What Is Macrocytic Anaemia


Macrocytic anaemia is a blood disorder characterised by the production of abnormally large red blood cells in the bone marrow. The size of blood cells is typically measured in femtoliters, and when it surpasses 100 fL, it is considered macrocytic. These unusually large blood cells lack the essential nutrients necessary for their normal functioning. Consequently, the increased cell size results in a reduced number of red blood cells and lower haemoglobin content, leading to inadequate oxygen levels in the blood. This impaired oxygen delivery to the body's tissues gives rise to a variety of symptoms and health issues. Depending on the underlying cause, macrocytic anaemia can be classified into different types, with deficiencies in vitamin B12 and folate being the most common culprits. Moreover, macrocytic anaemia can also serve as a potential indicator of an underlying health condition. Though not typically a severe illness, it is crucial to promptly address and manage the root causes of untreated macrocytic anaemia to avoid significant medical complications.

This article will comprehensively cover the different types, causes, signs and symptoms, diagnosis, and management of macrocytic anaemia.

Types of macrocytic anaemia

Macrocytic anaemia can be classified into two main types:1

  • Megaloblastic macrocytic anaemia

This type of macrocytic anaemia is primarily caused by deficiencies in vitamin B12 and/or folate. These essential nutrients play a crucial role in the production of red blood cells in the bone marrow. When there is a shortage of vitamin B12 or folate, the DNA synthesis in red blood cells is impaired, leading to the formation of large and immature cells called megaloblasts. These abnormal cells are less effective at carrying oxygen and have a shorter lifespan compared to healthy red blood cells.

  • Non-megaloblastic macrocytic anaemia

Non-megaloblastic macrocytic anaemia can occur due to various factors that affect nutrient absorption or interfere with the functions of the bone marrow, liver, or spleen. Unlike megaloblastic anaemias, DNA synthesis is normal. Conditions such as chronic alcohol use disorder (alcoholism), liver disease, and hypothyroidism are some of the underlying causes that can contribute to this type of macrocytic anaemia.

It is crucial to distinguish between these two types of macrocytic anaemias because their underlying causes are different. Identifying whether the anaemia is megaloblastic or non-megaloblastic helps doctors determine the appropriate treatment approach.

Causes of macrocytic anaemia

Medical conditions that lead to megaloblastic macrocytic anaemia include:2,3

  • Vitamin B12 deficiency - causes macrocytosis (large red blood cells) as it is essential for DNA synthesis. It is rarely due to a dietary deficiency, but it can happen if your body doesn't absorb enough Vitamin B12 due to certain conditions like after stomach surgery, pernicious anaemia, or problems in the small intestine. These problems may include small bowel bacterial overgrowth, tapeworm, familial factors, certain drugs, ileal bypass, ileal enteritis, or sprue
  • Folate deficiency - folate, also known as vitamin B9, is important for DNA synthesis. Folate deficiency can happen due to not having enough green leafy vegetables in your diet, increased needs during pregnancy, being born with low levels, certain conditions like sprue or alcoholism, and increased breakdown of blood cells in conditions like haemolysis or sickle cell disease
  • Medications - in non-alcoholic patients, the most common cause of macrocytosis is from certain medications. Usually, there is no associated anaemia. Some drugs that can cause macrocytosis include phenytoin, sulfa drugs, trimethoprim, hydroxyurea, methotrexate, and 6-mercaptopurine4

Medical conditions that lead to megaloblastic macrocytic anaemia are:

  • Liver diseases: the liver is involved in lipid synthesis, which is necessary for cell membranes, including those of red blood cells
  • Myelodysplastic syndrome: this group of disorders affects the bone marrow, leading to the production of unhealthy blood cells
  • Alcohol use disorder: drinking excessive alcohol can interfere with the absorption of vitamin B125
  • Hypothyroidism: this condition affects thyroid function and may be associated with macrocytic anaemia6
  • Diamond-Blackfan anaemia
  • Multiple myeloma

This list is not exhaustive, and there may be other medical conditions that can also cause macrocytic anaemia.

