Macrocytic anaemia

Question 1

Define macrocytic anaemia.

Answer 1

Anaemia associated with a high MCV of erythrocytes (>100fl in adults)

Question 2

What are the two main types of macrocytic anaemia?

Answer 2

1. Megaloblastic
2. Non-megaloblastic

Question 3

What is the aetiology of megaloblastic anaemia?

Answer 3

Deficiency of B12/folate required for the conversion of deoxyuridate to thymidylate, DNA synthesis and nuclear maturation.

Question 4

What are the causes of B12 deficiency?

Answer 4

B12 -

1. reduced absorption (post gasterctomy, pernicious anaemia, terminal ileal resection or disease e.g. Crohn’s disease, bacterial overgrowth, pancreatic insufficiency, fish tape-worm, metformin, omeprazole)
2. reduced intake (vegans)
3. abnormal metabolism (congenital transcobalamin II deficiency, inactivation of B12 by nitrous oxide)

Question 5

Which drugs can cause a megaloblastic macrocytic anaemia?

Answer 5

Drugs

1. Methotrexate (inhibition of dihydrofolate reductase)
2. Hydroxyurea (inhibition of ribonucleotide reductase)
3. Azathioprine
4. Zidovudine

Question 6

What are the causes of folate deficiency?

Answer 6

Folate -

1. reduced intake (alcoholics, elderly, anorexia)
2. increased demand (pregnancy, lactation, malignancy, chronic inflammation, chronic haemolysis, exfoliative dermatitis)
3. reduced absorption (jejunal disease e.g. coeliac disease, tropical sprue)
4. drugs (e.g. phenytoin, trimethoprim, methotrexate)

Question 7

What is the aetiology of non-megaloblastic macrocytic anaemia?

Answer 7

• Alcohol excess
• Liver disease
• Myelodysplasia
• Multiple myeloma
• Hypothyroidism
• Haemolysis (shift to immature red cells “reticulocytosis”)
• Drugs (e.g. tyrosine kinase inhibitors: imatinib, sunitinib)

Question 8

How common is macrocytic anaemia? Who is affected?

Answer 8

More common in elderly and females

Annual worldwide incidence of pernicious anaemia in those >40years old is ~25 in 100,000 (most common cause of vit B12 deficiency in the west)

Question 9

What are the signs and symptoms of anaemia?

Answer 9

• Non-specific sings of anaemia - tiredness, lethargy, dyspnoea
• FH of AI disease
• Hx of gastro surgery
• Symptoms of cause: weight loss, diarrhoea, steatorrhoea in coeliac disease

Signs:

• Anaemia - pallor, tachycardia
• Pernicious anaemia - mild jaundice, glossitis (red sore tongue), angular stomatitis (cheilitis), weight loss
• Signs of B12 deficiency - peripheral neuropathy, ataxia, subacute combined degeneration of the spinal cord, optic atrophy, dementia

Question 10

What is pernicious anaemia? What is the cause?

Answer 10

Autoimmune damage to the gastric parietal cells causing atrophic gastritis and consequent reduced production of intrinsic factor (IF) needed for B12 absorption in the terminal ileum.

May be associated with other autoimmune disease (e.g. vitiligo, hypothyroidism)

Question 11

What is subacute combined degeneration of the spinal cord?

Answer 11

Degeneration of the dorsal and lateral columns of the spinal cord causing loss of joint and position sense, ataxia and UMN weakness.

Partially or completely relieved by restoring vitamin B12 levels.

Question 12

What investigations are done to diagnose macrocytic anaemia?

Answer 12

Bloods:

• FBC - raised MCV; raised reticulocytes indicate rapid turnover (immature RBC)
• LFT - ?alcohol abuse
• Coombs’ test - exclude haemolytic anaemia
• Red cell folate
• Serum B12
• TFTs

Blood film - large erythrocytes (if compared to neutrophils, they may be the same size or slighly smaller indicating macrocytic anaemia). In megaloblastic anaemia: macroovalocytes, hypersegmented neutrophil nuclei (>5 lobes)

Schilling test - 2 part test to look for reduced absorption of radioactive B12 by testing urine and then to see if this is due to reduced IF (e.g. in pernicious anaemia). Only done if there are no serum anti-IF and diagnosis is in doubt.

BM biopsy - RARELY necessary: megaloblasts (nucleated red cells) or myelodysplastic changes.

Question 13

How do you manage macrocytic anaemia?

Answer 13

Pernicious anaemia -

IM hydroxycobalamin (x3/week for 2 weeks then every 3 months for life)

Folate deficiency

Oral folic acid 5mg/day for 1-4months or until complete haematologic recovery occurs

VitB12 deficiency

Treat first if present (folic acid may worse neurolgical complications of untreated Vit B12 deificiency). Same as pernicious anaemia treatment above

Question 14

What are the complications of macrocytic anaemia? What is the prognosis?

Answer 14

• In pernicious anaemia there is increased risk of gastric cancer
• In pregnancy folate deficiency predisposes to spinal cord anomalies

Prognosis - majority are treatable if there are no complications.

Question 15

How do you distinguish between the types of anaemia?

Answer 15

Question 16

Define sideroblastic anaemia and its biochemical features.

Answer 16

Sideroblastic anaemia occurs when the body is unable to incorporate iron into haemoglobin (despite adequate iron available). It can occur genetically or as part of myelodysplastic syndrome. Bloods will show high serum iron, decreased total iron-binding capacity, increased ferritin levels, and high transferrin saturation. For specific testing, Prussian blue staining of red blood cells in bone marrow will show ringed sideroblasts.

Can be microcytic if congenital, macrocytic if acquired.