Sideroblastic anaemia and megaloblastic anaemia

• Sideroblastic anaemia is a disorder of haem synthesis in the developing red cell: iron enters the mitochondria but cannot be turned into haem, so iron piles up around the nucleus and produces ringed sideroblasts.
• Megaloblastic anaemia is macrocytic anaemia caused by impaired DNA synthesis, almost always from lack of vitamin B12 (cobalamin) or folate; both vitamin B12 and folate are needed for the same one-carbon reactions that make DNA.
• The blood film separates the two from iron deficiency: in megaloblastic anaemia you see macro-ovalocytes and hypersegmented neutrophils, while in sideroblastic anaemia the diagnosis rests on ringed sideroblasts in the marrow.
• The crucial laboratory difference is methylmalonic acid (MMA): it rises in vitamin B12 deficiency, stays normal in folate deficiency, and homocysteine rises in both.
• Vitamin B12 deficiency damages the nervous system (subacute combined degeneration); folate deficiency never does, so vitamin B12 must be excluded or treated first whenever both deficiencies could coexist.

By the end of this page you should be able to:

1. Explain what a ringed sideroblast is, and distinguish congenital from acquired sideroblastic anaemia.
2. Describe the actions of vitamin B12 and folate in one-carbon metabolism, and list the common causes of deficiency of each.
3. Recognise the blood film of megaloblastic anaemia and interpret methylmalonic acid and homocysteine correctly.
4. Identify the neurological syndrome of severe vitamin B12 deficiency and decide when it is reversible.
5. Prescribe replacement therapy (route, dose and duration) according to the cause of the deficiency.
6. Adapt diagnosis and treatment of megaloblastic anaemia to a low-resource setting.

Sideroblastic anaemia is a family of disorders in which erythroid precursors accumulate iron in their mitochondria because haem synthesis is blocked at some step. On a bone marrow aspirate stained for iron these precursors show a ring of coarse iron granules encircling the nucleus: ringed (ring) sideroblasts. The block can be inherited (congenital) or acquired.

Megaloblastic anaemia is macrocytic anaemia (mean cell volume above the upper limit of normal) in which erythroid precursors become large and immature because DNA synthesis is slowed. The marrow is overcrowded with megaloblasts; the peripheral blood shows macro-ovalocytes and hypersegmented neutrophils. It is caused by lack of vitamin B12 or of folate (or, rarely, by thiamine-responsive variants), both of which are cofactors for the same reactions that supply thymidine and methionine.

The distinction is clinically useful because sideroblastic anaemia is microcytic or normocytic and is a problem of haem production, whereas megaloblastic anaemia is macrocytic and is a problem of DNA production. A patient can have both processes at once (for example mixed iron and vitamin B12 deficiency), which produces a normal or misleading mean cell volume.

Both conditions are uncommon compared with iron deficiency, and both are underdiagnosed. Pernicious anaemia, the commonest cause of vitamin B12 deficiency in adults in well-nourished populations, is an autoimmune disease of middle and older age and is more common in people with other autoimmune disease. Sideroblastic anaemia is rare overall: the inherited forms present in children or young adults, while acquired forms dominate in adults, especially in the myelodysplastic syndromes. Alcohol-related sideroblastic change and lead exposure are more common in settings with heavy alcohol use or occupational exposure.

Congenital (inherited) forms result from mutations in genes of haem synthesis or iron-sulphur cluster assembly. The classic example is X-linked sideroblastic anaemia from mutations in ALAS2, the erythroid enzyme that makes the first intermediate of haem, which responds at least partly to pyridoxine (vitamin B6). Rarer autosomal recessive forms involve SLC25A38 (a mitochondrial glycine transporter) or TRNT1, and mitochondrial variants produce syndromes such as Pearson and MLASA (mitochondrial myopathy, lactic acidosis and sideroblastic anaemia) ^[5].

Acquired causes are more common ^[6]:

• Alcohol, which reversibly impairs mitochondrial haem synthesis and iron handling.
• Lead, which poisons the haem pathway by inhibiting aminolevulinic acid dehydratase and produces a sideroblastic, microcytic anaemia ^[7].
• Drugs: isoniazid (through pyridoxine antagonism), chloramphenicol, linezolid and others. Their marrow changes usually reverse when the drug is stopped.
• Myelodysplastic syndromes, especially refractory anaemia with ring sideroblasts (MDS-RS), in which SF3B1 mutations are typical. The ringed sideroblasts here are part of a clonal marrow disorder rather than a nutritional problem.
• Copper deficiency (for example after gastric surgery or with excess zinc) can also produce ringed sideroblasts by impairing iron handling.

