Macrocytic Anemia

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Interesting Facts

Macrocytic anemia is a hemoglobin level below reference range with mean corpuscular volume greater than 100 fL
Megaloblastic macrocytic anemias are caused by impaired DNA synthesis and are recognizable by the appearance of large, oval RBCs and hypersegmented neutrophils on peripheral blood smear; other cytopenias may also be present
- Most common causes are vitamin B₁₂ deficiency and folate deficiency; condition may also be induced by a variety of drugs interfering with DNA synthesis
Nonmegaloblastic macrocytic anemias are caused by cell membrane abnormalities and appear on peripheral smear as large, round RBCs without hypersegmented neutrophils or other cytopenias
- Most commonly caused by alcohol use disorder, liver disease, hypothyroidism, or a reticulocytosis as a response to hemolytic anemia or acute blood loss
Macrocytic anemias typically develop relatively slowly; fatigue, exertional dyspnea, and tachycardia may be present. Symptoms of the underlying cause of the anemia may be present (eg, subtle cognitive or mood impairments, dystaxia)
Laboratory evaluation of macrocytic anemia is aimed at determining underlying cause. Initial evaluation steps include CBC (with particular attention to hemoglobin level, mean corpuscular volume, and RBC distribution width), peripheral smear assessment, and measuring reticulocyte count, vitamin B₁₂ level, and folate level
Treatment depends on underlying cause; vitamin B₁₂ and folate deficiencies are treated with oral or parenteral cobalamin or folic acid, respectively. Drug-induced anemia is usually managed with discontinuation of the offending drug, if possible
Megaloblastic anemias caused by vitamin B₁₂ or folate deficiency can be prevented in many cases by ingesting the recommended daily intake for age and physiologic status; patients with conditions associated with malabsorption may require monitoring and ongoing supplementation

Pitfalls

In addition to antineoplastic and immunomodulator drugs, many more commonly used drugs may contribute to vitamin B₁₂ or folate deficiency, especially in patients with a preexisting mild nutritional deficiency. Effects of these drugs may be underrecognized:
- Aspirin
- Metformin
- Phenytoin
- Long-term use of H₂ blockers or proton pump inhibitors
- Some antibiotics (eg, penicillins, erythromycin, tetracycline)
- Estrogens, including oral contraceptives

Terminology

Clinical Clarification

Macrocytic anemia is hemoglobin level below reference range with mean corpuscular volume greater than 100 fL

Classification

2 categories, based on mechanism of the macrocytosis
- Megaloblastic anemias
  - Group of disorders caused by defects in DNA synthesis
    - Most common underlying causes are deficiencies in vitamin B₁₂ (cobalamin) or folate and adverse effects from a variety of drugs
    - Characterized by presence of large (megaloblastic) erythroid precursor cells in bone marrow, and macro-ovalocytes and hypersegmented neutrophils on peripheral blood smear
- Nonmegaloblastic macrocytic anemia
  - Macrocytic anemias caused by RBC membrane defects
    - Most common underlying causes are alcohol use disorder, liver disease, and hypothyroidism
    - Characterized by macrocytosis on peripheral blood smear

Diagnosis

Clinical Presentation

History

Anemia develops slowly; patient usually remains asymptomatic until anemia is severe
May come to attention from low hemoglobin or hematocrit or elevated mean corpuscular volume on routine CBC
If tissue hypoxia is present, typical symptoms common to any severe anemia will be present
- Fatigue
- Weakness
- Lightheadedness
- Exertional dyspnea
- Palpitations
- Poor endurance
Symptoms of underlying cause may be present
- Vitamin B₁₂ and/or folate deficiency
  - Body stores of folate are limited and last only for a few months, while body stores of vitamin B₁₂ may last years after intake or absorption decreases; thus, symptoms of vitamin B₁₂ deficiency may be delayed
  - Newborns and infants may have nonspecific manifestations, including weakness, irritability, lethargy, feeding difficulties, vomiting and diarrhea, and failure to thrive
  - Glossalgia (tongue discomfort)
  - Neurologic symptoms of B₁₂ deficiency
    - Symmetrical distal numbness and tingling
    - Unsteady gait
    - Limb weakness
    - Neuropsychiatric symptoms
      - Mild forgetfulness
      - Subtle behavioral changes
      - Confusion
      - Memory loss
      - Paranoia
      - Hallucinations and delusions
  - Neurologic symptoms of folate deficiency are subtle and uncommon
    - Mild cognitive decline
    - Depression (with significant folate deficiency)
- Liver disease (alcoholic or nonalcoholic)
  - Fatigue and weakness may be multifactorial
  - Anorexia, weight loss, nausea, vomiting, and/or bloating
  - Right upper quadrant pain
  - If cirrhosis is present, symptoms of hepatic encephalopathy (eg, confusion) may manifest
- Hypothyroidism
  - Cold intolerance
  - Fatigue, generalized weakness
  - Slight weight gain
  - Constipation
  - Menstrual irregularity
Historical clues to underlying cause of macrocytic anemia may be present
- Alcohol use disorder
- Vegetarian or vegan diet
- Ingestion of raw fish
- Recent or long-term use of drugs (eg, antineoplastics, antiretrovirals, immunomodulators) that interfere with vitamin B₁₂ or folate absorption or utilization, as well as exposure to nitrous oxide
- History of bariatric surgery or gastrectomy
- Crohn disease, celiac disease, or intestinal bacterial overgrowth syndrome
- Comorbid condition resulting in increased vitamin B₁₂ and/or folate requirement
- Family history of autoimmune disease (eg, pernicious anemia, autoimmune thyroiditis, vitiligo)

