Macrocytic Anemia

Aka: Macrocytic Anemia, Megaloblastic Anemia, Megaloblastic Macrocytic Anemia, Non-megaloblastic Macrocytic Anemia

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II. Diagnosis

  1. See Hemoglobin Cutoffs for Anemia
  2. See Hematocrit Cutoffs for Anemia
  3. Macrocytosis
    1. Mean Corpuscular Volume > 100 fl
    2. MCV cutoff varies by age and per reference

III. Pathophysiology

  1. Macrocytosis is further divided based on Peripheral Smear (See below)
    1. Megaloblastic Macrocytic Anemia
    2. Non-megaloblastic Macrocytic Anemia
  2. Megaloblastic Macrocytic Anemia
    1. DNA and RNA synthesis disorder
    2. Affects Bone Marrow erythrocyte precursors
  3. Non-megaloblastic Macrocytic Anemia
    1. Secondary to Reticulocytosis (Reticulocytes are slightly larger than mature Red Blood Cells)
    2. Increased RBC production in response to Hemolysis, Hemorrhage or other red cell loss

IV. Causes: Megaloblastic Macrocytic Anemia

  1. See Medications Affecting Folate Metabolism
  2. Vitamin B12 Deficiency (Pernicious Anemia)
  3. Folate Deficiency (often Alcohol related)
  4. Atrophic Gastritis
  5. Gastrointestinal malabsorption
  6. Nitrous Oxide Abuse
  7. Primary Bone Marrow disorders

V. Causes: Non-megaloblastic Macrocytic Anemia

  1. See Medication Causes of Marrow Toxicity
  2. Alcohol Abuse
  3. Emphysema
  4. Hypothyroidism
  5. Accelerated Erythropoiesis (High Reticulocyte Index)
    1. Hemolytic Anemia
    2. Post-hemorrhagic Anemia
  6. Increased RBC membrane surface area
    1. Obstructive Jaundice
    2. Hepatic disease
    3. Post-splenectomy
  7. Bone Marrow disorders
    1. Myelophthisic Anemia
    2. Myelodysplastic Anemia (Myelodysplastic Syndrome)
    3. Aplastic Anemia
    4. Acquired Sideroblastic Anemia

VI. Causes: Spurious Macrocytosis (False Positive)

  1. Cold Agglutinins
    1. Causes Red Blood Cells to clump and appear larger
  2. Hyperglycemia
    1. Red cells from hemoconcentrated blood swell when diluted for testing
  3. Significant Leukocytosis
    1. Increased sample turbidity results in overestimation of red cell size

VII. Labs

  1. Peripheral Smear: Findings suggestive of Megaloblastic Anemia
    1. Neutrophil Hypersegmentation (>=6 lobes of nuclei)
    2. Megaloblastosis: Oval shaped Macrocytes
    3. Reticulocyte Index <1% (Reticulocytopenia)
      1. See Anemia for causes of Reticulocytosis
      2. By contrast, Reticulocytosis alone increases MCV
    4. Findings sensitive and specific (Early sign)
  2. Reflex studies usually obtained when macrocytosis identified
    1. Serum Vitamin B12
    2. RBC Folate (not Serum Folate which is inaccurate)
    3. Reticulocyte Count
    4. Thyroid Stimulating Hormone (TSH)

VIII. Evaluation: Step 1 - Peripheral Blood Smear

  1. Megaloblastic Anemia Anemia
    1. Go to step 2
  2. Non-megaloblastic Macrocytic Anemia
    1. Consider non-megaloblastic causes listed above
    2. Consider Hemolysis or Hemorrhage (Reticulocyte Count increased)
    3. Consider Alcoholism
    4. Check liver function panel (LFT)
    5. Check Thyroid Stimulating Hormone (TSH)

IX. Evaluation: Step 2 - Reticulocyte Count

  1. Reticulocyte Count less than 2%
    1. Go to step 3
  2. Reticulocyte Count greater than 2%
    1. Evaluate for Hemolytic Anemia

X. Evaluation: Step 3 - Serum Vitamin B12

  1. Vitamin B12 >400 pg/ml
    1. Go to Step 5
  2. Vitamin B12 100-400 pg/ml
    1. Go to Step 4
  3. Vitamin B12 <100 pg/ml
    1. Treat Vitamin B12 Deficiency with Vitamin B12 Replacement

