Macrocytosis is a medical condition characterised by the presence of abnormally large red blood cells in the bloodstream. Macrocytosis is not a standalone disease; rather, it often indicates an underlying health issue that requires medical attention and proper management.
This article explores the causes of macrocytosis and emphasises the significance of early identification and appropriate treatment. It also details the common signs and symptoms of macrocytosis, management, diagnosis and treatment options, plus frequently asked questions about the condition.
Causes of macrocytosis
Macrocytosis can be caused by various factors, such as:
- Vitamin B12 and folate deficiencies
- Iron deficiency
- Copper deficiency
- Alcohol use
- Certain medications (like methotrexate and hydroxyurea)
- Hypothyroidism and primary bone marrow disease (common in older patients)
- Impaired red blood cell production (macrocytic/megaloblastic/non-megaloblastic anaemia)1
Macrocytic anaemia can be mild (likely due to benign conditions) or marked (caused by primary bone marrow disease).1
Megaloblastic anaemia is characterised by deficiencies in folic acid and vitamin B12, and it can arise from reduced intake and/or malabsorption (poor uptake) of these nutrients into the body.1 Taking medications that impair DNA synthesis and/or having a pre-existing autoimmune condition can also lead to megaloblastic anaemia.1
Pernicious anaemia, a form of megaloblastic anaemia, is associated with autoimmune gastritis (a condition that causes inflammation of the stomach) that damages stomach cells that contribute to vitamin B12 malabsorption. Pernicious anaemia is treated with lifelong vitamin B12 administration is the treatment and regular stomach examinations.1
Non-megaloblastic anaemia is caused by abnormally shaped white blood cells (called hyper-segmented neutrophils), which occur due to conditions like:
- Alcoholism or excessive alcohol consumption
- Hereditary spherocytosis
- Liver disease 1
Overall, identifying and treating the underlying cause of macrocytosis as early as possible can lead to an excellent prognosis for macrocytic anaemia.2
Signs and symptoms of macrocytosis
Macrocytosis, often an indicator of an underlying health problem, may not present noticeable symptoms by itself. However, if symptoms do arise, they may include:
- Pale skin
- Shortness of breath
- Rapid heartbeat
- Difficulty concentrating
- Glossitis (inflamed tongue)1
The signs and symptoms will also vary based on the underlying cause.
For example, vitamin B12 deficiency can lead to:
- Mood disturbances
- Neurologic symptoms like memory loss and peripheral neuropathy
- Symptoms of primary bone marrow disease
- Gastrointestinal issues
- Underactive thyroid (hypothyroidism)
Folate deficiency shares common features with B12 deficiency, but patients will lack mood disturbances and neurological symptoms. Clues from prior surgeries, family history, and at-risk medications may help in diagnosis.
Macrocytosis itself does not cause direct complications, but it is linked to:
- Reduced exercise capacity
- Decreased function
- Increased mortality (due to macrocytic anaemia)
Management and treatment for macrocytosis
The management of macrocytosis depends on identifying and addressing its root cause. Your doctor will perform diagnostic tests to determine this for you and recommend treatment based on their findings.
Treatment may include measures such as:
- Taking vitamin B12 supplements to address vitamin B12 deficiency (oral supplement or intramuscular injection)
- Taking folic acid supplements and/or eating folate-rich foods to address folate deficiency (approximately 400 micrograms to 1 g per day, depending on the advice of your doctor)
- Taking iron and/or copper supplements or eating iron/copper-rich foods to address an iron/copper deficiency
- Reducing/eliminating alcohol from the diet to address alcohol-related macrocytosis
- Reviewing any medications that may be causing macrocytosis and exploring alternative treatments
- Addressing underlying medical conditions, such as gastrointestinal disorders, to improve nutrient absorption1
Only begin taking new supplements or significantly increase the amount of a nutrient you are taking under the guidance of your doctor, especially if you have any underlying medical conditions or are already taking any prescribed medications. It is also important to read any information provided in the supplement packet before taking it, to do your own research and always seek and follow the advice of your doctor.
