Macrocytic Anemia and Megaloblastic Anemia: What’s the Difference and How Do They Show Up in Women?

Macrocytic anemia is a type of anemia where blood cells are abnormally enlarged. Depending on the cause, macrocytic anemia is broken into two subtypes: megaloblastic anemia and non-megaloblastic anemia. No matter what is causing your anemia, you’ll likely feel fatigued, weak, and generally run down. Some anemia symptoms, however, such as neurological issues, may only occur in certain people, such as those who also have vitamin B12 deficiency. Treatments can include dietary adjustments, supplementation, and looking at your digestive health as a whole. Here’s what you need to know.

When we think about anemia, often the first thing that comes to mind is iron-deficiency anemia. But anemia can be caused by other nutrient deficiencies, as well as underlying conditions that affect your body’s ability to make the mature red blood cells needed to carry oxygen around your body for energy. We’re talking about macrocytic anemia, which has two subtypes, megaloblastic and nonmegaloblastic anemias. Here, we talk about what these are, how they differ, their causes and symptoms, and how to treat and manage anemia with a whole-body, functional medicine approach.

Understanding macrocytic anemia

When you have red blood cells that are larger than normal, you have macrocytosis, which affects 2 to 4 percent of the population. More than half (60 percent) of people with macrocytosis develop anemia. Read on to learn more about what this condition is, its types, causes, and symptoms.

What is macrocytic anemia?

Macrocytic anemia is a blood disorder where the red blood cells are larger than normal. Because red blood cells ferry oxygen from your lungs to the tissues around your body, they are necessary for energy production. Large red blood cells are abnormal, so they don’t function as they should, leading to symptoms in some people.

Types of Macrocytic Anemia

There are two types of macrocytic anemia:

Megaloblastic anemia: Anemia that is typically caused by a B vitamin deficiency.

Nonmegaloblastic anemia: Anemia that is caused by underlying conditions, lifestyle habits (like alcohol use), and genetic disorders.

Common causes of macrocytic anemia

There are numerous macrocytic anemia  causes:

Vitamin deficiency, specifically B9 (folate) and B12

Certain medications like methotrexate, some antibiotics, and some cancer drugs

Alcohol misuse

Inherited blood disorders and other genetic causes

Hypothyroidism (underactive thyroid)

Liver disease

Autoimmune conditions

Bone marrow disease

Surgery, such as gastric bypass or bowel surgery in IBD

Symptoms of macrocytic anemia

Having macrocytic anemia may contribute to symptoms that affect your energy, neurological function, and more. They’re easy to ignore. Symptoms like brain fog or tingling are often dismissed as stress or the result of a busy lifestyle, says registered dietitian nutritionist Kathryn Durston. “B12 and B9 deficiencies aren’t always top of mind from patients or even some providers, especially when symptoms are subtle or nonspecific.” This can delay diagnosis, she adds.

The following are macrocytic anemia symptoms:

Fatigue

Mood issues

Loss of balance

Memory loss

Tingling, burning, prickling, or skin-crawling sensations

Weakness, numbness, instability

GI symptoms like diarrhea, tongue inflammation/swelling, loss of appetite

Understanding megaloblastic anemia

Macrocytic anemia is divided into two subtypes, and these are largely differentiated due to causes like nutritional deficiency versus underlying conditions. Here’s a look at the vitamin deficiency-driven megaloblastic anemia.

What is megaloblastic anemia?

Megaloblastic anemia is a subtype of macrocytic anemia caused by impaired DNA synthesis. Because it is a subtype, people who have this anemia also have abnormally enlarged red blood cells that impact these cells’ ability to work well.

Main causes of megaloblastic anemia

Typically, the main cause of megaloblastic anemia is a deficiency in vitamin B9 (folate) and/or B12, which affects DNA synthesis, leading to the development of enlarged immature red blood cells in bone marrow called megaloblasts. These two vitamins, folate and B12, are needed for DNA synthesis.

Risk factors include restrictive diets (such as vegan diets), severe food allergies, chronic digestive disorders, or taking certain medications, says Durston, such as antiseizure, rheumatological, or cancer medications. H. pylori is another cause that functional providers assess for, as this infection reduces acid and attacks intrinsic factor, both of which impact B12 absorption.

Symptoms specific to megaloblastic anemia

Often, there are no symptoms at first. In fact, many people learn they have megaloblastic anemia after they do a routine blood test, and they find out that they happen to be low in folate or B12. As anemia worsens, you may then develop symptoms, such as:

Fatigue (especially fatigue that doesn’t resolve as you improve sleep habits)

Weakness

Shortness of breath, especially with exertion/exercise

Heart palpitations or tachycardia (where your heart feels as if it’s beating faster or fluttering)

Lightheadedness

Paleness

A “sluggish” brain or struggles with memory and recall

Tongue swelling

If you have B12 deficiency, you may also have neurological symptoms, including “pins and needles” sensations, balance problems, “electric shock” sensations, and visual problems. “Tingling, numbness, and tremor are symptoms I’ve seen in chronic B12 deficiency,” says Olivia Wagner, RDN, a functional dietitian specializing in women’s health and fertility.

