Macrocytosis 

 Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD  

 
Updated: Mar 20, 2014

 Background

 Pathophysiology
 Etiology
 Show All

References
Background
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.

Causes of macrocytosis are many and range from benign to malignant; thus, a complete workup
to determine etiology is essential.[1] 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. [2, 3, 4]

Pathophysiology
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. [5]

Vitamin B-12 and folate coenzymes are required for thymidylate and purine synthesis; thus, their
deficiency results in retarded DNA synthesis. In vitamin B-12 deficiency and folic acid deficiency,
the defect in DNA synthesis affects other rapidly dividing cells as well, which may be manifested
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 the13 C-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.[6] 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, alcoholism, and chronic obstructive pulmonary disease (COPD).

Patients with hepatic 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 chronic
alcoholism.[7, 8] Although the macrocytosis of alcoholism may be secondary to poor nutrition with a
resulting folate or vitamin B-12 deficiency, it is more often due to direct toxicity of the alcohol on
the marrow. The macrocytosis of alcoholism usually reverses only after months of abstinence
from alcohol.

The macrocytosis associated with COPD is attributed to excess cell water that is secondary to
carbon dioxide retention.

A murine study found that disruption of the Gardos channel (the erythrocyte Ca 2+ -activated
K+ channel [KCa3.1]) caused subtle erythrocyte macrocytosis and led to mild but progressive
splenomegaly.[9]

Etiology
Vitamin B-12 deficiency is a cause of macrocytosis. Because DNA synthesis requires
cyanocobalamin (vitamin B-12) 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 B-12 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:

 Lack of intrinsic factor in patients who have undergone gastrectomy or who

have pernicious anemia
 Malabsorption of vitamin B-12 secondary to small bowel bacterial overgrowth, tapeworm,
familial factors, drugs, ileal bypass, ileal enteritis, or sprue
Folate also is needed as a cofactor in the synthesis of DNA. Folate deficiency may be caused by
any of the following:

 Dietary deficiency
 Increased requirements of pregnancy
 Congenital deficiency
 Sprue
 Alcoholism
 Increased turnover due to conditions such as hemolysis or sickle cell disease, among
others
Inherited disorders of DNA synthesis include the following:

 Lesch-Nyhan syndrome
 Deficient enzymes for folate metabolism
 Homocystinuria
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:

 Folate antagonists (eg, methotrexate[10] )

 Purine antagonists (eg, 6-mercaptopurine [6-MP])
 Pyrimidine antagonists (eg, cytosine arabinoside [ara-C])
 Alkylating agents (eg, cyclophosphamide)
 Zidovudine (AZT)
 Trimethoprim
 Oral contraceptive pills
 Phenytoin
 Arsenic
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 intake directly affects 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.

Refractory anemias of the following types may cause macrocytosis:

 Myelodysplastic anemias
 Myelophthisic anemias (marrow replacement by neoplasm, granuloma, or fibrosis)
 Aplastic anemia
 Acquired sideroblastic anemia
Macrocytosis in patients with COPD is attributed to excess cell water secondary to carbon dioxide
retention.

Benign familial macrocytosis is an inherited syndrome in which patients have mild asymptomatic
macrocytosis.[11]

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 is a manifestation of hormone deficiency. More commonly, hypothyroid patients

exhibit a normocytic anemia. Artifactually elevated MCVs must be considered in certain patients.
These are observed less frequently with newer counting machines. Hyperglycemia and cold
agglutinins may cause artificially elevated MCVs.[12]

 
 
Proceed to Clinical Presentation
 

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History
The symptoms of macrocytosis are attributable either to the anemia itself or to the underlying
condition causing the anemia. They may include the following:

Dyspnea – This is a consequence of anemia; in acute or severe anemia, the volume of
hemoglobin in the blood is inadequate to provide appropriate oxygenation of the tissues

Headache – This is a symptom of anemia due to decreased oxygenation of the tissues

Fatigue – This may be attributed to underlying disease, if present, or to inadequate blood
volume

Sore tongue – This may reflect glossitis or atrophy of the tongue, which are common
findings in folate and vitamin B-12 deficiencies[13]

Diarrhea or other gastrointestinal (GI) symptoms – These may be present in patients with
tropical or celiac sprue; sprue may cause folate or vitamin B-12 deficiencies [14]

Paresthesia or gait disturbances – These suggest vitamin B-12 deficiency
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.[15] A thorough examination of the patient’s medication regimen is also
 crucial in the workup of macrocytosis; a variety of medications may have an effect on the MCV.
Recent acute blood loss may signal that reticulocytosis is causing the MCV increase.

