Vitamin B12 and Folate Deficiency

Introduction

Vitamin B12 (cobalamin) and folate (vitamin B9) are both essential cofactors for DNA synthesis. Deficiency of either slows the rate of DNA replication in rapidly dividing cells - most obviously the bone marrow - while RNA and protein synthesis continue relatively normally. The result is cells that grow and accumulate cytoplasm but divide too slowly: large, immature precursors called megaloblasts, and in the peripheral blood, macrocytic red cells.¹

The two deficiencies produce an almost identical blood picture, which is why they are considered together - but they differ in one crucial respect: only B12 deficiency causes neurological disease. Distinguishing them, and never treating one while ignoring the other, is the central safety issue in this topic.

Aetiology

Vitamin B12 deficiency

B12 is obtained only from animal products, bound to intrinsic factor (produced by gastric parietal cells) in the stomach, and absorbed in the terminal ileum. The liver stores several years' worth, so deficiency develops slowly.

• Pernicious anaemia - the commonest cause in the UK. An autoimmune condition with antibodies against intrinsic factor (specific) and/or gastric parietal cells (more sensitive but less specific), causing atrophic gastritis and failure of B12 absorption. Associated with other autoimmune disease (autoimmune thyroid disease, type 1 diabetes, vitiligo) and with an increased risk of gastric cancer
• Dietary deficiency - strict vegans, since B12 is found only in animal products
• Terminal ileal disease or resection - Crohn's disease, surgical resection
• Post-gastrectomy - loss of intrinsic factor-producing parietal cells
• Metformin - impairs B12 absorption with long-term use
• Chronic PPI use (reduces the acid needed to release B12 from food) and, rarely, bacterial overgrowth or fish tapeworm (Diphyllobothrium latum)

Folate deficiency

Folate is found in green leafy vegetables and is absorbed in the duodenum and jejunum. Body stores are small (a few months' worth), so deficiency develops much faster than with B12.

• Poor dietary intake - the commonest cause; alcohol excess is a frequent contributor
• Increased demand - pregnancy (hence routine periconceptual supplementation to prevent neural tube defects), haemolysis, malignancy, and any state of rapid cell turnover
• Malabsorption - coeliac disease, small bowel disease
• Drugs - methotrexate and trimethoprim (both folate antagonists), phenytoin and other anticonvulsants

Clinical features

Generic anaemic symptoms are shared with any anaemia: fatigue, lethargy, dyspnoea, pallor and, in the elderly, exacerbation of angina or heart failure.

Features suggesting B12 or folate deficiency specifically

• Glossitis - a smooth, sore, beefy-red tongue from papillary atrophy
• Angular stomatitis
• Mild jaundice - a lemon-yellow tinge from ineffective erythropoiesis causing low-grade intramedullary haemolysis
• Irritability and mild cognitive changes

Neurological features (B12 deficiency only)

Subacute combined degeneration of the spinal cord results from demyelination of the dorsal columns and corticospinal tracts, and can occur even without anaemia being apparent.²

• Symmetrical loss of vibration sense and proprioception (dorsal columns) - often the earliest sign, causing an unsteady, high-stepping (sensory ataxic) gait
• Peripheral sensory neuropathy - symmetrical, ascending, affecting the legs before the arms
• Progressive spasticity and upper motor neurone weakness (corticospinal tract involvement) as disease advances - so examination can show an unusual mix of absent ankle reflexes with extensor plantars
• Optic atrophy and neuropsychiatric changes (irritability, depression, and rarely psychosis - historically "megaloblastic madness") in advanced cases

Investigations

Full blood count and blood film

Macrocytic anaemia (MCV typically above 100 fL, often substantially higher). The blood film shows oval macrocytes and hypersegmented neutrophils (nuclei with 6 or more lobes) - the most specific film finding for megaloblastic anaemia. Pancytopenia can occur in severe deficiency, as DNA synthesis is impaired across all cell lines.

Confirming the deficiency and finding the cause

• Serum B12 and serum or red cell folate - red cell folate is more reliable than serum folate, which fluctuates with very recent intake
• Intrinsic factor antibodies - specific for pernicious anaemia (present in around 50-70% of cases); gastric parietal cell antibodies are more sensitive (around 90%) but less specific, and can be positive in other autoimmune conditions and in healthy older people
• Reticulocyte count - low despite the anaemia, reflecting ineffective erythropoiesis
• Unconjugated bilirubin and LDH may be mildly raised from intramedullary haemolysis, which can mimic haemolytic anaemia - but haptoglobin is typically normal and reticulocytes are low, distinguishing it
• Coeliac serology if malabsorption is suspected
• Consider endoscopy in pernicious anaemia given the associated increased risk of gastric cancer, per local guidance
• Methylmalonic acid and homocysteine (raised in B12 deficiency; homocysteine alone raised in folate deficiency) are useful when B12/folate levels are borderline, but are not first line

Differential diagnosis

The differential of a macrocytic anaemia is broader than B12/folate deficiency alone:

• Alcohol excess - a very common cause of macrocytosis, with or without anaemia, and can coexist with folate deficiency
• Hypothyroidism
• Liver disease
• Myelodysplastic syndrome - consider in the elderly, especially with other cytopenias or dysplastic features
• Drug-induced - hydroxycarbamide, azathioprine, zidovudine
• Reticulocytosis from haemolysis or bleeding can raise the MCV, since reticulocytes are larger than mature red cells

Management

Vitamin B12 deficiency

• Intramuscular hydroxocobalamin is first line, particularly where malabsorption (e.g. pernicious anaemia) is the cause and oral therapy would be unreliable. A typical regimen is 1 mg IM three times weekly for 2 weeks, then 1 mg every 3 months for life if the cause (e.g. pernicious anaemia) is not reversible³
• If there is neurological involvement, more frequent dosing is used (e.g. alternate days until no further improvement) and specialist/haematology input is appropriate
• Oral B12 may be used for dietary deficiency where absorption is intact (e.g. vegans without malabsorption)

Folate deficiency

• Oral folic acid 5 mg daily, typically for 4 months, or longer/lifelong if the underlying cause persists
• Dietary advice, and periconceptual folic acid where relevant

Complications

• Subacute combined degeneration of the spinal cord, which may be irreversible if treatment is delayed
• Severe anaemia precipitating high-output cardiac failure, particularly in the elderly
• Increased risk of gastric cancer in pernicious anaemia
• Neural tube defects in pregnancy from folate deficiency
• Neuropsychiatric disturbance

Red flags

Prognosis

The haematological response to treatment is rapid: a reticulocytosis appears within a few days, and the blood count normalises over several weeks.³ Folate deficiency responds particularly quickly to oral replacement.

Neurological recovery is far less predictable. Improvement can occur over months of treatment, but the longer subacute combined degeneration has been present before treatment starts, the less complete recovery tends to be, and established spasticity or ataxia may persist permanently - underscoring why early recognition, particularly in patients with neurological rather than haematological presentations, is so important.