Megaloblastic anemia vs. pernicious anemia

Folate and/or B12 deficiency can cause megaloblastic anemia. On the other hand, pernicious anemia can cause B12 deficiency. So, what is pernicious anemia? We’ll dive into that below.

What is pernicious anemia?

Pernicious anemia is another condition where there are not enough healthy red blood cells being made in your body. This is an autoimmune disorder where the body cannot properly absorb vitamin B12 from the diet due to a subpar production of intrinsic factor, a protein that transports B12 to the portion of the small intestine where the nutrient is absorbed. As a result, you develop B12 deficiency, and, yes, megaloblastic anemia. This is most common in people over 60 years old.

Symptoms of pernicious anemia

Pernicious anemia can take as long as five years to develop, and you may not feel any ill effects until then. (Thank your body, which learns to compensate and figure out how to send enough oxygen around to your tissues.) The thing is that pernicious anemia symptoms (like any anemia) aren’t always in-your-face apparent. Given that symptoms develop over time, and since the symptoms show up in many other conditions (not to mention phases of life, like an especially stressed-out season), they can be easy to miss.

Doctors might suspect pernicious anemia if you experience:

Fatigue and weakness

Loss of appetite and weight loss

Headache

Brain fog

Numbness

Balance problems

Mood issues like depression

Enlarged tongue, reduced sense of taste

Heart palpitations

Shortness of breath

Indigestion

Diarrhea

Risk factors for pernicious anemia in women

Although females and males have pernicious anemia at the same rates, there are a couple of risk factors. Those include people who are over age 60 and those who are of European ancestry. What’s more, having a history or family history of an autoimmune condition also puts you at risk for developing pernicious anemia. (Autoimmunity tends to run in families and if you have one condition, you’re more likely to develop another.) One autoimmune disorder to particularly watch is autoimmune gastritis, which occurs if your immune system attacks your stomach lining. It’s here where stomach cells release intrinsic factor, that ever-important protein for B12 absorption.

Diagnosing macrocytic and megaloblastic anemias

The first step in any diagnosis is through a medical appointment and physical exam. Be prepared to describe your symptoms and when they occur as best as you can.

If your doctor suspects anemia, they’ll want to run blood tests, including nutrient deficiency testing. That includes:

A complete blood count test. Doctors may also order an RBC (red blood cell) folate test to more accurately examine folate levels.

Peripheral blood smear. A provider will look at your blood cells under a microscope in a lab.

Reticulocyte count. Reticulocytes are immature red blood cells, and their numbers can be measured from a blood sample.

In functional medicine, however, additional testing may be recommended to decipher the root cause of your anemia, which is what will be used to drive treatment. “I always start with a basic blood panel, but I also run tests for B12, folate, methylmalonic acid (MMA), and homocysteine. In addition, I want to do a complete iron panel and a hemoglobin test,” says Wagner. This provides a full picture on how your body is using these vitamins and minerals. Additional investigation may involve stool testing to evaluate absorption of these vitamins. 

Treatment and management

Finding the right treatment hinges on uncovering the root cause of why you have macrocytic anemia. With the right treatment, you can improve anemia in one to two months.

Addressing vitamin deficiencies

If you have megaloblastic anemia due to a folate and/or B12 deficiency, treatment is getting enough of the B vitamin you are missing, which will be done via diet and possible supplementation. “If a deficiency or even an insufficiency in B12 or B9 is identified, the first step I recommend is evaluating your diet to see if intake can be improved through food sources alone,” says Durston. Food sources of folate include beef liver, cooked spinach, fortified cereal, rice, asparagus, Brussels sprouts, romaine lettuce, and avocado. B12 can be found in beef liver, clams and oysters, nutritional yeast, salmon and tuna, ground beef, and milk and yogurt.

Your clinician may also recommend taking an oral supplement, including folic acid to improve folate levels, as well as B12. B12 can also be given via injection or infusion. Another option is an oral B complex supplement, which includes a range of B vitamins, says Wagner. You may also need to take methylated B vitamins, which are vitamins already in their active form, allowing for better absorption, she adds. What’s important is to get pointed recommendations from your clinician.

Managing underlying conditions

If you have an underlying medical condition that is causing the anemia, you’ll need treatment for that condition. For example, if you have hypothyroidism that’s causing your anemia, your medical provider may prescribe a medication called levothyroxine (Synthroid). At Parsley Health, nutrition and lifestyle changes are at the core of thyroid healing, such as ensuring you have adequate iodine levels, practicing stress management, and improving your gut health.

Regular monitoring and follow-up

Macrocytic anemia isn’t something that’s okay to manage with a few supplements and be on your way. Routine blood tests can help track improvement and response to treatment. Talk to your clinician about when you should come back for a follow-up visit and how often you may need testing to check the health of your red blood cells. “I encourage regular testing every six to 12 months to ensure your protocol is working,” advises Durston. “I recommend not only testing B12 and folate but also your homocysteine and methylmalonic acid (MMA) levels, as these can be elevated with a functional deficiency.”

