymized data; therefore, informed consent was not required. Consent for publication Not applicable. References Sureda A, Corbacioglu S, Greco R, Kröger N, Carreras E, editors. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies [Internet]. 8th ed. 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Nutrients. 2025 Apr 23;17(9):1410. doi: 10.3390/nu17091410. PMID: 40362719; PMCID: PMC12073203. Lurz E, Horne RG, Määttänen P, Wu RY, Botts SR, Li B, Rossi L, Johnson-Henry KC, Pierro A, Surette MG, Sherman PM. Vitamin B12 Deficiency Alters the Gut Microbiota in a Murine Model of Colitis. Front Nutr. 2020 Jun 5;7:83. doi: 10.3389/fnut.2020.00083. PMID: 32582756; PMCID: PMC7291859. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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20:57:13","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9419543/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9419543/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107258823,"identity":"2bdb3efc-7529-45a9-a4c9-2287f7526600","added_by":"auto","created_at":"2026-04-19 12:41:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21770,"visible":true,"origin":"","legend":"\u003cp\u003ePrevalence of vitamin B12 deficiency (\u0026lt;300 pg/mL) in the GI-GvHD and non-GI-GvHD groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9419543/v1/64cf408cc618e22af65d9a5c.png"},{"id":107484978,"identity":"f3311963-93e5-49b7-801a-0d036e235d7a","added_by":"auto","created_at":"2026-04-22 02:33:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":514357,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9419543/v1/dd831782-8270-4c3b-af1f-f1285a8e35e7.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eVitamin B12 and Folate Deficiencies after Allo-HSCT: Association with Gastrointestinal Chronic Graft-versus-Host Disease and Anemia\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eVitamin B12 and folate cannot be synthesized by the human body and must be obtained from the diet. Without sufficient intake, deficiency develops. Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be particularly susceptible to vitamin deficiencies, especially in the presence of graft-versus-host disease (GvHD). GvHD is the most common non-infectious complication of allo-HSCT, resulting from donor immune response against host histocompatibility antigens [1]. It may involve multiple organs, including the gastrointestinal tract (GI-GvHD). Importantly, more than 60% of patients with acute GvHD and about one-third of those with chronic GvHD develop upper and/or lower gastrointestinal involvement, which affects sites critical for the absorption of vitamin B12 and folate [1-20].\u003c/p\u003e\n\u003cp\u003eGI-GvHD can impair vitamin absorption through mucosal injury, while GvHD-associated inflammation increases nutritional demands [1-30]. In addition, patients with GI-GvHD often avoid vitamin-rich foods for fear of worsening symptoms [13].\u0026nbsp;Other contributing factors include inadequate intake and side effects of medications commonly used (cytostatics, immunosuppressive treatment, proton pump inhibitors), which may reduce gastric acid or bile flow, impair absorption, or interfere with vitamin metabolism [1, 25-29]. Finally, small intestinal bacterial overgrowth (SIBO) may further exacerbate vitamin deficiencies in GI-GvHD recipients [18-20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the essential role of vitamin B12 and folate in erythropoiesis, their deficiency may contribute to post-transplant anemia, a clinically relevant complication in allo-HSCT recipients [27, 31]. Data on vitamin B12 and folate status in allo-HSCT recipients, particularly in the context of chronic GvHD, remain scarce.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In this study, we sought to determine the prevalence of vitamin B12 and folate deficiencies in adult allo-HSCT recipients, particularly those with gastrointestinal involvement of chronic GvHD, and to explore their association with post-transplant anemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to assess the prevalence of vitamin B12 and folate deficiencies after allo-HSCT and to investigate their association with gastrointestinal involvement of chronic GvHD and post-transplant anemia.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis retrospective, single-center study included allo-HSCT recipients transplanted between 2014 and 2023 who were followed in outpatient care. The study was approved by the local Ethics Committee (No AKBE/7/2026). Hospital records of all allo-HSCT recipients from the preceding ten years were initially screened for vitamin B12 or folate deficiency. As these deficiencies were relatively frequent, a more detailed analysis was undertaken. From this cohort, patients with chronic GvHD were selected if complete clinical data for the first two years after transplantation were available.