Vitamin B12 deficiency, also known as hypovitaminosis B12 or hypocobalaminemia, is not uncommon, with potentially serious sequelae if not adequately treated.
Vitamin B12 deficiency results in a reduction of two metabolic pathways 3:
- conversion of L-methylmalonyl coenzyme A into succinyl coenzyme A
- 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 anemia.
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 hypocobalaminemic cases may exhibit dementia, and even frank psychosis.
Myelosuppression is a common sequela of hypocobalaminemia due to the key role of vitamin B12 in DNA synthesis. Megaloblastic anemia 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.
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.
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:
- methylmalonic acid to succinyl coenzyme A
- homocysteine to methionine
- 5-methyltetrahydrofolate to tetrahydrofolate
Insufficient intrinsic factor
- pernicious anemia: commonest cause globally of B12 deficiency
- atrophic gastritis
- gastrectomy: producing postgastrectomy syndrome
- Crohn disease
- resection of ileum
- infective ileitis e.g. tapeworm
- transcobalamin II deficiency: transcobalamin is a carrier molecule for B12 in the plasma
- alcohol excess
- >75 years
- vegans/fastidious vegetarians
- 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. anesthesia) or recreational abuse
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.
- 1. Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. (2017) American family physician. 96 (6): 384-389. Pubmed
- 2. Carmel R. How I treat cobalamin (vitamin B12) deficiency. (2008) Blood. 112 (6): 2214-21. doi:10.1182/blood-2008-03-040253 - Pubmed
- 3. Flippo TS, Holder WD. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. (1993) Archives of surgery (Chicago, Ill. : 1960). 128 (12): 1391-5. doi:10.1001/archsurg.1993.01420240099018 - Pubmed
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