Physical Examination
The following physical findings may be noted:

 Glossitis suggests that the macrocytosis stems from deficiency of vitamin B-12, folate, or
both
 Tachycardia is usually modest and is common in patients with severe anemia
 Flow murmurs usually are noted only in patients with severe anemia
 Splenomegaly may be quite remarkable when the macrocytosis is due to hemolysis,
infiltrative disorders, or neoplasms
 Jaundice suggests liver disease or hemolysis, both of which may lead to an increased
MCV
 Conjunctival pallor is evident in patients with severe anemia
 Neurologic disorders, such as ataxia, loss of posterior column sensations, loss of deep
tendon reflexes (particularly ankle reflex), and confabulation, may suggest thiamine deficiency
Diagnostic Considerations
Diagnosis of the etiology of macrocytosis is required before the morbidity and mortality can be
determined. No complications are directly attributable to the increased size of the red cell;
complications are attributed to the condition causing the macrocytosis. Failure to diagnose and
treat the cause of the macrocytosis is a medicolegal pitfall. In addition to the conditions listed in
the differential diagnosis, liver disease should also be considered.

Differential Diagnoses
 Alcoholism
 Hemolytic Anemia
 Hypothyroidism
 Myelodysplastic Syndrome
Laboratory Studies
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
B-12 level may be low. If folate deficiency is the cause of the macrocytosis, the RBC folate level
likely will be decreased. As in vitamin B-12 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.
[16] 
Serum methylmalonic acid and homocysteine levels are increased early in vitamin B-12
deficiency, even before hematologic manifestations or decreases in B-12 levels are noted. [17]

Serum unconjugated bilirubin is expected to be elevated in hemolysis.

If vitamin B-12 deficiency is the cause of the macrocytosis, the serum vitamin B-12 level likely will
be decreased. A Schilling test was previously considered the criterion standard for further
investigation of a low vitamin B-12 level. However, many institutions no longer offer the Schilling
test. Alternative tests to the Schilling test are antibodies to parietal cells and intrinsic factor
antibodies.

A serum folate level may be obtained,[18] although an RBC folate level is more reliable because it
reflects the level over the lifespan of the RBC.

A study designed to identify the underlying causes of macrocytosis by analyzing hematological

features concluded that complete medical histories, analysis of red cell parameters, and
peripheral blood smears were simple and inexpensive tools that can be helpful in settings with
limited resources.[19]

Bone Marrow Biopsy and Aspiration

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 any vitamin B-12 or folate therapy or blood
transfusion because megaloblastic changes may reverse rapidly.

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.

Histologic Findings
On peripheral blood smear, large RBCs are evident. Depending on the etiology of the
macrocytosis, peripheral smear may reveal nucleated RBCs, target cells, RBC fragments,
hypersegmentation of neutrophils, immature WBCs, large platelets, or pancytopenia.

Depending on the etiology of the macrocytosis, the marrow may reveal hypercellularity,
megaloblastic changes, fibrosis, infiltration by tumor or granulomatous disease, leukemic
changes, or erythroid hyperplasia.

Approach Considerations
Evaluation usually can be performed on an outpatient basis. Medical treatment depends on the
etiology of the macrocytosis, the presence and severity of anemia, and the symptoms and
physical 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 administration of the offending drug. If the patient is suspected of abusing alcohol,
counsel abstention.

Patients deficient in vitamin B-12 or folate should receive replacement therapy. [20]Folate 1 mg/day
may be prescribed in patients with folate deficiency. Intramuscular vitamin B-12 injections (100-
1000 g/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.

Diet
If folate or vitamin B-12 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 B-12, and green leafy
vegetables are excellent sources of folate. Do not provide folate supplementation without vitamin
B-12 replacement therapy in any patient with vitamin B-12 deficiency or with suspected vitamin B-
12 deficiency; doing so may precipitate subacute combined degeneration of the spinal cord.

Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Vitamins
Class Summary
In macrocytosis associated with vitamin deficiencies, the deficient vitamin is replaced to meet
necessary dietary requirements. Used in metabolic pathways, DNA and protein synthesis.
View full drug information
Folic acid (Folacin-800)
 

Folic acid is an important cofactor for enzymes used in the production of red blood cells (RBCs).
View full drug information
Vitamin B-12 (CaloMist, Nascobal, Ener-B)
 

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans.

Vitamin B-12 is synthesized by microbes but not by humans or plants. Vitamin B-12 deficiency
may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or
diseases of the distal ileum.
View full drug information
Multivitamins (M.V.I.-12, Infuvite)
 

Multivitamins are used as dietary supplements.