SUMMARY:

Macrocytic anemia is defined by a mean corpuscular volume (MCV) >100 fL. In simple terms, this means the red blood cells are larger than normal. The most common causes of macrocytic anemia are alcoholism, vitamin B12 and folate deficiencies, and medications. Vitamin B12 (cobalamin) is a water-soluble vitamin commonly found in fish, meat, and dairy products. It is involved in neurologic function, red blood cell production, and as a cofactor for enzymes involved in DNA synthesis and metabolic function. Folate (Vitamin B9) is involved as a cofactor for many enzymes involved in DNA synthesis and metabolic function, similar to vitamin B12

SIGNS/SYMPTOMS:

General Anemia

• Fatigue/generalized weakness
• Shortness of breath
• Pale skin or mucus membranes
• Irregular or racing heartbeat
• Systolic murmur: Can occur in more severe anemia

More Specific to Vitamin B12 Deficiency

• Skin manifestations: Hyperpigmentation | Jaundice | Vitiligo
• Glossitis: Inflammation of the tongue resulting in a smooth, enlarged tongue
• Neuropsychiatric
  • Areflexia
  • Cognitive impairment (including dementia-like symptoms or acute psychosis)
  • Gait disturbances and loss of proprioception and vibratory sensation
  • Peripheral neuropathy
  • Olfactory Impairment
• Pregnancy or lactation:
  • Symptoms and risks to newborn or developing fetus can include (can also occur with folate deficiency)
    • Neural tube defects | Developmental delay | Failure to thrive | Hypotonia or ataxia | Anemia

RISK FACTORS/CAUSES:

Vitamin B12 Deficiency

Inadequate Intake

• Diets limited in meat, eggs, fish, or milk (e.g. vegetarian and/or especially vegan)

Lack or Impairment of Absorption

Normal physiology: Vitamin B12 is dissociated from food proteins by gastric acid and is then absorbed in the small intestine by binding with intrinsic factor which is secreted by parietal cells in the stomach

• Pernicious Anemia
  • Immune system mistakenly attacks the parietal cells of the stomach which reduces intrinsic factor and B12 absorption
  • More commonly seen in association with endocrine-related autoimmune disorders (e.g. diabetes or thyroid disease)
• Surgery to stomach or small intestine
  • Gastric bypass or gastrectomy which either bypass the area of usual vitamin B12 absorption or remove the primary source of intrinsic factor or gastric acid production
• Abnormal bacterial growth in small intestine
• Intestinal disease (e.g. Crohn’s or celiac disease)
• Chronic gastritis which impairs gastric acid or intrinsic factor production
• Age >50 years old
• Medications
  • Chronic proton pump inhibitors or H2-blockers
  • Metformin
  • Human immunodeficiency virus (HIV) treatment medications

Folate Deficiency (Vitamin B9)

• Inadequate intake or poor absorption
  • Very restrictive diets
  • More common in older adults
  • Alcoholism: 35% of patients with alcoholism are folate deficient
  • Commonly co-occurring with Vitamin B12 deficiency
  • Folate deficiency due to poor dietary intake is less common in developed nations due to the fortification of many foods with folate
• Medications
  • Anticonvulsants: e.g., Phenytoin
  • Treatments for cancer or autoimmune diseases: e.g., Methotrexate | Hydroxyurea
  • Antibiotics – e.g. Trimethoprim/sulfamethoxazole
  • Cholestyramine
  •  Metformin
• Other conditions
• Hypothyroidism
• Bone Marrow Dysplasia
• Liver disease

LABORATORY EVALUATION:

Complete Blood Count (CBC) – Hemoglobin, Hematocrit, Mean Corpuscular Volume (MCV)

• Hemoglobin
  • Initial screen for anemia itself
  • Anemia is defined as a hemoglobin level two standard deviations below normal for age and sex
• MCV
  • Microcytic: MCV <80 fL
  • Macrocytic: MCV >100 fL
  • Normocytic (MCV between 80 to 100 fL)

