QuestionSBA
QuestionChoice
The iron panel is not suggestive of iron deficiency anaemia
32026
d
Iron deficiency anaemia
QuestionChoice
The patient has macrocytic anaemia and is taking methotrexate without regular folate. Methotrexate therapy is a common cause of macrocytic anaemia due to folate deficiency
32023
a
Methotrexate
QuestionChoice
This is a rare cause of anaemia in rheumatoid arthritis. This is unlikely as reticulocyte count is not raised
32027
e
Autoimmune haemolytic anaemia
QuestionChoice
This is a common cause of anaemia in rheumatoid arthritis patients. This would typically present as normochromic normocytic anaemia
32024
b
Anaemia of chronic disease
QuestionChoice
Felty's syndrome is characterised by the triad of rheumatoid arthritis, neutropenia, and splenomegaly. The neutrophils are normal in this case
32025
c
Felty's syndrome
Concept
Chapter
# Summary 

Macrocytic anaemia is a type of anaemia characterized by the presence of larger-than-normal red blood cells (RBCs). It can be classified into megaloblastic and non-megaloblastic types. Megaloblastic anemia is primarily associated with impaired DNA synthesis, often due to deficiencies in vitamin B12 or folate, leading to the enlargement of RBC precursors and hypersegmented neutrophils on blood film. Non-megaloblastic macrocytic anaemia can be caused by various factors, and sometimes a patient may present with non-megaloblastic macrocytosis, without anaemia such as in pregnancy. Key investigations include FBC, blood film and measurement of specific vitamins such as folate and B12, and management centres on the underlying cause of the anaemia. For example, vitamin supplementation in B12/folate deficiency.


# Definition

Macrocytic anaemia refers to a condition in which red blood cells are larger than normal. It can be further classified into two main categories: megaloblastic and non-megaloblastic. Megaloblastic macrocytic anaemia is characterized by slow or impaired DNA synthesis, leading to delayed maturation of RBCs and, notably, hypersegmented neutrophils on blood film. Non-megaloblastic macrocytic anaemia may manifest as macrocytosis without the presence of anaemia.



# Epidemiology 

The epidemiology of macrocytic anaemia varies depending on the underlying cause. Megaloblastic macrocytic anaemia is often associated with vitamin B12 or folate deficiencies and is more prevalent in older adults. Non-megaloblastic macrocytic anaemia, on the other hand, can occur at any age and may be linked to factors such as alcohol consumption or pregnancy.


# Classification

Morphologically, macrocytic anaemia is usually typified by large RBCs due to abnormal RBC development, giant metamyelocytes and hypersegmented neutrophils (in the peripheral circulation). Macrocytic anaemia may be megaloblastic or non-megaloblastic.

## Causes of megaloblastic anaemia 

* **B<sub>12</sub> deficiency** 
    * reduced intake (eg. dietary) 
    * reduced absorption (eg. pernicious anaemia, inflammatory bowel disease, gastrectomy)
* **Folate deficiency**
* Drugs
    * hydroxycarbamide (previously called hydroxyurea)
    * azathioprine
    * cytosine arabinoside
    * azidothymidine


## Causes of non-megaloblastic/normoblastic macrocytic anaemia

* Liver disease
* Alcohol 
* Hypothyroidism
* Myelodysplastic syndrome
* Hypothyroidism
* Pregnancy (usually a mild macrocytosis)


# Signs and Symptoms 

- Fatigue and Weakness
- Pallor
- Shortness of Breath
- **Glossitis and "Beefy Tongue":** A distinctive sign of megaloblastic anaemia, glossitis, is the inflammation of the tongue, giving it a swollen and reddened appearance, often referred to as a "beefy tongue."
- **Neurological Symptoms:** Severe vitamin B12 deficiency can affect the nervous system, leading to neurological symptoms such as paresthesias (tingling and numbness), ataxia (impaired coordination), and cognitive impairment.
- Symptoms of associated conditions:
	- **Autoimmune Conditions:** Megaloblastic anemia, particularly pernicious anemia, is associated with autoimmune conditions such as autoimmune thyroid disease, type 1 diabetes, and autoimmune gastritis. Therefore, patients may present with features of these conditions.
	- **Hypothyroidism Symptoms:** In cases where megaloblastic anaemia is secondary to hypothyroidism, patients may exhibit classic hypothyroidism symptoms like fatigue, weight gain, cold intolerance, and changes in skin and hair.

