Macrocytic anaemia — Frequently asked questions (FAQ)
1) What does this algorithm cover?
The algorithm guides a structured assessment of macrocytic anaemia — increased MCV — integrating the peripheral blood smear, reticulocytes/reticulocyte index and testing for vitamin B12 and folate. It helps distinguish megaloblastic from non-megaloblastic macrocytosis, direct the differential diagnosis and guide treatment and referral criteria.
2) How is macrocytic anaemia defined and when should it be investigated?
Macrocytic anaemia is defined as anaemia with MCV > 100 fL. It should be investigated especially when persistent, symptomatic, associated with cytopenias — leukopenia/thrombocytopenia —, accompanied by abnormalities on the blood smear or when there is clinical suspicion of treatable causes, such as B12/folate deficiency, alcohol, drugs, hypothyroidism or liver disease.
3) Are there causes of pseudo-macrocytosis that may confuse interpretation?
Yes. Some situations may cause pseudo-macrocytosis or laboratory artefacts, such as cold agglutination, marked hyperglycaemia or extreme leukocytosis. In addition, reticulocytosis may increase MCV by itself. When results are unexpected, it may be appropriate to repeat the full blood count, confirm MCV/RDW and correlate with the blood smear.
4) What is the role of reticulocytes and RPI?
Reticulocytes help separate causes due to reduced production — low reticulocytes — from situations with an increased bone marrow response — raised reticulocytes —, such as haemolysis or bleeding. The RPI — reticulocyte production index — adjusts the reticulocyte percentage to the degree of anaemia; in practical terms, RPI > 2 suggests an adequate response and favours peripheral causes.
5) What distinguishes megaloblastic from non-megaloblastic macrocytosis?
Megaloblastic macrocytosis is typically associated with vitamin B12 and/or folate deficiency and may show macro-ovalocytes and hypersegmented neutrophils on the blood smear. Non-megaloblastic macrocytosis is more commonly associated with alcohol, liver disease, hypothyroidism, drugs, COPD, splenectomy and, in some cases, myelodysplastic syndromes.
6) When should vitamin B12 deficiency be suspected?
Vitamin B12 deficiency should be suspected in macrocytosis with megaloblastic changes, especially if there are neurological manifestations — paraesthesias, ataxia, impaired proprioception —, glossitis or risk factors such as autoimmune gastritis, gastric/ileal surgery, ileal disease, restrictive diet, metformin or PPI use. Borderline values with clinical suspicion may justify confirmatory tests — for example methylmalonic acid ± homocysteine — depending on availability.
7) Can folic acid be started without excluding vitamin B12 deficiency?
This is not recommended. Isolated folic acid supplementation may improve anaemia but does not correct vitamin B12 deficiency and may worsen or mask neurological manifestations. Whenever there is uncertainty, exclusion and/or correction of B12 deficiency should be prioritised before starting folate.
8) What are the most common causes of non-megaloblastic macrocytosis?
The most common causes include chronic alcohol misuse, liver disease, hypothyroidism, COPD, splenectomy and drugs — for example antineoplastic/immunomodulatory drugs, antiretrovirals, antiepileptics and some antimicrobials. Directed assessment should generally include liver function and TSH, as well as medication review and alcohol intake assessment.
9) When should myelodysplastic syndrome (MDS) be suspected and referral considered?
MDS should be suspected when macrocytosis is associated with other cytopenias — leukopenia and/or thrombocytopenia —, dysplastic changes on the blood smear, low reticulocytes, absence of reversible causes and/or lack of response after appropriate correction of deficiencies. In these scenarios, referral to Haematology for specialist assessment is appropriate.
10) When should haemolysis or bleeding be investigated?
When there is reticulocytosis — or raised RPI — with anaemia, haemolysis or bleeding should be considered. Investigation may include laboratory markers such as LDH, indirect bilirubin and haptoglobin and, when appropriate, a Coombs test. Reticulocytosis may explain the increased MCV, even without nutritional deficiency.
11) How long does the haematological response take after correcting the deficiency?
After starting appropriate treatment, clinical improvement and an increase in reticulocytes are usually observed within the first weeks, with progressive haemoglobin recovery. Absence of the expected improvement should prompt reassessment of adherence, diagnosis, persistence of causal factors — such as alcohol/drugs — and consideration of referral if there are signs of bone marrow disease.
