Macrocytic Anemia

Type of anemia characterized by a reduced number of red blood cells that are larger than normal, defined by an increased mean corpuscular volume (MCV) greater than 100 fL. It results from impaired red blood cell production, most commonly due to deficiencies of vitamin B₁₂ or folate, but it can also be caused by alcohol use, liver disease, hypothyroidism, certain medications, or bone marrow disorders. The mean corpuscular (or cell) volume (MCV) is the index most often used because it reflects the average volume of each red blood cell. It is calculated as follows: $MCV={Hematocrit \over RBC(cells/l)}$

Those with a high MCV are macrocytic.

Causes

Key Causes:

• Vitamin B12 deficiency – ↓ methionine & DNA synthesis

• Folate deficiency – ↓ DNA synthesis

• Drugs (methotrexate, hydroxyurea, 5-FU, zidovudine) – Antimetabolites that inhibit nucleotide synthesis

Vitamin B12 Deficiency

It only occurs after several years of reduced income. It is mainly manifested by changes in:

• hematopoiesis – Lack of dTTP for DNA synthesis leads to a slowdown in the division of (not only) erythrocyte precursors . However, RNA formation and protein synthesis are not affected (RNA contains uracil instead of thymidine) and so blood cells form a normal amount of hemoglobin (a small amount of large erythrocytes). Defective erythrocytes disappear more quickly, sometimes in the bone marrow ( ineffective erythropoiesis ). In the peripheral blood, there is also leukopenia with macrocytosis and hypersegmentation of neutrophil nuclei and thrombocytopenia . The bone marrow is hyperplastic. These manifestations can be suppressed by excessive intake of folic acid, which replaces the missing THF.
• GIT – leads to diarrhea.
• Neurons – demyelination of axons . The principle is the lack of methionine, which is necessary for the synthesis of choline and the phospholipid component of the myelin sheath. In excess, methylmalonyl-CoA occurs, from which defective lipids of the myelin sheath are formed. Typical is the involvement of the posterior and lateral spinal cords, funicular degeneration and peripheral neuropathy . Symptoms include paresthesia , deep sensory disorders , rarely paresis.
• Homocysteine ​​levels , which are manifested by insufficient conversion of homocysteine ​​to methionine. Homocysteine ​​accumulates and is a risk factor for thrombosis .

Folic acid deficiency anemia (or active form of tetrahydrofolate (THF)

Source: leafy vegetables, liver, meat; deficiency begins to manifest after several weeks to months .

Essential for the synthesis of purine bases (in the form of formyl-THF and methenyl-THF) and thymidine . In the formation of purines, it is produced from the reaction of THF, while in the synthesis of thymidine, dihydrofolate (DHF) is produced. This must be reduced back to THF in order to be used again. This is ensured by the enzyme dihydrofolate reductase, which is blocked by methotrexate .

The role of folic acid and vitamin B12 in metabolism

Folic acid deficiency

Affects:

• hematopoiesis – a similar picture as in vitamin B12 deficiency.
• GIT – Hunter's glossitis, intestinal resorption disorders, diarrhea.

The distinction between anemia from folic acid or vitamin B12 deficiency is made using serum levels of these substances.

Non-Megaloblastic Macrocytic Anemia

Macrocytosis without defective DNA synthesis — no hypersegmented neutrophils, no nuclear-cytoplasmic asynchrony.

Causes

• Alcoholism, most common non-megaloblastic cause alcohol is directly toxic to marrow causes peripheral neuropathy often with poor nutrition → combined B12/folate deficiency may cause macrocytosis without anemia

• Liver Disease, altered lipid metabolism → excess membrane lipids in RBCs → macrocytes. Also ↓ thrombopoietin → thrombocytopenia

• Hypothyroidism, associated with mild normo- or macrocytic anemia

• Reticulocytosis, reticulocytes are naturally larger. Seen in acute blood loss or hemolysis → transient macrocytosis

• Drugs, Zidovudine, 5-FU, chemotherapy → interfere with nucleic acid synthesis

Treatment

Macrocytic anemia should be treated by replacing folate or vitamin B12 to resolve the underlying cause. Folic acid, 1 mg to 5 mg orally daily, is recommended, and clinicians should encourage patients to consume folate-rich diets (eg, fortified cereals and leafy vegetables). Patients who are taking folate antimetabolites (eg, methotrexate) or pregnant women (especially those with a history of neural tube defects or taking antiepileptics) should take daily supplements to prevent deficiencies. Clinicians should not overlook vitamin B12 deficiency as a cause of macrocytic anemia.

Clinicians may prescribe empiric folate supplementation (400 µg to 1 mg/d) in patients receiving vitamin B12 replacement. Reticulocytosis will improve within 1 to 2 weeks, and anemia should resolve after 4 to 8 weeks.