# Differential Diagnosis


- **Megaloblastic Anaemia (Vitamin B12 or Folate Deficiency):** The primary differential diagnosis within the realm of macrocytic anaemia is megaloblastic anaemia, specifically caused by vitamin B12 or folate deficiency. Careful evaluation of vitamin levels, clinical symptoms, and peripheral blood smears can aid in the distinction.

- **Non-Megaloblastic Macrocytic Anaemia:** Macrocytosis, without the typical features of megaloblastic anemia, may result from various non-megaloblastic causes, including alcohol consumption, liver disease, or pregnancy. These cases may present as isolated macrocytosis without the broader clinical picture of anaemia.

- **Haemolysis:** Haemolytic anaemias, both inherited and acquired, can lead to an increase in reticulocyte count and macrocytosis, albeit for different reasons. Evaluating markers of haemolysis, such as elevated bilirubin levels or increased lactate dehydrogenase, can assist in distinguishing haemolytic anaemias from megaloblastic anaemias.

- **Liver Disease:** Patients with liver disease, particularly alcohol-related liver disease, can exhibit macrocytosis. Evaluation of liver function tests and consideration of underlying liver pathology is necessary in such cases.

- **Medications:** Certain medications, such as antiretroviral drugs and chemotherapy agents, can cause macrocytosis. A thorough medication history is important in identifying potential drug-induced macrocytosis.

- **Bone Marrow Disorders:** In rare cases, macrocytic anaemia can be associated with underlying bone marrow disorders, including myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs). A bone marrow biopsy may be warranted to evaluate these conditions.



# Investigations 

*  Investigations all patients should have include:
	* Full Blood Count (FBC): This reveals anaemia and macrocytosis. The presence of hypersegmented neutrophils in the blood film is characteristic of megaloblastic anemia.
	* Haematinics: Serum vitamin B12 and folate levels should be assessed to identify deficiencies.
	* Blood Film: A peripheral blood smear can show macrocytosis and the presence of hypersegmented neutrophils.
* Specific tests to investigate for underlying causes include:
	* TFTs to look for hypothyroidism
	* LFTs to assess liver function
	* Antibodies to intrinsic factor +/- gastric parietal cells, seen in pernicious anaemia
	* Markers of haemolysis - bilirubin, DAT testing, LDH

# Management

* **Megaloblastic Anaemia:**  In pernicious anemia, intramuscular hydroxocobalamin is typically administered to replace vitamin B12. 
* It is important to address vitamin B12 deficiency before folate replacement (if both are deficient) to avoid exacerbating neurological symptoms and precipitating subacute degeneration of the spinal cord (SACD). 
* In cases of folate deficiency, oral folate supplements are provided.
* **Non-Megaloblastic Anaemia:** The management of non-megaloblastic macrocytic anemia depends on the underlying cause, such as addressing alcohol consumption or providing support during pregnancy.

# NICE Guidelines

[NICE CKS - B12/Folate-deficiency anaemia](https://cks.nice.org.uk/topics/anaemia-b12-folate-deficiency/)




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Haematology
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Macrocytic Anaemia
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Macrocytosis
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Methotrexate can cause macrocytic anaemia due to folate deficiency, particularly in patients not receiving regular folate supplementation.
A 70 year old lady is admitted with an acute polyarthritic flare of her hands and knees. She has a past medical history of rheumatoid arthritis and migraines. Her regular medications include methotrexate, prednisolone and ibuprofen.


Bloods on admission are as follows:


||||
|--------------|:-------:|---------------|
|Haemoglobin|101 g/L|(M) 130 - 170, (F) 115 - 155|
|Platelets|400x10<sup>9</sup>/L|150 - 400|
|Mean Cell Volume (MCV)|108 fL|80 - 96|
|Ferritin|170 μg/L|12 - 200|
|Iron|20 μmol/L|(M) 14 - 31, (F) 11 - 30|
|Transferrin saturation|28 %|(M) 16 - 50 (F) 16 - 40|


 - White cell count and neutrophils normal
 - Reticulocyte count normal


What is the most likely cause of her anaemia?
a