Causes And Symptoms Of Macrocytosis

Introduction

Our blood is a vital fluid that sustains life. The red blood cells deliver essential nutrients and oxygen to every part of our body and remove their waste products in the form of carbon dioxide, flowing through our arteries and veins. Because of its key role, it is susceptible to various conditions, including macrocytosis. In this article, macrocytosis, its causes, and symptoms will be laid out clearly to bring awareness to the condition and, potentially, improve its management. 

What is macrocytosis?

Our red blood cells have an important role in gas exchange. They collect oxygen from the lungs to transport it to the rest of the organs, using it to carry out vital chemical reactions in our cells, which sustain life. One of the products of this reaction is carbon dioxide, which is a waste product that needs to be removed.

The red blood cells (RBC) must remove this waste product from organs and transport it to the lungs to be exhaled. This gas exchange is facilitated by the red blood cell's biconcave shape, making transport efficient. Individuals with macrocytosis suffer from enlarged red blood cells.¹ This is due to an abnormal development of the red blood cells or in just the membrane - this is known as megaloblastic change. This may make regular RBC gas exchange less efficient. 

Doctors can detect macrocytosis through a mean corpuscular volume (MCV), which is included in the complete blood count (CBC) test. This test is commonly used by doctors to track your health by studying red blood cells.¹

The normal MCV levels of a healthy adult range from 80 to 100 femtoliters (fL), mainly depending on age. If you are an adult with an MCV greater than 100 femtoliters (fL), this is a positive indicator of the condition.² These tests are usually quite accurate as they use an automated blood cell counter. However, other conditions such as hyperglycemia and marked leukocytosis can increase also the MCV. Additionally, laboratory errors such as leaving the blood sample at room temperature for too long or partially blocked machinery can provide false reads.¹  

If your results show a high MCV, don’t panic. Most macrocytosis cases don’t require any treatment or further testing. In fact, 1.7% to 3.6% of adults who go through a CBC test find out that they have macrocytosis, with people assigned male at birth being mainly affected. However, individuals with this condition are more susceptible to developing macrocytic anaemia. This is where not only are red blood cells larger than normal but there are fewer than them.³

Causes

So, what triggers the development of these abnormally large red blood cells? There are many causes, notably: 

• A deficiency in vitamin B12 and folate 
• Alcohol consumption 
• The use of medications

Not all macrocytosis can be explained - around 10% of patients with macrocytosis have unidentified causes.⁴

Nutritional deficiencies

Vitamin B12 deficiency

One of the most common causes of macrocytosis is a lack of vitamin B12. This vitamin is used in an important chemical reaction where methionine is made.³ This reaction facilitates the formation of methylenetetrahydrofolate, a compound used to make thymidine (T), one of the four building blocks that make up our DNA. If this building block cannot be made, DNA creation will be impaired, which will affect normal cell growth and division. This results in a large red blood cell size.

Vitamin B12 deficiency arises from many conditions, such as pernicious anaemia. This is an autoimmune condition, meaning that our immune defence attacks our own healthy cells. Prenicious anemia targets stomach cells that produce a protein called intrinsic factor, which helps the body absorb vitamin B12. Therefore, not enough vitamin B12 is absorbed and abnormal red blood cells are formed, leading to anaemia. The exact cause of this is not well understood, but it is more common in people with other autoimmune conditions and people assigned female at birth close to 60 years old.³ 

Folate deficiency

Found in animal products (such as the liver) and leafy vegetables, folic acid is an important B vitamin that is heavily involved in normal body functions. Adults should be consuming, at least, 240μg of folic acid each day, while pregnant or breastfeeding individuals should consume 400μg a day. This is then absorbed by the small intestine. 

If you are folate deficient, this means you are not getting enough folic acid in your diet or you have issues with its absorption. This is more common in individuals with conditions such as inflammatory bowel disease and coeliac disease. Some medications can also affect folic acid and prevent it from being absorbed. One of the most common treatments for folate deficiency, if increased dietary intake does not work, is using oral folic acid tablets.⁵  

Alcohol consumption and blood disorders

Research has shown a strong association between alcohol addiction and macrocytosis. In a study, between 64% to 80% of individuals diagnosed with macrocytosis were believed to have this condition due to alcohol consumption.⁶

An overuse of alcohol impairs normal red blood cell production by completely stopping it or producing abnormal-looking cells.⁵ The structurally abnormal cells are then quickly destructed by the body as a mechanism of defence (hemolysis), resulting in hemolytic anaemia. This is a condition where RBCs are destroyed quicker than they are made. In turn, the body tries to compensate for the loss of these RBCs by quickly releasing new ones from the bone marrow. However, these RBCs are immature and not fully formed, contributing to macrocytosis. 