Following your doctor's prescribed treatment may help you see improvements in reticulocyte (immature red blood cell) count, size and shape within 1-2 weeks, and anaemia resolving within approximately 4-8 weeks. During treatment, frequent monitoring is not necessary, but patients receiving long-term vitamin B12 supplementation via intramuscular injection may have yearly blood counts.
Ultimately, the management of macrocytosis varies based on its cause and the presence of associated anaemia. Mild macrocytosis without significant anaemia may not require treatment if no concerning features are found in the patient's history, physical exam, and initial tests.
For alcohol-related macrocytosis, cessation of alcohol consumption may lead to resolution after several months, preventing complications like liver disease.
In cases of significant anaemia or when most of a patient's red blood cells are significantly larger than average, further investigation is necessary to determine the cause for appropriate treatment.
Some patients may also require referral to specialists for specific conditions like dysplasia or blood cancers.3
The diagnosis of macrocytosis involves a comprehensive medical evaluation. First, your doctor will take a blood sample to:
- Measure red blood cell size, shape and count
- Count immature red blood cells (reticulocytes) in the blood
- Assess serum vitamin B12, folate and iron levels to identify nutrient deficiencies
- Test your thyroid gland, liver and kidney functions
Macrocytosis will cause red blood cells to be enlarged, misshapen and of an inconsistent size and types of white blood cells (called neutrophils) that are also misshapen. This, in conjunction with low serum vitamin B12 and folate levels, may indicate megaloblastic anaemia as the cause of symptoms (though these features are also seen in myelodysplastic syndrome (MDS) or drug-induced or inherited DNA synthesis disorders).
If a vitamin B12 or folate deficiency is ruled out, a reticulocyte (immature red blood cell) count should be obtained. A high reticulocyte count indicates acute blood loss or haemolysis as the cause of macrocytosis. Meanwhile, a low reticulocyte count may indicate alcoholism, liver dysfunction, hypothyroidism, or MDS as the cause.
Depending on the suspected cause, additional tests may be necessary, such as:
- Bone marrow aspiration
- Bone marrow imaging
- Bone marrow biopsy
- Serum protein electrophoresis
These tests may only be performed if the evaluation of blood samples is inconclusive or a specific cause is suspected. Bone marrow examination is also suggested for patients with abnormal circulating cells or those who are unresponsive to vitamin replacement treatment.2
Caution should be exercised in patients susceptible to iron deficiency or anaemia of chronic disease, as these conditions may mask the underlying cause of macrocytosis.3
Early identification and treatment of the underlying cause lead to an excellent prognosis for macrocytic anaemia. Specialist referral is usually unnecessary unless anaemia is unresponsive to treatment or there are indications of blood cancers such as myelodysplasia or leukaemia.1
How can I prevent macrocytosis?
Preventing macrocytosis involves maintaining a balanced diet that is rich in essential vitamins and minerals, particularly B12, folate, iron, and copper. Ensuring an adequate intake of these nutrients can support proper red blood cell production and prevent deficiencies that may lead to macrocytosis. Additionally, reducing alcohol consumption can help prevent alcohol-related macrocytosis. It is also essential to seek medical advice and review medications that may cause or contribute to macrocytosis, such as adjusting or discontinuing these medications with your doctor's guidance only.
How common is macrocytosis?
Studies have estimated that macrocytosis affects between 1.7-3.9% of the population and appears to be more common in people assigned male at birth (AMAB), older adults and people with certain dietary habits or medical conditions.3
Elderly patients are particularly prone to experiencing macrocytic anaemias, so there may be an increasing number of macrocytic anaemia cases due to the ageing population. Notably, myelodysplastic syndrome (MDS) is a significant cause of macrocytic anaemia in the elderly, and somatic mutations resembling MDS have been found in about 10% of individuals over 65 years old, even without any apparent symptomatic blood disorders.
