Concerned about macrocytosis and what it means for your health? The comprehensive exploration of the genetic influences behind this condition will empower you with the knowledge and solutions to take control of your well-being.

Introduction

Macrocytosis is a condition where red blood cells are larger than normal. Normally, red blood cells are all about the same size, but in macrocytosis, they become bigger. This can be a sign of various health issues, such as vitamin deficiencies, alcohol use, or certain genetic conditions. It is usually detected through a blood test that measures the size of your red blood cells.

Importance of understanding genetic factors 

Genes determine how a person looks and how their body functions. Some diseases, like macrocytosis, are caused when changes occur in the regulation of the genes. This is known as a mutation. Mutations can occur in everyone and these changes can have little or no impact. However, these changes can sometimes lead to diseases.

Most commonly, diseases are caused because of lifestyle choices, factors in the environment, and combinations of mutations. Specific changes occurring in a single gene could be the reason for thousands of diseases. Most diseases are rare and usually develop as a result of a mutated gene present in the DNA.

Overview of Macrocytosis

Definition of Macrocytosis 

Macrocytosis refers to a condition in which the red blood cells are larger than normal. This is reflected in the normal hemogram as an increase in mean corpuscular volume (MVC). The average MVC in adults is between 80 to 100 femtoliters.^1,2 A MVC that exceeds 100 fl is typically classified as macrocytosis. As MCV is generally lower in children when compared to adults, the cut-off value is lower for children. In asymptomatic patients, macrocytosis can be an incidental finding or sometimes be associated with symptoms of an underlying disease. The estimated prevalence of macrocytosis in the general population ranges between 1.7 to 3.6%.^1,2

Common signs and symptoms

Macrocytosis does not cause any symptoms or signs but there may be some signs related to the underlying disease. Mild anaemia can be asymptomatic. Most cases are diagnosed when a blood count is performed as part of an investigation for something other than signs of anaemia. Common signs and symptoms of people suffering from macrocytosis include:

• Fatigue 
• Weakness
• Dyspnea
• Palpitations
• Lightheadedness
• Syncope or near-syncopal events

Causes of macrocytosis

Macrocytosis is caused when normal maturation of the red blood cell nucleus is inhibited because of folic acid or B12 deficiency.³ Some other causes of macrocytosis can also include:

• Alcoholism
• Hypothyroidism
• Chronic liver disease
• Down syndrome
• Chronic obstructive pulmonary disease (COPD)

Basics of red blood cells and Macrocytosis

Normal red blood cell function

Red blood cells transport oxygen from the lungs to body tissues. Tissues produce energy with the oxygen and release waste, which is carbon dioxide. Red blood cells are responsible for taking the carbon dioxide waste to the lungs when we exhale. 

The transportation of oxygen from the lungs to other parts of the body is made possible by haemoglobin, a protein produced by red blood cells, which gives the cells a bright red colour. Red blood cells are disc or doughnut-shaped, microscopic, and surrounded by a notch in the middle. Mature red blood cells do not have a nucleus.

What happens in Macrocytosis?

In macrocytosis, the size of red blood cells is larger than usual. The cells are in a nucleated form (erythroblast) which is not the mature form of red blood cells. Macrocytosis can or can not be associated with anaemia. Macrocytic anaemia is associated with a reduced haemoglobin. 

Macrocytic anaemia can be further differentiated into two types, megaloblastic and non-megaloblastic. Megaloblastic is the abnormality of the nucleated red blood cell (erythroblast) present in the bone marrow where the maturation of the nucleus is delayed in comparison to the cytoplasm. This condition results from defective DNA synthesis in the cell.

Characteristics of enlarged red blood cells

How is macrocytosis detected?

