What Is Non-Megaloblastic Macrocytic Anemia? Causes And Symptoms

Anemia is a condition that occurs when your body doesn’t have enough healthy red blood cells or contains low levels of hemoglobin. This interferes with the cells’ ability to do their job.

Red blood cells contain hemoglobin, an iron-rich protein that binds with oxygen to be transported around the body. Having anemia means your blood is less able to carry oxygen to the body’s tissues. 

An estimated 22.8% of the global population has anemia. Around three million people in the US are affected by the condition.¹ ²

There are different types of anemia, including the following:

  • Iron deficiency anemia: This is the most common type of anemia and is caused by insufficient iron levels in the body.³

  • Aplastic anemia: A rare type of anemia where the bone marrow does not produce enough red blood cells.⁴

  • Hemolytic anemia: In this type of anemia, red blood cells are destroyed too early. This means the demand for red blood cells exceeds your body’s ability to produce them.⁵

  • Macrocytic anemia: Red blood cells are larger than normal in this type of anemia. This is called macrocytosis, where “macro” means large and “cytes” means cells.

Have you considered clinical trials for Anemia?

We make it easy for you to participate in a clinical trial for Anemia, and get access to the latest treatments not yet widely available - and be a part of finding a cure.

Megaloblastic vs. non-megaloblastic macrocytic anemia

Macrocytic anemia can be divided into two types: megaloblastic and non-megaloblastic.

Megaloblastic macrocytic anemia

Megaloblastic macrocytic anemia is caused by impaired DNA synthesis, which affects the initial production of red blood cells. This can occur due to nutritional deficiencies in vitamin B12 and/or folate, either due to insufficient dietary intake or malabsorption (this may occur in alcoholism and Crohn’s disease).⁶

In this type of anemia, the red blood cells keep getting larger and become oval in shape. They have insufficient components inside them to function properly and deliver oxygen to the body. For example, they may have less hemoglobin.

This type of macrocytic anemia can affect other blood cells, such as neutrophils.

Non-megaloblastic macrocytic anemia

In non-megaloblastic macrocytic anemia, the red blood cells have a normal, round shape. However, they are still larger than normal.

Several factors affect the size of the red blood cells in non-megaloblastic macrocytic anemia, including

  • An increase in the cell’s surface area

  • Excess deposits of certain substances inside the cells, such as lipids (fats) or water

  • An increase in the number of premature red blood cells (reticulocytes), which are larger than mature ones

  • Bone marrow toxicity (as a result of alcohol, for example)

Other blood cells are not usually affected in this type of macrocytic anemia.

What causes non-megaloblastic macrocytic anemia?

There are many possible causes of this type of anemia. Some are related to problems with the bone marrow itself. More commonly, the condition is caused by other factors that influence the size of the red blood cells.

Common causes of non-megaloblastic anemia include the following:

Liver disease

The liver plays an important role in healthy red blood cell production and regulation.

In people with liver disease, the metabolism of cholesterol and phospholipids is affected. As a result, these substances are deposited on red blood cell membranes in excess, which causes them to become large.

Removal of the spleen (splenectomy)

The spleen is responsible for processing red blood cells by removing the lipids from the cells’ membranes during the maturation process. When the spleen is removed, these lipids stay, which results in larger cells.

Chronic alcohol consumption

Alcoholism can cause both megaloblastic and non-megaloblastic macrocytic anemia. It contributes to 65% of macrocytic anemia cases.⁷

As a cause of liver disease, alcoholism can indirectly lead to non-megaloblastic anemia. It can also directly cause the condition as a result of damage and inflammation to the bone marrow (alcohol bone marrow toxicity). This affects red blood cell production.

Chronic obstructive pulmonary disorder (COPD)

In this respiratory condition, the body suffers from hypoxia (low oxygen levels). People with COPD may hyperventilate in response to hypoxia in some situations, leading to excess carbon dioxide retention. This could cause the amount of water retained in the red blood cells to increase, making them larger in size.⁸

There may be periods when the body tries to compensate for hypoxia by releasing unready immature large cells from the bone marrow, causing macrocytosis.⁹

Myelodysplastic syndrome (MDS)

MDS is a group of blood disorders that cause cells in the bone marrow to develop and function abnormally.

When you have MDS, the bone marrow cannot produce enough healthy red blood cells. The abnormal cells that are produced cause non-megaloblastic anemia.


This is a health condition caused by an underactive thyroid gland. The thyroid gland produces hormones that regulate your body’s metabolism. These hormones are also responsible for starting the production of erythropoietin, a hormone that stimulates bone marrow’s production of red blood cells.

Red blood cell production can slow down when the thyroid gland doesn’t produce enough hormones. This can result in either anemia with a low number of normal-sized red blood cells, or non-megaloblastic anemia, where red blood cells are too large.

