Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

Abstract

Vitamin A promotes development of mucosal tolerance and enhances differentiation of regulatory T cells. Vitamin A deficiency impairs epithelial integrity, increasing intestinal permeability. We hypothesized that higher vitamin A levels would reduce the risk of graft-versus-host disease (GVHD) through reduced gastrointestinal (GI) permeability, reduced mucosal injury, and reduced lymphocyte homing to the gut. We tested this hypothesis in a cohort study of 114 consecutive patients undergoing allogeneic stem cell transplant. Free vitamin A levels were measured in plasma at day 30 posttransplant. GI GVHD was increased in patients with vitamin A levels below the median (38% vs 12.4% at 100 days, P = .0008), as was treatment-related mortality (17.7% vs 7.4% at 1 year, P = .03). Bloodstream infections were increased in patients with vitamin A levels below the median (24% vs 8% at 1 year, P = .03), supporting our hypothesis of increased intestinal permeability. The GI mucosal intestinal fatty acid-binding protein was decreased after transplant, confirming mucosal injury, but was not correlated with vitamin A levels, indicating that vitamin A did not protect against mucosal injury. Expression of the gut homing receptor CCR9 on T-effector memory cells 30 days after transplant was increased in children with vitamin A levels below the median (r = -0.34, P = .03). Taken together, these data support our hypothesis that low levels of vitamin A actively promote GI GVHD and are not simply a marker of poor nutritional status or a sicker patient. Vitamin A supplementation might improve transplant outcomes.

Figure 1.

Vitamin A levels and transplant outcomes. (A) Free vitamin A levels in patient plasma 30 days posttransplant are in a narrow range and normally distributed with a median value of 1.296 ng/mL. (B) Vitamin A levels below the median are associated with increased incidence of grades 2-4 GVHD (38.6% vs 12.4% at 100 days, P = .0008). (C) Vitamin A levels below the median are associated with increased incidence of GI GVHD (30.4% vs 7% at 100 days, P = .002). (D) TRM was also increased in patients with vitamin A levels below the median compared with patients with vitamin A levels above the median (17.7% vs 7.4% at 1 year, P = .03).

Figure 2.

RBP levels and transplant outcomes. RBP4 levels measured in plasma day 30 posttransplant had no effect on transplant outcomes including cumulative incidence of GI GVHD (A) and TRM (B).

Figure 3.

Cumulative incidence of MBI-LCBIs. Incidence is higher in patients with vitamin A levels below the median at day 30 posttransplant compared with those with vitamin A levels above the median (24% vs 8% at 1 year, P = .03).

Figure 4.

Mucosal damage leads to increased incidence of GI GVHD and is increased in patients receiving a myeloablative conditioning regimen (MAC) compared with those receiving a reduced intensity conditioning regimen (RIC). (A) Cumulative incidence of GI GVHD is increased in patients with more mucosal damage as measured by I-FABP levels below the median (27% vs 18% at 100 days, P = .0024). (B) I-FABP levels are lower at day 7 posttransplant in patients who received MAC vs RIC, which correlates with increased mucosal damage.