Because of where vitamin B12 is absorbed, causes cluster into decreased intrinsic factor, inadequate intake, decreased ileal absorption and drugs. The following list (from a 2026 review of testing and treatment) includes ^[2]:

• Decreased intrinsic factor: autoimmune (atrophic) gastritis and pernicious anaemia, bariatric surgery, total or partial gastrectomy.
• Inadequate intake: vegan or vegetarian diet, older age, alcohol excess, eating disorders.
• Decreased ileal absorption: Crohn disease, coeliac disease, ileal resection, radiation enteritis.
• Drugs: metformin, proton pump inhibitors and H2-receptor blockers used long term, antiepileptics, colchicine.
• Recreational nitrous oxide, which inactivates the vitamin B12 molecule.
• Fish tapeworm (Diphyllobothrium species), which competes for vitamin B12 in the gut.

Pernicious anaemia deserves emphasis. It is an autoimmune destruction of gastric parietal cells leading to loss of intrinsic factor and acid. Autoantibodies to intrinsic factor (type 1, present in about 70% of patients, often coexisting with type 2 antibodies) and to parietal cells (80-90% in earlier disease, falling to about 55% in advanced disease) are the characteristic markers ^[3].

Folate deficiency arises from:

• Dietary lack and alcohol (which both reduces intake and impairs absorption and metabolism).
• Pregnancy and lactation, because demand rises sharply.
• Drugs that interfere with folate metabolism or absorption: methotrexate, trimethoprim, phenytoin and other anticonvulsants, sulphasalazine.
• Malabsorption (coeliac disease, tropical sprue) and small-intestinal disease.
• Increased cell turnover, as in haemolysis or malignancy.

Haem is built partly in mitochondria. When the pathway is blocked (genetic, toxic or clonal), the last step cannot consume iron, so iron accumulates in the mitochondria that cluster around the nucleus. The red cells that do emerge are hypochromic and microcytic, and the iron overload can itself damage tissues and organs. Removing the block (stopping alcohol or a drug, or giving pyridoxine to responsive forms) can restore haem synthesis.

Vitamin B12 and folate work together in one-carbon transfer:

• Folate supplies methyl groups; as 5,10-methylenetetrahydrofolate it gives its carbon to deoxyuridylate to make thymidylate, the rate-limiting step of DNA synthesis.
• Vitamin B12 is the cofactor of methionine synthase, which remethylates homocysteine to methionine using methyltetrahydrofolate. This step both supplies methionine and regenerates free tetrahydrofolate so folate can be used again for DNA.

When either is missing, thymidylate and methionine fall, DNA replication slows, and megaloblasts accumulate. Homocysteine rises in both deficiencies. Methylmalonic acid rises only in vitamin B12 deficiency, because vitamin B12 is also the cofactor of methylmalonyl-CoA mutase; folate plays no part in that reaction. This biochemical asymmetry is the basis of the laboratory distinction ^[2][3].

Nitrous oxide deserves a separate mechanism note: it oxidises the cobalt atom of vitamin B12 and inactivates the molecule. Total vitamin B12 may be normal, which is why methylmalonic acid or homocysteine should be checked first when nitrous oxide use is suspected ^[2].

Figure 1Hyperlobated Neutrophil (8612790151)

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Long description

A hypersegmented (hyperlobated) neutrophil with six or more nuclear lobes on a blood film, a feature of megaloblastic anaemia.

Figure 2Ringed sideroblast

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Long description

Bone marrow stained with Prussian blue showing a ringed sideroblast: an erythroblast with a ring of blue iron-laden granules around the nucleus.

Figure 3Micrograph of a red blood cell with basophilic stippling

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Long description

A red blood cell with basophilic stippling: fine blue-purple dots scattered through the cytoplasm.

• Bone marrow iron stain (sideroblastic): ringed sideroblasts with perinuclear iron granules.
• Blood film (megaloblastic): macro-ovalocytes, anisopoikilocytosis, and hypersegmented neutrophils (neutrophils with an increased number of nuclear lobes) ^[2][3].
• Marrow (megaloblastic): hypercellular marrow with large, immature erythroid precursors (megaloblasts), giant metamyelocytes and erythroid hyperplasia.

Both conditions present as anaemia: fatigue, pallor, breathlessness and palpitations. In pernicious anaemia the skin may have a pale yellow tinge and the tongue may be sore and smooth (atrophic glossitis). The haemoglobin can fall far before symptoms are dramatic, and in megaloblastic disease the anaemia is often macrocytic long before it is symptomatic.