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAllo-HSCT\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe type of conditioning was chosen at the responsible physician\u0026rsquo;s discretion and depended on the underlying hematological disease. GvHD prophylaxis consisted of a calcineurin inhibitor (cyclosporin or tacrolimus) combined with a short course of either methotrexate or mycophenolate mofetil. All patients with unrelated or mismatched donors received anti-T-cell globulin (2.5\u0026ndash;5 mg/kg daily) as part of the conditioning regimen for 2\u0026ndash;3 days prior to transplantation. Acute and chronic GvHD were diagnosed and graded based on clinical symptoms and/or biopsies according to established criteria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Acute GvHD was graded using MAGIC criteria, whereas chronic GvHD severity was assessed according to the 2014 National Institutes of Health (NIH) Consensus Criteria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Immunosuppressive therapy was discontinued 6\u0026ndash;8 months after allo-HSCT in the absence of clinically significant GvHD.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eVitamin Assessment\u003c/h3\u003e\n\u003cp\u003eVitamin B12 and folate levels were determined during routine follow-up at least once a month during the first year after transplantation and every two months in the second year after transplantation. The lowest values recorded within the first two years post-transplantation were analyzed. The laboratory's reference ranges were 197\u0026ndash;771 pg/mL for vitamin B12 and 3.9\u0026ndash;26.8 ng/mL for folate. Vitamin B12 deficiency was defined as low (\u0026lt;\u0026thinsp;200 pg/mL), or marginal (200\u0026ndash;300 pg/mL) according to the National Health and Nutrition Examination Survey (NHANES) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Folate deficiency was defined as serum levels below 3 ng/mL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eAnemia and erythrocyte indices\u003c/h3\u003e\n\u003cp\u003eAnemia was defined using commonly applied hemoglobin thresholds (women\u0026thinsp;\u0026lt;\u0026thinsp;12 g/dL, men\u0026thinsp;\u0026lt;\u0026thinsp;13.5 g/dL), consistent with World Health Organization criteria. Severity was categorized into mild, moderate, and severe based on established hemoglobin thresholds (mild: \u0026ge;10 to below the lower limit of normal; moderate: 8.0\u0026ndash;9.9 g/dL; severe: \u0026lt;8.0 g/dL) The reference range for MCV was 80.7\u0026ndash;95.5 fL [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using Microsoft Excel (Microsoft 365), Jamovi (v2.3.34), and R (v4.0.3). Continuous variables were compared using the Mann\u0026ndash;Whitney U test, categorical variables using the chi-square or Fisher\u0026rsquo;s exact test, and correlations using Spearman\u0026rsquo;s rank correlation. A two-sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eVitamin status in the overall transplant population\u003c/h2\u003e \u003cp\u003eRecords of 382 (177 men) allo-HSCT recipients were screened. In 41 patients, vitamin B12 and folate levels were not measured. In the remaining population of 341 patients, a total of 4,490 vitamin B12 and 5,279 folate levels were obtained. The median B12 level was 425 pg/mL, and the median folate level was 7.1 ng/mL. At least one vitamin B12 level\u0026thinsp;\u0026lt;\u0026thinsp;300 pg/mL was found in 189 patients (49%), including 64 (17%) with levels\u0026thinsp;\u0026lt;\u0026thinsp;200 pg/mL. At least one folate level\u0026thinsp;\u0026lt;\u0026thinsp;3 ng/mL was identified in 175 patients (46%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSelection of the chronic GvHD patients\u003c/h2\u003e \u003cp\u003eThe study population comprised 68 allo-HSCT recipients, including 35 (51.5%) men. The median age at allo-HSCT was 45.5 years (range, 18\u0026ndash;69). Patients were transplanted from HLA-identical siblings (N\u0026thinsp;=\u0026thinsp;25, 37%), matched unrelated donors (N\u0026thinsp;=\u0026thinsp;30, 44%), mismatched unrelated donors (N\u0026thinsp;=\u0026thinsp;9, 13%), and haploidentical related donors (N\u0026thinsp;=\u0026thinsp;4, 6%). Forty patients (59%) received myeloablative conditioning (MAC), 24 (35%) reduced-intensity conditioning (RIC), and 4(6%) nonmyeloablative conditioning (NMA). More than 95% of patients received a combination of a calcineurin inhibitor and glucocorticosteroids (local or systemic); two patients additionally received methotrexate and one received ruxolitinib.