Vitamin B12 and Vitamin B9 (Folic Acid)
Pathophysiology—Vitamin B12 is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B12 deficiency.23 Monitoring and rapid supplementation of vitamin B12 can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.84
Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B12 levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).84 Interestingly, this study did not find a significant difference in serum vitamin B12 levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B12 deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.
Cutaneous Manifestations—Both vitamin B12 and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.85,86 Systemic symptoms of patients with vitamin B12 and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B12 deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.87
Diagnosis and Monitoring—In patients with suspected vitamin B12 and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B12 and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B12 deficiency but not in folate deficiency.88 Cut-off values for vitamin B12 deficiency are less than 200 to 250 pg/mL forserum vitamin B12 and/or an elevated level of methylmalonic acid (>0.271 µmol/L).89 A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.90 A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B12 or folate deficiency.
Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B12 can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B12 can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.89
Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.91 Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.1 Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.92