Megaloblastic anaemia and B12 deficiency

Definition. A macrocytic anaemia caused by impaired DNA synthesis from vitamin B (cobalamin) or folate 12 deficiency, producing nuclear-cytoplasmic asynchrony and ineffective erythropoiesis.

Physiology of B absorption. Dietary B binds R-protein, is released by pancreatic proteases, binds intrinsic 12 12 factor from gastric parietal cells, and is absorbed in the terminal ileum. Body stores last 3–5 years, whereas folate stores last only 3–4 months.

Causes of B deficiency in the elderly. Food-cobalamin malabsorption from atrophic gastritis and 12 hypochlorhydria is the commonest cause in old age; pernicious anaemia (autoimmune, with anti-intrinsic factor and anti-parietal cell antibodies); gastrectomy or bariatric surgery; terminal ileal disease or resection; bacterial overgrowth; tropical sprue; strict vegetarian diet (very relevant in India); and drugs — metformin, proton pump inhibitors, H blockers, colchicine and nitrous oxide.

Causes of folate deficiency. Poor intake and alcoholism, malabsorption (coeliac disease, tropical sprue), increased demand (haemolysis, malignancy, pregnancy), and drugs — methotrexate, trimethoprim, phenytoin and sulfasalazine.

General clinical features. Insidious anaemia with lemon-yellow pallor and mild jaundice, glossitis (beefy red smooth tongue), angular stomatitis, anorexia and weight loss; frail patients may present with heart failure.

Neurological features (B only, and may occur without anaemia). Subacute combined degeneration of the 12 cord — symmetrical paraesthesiae, loss of vibration and joint position sense, sensory ataxia, and spastic paraparesis with extensor plantars but absent ankle jerks. Also peripheral neuropathy, optic atrophy, dementia, depression and psychosis ("megaloblastic madness"). Folate deficiency does not cause subacute combined degeneration.

Laboratory findings. Raised MCV (often >110 fL), oval macrocytes and hypersegmented neutrophils (5% with five lobes or any six-lobed cell), pancytopenia when severe, and a low reticulocyte count. Ineffective erythropoiesis gives a raised LDH and unconjugated bilirubin with low haptoglobin, mimicking haemolysis or TTP (pseudo-thrombotic microangiopathy). Marrow shows megaloblasts and giant metamyelocytes.

Confirming the deficiency. Serum B <200 pg/mL (148 pmol/L) is diagnostic; for indeterminate values of 200– 12 350 pg/mL measure serum methylmalonic acid (raised in B deficiency only) and homocysteine (raised in 12 both B and folate deficiency). Holotranscobalamin (active B ) is an alternative first-line test. Add serum and 12 12 red cell folate, anti-intrinsic factor antibody (highly specific, poorly sensitive) and anti-parietal cell antibody, and gastroscopy for atrophic gastritis (risk of gastric cancer and carcinoid).

Treatment. Hydroxocobalamin 1000 µg intramuscularly on alternate days for 1–2 weeks, then 1000 µg every 2–3 months for life. If there are neurological features, continue alternate-day injections until no further improvement occurs, then maintain 2-monthly. Oral cyanocobalamin 1000–2000 µg daily is effective for dietary deficiency and food-cobalamin malabsorption. Folate deficiency is treated with folic acid 5 mg daily.

Cautions and monitoring. Never give folate alone when B deficiency is possible — it precipitates or 12 worsens subacute combined degeneration. Expect a reticulocytosis at day 5–7 and a rising haemoglobin within 1–2 weeks. Watch for hypokalaemia during the response, and for unmasked iron deficiency (falling MCV with a dimorphic film). Screen for thyroid disease and other autoimmune conditions in pernicious anaemia.

NICE NG239 (March 2024) — Vitamin B deficiency in over-16s. Test using either total B or active B 12 12 12 (holotranscobalamin); use serum methylmalonic acid for indeterminate results; do not delay replacement while awaiting results if there are neurological symptoms or megaloblastic anaemia; and offer lifelong intramuscular replacement after total gastrectomy, complete terminal ileal resection, or when autoimmune gastritis is the cause.

Metformin-associated B deficiency is now formally classified as a common adverse effect by regulators, 12 with periodic B testing advised in long-term metformin users, particularly those with anaemia or neuropathy.