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of GI-GvHD and non-GI-GvHD populations\u003c/h2\u003e \u003cp\u003eThis GvHD group was stratified into GI-GvHD and non-GI-GvHD subgroups. The distribution of global cGvHD severity differed between groups due to organ involvement patterns. The GI-GvHD group comprised 42 patients (overlap syndrome, n\u0026thinsp;=\u0026thinsp;7; classic chronic GvHD, n\u0026thinsp;=\u0026thinsp;35), including 12 (28%) with moderate and 30 (72%) with severe global cGvHD. Gastrointestinal involvement among patients with GI-GvHD was graded as follows: grade 1 (n\u0026thinsp;=\u0026thinsp;23, 33.8%), grade 2 (n\u0026thinsp;=\u0026thinsp;13, 19.1%), and grade 3 (n\u0026thinsp;=\u0026thinsp;6, 8.8%). Histopathological confirmation of GI-GvHD was available in 15 patients (7 classified as \u0026ldquo;likely\u0026rdquo; and 8 as \u0026ldquo;possible\u0026rdquo;).\u003c/p\u003e \u003cp\u003eThe control group included 26 patients (38.2%) with cGvHD involving organs other than the gastrointestinal tract (mild, n\u0026thinsp;=\u0026thinsp;14; moderate, n\u0026thinsp;=\u0026thinsp;5; severe, n\u0026thinsp;=\u0026thinsp;7).\u003c/p\u003e \u003cp\u003eGastrointestinal colonization with multidrug-resistant bacteria was documented in 23 patients with GI-GvHD, including 6 with \u003cem\u003eClostridioides difficile\u003c/em\u003e; colonization status was unavailable for 15 patients, and 4 had no evidence of colonization. Comprehensive patient characteristics for both groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics in the GI-GvHD and non-GI-GvHD groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients in GI-GvHD group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercentage of GI-GvHD group (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNumber of patients in non-GI-GvHD group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePercentage of non-GI-GvHD group (n-26)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConditioning\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDonor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehaplo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGlobal severity score of cGvHD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGI tract score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAML- acute myeloid leukemia, MDS- myelodysplastic syndrome, ALL- acute lymphoblastic leukemia, AA- aplastic anemia, MPN- myeloproliferative neoplasm, MAC- myeloablative conditioning, NMA- non-myeloablative conditioning, RIC- reduced intensity conditioning, MRD- matched related donor, MUD- matched unrelated donor, MMUD- mismatched unrelated donor, haplo- haploidentical donor\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eVitamin status in the GI-GvHD group vs non-GI-GvHD group\u003c/h2\u003e \u003cp\u003eThe median vitamin concentrations in the chronic GvHD cohort were 293 pg/mL for vitamin B12 (range, 114\u0026ndash;800) and 3.5 ng/mL for folate (range, 1.55\u0026ndash;13.0).\u003c/p\u003e \u003cp\u003eMedian serum vitamin B12 levels were lower in the GI-GvHD group than in patients without GI involvement (258 vs. 442 pg/mL). Vitamin B12 deficiency (\u0026lt;\u0026thinsp;300 pg/mL) was significantly more frequent in patients with GI-GvHD than in those without GI involvement (88.6% vs. 11.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a large effect size (Cramer\u0026rsquo;s V\u0026thinsp;=\u0026thinsp;0.56). The prevalence of vitamin B12 deficiency (\u0026lt;\u0026thinsp;300 pg/mL) in the GI-GvHD and non-GI-GvHD groups is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eMedian folate levels were also lower in the GI-GvHD group than in the non-GI-GvHD group (3.2 vs. 4.0 ng/mL). Folate deficiency (\u0026lt;\u0026thinsp;3 ng/mL) was observed in 84.6% of patients with GI-GvHD and in 15.4% of patients without GI involvement; this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.110).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between vitamin status and GI-GvHD severity\u003c/h2\u003e \u003cp\u003eA moderate negative correlation was observed between GI-GvHD severity and vitamin B12 levels (Spearman\u0026rsquo;s rho\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.46; 95% CI, \u0026minus;\u0026thinsp;0.63 to \u0026minus;\u0026thinsp;0.24; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A weaker but still significant negative correlation was also found for folate levels (rho\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.27; 95% CI, \u0026minus;\u0026thinsp;0.49 to \u0026minus;\u0026thinsp;0.03; p\u0026thinsp;=\u0026thinsp;0.024).