Macrocytic Anaemia

Macrocytic anaemia is anaemia (haemoglobin under 130 g/L in men, 120 g/L in non-pregnant women) with a mean corpuscular volume over 100 fL. It is divided into megaloblastic anaemia (impaired DNA synthesis from vitamin B12 or folate deficiency, with oval macrocytes and hypersegmented neutrophils) and non-megaloblastic macrocytosis (round macrocytes).

• Megaloblastic causes: vitamin B12 deficiency (pernicious anaemia, the commonest cause, from autoimmune gastritis with intrinsic factor antibodies; gastrectomy or gastric bypass; ileal disease or resection, Crohn disease; fish tapeworm; bacterial overgrowth; strict vegan diet; metformin; proton pump inhibitors and H2 blockers; nitrous oxide misuse), folate deficiency (poor diet, alcohol, malabsorption such as coeliac disease, pregnancy, haemolysis, drugs such as methotrexate, trimethoprim, phenytoin and sulfasalazine), and rare causes (orotic aciduria, drug effects of hydroxycarbamide, azathioprine, antiretrovirals such as zidovudine).
• Non-megaloblastic causes: alcohol (the commonest cause of macrocytosis without anaemia), liver disease, hypothyroidism, reticulocytosis (haemolysis, bleeding recovery), myelodysplastic syndrome, aplastic anaemia, multiple myeloma, smoking, pregnancy, and drugs.
• Vitamin B12 deficiency affects about 5 percent of adults and up to 20 percent of those over 60; neurological damage can occur without anaemia and may become irreversible.

• Anaemia: fatigue, pallor, breathlessness, palpitations, and a lemon yellow tinge (mild jaundice from ineffective erythropoiesis).
• Gastrointestinal: sore smooth red tongue (glossitis), angular stomatitis, anorexia, weight loss, diarrhoea.
• Neurological (B12 only): symmetrical paraesthesia of the hands and feet, numbness, loss of vibration and proprioception, ataxia, weakness, spasticity (subacute combined degeneration of the cord), visual disturbance (optic neuropathy), memory loss, irritability, depression, dementia, and psychosis.
• Others: hyperpigmentation, infertility, thrombosis from hyperhomocysteinaemia, and in children failure to thrive.
• Associated autoimmune disease: thyroid disease, vitiligo, type 1 diabetes, Addison disease.
• History: diet, alcohol, medicines, surgery, gastrointestinal symptoms, family history, and nitrous oxide use.

• FBC: raised MCV (often over 110 fL in megaloblastic anaemia), low or normal haemoglobin, low reticulocytes, low white cell and platelet counts in severe disease.
• Blood film: oval macrocytes, hypersegmented neutrophils (5 or more lobes), anisopoikilocytosis, and Howell-Jolly bodies; round macrocytes with target cells in liver disease and alcohol.
• Serum vitamin B12: under 148 pmol/L (200 nanograms/L) indicates deficiency; 148 to 258 pmol/L (200 to 350 nanograms/L) is borderline, and methylmalonic acid (raised) or homocysteine (raised) confirms deficiency.
• Serum folate under 7 nmol/L (3 micrograms/L) or red cell folate under 340 nmol/L indicates deficiency.
• Intrinsic factor antibodies (specific for pernicious anaemia) and parietal cell antibodies; gastrin level; coeliac serology.
• Other tests: reticulocyte count, lactate dehydrogenase (very high in megaloblastic anaemia), bilirubin, liver function and gamma glutamyl transferase, thyroid function, glucose, renal function, HIV, and serum protein electrophoresis.
• Bone marrow examination if pancytopenia, unexplained macrocytosis without a cause, abnormal film, or suspected myelodysplasia.
• Endoscopy for gastric cancer risk in pernicious anaemia when indicated.

General principles

• Identify and treat the cause; check both B12 and folate before treatment; never give folic acid alone to a patient with B12 deficiency or unknown B12 status, since it may correct anaemia while neurological damage progresses.
• Start treatment urgently in severe anaemia, neurological features, or pregnancy.

Vitamin B12 deficiency

• Without neurological involvement: hydroxocobalamin 1 mg intramuscularly three times a week for 2 weeks (alternate days), then 1 mg every 3 months for life in pernicious anaemia, gastric or ileal disease; for dietary deficiency, oral cyanocobalamin 50 to 150 micrograms daily between meals can be used, or 1000 micrograms daily if poor adherence is not a concern and absorption is intact.
• With neurological involvement: hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement (up to 3 weeks), then 1 mg every 2 months for life; urgent specialist input.
• High dose oral cyanocobalamin 1000 to 2000 micrograms daily is an effective alternative in malabsorption when injections are not possible.
• Monitor: reticulocyte response peaks at 5 to 8 days; haemoglobin rises about 10 g/L a week and normalises in 8 weeks; check potassium in the first week in severe anaemia (hypokalaemia can occur), and serum iron or ferritin because iron deficiency may be unmasked. Neurological recovery is slow and may be incomplete.
• Pernicious anaemia: regular review for gastric cancer symptoms, osteoporosis and thyroid disease.

Folate deficiency

• Folic acid 5 mg orally once daily for 4 months (until haemoglobin normal and the underlying cause treated), or longer for chronic haemolysis, malabsorption or ongoing risk; give hydroxocobalamin first or with folic acid if B12 status is uncertain.
• Treat the cause: stop causative drugs when possible, correct diet (green leafy vegetables, legumes, fortified cereals), treat coeliac disease with a gluten free diet, and treat alcohol use disorder (abstinence, thiamine 100 mg daily).
• Higher doses (5 mg) are needed in methotrexate toxicity and pregnancy; folinic acid (calcium folinate) 15 mg orally for methotrexate or trimethoprim toxicity.

Non-megaloblastic macrocytosis

• Alcohol: abstinence, thiamine and folate; MCV falls over 2 to 4 months. Liver disease: treat the cause. Hypothyroidism: levothyroxine 1.6 micrograms/kg daily (start 25 to 50 micrograms in older adults and those with cardiac disease). Drug effect: review with the prescriber. Myelodysplasia and aplastic anaemia: refer to haematology urgently.

Transfusion

• Avoid unless life threatening heart failure or severe symptomatic anaemia (haemoglobin under 50 g/L); if needed give slowly one unit over 4 hours with diuretic cover, because of the risk of fluid overload.

Follow up

• Check FBC at 2 and 8 weeks, then at 6 and 12 months; recheck B12 after 1 year; refer to haematology for pancytopenia, unexplained macrocytosis, or failure to respond.

Special groups

• Pregnancy: folic acid 5 mg daily for known folate deficiency, haemoglobinopathy, or previous neural tube defect (400 micrograms daily as prevention); treat B12 deficiency with injections.
• Strict vegans and breastfeeding mothers: supplement with oral cyanocobalamin 50 micrograms daily or 2000 micrograms weekly; check the infant if B12 deficiency is suspected.