Macrocytic Anaemia

Question 1

… anaemia describes the presence of a reduced haemoglobin concentration and an increase in the mean corpuscular volume (MCV).

Answer 1

Macrocytic anaemia describes the presence of a reduced haemoglobin concentration and an increase in the mean corpuscular volume (MCV).

Question 2

Normal RBC haemoglobin concentration for males is approximately 130-175 g/L and for females approximately 120-155 g/L. A haemoglobin (Hb) concentration below this levels is considered to be anaemic.

Answer 2

Normal RBC haemoglobin concentration for males is approximately 130-175 g/L and for females approximately 120-155 g/L. A haemoglobin (Hb) concentration below this levels is considered to be anaemic.

Question 3

The MCV describes the mean volume of erythrocytes and is measured in femtolitres (fL). The standard range for erythrocytes is …

Answer 3

The MCV describes the mean volume of erythrocytes and is measured in femtolitres (fL). The standard range for erythrocytes is 82-99 fL. Levels > 99 fL are considered macrocytic.

There are numerous causes of a macrocytic anaemia. These can be divided into the megaloblastic (which include B12 and folate deficiency) and non-megaloblastic anaemias (which include a wide range of pathologies).

Question 4

There are numerous causes of a macrocytic anaemia. These can be divided into the megaloblastic and non-megaloblastic anaemias

Answer 4

Question 5

Symptoms -macrocytic anaemia

Answer 5

Fatigue
Weakness
Paraesthesia
Dyspnoea
Gastrointestinal symptoms (e.g. nausea, dyspepsia)
Weight loss

Question 6

Signs of macrocytic anaemia

Answer 6

Atrophic glossitis
Pallor
Fever
Splenomegaly
Evidence of underlying disease

Question 7

Megaloblasts are immature red cells with large nuclei seen in …

Answer 7

Megaloblasts are immature red cells with large nuclei seen in B12 & folate deficiency.

Question 8

Vitamin B12 deficiency

Answer 8

Vitamin B12 (cobalamin) is found in meats and diary products. It is an essential vitamin for DNA synthesis in cells undergoing rapid proliferation.

Question 9

Epidemiology

Vitamin B12 deficiency

Answer 9

Epidemiology

Vitamin B12 is predominantly found in meat and dairy products (due to bacterial synthesis) and is not present in plants. Thus, dietary deficiency is uncommon and typically seen only in strict vegans.

The overall burden of vitamin B12 deficiency increases with age but is less common than folate deficiency. Unlike folate, vitamin B12 stores last for years before deficiency develops.

Question 10

Absorption of vitamin B12 is a complex process; it is aided by a key glycoprotein, i…

Answer 10

Absorption of vitamin B12 is a complex process; it is aided by a key glycoprotein, intrinsic factor (IF).

Question 11

Parietal cells, found in the gastric epithelium, secrete IF. IF binds to vitamin B12 within the intestines. The subsequent vitamin B12-IF complex binds to receptors within the terminal ileum where it is absorbed.

Causes of vitamin B12 deficiency include:

Answer 11

Inadequate intake (e.g. strict vegetarians, vegans)
Inadequate secretion of intrinsic factor (e.g. pernicious anaemia, gastrectomy)
Malabsorption (e.g. Crohn’s, tropical sprue)
Inadequate release of B12 from food (e.g. gastritis, alcohol abuse)

Question 12

Vitamin B12 deficiency is most commonly due to …

Answer 12

Vitamin B12 deficiency is most commonly due to pernicious anaemia (PA).

Question 13

Blood film vit B12 deficiency

Answer 13

Blood film reveals a megaloblastic anaemia +/- hypersegmented neutrophils.

Question 14

Investigations

Vitamin B12 deficiency

Answer 14

Investigations help demonstrate the reduction in vitamin B12 and the development of anaemia. These include full blood count (FBC), blood film, haematinics, lactate dehydrogenase​ (LDH) and liver function tests (LFTs).

Blood tests usually reveal profoundly macrocytic anaemia with a raised MCV. Bilirubin and LDH may be slightly elevated - indicating increased turnover of abnormal progenitors in the bone marrow. If a bone marrow aspirate is taken, megaloblastic erythropoiesis, marked erythroid hyperplasia with ineffective erythropoiesis with the development of giant metamyelocytes, may be demonstrated.

