Macrocytic Anaemias

Classification of anaemia

Red cellappearance

Small cells(microcytes)

Large cells (macrocytes) Normal sizedcells

Indices Low MCV<80fl

High MCV >96fl NormalMCV

Appearanceof bonemarrow

Megaloblastic Normoblastic

Diagnosis Iron def.ThalassaemiaACD

Vitamin B12or folatedeficiency

Liver diseaseAlcoholMDS

Acute bldloss, ACD:Infection,Collagen dzMalignancy

Aetiology

• Deficiency of Vitamin B12 or Folate in which the bone marrow is megaloblastic.

• Other causes with normoblastic bone marrow. Non-megaloblastic.

Megaloblastic anaemia

• Bone marrow contains erythroblasts with delayed nuclear maturation due to defective DNA synthesis = megaloblasts.

• Contain large immature nuclei. Chromatin is finely dispersed and has an opened stippled appearance.

• MCV >96 fl.• Blood film shows macrocytes with

hypersegmented polymorphs.

Deficiency of B12 or folate• Diet

– B12: Veganism, poor quality diet– Folate: Poor quality diet, old age, poverty.

• Malabsorption– Gastric causes of B12: Pernicious anaemia,

intrinsic factor deficiency, gastrectomy– Intestinal causes of B12: Ileal resection,

Crohn’s, Tropical sprue

Deficiency continued– Intestinal causes of folate: Tropical sprue,

jejunal resection

• Increased cell turnover– Folate: Pregnancy,chronic haemolytic anaemia,

malignancy, lympho/myeloproliferative disease

• Renal loss– Folate: CHF, dialysis

• Drugs– Folate: eg anticonvulsants, sulphasalazine, ABs

Vitamin B12• Av. Diet contains 5-30ug, with 2-3ug absorbed.

Average stores 2-3mg, mainly in the liver (approx 18 months’ worth).

• Found in meat, fish, eggs and milk.• Absorbed through ileum, facilitated by I.F.

(secreted by parietal cells).• Commonest cause is pernicious anemia. (Atrophy

of gastric mucosa with failure of I.F. production & B12 malabsorption.)

Folate

• Daily requirement folate 100-200ug. Normal diet 200-300ug.

• Absorbed in upper S.I. Body store about 4 months.• Found in green vegetables e.g. spinach & broccoli

& offal e.g. liver & kidney• Cooking causes a loss of 60-90% of folate.

General Symptoms

• Of anaemia:– Fatigue

– Headaches

– Faintness

– Breathlessness

– Angina with effort

– Intermittent claudication

– Palpitations

General Signs (again, of anaemia)

• Pallor• Tachycardia• Systolic flow murmur• Cardiac failure• Rarely papilloedema and retinal haemorrhages

post acute bleed.

Consequences specific to B12 or folate

• Vitamin B12 neuropathy: due to symmetrical damage to peripheral nerves & posterior & lateral columns of the spinal cord.– Legs affected more.

– Psychiatric & visual disturbances may also occur.

• Neural tube defects: Folic acid supplements reduce the incidence of neural tube defects (spina bifida, encephalocoele and anencephaly) in the fetus.

Consequences

• Gonadal dysfunction: B12 or folate deficiency may cause sterility, but is reversible.

• Epithelial changes• Cardiovascular disease: raised homocysteine has

been associated with arterial obstruction & venous thrombosis.

Investigations

• FBC: MCV >96 fl, neutropenia, thrombocytopenia– Blood film: oval macrocytes and hypersegmented

neutrophils. Severe: absence of haptoglobins

• Serum B12: normal ref = 160-600pmol/L. Borderline low 140-160pmol/L. Assayed via radioisotope dilution or immunological assays.– Parietal cell & I.F. antibodies.

– Schilling test

Investigations• Folate serum: normal ref = 8.0-35.0nmol/L.• Folate, red cell: better indicator of stores but

expensive & not always used.– Antigliadin, antiendomysial antibodies. (positive in

gluten induced enteropahty)

• LFT’s: increase of unconjugated bilirubin• TFT’s• (Serum homocysteine: increased in B12 & folate.)

Investigations

• Bone marrow biopsy: megaloblastic erythroblasts & giant metamyelocytes. Or alternative dx e.g. MDS, aplastic anaemia, myeloma.

• Endoscopy: gastric biopsy (B12, to exclude gastric ca or polyps), duodenal biopsy (folate).

Interrelationship between B12 & folate deficiencies

1 Deficiency

Serum B12

Serum Folate

Red Cell Folate

B12 N N

Folate N

Treatment• B12: initially with 6 injections of hydroxo-cobalamin 1mg,

intervals eg weekly– then 4 injections over the year.– Pernicious anaemia and total gastrectomy or ileal resection

req maintenance

injections– Eat fortified foods

• Folate: folic acid, 5mg po OD• NB occasionally giving folate can mask symptoms of B12

deficiency long enough for neurological damage -> care to check B12 levels when prescribing folate!