Review: cobalamin deficiency and mental impairment in elderly people.

Introduction

Little is known about the relationship between cobalamin deficiency and mental impairment in elderly people, but cobalamin deficiency may be an important cause of mental disturbances. Cobalamin deficiency increases with advancing age and is found in 3% to 42% of persons aged 65 and over[1-6]. The large variation in these values may be the result of several factors including differences in the population groups studied, assay techniques, cut-off levels, and exclusion criteria. The increased prevalence of low serum cobalamin with advancing age is generally regarded as a consequence of disease rather than a physiological phenomenon[2, 5, 7].

Ageing is associated with a mild decline of cognitive skills but a severe decline of complex cognitive function may be attributed to extrinsic factors, such as cobalamin deficiency[8]. In elderly people with cobalamin deficiency, mental impairment is more often found than are the so-called classical manifestations, such as megaloblastic anaemia and neuropathy and this is often associated with abnormal serum cobalamin values[2, 9-15]. Improvement of mental impairment as a result of treatment with cobalamin is possible, especially in an early stage of the deficiency, before the symptoms and signs become irreversible[12]. It has been reported, however, that only 34% of patients with low serum levels of cobalamin received appropriate therapy[16]. Diagnosis and treatment of cobalamin deficiency is at present a major problem because of the insensitive diagnostic methods and unfamiliarity with the atypical presentations of cobalamin deficiency in elderly patients.

Causes of cobalamin deficiency

Cobalamin is assimilated in the human body in a complex way. On entering the stomach, protein-bound cobalamin is split by hydrochloric acid and forms a complex with R-binding protein. Cobalamin is then transferred to intrinsic factor by means of pancreatic enzymes. This complex is internalized through specific receptors on the mucosa of the distal ileum and intrinsic factor is removed. Subsequently, cobalamin is bound to transcobalamin II with which it circulates in the plasma until it binds to receptors on cells throughout the body and is absorbed. Several causes of cobalamin deficiency in elderly people have been reported (Table I). The most common is pernicious anaemia, in which intrinsic factor secretion has ceased. This condition is associated with antibodies to gastric parietal cells, gastric mucosal atrophy, hypo- and achlor-hydria[17, 18]. Malabsorption of cobalamin due to intrinsic factor deficiency can be measured by the Schilling test. In elderly people, however, low cobalamin is often found with normal Schilling test results. Several studies have shown that this phenomenon can be the result of protein-bound cobalamin malabsorption, in which the release of cobalamin from its dietary protein bound state is impaired, often owing to achlorhydria[11, 19-21].

Atrophic gastritis is the most common cause of hypo- or achlor-hydria in elderly people[22] and is characterized by a partial loss of fundic glands and a corresponding decrease in parietal cell mass. Gastric atrophy involves the complete loss of fundic glands, and is characteristic of pernicious anaemia[17, 22]. Of persons aged 60 and over, 32% have atrophic gastritis and at ages over 70, the prevalence increases to 50%[22]. Non-invasive methods that have been used as indicators of atrophic gastritis include the presence of circulating parietal-cell antibodies, and elevated gastrin and low pepsinogen (PG) levels in serum. The ratio of PG I to PG II, in combination with the absolute PG I level, can be used to detect mild or moderate atrophic gastritis, which is not detected by other methods[21, 22].

 
Table I. Main causes of cobalamin deficiency in elderly people 

 
1. Dietary insufficiency 
2. Intrinsic factor deficiency: 
    Gastric atrophy 
    Gastrectomy 
    Congenital deficiency 
3. Achlorhydria 
    Atrophic gastritis 
    Medication 
4. Protein-bound malabsorption 
5. Competition for cobalamin: 
    Bacterial proliferation 
    Parasites 

Cobalamin deficiency due to protein-bound cobalamin malabsorption has been noted particularly in patients with neuropsychiatric abnormalities [9, 11, 23, 24]. There is a positive correlation between levels of cobalamin and PG I in serum in demented patients, indicating that atrophic gastritis could be a cause of their low serum cobalamin values.

Protein-bound cobalamin malabsorption is not always a consequence of gastric dysfunction. It has been shown that nearly 50% of patients with low serum cobalamin and a normal Schilling test are unable to absorb protein-bound cobalamin as opposed to the free cobalamin used in the Schilling test[11, 16, 21, 25]. In half of these cases there was no evidence of gastric abnormalities[19, 21]. It is conceivable that salivary abnormalities or, more likely, upper intestinal or pancreatic abnormalities may sometimes be responsible for the …