In this CCC we will discuss the causes of megaloblastic macrocytic anaemias, those being vitamin B12 deficiency and folate deficiency. We will then end this topic by covering pernicious anaemia as this relates to B12 deficiency.
We can classify anaemias based in the size of the RBC which is reflected as the MCV (mean corpuscular/cell volume).
A normal MCV lies between 80-100fL.
We can therefore classify anaemias as:
- Microcytic - <80fL
- Normocytic - 80-100fL
- Macrocytic - >100fL
As we can see, vitamin B12 and folate deficiency are the only 2 causes of megaloblastic macrocytic anaemia.
What is the difference between normoblastic and megaloblastic?
- Normoblastic - bone marrow produces normal, healthy precursor cells.
- Megaloblastic - bone marrow produces unusually large, abnormal precursor cells
Vitamin B12 deficiency is a common condition that can lead to neurological, psychiatric, haematological disorders. Vitamin B12 is also known as cobalamin. It is an essential vitamin, meaning it needs to be obtained exogenously as our body is unable to produce it endogenously (through diet or supplementation). Dietary sources of B12 include meat, poultry, milk and eggs. Our liver stores B12 and can remain for years, so a deficiency means that is a long-term issue.
Pathophysiology
The aetiologies of vitamin B12 deficiency can be broken down into:
- Decreased dietary intake
- Decreased gastric breakdown of vitamin B12 from food
- Malabsorption
Before we discuss these further, let’s recap how vitamin B12 is absorbed and used within the body:
Dietary sources of vitamin B12 are ingested and released from the food through gastric acid. Free B12 binds to intrinsic factor (IF) which is produced by parietal cells from the fundus of the stomach. IF binds to B12 to form vitamin B12-IF complex. This complex then travels to the terminal ileum where it binds to transcobalamin to form a transcobalamin-B12 complex (holotranscobalamin) which allows it to be absorbed into the bloodstream.
Vitamin B12 is needed for DNA synthesis (especially in myelin producing oligodendrocytes) and is related very closely to folate metabolism. B12 is important for the conversion of methylmalonic acid → succinyl CoA.
B12 and folic acid are both important for the conversion of homocysteine → methionine. Methionine is important for neural function.
B12 and folic acid are both believed to be important for normal haematopoiesis and bone marrow function.
As a result if there is a severe deficiency we can see neurological and haematological disorders. Psychiatric disorders such as dementia, depression and cognitive impairment is also related to B12 deficiency.
⚠️ Risk factors
- Vegans - due to lack of dietary intake.
- Age >65
- GI surgery
- Atrophic gastritis - destruction of parietal cells prevents IF production and therefore the complex is not able to bind and be absorbed.
- Pernicious anaemia - autoimmune attack on parietal cells prevents IF production.
- Malabsorption syndromes - such as coeliac disease, Crohn’s disease, SBBOS.
- PPIs, metformin, H2 receptor antagonists
- Anticonvulsant drugs - such as carbamazepine. The mechanism is not quite clear though.
😷 Presentation
- ⭐️ Peripheral neuropathy causing paraesthesias
- Loss of DCML (fine touch, proprioception and vibration) - this is because B12 deficiency affects the dorsal column and DCML more than the CST and lateral column.
- Mood and cognitive changes - in patients with dementia, vitamin B12 deficiency should always be excluded.
- Visual changes
- Positive Romberg’s test - indicative of dorsal column degeneration.
- Sensory ataxia - also indicative of dorsal column degeneration.
- Fatigue - indicative of anaemia.
- Pallor
- Petechiae - red/brown/purple spots on the skin indicative of bleeding beneath the skin.
- Glossitis
- Angular stomatitis/cheillitis
🔍 Investigations
- FBC - it is useful to diagnose severe and prolonged B12 deficiency but for early deficiency it is not as useful.
- Low Hb
- High MCV - macrocytic anaemia.
- High MCH
- Peripheral blood smear - large, oval-shaped RBCs and we may also hypersegmented neutrophils.
- Serum B12 - of course will be low.
- <148pmols/L - probable deficiency.
- 148 - 258pmols/L - possible deficiency.
- >258pmols/L - unlikely deficiency. However, does not rule out diagnosis especially if we suspect pernicious anaemia.
- Reticulocyte count - helps differentiate between B12 deficiency and haemolytic anaemia.
