Pay attention to what your red blood cells want to tell you: Macrocytosis and its importance as an indicator of serious health problems.

Overview

Macrocytosis refers to when the erythrocytes, commonly known as red blood cells, are larger than normal. It is a sign of an underlying health condition like for example Vitamin B12 deficiency, liver disease, alcoholism etc.¹

That's why prognostic research is of vital importance in this case, as it provides essential information for understanding, predicting and improving future clinical outcomes in those people who might have a specific health condition.²

Aetiology of macrocytosis

Although Macrocytosis isn't a specific disease, this condition is usually produced by an abnormal red blood cell production development, abnormal red blood cell membrane composition, increased reticulocyte count, or a combination of these 3 factors.¹

Common causes of macrocytosis

Vitamin B12 and Folate Deficiency

Vitamin B12 and B9 (commonly called folate) deficiency is a type of anaemia that occurs when there is a lack of vitamin B12 or folate, causing macrocytosis.

What do macrocytosis and Vitamin B-12, B9 deficiency have in common?

Red blood cells are responsible for carrying oxygen throughout the body through a substance called haemoglobin. Anaemia causes a reduction of haemoglobin in each red blood cell. As a consequence, people who suffer from this condition experience certain symptoms such as extreme tiredness, sore and red tongue, mouth ulcers, problems with vision, and even psychological problems, which can range from mild depression or anxiety to confusion and dementia.³

Alcoholism

While it is true that not every alcoholic person suffers from macrocytic anaemia, the statistics are much higher than for a person without an alcohol use disorder. Alcoholism is generally associated with vital vitamin deficiencies and malnutrition, which are directly linked to macrocytic anaemia.⁴

Liver disease

Vitamin B12 and folate are essential for the synthesis of thymidylate and purines, which are basic components in DNA synthesis. Without them, DNA synthesis becomes defective, impairing cells from dividing correctly and thereby altering their size. This can affect liver function and can lead to macrocytosis.^5,6

Hypothyroidism

This condition involves reduced production of thyroid hormone. Thyroid hormone stimulates the production of erythrocyte precursors through erythropoietin, which affects the formation of blood cells. As a result, red blood cell production and their shape are affected, leading to anaemia.⁷

Medications 

Multiple medications can lead to macrocytosis. The most well-known are chemotherapy drugs used in cancer treatment, Zidovudine for antiretroviral therapy (ART) in treating HIV, and hydroxyurea for sickle cell disease.^8,9

Other causes are also important to pay attention to other causes, which include:

Bone marrow disorders

When there are disorders in the bone marrow, a large number of reticulocytes are released into the peripheral circulation, causing macrocytosis.¹⁰

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a rare type of blood cell cancer.¹¹

Macrocytosis is associated with Myelodysplastic Syndrome (MDS), due to two main causes: dyserythropoiesis (abnormal production of red blood cells in the bone marrow) and a reduced number of mitotic divisions during the maturation process of early erythroid cells. As a result, the red blood cells produced in the bone marrow will be larger than normal due to issues in their maturation and cell division processes.¹²

Aplastic anaemia

Aplastic anaemia is a rare condition that consists of a bone marrow failure syndrome characterized by the inability to produce enough mature blood cells to make the bodywork. Although this type of anaemia is typically normocytic, it can also lead to macrocytosis in association with stress erythropoiesis and elevated levels of fetal haemoglobin.¹³

Diagnostic evaluation

Males are more commonly affected by this condition and both macrocytosis and macrocytic anaemia are associated as the age advances.

First test 

Diagnostic evaluation should start by performing a peripheral blood smear and a Complete Blood Count (CBC). In some laboratories, reticulocyte indices are also performed to assess how the bone marrow is responding. These initial steps help to better understand the cause of the macrocytosis and guide appropriate treatment.¹⁰

Complete blood count (CBC)

It is a blood test that measures the quantities and sizes of all the different types of blood cells. It is important to highlight that MCV (mean corpuscular volume) is part of this test and measures the average size of your red blood cells. 

Peripheral blood smear (PBS)

This is a blood test similar to a CBC. The main difference is that the results are analyzed under a microscope instead of by a machine. It is commonly used to confirm the results of CBC.¹

Reticulocyte count

This method measures the number of immature red blood cells (reticulocytes) in your bone marrow. This method checks if your bone marrow is producing enough healthy red blood cells.¹⁴

Follow-up tests

• Vitamin B12 and Folate Levels
• Liver Function Tests
• Thyroid Function Tests

TSH (thyroid-stimulating hormone) test: These tests focus on measuring the levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) in the blood. A high TSH level and a low T4 level in the blood mean an underactive thyroid.¹⁵

Triiodothyronine (T3) test: The level of a hormone called triiodothyronine (T3) is also checked, although this is not often offered.¹⁵