Other investigations are directed towards identifying the underlying cause of vitamin B12 deficiency. These can include: Schilling’s test, gastroscopy and serological assessment (e.g. autoantibodies seen in PA).

Question 15

Management of vitamin. B12 deficiency

Answer 15

Management involves B12 replacement & treatment of the underlying cause.
Treatment typically takes the form of intramuscular hydroxocobalamin. A dose of 1 mg, three times a week for two weeks, followed by maintenance of 1 mg every three months.

Importantly, in patients with co-existing folate deficiency, B12 must be replaced first as folate replacement in this setting may precipitate neurological complications (e.g. subacute degeneration of the cord).

Question 16

Subacute degeneration of the cord

Answer 16

Traditionally, presents insidiously with numbness, weakness and paraesthesia affecting the lower extremities in a symmetrical manner. As the condition progresses, it can lead to ataxia (unsteady, uncoordinated movement), sensory deficit and autonomic dysfunction (e.g. bladder/bowel dysfunction). These features may be accompanied by peripheral nerve involvement.

On examination, dorsal column involvement is demonstrated by loss of vibrational sense, proprioception (position sense) and ataxia. Involvement of the lateral columns can lead to pyramidal weakness, hyperreflexia and upgoing planters (positive Babinski sign).

Rather confusingly, lateral column involvement, and hence pyramidal tract involvement, may lead to mixed neurological signs (e.g. extensor plantar response with reduced/absent ankle reflexes) due to coexisting peripheral neuropathy. Other features include visual disturbance, memory impairment and psychiatric symptoms.

Question 17

… refers to vitamin B12 deficiency as a result of autoimmune destruction of the gastric epithelium.

Answer 17

Pernicious anaemia (PA) refers to vitamin B12 deficiency as a result of autoimmune destruction of the gastric epithelium.

Question 18

Patients with PA typically develop chronic gastric inflammation, which may lead to gastric atrophy. Over time, the basal secretion of IF is severely decreased leading to the development of …

Answer 18

Patients with PA typically develop chronic gastric inflammation, which may lead to gastric atrophy. Over time, the basal secretion of IF is severely decreased leading to the development of vitamin B12 deficiency.

Question 19

Pernicious anaemia

Auto-antibodies

Associated with the development of a number of auto-antibodies:

Answer 19

Anti-parietal cell antibodies - directed against the parietal cell membrane; sensitive, but not very specific.
Anti-IF antibodies - directed against intrinsic factor; sensitivity less than that of anti-parietal cell antibodies (est. 50-70%), but a specificity of almost 100%.

Question 20

… test is the classic investigation for the diagnosis of PA - though is now rarely used in clinical practice. The test is divided into two stages:

Answer 20

Stage 1: Ingestion of oral radiolabelled vitamin B12 followed by an IM injection of unlabelled vitamin B12. The IM injection is given to prevent radiolabelled B12 binding in vitamin B12 depleted tissue. A 24-hour urine collection is then taken, which should show an 8-40% excretion of radiolabelled vitamin B12 in normal subjects. A low level of radiolabelled vitamin B12 excretion indicates abnormal absorption.
Stage 2: If stage 1 is abnormal, the test can be repeated 3-7 days later. The only addition is an oral administration of IF at the same time. If there is an increase in the excretion of radiolabelled vitamin B12 the cause is secondary to IF deficiency (i.e. PA). If there is no increase in the excretion of radiolabelled vitamin B12 the cause is secondary to malabsorption at the terminal ileum.

Question 21

Patients with pernicious anaemia have an increased risk of …

Answer 21

Patients with pernicious anaemia have an increased risk of gastric malignancy. The role of routine screening is currently inconclusive, but patients do warrant an initial assessment of the upper GI tract with endoscopy at the time of diagnosis.

Question 22

Folate deficiency

Answer 22

Folate (vitamin B9) is an important molecule which acts as a cofactor in amino acid metabolism and DNA/RNA synthesis.
Folate is commonly found in a variety of food sources, but due to its rate of loss being 10-20 times greater than B12, deficiency states can develop much more rapidly.

