How do you evaluate macrocytosis without anemia?

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

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.

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

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.

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

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.