Macrocytic anaemia is a blood disorder characterised by the production of abnormally large and reduced numbers of red blood cells. This condition typically occurs when there is insufficient intake of vitamin B12 or when the body’s ability to absorb vitamin B12 is impaired.

Introduction

Macrocytic anaemia affects millions worldwide, characterised by abnormally large red blood cells and a decrease in the numbers of these cells. This is a result of impaired DNA synthesis, in which vitamin B12 plays a critical role. 

The prevalence of macrocytic anaemia in the UK is 4%. This condition can significantly impact a person’s health and needs to be promptly identified and treated.¹  

Overview of vitamin B12 

Vitamin B12, also known as cobalamin, is a water-soluble vitamin critical as a cofactor for many bodily functions, particularly in blood and nerve cell production. It is absorbed in the stomach and small intestine, so any gastric damage can impair its absorption.²

Vitamin B12 is primarily found in animal foods like meat, fish, dairy products, and eggs, with beef liver and oysters being particularly rich sources. Plant-based foods generally do not contain vitamin B12 unless fortified. While most people meet their vitamin B12 needs through diet or supplements, those with specific conditions may develop deficiency.³

Pathophysiology of macrocytosis

Mechanism of macrocytosis 

Erythropoiesis is the process by which red blood cells are produced. Normally, red blood cells are produced in the bone marrow and released into the bloodstream once they are fully mature and functional. However, when DNA synthesis is disrupted, the bone marrow starts to produce macrocytes, which are immature and oversized red blood cells. ⁶

Role of vitamin B12 in erythropoiesis 

Vitamin B12, in the form of methyl B12, is a must-have cofactor for the progress of DNA synthesis. Additionally, vitamin B12 is vital for methylation reactions, which are crucial for neurological function. Thus, a deficiency can have widespread effects beyond just blood cell production. ³

Causes of vitamin B12 deficiency

Dietary insufficiency 

Vegetarians face higher risks of Vitamin B12 deficiency because it's primarily found in animal products. About 50-60% of vegetarians develop this deficiency, which can take 10-20 years to reach critical levels. Pregnant assigned female at birth (AFAB)  on strict vegan diets can also affect the vitamin B12 level in their infants.⁴

Low intake of vitamin B12-rich food is an obvious cause of deficiency. Malnutrition has been shown as a predictor for all vitamin deficiency. Additionally, food insecurity is a major concern, as research shows that 89% of adults with food insecurity have vitamin B depletion.

Absorption issues 

Pernicious anaemia

Pernicious anaemia, a common malabsorption cause of B12 deficiency¹, is an autoimmune condition where the stomach lacks intrinsic factor, which is necessary for B12 absorption. 

Gastrointestinal disorders

Gastrointestinal diseases that damage the intestinal cell's surface can lead to vitamin B12 absorption issues. Gastric infections, Crohn’s disease, celiac disease, and inflammatory bowel disease, where the gastric cells are inherently abnormal, can result in malabsorption of vitamin B12.⁶

Bariatric surgery can decrease the ability to absorb vitamin B12. The vitamin B12 level will gradually reduce for 1-2 years after surgery until deficiency occurs.⁴

Impaired immune system

People diagnosed with HIV which progresses to AIDS often have low levels of vitamin B12, primarily due to vitamin B12 malabsorption.

Pancreatic insufficiency

Usually, the pancreas creates a transport protein for vitamin B12 ⁷. When this progress is ineffective, vitamin B12 deficiency occurs. 

Medication interference 

Certain medications can affect vitamin B12 absorption. Prolonged use of anti-inflammatory drugs such as metformin (to treat diabetes), or proton pump inhibitors (for acid reflux), can reduce B12 absorption over time. Oral contraceptive drugs can lead to mild deficiency.⁴

Genetic factors 

Infants and children with specific gene mutations might lack the ability to normally absorb, transport, or metabolise vitamin B12, leading to deficiency despite adequate dietary intake.

Clinical symptoms of vitamin B12 deficiency

Some people with vitamin B12 deficiency might not develop any symptoms, even anaemia.

Hematological symptoms 

Anaemia is common when vitamin B12 is insufficient. Nonspecific symptoms can occur such as tiredness, weakness, increased heart rate, shortness of breath or light headache. Jaundice may also occur due to the breakdown of red cell precursors in the bone marrow.⁶

Neurological symptoms

Peripheral neuropathy

The lack of vitamin B12 can impact the central nervous system. The main concern of this condition is the gradual impairment of the spinal cord. When this happens, people can experience the sensation of numbness, itching and burning on limbs, spasticity and impaired mobility if not treated timely.