Physical examination

Physical examination findings may be normal
Tachycardia and tachypnea may be present if anemia is severe
Physical examination is targeted toward possible underlying cause of macrocytic anemia and—in the case of megaloblastic anemia—determining if neurologic damage is present
- A variety of physical findings are common to both vitamin B₁₂ and folate deficiency
  - Jaundice can occur from intramedullary and extravascular hemolysis; combination of pallor and jaundice usually produces a lemon-yellow skin color in white patients
  - Hyperpigmentation may be present in a small percentage of patients
  - Atrophic glossitis (swollen, red, smooth, beefy tongue) or oral mucosal ulcers may be present
  - Neuropsychiatric abnormalities may be present but are often more subtle in folate deficiency as compared to vitamin B₁₂ deficiency
    - Memory or cognitive issues may be noted on mental status examination
    - Altered level of consciousness, if deficiency is severe
- Physical findings suggesting vitamin B₁₂ deficiency
  - Vitiligo (suggests possibility of autoimmune disease sometimes associated with pernicious anemia)
  - Neurologic findings may precede anemia
    - Sensory loss (vibration and proprioception), which may be prominent in the hands
    - Symmetrical decrease in lower extremity sensation accompanied by altered, shuffling gait
    - Positive Romberg sign
    - Dorsal and lateral spinal column damage is a classic (but late) finding
      - Truncal sensory level (especially of thoracic and cervical cord)
      - Limb weakness and spasticity
      - Reflex testing abnormalities: diffuse hyperreflexia, absent ankle jerks; extensor plantar responses may be present
  - With severe deficiency, perceptual abnormalities (ie, delusions, hallucinations) on mental status examination
- Physical findings with nonmegaloblastic macrocytic anemia
  - Stigmata of liver disease in patients with alcohol use disorder or liver disease from other cause
    - Telangiectasias
    - Jaundice
    - Palmar erythema
    - Gynecomastia
    - Testicular atrophy
    - Hepatosplenomegaly and ascites
  - If hypothyroidism is the cause of the macrocytic anemia, there may be bradycardia; generalized nonpitting edema (myxedema); a thickened tongue; dry, brittle hair or alopecia; and a palpable thyroid gland, which may be nodular or firm