The defining syndrome is subacute combined degeneration of the spinal cord: demyelination of the posterior columns (loss of vibration and proprioception) and the lateral columns (spastic weakness, hyperreflexia, upgoing plantars), producing a sensory ataxia with a positive Romberg sign. Paraesthesiae usually begin in the feet and ascend; an ataxic gait, leg stiffness, numbness of the hands and feet, and impaired position sense follow ^[3][4]. Cognitive change, memory impairment, depression, irritability and psychosis are well recognised, as are optic atrophy and autonomic symptoms ^[3][4].

Nerve damage is the serious, time-critical complication: parenteral therapy is needed to halt it, and recovery can be slow and incomplete if treatment is delayed. The marrow abnormality does not track the brain abnormality, so patients can have severe neurological disease with a normal haemoglobin ^[2][3].

Folate deficiency causes the same megaloblastic anaemia but no neurological syndrome. It is, however, a serious cause of neural tube defects in the fetus when the mother is deficient in early pregnancy ^[1].

Megaloblastic anaemia must be told apart from other macrocytic and pancytopenic disorders; sideroblastic anaemia must be told apart from other microcytic anaemias.

Blood film and marrow. The first clues are on the film: macro-ovalocytes and hypersegmented neutrophils point to megaloblastic change; pancytopenia can occur in severe disease. A full blood count with MCV, RDW, reticulocytes and platelets is essential. Bone marrow examination with an iron stain is needed whenever a sideroblastic process is suspected or when the film is atypical: ringed sideroblasts establish the diagnosis, and the marrow also assesses dysplasia and MDS.

Vitamin and metabolite assays. Total serum vitamin B12 is usually the first test; active vitamin B12 (holotranscobalamin) is useful when total B12 is indeterminate or in pregnancy. Folate is measured in serum or red cells. When total or active vitamin B12 is inconclusive, MMA and homocysteine help:

• MMA under 270 nmol/L makes cobalamin deficiency unlikely; MMA above this level supports it ^[2][3].
• Homocysteine above 15 micromol/L is commonly used as a cut-off; a value above 12 micromol/L is suggested by some ^[3].
• Homocysteine is elevated in folate deficiency too; MMA is typically normal in folate deficiency ^[2][3].
• In nitrous oxide exposure, total and active vitamin B12 may be normal despite tissue deficiency, so MMA or homocysteine should be the initial tests ^[2].

Cause hunting. In suspected pernicious anaemia, test for intrinsic factor antibodies before giving vitamin B12 injections (antibodies can become falsely positive after dosing), and consider parietal cell antibodies and gastrin or endoscopy if antibodies are negative ^[3]. For vitamin B12 deficiency without an obvious cause, test for coeliac and Helicobacter pylori infection ^[2]. For sideroblastic anaemia, check drugs, alcohol history, blood lead when exposure is possible, copper and zinc, and arrange haematology review for MDS.

There is no single accepted diagnostic score for either condition. For megaloblastic anaemia the diagnosis is a clinical-laboratory combination: macrocytic anaemia with a compatible blood film and a low or borderline vitamin level, supported by metabolites. For vitamin B12 deficiency, total serum vitamin B12 under about 200 pg/mL suggests deficiency and 200-300 pg/mL is borderline ^[3]. The serum vitamin B12 value can be falsely high in renal failure, myeloproliferative disease, liver disease or in the presence of intrinsic factor antibodies interfering with the assay, and falsely low in pregnancy, folate deficiency and hypothyroidism ^[3].

For pernicious anaemia, intrinsic factor antibodies are highly specific (almost 100%) but have sensitivity of only about 50-70%; sensitivity rises towards 80% as disease progresses. Parietal cell antibodies are more sensitive (85-90%) but less specific ^[3].

Sideroblastic anaemia is confirmed by bone marrow: the presence of ringed sideroblasts is the defining finding, with genetic testing in suspected congenital disease and clonal analysis in suspected MDS.

• Treat the cause: stop alcohol or the offending drug; remove lead exposure; treat MDS or copper deficiency.
• Congenital X-linked (ALAS2) forms often improve with pyridoxine (vitamin B6), which restores activity of the defective enzyme. Response should be assessed on the blood count over weeks to months.
• Transfusion and iron chelation are used for severe, transfusion-dependent disease; specific MDS therapies are haematology-led decisions.
• Avoid unnecessary iron in sideroblastic patients who are iron overloaded.

