Basics
Description
- Macrocytosis refers to a blood condition in which red blood cells (RBCs) are larger than normal. It is reported in terms of mean corpuscular volume (MCV). Normal MCV values range from 80 to 100 fL and vary by age and reference laboratory.
- No complications arise from macrocytosis itself as an isolated finding; however, its identification can provide important information regarding the presence of an underlying state.
- In the appropriate clinical setting, MCV values above the upper limit of normal or those that differ significantly from the patient 's baseline values may require further clinical and laboratory assessment to determine the underlying cause of macrocytosis.
- Macrocytosis with associated anemia (macrocytic anemia) can be broadly classified as megaloblastic or nonmegaloblastic anemia. This categorization is important and frequently aids in determining the etiology of the anemia.
- Megaloblastic anemia describes an anemic state characterized by the presence of abnormally large RBCs (macro-ovalocytes) and hypersegmented neutrophils in the peripheral blood and bone marrow.
Epidemiology
- The incidence and prevalence is unknown.
- The most frequent causes of megaloblastic anemia are disorders resulting in vitamin B12 (cobalamin) or folate deficiency.
Risk Factors
- Premature infants
- Malnutrition
- Strict vegetarians without milk, cheese, or egg intake
- Partial or total gastrectomy, ileal resection
- Infants fed goat 's milk
- Bone marrow disorders
- Helicobacter pylori infection
- Crohn disease
- Zollinger-Ellison syndrome
- Orotic aciduria
- Lesch-Nyhan syndrome
- Exocrine pancreatic disease
- Intestinal tapeworm
- Chronic dialysis
- Therapy with certain anticonvulsants
- Therapy with certain HIV antiretroviral medications
- Therapy with certain chemotherapy agents
Pathophysiology
- Megaloblastic anemia is a direct result of ineffective or dysplastic erythropoiesis caused by a defect in DNA synthesis that interferes with cellular proliferation and maturation.
- When vitamin B12 or folate is deficient, RBC proliferation and maturation result in large erythroblasts with nuclear/cytoplasmic asynchrony. The erythroblasts become large, oval shaped, and contain a characteristic immature, lacy nucleus. These bone marrow features are called "megaloblastic. "
Etiology
- The most common etiologies of megaloblastic anemia are vitamin B12 or folate deficiencies.
- Medications are another less common cause of megaloblastic anemia.
- Pernicious anemia is a common cause in adults but rare in children. Pernicious anemia is a type of vitamin B12 deficiency anemia and is caused by a decrease in the secretion of intrinsic factor (IF) by gastric parietal cells in the setting of autoimmune atrophic gastritis. IF is a protein essential for absorption of vitamin B12 in the ileum.
Diagnosis
History
- Pallor, fatigue, poor appetite, irritability
- Malabsorption/diarrhea, steatorrhea, weight loss
- Neurologic symptoms primarily seen in vitamin B12 deficiency:
- Paresthesias, altered gait, impaired vision, psychiatric symptoms
- Diet history
- General malnutrition
- Personal history of strict veganism
- Infants with vegan mothers
- Infants fed goat 's milk
- Family history of pernicious anemia or autoimmune diseases
- Surgical history of partial or total gastrectomy, ileal resection, splenectomy
- Drug history
- Anticonvulsants
- Chemotherapy agents, particularly antimetabolites
- HIV antiretrovirals
- Metformin
- Aminosalicytes
- Nitrous oxide, use and abuse
Physical Exam
- Pallor, pale conjunctiva
- Glossitis: smooth, tender tongue
- Neurologic findings
- Muscular weakness
- Peripheral neuropathy
- Abnormal position and vibratory sensation
- Ataxia
- Positive Babinski test
- Psychiatric and cognitive changes
Diagnostic Tests & Interpretation
Lab
- Complete blood count with differential
- Decreased hemoglobin
- Increased MCV
- Increased red cell distribution width (RDW)
- May have normal or decreased white blood cell count and platelets depending on degree of megaloblastosis
- Peripheral blood smear
- Macro-ovalocytes
- Hypersegmented neutrophils
- Poikilocytosis: abnormally shaped RBCs
- Anisocytosis: abnormal variation in size of RBCs
- Reticulocyte count: low
- Increased LDH
- Decreased haptoglobin
- Increased homocysteine levels
- Serum vitamin B12 level:
- <100 pg/mL: vitamin B12 deficiency
- 100 " 400 pg/mL: borderline result; check serum methylmalonic acid (MMA) and homocysteine levels to help differentiate between vitamin B12 deficiency and folate deficiency
- >400 pg/mL: vitamin B12 deficiency is unlikely; check RBC folate level
- RBC folate level: low in folate deficiency
- If the above testing does not reveal an obvious diagnosis, consider further testing:
- Comprehensive metabolic panel to look for liver and kidney disease, hemolysis, hematologic malignancies or disorders
- Thyroid-stimulating hormone to look for thyroid disorders
- Bone marrow examination
Alert
Coexistent microcytic anemias due to iron deficiency, thalassemias, and chronic disease can obscure the diagnosis of megaloblastic anemia by lowering the MCV. Hypersegmented neutrophils will still persist in the peripheral blood smear and aid in diagnosis.