Causes and Risk Factors

Causes

Megaloblastic anemia
- Vitamin B₁₂ deficiency
  - Vitamin B₁₂ is present only in animal products
  - Deficiency can be caused by a variety of mechanisms
    - Malabsorption (most common)
      - Severe when mechanism involves disruption of intrinsic factor-B₁₂ complex binding to a receptor in the terminal ileum
        Surgical procedures such as gastrectomy, gastric bypass, or ileal resection
        Autoimmune gastritis affecting intrinsic factor (pernicious anemia)
      - Milder when mechanism is failure of gastric digestion and release of B₁₂ from food
        Nonimmune chronic gastritis
        Chronic pancreatic disease
        Use of drugs that block gastric acid
        Use of metformin
    - Except in strict vegans, rarely results from dietary deficiency alone
- Folate deficiency
  - Folate is present in leafy greens and in animal products
  - Deficiency is nearly always caused by decreased intake, especially in the setting of increased physiologic demand (eg, pregnancy) or decreased absorption (eg, alcohol use disorder)
    - Dietary deficiency is now rare in North America (except in patients with alcohol use disorder), where fortification of grain-based food is required, but still occurs in Europe and elsewhere
- Drug-induced
  - Drugs that interfere with DNA synthesis (eg, purine or pyrimidine analogues) result in rapid development of megaloblastic anemia, which may be severe
  - A wide variety of drugs can impair bioavailability, absorption, and transport of folic acid or vitamin B₁₂, typically resulting in milder anemia
- Rare causes of megaloblastic anemia include inborn errors of metabolism, thiamine-responsive megaloblastic anemia, and erythroleukemia
Nonmegaloblastic macrocytic anemia
- Most common causes:
  - Alcohol use disorder
  - Advanced liver disease
- Less common causes:
  - Hypothyroidism
  - Reticulocytosis
    - Increased mean corpuscular volume caused by increased percentage of reticulocytes (detected as larger than normal cells on automated cell counters) may be a response to hemolytic anemia, recent acute blood loss, and hypoxia
- Rare causes:
  - Myelodysplastic syndrome
  - Congenital dyserythropoietic anemia
  - Erythroleukemia
  - Copper deficiency

Risk factors and/or associations

Age

More likely in elderly patients, owing to dietary deficiencies resulting in megaloblastic anemia

Sex

Pregnant women have a physiologic increase in mean corpuscular volume by about 4 fL

Other risk factors/associations

More likely in patients with alcohol use disorder and those living in poverty, owing to dietary deficiencies resulting in megaloblastic anemia
Specific risk factors for vitamin B₁₂ deficiency
- Diets not including sufficient vitamin B₁₂ intake (eg, vegetarian, vegan); exclusively breastfed infants of vegetarian, vegan, or otherwise vitamin B₁₂–deficient mothers
- Conditions that may impair absorption
  - Autoimmune gastritis
  - Gastric bypass surgery
  - Gastrectomy, partial or total
  - Zollinger-Ellison syndrome
  - Pancreatic insufficiency
  - Crohn disease
  - Celiac disease
  - Blind loop syndrome and other intestinal bacterial overgrowth syndromes
  - Fish tapeworm infestation
Specific risk factors for folate deficiency
- Decreased oral intake of folate
  - Most likely to occur if both conditions are met:
    - Poor dietary intake of naturally folate-rich foods
    - Patient resides in a country where folate fortification of grains and cereal products is not mandatory
      - Fortification is required in the United States, Canada, and a few countries in Central and South America; not required in Europe
  - Risk of developing folate deficiency is elevated with a daily alcohol intake that exceeds 80 g
- Decreased absorption
  - Crohn disease
  - Celiac disease
  - Gastric bypass surgery
- Increased demand states
  - Puberty
  - Pregnancy
  - Chronic hemolytic anemia
  - Exfoliative dermatitis
- Hemodialysis (macrocytosis may be a result of folate loss or reticulocytosis after erythropoietin administration)
Pharmacologic risk factors
- Drugs causing rapid onset of megaloblastic anemia (interfere with purine or pyrimidine synthesis)
  - Immunomodulators
    - Azathioprine
    - Leflunomide
    - Mycophenolate mofetil
    - Teriflunomide
  - Antineoplastics
    - Capecitabine
    - Cladribine
    - Cytosine arabinoside
    - Fludarabine
    - Fluorouracil
    - Gemcitabine
    - Hydroxyurea
    - Methotrexate (also used as an immunomodulator)
    - Mercaptopurine (also used as an immunomodulator)
    - Pentostatin
    - Thioguanine
  - Antiretrovirals
    - Zidovudine
    - Stavudine
    - Lamivudine
  - Antibiotics
    - Trimethoprim
  - Other drugs
    - Nitrous oxide (even short exposures inactivate vitamin B₁₂ and may cause anemia if underlying B₁₂ level is borderline; recreational abuse is also implicated)
    - Gadolinium
- Drugs causing milder anemia of slower onset (decreased absorption or availability of folate or vitamin B₁₂)
  - Drugs affecting vitamin B₁₂
    - Metformin (use for more than 4 months)
    - H₂ receptor antagonists (H₂ blockers; use for more than 12 months)
    - Proton pump inhibitors (use for longer than 12 months)
    - Antitubercular drugs
      - Aminosalicylic acid
      - Cycloserine
      - Isoniazid
    - Colchicine
  - Drugs affecting folate
    - Antibiotics
      - Ampicillin and other penicillins
      - Chloramphenicol
      - Erythromycin
      - Nitrofurantoin
      - Tetracycline
    - Anticonvulsants
      - Phenobarbital
      - Phenytoin
    - Antimalarials
      - Artemether lumefantrine
      - Pyrimethamine
      - Quinine and related drugs (ie, chloroquine, primaquine)
      - Sulfadoxine-pyrimethamine
    - Antineoplastics
      - Pemetrexed
      - Raltitrexed
    - Estrogens, including birth control pills
    - Alcohol (effect is based on multiple mechanisms)
- Drugs associated with macrocytic anemia based on other or unknown mechanism
  - Arsenic
  - Asparaginase
  - Benzene
  - Sodium nitroprusside
  - Sulfasalazine

