What is macrocytic anemia?

Macrocytic anemia is a disease in which red blood cells are too large. Enlarged red blood cells are not fully developed and cannot function properly. This results in reduced oxygen delivery to all cells in the body, which can lead to fatigue and low energy.

This condition can be caused by vitamin B12 deficiency, liver disease, alcohol, certain types of cancer, and more. It is important for your healthcare team to find out the cause, as macrocytic anemia can improve with appropriate treatment.

Long-term prevention through diet or supplements or other lifestyle changes, such as avoiding alcohol, is sometimes necessary.

Types of Macrocytic Anemia

Macrocytic anemia is characterized by macrocytosis, or large red blood cells. The types of macrocytic anemia are classified by the shape of the red blood cells.

These types are megaloblastic macrocytic anemia and non-megaloblastic macrocytic anemia, which are:

  • Megaloblastic giant cell anemia occurs when red blood cells are large, immature, and structurally abnormal. Granulocytes are a type of white blood cell that may also be hyperfractionated. This is usually related to a deficiency of vitamin B12, a deficiency of folic acid (vitamin B9), or a condition that interferes with the action of these vitamins.
  • Non-megaloblastic macrocytic anemia occurs when the red blood cells are large without the structural abnormalities seen in megaloblastic macrocytic anemia. This type is often associated with liver disease, alcohol use disorder, myelodysplastic syndrome (MDS), or hypothyroidism (underactive thyroid).

What are the symptoms of macrocytic anemia?

Macrocytic anemia usually develops slowly over time. Red blood cells typically circulate for a few months before the body naturally breaks them down and produces new cells. It takes a while for the enlarged red blood cells to cause symptoms because there are usually healthy red blood cells in the circulation.

In macrocytic anemia, macrocytic blood cells circulate throughout the body, but they do not deliver sufficient amounts of oxygen to body tissues. This can lead to nonspecific symptoms that may gradually worsen.

Effects can include:

  • full body fatigue
  • overall weakness
  • Dizziness
  • headache
  • lack of motivation or depression
  • pale complexion
  • foggy thinking
  • diarrhea
  • glossitis (inflammation of the tongue)
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If you have a history or risk factors for macrocytic anemia, it is important to be on the lookout for these symptoms. They may be an indicator that you are developing anemia – a decrease in the number or function of red blood cells.

Causes of macrocytic anemia

Macrocytic anemia has a variety of causes. You may have this disorder for just one of these reasons, but you can also have more than one.

Possible causes of macrocytic anemia include:

  • Vitamin B12 deficiency: Foods that contain this nutrient include meat, chicken, shellfish, dairy products, eggs, and fortified grains.
  • Folic acid deficiency: You can get this nutrient from leafy dark green vegetables, beans, nuts, seeds and fruits.
  • Malabsorption: Conditions such as inflammatory bowel disease (IBD, the chronic inflammatory disease Crohn’s disease, and ulcerative colitis) or gastric bypass surgery (bariatric surgery to reduce the size of the stomach) can prevent adequate absorption of vitamin B12 or folic acid.
  • Pernicious anemia: This blood disorder affects the absorption of vitamin B12.
  • Drugs: There are several drugs that can cause macrocytic anemia, sometimes by interfering with folic acid activity. Examples include Azulfidine (sulfasalazine), Hydrea (hydroxyurea), and Dilantin (phenytoin). There are a lot more.

Liver disease, alcoholism, hypothyroidism (underactive thyroid), myelodysplastic syndrome (disease of the bone marrow), leukemia (blood cancer), and some other cancers can also cause macrocytic anemia.

How macrocytic anemia develops

Macrocytic anemia occurs when red blood cells are developing, but they do not progress to a mature and fully functional state.

Megaloblastic macrocytic anemia occurs because vitamin B12 and folic acid are required for the development of the genetic component of red blood cells. When these vitamins are deficient, the cellular portion of the red blood cell develops, but the genetic component does not develop sufficiently. This makes the cells larger, but not functioning properly.

