Vitamin B12 Deficiency Emerges as Hidden Burden in Gut Graft-Versus-Host Disease After Stem Cell Transplants

Patients who undergo allogeneic hematopoietic stem cell transplantation, one of the most demanding procedures in modern medicine, may face a largely hidden nutritional hazard long after their infusion day. A new retrospective study from the Medical University of Warsaw, published in Annals of Hematology, reports that nearly half of transplant recipients develop vitamin B12 deficiency within the first two years after transplantation, and that the problem is dramatically concentrated among patients whose chronic graft-versus-host disease attacks the gastrointestinal tract. The finding adds a measurable biochemical signature to a complication that has long been recognized clinically but poorly quantified at the level of micronutrients.

The research team, led by Ewa Karakulska-Prystupiuk and colleagues in Warsaw, analyzed 341 patients who received allogeneic stem cell transplants between 2014 and 2023. For each patient, the investigators recorded the lowest vitamin B12 and folate levels measured within two years after the transplant, applying deficiency thresholds derived from the NHANES population surveys. The results were striking: 49 percent of patients showed reduced vitamin B12 levels below 300 pg/mL, with 17 percent falling below 200 pg/mL, and folate deficiency, defined as a level under 3 ng/mL, affected 46 percent of the cohort.

Graft-versus-host disease occurs when donor immune cells recognize the recipient’s tissues as foreign and mount an attack. When this process becomes chronic and involves the gastrointestinal tract, the lining of the gut—the very tissue responsible for absorbing nutrients—is inflamed and damaged. The Polish team hypothesized that this mucosal injury, combined with reduced dietary intake and the effects of immunosuppressive drugs, would translate into measurable vitamin depletion, particularly for B12 and folate, both of which are absorbed through intestinal mechanisms vulnerable to inflammatory damage.

To test this, the investigators carved out a subgroup of 68 patients with confirmed chronic graft-versus-host disease, whose median age was 45.5 years. Among them, 42 had gastrointestinal involvement. When the researchers compared median vitamin levels between the two groups, the difference was unequivocal. Patients with gastrointestinal chronic graft-versus-host disease had a median vitamin B12 level of 258 pg/mL, versus 442 pg/mL in patients whose chronic disease spared the gut. Deficiency was documented in 88.6 percent of the gastrointestinal group, compared with just 11.4 percent of the others, a difference that reached high statistical significance with a p value below 0.001.

Perhaps even more telling was the dose-response relationship. The researchers found an inverse correlation between the severity of gastrointestinal graft-versus-host disease and vitamin B12 concentrations: the worse the gut involvement, the lower the circulating B12. This gradient supports a mechanistic interpretation in which progressive mucosal destruction progressively impairs the absorption machinery—including the ileal uptake pathway that normally captures vitamin B12 bound to intrinsic factor—rather than the deficiency arising from a single binary event.

Folate, the other B vitamin central to red blood cell production and DNA synthesis, followed a similar directional pattern. Levels were lower in the gastrointestinal group, consistent with the idea that an inflamed gut absorbs less of this nutrient as well, but the difference did not reach statistical significance. The authors suggest this may reflect folate’s more diffuse absorption along the small intestine, or the confounding influence of supplementation practices, though the precise explanation remains a question for future work.

The study then turned to anemia, one of the most persistent quality-of-life problems after transplantation. At 12 months post-transplant, hemoglobin concentrations were significantly lower in patients with gastrointestinal chronic graft-versus-host disease, 12.2 g/dL versus 13.25 g/dL in those without gut involvement, with a p value of 0.006. Since both vitamin B12 and folate deficiencies classically cause macrocytic anemia—oversized, underperforming red cells—one might expect the vitamin deficits to explain the anemia. They did not. Macrocytic anemia predominated in both patient groups, but it was not associated with the vitamin deficiencies, indicating that the red cell failure after transplantation stems from multiple converging causes rather than a single nutrient shortfall.

This dissociation is arguably the study’s most instructive result. Post-transplant anemia can arise from ongoing inflammatory suppression of the bone marrow, iron dysregulation, renal dysfunction, medications, and the residual effects of the conditioning regimen itself. The Warsaw data suggest that clinicians cannot assume that correcting B12 or folate levels will resolve anemia in these patients, and conversely, that a normal blood film does not rule out dangerous vitamin depletion. The two problems run on separate tracks, and each demands its own surveillance.

The practical implications are considerable. Vitamin B12 deficiency is not a benign laboratory curiosity; untreated, it can produce neurological injury, cognitive impairment, and worsening fatigue in a population already burdened by treatment toxicities. Given that roughly nine in ten patients with gastrointestinal chronic graft-versus-host disease in this cohort were deficient, the authors’ findings argue for routine, periodic measurement of B12 and folate in this subgroup, with a low threshold for supplementation even in the absence of anemia. Whether prophylactic supplementation should extend to all transplant recipients remains an open question the retrospective design cannot answer.

The study does carry the inherent limits of a single-center retrospective analysis, and vitamin levels were defined by the lowest recorded value rather than serial trends, which may capture transient dips. Still, the size of the cohort, the uniform threshold definitions, and the striking statistical separation between patient groups give the findings weight. As survival after allogeneic stem cell transplantation continues to improve, attention is steadily shifting from survival alone to the long-term functional health of survivors. Identifying a preventable, treatable deficiency affecting nearly half of all recipients—and nearly all of those with gut-directed graft-versus-host disease—is a concrete step in that direction, one that could translate into simple blood tests and inexpensive supplements protecting patients from an entirely avoidable secondary burden.

Subject of Research: Vitamin B12 and folate deficiency after allogeneic hematopoietic stem cell transplantation and its link to gastrointestinal chronic graft-versus-host disease and anemia.

Article Title: Vitamin B12 and folate deficiencies after allo-HSCT: association with gastrointestinal chronic graft-versus-host disease and anemia

Article References: Karakulska-Prystupiuk, E., Kumorek, A., Tomaszewska, A., Kacprzyk, P., Biliński, J., Jędrzejczak, W. W., & Basak, G. W. (2026). Vitamin B12 and folate deficiencies after allo-HSCT: association with gastrointestinal chronic graft-versus-host disease and anemia. Annals of Hematology. https://doi.org/10.1007/s00277-026-07276-7

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07276-7

Keywords: allogeneic stem cell transplantation, vitamin B12 deficiency, folate deficiency, graft-versus-host disease, gastrointestinal GvHD, anemia, macrocytic anemia, hematology, bone marrow transplant, post-transplant care, malnutrition, Annals of Hematology