QuestionSBA
QuestionChoice
Alcoholism is a cause of macrocytosis. It can also be associated with alcoholic neuropathy. However, this patient reports only drinking four units a week, which is within the recommended weekly intake for alcohol. Patients are not always honest about their alcohol intake, but given their history of autoimmune disease and current neurological signs, vitamin B12 deficiency secondary to pernicious anaemia is the more likely diagnosis
33685
c
Alcoholism
QuestionChoice
Hypothyroidism can cause macrocytosis. This patient has hypothyroidism; however, their thyroid function tests are normal. As their thyroid disease is well controlled, it is unlikely that this is causing their macrocytosis. In addition, autoimmune hypothyroidism (the most common cause of hypothyroidism in the UK) is associated with other autoimmune diseases, including pernicious anaemia. Hypothyroidism is unlikely to cause this patient's neurological signs
33684
b
Hypothyroidism
QuestionChoice
Pernicious anaemia is an autoimmune condition with antibodies targeting intrinsic factor and/or gastric parietal cells. Intrinsic factor is a cofactor produced by gastric parietal cells essential for the absorption of vitamin B12 in the terminal ileum. Therefore, pernicious anaemia can cause a vitamin B12 deficiency. This presents as a macrocytic anaemia with other signs of anaemia, including tiredness and pallor. In addition, B12 deficiency can cause neurological symptoms including paraesthesia, weakness and acute degeneration of the cord in severe cases. As pernicious anaemia is an autoimmune condition, it is associated with other autoimmune disorders, including type 1 diabetes and autoimmune thyroid disorders
33683
a
Pernicious anaemia
QuestionChoice
Type 1 diabetes is associated with diabetic neuropathy and can cause tiredness when the patient is hyperglycemic. However, this patient's type 1 diabetes is well controlled (HbA1c <48 mmol/mol), and this would not explain the macrocytosis in his blood results. Therefore, vitamin B12 deficiency secondary to pernicious anaemia is the more likely diagnosis
33687
e
Diabetic neuropathy
QuestionChoice
Iron deficiency anaemia presents with a microcytic anaemia. This patient has a macrocytic anaemia, making iron deficiency anaemia less likely
33686
d
Iron deficiency anaemia
Concept
Chapter
# Summary

Pernicious anaemia is a type of megaloblastic anaemia primarily caused by the inability to absorb vitamin B12, essential for red blood cell production, due to autoimmune destruction of the gastric parietal cells. This disorder can lead to a variety of symptoms, including fatigue, pallor, and neurological deficits. Diagnosis often involves blood tests revealing abnormal red blood cells and low levels of vitamin B12. Management primarily involves life-long replacement treatment with cobalamin as well as monitoring for potential complications such as gastric cancer and carcinoids.

# Definition

Pernicious anaemia is a deficiency in RBCs caused by lack of vitamin B<sub>12</sub> in the blood

In the strictest sense, it is caused by autoimmune impairment of intrinsic factor production

The term is also widely used to describe B<sub>12</sub> deficiency-related anaemia secondary to other causes as well.

# Pathophysiology

The pathophysiology of pernicious anaemia primarily revolves around the autoimmune destruction of gastric parietal cells, which play a central role in the absorption of vitamin B12. This complex process involves several key factors:

1. **Autoimmune Attack:** In pernicious anaemia, the body's immune system mistakenly targets and destroys gastric parietal cells. These cells are responsible for producing intrinsic factor, a protein necessary for vitamin B12 absorption.

2. **Intrinsic Factor Deficiency:** As a result of autoimmune destruction, intrinsic factor levels decrease, leading to impaired vitamin B12 absorption in the ileum, the final part of the small intestine.

3. **Vitamin B12 Deficiency:** Reduced absorption of vitamin B12 results in a deficiency of this essential nutrient. Vitamin B12 is crucial for erythropoiesis (the formation of red blood cells) and the maintenance of the nervous system.

4. **Megaloblastic Changes:** Vitamin B12 deficiency leads to impaired DNA synthesis in developing blood cells. This results in megaloblastic changes, causing larger, structurally abnormal red blood cells (megaloblasts) in the bone marrow. These larger cells are less effective at carrying oxygen, leading to anaemia.


6. **Haemolysis:** Pernicious anaemia can lead to haemolysis (the breakdown of red blood cells) due to their structural abnormalities. .