Usually, blood tests are done to rule out macrocytosis.⁴ The blood tests for detecting macrocytosis include:

• Complete blood count
• Reticulocyte count 
• Blood smear also known as peripheral smear
• Folate and vitamin B12 levels
• Methylmalonic acid levels 
• Homocysteine levels

The analysis of the blood smear confirms the condition of macrocytosis. The blood smear provides images of the shape and size of red blood cells. A high MVC (Mean corpuscular count) on complete blood count indicates macrocytosis. Other indicators for macrocytosis include:

• Platelets of unusual size and shape
• Neutropenia
• Thrombocytopenia
• Howell-Jolly bodies 
• Hypersegmentation of granulocytes

Several tests for confirming macrocytosis may be done if the person has a deficiency of vitamin B12 (Schilling test), liver and renal function, T4 levels tests and iron studies.

Genetic causes of Macrocytosis

Megaloblastic anaemia 

Megaloblastic anaemia is characterised by abnormally large, structurally unusual blood cells (megaloblasts) that do not function normally.⁵ A lack of healthy, fully mature red blood cells can lead to fatigue, pale skin, and dizziness. Megaloblastic anaemia has multiple causes including cobalamin (vitamin B12) or folic acid (vitamin B9) deficiency being the two most common causes.⁵ Dihydrofolate reductase deficiency is another rare cause resulting in megaloblastic anaemia. Vitamin B12 and vitamin B9 play important roles in the production of red blood cells.

Thalassemia

Thalassemia is a hereditary disease which affects the body’s ability to produce normal haemoglobin.⁶ Overall, haemoglobin protein production and production of red blood cells in the bone marrow is reduced. The condition in which there are few red blood cells in the body is called anaemia. As red blood cells play an important role in delivering oxygen to the body's tissues, not having enough red blood cells can deprive the body of the oxygen it requires to function properly.⁶

Myelodysplastic syndromes

Myelodysplastic syndromes are a group of conditions caused by abnormal or dysfunctional blood cells.⁷ Myelodysplastic syndromes are caused by a problem with the spongy substance in the bones where the blood cells are made, called the bone marrow. These syndromes occur when something hinders the process of blood cell maturation leaving the cells unmatured. The blood cells do not mature and die after entering the bloodstream or inside the bone marrow.⁷ Over a period of time, more immature cells are formed leading to fatigue, anaemia, leukopenia, and thrombocytopenia.

All the above-mentioned genetic causes can eventually lead to macrocytosis. 

Treatment and management 

How is macrocytosis treated?

The treatment for macrocytosis depends on its cause and whether the patient also has anaemia or not. Treatment might not be required if the condition is mild, with slightly enlarged red blood cells (MCV < 115) and the patient has no significant anaemia or other concerning symptoms. People drinking alcohol on a daily basis may need to stop alcohol consumption to help reduce the size of the red blood cells and improve any related anaemia within a span of a few months. Additionally, other changes in the bone marrow caused by alcohol can also be reversed.⁴

If there is significant anaemia or if the MCV is 115 or higher, more tests are needed to find the cause, which will guide the right treatment. Vitamin B12 can be taken orally if it can be absorbed properly, otherwise, it can be given by a monthly injection. Daily oral folic acid might also be prescribed. Medications causing the issue should be adjusted or stopped if needed.⁴

Summary

Macrocytosis is characterised by abnormally large red blood cells, and can indicate various health issues, including genetic conditions. This condition is often detected through blood tests and can be associated with symptoms like fatigue, weakness, and shortness of breath. Understanding the genetic influences behind macrocytosis is crucial for proper diagnosis and treatment.

Genetic factors play a significant role in macrocytosis. Key genetic causes include:

• Megaloblastic Anaemia: Caused by deficiencies in vitamin B12 or folic acid, leading to large, abnormal red blood cells
• Thalassemia: A hereditary disorder affecting haemoglobin production, resulting in fewer red blood cells and anaemia
• Myelodysplastic Syndromes: Conditions where blood cell maturation is impaired, leading to dysfunctional blood cells and potential macrocytosis

Treatment depends on the underlying cause. Mild cases may not require treatment, while significant anaemia or high MCV levels require further testing and specific interventions, such as vitamin supplementation or adjusting medications.