XI. Evaluation: Step 4 - Methylmalonic acid (MMA) and Serum Homocysteine Levels

  1. Normal Methylmalonic acid (MMA)
    1. Increased Homocysteine: Go to Step 5
    2. Normal Homocysteine: Go to Step 6
  2. Increased MMA (with normal or increased Homocysteine)
    1. Treat Vitamin B12 Deficiency with Vitamin B12 Replacement

XII. Evaluation: Step 5 - RBC Folate (not Serum Folate which is inaccurate)

  1. Serum Folic Acid normal
    1. Go to Step 6
  2. Serum Folic Acid low
    1. Treat Folate Deficiency with Folic Acid supplementation

XIII. Evaluation: Step 6 - Nondiagnostic Findings

  1. Consider other causes above
  2. Consider Medication Causes of Macrocytic Anemia
  3. Consider Bone Marrow Biopsy for myeloproliferative disorder evaluation

XIV. References

  1. Brigden (1995) Postgrad Med 97(5):171-86 [PubMed]
  2. Kaferle (2009) Am Fam Physician 79(3): 203-8 [PubMed]
  3. Wang (2016) Am Fam Physician 93(4): 270-8 [PubMed]

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Related Studies

Ontology: Anemia, Macrocytic (C0002886)

Definition (MSH) Anemia characterized by larger than normal erythrocytes, increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (MCH).
Concepts Disease or Syndrome (T047)
MSH D000748
SnomedCT 234356001, 191151004, 191277004, 83414005
English Anemias, Macrocytic, Macrocytic Anemias, ANAEMIA MACROCYTIC, ANEMIA MACROCYTIC, Macrocytic anaemia -unsp cause, Macrocytic anaemia of unspecified cause, Macrocytic anemia -unsp cause, Macrocytic anemia of unspecified cause, Macrocytic anemia NOS, macrocytic anemia (diagnosis), macrocytic anemia, Macrocytic anaemia NOS, Anemia macrocytic, Anemia, Macrocytic [Disease/Finding], Anemia, Macrocytic, macrocytic anemias, Anaemia;macrocytic, anemia disorders macrocytic, anemia macrocytic, Anemia, macrocytic, Macrocytic anemia of unspecified cause (disorder), Macrocytic anaemia of unspecified cause (disorder), Anaemia macrocytic, Macrocytic anemia, Macrocytic anaemia, Macrocytic anemia (disorder), macrocytic; anemia, anemia; macrocytic, Macrocytic Anemia, macrocytic anaemia, Anemia;macrocytic
French ANEMIE MACROCYTAIRE, Anémie macrocytaire SAI, Anémie macrocytaire
Portuguese ANEMIA MACROCITICA, Anemia macrocítica NE, Anemia macrocítica, Anemia Macrocítica
Spanish ANEMIA MACROCITICA, Anemia macrocítica NEOM, anemia macrocítica de causa no especificada (trastorno), anemia macrocítica de causa no especificada, Macrocytic anaemia of unspecified cause, Macrocytic anemia of unspecified cause, anemia macrocítica (trastorno), anemia macrocítica, Anemia macrocítica, Anemia Macrocítica
Dutch macrocytaire anemie, macrocytaire anemie NAO, macrocytische anemia, anemie; macrocytair, macrocytair; anemie, anemie macrocytair, Anemie, macrocytaire, Macrocytaire anemie
German Anaemie makrozytaer NNB, Anaemie makrozytaer, ANAEMIE MAKROZYTAER, makrozytaere Anaemie, Anämie, makrozytäre
Italian Anemia macrocitica NAS, Anemia macrocitica
Japanese 大球性貧血ＮＯＳ, 大球性貧血, ﾀﾞｲｷｭｳｾｲﾋﾝｹﾂNOS, ﾀﾞｲｷｭｳｾｲﾋﾝｹﾂ
Swedish Anemi, makrocytär
Finnish Makrosyyttinen anemia
Russian ANEMIIA MAKROTSITARNAIA, DAIKA-IANGA VROZHDENNAIA GEMOLITICHESKAIA ANEMIIA, АНЕМИЯ МАКРОЦИТАРНАЯ, ДАЙКА-ЯНГА ВРОЖДЕННАЯ ГЕМОЛИТИЧЕСКАЯ АНЕМИЯ
Czech Makrocytová anémie, Makrocytová anémie NOS, makrocytární anemie, anémie makrocytární
Croatian ANEMIJA, MAKROCITNA
Polish Niedokrwistość makrocytowa
Hungarian Macrocytás anaemia k.m.n., Macrocytás anaemia, macrocytás anaemia, macrocytaer anaemia
Norwegian Makrocytær anemi
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Anemia, Megaloblastic (C0002888)

