Transfusion-dependent anemia secondary to vitamin C deficiency

Scurvy, or the syndrome of vitamin C deficiency, is rare in industrialized nations though is still seen in underserved populations and those with risk factors for severe malnutrition. It presents with fatigue, myalgias, arthralgias, skin and mucosal bleeding, perifollicular hemorrhage, gingivitis, and coiled body hair. Mild anemia occurs in many cases due to hemorrhage, hemolysis, impaired erythropoiesis, or associated folate deficiency.1-4 We present a case of scurvy manifesting with profound transfusion-dependent anemia. A 57-year-old man presented to the emergency department due to symptomatic anemia (hemoglobin 5.7 g/dl). He noted 2 weeks of dyspnea on exertion, dizziness, arthralgias, myalgias, and easy bruising. Vitals were notable for hypotension at 72/54 mmHg. Physical exam demonstrated bilateral lower extremity edema, tenderness, and ecchymoses. Hemoglobin was 5.1 g/dl and reticulocyte count was 0.15 × 1012/L (0.03–0.08 × 1012/L). Elevated total bilirubin and lactate dehydrogenase were noted due to a known resolving quadriceps hematoma. Haptoglobin and direct antiglobulin test (DAT) were normal. Normal prothrombin time (PT) (14.6 s), aPTT (31 s), and fibrinogen (322 mg/dl) provided no evidence for coagulopathies. Vitamin B12 was deficient (129 pg/ml), and he received 1000 mcg daily oral B12 replacement beginning on day 14, with no improvement in the anemia. The folate level was normal (4.7 ng/ml) and the mean corpuscular volume was normocytic (95 fl). As a result, homocysteine and methylmalonic acid were not tested. No source of bleeding was identified on colonoscopy, esophagogastroduodenoscopy, computed tomography (CT) of the chest/abdomen/pelvis, CT angiogram of the abdomen/pelvis/lower extremities, tagged red blood cell study, bilateral lower extremity CT, and right femur magnetic resonance imaging. Peripheral smear showed hypochromic, normocytic anemia. Bone marrow biopsy showed no dysplasia or blasts, intact trilineage hematopoiesis, hypocellular marrow (5%–25%), and no gelatinous transformation.5 He required 20 units of packed red blood cell (pRBC) transfusions over the 26-day-long admission. He was then transferred to a tertiary care center for further management. The vitamin B12 replacement was switched from oral to intramuscular 1000 mcg daily for 7 days, without improvement in pRBC transfusion requirements. A capsule endoscopy was unremarkable. Assessments for infections (human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, parvovirus, hepatitis B virus, hepatitis C virus), coagulopathies (INR, aPTT, PT, fibrinogen), hemolysis (haptoglobin, lactate dehydrogenase, DAT), pernicious anemia (parietal cell antibodies), autoimmune processes (C3, C4, CH50, anti-Jo antibody, CRP, ESR), and factor deficiencies (factor 10 assay, factor 13 assay) were normal. The total bilirubin remained elevated at 2.0 mg/dl. A repeat peripheral blood smear and bone marrow biopsy were not significantly changed. He required 10 more units of pRBCs. On day 28, the patient described months of a micronutrient-poor diet consisting universally of simple carbohydrates. Physical exam revealed persistent lower extremity edema and ecchymoses, subcutaneous hemorrhages, perifollicular changes, coiled body hair, and gingival erythema (Figure 1). Vitamin C levels were collected on days 29 and 31, which resulted as undetectable (<5 umol/L) on day 32. Vitamin C supplementation was initiated at 250 mcg twice daily. Three days later, no further pRBC transfusions were needed, and after 4 days, the vitamin C level was 14 umol/L (LLN 23 umol/L). In 1 week, the hemoglobin was 9.1 g/dl and continued to rise to 15.9 g/dl about 5 months later. While anemia may occur in up to 80% of patients with scurvy, it is typically mild.2 There are case reports of it being transfusion-refractory and transfusion-dependent.6, 7 Unlike these cases, our patient had no identifiable source of bleeding and required significantly more pRBC transfusions—nearly 30 units in a 6-week period. The mechanism of scurvy-associated anemia is multifactorial and may involve hemorrhage, hemolysis, impaired erythropoiesis, and folate deficiency.1-4 Vitamin C deficiency causes improper collagen synthesis, leading to impaired blood vessel wall integrity and subsequent extravasation of erythrocytes.2, 3 Vitamins C, B9, and B12 are necessary for erythropoiesis. More specifically, the crosstalk of vitamin C with the enzyme isocitrate dehydrogenase 1 (IDH1) has been shown to regulate the final steps of erythropoiesis, during which vitamin C scavenges reactive oxygen species to rescue erythroid differentiation.8 Deficiency of vitamins B9 and B12 may occur in patients with scurvy due to insufficient dietary intake or due to vitamin C's effects on their metabolism.1-4 Since vitamin C functions as an antioxidant to maintain erythrocyte membranes, vitamin C deficiency may lead to unopposed oxidant injury in erythrocytes and subsequent hemolysis.2, 3, 9, 10 In this patient, no hemorrhagic source was identified on extensive imaging and endoscopic evaluation, and the petechiae and ecchymoses incompletely explain the degree of anemia. There was no evidence for hemolysis, except for an indirect hyperbilirubinemia, which suggests a minimal role of hemolysis in this patient's extreme anemia. The patient's severe reticulocytopenia and transfusion dependence suggest that the primary etiology was severe impairment of erythropoiesis, despite normal bone marrow morphology. Replacement of vitamin B12 and normal folate levels did not restore reticulocytosis. Only when given high-dose vitamin C did reticulocytosis rapidly increase, transfusion dependence ceases, and the anemia completely resolve. In conclusion, scurvy is rare in industrialized nations and there is little literature on it presenting with transfusion-dependent anemia. The mechanism by which vitamin C deficiency leads to anemia is multifactorial and, as demonstrated in this case, incompletely understood. Further research is needed to understand the role of vitamin C deficiency in hemolysis and erythropoiesis. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.