Macrocytic Anemia: Symptoms, Causes, Treatment, And More

Anemia is any condition where you don't have enough healthy red blood cells to carry oxygen to the various parts of your body. One variation is macrocytic anemia or macrocytosis, characterized by red blood cells larger than normal.

What is macrocytic anemia?

Macrocytic anemia is, in plain terms, a form of anemia in which your body produces unusually large red blood cells, but these cells do not effectively transport oxygen.

It falls into two basic types:

Megaloblastic anemia

This type of macrocytic anemia is caused by a lack of vitamin B12 (cobalamin) or vitamin B9 (folate). These large and abnormal red blood cells have a shorter time span than usual red blood cells.

Additionally, under the microscope, the blood can show hypersegmented neutrophils. Neutrophils are white blood cells that typically have three or four segments in their nuclei or center portions. In this condition, they have six or more.

Nonmegaloblastic anemia

This is caused by medical conditions that interfere with proper nutrient absorption. These types have completely different causes and treatments but are easy to differentiate in a lab test.

Symptoms of macrocytic anemia

Macrocytic anemia often has no symptoms until it becomes severe. It may sometimes be found when the blood is checked for another reason. If symptoms exist, they include:

• Diarrhea

• Glossitis (swelling or redness of tongue)

• Anorexia

• Peripheral neuropathy and gait instability (only for megaloblastic anemia)

• General symptoms of anemia include pallor and fatigue

Macrocytic anemia is also sometimes secondary to another condition that may have a different set of symptoms.

Causes of macrocytic anemia

As already mentioned, the two types of macrocytic anemia have different causes:

Megaloblastic macrocytic anemia

This is almost always caused by a severe deficiency in either vitamin B12, folic acid, or both. This includes the inability to properly utilize vitamin B12.

B12 deficiency is most often caused by pernicious anemia. This is most often caused by atrophic gastritis, a weakening of the stomach lining, or an autoimmune condition that attacks the intrinsic factor protein essential for absorbing vitamin B12. 

Pernicious anemia is more common in people of Scandinavian or Northern European descent. It can be associated with a variety of other diseases, including hypothyroidism, primary ovarian failure, and celiac disease.¹

Malabsorption due to gastritis, tapeworm infection, or a gastric bypass is another cause. If you have had a gastric bypass, you should supplement B12, and the dose has to be fairly high. Your doctor can guide you on the proper dose for your condition. 

Vegans and vegetarians, especially the former, should also consider supplementing B12 due to their lack of vitamin B12-rich foods, such as meat, poultry, and eggs. Vegans, in particular, can become deficient enough in B12 to develop significant health problems. Fortified cereals are a good source of B12 for people eating a plant-based diet.

Folic acid deficiency is rare in the western world as most cereals and grains are fortified. Still, it can occur in people with restrictive diets or an eating disorder like anorexia. 

Chronic alcohol use can also cause folic acid deficiency and malabsorptive conditions such as celiac disease and short bowel syndrome. If you are pregnant, your fetus requires a significant amount of folate to develop properly, and most doctors recommend that pregnant people supplement folic acid.

A small minority of cases are caused by antineoplastic drugs such as hydroxyurea. This is used to treat some forms of leukemia, immunosuppressants, or rare metabolic disorder. One of them is hereditary orotic aciduria, a recessive condition that causes elevated levels of orotic acid in the urine and delayed physical and intellectual development in children.

Nonmegaloblastic macrocytic anemia

Nonmegaloblastic macrocytic anemia has a wider range of causes, varying from easily treatable to life-threatening. These include:

• Heavy alcohol consumption

• Hereditary spherocytosis, associated with jaundice and enlarged spleen

• Hypothyroidism

• Liver disease due to lipid deposition in the cell membrane

• Excess red blood cell consumption during hemolysis or pregnancy

• Primary bone marrow disease

• Down syndrome

• Nonalcoholic liver disease

This form of anemia is sometimes falsely detected. Temporary increases in red blood cell size can be caused by, for example, hyperglycemia. Operator error can also sometimes cause false positives, and as this form of anemia may be asymptomatic, multiple tests might be taken to ensure an accurate result.

How is macrocytic anemia diagnosed?

As macrocytic anemia is often asymptomatic until advanced, many cases are found when a complete blood count is taken for other reasons, including routine checkups.

A complete blood count means that a blood sample is taken, and then a lab measures the number of red blood cells in the sample. The size of cells may also be observed using a microscope.

