Overview

Our blood has a complex setup that makes it very intriguing. With it varying from person to person, it is a complicated chain of networks that work together. In this article, we will tackle two cases that can affect our blood, known as macrocytosis and reticulocytosis.

So let us start off with an overview of each. What is macrocytosis? It is defined as mean corpus volume (MCV) that is 100fL or greater, which means the red blood cells (RBCs) are bigger than normal.^1,2 This condition can rise due to multiple causes and will be discussed below in the article.

Macrocytosis can be classified into either megaloblastic or non-megaloblastic, however because mechanisms of macrocytosis are not entirely known and understood, the distinction between the two can be artificial.¹ Patients that have macrocytosis without anaemia may not present any symptoms and in a lot of cases does not cause any significant clinical issues.³ When tackling macrocytosis, patients should be screened for anaemia symptoms such as fatigue, shortness of breath, dizziness/light-headedness, and fainting.³

Now moving to reticulocytosis, which is the production of ‘immature’ red blood cells; our bone marrow makes 200 billion reticulocytes every day, as they develop they decrease their plasma membrane by 20%, shedding out organelles that it does not require, and transform into mature red blood cells.⁴ This is a normal physiological function in our bodies, however, it can increase in some illnesses that will also be discussed in the sections below. Reticulocytes can be used to assess bone marrow activity, specially in response to anaemia.⁵

So, to further elaborate on the causes and diagnosis of the two conditions, the sections below will shed light on those areas.

Causes of macrocytosis

Macrocytosis can be classified into megaloblastic and non-megaloblastic, with the difference between the two processes being the presence of large oval RBCs and hyper segmented neutrophils in megaloblastic process and the absent in non-megaloblastic case.¹ Non-megaloblastic macrocytosis has round macrocytes or macro-reticulocytes instead.¹ Additionally, Megaloblastic macrocytosis deals with vitamin B12 and folate deficiencies.¹

Table 2 will include a summary of the differential diagnosis of macrocytosis.

Table 2. Differential diagnosis of macrocytosis.¹

Specific causes of macrocytosis

Vitamin deficiency:

• Vitamin B12: this deficiency can be related to prolonged vegan diets as this vitamin is found in animal products like dairy, eggs, and red meats.^{3, 6} The absorption of this vitamin relies on normal stomach and small intestine functions; intrinsic factors in the stomach and intestines are required to absorb vitamin B12.³ If there is an interference with these intrinsic factors (e.g. immune interference) then the absorption of B12 will be hindered.³ Other causes that can affect its absorption include pernicious anaemia, coeliac disease, inflammatory bowel disease, gastritis, or a complication from gastrointestinal surgeries.³ It can also rise as an adverse reaction to medicines (e.g. proton pump inhibitors, metformin), or as an effect of nitrous oxide abuse.³
• Folate (Vitamin B9): this deficiency can be either from a diet or due to a gastrointestinal absorption issue as folate is reliant on small intestine health/function; dietary deficiency is more common in cases that involve alcoholism or the elderly.³ Vitamin B9 absorption can be affected by coeliac disease, inflammatory bowel disease, or medications (HIV medication like methotrexate).³ Low intake of folate can lead to deficiency, along with conditions that require more intake like pregnancy or chronic haemolysis.³ Also, ethanol can hinder the absorption of folate, as well as its metabolism.³

HIV medications

These medications (e.g. methotrexate, phenytoin) can lead to macrocytosis because they will interfere with DNA production, leading to megaloblastic changes.¹

Bone marrow disorder or dysfunction

Myeloproliferative disorders, also known as refractory anaemia, can be a common cause for macrocytosis and anaemia (more so in elderly than young patients).¹

Alcohol abuse

Alcoholism can affect our blood and cause macrocytosis, primarily through its toxic effects, and secondary through folate deficiency.¹ Abstinence from alcohol quickly fixes the MCV back to normal levels.¹