Replacement route and dose depend on cause and severity. The following regimens come from a 2026 Australasian review ^[2]:

• Irreversible malabsorption (pernicious anaemia, autoimmune gastritis, total gastrectomy, terminal ileal resection): hydroxocobalamin 1000 micrograms intramuscularly on alternate days for 1-2 weeks then weekly for 4-8 weeks, then every 3 months lifelong. Oral therapy is unreliable even at high doses.
• Partial or potentially reversible malabsorption (coeliac disease, Crohn disease, partial gastrectomy, bariatric surgery): same loading; maintenance with intramuscular hydroxocobalamin 1000 micrograms every 3 months, or high-dose oral cyanocobalamin (at least 1 mg daily) once biochemical correction is proven. ^[2]
• Severe symptomatic deficiency or neurological involvement (including subacute combined degeneration): aggressive loading with hydroxocobalamin 1000 micrograms intramuscularly on alternate days until no further improvement, often at least 2-3 weeks, then 1000 micrograms every 3 months lifelong. Rapid parenteral therapy is needed to prevent irreversible neurological damage.
• Drug-induced deficiency (metformin, proton pump inhibitors, H2 blockers, colchicine): oral cyanocobalamin 1 mg daily or intramuscular hydroxocobalamin, continued only until the offending drug is stopped and the deficiency corrected; retest 3-6 months later. ^[2]
• Pure dietary insufficiency (vegan or vegetarian diet, malnutrition): high-dose oral cyanocobalamin 1 mg daily (no loading), then 1 mg daily or 1-2 mg weekly long term. Intramuscular therapy is reserved for poor adherence or social barriers. ^[2]
• Nitrous oxide-induced deficiency: hydroxocobalamin 1000 micrograms intramuscularly daily for one week, then weekly for 4 weeks, then monthly until recovered (up to 3 months); ongoing replacement is rarely needed once use stops and stores are repleted. Recovery of neurological function may be slow and incomplete. ^[2]

Monitoring the response. Most patients feel better within 2 weeks; reticulocytosis begins within 3-5 days and haemoglobin usually normalises within 4-8 weeks ^[2]. Intensive loading of vitamin B12 can unmask folate deficiency, precipitate iron deficiency and cause hypokalaemia, so folate and iron should be checked in severe disease ^[2]. Neurological improvement is gradual (6-12 weeks).

Folate replacement. Folic acid is given only after vitamin B12 deficiency has been excluded or treated. A standard oral preparation is used until the haemoglobin recovers and stores are repleted. Giving folic acid alone to a patient who is also vitamin B12 deficient corrects the blood count while allowing the neurological damage to progress, because the megaloblastic mask is lifted.

• Untreated vitamin B12 deficiency: subacute combined degeneration, which may not be fully reversible; permanent cognitive, visual or autonomic damage.
• Untreated severe anaemia: heart failure, high-output states, and in pregnancy adverse fetal outcomes.
• Folate deficiency: neural tube defects in offspring; associations with recurrent pregnancy loss.
• Sideroblastic disease: iron overload affecting heart, liver and endocrine organs; transformation to MDS or acute leukaemia in clonal disease.

Nutritional and drug-induced sideroblastic anaemia and simple megaloblastic anaemia are reversible if the cause is removed early. Pernicious anaemia and post-gastrectomy deficiency require lifelong replacement. Congenital sideroblastic anaemia is lifelong, although some forms respond partially to pyridoxine. MDS-related sideroblastic anaemia follows the course of the underlying syndrome.

There is no role for population-wide screening. Screening is targeted at risk groups: older adults with unexplained macrocytosis or cognitive change, vegans and vegetarians, patients after bariatric or gastric surgery, and those on long-term metformin, acid suppression or anticonvulsants. Pregnant women should have adequate folate and vitamin B12 prophylaxis.

• Pregnancy. Folate demand rises; prophylaxis prevents neural tube defects. Vitamin B12 deficiency also matters for fetal neurodevelopment. Active vitamin B12 is the preferred test in pregnancy because total vitamin B12 falls physiologically.
• Children. Congenital sideroblastic forms present early; inherited vitamin B12 disorders are investigated when a young patient has pancytopenia or failure to thrive.
• Older adults. Atrophic gastritis is common; vitamin B12 deficiency may present with cognitive decline without anaemia.

• Total serum vitamin B12 is more widely available than active vitamin B12, MMA and homocysteine. Where metabolites are not available, a therapeutic trial of intramuscular vitamin B12 with clinical follow-up is reasonable in high-suspicion cases.
• Folate is cheap and widely available; but in any setting folic acid should not be given without considering or covering vitamin B12 deficiency.
• Ringed sideroblasts require a stained marrow aspirate; where marrow examination is unavailable, the combination of a microcytic anaemia with systemic iron overload signs and a suggestive history (alcohol, lead, isoniazid) supports the diagnosis provisionally.
• Lead exposure is prevented by environmental and occupational hygiene; anaemia testing alone will not find the cause without an exposure history.
• Hydroxocobalamin 1000 micrograms intramuscularly is inexpensive and can be given in primary care without specialist equipment.

Anaemia: approach and iron deficiency.