Diagnostic Procedures

From Bain BJ: The peripheral blood smear. In: Goldman L et al, eds: Goldman-Cecil Medicine. 25th ed. Philadelphia, PA: Saunders; 2016:1052-9.e2, Figure 157-4.Macrocytic anemia. – A macrocyte is recognized on a blood film as a cell with a diameter that is considerably greater than that of the nucleus of a small lymphocyte. In addition, this smear shows oval macrocytes (also known as macro-ovalocytes), defined as cells that are larger than normal and oval in shape (arrow). They are of considerable diagnostic importance, being characteristic of megaloblastic anemia; they can also be seen in dyserythropoiesis (×1000).

Primary diagnostic tools

Macrocytic anemia is confirmed when CBC shows hemoglobin below reference range, accompanied by an elevated mean corpuscular volume of greater than 100 fL
Additional evaluation is required to determine underlying cause of the condition
- Classically, initial assessment of peripheral smear—aided by RBC distribution width on CBC—determines if the appearance is consistent with megaloblastic or nonmegaloblastic process
  - If consistent with megaloblastic process, obtain vitamin B₁₂, folate, and (in some cases) homocysteine and methylmalonate levels
  - If consistent with nonmegaloblastic anemia, review history and physical examination for clues to underlying cause of anemia; obtain reticulocyte count and additional laboratory evaluation for common causes of macrocytic anemia (ie, liver disease, hypothyroidism)
- In current practice, vitamin B₁₂ and folate levels are usually obtained as initial steps upon discovery of all macrocytic anemias
  - Peripheral smear signs can be subtle and easily missed; it can be difficult to obtain a smear review in some situations
  - Long-term consequences of missing a deficiency can be serious