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eHematologic outcomes\u003c/h2\u003e \u003cp\u003eIn all analyzed GvHD patients, the median hemoglobin concentration measured 12 months after allo-HSCT was 12.65 g/dL (range, 7.40\u0026ndash;16.00) irrespective of sex and the median MCV was 98.50 fL (range, 83.0-116.0). Anemia, defined using sex-specific hemoglobin thresholds, was diagnosed in 30/42 (71%) patients with GI-GvHD at day 100, in 22/42 (52%) at 1 year, and in 13/42 (31%) at 2 years after allo-HSCT; it was macrocytic in 56%, 63%, and 61%, respectively. In the non-GI-GvHD group, anemia was diagnosed in 19/26 (73%) patients at day 100, in 10/26 (38%) at 1 year, and in 4/26 (15%) at 2 years after allo-HSCT; it was macrocytic in 57%, 60%, and 100%, respectively. While the majority of patients had iron overload, 4 patients with GI-GvHD had iron deficiency. The occurrence of anemia in both groups at day 100, 1 year, and 2 years after allo-HSCT, by grade and type (macrocytic vs. normocytic), is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Hemoglobin concentration assessed one year after allo-HSCT was significantly higher in the non-GI-GvHD group than in the GI-GvHD group (median, 13.25 vs. 12.2 g/dL; p\u0026thinsp;=\u0026thinsp;0.006), with a moderate effect size (rank-biserial correlation\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.40). In sex-stratified analyses, the difference remained significant in women (13.2 vs. 12.1 g/dL; p\u0026thinsp;=\u0026thinsp;0.025) but not in men. However, no correlation was found between macrocytic anemia (MCV\u0026thinsp;\u0026gt;\u0026thinsp;100 fL) and vitamin B12 or folate deficiency.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOccurrence of anemia at day 100, 1 year, and 2 years after allo-HSCT, by grade and type (macrocytic vs. normocytic) in GI-GvHD and non-GI- GvHD groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTime point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAnemia-No of patients (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eAnemia grade-n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eMacrocytic anemia\u003c/p\u003e \u003cp\u003e-n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMacrocytosis \u0026gt;\u0026thinsp;95fL without anemia-n(%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003esevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMCV\u003c/p\u003e \u003cp\u003e95-105fL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMCV\u0026gt;105fL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eGI-GvHD patients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDay 100\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30(71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17(57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10(33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3(10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2(6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9/42(21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1 year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6(27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8(36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14/42(33%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2 years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5(38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3(23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14/42(33%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003enon-GI-GvHD patients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDay 100\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10(53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7(37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6/26(23%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1 year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10/26(38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2 years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3(75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1(25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10/26(38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecipients of allo-HSCT represent a growing population, and the management of late transplant-related complications is essential for improving long-term survival [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Among these complications, nutritional deficiencies may be particularly relevant, as effective hematopoietic recovery depends on adequate substrate availability for erythropoiesis and tissue repair. Despite their potential clinical importance and relative ease of correction, data on vitamin B12 and folate status in allo-HSCT recipients, especially in those with chronic GvHD, remain limited.\u003c/p\u003e \u003cp\u003eIn the general population, cobalamin deficiency affects approximately 10\u0026ndash;26% of individuals, whereas folate deficiency is relatively uncommon (1\u0026ndash;2%) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In contrast, in our cohort, decreased vitamin B12 levels were observed in 49% of patients (including 17% with levels\u0026thinsp;\u0026lt;\u0026thinsp;200 pg/mL), and low folate levels in 46%.\u003c/p\u003e \u003cp\u003eData in HSCT recipients are scarce; in a retrospective pediatric study conducted at 6 months post-transplant, vitamin B12 deficiency was reported in 19% and folate deficiency in 11.3% of patients [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, that study excluded individuals with active gastrointestinal GvHD, limiting direct comparability with our findings.