Signs and symptoms of macrocytic anaemia

Symptoms of macrocytic anaemia:7

  • Weakness
  • Paleness of skin, conjunctiva, mucus membranes
  • Fatigue
  • Shortness of breath (dyspnea) due to insufficient oxygenation of tissues
  • Headache resulting from decreased oxygen levels
  • Sore tongue, which may reflect glossitis or tongue atrophy in cases of folate and vitamin B12 deficiencies
  • Gastrointestinal symptoms like diarrhoea, which may be present in conditions such as tropical or coeliac sprue causing folate or vitamin B12 deficiencies
  • Paresthesia (tingling sensation) or gait disturbances, suggesting vitamin B12 deficiency

It's important to remember that mild anaemia often doesn't show any noticeable symptoms and is usually discovered accidentally during a routine physical examination or while investigating other health concerns or symptoms. Anaemia can develop gradually, and a person may not notice any symptoms until it becomes severe. Proper diagnosis and evaluation by a healthcare professional are essential to identify the specific type of anaemia and its underlying cause.

Management and treatment for macrocytic anaemia

The first step in managing macrocytic anaemia is to identify and treat its underlying cause. Healthcare providers conduct evaluations and blood tests to determine if nutrient deficiencies, such as vitamin B12 or folate, are the culprits. In cases of impaired nutrient absorption, addressing the underlying condition and providing necessary supplements are important.8

Outpatient evaluation is typically sufficient, but specialist consultations may be sought based on the patient's condition. Symptomatic anaemic patients with severe anaemia may receive blood transfusions with packed red blood cells. If a drug is suspected as the cause, discontinuing its administration is crucial.9

Nutrient replacement therapy is essential for those with vitamin B12 or folate deficiencies. Folate deficiency can be treated with 1 mg/day of folate supplementation, while vitamin B12 deficiency may require intramuscular injections.

Dietary interventions involve consuming foods rich in vitamin B12 (chicken, fortified grains, eggs, red meat, shellfish, and fish) and folate (dark leafy greens, lentils, enriched grains, oranges).

Regular follow-up visits with healthcare providers help monitor progress and treatment effectiveness. By addressing the underlying cause and providing appropriate treatments, the management of macrocytic anaemia aims to improve red blood cell production and prevent complications associated with untreated anaemia.


Diagnosing macrocytic anaemia involves a comprehensive evaluation using various blood tests and peripheral blood smear morphology. The key diagnostic tests include:10,11

  • Complete blood count (CBC) with platelet count: this helps assess red blood cell count, haemoglobin concentration, haematocrit, white blood cell (WBC) count, and platelet count, which may be decreased in primary marrow disturbances
  • Mean cell volume (MCV): an MCV greater than 100 fL indicates macrocytosis, a hallmark of macrocytic anaemia
  • Peripheral blood smear: the appearance of red blood cells under the microscope can provide important clues to the underlying cause. Round macrocytes suggest liver or marrow infiltrative disease, while oval macrocytes tend to indicate a megaloblastic disorder
  • Reticulocyte count: it helps determine if haemolysis (breakdown of red blood cells) is present and indicates bone marrow function. Elevated reticulocytosis (increased percentage of reticulocytes in the blood) suggests haemolytic anaemias, while a count lower than 1% indicates inadequate marrow production
  • Additional tests: Coombs test, lactate dehydrogenase (LDH) levels, haptoglobin levels, serum total homocysteine, serum methylmalonic acid, and serum unconjugated bilirubin can aid in identifying specific causes, such as autoimmune haemolytic anaemias, megaloblastic anaemias, and vitamin B12 or folate deficiencies

A thorough analysis of medical histories, red cell parameters, and peripheral blood smears is essential in diagnosing the underlying causes of macrocytosis, especially in settings with limited resources.


Untreated or poorly managed macrocytic anaemia can give rise to various complications due to impaired oxygen-carrying capacity of abnormal red blood cells. Some potential complications include persistent fatigue, weakness, and reduced physical stamina due to insufficient oxygen supply to body tissues. Severe cases may result in shortness of breath even during mild physical activities. Additionally, untreated vitamin B12 deficiency-related macrocytic anaemia can lead to cognitive issues, memory loss, difficulty concentrating, and mental confusion. Neurological problems like numbness, tingling sensations, and difficulty with balance and coordination may also occur.

In pregnant individuals, untreated macrocytic anaemia can lead to complications such as preterm birth, low birth weight, and developmental issues, especially neural tube defects, in the baby. Furthermore, anaemia weakens the immune system, increasing the risk of infections and illnesses. Prolonged and severe macrocytic anaemia may strain the heart as it compensates for the decreased oxygen-carrying capacity, leading to an increased risk of heart failure and other cardiovascular problems. Insufficient oxygen supply also impairs wound healing, hindering the body's ability to recover from injuries.


How can I prevent macrocytic anaemia

Macrocytic anaemia can arise due to various factors, including underlying illnesses beyond our control. However, it is possible to minimise the risk and prevent severe anaemia by adopting some preventive measures.

