Macrocytosis refers to red blood cells which are larger than normal. It does not cause any symptoms itself.
Macrocytic anaemia causes symptoms that you get with any other kind of anaemia. If it's mild you may not get any symptoms. You're more likely to notice symptoms if you are older or have coronary heart disease. Younger people can be quite anaemic without noticing any problems at all.
Symptoms you may notice include:
- Breathlessness on exercise.
- The sensation of a 'thumping' heart (palpitations).
- Symptoms of heart failure.
If you have angina, you may notice your chest pains getting worse.
If your macrocytic anaemia is due to vitamin B12 deficiency you may also notice nervous system problems such as pins and needles, numbness, vision changes and unsteadiness. You may also develop psychological problems such as depression and confusion. Normally these symptoms only develop if the deficiency is severe and it has been left untreated for a long time.
A doctor examining you may notice that you:
- Look paler than normal (the nails and tongue are a good place to check).
- Have a bounding pulse (a pulse which feels stronger and more powerful than normal).
- Have signs of heart failure.
- Have a heart murmur between the left second and third ribs when the heart is contracting (a pulmonary flow murmur).
You may notice some of these signs yourself.
Causes of macrocytosis
Macrocytosis without anaemia can be caused by:
- Medicines such as azathioprine.
- Alcohol dependency.
- Vitamin B12 deficiency.
- Folate deficiency.
- Non-alcoholic liver disease.
Depending on severity and how long the person has had the condition, some of these causes can eventually lead to anaemia.
There are two types of macrocytic anaemia:
- Megaloblastic macrocytic anaemia
- Non-megaloblastic macrocytic anaemia
The difference is in the presence or absence of megaloblasts. These are large, abnormally developed red blood cells visible when a pathologist uses a microscope to look at a slide smeared with blood.
Causes of macrocytic megaloblastic anaemia include:
- Serum B12 deficiency (when associated with a low haemoglobin, this is called pernicious anaemia).
- Surgery that removes a part of the stomach (gastrectomy) or part of the gut called the ileum (ileal resection), causing difficulty in absorbing vitamin B12 from the diet.
- Infection of the gut with germs (bacteria) or parasites (organisms that live in the body and obtain nutrition from it).
- HIV infection.
- Deficiency of vitamin B12 in the diet - this can happen in strict vegans but even then it is rare.
- Folic acid deficiency. This can be due to:
- Not eating enough foods containing folic acid. Foods high in folic acid include broccoli, Brussels sprouts, asparagus, peas, chickpeas and brown rice.
- Medical conditions affecting the gut - for example, coeliac disease.
- Inflammatory conditions such as Crohn's disease.
- Some blood disorders can lead to a very high turnover of red blood cells - for example, sickle cell disease and thalassaemia. Normal amounts of folic acid in the diet may then not be enough and supplements may need to be taken.
- Some medicines interfere with folic acid. Therefore, you may need to take extra folic acid whilst taking certain medicines. These include colestyramine, sulfasalazine, methotrexate and some anticonvulsant medicines used to treat epilepsy. If you need dialysis then you may be recommended to take folic acid supplements.
Causes of macrocytic non-megaloblastic anaemia include:
- Alcohol dependency.
- Liver disease.
- Severe underactivity of the thyroid gland (hypothyroidism).
- An increase in the number of immature red blood cells called reticulocytes (reticulocytosis).
- Other blood disorders including myeloid leukaemia, aplastic anaemia (a condition affecting the bone marrow) and some other rare blood conditions.
- Medicines that affect how the genetic material DNA is produced, such as azathioprine.
How are macrocytosis and macrocytic anaemia diagnosed?
These conditions will show up on a blood film. Your doctor may have arranged this test as part of a routine check or because you have felt unwell (see the section on symptoms, above). Once the condition has been diagnosed, further tests will be arranged to find the cause. You may also need tests to check whether you have any conditions that people who have macrocytosis or macrocytic anaemia frequently develop.
The tests may include:
- A reticulocyte count. This may be raised if there is a rapid turnover of red blood cells - for example, in conditions in which red cells are destroyed, such as haemolytic anaemia. If you're found to have such a condition, more tests (for example, a Coombs' test) may be needed to investigate the cause.
- The level of folate in your blood.
- The level of serum B12 in your blood.
- Tests of your liver function.
- Checks to rule out conditions which people with some types of macrocytic anaemia develop, such as diabetes, underactive thyroid gland, and homocystinuria (a condition in which a chemical called homocystine and related substances build up in the blood and urine).
- If some blood disorders are suspected, you may need a bone marrow examination, but this is the exception rather than the rule.
- Other tests may be needed if your doctor suspects other conditions need to be ruled out.
If it has been identified that your macrocytosis is caused by a deficiency, this will need to be treated, whether or not you have anaemia.
You will also need treatment for the condition that caused the deficiency in the first place.
If you have vitamin B12 deficiency you will usually be offered an injectable form of the vitamin called hydroxocobalamin. Your doctor or practice nurse will usually inject this into a muscle
You will need the injections every other day for a couple of weeks and then every 2-3 months for life. If you have symptoms related to the nervous system, you will need injections every couple of days until your symptoms improve and then every couple of months.
B12 tablets (cyanocobalamin) are also available but do not work very well if your deficiency is due to difficulties with absorption. However, they are sometimes recommended in rare cases where the deficiency is due to lack of vitamin B12 in the diet. They can be stopped if the amount of B12 in the diet increases. A dietician may be able to help you with this.
If you have folic acid deficiency you will be advised to take folic acid tablets. 5 mg daily for four months is usually sufficient after which the dose may be reduced. If you have severe deficiency you may require folate injections for a while.
If you have vitamin B12 and folic acid deficiency it's important that the B12 deficiency be treated first; otherwise, serious spinal cord complications (subacute combined degeneration of the cord) can occur.
Treatment of the underlying cause will depend on the condition. For example, if your deficiency was due to excessive use of alcohol, this will need to be addressed.
Further reading and references
Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use; European Society for Medical Oncology (2010)
Guidelines for the Diagnosis and Management of Adult Aplastic Anaemia; British Committee for Standards in Haematology (2015)
Clinical Practice Guideline Anaemia of Chronic Kidney Disease; The Renal Association, 2017 - updated February 2020
Anaemia - iron deficiency; NICE CKS, November 2021 (UK access only)