\u003c/p\u003e \u003cp\u003eImportantly, vitamin B12 deficiency in our analysis was strongly associated with gastrointestinal involvement of chronic GvHD and correlated with its severity. Patients with GI-GvHD had significantly lower median B12 levels and a markedly higher prevalence of deficiency compared with those without gastrointestinal involvement. These findings suggest that GI involvement may represent a clinically relevant contributor to vitamin B12 deficiency in allo-HSCT recipients.\u003c/p\u003e \u003cp\u003eSeveral mechanisms may underlie this association in HSCT recipients, including reduced intake due to gastrointestinal symptoms, malabsorption related to mucosal injury, alterations in the intestinal microbiome, and increased metabolic demands associated with tissue repair and depletion of body stores (e.g. liver dysfunction). These factors are likely to coexist and may be particularly pronounced in patients with GI-GvHD [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Complications of high-dose or prolonged corticosteroid therapy (the first-line treatment for GvHD) [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], such as muscle loss and weight gain, may also increase the demand for these vitamins.\u003c/p\u003e \u003cp\u003eGastrointestinal GvHD shares several clinical and functional features with inflammatory bowel diseases [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], particularly Crohn\u0026rsquo;s disease, including chronic mucosal inflammation and involvement of both the upper and lower gastrointestinal tract [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In this context, mechanisms such as small intestinal bacterial overgrowth (SIBO) and microbiome alterations may further impair nutrient absorption, although their role in allo-HSCT recipients remains insufficiently defined [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, early recognition and supplementation of vitamin deficiencies may be especially important in patients with GI involvement, in whom symptoms of deficiency may overlap with manifestations of GvHD, complicating diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Moreover, the need for chronic supplementation may potentially serve as an indirect marker of the severity of inflammation and functional impairment of the small intestine. This is particularly relevant, as direct assessment of this region is often limited by patients\u0026rsquo; clinical condition, and histological grading of GvHD correlates poorly with clinical symptoms [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnemia was highly prevalent in the post-transplant population, particularly in patients with GI involvement of cGvHD, in whom it also appeared to persist longer over time. While the frequency of anemia at day 100 was comparable between groups, a divergence became evident during follow-up, with a consistently higher proportion of affected patients in the GI-GvHD group at both 1 and 2 years post-transplant. This suggests that GI involvement may be associated not only with the occurrence but also with the chronicity of anemia.\u003c/p\u003e \u003cp\u003eThis observation was further supported by hemoglobin levels, which were significantly lower in the GI-GvHD group at 12 months post-transplant. Interestingly, this difference was primarily driven by female patients, whereas no statistically significant difference was observed in males. This sex-specific discrepancy differs from previous reports [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], in which male sex has been associated with a higher susceptibility to vitamin B12 deficiency\u0026ndash;related anemia. This inconsistency may reflect the relatively small sample size in subgroup analyses and differences in patient characteristics.\u003c/p\u003e \u003cp\u003eDespite the high prevalence of vitamin deficiencies, particularly vitamin B12 deficiency in patients with GI involvement, no clear relationship was found between vitamin levels and macrocytic anemia. Although macrocytic anemia predominated in both groups, it did not reflect differences in vitamin status, suggesting a complex etiology.\u003c/p\u003e \u003cp\u003ePost-transplant anemia likely reflects the interplay of multiple mechanisms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] with potential contributions from immune-mediated, drug- induced, infection- related, or microangiopathic mechanisms, which were not evaluated in detail in the present study [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In particular, chronic inflammation related to GvHD, ongoing immunosuppressive therapy, and impaired bone marrow function are likely to play a major role. Almost all patients in our GvHD cohort were receiving immunosuppressive treatment, mainly calcineurin inhibitor (CNIs) which may contribute to microangiopathic haemolytic anemia. Anemia observed during ruxolitinib therapy (a second-line treatment for GVHD) [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] is thought to result from inhibition of JAK2-dependent erythropoietin signalling [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], while methotrexate may further contribute through its antifolate effects [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSecond, the use of nadir vitamin levels in the analysis may not reflect their temporal relationship with hemoglobin or MCV values, potentially obscuring direct associations.