Peripheral Blood Smear

• Can help further characterize the anemia as a megaloblastic or a non-megaloblastic process, as well as rule out other causes of anemia including bone marrow dysplasias
• Megaloblastic anemia
  • Characterized by macro-ovalocytes (large oval red blood cells) and hyper-segmented neutrophils
  • More indicative of a B12 or folate deficiency
• Non-megaloblastic anemia
  • Characterized by round macrocytes or macro-reticulocytes
  • More likely to be caused by alcoholism

Reticulocyte Count

• Reticulocytes: Newly formed immature red blood cells
• Parameter used to evaluate adequate, increased, or decreased production of red blood cells
• Low reticulocyte count can have multiple causes, but nutritional deficits such as folate or vitamin B12 deficiency can reduce reticulocyte counts

Additional Testing for Megaloblastic Anemia with High Suspicion for Vitamin B12/Folate Deficiency

• Vitamin B12 level
  • Levels can be artificially elevated in patients with alcoholism, liver disease, or cancer
  • Thresholds vary, but generally levels <200 pg/mL are indicative of vitamin B12 deficiency
• Methylmalonic acid
  • High in a vitamin B12 deficiency
  • Can be obtained when the initial B12 level is normal or borderline but still high suspicion for deficiency
• Homocysteine level
  • Will be elevated in both folate deficiency and B12 deficiency
  • If methylmalonic acid is normal, and homocysteine is high, consider folate deficiency alone
• RBC Folate level
  • Low in folate deficiency
  • Some organizations do not recommend ordering RBC folate levels for the diagnosis of folate deficiency and instead promote empirically treating in the setting of macrocytic anemia due to the low risk of folate replacement, high benefit of replacement, and high cost of the laboratory test

Note: Serum folate level fluctuates rapidly with dietary intake and are thus not useful in determining folate stores and folate deficiency

• If concern for Pernicious Anemia is present based on work-up
  • Anti-intrinsic factor antibodies: Elevated in pernicious anemia
  • Serum gastrin level: Elevated | Consider when anti-intrinsic factor is negative and clinical suspicion is still high

Non-Megaloblastic Process or Negative B12/Folate Deficiency

• Depending on clinical picture and co-morbid conditions consider
  • TSH | Liver function testing | Bone marrow biopsy

TREATMENT:

Vitamin B12 Deficiency

• Neurologic deficits
  • Vitamin B12 1000 mcg deep sq or IM three times per week for up to three weeks or until deficits resolve
• No neurologic deficits
  • Consider oral supplementation with Vitamin B12 1000 mcg daily
• Vitamin B12 deficiency can coexist with folate deficiency
  • Always replace vitamin B12 first to prevent subacute combined degeneration of the spinal cord
• Treatment is usually continued indefinitely, especially if no underlying correctable cause of the deficiency is determined or in the case of pernicious anemia

Note: Guidelines recommend 1mg of oral vitamin B12 daily in gastric surgery patients due to the high risk and prevalence of vitamin B12 deficiency in this population

Folate Deficiency

• Oral replacement is most common
  • Usual dose is 1 to 5mg folic acid orally daily
• All prenatal vitamins contain folic acid
  • It is encouraged for all females of childbearing potential and especially those considering childbearing to take a prenatal vitamin with at least 0.4 mg of folic acid to prevent neural tube defects in the developing fetus
  • Females at high risk of folate deficiency or neural tube defects should supplement with 4mg per day orally
  • Supplementation should start 3 or more months prior to conception and continue through week 12 of gestation
• Many foods in developed countries are fortified with folate, thus limiting nutritional deficiency
• Alcohol cessation is key if applicable

Learn More – Primary Sources:

Vitamin B12 Deficiency: Recognition and Management

Evaluation of Macrocytosis

ACOG Practice Bulletin 187: Neural Tube Defects

American Society for Clinical Pathology – Blood folate levels: Choosing Wisely

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