Cognitive changes and dementia

Impaired cognition is a common consequence of vitamin B12 deficiency, particularly in the elderly. Symptoms may include somnolence (excessive sleepiness), irritability, changes in taste and smell, and impaired vision. 

Gastrointestinal symptoms 

Glossitis, which is defined as the inflammation of the tongue, is a common presentation of low vitamin B12.⁴ The underlying pathway is due to the cells within the tongue being sensitive to DNA synthesis progress.⁷

Diagnosis of macrocytosis due to vitamin B12 deficiency

There is no "gold standard" test to identify the condition. A range of tests are used. 

Laboratory tests

Full  blood count (FBC) and mean corpuscular volume (MCV) 

Normal blood tests are capable of recognizing macrocytosis. FBC can reveal the number and MCV can tell the abnormal size of the blood cells. Normally, red blood cells range in size from 80 to 100 femtoliters (fL). In individuals with macrocytosis, red blood cells are abnormally large, > 100 fL.¹

Serum vitamin B12 levels

In the UK, serum vitamin B12 levels are typically the first-line test for individuals presenting with macrocytosis. There is no optimal cut-off point to define the deficiency state and the decision should be carefully considered by general practitioners.⁴

Homocysteine and methylmalonic acid levels

Both plasma methylmalonic acid and homocysteine are considered second-line tests. While both methods can be useful in clarifying any uncertains, methylmalonic levels appear to be more specific. However, the availability of these tests in the UK is still limited. ⁴

Differential diagnosis 

In addition to Vitamin B12 deficiency, several factors can cause macrocytosis. Alcoholism is one of the most common causes, whether or not it is accompanied by anaemia. ¹ Folate deficiency is another factor, as this compound also joins the progression of DNA synthesis. Hence, a comprehensive medical history is required to fully diagnose.⁶

Management and treatment

Treatment should be promptly to prevent the development of symptoms.  

Vitamin B12 supplementation 

Oral vs. intramuscular administration

Both oral and intramuscular forms of Vitamin B12 supplementation are equally effective in treating vitamin B12 deficiency, according to research. The choice between them depends on individual preference. Both methods are safe with minimal risk of side effects.⁵

Dosage and duration

In the UK, vitamin B12 supplementation typically starts with 1000 μg administered intramuscularly three times a week for 2 weeks. For patients with neurological symptoms, treatment continues until improvement ceases. Afterwards, maintenance doses are given every 2 or 3 months, depending on the presence of neurological symptoms.

A low 50 μg oral dose of vitamin B12 is licensed in the UK, but its prescription for those with deficiency should be carefully managed by general practitioners to ensure adequate improvement in brain function.

Addressing underlying causes 

Dietary modifications

Patients should keep a food diary to assess their current diet. If a low intake of Vitamin B12-rich foods is identified, individuals should be educated on modifying their diets.

Treatment of gastrointestinal disorders

If a gastrointestinal problem is the cause of the deficiency, it should be prioritised for treatment. Patients should be closely monitored by healthcare practitioners.

Monitoring and follow-up 

After completing treatment, patients should strictly comply with maintenance dosage and dietary modification. If people succeed in compliance, no further tests are needed. Blood tests can be performed if people want to or any symptoms occur. Moreover, people should clearly understand their symptoms so that they can promptly see a general practitioner if they feel unwell.⁴

Prevention strategies

Education on dietary sources

The European Food Safety Authority recommends 4.0 μg/day of vitamin B12 for adults, and it is not difficult to meet this requirement. For instance, 80 grams of ground beef with 15% fat provides 100% of the daily recommended amount. One portion of breakfast cereal which is fortified with vitamin B12 can also provide 25% of daily value.³

Supplements

People who are at risk, such as pregnant assigned females at birth (AFAB),the elderly, vegan diets, those allergic to dairy products, those post-bariatric surgery or people with suspicious symptoms should attend diagnostic tests for vitamin B12 deficiency and add supplements daily. There are currently no upper limits of this vitamin and a high intake of vitamin B12 supplements can be considered as safe.

Summary

Vitamin B12 deficiency plays a significant role in the development of macrocytic anaemia, a condition that can severely impact health. Recognizing the signs and symptoms, understanding the underlying causes, and implementing effective treatment strategies are essential for managing this condition. Public health initiatives and individual efforts to maintain adequate B12 levels can help prevent deficiency and its associated complications.