Imaging
Diagnostic imaging with a barium study may be needed to rule out gastrointestinal anomalies.
Diagnostic Procedures/Other
- Consider a referral to a hematologist for a bone marrow examination if the diagnosis remains unclear.
- Diagnostic testing for pernicious anemia may include the following:
- Serum anti-IF antibodies, gastric parietal cell antibodies, pepsinogen (PG) I and II, gastrin
- Schilling test
Differential Diagnosis
The differential diagnosis for megaloblastic anemia is large and should include other causes of macrocytic anemia:
- Vitamin B12 deficiency
- Folate deficiency
- Bone marrow disorders (e.g., myelodysplastic syndrome)
- Marked reticulocytosis
- Hemolytic anemia
- Hemorrhage
- Severe hyperglycemia
- Chronic alcohol abuse
- Chronic liver disease
- Hypothyroidism
- Splenectomy
- Chronic lung disease with hypoxia
- Heavy smoking
- Pregnancy
- Medications (as listed in "History " )
- Arsenic poisoning
Treatment
Alert
It is imperative that vitamin B12 deficiency is diagnosed correctly. Treatment of undiagnosed vitamin B12 deficiency with folate replacement will not improve the neurologic deficits and may worsen the condition while improving the hematologic parameters.
Medication
- Folate deficiency
- Folic acid 1 " 5 mg PO daily for 1 " 4 months or until complete hematologic recovery occurs
- Long-term treatment is not warranted except in certain cases of malnutrition or ongoing hemolysis.
- Several forms and administration regimens exist for vitamin B12 deficiency:
- Cyanocobalamin 1,000 mcg/day IM or SQ for 2 " 7 days based on clinical response, followed by 100 mcg weekly for 1 month, then monthly maintenance doses thereafter
- Hydroxycobalamin 1,000 mcg IM every 1 " 3 months is also an effective therapy due to its long half-life in the tissues.
- Oral cyanocobalamin 1,000 " 2,000 mcg/day for 1 month, followed by 125 " 150 mcg/day
- In some cases, nasal and sublingual cyanocobalamin may also be useful in replenishing vitamin B12 stores.
- In the majority of patients (e.g., pernicious anemia), treatment is usually lifelong due to abnormal absorption.
Alert
Hypokalemia associated with vitamin B12 repletion can be life threatening. For severe anemia, a lower initial dose of cyanocobalamin of 0.2 mcg/kg/dose IM or SQ for 2 days followed by the above regimen(s) has been recommended. The clinician should anticipate this complication and provide a potassium supplement if needed.
Follow-up Recommendations
Patient Monitoring
- Metabolic abnormalities begin to normalize within the first 1 " 2 days following treatment with parenteral vitamin B12.
- Reticulocytosis occurs about 3 " 4 days, peaking at 1 week, followed by a rise in hemoglobin within 10 days and a fall in MCV. The hemoglobin will normalize by 8 weeks. A delayed response suggests the presence of an additional abnormality or an incorrect diagnosis.
- Hypersegmented neutrophils disappear at 10 " 14 days.
- During this period, the patient might note an improved feeling of well-being, long before there are any changes in the degree of anemia.
- Dementia and depression often respond to therapy, whereas other neurologic abnormalities improve gradually over a period of 6 months and may not return to normal.
Prognosis
- In cases of dietary deficiencies, the prognosis is good.
- Inborn errors of metabolism with associated megaloblastic anemia generally has a poor outcome.
Complications
- Patients with severe anemia may have accompanying heart failure because of the anemia itself and myocardial hypoxia. However, due to its insidious onset, this is a rare finding in megaloblastic anemias.
- Neurologic complications from vitamin B12 deficiency
- Concomitant folate deficiency can complicate the diagnosis of vitamin B12 deficiency.
Additional Reading
- Aslinia F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis. Clin Med Res. 2006;4(3):236 " 241. [View Abstract]
- Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009;79(3):203 " 208.
- Wickramasinghe SN. Diagnosis of megaloblastic anaemias. Blood Rev. 2006;20(6):299 " 318. [View Abstract]
Codes
ICD09
- 281.3 Other specified megaloblastic anemias not elsewhere classified
- 289.89 Other specified diseases of blood and blood-forming organs
- 281.2 Folate-deficiency anemia
ICD10
- D53.1 Other megaloblastic anemias, not elsewhere classified
- D75.89 Other specified diseases of blood and blood-forming organs
- D51.8 Other vitamin B12 deficiency anemias
SNOMED
- 53165003 Megaloblastic anemia (disorder)
- 397073000 Macrocytosis red cells (finding)
- 49472006 Megaloblastic anemia due to vitamin B12 deficiency (disorder)
- 34925000 Megaloblastic anemia due to inborn errors of metabolism (disorder)
- 15332004 Goats ' milk anemia (disorder)
FAQ
- Q: What are the common dietary sources of vitamin B12?
- A: Red meat, liver, seafood, chicken, dairy products, eggs
- Q: What are the common dietary sources of folate?
- A: Vegetables (especially green, leafy ones), legumes/beans, peanuts, liver. Since 1998, many grain food products have been fortified with folate in the United States and Canada, including breads, cereals, flours, pastas, and rice.