Question 23

Epidemiology of macrocytic anaemia

Answer 23

In general, megaloblastic anaemia and folate deficiency are seen most commonly in countries where malnutrition is problematic.

Exact epidemiology of folate deficiency is not well known, but high-risk patient groups include: children, pregnant women and the elderly.

Question 24

Aetiology & pathophysiology - Folate deficiency

Answer 24

Folate is found in both animals and plants, and the daily requirement of folate is approximately 100-200 micrograms per day.

Absorption of folate occurs within the proximal part of the small intestines (e.g. duodenum & jejunum).

There are plenty of hepatic stores of folate (approx. 8-20 mg), but this reserve is lost rapidly from cellular metabolism and the shedding of epithelial cells. There is an estimated loss of 1-2% of stores per day. Therefore, folate deficiency can develop after months, compared to vitamin B12 deficiency, which tends to develop over years.

Question 25

Causes of folate deficiency:

Answer 25

Inadequate dietary intake
Malabsorption (e.g. coeliac disease, Crohn’s disease)
Increased requirements (e.g. pregnancy, malignancy)
Increased loss (e.g. Chronic liver disease)
Other (e.g. anti-convulsants, ETOH abuse)

Question 26

Features of folate deficiency

Answer 26

Features of folate deficiency are primarily related to the underlying anaemia. Clinical features may include weakness, fatigue, pallor and other evidence of malnutrition.

Other clinical features will be related to the underlying cause of folate deficiency. For example, in Coeliac disease, there may be evidence of gastrointestinal symptoms such as diarrhoea, bloating, dyspepsia and abdominal discomfort.

Question 27

Diagnosis of folate deficiency is based on a series of blood tests, which show the development of megaloblastic anaemia with a high MCV and low folate stores.

Answer 27

Blood tests include: FBC, blood film, haematinics and red cell folate. Red cell folate is a better measure of levels than serum folate, since levels are affected even with a short period of deficiency.

Importantly, levels of folate may be affected by vitamin B12 deficiency and it may be difficult to distinguish between the two.

In general, normal levels of vitamin B12 make the diagnosis of folate deficiency most likely. If levels of vitamin B12 are normal/reduced then a Schilling’s test can help differentiate. In clinical practice, a trial with folic acid is often employed.

If B12 deficiency cannot be completely ruled out, then replacement of B12 and folate should occur together. This is because replacement of folic acid only in the presence of vitamin B12 deficiency may cause significant neurological disease.

Question 28

General management of folate deficiency

Answer 28

General management of folate deficiency is to treat the underlying cause if required and to provide supplemental folic acid.

Folic acid is usually given as a once daily oral dose of 5 mg for up to four months. Levels can be repeated in primary care. Importantly, pregnant women should receive folate supplementation prior to conception until 12 weeks (400 mcg or 5 mg daily) due to the risk of neural tube defects.

Question 29

A group of macrocytic anaemias that do not lead to megaloblastic erythropoiesis.

Answer 29

Causes of non-megaloblastic anaemia are varied and include:

Chronic alcohol use
Hypothyroidism
Haemolytic anaemia
Medications (e.g. cyclophosphamide​)
Haematological malignancies

Question 30

Causes of non-megaloblastic anaemia are varied and include:

5

Answer 30

Causes of non-megaloblastic anaemia are varied and include:

Chronic alcohol use
Hypothyroidism
Haemolytic anaemia
Medications (e.g. cyclophosphamide​)
Haematological malignancies

Question 31

What is the most common cause of a non-megaloblastic anaemia?

Answer 31

Chronic alcohol use is the most common cause of a non-megaloblastic anaemia. It is thought to be due to the toxic effects of acetaldehyde on erythrocyte progenitors.

Question 32

Many medications may be implicated in the development of macrocytic anaemia, usually from the inhibition of metabolic pathways needed for erythropoiesis. Causative drugs include c…​, hydroxyurea and a….

Answer 32

Many medications may be implicated in the development of macrocytic anaemia, usually from the inhibition of metabolic pathways needed for erythropoiesis. Causative drugs include cyclophosphamide​, hydroxyurea and azathioprine.