Laboratory

For all patients
- CBC
  - Hemoglobin level will be lower than the reference range for age and/or gender
    - WHO definitions of anemia
      - Children aged 6 months to 59 months: less than 11 g/dL
      - Children aged 5 to 11 years: less than 11.5 g/dL
      - Children aged 12 to 14 years: less than 12 g/dL
      - Adults and adolescents aged 15 years or older
        Nonpregnant women: less than 12 g/dL
        Pregnant women: less than 11 g/dL
        Men: less than 13 g/dL
    - Reference range is lower for elderly patients (hemoglobin levels less than 12 g/dL in both sexes)
    - Compared to white adults, black adults appear to have slightly lower anemia thresholds
  - Mean corpuscular volume will be higher than the age-appropriate reference range
    - Adults: greater than 100 fL
    - Reference range is lower for children, except from birth through age 6 months, when it is higher
    - During pregnancy, mean corpuscular volume is higher, by about 4 fL
    - Average size of reticulocyte is 160 fL; therefore, reticulocytosis can result in a high mean corpuscular volume anemia in the setting of hemolysis or recent blood loss
  - RBC distribution width
    - Provides a quantitative measure of anisocytosis (variation in RBC size)
    - With megaloblastic anemia, cell size varies owing to progressively more severe effects of vitamin B₁₂ or folate deficiencies on newer RBC production; therefore, RBC distribution width is elevated
      - Poikilocytosis (variation in shape) results from both ineffective erythropoiesis and hemolysis that occurs in megaloblastosis; may also contribute to elevated RBC distribution width
    - RBC distribution width should be within reference range for nonmegaloblastic macrocytic anemia
  - Leukopenia and thrombocytopenia (pancytopenia) may be present with megaloblastic anemias
- Peripheral blood smear assessment
  - Usually triggered on an automated CBC if abnormal cells are detected, but should be specifically ordered in the setting of a macrocytic anemia or suspicion of vitamin B₁₂ or folate deficiency
  - In the setting of macrocytic anemia, the following parameters help to guide remainder of laboratory evaluation:
    - RBC morphology
      - Macrocytic RBCs are oval with megaloblastic anemia (eg, caused by vitamin B₁₂ or folate deficiency); also known as a macro-ovalocyte
      - Macrocytic RBCs are round in nonmegaloblastic macrocytic anemia (eg, caused by liver disease)
    - Presence or absence of hypersegmented neutrophils
      - Microscopically assess average number of nuclear lobes that are either distinct or connected to a neighboring lobe by only a linear chromatin band
      - Defined as a neutrophil with 6 or more lobes; however, the presence of 5 or more lobes in 5% or more of neutrophils is generally considered evidence of hypersegmentation and requires evaluation of underlying cause
        Not pathognomonic; reported in iron deficiency anemia
      - May be first morphologic change seen in patients with megaloblastic anemia (before appearance of macrocytosis) and last morphologic change to disappear after treatment
        However, not considered a sensitive marker in early vitamin B₁₂ deficiency
    - Polychromasia
      - Increased numbers of large, blue-gray RBCs suggest an increased reticulocyte count
    - Presence of target cells and/or acanthocytes (spur cells) suggests liver disease, although they may be present in a variety of other disorders
    - Circulating megaloblasts may be seen
For patients with apparent megaloblastic anemia (alternative approach is to obtain these tests in all patients with macrocytic anemia):
- Vitamin B₁₂ level
  - Deficiency: level below 150 pg/mL
  - Levels of 150 to 399 pg/mL are considered low or within reference range and require further evaluation of metabolite levels that rise in vitamin B₁₂ deficiency (ie, methylmalonate level)
  - If vitamin B₁₂ level is decreased and pernicious anemia is suspected, additional evaluation to determine cause may be indicated (eg, serum intrinsic factor antibodies, endoscopy with gastric biopsy)
- Folate level
  - Serum folate
    - Deficiency: level below 4 mcg/L
    - Levels above 4 mcg/L are considered within reference range; however, levels of 4 to 8 mcg/L when associated with high plasma levels of homocysteine may represent incipient tissue effects leading to megaloblastic anemia
      - These borderline low levels are not indicative of deficiency when homocysteine levels are within reference range
  - RBC folate
    - Not routinely used; may be helpful in the presence of strong clinical suspicion of folate deficiency despite a serum folate level within reference range
- Serum (or plasma) methylmalonate level
  - Indicated when vitamin B₁₂ level is borderline and/or if there is a high suspicion of deficiency
  - If level is elevated, most sensitive and specific test for identifying vitamin B₁₂ deficiency
  - If level is low, strongly suggestive of normal vitamin B₁₂ status
- Plasma homocysteine level
  - Indicated when vitamin B₁₂ or folate levels are borderline
  - Homocysteine will be elevated in both vitamin B₁₂ and folate deficiencies
- Although nondiagnostic, the following abnormal laboratory findings are often present in megaloblastic anemia as a result of ineffective erythropoiesis:
  - Increased lactate dehydrogenase level
  - Increased serum iron level
  - Increased ferritin level
  - Increased transferrin saturation level
For patients with apparent nonmegaloblastic anemia:
- Reticulocyte count
  - Increased numbers of reticulocytes are present when there is increased marrow erythroid activity with acute blood loss or hemolysis
    - Reference range: about 1%
    - Reticulocyte count should be corrected for hematocrit
      - Corrected reticulocyte count = reticulocyte % × (hematocrit % / 45)
    - Average size of a reticulocyte is 160 fL, much larger than a normal RBC (80-100 fL)
    - A high number of reticulocytes in the setting of acute blood loss or hemolytic anemia will therefore increase the mean corpuscular volume, leading to an interpretation of a macrocytic anemia
  - Presence of hemolytic anemia should be confirmed by measuring serum bilirubin and lactate dehydrogenase levels, which will be increased, and serum haptoglobin level, which will be decreased
- Other laboratory tests to assess underlying cause of nonmegaloblastic macrocytic anemia
  - TSH
  - Liver function tests, if liver disease as a potential cause of macrocytic anemia is not already evident