Who is at risk of macrocytosis?
Those with dietary restrictions, such as vegetarians and vegans, may be at risk because they might not obtain enough essential nutrients like vitamin B12 and folate from their diet. Similarly, individuals with gastrointestinal disorders, such as coeliac disease or inflammatory bowel disease, may experience impaired nutrient absorption, leading to a higher risk of macrocytosis. Chronic alcohol consumption can also make people more susceptible to macrocytosis, as alcohol can directly affect red blood cell production and interfere with bone marrow function. Furthermore, individuals taking specific medications may be at an increased risk of developing macrocytosis due to the drugs' effects on DNA synthesis or nutrient utilisation.
What can I expect if I have macrocytosis?
If you are diagnosed with macrocytosis, your doctor will conduct further tests to determine the underlying cause of the condition. The treatment plan will be tailored to address the specific cause, and regular monitoring may be necessary to track progress and ensure your condition is being effectively managed. 3
The prognosis for macrocytosis varies depending on the underlying cause and any associated medical conditions. Patients with macrocytic anaemia and chronic renal failure tend to have the lowest survival rates, with a 40% survival rate five years after diagnosis. Nutritional deficiencies are also linked to poor survival, with a 52% survival rate. On the other hand, macrocytosis resulting from multifactorial causes, including medication reactions, generally has better survival rates.3
Alcohol-related macrocytosis, without significant anaemia or liver disease, is considered relatively benign (unharmful). Understanding the cause of macrocytosis and addressing any underlying conditions is therefore crucial for determining the overall prognosis and ensuring appropriate management. Regular follow-up with healthcare providers can help monitor the condition and make necessary adjustments to the treatment plan as needed.3
When should I see a doctor?
If you experience unexplained fatigue, weakness, or other symptoms of anaemia, it is important to promptly seek medical attention from your GP, as early diagnosis and treatment can help prevent complications related to macrocytosis. When you visit the doctor, they will conduct a thorough history and physical examination to identify the potential causes of macrocytosis. If macrocytosis is present without anaemia, it may have minimal clinical significance, but further investigation is still necessary.1
Your doctor will screen for anaemia symptoms, such as pallor (unusually pale complexion) and tachycardia (fast heart rate), to assess your overall health. During the evaluation, they will also inquire about your medications, alcohol use, and dietary intake of essential nutrients like folate and vitamin B12.1
Neurological symptoms may also indicate a deficiency in vitamin B12. So, if you experience frequent vision loss, memory loss, fatigue, irritability, and difficulty walking and/or speaking, you should contact your doctor straight away, as these symptoms could indicate a serious health problem or damage to your nervous system.
Macrocytosis serves as a crucial indicator of underlying health issues that require attention and treatment. If you suspect or are diagnosed with macrocytosis, working closely with healthcare professionals can lead to better outcomes and a healthier future.
Your doctor will review your dietary habits, such as nutritional intake and alcohol consumption, as well as any medications you are taking that may be affecting your red blood cells. They will also perform any necessary diagnostic tests to investigate any underlying medical conditions that could be the root cause of your symptoms.
Overall, by understanding the causes and symptoms of macrocytosis, you can be well-placed to seek early medical intervention to manage and treat your condition and improve your overall well-being.
- Kauffmann T, DS E. Macrocytosis [Internet]. europepmc.org. 2020 [cited 2023 Jul 22]. Available from: https://europepmc.org/article/NBK/nbk560908
- Nagao T, Hirokawa M. Diagnosis and treatment of macrocytic anemias in adults. Journal of General and Family Medicine [Internet]. 2017 Apr 13;18(5):200–4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689413
- Green R, Dwyre DM. Evaluation of Macrocytic Anemias. Seminars in Hematology. 2015 Oct;52(4):279–86.