Cobalamine or vitamin B12 is a hydrosoluble vitamin, essential in the process of DNA synthesis, haematopoiesis and neuronal cell proliferation and maturation. Vitamin B12 deficiency is a relatively common condition, especially in elderly population, and is associated with potentially severe haematological and neurological complications, especially when it is not diagnosed in the initial phase of symptoms appearance.1
It is difficult to estimate the prevalence of this condition; however data provided by the National Health and Nutrition Examination Survey showed that 3.2% of the over-50 population has low blood levels of vitamin B12.2 The more common clinical manifestations of vitamin B12 deficiency are reported in the box.3
Whilst the link between hypovitaminosis B12 and development of megaloblastic anaemia is nowadays well-known, the mechanisms that cause neurological lesions are less understood; it is however hypothesised a damage at the myelin sheath level, which might be followed by neurological signs and symptoms like paraesthesia, postural instability and, in the most severe cases, memory and central vision loss. The risk factors linked to vitamin B12 deficiency can be principally attributed to insufficient nutritional intake (for example in elderly people or vegetarians) or to absorption alterations at intestinal level (for example in case of Crohn disease or intestinal resection).3 However, recent studies have established a significant nexus between hypovitaminosis B12 and prolonged use of some classes of drugs, among which metformin4 and gastric secretion inhibitors.
Gastric secretion inhibitors
Vitamin B12 taken in by diet and in presence of acid secretion is released from foods, bounds to the produced gastric intrinsic factor (by parietal cells) and is then absorbed at the intestinal tract level (ileum). Gastric secretion inhibitor drugs – proton pump inhibitors and histamine H2 receptor antagonists – by reducing the production of hydrochloric acid could lead to poor absorption of vitamin B12. On the basis of this hypothesis, many studies have been conducted in order to establish a relation between the prolonged use of these drugs and hypovitaminosis B12; so far the available results have showed contrasting data.5-6
Lam and colleagues have recently published on JAMA the results of a case-control study which shows a significant correlation between long-term use of gastric secretion inhibitors drugs and increased risk of vitamin B12 deficiency.7 The study has been conducted by analysing data from the clinical files of 210,155 patients; then the exposition to gastric secretion inhibitor drugs has been evaluated among 25,956 patients with initial diagnosis of vitamin B12 deficit, comparing them with 184,199 healthy controls.
Among these cases, 3,120 patients (12%) had been taken proton pump inhibitors for two or more years, 1,087 (4.2%) had been taken anti-H2 for the same period and 21,749 had not taken any gastric secretion inhibitor. The data analysis showed that a new diagnosis of vitamin B12 deficiency was more frequent among those who had taken proton pump inhibitors or H2 antagonists for a minimum period of 2 years in respect to those who had never taken any of these drugs (odds ratio for pump inhibitors 1.65, 95% confidence interval, 1.58 to 1.73; odds ratio for H2 antagonists 1.25, 95% confidence interval, 1.17 to 1.34).
In particular, doses higher than 1.5 tablets per day of pump inhibitors were more associated to vitamin B12 deficiency than lower doses; a similar result was reported for H2 antagonists too. The association between gastric secretion inhibitors drugs and risk of vitamin B12 deficiency was stronger in women and young patients; besides, hypovitaminosis B12 decreased after these drugs were discontinued.
|Clinical manifestations of vitamin B12 deficiency3|
|Anaemia (macrocytic, megaloblastic), Thrombocytopenia|
|Cognitive impairment, Gait abnormalities, Irascibility, Peripheral neuropathy, Weakness|
In Italy, drugs for gastrointestinal apparatus and metabolism represent the fourth therapeutic class in term of highest public expense, with data indicating a consumption increase of 3.3% for 2013 in respect to the previous year. In particular, the sub-class of proton pump inhibitors is at the first place both in terms of spending and consumptions.8
Data provided by Lam’s study on a possible association between the use of gastric secretion inhibitors drugs and vitamin B12 deficiency add further evidences that could significantly contribute to the debate and urge the physician prescribing them to careful consider the correct use of this drug class. More attention should be paid for patients at higher risk of hypovitaminosis B12 (for example those with autoimmune atrophic gastritis), in order to promptly intervene, avoiding further complications due to the ongoing pharmacological therapy.
Pharmacology Unit, DIMEC, University of Bologna
- Dtsch Arztebl Int 2008;105:680-5. CDI
- Am Fam Physician 2011;83:1425-30.
- Brit Med J 2010;340:c2181. CDI
- Ann Pharmacother 2002;36:812-6. CDI NS
- Aliment Pharmacol Ther 2008;27:491-7.CDI NS
- JAMA 2013;310:2435-42. CDI
- AIFA. L’uso dei farmaci in Italia. Rapporto Nazionale gennaio-settembre 2013.