Macrocytosis is a term used to describe erythrocytes that are larger than normal, typically reported as mean cell volume (MCV) greater than 100 fL. The amount of hemoglobin increases proportionately with the increase in cell size. Therefore, if the increase in MCV is not related to macrocytic anemia, the mean cell hemoglobin concentration (MCHC) also increases in proportion.[1] Increased MCV is an indication of macrocytic anemia when any of the following is present[2] :
Causes of macrocytosis are many and range from benign to malignant; thus, a complete workup to determine etiology is essential.[3] Macrocytosis may occur at any age, but it is more prevalent in older age groups because the causes of macrocytosis are more prevalent in older persons.[4, 5, 6]
The most common cause of macrocytic anemia is megaloblastic anemia, which is the result of impaired DNA synthesis. Although DNA synthesis is impaired, RNA synthesis is unaffected, leading to a buildup of cytoplasmic components in a slowly dividing cell. This results in a larger-than-normal cell. The nuclear chromatin of these cells also has an altered appearance.[7]
Vitamin B12 and folate coenzymes are required for thymidylate and purine synthesis; thus, their deficiency results in retarded DNA synthesis. In vitamin B12 deficiency and folic acid deficiency, the defect in DNA synthesis affects other rapidly dividing cells as well, which may manifest as glossitis, skin changes, and flattening of intestinal villi.
DNA synthesis may also be delayed when certain chemotherapeutic agents are used, including folate antagonists, purine antagonists, pyrimidine antagonists, and even folate antagonist antimicrobials.
Hydroxyurea, an agent now commonly used to decrease the number of vaso-occlusive pain crises in patients with sickle cell disease, interferes with DNA synthesis, causing macrocytosis by which compliance with therapy may be monitored. Patient compliance with zidovudine, an agent used in the treatment of patients with HIV infection, may be monitored in the same way.
Sternfeld et al, in a study using the 13C-methionine breath test to analyze hepatic mitochondrial function in vivo in antiretroviral-treated HIV-infected patients with macrocytosis, found a significantly negative correlation between mean corpuscular erythrocyte volume and the breath test results.[8] They concluded that there is an association between an increase in mean corpuscular erythrocyte volume from treatment with nucleoside reverse transcriptase inhibitors and the hepatic mitochondrial function in vivo.
Nonmegaloblastic macrocytic anemias are those in which no impairment of DNA synthesis occurs. Included in this category are disorders associated with increased membrane surface area, accelerated erythropoiesis, alcohol use disorder, and chronic obstructive pulmonary disease (COPD).
Patients with liver disease and obstructive jaundice have macrocytosis that is secondary to increased deposition of cholesterol or phospholipids on the membranes of circulating red blood cells (RBCs). Similarly, in splenectomized patients, RBC membrane lipids that usually are removed during maturation in the spleen are not effectively removed, and the result is a larger-than-normal cell.
In patients with hemolytic anemia or posthemorrhagic anemia, the reticulocyte count increases. The reticulocyte, an immature RBC, is approximately 20% larger than the more mature RBC. When the reticulocyte is released prematurely from the marrow, its volume is averaged with the volume of the more mature RBC, and the resultant MCV is increased.
Macrocytosis, sometimes without associated anemia, is often evident in persons with alcohol use disorder.[9, 10] Although the macrocytosis in these cases may be secondary to poor nutrition with a resulting folate or vitamin B12 deficiency, it is more often due to direct toxicity of the alcohol on the marrow. The macrocytosis of alcohol use disorder usually reverses only after months of abstinence from alcohol.
Vitamin B12 deficiency is a cause of macrocytosis. Because DNA synthesis requires cyanocobalamin (vitamin B12) as a cofactor, a deficiency of the vitamin leads to decreased DNA synthesis in the erythrocyte, thus resulting in macrocytosis. A dietary deficiency of vitamin B12 is rare and usually only occurs in elderly persons on a "tea-and-toast diet" or in strict vegan vegetarians. However, deficiency can result from the following:
Folate also is needed as a cofactor in the synthesis of DNA. Folate deficiency may be caused by any of the following:
Inherited disorders of DNA synthesis include the following:
Other genetic conditions associated with macrocytosis include the following:
Drug-induced macrocytosis is the most common cause in nonalcoholic patients. Usually, no associated anemia is present. The following categories of drugs are known to cause macrocytosis:
The tyrosine kinase inhibitors sunitinib and imatinib have been shown to induce macrocytosis when used in patients with a variety of cancers, including renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and breast cancer.[17] In patients with RCC, the development of macrocytosis following the institution of sunitinib treatment may potentially serve as a positive prognostic factor for overall survival.[20] Similarly, macrocytosis in patients with breast cancer treated with a CDK4/6 inhibitor has been linked with improved survival.[21]
Reticulocytosis may be due to posthemorrhagic blood loss or hemolysis. Reticulocytes are immature red cells released in response to decreased hematocrit levels.
