What Is Macrocytic Anemia?

A Red Blood Cell Deficiency With Enlarged Red Blood Cells

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Macrocytic anemia is a condition in which red blood cells are too large. The enlarged red blood cells are not fully developed and do not function the way they should. This causes diminished oxygen delivery to all cells of the body, resulting in fatigue and low energy.

This condition can be caused by vitamin B12 deficiency, liver disease, alcohol, some types of cancer, and more. It is important for your medical team to identify the cause because macrocytic anemia can improve with the appropriate treatment.

Sometimes long-term prevention is necessary with diet or supplements or with other lifestyle modifications, such as avoiding alcohol. 

Red blood cells are too large in macrocytic anemia

Ed Reschke / Getty Images

Types of Macrocytic Anemia

Macrocytic anemia is characterized by macrocytosis, which is large red blood cells. Types of macrocytic anemia are categorized by the shape of the red blood cells. 

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

  • Megaloblastic macrocytic anemia occurs when the red blood cells are large, immature, and structurally abnormal. Granulocytes, a type of white blood cell, may also be hyper-segmented. This is typically associated with vitamin B12 deficiency, a deficiency in folate (vitamin B9), or conditions that interfere with the action of these vitamins. 
  • Non-megaloblastic macrocytic anemia occurs when the red blood cells are large but don't have the structural abnormalities seen in megaloblastic macrocytic anemia. This type is more often associated with liver conditions, 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 normally circulate for several months before the body naturally breaks them down and makes new ones. It takes a while for the enlarged red blood cells to cause symptoms, because there are usually healthy red blood cells in circulation as well. 

With macrocytic anemia, the large red blood cells circulate throughout the body, but they do not deliver an adequate amount of oxygen to the body’s tissues. This causes nonspecific symptoms that can progressively worsen. 

Effects can include:

  • Generalized fatigue 
  • Overall weakness 
  • Dizziness
  • Headaches
  • Lack of motivation or depression 
  • Pale skin
  • Foggy thinking 
  • Diarrhea 
  • Glossitis (inflammation of the tongue)

If you have a history or risk factors for macrocytic anemia, it’s important that you are alert to these symptoms. They can be indicators that you are developing anemia—which is a diminished red blood cell number or function.

Causes of Macrocytic Anemia

There are several causes of macrocytic anemia. You can develop the condition due to just one of the causes, but you can also have more than one cause. 

Reasons that macrocytic anemia may develop include:

  • Vitamin B12 deficiency: Foods that contain this nutrient include meat, chicken, shellfish, dairy, eggs, and enriched grains. 
  • Folate deficiency: You can get this nutrient from leafy dark-green vegetables, beans, nuts, seeds, and fruit. 
  • Malabsorption: Conditions such as inflammatory bowel disease (IBD, the chronic inflammatory conditions Crohn's disease and ulcerative colitis) or gastric bypass surgery (weight-loss surgery that reduces the size of the stomach) can prevent adequate vitamin B12 or folate absorption.
  • Pernicious anemia: This blood disorder affects the absorption of vitamin B12.
  • Medications: Several medications can cause macrocytic anemia, sometimes due to interference with folic acid activity. Examples include Azulfidine (sulfasalazine), Hydrea (hydroxyurea), and Dilantin (phenytoin). There are many more.

Liver disease, alcohol use, hypothyroidism (underactive thyroid gland), myelodysplastic syndrome (bone marrow disease), leukemia (blood cancer), and some other types of cancer 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 functioning state.

Megaloblastic macrocytic anemia develops because vitamin B12 and folate are needed for the development of the genetic components of red blood cells. When these vitamins are lacking, the cellular portion of the red blood cell develops, but the genetic component does not adequately develop. This makes the cell large, but not properly functional.

How Macrocytic Anemia Is Diagnosed 

Macrocytic anemia doesn’t usually cause physical signs that are detected with a clinical examination. You might have other signs that are associated with the underlying cause.

For example, if you have severe liver disease, you could have jaundice (skin and whites of the eyes are yellowish), or you could have enlarged lymph nodes if you have cancer.

If you have macrocytic anemia associated with alcohol use, you may have peripheral neuropathy (nerve damage usually in the hands and feet that affects sensation or movement) due to alcohol use and/or signs of liver damage. However, these physical signs develop at late stages, and macrocytic anemia can develop before these changes. 

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

Tests that can identify macrocytic anemia:

  • Hemoglobin: A standard CBC measures hemoglobin, which is a protein in the red blood cells that carries oxygen. A hemoglobin below 12 grams per deciliter (g/dL) is a sign of anemia.
  • Red blood cell indices: The CBC measures red blood cell indices, which are specific assessments of the red blood cell. A mean corpuscular volume higher than 100 femtoliters (fL) indicates large-sized, macrocytic red blood cells.
  • Blood smear: This is a microscopic evaluation of a blood sample that can provide an assessment of whether the red blood cells are macrocytic or megaloblastic, and it may 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 that is often part of a yearly physical, and it is also done to assess problems such as persistent fatigue, fevers, and unexplained weight loss. A blood smear or reticulocyte count may be done when there is a specific concern about the health or function of the red blood cells. 

Medication Monitoring

Medications that can cause macrocytic anemia do not always cause this side effect for everyone, so your doctors may monitor your CBC if you are taking a medication that puts you at risk.

Another important component of the diagnosis is the determination of the underlying cause. Testing for the cause is guided by risk factors and other signs or symptoms.

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

Tests your healthcare provider may order for you include:

  • Vitamin B12 level (blood test)
  • Folate level (blood test)
  • Intrinsic factor antibodies, parietal cell antibodies, or gastrin level to identify pernicious anemia (blood tests)
  • Liver function tests (blood tests)
  • Bone marrow biopsy to assess blood cancer (procedure to take a sample of bone marrow for examination in a lab)
  • A liver imaging test, such as a computerized tomography (CT) scan

Treatment for Macrocytic Anemia

The treatment of macrocytic anemia depends on the cause. Treatment and prevention are closely linked together. 

Treatments can include:

  • Dietary modification to incorporate vitamin B12 and folate 
  • Vitamin B12 or folate supplementation
  • Discontinuing causative medication 
  • Discontinuing alcohol, preferably through an alcohol treatment program 
  • Cancer treatment for leukemia or myelodysplastic syndrome 
  • Treatment for hypothyroidism 

The treatment can help resolve the range of effects of the underlying condition, including macrocytic anemia.  

Prognosis: What to Expect 

Generally, macrocytic anemia is expected to improve with treatment. It can take weeks or longer for symptoms to resolve and for the blood tests to normalize. It is important to maintain consistent treatment and to have your red blood cell measurements monitored at regular intervals as directed by your doctor. 

Summary 

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, medication, alcohol, liver disease, and hyperthyroidism.

It can be diagnosed with blood tests. The treatment is focused on the management of the underlying condition. After treatment, anemia can resolve over the course of weeks or months, and it may require ongoing treatment. 

A Word From Verywell 

If you have symptoms of anemia, it’s important that you get medical attention. The effects are vague and can develop due to many different reasons. Once you know the cause of your symptoms, you can get started on your treatment.

You should feel an improvement in your symptoms, and you might notice a recurrence of symptoms if you ever develop macrocytic anemia again. Depending om the cause an severity of your anemia you can remain on treatment for the long term, or you can resume treatment as needed.

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