Special considerations for women

Wagner points out that B vitamins are important for healthy cycles and fertility. “In people who have crampy, heavy periods, I see a lot of suboptimal levels of these vitamins.” She also adds that she’d advise females navigating hormone health issues or fertility problems to monitor their nutrient levels.

If you are hoping to become pregnant, you’ll want to take 400 mcg of folic acid (the synthetic form of folate) as a supplement every day. Doing so helps prevent neural tube defects, which are birth defects that affect the baby’s brain and spine.

In addition, thyroid problems are more prevalent in individuals born female compared to individuals born male, and they’re also likely to arise during pregnancy. Autoimmune conditions are also more likely to develop in females, and certain types of anemia (pernicious anemia) are caused by autoimmunity.

Heavy menstrual bleeding, which can also occur during perimenopause when hormones are fluctuating wildly, increases the risk for iron-deficiency anemia.

Preventative measures and lifestyle recommendations

We can’t prevent every health problem, but an overall healthy, balanced lifestyle goes a long way in setting up the foundation for your body to function well. Make sure you’re consuming a diet that contains foods that provide ample amounts of folate and B12.

In addition, “there are some lifestyle considerations to keep in mind when managing anemia, such as limiting alcohol consumption and managing stress that can impact your nutrient status,” says Durston. She often recommends box breathing, yoga, binaural beats, and guided meditation.

See your clinician regularly to check the status of your health, including simple blood testing like a complete blood count, and make an appointment if you experience symptoms of anemia, such as fatigue, weakness, mood problems, and neurological symptoms, that are affecting your ability to work a full day, spend time with those you love, and pursue hobbies. Macrocytic anemia isn’t the only cause of these symptoms, so a thorough investigation will help rule out others, including multiple sclerosis.

Holistic approach to anemia management at Parsley Health

Anemia management with a functional health provider isn’t just about one thing. It’s not about eating a diet containing folate- or B12-packed foods or making sure you pop a B Complex every day.  “It’s shocking to me how many people I see are deficient in B12 but eat a healthy diet that includes protein and leafy greens. I always ask ‘how did we get here?’” says Wagner. This means searching for the root cause. Is it diet-related? Or are you not digesting and absorbing nutrients properly due to a digestive disorder like Celiac, Crohn’s, or SIBO? Do you have trouble breaking down food due to problems that affect your stomach acid levels like an H. Pylori infection or a long history of taking proton-pump inhibitors (PPIs) for acid reflux? Is there evidence that there may be yeast overgrowth in the gut? A full investigation is important to help you regain your health.

Frequently Asked Questions (FAQs)

What is the main cause of macrocytic anemia?

Macrocytic anemia is categorized into two types, called megaloblastic anemia and nonmegaloblastic anemia. The main cause for megaloblastic anemia is a deficiency in folate (vitamin B9) and/or B12.

Which drugs cause macrocytic anemia?

Medications like methotrexate, some antibiotics, and some cancer drugs may affect the formation of red blood cells to cause macrocytic anemia.

Why does liver disease cause macrocytic anemia?

Liver disease causes macrocytic anemia, as one cause of liver disease is alcohol use disorder. Alcohol use itself can cause B12 or folate deficiency. Liver disease also affects the structure of red blood cells.

How does hypothyroidism cause macrocytic anemia?

Hypothyroidism negatively affects immature red blood cells in the bone marrow, potentially leading to macrocytic anemia.

What is megaloblastic anemia caused by?

The main cause of megaloblastic anemia, which is a subtype of macrocytic anemia, is vitamin B9 (folate) and/or B12 deficiency.

What is the difference between B12 deficiency and megaloblastic anemia?

B12 deficiency can cause megaloblastic anemia, a blood disorder. B12 deficiency doesn’t always cause problems, however, and the development of anemia can take years.

What are the blood results for megaloblastic anemia?

Several blood tests can be used to identify a macrocytic/megaloblastic anemia, which include a complete blood count, peripheral smear, and reticulocyte count.

Conclusion

Functional medicine providers like those at Parsley Health step back and look at the big picture of you, relying on individualized care plans that provide a well-rounded approach with nutrition, supplementation, and lifestyle adjustments. Rather than only identifying anemia, they will look closer and deeper to uncover the root cause of your symptoms. Once we tackle those, you will begin to feel better again.

Key Takeaways

Macrocytic anemia is a type anemia where red blood cells are abnormally enlarged. Megaloblastic anemia is a subtype of macrocytic anemia, with the primary cause being folate (vitamin B9) and/or B12 deficiency.

Treatment involves resolving nutrient deficiencies through dietary changes and possible supplementation, identifying and managing underlying conditions, and regular blood testing to monitor how well treatment is working.

A functional medicine approach to anemia focuses on the root cause of vitamin deficiencies or other health problems that are causing the anemia.