Overview

Have you ever wondered how disruption in the production and growth of blood cells could impact a person? This is exactly what takes place in a group of blood disorders as a result of immature blood cells being produced by the bone marrow, called myelodysplastic syndromes, in which macrocytosis is one of the conditions that is associated with this group of disorders. Macrocytosis is characterised by the abnormally large red blood cells present in the patient's blood due to the interference in the maturation of these cells, resulting in a low blood cell count and often associated with anaemia. 

Introduction to myelodysplastic syndromes 

Myelodysplastic syndromes encompass a group of bone marrow disorders characterised by abnormalities in the development of blood cells. In a healthy person, the blood stem cell, also referred to as an immature cell, can differentiate into either lymphoid or myeloid cells. These cells will then go on and mature to become the cells we commonly know in the blood, such as red blood cells, platelets and white blood cells. However, patients with myelodysplastic syndrome experience a disruption in the balance of haematopoiesis, where blood cells cannot properly mature and develop.¹ These immature blood cells cannot function like their usual normal counterparts, resulting in the bone marrow being unable to produce a sufficient amount of mature and healthy blood cells. This will overall result in lower levels of red and white blood cells and platelets as some of the existing space has already been occupied by immature and non-functional blood cells.²

What is macrocytosis?

Macrocytosis, also referred to as megalocytosis or macrocythemia, is a haematological condition where the red blood cells are abnormally enlarged.³ This condition is usually associated with anaemia since macrocytosis impacts the production and maturation of healthy and functional red blood cells, resulting in a lower level of haemoglobin in the blood. This means less oxygen and nutrients will be pumped around the body, and can result in severe medical consequences if not treated. The prevalence of macrocytosis is around 1.7% to 3.9% of the general population, and around 60% with this condition also have anaemia due to its impact on the red blood cells.⁴

Causes and risk factors

Macrocytosis has a wide range of causes, ranging from nutritional deficiencies to side effects caused by other treatments. 

One of the major causes of macrocytosis is due to deficiency in vitamins B12 and B9. Vitamin B12 is crucial in the formation of red blood cells, in which it acts as the cofactor in the synthesis of the haem, which is part of haemoglobin in charge of carrying and transporting in blood.⁵ This vitamin also plays an important role in the synthesis of S-adenosylmethionine, which is involved in helping methylate homocysteine to methionine.⁵ S-adenosylmethionine has a vital role in the maturation of red blood cells, so without vitamin B12, the red blood cells will not be able to produce and mature normally. On the other hand, vitamin B9, commonly known as folate, is also needed for the growth and development of red blood cells. Like vitamin B12, they are crucial in the production of red blood cells, which are essential as part of the bone marrow, which is where red blood cells are produced.⁵ They are also needed for the maturation of red blood cells to maintain their size and shape, and if deficient, would result in the production of large red blood cells. 

Alcohol is another major cause of macrocytosis. It can hinder the production of red and white blood cells in the bone marrow as alcohol can directly induce toxic damage to the organ and can also interfere with the maturation of the red blood cells.⁶ These immature cells are usually defective and destroyed, lowering the red blood count and resulting in macrocytic anaemia. Excessive drinking can also result in liver damage,⁷ which could lead to macrocytosis. The red blood cells of patients with liver diseases have an altered lipid composition in their membrane,⁸ where there is a higher amount of cholesterol, and this can cause the membrane to have less fluidity and have a more rigid shape, unable to carry as much oxygen. This is why people who frequently consume alcohol will be more at risk of having macrocytosis. 

Other cases of macrocytosis could be due to the side effects of medications and treatments. Some drugs could impact the development of red blood cells by interfering with the synthesis of the DNA involved in these processes. Examples of this would be antiretroviral drugs, such as zidovudine and stavudine,⁹ or chemotherapeutic agents used in cancer treatments, like hydroxyurea¹⁰ and methotrexate.¹¹ Some medications affect the absorption and intake of the vitamins mentioned previously.

Some other risk factors of macrocytosis include age, in which risk increases with age⁴ and people with Down syndrome¹² are also more likely to be at risk as well. 

Symptoms and diagnosis

In most cases, if the patient with macrocytosis does not have anaemia present, they would not present any particular symptoms and signs. On the other hand, when macrocytosis with anaemia is present, the patient would generally display common symptoms of anaemia:¹⁴

• Fatigue
• Dyspnea 
• Palpitations
• Overall weakness
• Lightheadedness
• Skin pallor

Since the causes of the origin of macrocytosis are varied, patients will display different unique symptoms accordingly as well. For example, if macrocytosis is caused by a deficiency in vitamin B12, the patient will also experience paresthesia and glossitis,¹⁴ whereas macrocytosis caused by liver damage and dysfunction would lead to clinical manifestations, such as jaundice,¹⁴ cirrhosis¹⁵ and gynecomastia.¹⁶ Furthermore, macrocytosis results in macrocytic anaemia, where the patient might potentially experience symptoms, such as petechiae, ecchymosis and epistaxis.³

Macrocytosis can be diagnosed by carrying out blood tests, emphasising the mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values. The MCV value is a measurement of the average size and volume of the red blood cells, whereas the MCH value provides the average amount of haemoglobin present in each red blood cell. When these values are higher than the normal range, it indicates that there is a lack of healthy red blood cells in the blood and the presence of immature red blood cells, suggesting that the patient has macrocytosis.³ Other methods will also be used to diagnose macrocytosis and identify its causes. Looking into the patient's history can provide information regarding medication, dietary and lifestyle habits and family history, which can offer more insight as to what the cause of macrocytosis is and how to treat it. In contrast, physical exams can be used to look for signs associated with macrocytosis, such as inflammation of the tongue or extremely pale skin. In some cases, samples of the patient's bone marrow might need to be removed for further testing through laboratory analysis.

Treatment, management and prevention

The treatment for each patient varies, depending on what the underlying cause of macrocytosis is and its severity. Treatment is not usually required for those who have an MCV value lower than 115 fL and do not show signs of further complications or anaemia.³ Patients who suffer from macrocytosis due to vitamin deficiency will be given supplements of their corresponding vitamin to help maintain an adequate level of the corresponding vitamin. Dietary adjustments will also need to be made to ensure that the patient is taking in sufficient amounts of nutrients. Examples of vitamin B12-rich foods include lean meats, eggs and seafood, whereas dark leafy vegetables or fruits are a great source of folate. Treating alcohol-related macrocytosis requires alcohol cessation for a few months and those who are suffering from medication-caused macrocytosis should discontinue the use of medications or the treatments of the drugs that are causing the condition. 

Caution needs to be taken with lifestyle habits to prevent macrocytosis, including having a balanced diet with the required nutrients and the consumption of alcohol. Regular body checkups, including blood tests, would be advised to ensure early detection of macrocytosis or any potential signs associated with the condition, such as liver dysfunction or nutrient deficiency, so action could be taken earlier on. However, these prevention measures vary for each person, depending on their background and situation, such as pregnant women having a higher demand for B12 and folate¹⁷ or vegans since a major source of these vitamins comes from animal products. If in doubt or have any concerns, it is important to consult a doctors or nutritionist to seek advice for maintaining a healthy lifestyle. 

Summary

Macrocytosis is a condition where the patient's red blood cells do not mature and develop properly, resulting in the production of non-functional and immature red blood cells, resulting in low levels of haemoglobin in the blood. The causes of macrocytosis could vary for each patient, including vitamin B12 and folate deficiency, alcoholism, liver dysfunction and interference with medications.