Definition (NCI) Anemia characterized by the presence of unusually large erythroblasts in the bone marrow called megaloblasts. It is usually caused by vitamin B12 or folic acid deficiency. Other causes include toxins and drugs.
Definition (MSH) A disorder characterized by the presence of ANEMIA, abnormally large red blood cells (megalocytes or macrocytes), and MEGALOBLASTS.
Definition (CSP) anemias associated with impaired DNA synthesis in bone marrow progenitor cells leading to odd shaped, macrocytic, or dysfunctional erythrocytes; usually caused by B12 or folate deficiency.
Concepts Disease or Syndrome (T047)
MSH D000749
ICD10 D53.1
SnomedCT 234357005, 154788000, 267554004, 191165002, 154792007, 191138009, 191166001, 53165003
English Anemia, Megaloblastic, Anemias, Megaloblastic, Megaloblastic Anemias, ANAEMIA MEGALOBLASTIC, ANEMIA MEGALOBLASTIC, Megaloblastic anaemia NOS, Megaloblastic anemia NOS, [X]Megaloblastic anaemia NOS, [X]Megaloblastic anemia NOS, megaloblastic anemia, megaloblastic anemia (diagnosis), Anemia megaloblastic, Anemia, Megaloblastic [Disease/Finding], megaloblastic anemias, megaloblastic, anemia megaloblastic, Anaemia - megaloblastic, Anemia - megaloblastic, [X]Megaloblastic anemia NOS (disorder), Megaloblastic anaemia NOS (disorder), Megaloblastic anemia NOS (disorder), Anaemia megaloblastic, Megaloblastic anemia, Megaloblastic anaemia, Megaloblastic anemia (disorder), megaloblastic; anemia, anemia; megaloblastic, Megaloblastic Anemia, Megaloblastic anemia, NOS, Anaemia;megaloblastic, Anemia;megaloblastic, megaloblastic anaemia
French ANEMIE MEGALOBLASTIQUE, Anémie mégaloblastique SAI, Anémie mégaloblastique
Portuguese ANEMIA MEGALOBLASTICA, Anemia megaloblástica NE, Anemia megaloblástica, Anemia Megaloblástica
Spanish ANEMIA MEGALOBLASTICA, Anemia megaloblástica NEOM, anemia megaloblástica, SAI, anemia megaloblástica, SAI (trastorno), Megaloblastic anemia NOS, [X]anemia megaloblástica, SAI (trastorno), Megaloblastic anaemia NOS, [X]anemia megaloblástica, SAI, anemia megaloblástica (trastorno), anemia megaloblástica, Anemia megaloblástica, Anemia Megaloblástica
Dutch megaloblastische anemie NAO, anemie megaloblastisch, megaloblastaire anemie, anemie; megaloblastair, megaloblastair; anemie, megaloblastische anemie, Anemie, megaloblastaire, Megaloblastaire anemie
German Anaemie megaloblastisch NNB, Anaemie megaloblastisch, megaloblastische Anaemie, ANAEMIE MEGALOBLASTISCH, megaloblastaere Anaemie, Anämie, megaloblastische, Megaloblastenanämie
Italian Anemia megaloblastica NAS, Anemia megaloblastica
Japanese 巨赤芽球性貧血, 巨赤芽球性貧血ＮＯＳ, ｷｮｾｷｶﾞｷｭｳｾｲﾋﾝｹﾂNOS, ｷｮｾｷｶﾞｷｭｳｾｲﾋﾝｹﾂ
Swedish Megaloblastanemi
Finnish Megaloblastianemia
Russian ANEMIIA MEGALOBLASTNAIA, АНЕМИЯ МЕГАЛОБЛАСТНАЯ
Czech Megaloblastová anémie, Megaloblastová anémie NOS, Anémie megaloblastová, megaloblastická anémie, megaloblastová anémie, anémie megaloblastická
Croatian Not Translated[Anemia, Megaloblastic]
Polish Niedokrwistość megaloblastyczna
Hungarian Megaloblastos anaemia k.m.n., Megaloblasztos anémia, Megaloblastos anaemia
Norwegian Megaloblastanemi
Derived from the NIH UMLS (Unified Medical Language System)

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