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How do you evaluate macrocytosis without anemia?
Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin deficiencies (especially B12 deficiency), and liver function tests (SOR: B, inconsistent prospective cohort studies). Thyroid testing may be useful for older patients (SOR: B, prospective study). Reticulocyte count and bone marrow evaluation, although important to rule out hemolysis and myelodysplastic changes, may not be necessary for patients with isolated macrocytosis without anemia (SOR: B, prospective cohort studies). In unexplained macrocytosis, bone marrow evaluation may show early marrow changes, particularly in the elderly (SOR: B, prospective cohort study).
Evidence summary
Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.1-4 As many as 60% to 80% of primary care patients may not have anemia.3,4
Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.3
TABLE
Causes of macrocytosis: What prospective studies show
| CAUSE | PERCENT OF PATIENTS BY STUDY | ||||
|---|---|---|---|---|---|
| DAVIDSON 6 (N=200) | BREEDVELD 1 (N=70) | KEENAN 5 (N=80) | SAVAGE 7 (N=300) | MAHMOUD 10 (N=124) | |
| Alcohol | 18 | 27 | 36 | 26 | 14 |
| Vitamin deficiency | 13 | 39 (6% had both deficiencies) | 16 | 6 | 24 |
| B12 | 8 | 23 | 10 | 5 | 12 |
| Folate | 5 | 10 | 6 | 1 | 12 |
| Medications | 30 | 1 | —* | 37 | 2 |
| Liver disease | 16 | 3 | 9 | 6 | 2 |
| Hematologic disease | 15 | 19 | 14 | 14 | 20 |
| Malignancy/premalignancy | 15 | 13 | 11 | 6 | 20 |
| Reticulocytosis | 0 | 6 | 3 | 8 | —† |
| Hypothyroidism | —† | 3 | 6 | 1 | 12 |
| Unexplained | 23 | 9 | 28 | 7 | 19 |
| * Excluded patients on cytotoxic and chemotherapeutic medications | |||||
| † Not evaluated. | |||||
Clues in the history, physical exam, and lab results
A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.
Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B12 level may not rule out a true B12 deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.8 In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B12 deficiency has been ruled out.7,9
Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.5 Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.10
What these 2 tests may, or may not, tell you
Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B12 and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.
In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,1 and the other found that reticulocytosis rarely caused macrocytosis.5 A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.7 A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.4
Bone marrow biopsy may reveal dysplastic changes, but not a Dx
A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.10
Recommendations
We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.11
Acknowledgments
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
1. Breedveld FC, Bieger R, van Wermeskerken RKA. The clinical significance of macrocytosis. Acta Med Scand. 1981;209:319-322.
2. Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting. J Gen Intern Med. 1990;5:192-197.
3. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am. 1992;76:581-597.
4. Seppa K, Heinila K, Sillanaukee P, et al. Evaluation of macrocytosis by general practitioners. J Stud Alcohol. 1996;57:97-100.
5. Keenan WF. Macrocytosis as an indicator of human disease. J Am Board Fam Pract. 1989;2:25-26.
6. Davidson RJL, Hamilton PJ. High mean red cell volume: its incidence and significance in routine haematology. J Clin Pathol. 1978;31:493-498.
7. Savage DG, Ogundipe A, Allen RH, et al. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000;319:343-352.
8. Cravens DD, Nashelsky J, Oh RC. How do we evaluate a marginally low B12 level? J Fam Pract. 2007;56:62-63.
9. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med. 2001;110:88-90.
10. Mahmoud MY, Lugon M, Anderson CC. Unexplained macrocytosis in elderly patients. Age Ageing. 1996;25:310-312.
11. Hoffman R, Benz EJ, Shattil SJ. Hematology: Basic Principles and Practice. 4th ed. Philadelphia: Churchill Livingstone; 2005.
Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin deficiencies (especially B12 deficiency), and liver function tests (SOR: B, inconsistent prospective cohort studies). Thyroid testing may be useful for older patients (SOR: B, prospective study). Reticulocyte count and bone marrow evaluation, although important to rule out hemolysis and myelodysplastic changes, may not be necessary for patients with isolated macrocytosis without anemia (SOR: B, prospective cohort studies). In unexplained macrocytosis, bone marrow evaluation may show early marrow changes, particularly in the elderly (SOR: B, prospective cohort study).
