The presentations of macrocytic anemia are dependent on the underlying cause. Patients with vitamin B12 deficiency complain of mood disturbances and neurologic symptoms like loss of balance, memory loss, paresthesias, peripheral neuropathy. The remainder of symptoms is specific to the underlying cause (constitutional symptoms from primary bone marrow disease, gastrointestinal upset from enteral malabsorption, or hypoactive metabolism from hypothyroidism). Folate deficiency has common features except neuropsychiatric complaints. Prior surgeries include a gastric bypass for weight loss or ileal resection for colonic pathologies. Family or personal medical histories reveal autoimmune diseases or hemolytic anemias. Certain medical conditions require at-risk medications. Review of dietary intake reveals excessive alcohol consumption or limited food choices (“tea and toast”). 

Physical exam may reveal nonspecific anemia findings (conjunctival pallor), neurologic deficits if vitamin B12 deficient (impaired proprioception or vibration, positive Romberg sign), and stigmata of underlying diseases (glossitis from autoimmune atrophic gastritis, hepatosplenomegaly from familial hemolytic anemias, hypopigmentation from vitiligo, or jaundice and spider angiomata from alcohol abuse).

Initial evaluation of macrocytic anemia includes a thorough history and physical followed by limited labs (PBS, reticulocyte count, and serum B12). Pure RBC indices will underestimate the presence of macrocytosis by 30% because MCV represents the mean distribution curve of all RBCs and fails to identify smaller macrocytes. If the PBS is normal, no megaloblastic RBCs,  order additional testing for liver and thyroid diseases (aminotransferases and thyroid stimulating hormone), the most common causes of non-megaloblastic anemia. If there are megaloblastic RBCs on PBS, check the reticulocyte count: less than 1% indicates underproduction, while greater than 2% is associated with hyperproliferation due to hemolysis or hemorrhage (commence hemolytic anemia work-up). If hyperproliferative, look at the B12 level. Values less than 100 pg/mL indicate deficiency. Order RBC folate level (not serum folate due to lack of sensitivity) for B12 above 400 pg/mL; low levels indicate folate deficiency and normal ones may need further investigation with bone marrow evaluation. Measure homocysteine and methylmalonic acid (MMA) in patients with B12 100 pg/mL to 400 pg/mL; these are biochemical compounds important in pathways involving cell metabolism and use folate and vitamin B12 as cofactors. Both or MMA only are elevated in vitamin B12 deficiency; homocysteine is elevated in folate deficiency. Normal values may warrant hematology consultation for bone marrow studies. Specialist consults are recommended in patients with abnormal myeloid morphology on PBS (disordered immaturity, hypo-granulated or hypo-segmented neutrophils, or additional cytopenias).

Work-up for specific causes of megaloblastic anemia should be based on presentation. Antibodies for intrinsic factor or parietal cells are indicative of pernicious anemia. The Schilling test, once used to measure vitamin B12 uptake before and after administration of intrinsic factor, has fallen out of favor. [3][8]

Treat macrocytic anemia by replacing folate or vitamin B12 and targeting the underlying cause. Give folic acid orally, 1 mg to 5 mg daily, and encourage diets with foods rich in folate (fortified cereals, leafy vegetables). Patients who are taking folate antimetabolites or pregnant women (especially those with a history of neural tube defects or taking antiepileptics) should take daily supplements to prevent deficiencies. It is important to not overlook vitamin B12 deficiency as a cause for macrocytic anemia, treatment of folate deficiency but not vitamin B12 deficiency will resolve the anemia but not the neurologic effects. Prescribe 1000 micrograms oral vitamin B12 daily for 1 month followed by 125 to 250 micrograms daily or administer 1000 micrograms intramuscular B12 every week for 4 weeks then monthly to replace vitamin B12 stores, the latter of which is preferred for patients with pernicious anemia or altered gastrointestinal anatomy. Clinicians may prescribe empiric folate supplementation (400 micrograms to 1 g/day) in patients receiving vitamin B12 replacement. Reticulocytosis will improve within 1 to 2 weeks, and anemia should resolve after 4 to 8 weeks. There is no need to monitor RBC indices or recheck folate or vitamin B12 levels and their metabolites during active treatment, though some physicians check yearly complete blood counts in patients taking long-term vitamin B12 therapy. Neurologic symptoms from vitamin B12 deficiency take longer. Macrocytosis related to alcohol use resolves with abstinence. Other non-megaloblastic anemias improve when the underlying conditions are treated. 

In other instances, macrocytosis is indicative of medical compliance (ex. methotrexate or zidovudine) and does not need additional management beyond supplements to prevent anemia.[9][10]

• Folate deficiency anemia
• Anemia due to liver disease
• Hypothyroidism
• Myelodysplastic syndrome
• Alcoholism

With early identification and treatment of underlying cause, the prognosis for macrocytic anemia is excellent. Specialist referral is rarely needed unless anemia is resistant to therapy or there is evidence of underlying myelodysplasia or leukemia.

Patients with chronic megaloblastic anemia from vitamin B12 deficiency can develop permanent neurologic damage referred to as subacute combined neurodegeneration. Patients will have gait ataxia, memory loss, peripheral neuropathy, and psychiatric disturbances. Patients with macrocytic anemia from underlying conditions will experience complications of their respective diseases.

Macrocytic anemia is a special blood disorder in which the body is not able to form enough blood cells because it lacks necessary nutrients. Some patients do not eat enough foods with these nutrients (folate or vitamin B12), while others cannot absorb it or have an underlying condition that makes it difficult for the body to keep up with its needs. Patients may feel tired, have memory or mood disturbances, or notice tingling in the arms and legs. Physicians can diagnose the anemia during an office visit and lab work. Treatment involves addressing the underlying cause and nutrient supplementation.

With early identification and treatment of underlying cause, the prognosis for macrocytic anemia is excellent. Specialist referral is rarely needed unless anemia is resistant to therapy or there is evidence of underlying myelodysplasia or leukemia. This anemia is the most underestimated of all forms and physicians should not hesitate to treat due to its unique side effects.

Today, healthcare workers encounter many cases of macrocytic anemia than in the past. Further, as the population ages, many more cases of macrocytic anemia are likely to be seen in the future. The other thing of note is that there are many causes of macrocytic anemia including medications; thus the management of these patients is an interprofessional. It is important to educate the patient that some of the more common causes of macrocytic anemia include deficiency of folate and cobalamin. In addition, several reverse transcriptase inhibitors used to treat HIV can also cause macrocytic anemia and hence the pharmacist should encourage the patient to regular blood tests. Another common cause of macrocytic anemia is alcohol abuse; however, with abstinence, this anemia is rapidly corrected. Finally, patients should be educated about foods that are rich in folate and cobalamin.[11][12]

Outcomes

When the cause of the macrocytic anemia is dietary, the condition can be reversed with dietary changes. For those who fail to comply with diet, they are at risk for anemia related cardiac complications, neurological damage, and defects in fetal development. When the cause is a malignancy, the prognosis is guarded. [13][14]