Macrocytic Anemia: Folate and Vitamin B12 Deficiency

Topics / Medical / Blood and Related Disorders

Summary This is a brief summary of macrocytic anemia. We focus on Folate and Vitamin B12 deficiency.

Basics

Anemia is described by the EML as an, “reduction in the absolute number of circulating red blood cells and most commonly diagnosed when the hemoglobin concentration is reduced below the reference range for age and gender”

This type of anemia is due to a folate and/or vitamin B12 deficiency. There are other many causes of a macrocytic anemia; however, this article will focus on B12 and folate deficiency. In our setting, it is important to keep in mind that liver/alcohol disease and drugs such as ARVs (Zidovudine) can cause a macrocytic anemia.

Folate deficiency is more common than in B12 deficiency. It is said that folate storage lasts for around 4 months while B12 deficiency for around 2-4 years. This is the reason why during pregnancy, we provide pregnant women with Iron and Folate supplements AND NOT B12 supplements.

Chemical Pathology Notes

Folates:

Folate/folic acid is important for the synthesis of purines, pyrimidines, glycine and methionine (from homocysteine). Hence, it is important in DNA/RNA synthesis and hence a deficiency will affect ALL cell lines.
Folate deficiency and B12 deficiency have very similar hematological similarities.
Vitamin B12 is NEEDED for the conversion of Methyl Tetrahydrofolate (THF) into THF. In this process, Homocysteine is converted into Methionine. This means that because of the relationship described before, a Vitamin B12 deficiency will cause a functional folate deficiency.

Vitamin B12

Cyanocobalamin is needed for the conversion of L-mathylmanolyl-CoA into Succinyl-CoA AND for the formation of methionine from homocysteine. It is important to highlight that vitamin B12 is necessary for myelin formation and hence a deficiency may result in neurological manifestations (e.g peripheral neuropathy). As highlighted above, vitamin B12 in the folate pathway and hence a deficiency of vitamin B12 will present with a megaloblastic anemia as well. The neurological manifestations are due to increased toxic metabolites (homocysteine) and decreased methionine which is needed for myelin synthesis.
Intrinsic Factor (produced by the gastric parietal cells) form a complex with vitamin B12, which helps its absorption by binding to specific receptor in the distal ileum. In the blood, vitamin B12 is bounded to transcobalamin-II (TC-II), which takes it to target sites. A lack of TC-II may also lead to a megaloblastic anemia because B12 will not be able to reach the bone marrow in sufficient amounts.

Causes

Megaloblastic Macrocytic Anemia:
1. Vitamin B12 deficiency
  1. Dietary deficiency: Found in liver, fish and milk. Not really in vegetables, fruits or cereals. Therefore, vegetarians are prone to developing this type of anemia. Alcoholism
  2. States of malabsorption:
    1. Lack of intrinsic factor or parietal cells
      1. Pernicious anemia
      2. Atrophic gastritis
      3. Post-gastrectomy
    2. Ileal malabsorption
      1. Ileal resection
      2. Chrohn’s disease
    3. Bacterial overgrowth/Parasites
  3. Defective Vitamin B12 transport: Transcobalamin deficiency
2. Folate deficiency
  1. Dietary deficiency: Folate is found mainly in leafy vegetables and in meat, this is usually the most common; Alcoholism
  2. States of high demand: Pregnancy, in states of increased cell turnover
  3. Usage of certain drugs: such as folate antagonists(methotrexate), anticonvulsants (Sodium Valproate/Epilim), Contraceptive pill
  4. States of malabsorption: Coeliac’s disease
Non-Megaloblastic Macrocytic Anemia
1. Liver/alcohol disease
2. Hemoglobinopathies
3. Hypothyroidism
4. Myelodystrophy
5. Drugs (cytotoxic, immunosuppressant eg methotrexate, AZT, anticonvulsants)

Presentation

General symptoms/signs of anemia: e.g fatigue, pallor
Specific symptoms/signs of B12 deficiency: peripheral neuropathy, ataxia, optic nerve atrophy, dementia, psychosis, depression, hyperhomocysteinemia, Hunter’s glossitis, angular stomatitis

Investigations

There is an article that describes a bit more general investigations for anemia.
Findings
1. Elevated MCV (Macrocytosis)
2. Pancytopenia: Affects all cell lines: Red blood cells, White blood cells, and platelets.
3. FBC Smear: Oval macrocytes, hypersegmentation of neutrophils, thrombocytopenia with giant platelets. There may also be a left shift in neutrophils (more immature)
4. Folate studies: Plasma folate AND red cell folate. In folate deficiency they will both be low, however, in B12 deficiency, there will be high plasma folate but low red cell folate.
5. Vitamin B12 studies:
  1. Serum B12
  2. Intrinsic factor antibodies, antiparietal cell antibodies
  3. Schilling test

Treatment

Treat the underlying cause
Dietary Modification
While waiting for the results, you should give vitamin B12 AND folate together to prevent permanent neurological deficit. Once you find out the type of anemia then you can narrow down the treatment
Folic acid Deficiency: Folic acid 5mg PO daily until the Hb returns to normal.
Vitamin B12 Deficiency: Vitamin B12 1mg daily for 5 days, then 1mg weekly for 3 doses (3 weeks). This is then followed up with 1mg Vitamin B12 IM every second month. In patients with pernicious anemia this monthly treatment is for life.
These patients may also benefit from Iron Supplementation since we are increasing red cell turnover
Notes: The anemia will usually correct in around 1-2 months. The WCC and the platelets take around 1 week to correct. Failure to correct should make you suspect other causes of macrocytosis.

Prophylaxis

Vitamin B12 Prophylaxis:
1. Indications: post total gastrectomy, post ileal resection
2. Vitamin B12 IM 1mg every second month for life
Folate Prophylaxis
1. Indication: Increased demands (pregnancy, chronic hemodialysis), myeloproliferative disorder, hemolytic anemias
2. Folate 5mg PO oral daily

Further Reading 1. The National Department of Health, South Africa: Essential Drugs Programme. Primary Healthcare Standard Treatment Guideline and Essential Medicine List. 7th ed. South African National Department of Health; 2020.

Published on 16 August 2022

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