Long-term alcohol abuse can result in macrocytosis through a direct effect on bone marrow. This effect is not related to the presence of liver disease or vitamin deficiency and resolves only after months of abstinence from alcohol. In addition, persons with alcohol use disorder may have secondary megaloblastosis from vitamin B12 and folate deficiency due to poor nutritional intake.
Heroin users have been found to have rates of macrocytosis 5 to 10 times higher than those in the general population. However, a study of 958 patients with a heroin use disorder entering methadone maintenance treatment found that high rates of comorbid alcohol use were more likely to be the cause of macrocytosis in this population.[22]
Refractory anemias of the following types may cause macrocytosis:
Macrocytosis in patients with COPD is attributed to excess cell water secondary to carbon dioxide retention.
Macrocytosis of liver disease is secondary to increased cholesterol and phospholipids deposited on membranes of circulating erythrocytes. This deposition effectively increases the surface area of the erythrocyte.
Hypothyroidism can result in macrocytic anemia. More commonly, however, anemia associated with hypothyroidism is normocytic.
Artifactual elevation of the MCV must be considered in certain patients, although this occurs less frequently with newer cell-counting machines. Hyperglycemia and cold agglutinins may cause artifactually elevated MCVs.[23]
The symptoms of macrocytosis are attributable either to the anemia itself or to the underlying condition causing the anemia. They may include the following:
A history of alcohol abuse may be an important clue to the cause of the increased mean cell volume (MCV). Long-term use of alcohol may have a direct toxic effect on the bone marrow, causing macrocytosis; in addition, macrocytosis may result from poor nutritional intake in this population.[26] An increased prevalence of depression and psychosis have been reported in patients with macrocytosis; those psychiatric disorders may share a common etiology with macrocytosis (eg, vitamin B12 deficiency).[27]
A thorough examination of the patient’s medication regimen is also crucial in the workup of macrocytosis, because a variety of medications may have an effect on the MCV. Recent acute blood loss may signal that reticulocytosis is causing the MCV increase.
The following physical findings may be noted:
A complete blood count (CBC) with platelet count is indicated. The hemoglobin concentration and hematocrit may help guide diagnosis and determine the presence and severity of anemia. White blood cell (WBC) and platelet counts may be decreased in primary marrow disturbances. Mean cell volume (MCV) is a calculated average red blood cell (RBC) volume. An MCV greater than 100 fL is macrocytosis by definition. Because evaluation of RBC size is key to the diagnosis of an anemia, the MCV is considered to be the most important of the RBC indices.
Peripheral blood smear morphology may be helpful. Round macrocytes suggest liver or marrow infiltrative disease, whereas oval macrocytes tend to suggest a megaloblastic disorder. This study provides clues to the etiology of macrocytosis. Hypersegmented neutrophils and macro-ovalocytes strongly suggest megaloblastic anemia. Nucleated RBCs, teardrop cells, decreased or large platelets, and immature WBCs are often present in myelophthisic disease and leukemias.
The reticulocyte count helps determine whether hemolysis is present; it can also indicate malfunctioning bone marrow. Marked reticulocytosis (>4%) is to be expected in hemolytic anemias. A reticulocyte count lower than 1% indicates inadequate marrow production. The reticulocyte count must be corrected for the degree of anemia present.
If the reticulocyte count is elevated, a Coombs test should be performed to aid in identifying the cause of hemolysis. A positive direct Coombs test finding is to be expected in autoimmune hemolytic anemias, hemolytic transfusion reactions, and some drug-induced anemias (eg, those caused by penicillin, methyldopa, some cephalosporins, or sulfonamides).
Lactate dehydrogenase (LDH) levels are elevated in both intravascular and extravascular hemolysis, including the ineffective erythropoiesis that occurs in megaloblastic anemias.
Because the haptoglobin binds free hemoglobin, a low or absent haptoglobin level indicates intravascular hemolysis.