How to Diagnose Macrocytic Anemia

Macrocytic anemia usually does not cause the signs found on clinical examination. You may have other signs related to the root cause.

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For example, if you have severe liver disease, you may develop jaundice (yellowing of the skin and whites of the eyes), or if you have cancer, you may develop swollen lymph nodes.

If you have macrocytic anemia associated with alcohol use, you may have peripheral neuropathy (nerve damage that affects sensation or movement, usually in the hands and feet) as a result of alcohol use and/or signs of liver damage. However, these signs appear late, and macrocytic anemia may precede these changes.

Macrocytic anemia can be diagnosed by a complete blood count (CBC), red blood cell index, and blood smear.

Tests that can identify macrocytic anemia:

  • Hemoglobin: Standard CBC measures hemoglobin, the oxygen-carrying protein in red blood cells. A hemoglobin level below 12 grams per deciliter (g/dL) is a sign of anemia.
  • Red blood cell index: The CBC measures the red blood cell index, which is a specific assessment of red blood cells. Mean erythrocyte volumes above 100 femtoliters (fL) indicate large erythrocytes.
  • Blood smear: This is a microscopic evaluation of a blood sample that can assess whether the red blood cells are macrocytic or megaloblastic and can also detect other abnormalities, such as cancer cells.
  • Reticulocyte count: This is a count of immature red blood cells.

Generally, a CBC is a routine blood test, usually part of an annual physical, and is also used to assess problems such as persistent fatigue, fever, and unexplained weight loss. A blood smear or reticulocyte count may be done when there is particular concern about the health or function of the red blood cells.

drug monitoring

Drugs that can cause macrocytic anemia don’t always cause this side effect for everyone, so your doctor may monitor your CBC if you’re taking a drug that puts you at risk.

Another important part of diagnosis is determining the root cause. Etiological testing is guided by risk factors and other signs or symptoms.

Other diagnostic tests you may have will be tailored to your situation.

Tests your healthcare provider may order for you include:

  • Vitamin B12 levels (blood test)
  • Folate level (blood test)
  • Intrinsic factor antibody, parietal cell antibody, or gastrin levels to identify pernicious anemia (blood test)
  • Liver function tests (blood tests)
  • Bone marrow biopsy to evaluate for blood cancer (a procedure in which a sample of bone marrow is taken in a laboratory for testing)
  • Liver imaging tests, such as computed tomography (CT) scans

Treatment of macrocytic anemia

Treatment of macrocytic anemia depends on the cause. Treatment and prevention are closely related.

Treatment includes:

  • Diet modification to include vitamin B12 and folic acid
  • Vitamin B12 or folic acid supplements
  • Stop the causative drug
  • Stop drinking, preferably through an alcohol treatment program
  • Cancer treatment for leukemia or myelodysplastic syndrome
  • Treatment of hypothyroidism

This treatment can help address the scope of the underlying disease, including macrocytic anemia.

Prognosis: what to expect

In general, macrocytic anemia is expected to improve with treatment. It may take weeks or more for symptoms to subside and blood tests to normalize. It is important to maintain consistent treatment and regularly monitor red blood cell measurements as directed by your doctor.


Macrocytic anemia can cause the same symptoms as most types of anemia, including low energy and generalized weakness. This condition can develop due to nutritional deficiencies, cancer, drugs, alcohol, liver disease, and hyperthyroidism.

It can be diagnosed with a blood test. Treatment focuses on the management of the underlying disease. After treatment, the anemia resolves within weeks or months and may require continued treatment.

VigorTip words

Always seek medical attention if you have symptoms of anemia. The effects are vague and can develop for many different reasons. Once you know the cause of your symptoms, you can begin treatment.

You should feel an improvement in your symptoms, and if you have macrocytic anemia again, you may notice a return of your symptoms. Depending on the cause and severity of the anemia, you can receive long-term treatment or resume treatment as needed.