# Epidemiology

Pernicious anaemia is more common in individuals of Northern European, Scandinavian, and African descent, typically affecting adults aged 60 or older. It is often associated with other autoimmune conditions, such as autoimmune thyroid diseases and type 1 diabetes. The prevalence of pernicious anaemia may be underestimated due to underdiagnosis.

# Aetiology

Pernicious anaemia is primarily autoimmune in nature, with the destruction of gastric parietal cells leading to a lack of intrinsic factor. Contributing factors may include genetics, as pernicious anaemia can run in families. Other autoimmune conditions are often comorbid with this disorder.

# Signs and Symptoms

* Fatigue
* Pallor
* Glossitis - inflammation of the tongue, leading to a smooth, beefy-red appearance.
* Neurological Symptoms and subacute combined degeneration of the cord: Pernicious anaemia may cause neuropathy, affecting balance, sensation, and coordination.
* Jaundice - due to haemolysis
* Cognitive Impairment - memory problems, confusion, and mood changes may occur

# Differential Diagnosis

* **Iron-Deficiency Anaemia (IDA):** Both conditions can lead to anaemia, but IDA is characterised by low ferritin levels and microcytic RBCs, whereas pernicious anaemia causes megaloblastic changes.
* **Folate Deficiency Anaemia:** Like pernicious anaemia, folate deficiency leads to megaloblastic anaemia, but serum levels of vitamin B12 and folate help differentiate the two.
* **Myelodysplastic Syndromes (MDS):** MDS can mimic the clinical and laboratory findings of pernicious anaemia but often occurs in older adults and involves specific bone marrow abnormalities.


# Investigations

* Full Blood Count (FBC): Reveals macrocytic anaemia and may show hypersegmented neutrophils.
	- Low haemoglobin level
	- High MCV
	- High mean corpuscular haemoglobin (MCH)
	- Normal mean corpuscular haemoglobin concentration (MCHC)
	- Low reticulocyte count
- Blood smear - abnormally large and oval-shaped RBCs 
* Vitamin B12 Assays: Measure serum vitamin B12 levels, which are typically low in pernicious anaemia.
* Intrinsic Factor Antibodies: These antibodies help confirm the autoimmune nature of the condition. This test is highly specific.
* Parietal cell Antibodies: This test is highly sensitive.
* Bone Marrow Aspiration and Biopsy: May show megaloblastic changes in erythropoiesis.


Pernicious anaemia is associated with atrophic body gastritis – diagnostic criteria are based on histologic evidence of gastric body atrophy associated with hypochlorhydria.

**Note**: 'active' vitamin B<sub>12</sub> or holotranscobalamin is a more sensitive measure of vitamin B<sub>12</sub> deficiency – total vitamin B<sub>12</sub> is mostly bound to carrier proteins.


# Management

Management of patients with pernicious anaemia is **lifelong replacement** by **quarterly treatment with hydroxycobalamin** and close monitoring to ensure early diagnosis of any subsequently unmasked iron deficiency. Folate replacement is also often necessary.


# Complications

Patients should be advised about possible long-term gastrointestinal consequences, such as gastric cancer and carcinoid.

Vitamin B<sub>12</sub> is required for the nervous system so, in vitamin B<sub>12</sub> deficiency, always consider: 

- Peripheral neuropathy
- Subacute combined degeneration of the cord
- Optic atrophy 
- Dementia

Vitamin B<sub>12</sub> deficiency can be associated with other autoimmune disorders such as hypothyroidism and vitiligo.

# NICE Guidelines

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


753
2399
Pernicious anaemia
Topic
8
Haematology
6737
A 33 year old patient presents to the GP with a four-month history tiredness and a one-month history of pins and needles in their legs. They have a past medical history of type 1 diabetes and hypothyroidism. They drink 6 units of alcohol per week. Their blood results are shown below:


||||
|--------------|:-------:|---------------|
|Haemoglobin|105  g/L|(M) 130 - 170, (F) 115 - 155|
|White Cell Count|7x10<sup>9</sup>/L|3.0 - 10.0|
|Platelets|303x10<sup>9</sup>/L|150 - 400|
|Mean Cell Volume (MCV)|105 fL|80 - 96|
|HbA1c (Glycated Haemoglobin)|47 mmol/mol|20 - 42 or 4-6%|
|Thyroid Stimulating Hormone|3.6 mU/L|0.3 - 4.2|
|Free T4|14 pmol/L|9 - 25|


Which of the following is the most likely cause of this patient's blood results?
a