Alcoholism also leads to macrocytic anaemia. This is caused by drinking over 80g of alcohol daily, which is around 5-6 alcoholic beverages. In fact, before patients who are alcoholic have macrocytic anaemia, around 90% of them will have macrocytosis, as they will have higher MCV levels (greater than 100 fL). Therefore, if a patient has a high MCV, it not only tells us that they have macrocytosis but also suggests that they may be alcoholic. 

We can then perform tests such as the:

• Michigan Alcoholism Screening Test (MAST): 25-question-based test, which aims to identify individuals with alcoholism
• γ‐glutamyltransferase (GGT) levels: An enzyme found mainly in the liver but is elevated in the blood of patients suffering from alcoholism due to liver disease

Patients who decrease alcohol consumption will also recover from the high MCV levels.⁵

Low thyroid functions (hypothyroidism)

Our thyroid (located in the front of the neck and beneath the voice box) has an important role in releasing hormones such as erythropoietin while stimulating RBC production. Hypothyroidism is a condition where the thyroid does not work as efficiently, and so, releases fewer hormones into the bloodstream involved in making red blood cells.

This decreases the number of RBCs released, leading to anaemia, and affects their formation. As a result, many irregularly shaped red blood cells are formed, such as enlarged RBCs (macrocytosis). The overall result is macrocytic anaemia.⁵  

Symptoms

If you have macrocytosis, you will generally not be aware that you have it as it is often symptomless. It is usually only detected through blood tests. However, you may have symptoms depending on the specific cause of your macrocytosis.

For example, if your main cause of macrocytosis is hemolytic anaemia, you may experience feelings of tiredness and weakness. You may also sometimes feel dizzy. This is due to inefficient oxygen delivery from RBCs. In more serious cases, some patients have an enlarged spleen or liver (splenomegaly and hepatomegaly respectively).

This is because the spleen and liver have a role in removing damaged red blood cells from the bloodstream, and in the case of hemolytic anaemia, where this is increased, they become larger to support their increased function.⁵ 

If you have vitamin B12-deficiency anaemia, you may experience all the regular anaemia symptoms, such as tiredness, headaches, and dizziness. You may also find that you have grey hair. But if this type of anaemia is not treated, it can affect your nervous system, including your brain as this vitamin is required for efficient brain and nerve function. Therefore, symptoms relating to the nervous system, such as:

• Difficulty walking
• Pain
• Memory loss
• Problems with vision
• Mood swings
• Depression
• Feelings of confusion
• Forgetfulness
• Can’t taste/smell properly
• Muscles moving uncontrollably

Other symptoms, such as glossitis (painful red tongue) and diarrhoea can also occur.⁵ 

Medication and treatment

Several common drugs cause macrocytosis as they affect normal cell availability. They also affect the use of vitamin B12 and folic acid by affecting their delivery to cells, absorption, transport in plasma or by fully destroying them. These drugs include:

• Hydroxyurea – treats cancer
• Zidovudine – treats HIV
• Antiretroviral agents – treat HIV
• Valproic acid – treats epilepsy, bipolar disorder, migraines and headaches
• Phenytoin – treats epilepsy and seizures
• Methotrexate – treats ectopic pregnancies, autoimmune diseases and cancer
• Azathioprine – treats rheumatoid arthritis

Take note that these medications may be used to treat other conditions not mentioned.⁵ 

Summary

• Patients with macrocytosis have enlarged red blood cells
• This could affect efficient gas transportation around the body, which is the function of red blood cells
• Macrocytosis often does not present any symptoms within itself, and so many people do not know that they have the condition
• It is usually detected by elevated MCV levels, a type of blood test
• There are many causes of macrocytosis, such as nutritional deficiency, alcoholism, hypothyroidism, and use of medications
• As a result of macrocytosis, many patients may develop anaemia, macrocytic or hemolytic anaemia, resulting in symptoms such as feeling tired, dizzy, and having trouble walking
• If you feel like you relate to any of the symptoms, it may be best to get your MCV levels checked