If macro-ovalocytes and hypersegmented neutrophils are noted on peripheral smear, the vitamin B12 level may be low. If folate deficiency is the cause of the macrocytosis, the RBC folate level likely will be decreased. As in vitamin B12 deficiency, peripheral smear may reveal hypersegmented neutrophils and macro-ovalocytes.
Serum total homocysteine levels are almost always elevated in patients with folate deficiency because folate is required in the remethylation step that converts homocysteine to methionine.[28] Serum methylmalonic acid and homocysteine levels are increased early in vitamin B12 deficiency, even before hematologic manifestations or decreases in B12 levels are noted.[29]
Serum unconjugated bilirubin is expected to be elevated in hemolysis.
If vitamin B12 deficiency is the cause of the macrocytosis, the serum vitamin B12 level likely will be decreased. A Schilling test was previously considered the criterion standard for further investigation of a low vitamin B12 level. However, many institutions no longer offer the Schilling test. Alternatives to the Schilling test are assays for antibodies to parietal cells and intrinsic factor antibodies.
A serum folate level may be obtained,[30] although an RBC folate level is more reliable because it reflects the level over the lifespan of the RBC. However, although macrocytic anemia is a common reason for folate testing, in developed countries with folic acid fortification, most patients with macrocytosis do not have folate deficiency and folate testing may have limited diagnostic benefit.[31, 32]
A study designed to identify the underlying causes of macrocytosis by analyzing hematologic features concluded that complete medical histories, analysis of RBC parameters, and peripheral blood smears were simple and inexpensive tools that can be helpful in settings with limited resources.[33]
Bone marrow biopsy and aspiration are performed to determine whether the marrow is functioning adequately and also may reveal replacement of marrow with tumor, granuloma, or fibrosis. The bone marrow should be obtained before instituting vitamin B12 or folate therapy or blood transfusion because megaloblastic changes may reverse rapidly in those cases.
The bone marrow in megaloblastic anemias is usually hypercellular, with all cell lines proliferating. Marked erythroid hyperplasia may occur to the point at which the myeloid-erythroid ratio is reversed. Nuclear-chromatin dissociation with a young-appearing nucleus and abundant mature-appearing cytoplasm may occur. Granulocytic hyperplasia with giant metamyelocytes and bands is often noted.
On peripheral blood smear, large RBCs are evident. Depending on the etiology of the macrocytosis, peripheral smear may reveal any of the following:
Depending on the etiology of the macrocytosis, bone marrow biopsy may reveal any of the following:
Medical treatment depends on the etiology of the macrocytosis, the presence and severity of anemia, and the symptoms and physical examination findings. Hematologic and oncologic consultation should be obtained as necessary. After the appropriate laboratory studies are obtained, the symptomatic anemic patient may undergo transfusion with packed red blood cells (RBCs).
If a drug is thought to be the cause of the macrocytic anemia, especially if hemolysis is occurring, discontinue the offending drug. If the patient is suspected of abusing alcohol, counsel abstention.
Patients deficient in vitamin B12 or folate should receive replacement therapy.[34] Folate, 1 mg/day, may be prescribed in patients with folate deficiency. Intramuscular vitamin B12 injections (100-1000 mcg/mo), continued indefinitely, may be prescribed.
Treat malignancies, granulomatous diseases, and chronic obstructive pulmonary disease (COPD) according to the standards appropriate for each. Hospitalization may be required to treat some causes of macrocytosis, especially acute leukemias. Outpatient follow-up depends on the cause of the macrocytosis.
If folate or vitamin B12 deficiency is the cause of the macrocytosis, modify the diet to include foods rich in these vitamins. Red meat is a good source of vitamin B12, and green leafy vegetables are excellent sources of folate. Do not provide folate supplementation without vitamin B12 replacement therapy in any patient with vitamin B12 deficiency or with suspected vitamin B12 deficiency; doing so may precipitate subacute combined degeneration of the spinal cord.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Folic acid is an important cofactor for enzymes used in the production of red blood cells (RBCs).
Clinical Context: Vitamin B12 is synthesized by microbes but not by humans or plants. Vitamin B12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.
Clinical Context: Multivitamins are used as dietary supplements.
In macrocytosis associated with vitamin deficiencies, the deficient vitamin is replaced to meet necessary dietary requirements. Used in metabolic pathways, DNA and protein synthesis.