\u003c/p\u003e \u003cp\u003eImportantly, iron deficiency was rare in this cohort, with most patients demonstrating features of iron overload, further supporting the notion that anemia in this setting is not primarily driven by iron deficiency.\u003c/p\u003e \u003cp\u003eFinally, so-called \u0026ldquo;functional\u0026rdquo; deficiencies may not always manifest with classical hematologic features such as macrocytosis. Notably, symptoms of B12 deficiency may occur despite normal or even elevated serum levels, particularly in patients with hepatic dysfunction (common post-HSCT), due to impaired clearance of transport proteins, oxidative stress, and reduced intracellular utilization [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Even moderate deficiencies may be clinically relevant and contribute to multiple post-transplant complications. Importantly, symptoms of vitamin B12 deficiency may overlap with those of GvHD-related complications and post-traumatic stress disorder (PTSD) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study has several limitations. We assessed only serum vitamin B12 levels, and did not measure functional metabolites. At present, there is no universally accepted gold standard for diagnosing cobalamin deficiency [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Both methylmalonic acid (MMA) and homocysteine levels are influenced by other factors, such as impaired kidney function. In addition, vitamin B12 levels may appear low in the presence of folate deficiency.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, vitamin B12 deficiency is highly prevalent in allo-HSCT recipients and strongly associated with gastrointestinal involvement of chronic GvHD. However, its lack of association with macrocytic anemia highlights the complex and multifactorial nature of post-transplant anemia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe thank all the patients, their families and the members of staff involved in their care\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive any financial support \u0026nbsp;for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are derived from medical records and were analyzed anonymously.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ewa Karakulska-Prystupiuk, Aleksandra Kumorek. The first draft of the manuscript was written by Ewa Karakulska-Prystupiuk and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eConceptualization: Ewa Karakulska-Prystupiuk\u003c/p\u003e\n\u003cp\u003eMethodology: Ewa Karakulska-Prystupiuk\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFormal analysis and investigation: Ewa Karakulska-Prystupiuk\u003c/p\u003e\n\u003cp\u003eWriting - original draft preparation: Ewa Karakulska-Prystupiuk,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWriting - review and editing: Ewa Karakulska-Prystupiuk, Aleksandra Kumorek, Agnieszka Tomaszewska, Piotr Kacprzyk, Jarosław Biliński, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003eResources: Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003eSupervision: Agnieszka Tomaszewska, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethical consent was approved by the Medical University of Warsaw, Bioethical Commission. (No. AKBE/7/2026).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was based on anonymized data; therefore, informed consent was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSureda A, Corbacioglu S, Greco R, Kr\u0026ouml;ger N, Carreras E, editors. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies [Internet]. 8th ed. Cham (CH): Springer; 2024. 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Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clin Exp Immunol. 1999 Apr;116(1):28-32. doi: 10.1046/j.1365-2249.1999.00870.x. PMID: 10209501; PMCID: PMC1905232.\u003c/li\u003e\n \u003cli\u003eHabtie TE, Zemariam AB, Dagnaw BW, Alamaw AW, Feleke SF, Adisu MA. The Immunomodulatory Effect of Vitamin B12 in Pernicious Anemia: A Systematic Review. Oxid Med Cell Longev. 2025 May 26;2025:8463993. doi: 10.1155/omcl/8463993. PMID: 40458194; PMCID: PMC12129597.