Differential Diagnosis

Initial differentiation of megaloblastic from a nonmegaloblastic macrocytic anemia is by review of a peripheral blood smear
- Megaloblastic features
  - Oval, macrocytic RBCs
  - Hypersegmented neutrophils are present
- Nonmegaloblastic features
  - Round, macrocytic RBCs
  - No hypersegmented neutrophils present
If anemia appears to be megaloblastic, the most common and important causes are vitamin B₁₂ deficiency and folate deficiency; drug effect must also be considered if there is suggestive history
- Differentiating vitamin B₁₂ deficiency from folate deficiency
  - Historical features
    - Onset of anemia is very slow (usually over years) with vitamin B₁₂ deficiency because body stores do not rapidly decrease; however, folate deficiency develops more rapidly (over weeks to months)
    - There may be no symptoms in early stages of either underlying cause
    - Neurologic symptoms may appear before or after appearance of hematologic abnormalities in vitamin B₁₂ deficiency
      - Peripheral neuropathies
      - Spinal cord neuropathy (both dorsal and lateral columns)
        Truncal sensory level
        Upper motor neuron signs of limb weakness, spasticity, and extensor plantar responses
  - Distinguish between conditions with laboratory testing
    - Vitamin B₁₂ and folate levels are usually sufficient to make diagnosis
    - Metabolite levels (ie, homocysteine, methylmalonate) can make the distinction if either B₁₂ or folate levels are borderline
    - These 2 conditions can coexist
- Differentiation of drug-induced megaloblastic anemia from anemia caused by simple vitamin B₁₂ and/or folate deficiency
  - Current or recent use of prescription drugs that are purine or pyrimidine inhibitors are likely to cause rapid onset of megaloblastic anemia
    - Review of drug history will reveal use of an implicated antineoplastic agent, immunomodulator, antiretroviral, or other drug that works by this mechanism (eg, recreational or occupational exposure to nitrous oxide)
    - Vitamin B₁₂ and folate levels may be within reference range
  - A wide variety of commonly used drugs may result in abnormal absorption, metabolism, or processing of 1 or both vitamins and can cause more gradual anemia; these include alcohol, aspirin, oral contraceptives, tetracyclines, penicillins, erythromycin, trimethoprim, phenytoin, methotrexate, and (in long-term use) metformin, H₂ blockers, or proton pump inhibitors
    - Vitamin B₁₂ and folate levels may be within reference range or low, depending on drug mechanism of action
- Conditions that may obscure diagnosis of megaloblastic anemia
  - Comorbid microcytic anemia
    - There will be marked anisocytosis with dimorphic population of RBCs
    - Macrocytic anemia may not be suspected because mean corpuscular volume will be within reference range (based on averaging cell sizes); however, RBC distribution width will be markedly increased
    - Hypersegmented neutrophils will usually be present
    - Consider this situation in patients with conditions where both processes are likely to occur:
      - Gastric bypass surgery
      - Celiac disease
If peripheral smear is not consistent with a megaloblastic picture, and/or vitamin B₁₂ and folate levels are within reference range, consider causes of nonmegaloblastic anemia
- Alcohol use disorder
  - May be obvious from history or strongly suspected based on physical examination or laboratory test results
  - Can result in macrocytosis (nonmegaloblastic) with or without anemia, or may result in megaloblastic anemia due to comorbid vitamin B₁₂ and/or folate deficiency
    - Obtain both vitamin B₁₂ and folate levels in patients suspected of alcohol use disorder
- Liver disease
  - Often obvious from history, physical examination, and liver function test results
- Hypothyroidism
  - Anemia associated with hypothyroidism is usually normocytic or macrocytic
  - Consider if suggestive symptoms or signs are present
  - TSH is the initial diagnostic laboratory test
- Copper deficiency, especially in a patient who has had gastric bypass surgery
  - Leads to macrocytic anemia
  - However, mean corpuscular volume may be also be microcytic or normocytic
    - These patients often have concomitant deficiencies in iron, vitamin B₁₂, and folate, all of which develop at different rates after surgery
  - Differentiate by obtaining copper (and ferritin) level, as well as vitamin B₁₂ and folate levels
If common causes of macrocytic anemia have been ruled out, consider rarer causes. Referral to hematologist for further evaluation is recommended; bone marrow biopsy may be required
- Consider a variety of inborn errors of metabolism in children
- Myelodysplastic syndrome
  - Group of clonal hematopoietic disorders resulting in ineffective hematopoiesis primarily affecting older adults; may occur at younger ages after exposure to ionizing radiation and cytotoxic chemotherapies
  - Characterized by macrocytic anemia, nonelevated reticulocyte count, peripheral blood cytopenias, and abnormal cell morphology on blood and bone marrow examination
  - May transform into secondary acute myeloid leukemia in some patients
- Thiamine-responsive megaloblastic anemia
  - Rare autosomal recessive disorder
  - Characterized by triad of megaloblastic anemia, diabetes mellitus, and sensorineural deafness
  - Responds to pharmacologic doses of thiamine
- Congenital dyserythropoietic anemia
  - Family of inherited refractory anemias: types I and II are autosomal recessive; type III is autosomal dominant or sporadic
  - Characterized by macrocytic anemia in types I and II, with inappropriately low reticulocyte count for the degree of anemia; splenomegaly and jaundice are usually present
  - Bone marrow examination shows erythroid multinuclearity, ineffective erythropoiesis, and secondary hemosiderosis
- Erythroleukemia
  - Rare, aggressive acute leukemia
  - Presentation is typically with pancytopenia and nucleated RBCs on peripheral smear
  - Bone marrow examination shows predominant cell in marrow is the erythroblast, with marked erythroid hyperplasia and dyserythropoiesis