Evidence summary
Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.1-4 As many as 60% to 80% of primary care patients may not have anemia.3,4
Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.3
TABLE
Causes of macrocytosis: What prospective studies show
| CAUSE | PERCENT OF PATIENTS BY STUDY | ||||
|---|---|---|---|---|---|
| DAVIDSON 6 (N=200) | BREEDVELD 1 (N=70) | KEENAN 5 (N=80) | SAVAGE 7 (N=300) | MAHMOUD 10 (N=124) | |
| Alcohol | 18 | 27 | 36 | 26 | 14 |
| Vitamin deficiency | 13 | 39 (6% had both deficiencies) | 16 | 6 | 24 |
| B12 | 8 | 23 | 10 | 5 | 12 |
| Folate | 5 | 10 | 6 | 1 | 12 |
| Medications | 30 | 1 | —* | 37 | 2 |
| Liver disease | 16 | 3 | 9 | 6 | 2 |
| Hematologic disease | 15 | 19 | 14 | 14 | 20 |
| Malignancy/premalignancy | 15 | 13 | 11 | 6 | 20 |
| Reticulocytosis | 0 | 6 | 3 | 8 | —† |
| Hypothyroidism | —† | 3 | 6 | 1 | 12 |
| Unexplained | 23 | 9 | 28 | 7 | 19 |
| * Excluded patients on cytotoxic and chemotherapeutic medications | |||||
| † Not evaluated. | |||||
Clues in the history, physical exam, and lab results
A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.
Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B12 level may not rule out a true B12 deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.8 In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B12 deficiency has been ruled out.7,9
Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.5 Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.10
What these 2 tests may, or may not, tell you
Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B12 and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.
In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,1 and the other found that reticulocytosis rarely caused macrocytosis.5 A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.7 A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.4
Bone marrow biopsy may reveal dysplastic changes, but not a Dx
A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.10
Recommendations
We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.11
Acknowledgments
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin deficiencies (especially B12 deficiency), and liver function tests (SOR: B, inconsistent prospective cohort studies). Thyroid testing may be useful for older patients (SOR: B, prospective study). Reticulocyte count and bone marrow evaluation, although important to rule out hemolysis and myelodysplastic changes, may not be necessary for patients with isolated macrocytosis without anemia (SOR: B, prospective cohort studies). In unexplained macrocytosis, bone marrow evaluation may show early marrow changes, particularly in the elderly (SOR: B, prospective cohort study).
Evidence summary
Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.1-4 As many as 60% to 80% of primary care patients may not have anemia.3,4
Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.3
TABLE
Causes of macrocytosis: What prospective studies show
| CAUSE | PERCENT OF PATIENTS BY STUDY | ||||
|---|---|---|---|---|---|
| DAVIDSON 6 (N=200) | BREEDVELD 1 (N=70) | KEENAN 5 (N=80) | SAVAGE 7 (N=300) | MAHMOUD 10 (N=124) | |
| Alcohol | 18 | 27 | 36 | 26 | 14 |
| Vitamin deficiency | 13 | 39 (6% had both deficiencies) | 16 | 6 | 24 |
| B12 | 8 | 23 | 10 | 5 | 12 |
| Folate | 5 | 10 | 6 | 1 | 12 |
| Medications | 30 | 1 | —* | 37 | 2 |
| Liver disease | 16 | 3 | 9 | 6 | 2 |
| Hematologic disease | 15 | 19 | 14 | 14 | 20 |
| Malignancy/premalignancy | 15 | 13 | 11 | 6 | 20 |
| Reticulocytosis | 0 | 6 | 3 | 8 | —† |
| Hypothyroidism | —† | 3 | 6 | 1 | 12 |
| Unexplained | 23 | 9 | 28 | 7 | 19 |
| * Excluded patients on cytotoxic and chemotherapeutic medications | |||||
| † Not evaluated. | |||||
Clues in the history, physical exam, and lab results
A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.
Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B12 level may not rule out a true B12 deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.8 In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B12 deficiency has been ruled out.7,9
Liver disease—which may be confounded by alcohol abuse, medications, or cancer—is a common cause of macrocytosis.5 Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.10
What these 2 tests may, or may not, tell you
Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specific recommendations exist for these tests in the absence of anemia. A peripheral smear can detect megaloblastic changes typical of B12 and folate deficiency and other marrow disorders, especially myelodysplastic changes. Peripheral smear findings and reticulocytosis can also show evidence of hemolysis. However, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia.
In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,1 and the other found that reticulocytosis rarely caused macrocytosis.5 A prospective study of 300 hospitalized patients with macrocytosis found that 100% of marrow disorders and hemolysis that caused macrocytosis also caused an associated anemia.7 A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.4
Bone marrow biopsy may reveal dysplastic changes, but not a Dx
A prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many as 60% were diagnosed by blood tests alone. All the remaining patients with unexplained macrocytosis underwent bone marrow biopsy, which showed early dysplastic changes in 39%, but did not provide a diagnosis in nearly 50%. Twelve percent were found to have myelodysplastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.10
Recommendations
We were unable to find published guidelines for the evaluation of macrocytosis without anemia by the American Society of Hematology, the British Committee for Standards in Haematology, or in an authoritative hematology text.11
Acknowledgments
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
1. Breedveld FC, Bieger R, van Wermeskerken RKA. The clinical significance of macrocytosis. Acta Med Scand. 1981;209:319-322.
2. Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting. J Gen Intern Med. 1990;5:192-197.
3. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am. 1992;76:581-597.
4. Seppa K, Heinila K, Sillanaukee P, et al. Evaluation of macrocytosis by general practitioners. J Stud Alcohol. 1996;57:97-100.
5. Keenan WF. Macrocytosis as an indicator of human disease. J Am Board Fam Pract. 1989;2:25-26.
6. Davidson RJL, Hamilton PJ. High mean red cell volume: its incidence and significance in routine haematology. J Clin Pathol. 1978;31:493-498.
7. Savage DG, Ogundipe A, Allen RH, et al. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000;319:343-352.
8. Cravens DD, Nashelsky J, Oh RC. How do we evaluate a marginally low B12 level? J Fam Pract. 2007;56:62-63.
9. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med. 2001;110:88-90.
10. Mahmoud MY, Lugon M, Anderson CC. Unexplained macrocytosis in elderly patients. Age Ageing. 1996;25:310-312.
11. Hoffman R, Benz EJ, Shattil SJ. Hematology: Basic Principles and Practice. 4th ed. Philadelphia: Churchill Livingstone; 2005.
1. Breedveld FC, Bieger R, van Wermeskerken RKA. The clinical significance of macrocytosis. Acta Med Scand. 1981;209:319-322.
2. Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting. J Gen Intern Med. 1990;5:192-197.
3. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am. 1992;76:581-597.
4. Seppa K, Heinila K, Sillanaukee P, et al. Evaluation of macrocytosis by general practitioners. J Stud Alcohol. 1996;57:97-100.
5. Keenan WF. Macrocytosis as an indicator of human disease. J Am Board Fam Pract. 1989;2:25-26.
6. Davidson RJL, Hamilton PJ. High mean red cell volume: its incidence and significance in routine haematology. J Clin Pathol. 1978;31:493-498.
7. Savage DG, Ogundipe A, Allen RH, et al. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000;319:343-352.
8. Cravens DD, Nashelsky J, Oh RC. How do we evaluate a marginally low B12 level? J Fam Pract. 2007;56:62-63.
9. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med. 2001;110:88-90.
10. Mahmoud MY, Lugon M, Anderson CC. Unexplained macrocytosis in elderly patients. Age Ageing. 1996;25:310-312.
11. Hoffman R, Benz EJ, Shattil SJ. Hematology: Basic Principles and Practice. 4th ed. Philadelphia: Churchill Livingstone; 2005.
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