Bone marrow biopsy (if indicated): They are performed with local anaesthesia at the top of the pelvic bone. A thick needle is used to extract a small amount of bone marrow tissue, and the size and quality of the red blood cells are analyzed. This method is most commonly used in diseases such as leukaemia.¹⁶

Clinical manifestations

Macrocytosis without anaemia is unlikely to show specific signs or symptoms and it is frequently detected accidentally during routine blood tests. Patients should be evaluated for signs of anaemia, including fatigue, generalized weakness, dyspnea, palpitations, lightheadedness, and syncopal or near-syncopal events.^1,17

Neurological symptoms can also be common. They are generally associated with a lack of vitamin B12 and often cause vision problems, memory loss, pins and needles, loss of physical coordination (ataxia), and damage to parts of the nervous system (peripheral neuropathy), particularly in the legs.³

Prognostic implications

The prognosis for people who have underlying conditions depends on the level of the underlying condition and their specific situation. Addressing the underlying cause is important and it can reverse macrocytosis.¹⁵

Nevertheless, individuals with macrocytic anaemia and concurrent chronic renal failure have the poorest survival rates (40% at 5 years), with nutritional deficiencies also contributing to these outcomes which are also associated with poor survival (52%). Macrocytosis related to alcohol can usually be reversed within several months after alcohol cessation, as long as there is no significant anaemia or liver disease. Survival rates are higher when this condition is due to multiple causes (such as medications) rather than a single cause. This is basically because, in general, when it is caused by a single factor, the severity of that cause tends to be greater.^1,18

Management strategies

Monitoring and follow-up

Management of macrocytosis depends on the condition's causes and state, whether anaemia has developed or not. If the macrocytosis has MCV < 115 without significant anaemia and no concerning features, it does not need any treatment. 

When significant anaemia is present or the MCV is 115 or greater, more investigation should be done to detect the main cause and develop an effective strategy. Unless a reversible cause is identified, patients will need to adjust to long-term therapy. The relapse of macrocytic anaemia occurs approximately 65 months after cessation of treatment if it has not been completed.^10,19

Treatment approaches for underlying causes

The most popular therapies for treating vitamin B12 deficiency are oral therapy and intramuscular therapy and may include diet modification and dietary supplements or injections. In case of folate deficit, daily oral folic acid may be prescribed.^10,17,19

To address an alcohol use disorder, the primary solution is to seek professional help to prevent a return to drinking. Behavioural therapies can help people develop skills to avoid and overcome triggers, such as stress.²⁰

An underactive thyroid (hypothyroidism) is usually treated by taking daily hormone replacement tablets called levothyroxine.^7,21

Liver damage is very difficult to reverse but healthy lifestyle changes can help with some types of liver disease. The goal of the treatment focuses on slowing down the buildup of scar tissue and preventing or treating any resulting problems. If the situation worsens(cirrhosis), you may need a liver transplant. ^18,22

FAQs

How can I reduce my risk of having macrocytosis?

Even so, it is very unlikely to prevent all causes of macrocytosis. However, healthy habits can greatly reduce the risk. For example, eating foods rich in vitamin B12 and folate and limiting your alcohol consumption can reduce your risk of macrocytic anaemia.

Also, it is important to perform annual blood tests. Macrocytosis is usually an incidental finding on routine blood work. Early diagnosis and treatment can often stop a condition from becoming more severe.⁸

What foods are rich in vitamin B12 and folate?

The best sources of vitamin B12 are:

• Meat, salmon, cod, milk, cheese, eggs, some fortified breakfast cereals
• Adults need approximately 0.0015mg a day of vitamin B12²³

The best sources of folic acid are:

• Broccoli, brussels sprouts, liver, spinach, asparagus, peas, chickpeas, brown rice, fortified, breakfast, cereals
• Adults need 0.2mg of folic acid a day²³

Is macrocytosis hereditary?

Benign familial macrocytosis is an inherited syndrome in which patients have mild asymptomatic macrocytosis. Furthermore, persons with Down syndrome have a higher chance of developing macrocytosis.²⁴

Summary

Macrocytosis is a condition caused by the enlargement of red blood cells. It rarely presents symptoms and is usually associated with underlying health conditions. Common causes include nutritional deficiencies, alcoholism, liver disease, hypothyroidism, and certain medications. Less common causes involve bone marrow disorders and myelodysplastic syndromes.

Diagnosis starts with blood tests like CBC and peripheral blood smear, followed by tests for vitamin levels, liver and thyroid function, and possibly a bone marrow biopsy.

Prognosis varies with the underlying condition, with better outcomes when the cause is addressed. Management will include treating the underlying cause, such as vitamin supplementation or professional help for alcohol use disorders. Regular monitoring and follow-up are essential for effective management.