Hypothyroidism

Hypothyroidism refers to decreased production of thyroid hormones.⁷ These hormones are important in the production of erythropoietin, which is important for blood production.⁷ In hypothyroidism erythropoietin is decreased, leading to anaemia, which in turn can lead to macrocytosis. ⁷

Reticulocytosis

Reticulocytosis can lead to direct increase in MCV as reticulocytes are larger than mature blood cells, hence causing macrocytosis.³ People who do distance running have shown macrocytosis (although rare) through constant foot pounding that caused haemolysis.¹  

Causes of reticulocytosis

Causes of reticulocytosis can be due to:

Haemolysis

Haemolytic anaemia: this process causes the premature destruction of RBCs, which can either be due to antibodies or non-immune break down.⁸ If the cause is due to the person’s antibodies, then this classifies it as autoimmune haemolytic anaemia (AIHA).⁸ Once there is loss of RBCs, the bone marrow will respond to this anaemia and start the production of reticulocytes, hence leading to reticulocytosis and macrocytosis.⁸

Haemorrhage

Acute and chronic blood loss: blood loss can lead to the loss of RBCs, which sometimes can lead to anaemia and other complications.⁹ This prompts the bone marrow to pump up the reticulocyte production.

Reaction to treatment

• Iron supplements: in cases of anaemia, the iron supply will be lower as it’s required for multiple processes (e.g. bone marrow erythropoiesis).⁹ Sometimes iron deficiency can be due to surgery.⁹ Simple iron supplements can give the body the boost it requires to start reticulocytosis.⁹
• Vitamin B12 or B9 supplements: vitamin B12 or folate deficiencies can affect reticulocyte count as in these deficiencies there is a reduced blood cell production.¹⁰ Once the supplements are administered, reticulocyte count shows an increase as haematopoiesis improves.¹⁰

Hypoxia

Hypoxia refers to the low levels of oxygen in the tissues, where this insufficient level can affect homeostasis.¹¹ Once this occurs, the kidneys will sense this decrease and stimulate the body to produce more blood cells, and as a result reticulocytosis.¹² This can occur in chronic obstructive pulmonary disease (COPD) or as an adaptation to high altitude.^{13, 14}

Diagnosis

If macrocytosis or reticulocytosis are suspected, there are multiple tests done to assess the case:

• Blood tests: these include complete blood count, reticulocyte count, and peripheral blood smears to assess the condition of the patient’s blood.³ In some cases, bone marrow aspiration/biopsy would be required for further evaluation (e.g. malignancies)³
• Differential diagnosis: to further identify the cause of reticulocytosis or macrocytosis, more specific tests are required - for example, correlating patient history with the clinical symptoms, performing more specific tests like testing vitamin B12 and B9 levels, thyroid hormones, liver and kidney function tests³

Treatment and therapy

The first approach to treatment of macrocytosis and reticulocytosis would be treating the underlying illness/disease. For mild cases of macrocytosis, described as MCV < 115fL with no significant symptoms or presence of anaemia, no treatment is required.³ In case of alcohol abuse, abstinence from alcohol can resolve the issue.³ Vitamin supplements can also be a treatment in case of deficiencies.³ In some cases, blood transfusions might be required as it can help people who have hypoxia and anaemia symptoms.¹⁵

Furthermore, after sorting the underlying cause of disease, it is important to have regular monitoring and follow-up by your healthcare provider to make sure treatment is being effective. Additionally, regular blood tests and monitoring response to treatment is important to make appropriate adjustments to each patient and look for any complications or side effects of treatment.

Summary

Our health can impact our bodies in different ways, one of them being our blood cells. In this article, we discussed macrocytosis (production of enlarged RBCs) and reticulocytosis (production of immature RBCs). While macrocytosis and reticulocytosis are not severe conditions, they can lead to serious medical conditions if the underlying cause is not treated. It is important to understand macrocytosis and reticulocytosis, their cause and diagnose them appropriately along with their associated illness. Sometimes the treatment can be as simple as taking a vitamin supplement, and sometimes it might require more intrusive treatment like blood transfusions.