Vitamin B₁₂ deficiency, also known as hypovitaminosis B₁₂ or hypocobalaminaemia, is not uncommon, with potentially serious sequelae if not adequately treated.

Clinical presentation

Vitamin B₁₂ deficiency results in a reduction of two metabolic pathways ³: 

1. conversion of L-methylmalonyl coenzyme A into succinyl coenzyme A

2. conversion of homocysteine into methionine

These are critical in myelin maintenance (methylation of myelin basic protein) and DNA synthesis. As a result, deficiency can presents with a wide spectrum of dysfunction, from no symptoms at all (i.e. subclinical disease) to florid CNS involvement and myelosuppression.

Many cases initially present with mild non-specific symptoms e.g. tiredness, usually a manifestation of the associated megaloblastic anaemia.  

Demyelination is a feature of the condition with progressive neurological deficits, including peripheral neuropathy, loss of spinal reflexes, and poor vibrational and proprioception sense. End stage chronic hypocobalaminaemic cases may exhibit dementia, and even frank psychosis. 

Myelosuppression is a common sequela of hypocobalaminaemia due to the key role of vitamin B₁₂ in DNA synthesis. Megaloblastic anaemia is the commonest result of this.

CNS disease is potentially the most serious manifestation, with the demyelination leading to subacute combined degeneration of the spinal cord.

Diagnosis

Although total serum B₁₂ levels are usually sufficient for the diagnosis, it should be noted that this assay does not distinguish between active circulating B₁₂ (containing reduced monovalent cobalt - Co+) and the inactive form (containing oxidised divalent cobalt - Co++). This is important in some clinical settings such as nitrous oxide abuse ³. 

Pathology

There are significant stores of vitamin B₁₂ (cobalamin) in the hepatocytes meaning that symptoms may not become evident for up to a decade after biochemical depletion first occurs.

The effects of insufficient cobalamin levels are the result of cellular inability to perform three metabolic reactions: 

1. methylmalonic acid to succinyl coenzyme A

2. homocysteine to methionine

3. 5-methyltetrahydrofolate to tetrahydrofolate

Aetiology

Insufficient intrinsic factor

• pernicious anaemia: commonest cause globally of B₁₂ deficiency

• atrophic gastritis

• gastrectomy: producing postgastrectomy syndrome

• genetic

Ileal malabsorption

• Crohn disease

• resection of ileum

• infective ileitis e.g. tapeworm

Genetic

• transcobalamin II deficiency: transcobalamin is a carrier molecule for B₁₂ in the plasma

Nutritional

• alcohol excess

• vegans/fastidious vegetarians 

Pharmacological

• H₂ histaminergic antagonists (e.g. ranitidine) for >1 year

• metformin for >4 months

• proton pump inhibitors (PPIs) for >1 year

• nitrous oxide exposure (e.g. anaesthesia) or recreational abuse ³

Other

• POEMS syndrome ⁴

Radiographic features

In established hypovitaminosis B₁₂ the main findings are of subacute combined degeneration of the spinal cord.

Treatment and prognosis

The mainstay of treatment is vitamin B₁₂ supplementation.

The neurological dysfunction starts to respond to treatment within seven days and there is usually complete resolution in three months. Unfortunately, 6% of patients treated for subacute combined degeneration of the spinal cord are left with permanent residual functional deficit ².

See also

• elevated vitamin B₁₂

• subacute combined degeneration of the spinal cord (SACD)