Hemolytic anemia or bleeding

In these situations, the bone marrow tries to overcompensate for the loss of red blood cells by producing more. However, many of these cells are still in the immature stage (reticulocytes). These immature cells are larger in size than mature cells.

Symptoms of non-megaloblastic anemia

Most symptoms associated with this type of anemia are effects of the underlying condition that is causing the anemia.

The symptoms that are specific to non-megaloblastic anemia may not be noticeable during its early stages because the condition develops over time.

Healthy red blood cells function for a few months before they die. Therefore, it may take some time before your count of abnormal cells is high enough to cause symptoms.

When the abnormal red blood cells circulate in the body and provide less oxygen to the organs and tissues, this may lead to anemia symptoms such as:

  • Dizziness, fainting

  • Shortness of breath

  • Headache

  • Fast or irregular heartbeat

  • Pale skin

  • Feeling weak

  • Feeling tired

  • Chills

Speak to your doctor if you develop any of these symptoms, especially if they persist.

Other symptoms may be specific to the underlying cause of the anemia, such as alcoholism, liver disease, chronic obstructive pulmonary disease, or hypothyroidism.

How is non-megaloblastic macrocytic anemia diagnosed?

Physical examination and laboratory tests are used to diagnose non-megaloblastic macrocytic anemia.

In a physical examination, your doctor may look for signs such as fatigue, pale skin, and rapid heart rate. Additionally, you may be asked about your diet and other medical conditions.

The following are laboratory tests that may be used to diagnose non-megaloblastic macrocytic anemia:¹⁰

Complete blood count (CBC)

The test is used to measure the number and size of the mature and immature red blood cells. It’s also known as a reticulocyte count.

A CBC also measures your hemoglobin levels. If the blood test shows low hemoglobin levels with the presence of large red blood cells, your doctor may prescribe a peripheral blood smear.

Peripheral blood smear (PBS)

This test examines and analyzes blood cells through a microscope to provide an overview of their shape and size.

Bone marrow examination

Your doctor may request this test if the results of the previous tests showed confirmed anemia and abnormalities in the size or shape of the red blood cells.

A doctor will take a sample of your bone marrow and examine it to help with diagnosis. They will look for evidence of an abnormal increase in your bone marrow cells, fast multiplication, and some irregularities in shape. Severe changes could indicate you have a serious blood disorder, such as myelodysplastic syndrome.

The lowdown

Non-megaloblastic macrocytic anemia is a type of anemia where the red blood cells are larger than normal. This can cause symptoms such as weakness, tiredness, shortness of breath, dizziness, and headache.

The condition can occur for several reasons that can affect the size of the circulating red blood cells, including alcoholism, liver disease, removal of the spleen, hypothyroidism, COPD, and hemolytic anemia.

Non-megaloblastic macrocytic anemia differs from the megaloblastic type. This occurs when DNA synthesis is impaired due to vitamin B12 and/or folate deficiencies, which affect the production of red blood cells.

Physical examination, medical history, and laboratory testing is used to diagnose non-megaloblastic macrocytic anemia.

Frequently asked questions

What are some long-term complications of non-megaloblastic macrocytic anemia?

Non-megaloblastic macrocytic anemia can cause cardiovascular issues, including irregular heartbeat, enlarged heart, heart attacks, and heart failure. It’s also possible to experience complications from the underlying condition causing the anemia.

In pregnant women, this type of anemia can lead to bleeding and premature birth. It can also cause the baby to be born with low weight or anemia.

In children, untreated anemia can affect their neurological and cognitive development.

Can non-megaloblastic macrocytic anemia be prevented?

Some cases of non-megaloblastic macrocytic anemia can be prevented by reducing your risk of developing the health conditions that can cause it. Maintaining a healthy diet and weight, abstaining from smoking, and avoiding excessive alcohol consumption can help you avoid these conditions.

How is non-megaloblastic macrocytic anemia treated?

While megaloblastic macrocytic anemia is treated by supplementing folate and/or vitamin B12 to overcome nutritional deficiencies, treatment for non-megaloblastic macrocytic anemia centers on treating the underlying cause.¹¹

Can non-megaloblastic macrocytic anemia be cured?

Yes, if the underlying cause of non-megaloblastic macrocytic anemia is identified and treated.

Have you considered clinical trials for Anemia?

We make it easy for you to participate in a clinical trial for Anemia, and get access to the latest treatments not yet widely available - and be a part of finding a cure.

Discover which clinical trials you are eligible for

Do you want to know if there are any Anemia clinical trials you might be eligible for?
Have you taken medication for Anemia?
Have you been diagnosed with Anemia?