If macrocytosis is found, the sample can also be checked for megaloblastic symptoms. If there are no megaloblastic cells and no symptoms of anemia, another test may be taken to avoid a false positive, especially if you are diabetic.

Doctors may also check for serum levels of B12 and folic acid to look for deficiencies.

Who is at increased risk of macrocytic anemia?

Risks of macrocytic anemia are higher in the following groups:

• Vegans and, to a lesser extent, vegetarians

• Pregnant women

• People with a thyroid condition, particularly hypothyroidism

• People of Scandinavian or northern European descent

• Women with primary ovarian insufficiency, defined as premature menopause before the age of 40

• People with a malabsorptive condition such as celiac disease, tropical sprue, or short bowel syndrome

• People with chronic hemolysis

• People with anorexia or another eating disorder

• People with avoidant-restrictive food intake disorder (ARFID), a condition that causes extreme diet restrictions and can thus lead to deficiency

• People who have had gastric bypass surgery

• Older adults

• Alcoholics and others who drink regularly and excessively

• People with bone marrow disease such as bone marrow dysplasia or reticulocytosis

The most common cause of this type of anemia remains vitamin B12 or folic acid deficiency.

Complications associated with macrocytosis

Many people with macrocytic anemia never experience symptoms. However, more severe cases can cause complications, which include:

• Permanent neurological issues from B12 deficiency, most often peripheral neuropathy, but also including awkward gait, memory loss, and psychiatric issues

• Neural tube defects in a developing fetus

Some forms of this anemia are caused by underlying conditions that may have complications if not properly treated.

How is macrocytic anemia treated?

The primary cause of macrocytic anemia is a deficiency in B12 and/or folic acid. Treatment thus consists of either increasing the intake of one or both or addressing the condition causing poor absorption.

For people with pernicious anemia, the treatment is typically regular injections of B12 into the muscle. This bypasses the gut and, thus, the issues causing malabsorption. Severe B12 deficiency may also require a series of injections to resolve the deficiency, but they may not be needed long-term.

Mild macrocytic anemia may be treated with oral supplementation and dietary changes to increase B12 and/or folic acid intake. For example, if you have a folate deficiency, your doctor may recommend increasing your intake of green leafy vegetables.

If you are drinking excessively, then you may be referred to an alcohol treatment program. Reducing alcohol intake generally improves the absorption of B12. Alcoholism can also cause a variety of other health conditions. 

If you have an eating disorder, treating it can resolve the situation. ARFID, however, is hard to treat, and people with the condition may need to take supplements.

If the condition is caused by medication, your doctor may want to try an alternative medicine or adjust the dosage.

Addressing any underlying conditions is a key part of treating macrocytic anemia.

Can you prevent macrocytic anemia?

Many causes of macrocytic anemia, especially nonmegaloblastic, cannot be prevented. However, the most common cause, B12 deficiency, can be. 

Eat a healthy, balanced diet. If you are restricting or eliminating animal products from your diet, consider oral supplementation or consuming fortified foods to compensate. B12 is rare in plant sources and often less easily absorbed.

If you are vegan, choose a supplement marked as vegan (not all are) or consume fortified foods such as plant milk.

If you are pregnant or trying to become pregnant, supplement folic acid immediately. While our diet typically contains enough folate, it is not always enough for the added demands of a growing fetus. Your baby needs folic acid to grow a proper nervous system.

You should start supplementing before you engage in unprotected sex to ensure that your fetus is supported even before you know for sure that you are pregnant.

Avoid excessive consumption of alcohol and get help if you are developing an alcohol problem. Addiction is a disease, and there is no shame in seeking treatment. You should also seek treatment for eating disorders.

If you are on medication for a thyroid issue, make sure to keep taking your medication.

Get your blood screened with a complete blood count regularly so that if you are developing mild anemia, it can be spotted before you get symptoms. If your doctor says you don't have enough B12 in your system, you need to look at your diet and ensure you are consuming enough.

The lowdown

There are two types of macrocytic anemia and a variety of causes. However, the most common cause is a deficiency of either B12 or folic acid (or both). Getting enough B12 is essential for your overall health.

Most cases of macrocytic anemia are mild and are found during routine screening, but sometimes they can be part of a life-threatening underlying condition. Talk to your doctor if you have any symptoms of anemia and get a blood test to establish the type and cause so that it can be treated before it causes further problems.