Myelodysplastic syndrome (MDS) is a diagnosis that requires explicit consideration whenever macrocytosis with unexplained cytopenia (anaemia, neutropenia, or thrombocytopenia) is present in a patient over 60 — it is a clonal bone marrow disorder in which haematopoietic stem cells produce morphologically abnormal cells that fail to mature normally, leading to ineffective erythropoiesis. In MDS the film may show dysplastic neutrophils or abnormal platelets; macro-ovalocytes with hypersegmented neutrophils instead point to B12/folate deficiency. MDS becomes more common with age. The clinical presentation: fatigue from anaemia (the most common symptom), recurrent infections (neutropenia), and bruising/bleeding (thrombocytopenia). The WHO MDS classification (2022) has multiple subtypes determined by cytogenetics and bone marrow morphology. GPs should refer to haematology any patient with unexplained macrocytic anaemia (particularly with cytopenia, dysplastic features on film, or age over 60) when B12, folate, thyroid, alcohol, and drug causes have been excluded.

Alcohol is the most common cause of isolated macrocytosis in UK primary care — in a patient presenting with incidental MCV elevation without anaemia, alcohol should be the first consideration. The mechanism of alcohol-induced macrocytosis is multifactorial: direct toxic effect of acetaldehyde on developing red cell precursors (acetaldehyde is incorporated into red cell membrane lipids, altering membrane fluidity and shape), secondary folate deficiency (poor diet in heavy drinkers + alcohol-induced folate malabsorption), and direct toxic effect on the bone marrow. The key clinical point: alcohol macrocytosis causes large round macrocytes (without hypersegmented neutrophils — unlike megaloblastic macrocytosis), and the MCV may take several months to fall after abstinence. Persistent macrocytosis despite abstinence should prompt reassessment for other causes. The AUDIT-C at every macrocytosis consultation is essential — many patients under-declare alcohol use.

The blood film is the most information-rich investigation in the macrocytosis workup — the morphological findings narrow the differential diagnosis dramatically and guide subsequent targeted investigations. The hypersegmented neutrophil is the single most specific finding for megaloblastic haematopoiesis: any neutrophil with 6 or more lobes, or more than 5% of neutrophils with 5 lobes, constitutes hypersegmentation and strongly suggests B12 or folate deficiency (or antifolate drugs such as methotrexate). No single laboratory test is definitive for B12 deficiency, so interpret the film in clinical context (BSH). The oval macrocyte (elliptocyte with one blunt and one pointed end) is the characteristic red cell shape in megaloblastic anaemia — it differs from the round macrocytes of alcohol and liver disease. GPs who request a blood film alongside FBC are getting information that automated cell analysers cannot provide — and the film result should prompt specific targeted investigation rather than a generic 'macrocytosis workup' approach.

The trimethoprim + methotrexate interaction is a potentially fatal combination that every GP must know — trimethoprim (even at standard doses) inhibits dihydrofolate reductase, the same enzyme that methotrexate targets. Co-prescribing trimethoprim to a patient on methotrexate (for rheumatoid arthritis, psoriasis, or cancer) can cause acute severe methotrexate toxicity with: sudden severe pancytopenia, mucositis, severe diarrhoea, and sepsis. Case series show deaths from this interaction. The mechanism: trimethoprim blocks the folate pathway that allows cells to recover from methotrexate toxicity. The safety rule: avoid co-prescribing trimethoprim or co-trimoxazole with methotrexate where possible — choose an alternative antibiotic (e.g. nitrofurantoin for UTI). If the combination is unavoidable, it requires specialist oversight and a clear monitoring plan. This interaction is listed in the BNF under 'interactions' for both trimethoprim and methotrexate, and should be checked at every prescription using the clinical system's drug interaction alert.

Pernicious anaemia (autoimmune gastritis) carries an increased risk of gastric adenocarcinoma and type I gastric neuroendocrine tumours, but NICE NG239 does not recommend routine gastroscopy or surveillance for everyone with autoimmune gastritis. Refer for gastroscopy when there are new or worsening upper-GI symptoms such as dyspepsia, nausea or vomiting, and follow NICE NG12 (updated April 2026) for suspected upper-GI cancer. Any surveillance interval is set by gastroenterology from the endoscopic and histological findings. See the B12 deficiency algorithm.

Folic acid dose selection is important — the standard prescribed dose for treating folate deficiency or B12 deficiency haematological complications is 5 mg OD (high-dose) for 4 months. This is different from: (1) the pregnancy prevention dose (400 mcg/day — low-dose for neural tube defect prevention in normal-risk pregnancy); (2) the high-risk pregnancy dose (5 mg/day — for previous or family history of NTD, type 1 or type 2 diabetes, certain haematological conditions, or medicines affecting folate absorption or metabolism; not for BMI alone — NICE NG247); and (3) the co-prescription with methotrexate (5 mg weekly, on a different day to methotrexate — not daily). Prescribing the wrong dose is a common error: prescribing 400 mcg for treatment of established deficiency (insufficient); prescribing 5 mg daily indefinitely for a woman taking methotrexate (exceeds the weekly requirement and may reduce methotrexate efficacy). GPs should also recall that folic acid must never be prescribed alone in a B12-deficient patient without simultaneously treating the B12 deficiency.

The GP's role in MDS is recognition, referral and supportive care. Disease-modifying treatment, transfusion and iron chelation are specialist haematology decisions and change quickly, so follow the haematology team's plan. Patients on haematology treatment who develop fever, infection or bleeding need urgent assessment as advised by their specialist team.

The folic acid pre-conception advice is one of the most important primary prevention interventions in UK primary care — neural tube defects (NTDs: spina bifida, anencephaly) affect approximately 1,000 pregnancies per year in the UK, and folic acid supplementation (400 mcg/day) started at least 1 month before conception and continued through the first trimester reduces NTD risk by approximately 70%. Despite decades of public health messaging, only approximately 30% of women take folic acid pre-conception because many pregnancies are unplanned. Mandatory fortification of non-wholemeal wheat flour with folic acid was legislated in 2024 and applies from 13 December 2026 (0.25 mg per 100 g flour) — the Government estimates it will prevent around 200 NTD-affected pregnancies a year (about 20% of UK cases). GPs should still advise folic acid supplementation to all women planning pregnancy, noting that food fortification does not substitute for supplementation in the pre-conception period.

The absence of a reticulocyte response 7-10 days after starting B12 (or folate) treatment is an important clinical signal — if the reticulocyte count does not rise above normal within 5-10 days of IM hydroxocobalamin injection in a patient with megaloblastic anaemia, the diagnosis must be reconsidered. Possible explanations: concurrent iron deficiency (iron is required for new red cell production — supplement simultaneously), concurrent infection or inflammation suppressing the reticulocyte response, incorrect diagnosis (MDS rather than megaloblastic anaemia — MDS may present with macrocytosis and fail to respond to B12/folate), co-existing coeliac disease with malabsorption, or very severe bone marrow failure requiring longer recovery. An absent or minimal reticulocyte response at day 7-10 should prompt blood film review and haematology referral.