Treatment

Goals

Improve symptoms of anemia and return hemoglobin level to reference range
For megaloblastic anemia caused by vitamin B₁₂ or folate deficiency, additional goal is to prevent neurologic and other associated complications

Disposition

Admission criteria

Most macrocytic anemias are treated on an outpatient basis
- Admission may be required for severe anemia with cardiopulmonary complications (eg, angina, heart failure)

Recommendations for specialist referral

Many patients with macrocytic anemia can be managed by a primary care physician, including those with folate and vitamin B₁₂ deficiencies
If there are diagnostic or therapeutic uncertainties, refer to hematologist
If drug-induced megaloblastic anemia is present, consulting the appropriate subspecialist and a clinical pharmacologist may add benefit in selecting best alternative drug therapy that will not affect DNA synthesis

Treatment Options

Macrocytic anemias are usually of gradual onset and well compensated; transfusion is required only when anemia is severe (hemoglobin level of 7 g/dL or lower) or when accompanied by acute coronary syndrome or hemodynamic instability

Underlying cause of macrocytic anemia determines treatment

Vitamin B₁₂ deficiency
- Low-quality evidence shows that oral and intramuscular vitamin B₁₂ have similar effects in terms of normalizing serum vitamin B₁₂ levels
  - 1% to 4% of an oral dose (typically 1000 mcg is given) is absorbed even in patients with deficient intrinsic factor, thus allowing adequate daily intake (2.4 mcg for adults)
- In patients with severe deficiency or severe neurologic symptoms, intramuscular therapy leads to more rapid improvement
- Lifelong treatment is required for some underlying conditions (eg, pernicious anemia)
Folate deficiency
- Patients with deficiency resulting from poor nutrition or increased physiologic demand are treated with oral folate supplements
- If caused by decreased absorption associated with intestinal disease, give via injection
- Treatment is continued until hematologic recovery occurs (usually 1-4 months)
- If deficiencies in both vitamin B₁₂ and folate are present, begin vitamin B₁₂ replacement first, as replacement of folate can worsen neurologic manifestations of vitamin B₁₂ deficiency
Drug-induced megaloblastic anemia
- Discontinue causative agent if possible, or switch to an appropriate alternative
  - If the drug must be continued, ensure that folate and vitamin B₁₂ intakes are optimal
Anemia resulting from liver disease or hypothyroidism (without concomitant vitamin B₁₂ or folate deficiency) usually improves with correction or improvement of the underlying condition
- Refer patients with alcohol use disorder to treatment programs that will help them find support