  1. Monitor your health: pay attention to your overall well-being and be vigilant for symptoms like persistent fatigue and weakness. If you notice any changes in your body, such as unexplained tiredness, consult your healthcare provider promptly
  2. Maintain a balanced diet: ensuring a healthy diet is crucial in preventing macrocytic anaemia. Include foods rich in vitamin B12 and folate in your meals. For instance, red meat and chicken are excellent sources of vitamin B12, while beans and dark leafy greens provide folate. Vegetarians and vegans can consider fortified breakfast cereals for vitamin B12 supplementation12
  3. Limit alcohol consumption: excessive alcohol intake can contribute to macrocytic anaemia. Moderating alcohol consumption can help reduce the risk of developing this condition
  4. Medication review: if you are taking antiretroviral drugs for HIV, antiseizure medications, or chemotherapy drugs, discuss potential risks with your doctor. Some medications may increase the likelihood of developing macrocytic anaemia, and your healthcare provider can monitor and manage your health accordingly

How common is macrocytic anaemia

Megaloblastic anaemia, which affects 2-4% of the population, can occur in individuals of all age groups, with the incidence increasing with age. It is more commonly observed in older age groups and tends to affect people assigned male at birth (AMAB) more than those assigned female at birth. Additionally, megaloblastic anaemia is more prevalent in developing countries where resources may be limited.13,14

Who is at risk of macrocytic anaemia

Individuals who are at risk of developing macrocytic anaemia include those with certain dietary habits or medical conditions that can lead to nutrient deficiencies. Vegetarians and vegans, for instance, may be at risk due to insufficient intake of vitamin B12 found predominantly in animal products. Likewise, individuals with limited access to a balanced diet, especially in developing countries, may be prone to deficiencies in vitamin B12 and folate. Elderly individuals are also at an increased risk, as age-related changes can affect nutrient absorption and utilisation. People with conditions such as alcohol use disorder, coeliac disease, gastrointestinal disorders, or those under certain medications like anticonvulsants are also more susceptible to macrocytic anaemia. Proper awareness, regular health check-ups, and a balanced diet can help identify and address risk factors early, reducing the likelihood of developing macrocytic anaemia.

What can I expect if I have macrocytic anaemia

The majority of individuals with macrocytic anaemia typically experience recovery after receiving appropriate vitamin supplements. However, the prognosis or expected outcome may vary depending on the underlying condition and individual circumstances of those with associated medical conditions.

When should I see a doctor

If you experience any symptoms of macrocytic anaemia, such as persistent fatigue, weakness, shortness of breath, sore tongue, gastrointestinal symptoms, or neurological issues like numbness or difficulty with balance, it is essential to seek medical attention promptly. Additionally, if you have risk factors for macrocytic anaemia, such as a poor diet, chronic alcohol consumption, or certain medical conditions, it is advisable to consult a healthcare provider for proper evaluation and diagnosis. Early detection and management can help prevent potential complications and ensure appropriate treatment.


Macrocytic anaemia is characterised by abnormally large red blood cells, resulting in reduced oxygen-carrying capacity and various symptoms. It can be classified into megaloblastic and non-megaloblastic types, with deficiencies in vitamin B12 and folate as common causes. Medical conditions like liver diseases, myelodysplastic syndrome, and chronic alcohol use can also contribute to the condition. Symptoms include weakness, fatigue, shortness of breath, and neurological issues. Proper diagnosis involves blood tests and peripheral blood smear morphology. Treatment focuses on addressing the underlying cause, with nutrient replacement therapy and dietary interventions. Untreated macrocytic anaemia can lead to complications such as cognitive problems, infections, and cardiovascular issues. Prevention involves maintaining a balanced diet, limiting alcohol consumption, and monitoring health. Megaloblastic anaemia affects 2-4% of the population and is more common in older age groups and people AMAB. Those at risk include vegetarians, individuals with limited access to a balanced diet, elderly individuals, and those with certain medical conditions or medications. Seeking medical attention promptly for symptoms or risk factors is essential for early diagnosis and management.


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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Lasha Chkhikvadze

Doctor of Medicine, American MD Program, Tbilisi State Medical University, Georgia

Lasha is a 6th year medical student who is currently striving to start a residency program in Internal Medicine in the US. He actively engages in multiple medical research projects and eagerly participates in medical conferences to stay updated in his field. Staying up-to-date with the latest news in the field is a priority for him. Lasha takes pleasure in sharing his wealth of knowledge, and he considers Klarity an enigmatic platform that allows him to do so effectively.

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