- Low reticulocyte count indicares B12 deficiency while haemolytic anaemia it will be raised.
Other investigations we may choose to do include:
- Anti-intrinsic factor antibody (anti-FAB) - indicative of pernicious anaemia. More useful than antiparietal cell antibodies.
- Antiparietal cell antibody - also indicative of pernicious anaemia.
- Serum gastrin - will be elevated if there is achlorhydria or pernicious anaemia as it stimulates gastric acid secretion, thus no negative feedback mechanism will prevent its release.
- Methylmalmonic acid, homocysteine, holotranscobalamin - all markers of B12 deficiency.
🧰 Management
🧠 Neurological involvement
- Seek specialist advice
- Hydoroxocobalamin - 1mg IM on alternate days until no improvement, then give 1mg IM every 2 months.
🩸 No neurological involvement
- Hydroxocobalamin - 1mg IM 3x weekly for 2 weeks (6 doses total).
- Maintenance then depends on if it is diet related or not:
- Diet related - cyanocobalamin tablets daily between meals or hydroxocobalamin injection twice a year.
- Not diet related - hydroxocobalamin 1mg IM every 2-3 months for life.
Asymptomatic/borderline patients:
Require dietary supplementation and can use multivitamins to replenish the stores.
Folate deficiency is another cause of megaloblastic anaemia but unlike B12 deficiency it has an absence of neurological signs.
Pathophysiology
Folate is mainly found in green leafy vegetables and legumes. Humans are unable to synthesise their own folate.
Folate is mostly converted to 5-methyl-tetrahydrofolate (5-methyl-THF). It is then catalysed to → tetrahydrofolate (THF) by the enzyme methionine synthase. Methionine synthase is B12 dependant.
THF is a an essential co-enzyme for DNA synthesis and repair(conversion of DUMP → DTMP), methylation and NADPH generation.
Folate is also required for normal development of the CNS in the embryo and foetus. Folate deficiency increased the risk of neural tube defects in the developing embryo. It’s role in causing this isn’t fully understood but it is believed to be due to decreased methylation of DNA which causes variation in gene expression.
⚠️ Risk factors
- >65 years age
- Alcohol-use disorder
- Pregnancy and lactation
- Malabsorption disorders
- Trimethoprim, methotrexate, sulfasalazine, pyrimethamine
😷 Presentation
Typical anaemia symptoms such as:
- Fatigue is the most common presentation by far.
- Weight loss
- Shortness of breath upon exertion due to decreased oxygen carrying capacity.
- Palpitations
- Pallor
- Dizziness
- Dyspnoea
- Hair loss - but evidence is unclear if this is true or not.
- Atrophic glossitis - glossitis with atrophy of papillae.
- Angular stomatitis
⭐️ This is because the hallmark of folate deficiency is megaloblastic anaemia.
Neurological symptoms are not typical with folate deficiency, however, children who have had severe antenatal folate deficiency often have severe neurological dysfunction and NTDs such as spina bifida and anencephaly.
🔍 Investigations
- Peripheral blood smear - large, oval-shaped RBCs and we may also hypersegmented neutrophils.
- FBC
- Raised MCV
- Raised MCH
- Low Hb
- Low reticulocyte count - will be low.
Serum folate is the earliest indicator of a folate deficiency, however, about 5% of patients will have normal serum folate levels with folate deficiency. Therefore, RBC folate is a better indicator of folate status, but it does cost more to do.
🚨 Serum B12 should also be done! It is extremely important to rule out co-existing B12 deficiency before implementing folic acid treatment as this can mask the neurological complications that arise with untreated B12 deficiency.
🚨 Management
In pregnancy or during lactation, a woman is at risk of folate deficiency and then is advised to take and continue folic acid supplements. During pregnancy it also helps reduce risk of NTDs. However, the critical time for beginning supplementation is 1 month prior to conception (for planned pregnancies).
- Folic acid - GPs should prescribe 5mg daily oral supplements for women planning on conceiving.
- Oral folic acid - is the mainstay of treatment. 5mg orally OD.
Other at risk groups include patients with malabsorptive disorders, haemolytic disorders, or patients on chronic dialysis. They should be given 1mg orally OD of folic acid as well.
If at risk due to medications such as DHFR inhibitors then we can give folinic acid instead. This is converted to the active THF form without the need for DHFR.