Drug therapy

Treatment of vitamin B₁₂ and folate deficiency
- Vitamin B₁₂
  - Cyanocobalamin (adolescents and adults)
    - Oral dosing
      - Effect is similar to intramuscular injection when deficiency is not severe or accompanied by neurologic dysfunction
        Vitamin B12 (Cyanocobalamin) Oral tablet; Adolescents: 1,000 to 2,000 mcg/day PO for 1 to 2 weeks, followed by 500 to 1,000 mcg/day PO.
        Vitamin B12 (Cyanocobalamin) Oral tablet; Adults: 1,000 to 2,000 mcg/day PO for 1 to 2 weeks, followed by 500 to 1,000 mcg/day PO.
    - Intramuscular or subcutaneous dosing
      - Vitamin B12 (Cyanocobalamin) Solution for injection; Adolescents†: 1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is the usual dosage.
      - Vitamin B12 (Cyanocobalamin) Solution for injection; Adults: 1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is usual dosage; FDA-approved dosage is 100 mcg IM/subcutaneously once daily for 6 or 7 days; after clinical improvement and if reticulocyte response seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly. Administer with folic acid, if needed.
  - Hydroxocobalamin (children and adults)
    - Hydroxocobalamin Solution for injection; Children: 100 mcg IM per dose for a total of 1—5 mg given over a period of 2 or more weeks, then 30—50 mcg IM q4 weeks.
    - Hydroxocobalamin Solution for injection; Adults: 30 mcg IM once daily for 5—10 days, then 100—200 mcg IM monthly.
- Folic acid
  - Folic Acid Oral tablet; Infants: 15 mcg/kg PO, subcutaneously, or IM once daily. Alternatively, 50 mcg PO, subcutaneously, or IM once daily.
  - Folic Acid Oral tablet; Children 1—10 years: 1 mg PO, subcutaneously, or IM once daily as initial dosage. The maintenance dose is 0.1—0.4 mg PO once daily.
  - Folic Acid Oral tablet; Adults, Adolescents, and Children > = 11 years: 1 mg PO, subcutaneously, or IM once daily. The maintenance dose is 0.4 mg PO once daily.

Monitoring

There are no specific guidelines for monitoring macrocytic anemia after treatment
Some experts measure CBC, vitamin B₁₂ level, and methylmalonate level annually

Complications and Prognosis

Complications

Although uncommon, macrocytic anemia—if severe—may result in chest pain or worsening heart failure in patients with underlying cardiac disease
Nonhematologic complications of vitamin B₁₂ deficiency include increased risk of spinal cord demyelinating disease, cognitive impairment, osteopenia, and vascular occlusive disease, as well as neural tube defect pregnancy
Nonhematologic complications of folate deficiency include increased risk of neural tube defect pregnancy, mood disturbance, and increased risk of vascular occlusive disease

Prognosis

Anemia caused by vitamin B₁₂ and/or folate deficiency typically responds rapidly to treatment
Anemia caused by alcohol use disorder usually resolves with abstinence of alcohol

Screening and Prevention

Screening

Screening tests

Screening for macrocytic anemia, in general, is not recommended
Screening for vitamin B₁₂ and folate levels may be indicated if specific risk factors for deficiency are present (eg, gastric bypass surgery)

Prevention

Megaloblastic anemia caused by dietary deficiency or impaired absorption of vitamin B₁₂ and folate can be prevented with diet (or supplementation) including adequate nutrient content
- Recommended dietary allowances of vitamin B₁₂
  - Infants aged 0 to 6 months: 0.4 mcg
  - Infants aged 6 to 12 months: 0.5 mcg
  - Children aged 1 to 3 years: 0.9 mcg
  - Children aged 4 to 8 years: 1.2 mcg
  - Children aged 9 to 13 years: 1.8 mcg
  - Children aged 14 to 18 years: 2.4 mcg
  - Adults: 2.4 mcg
  - Pregnant women: 2.6 mcg
  - Lactating women: 2.8 mcg
  - Patients with medical or surgical comorbidities resulting in decreased or altered ability to absorb vitamin B₁₂ from food require supplements to prevent deficiency
    - After bariatric surgery: 350 to 500 mcg daily (oral) or 1000 mcg (intramuscular or subcutaneous)
- Recommended dietary allowances of folate
  - Infants aged 0 to 6 months: 65 mcg
  - Infants aged 6 to 12 months: 80 mcg
  - Children aged 1 to 3 years: 150 mcg
  - Children aged 4 to 8 years: 200 mcg
  - Children aged 9 to 13 years: 300 mcg
  - Children aged 14 to 18 years: 400 mcg
  - Adults: 400 mcg
  - Pregnant women: 600 mcg
  - Lactating women: 500 mcg
  - Patients with medical or surgical comorbidities resulting in decreased or altered ability to absorb folate from food require supplements to prevent deficiency
    - After bariatric surgery: 400 to 800 mcg daily supplement (usually obtained from a multivitamin)
- Patients likely to become deficient are most in need of supplementation (eg, those with gastric bypass, gastritis, or celias disease)

Seek Additional Information

Green R et al: Evaluation of macrocytic anemias. Semin Hematol. 52(4):279-86, 2015

Reference

Macrocytic anemia