\u003c/li\u003e\n \u003cli\u003eCuvelier GDE, Schoettler M, Buxbaum NP, Pinal-Fernandez I, Schmalzing M, Distler JHW, Penack O, Santomasso BD, Zeiser R, Angstwurm K, MacDonald KPA, Kimberly WT, Taylor N, Bilic E, Banas B, Buettner-Herold M, Sinha N, Greinix HT, Pidala J, Schultz KR, Williams KM, Inamoto Y, Cutler C, Griffith LM, Lee SJ, Sarantopoulos S, Pavletic SZ, Wolff D. Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force. Transplant Cell Ther. 2022 Aug;28(8):426-445. doi: 10.1016/j.jtct.2022.05.038. Epub 2022 May 31. PMID: 35662591; PMCID: PMC9557927.\u003c/li\u003e\n \u003cli\u003eYu W, Wang Y, Zhou Y, Wu D. Exploring the relationship between vitamin B12, methylmalonic acid levels and all-cause mortality in heart failure populations: insights from the NHANES database. Front Nutr. 2025 Jun 25;12:1597305. doi: 10.3389/fnut.2025.1597305. PMID: 40635893; PMCID: PMC12237664.\u003c/li\u003e\n \u003cli\u003eKelkar AH, Antin JH, Shapiro RM. Long-term health outcomes of allogeneic hematopoietic stem cell transplantation. Front Oncol. 2023 Apr 12;13:1175794. doi: 10.3389/fonc.2023.1175794. PMID: 37124489; PMCID: PMC10130410.\u003c/li\u003e\n \u003cli\u003eVelasco-Aburto S, Llama-Palacios A, S\u0026aacute;nchez MC, Ciudad MJ, Collado L. Nutritional Approach to Small Intestinal Bacterial Overgrowth: A Narrative Review. Nutrients. 2025 Apr 23;17(9):1410. doi: 10.3390/nu17091410. PMID: 40362719; PMCID: PMC12073203.\u003c/li\u003e\n \u003cli\u003eLurz E, Horne RG, M\u0026auml;\u0026auml;tt\u0026auml;nen P, Wu RY, Botts SR, Li B, Rossi L, Johnson-Henry KC, Pierro A, Surette MG, Sherman PM. Vitamin B12 Deficiency Alters the Gut Microbiota in a Murine Model of Colitis. Front Nutr. 2020 Jun 5;7:83. doi: 10.3389/fnut.2020.00083. PMID: 32582756; PMCID: PMC7291859.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"allogeneic hematopoietic stem cell transplantation, chronic graft-versus-host disease, gastrointestinal graft-versus-host disease, vitamin B12 deficiency, folate deficiency, post-transplant anemia","lastPublishedDoi":"10.21203/rs.3.rs-9419543/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9419543/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAllo-HSCT recipients, particularly those with gastrointestinal graft-versus-host disease (GI-GvHD), are at increased risk of vitamin B12 and folate deficiencies due to multiple factors, including mucosal injury, reduced intake and drug effects. Data on their prevalence in this population remain limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAims\u003c/strong\u003e\u003cbr\u003e\nTo assess the prevalence of vitamin B12 and folate deficiencies after allo-HSCT and their association with gastrointestinal chronic GvHD and post-transplant anemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nThis retrospective single-center study included allo-HSCT recipients transplanted between 2014 and 2023. Vitamin levels were defined using the lowest recorded values within two years post-transplant. Deficiency thresholds followed NHANES criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nAmong 341 allo-HSCT recipients, decreased vitamin B12 levels (\u0026lt;300 pg/mL) were observed in 49% of patients (17% \u0026lt;200 pg/mL), and folate deficiency (\u0026lt;3 ng/mL) in 46%.\u003c/p\u003e\n\u003cp\u003eA subgroup of 68 patients with chronic GvHD was analyzed (median age 45.5 years). Gastrointestinal involvement was present in 42 patients.\u003c/p\u003e\n\u003cp\u003eMedian vitamin B12 levels were lower in the GI-GvHD group than in those without GI involvement (258 vs. 442 pg/mL), and deficiency was more frequent (88.6% vs. 11.4%, p \u0026lt; 0.001), with an inverse correlation with GI-GvHD severity (p \u0026lt; 0.001). Folate levels showed a similar trend without statistical significance.\u003c/p\u003e\n\u003cp\u003eAt 12 months post-transplant, hemoglobin concentrations were lower in the GI-GvHD group (12.2 vs. 13.25 g/dL, p = 0.006). Macrocytic anemia predominated in both groups but was not associated with vitamin deficiencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003cbr\u003e\nVitamin B12 deficiency is common after allo-HSCT recipients and strongly associated with gastrointestinal chronic GvHD. Its lack of association with macrocytic anemia suggests that post-transplant anemia is multifactorial.\u003c/p\u003e","manuscriptTitle":"Vitamin B12 and Folate Deficiencies after Allo-HSCT: Association with Gastrointestinal Chronic Graft-versus-Host Disease and Anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:41:25","doi":"10.21203/rs.3.rs-9419543/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3c6fd165-8a53-4069-9045-38db912d39ed","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66322994,"name":"Hematology"}],"tags":[],"updatedAt":"2026-04-19T12:41:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:41:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9419543","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9419543","identity":"rs-9419543","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}