Deficiency of cobalamin and/or folate results finally in macrocytic anemia. In addition, cobalamin deficiency may produce neurological and neruopsychiatric symtoms. However, the interplay between cobalamin and folate is complex. Some studies have shown a correlation between depression, cognitive dysfunction, and folate deficiency (1). Both cobalamin and folate are necessary for the essential re-methylation of homocysteine to methionine. Thus, it may be difficult to define whether body stores of cobalamin or folate or both are running low.

In the typical case with megaloblastic anemia and low concentrations of serum cobalamin, there is no diagnostic difficulty. However, nowadays most cases appear in an earlier stage of deficiency with less pronounced symptoms. In such patients, the determination of vitamin concentrations in serum are of limited value; however, the lower the vitamin concentrations, the higher the probability of deficiency.

The diagnostic difficulties are illustrated in a study demonstrating that 40% of patients with serum cobalamin below 130 pmol/L lacked signs of B12 malabsorption or B12 malnutrition (2). In contrast, 30% of patients in the lower reference range (130-200 pmol/L) had signs of B12 malabsorption or B12 malnutrition (2). The interpretation of serum folate poses analogous problems. The reference range is estimated to lie between 5-15 nmol/L.

From about 1990, methylmalonic acid (MMA) and homocysteine (Hcy) were launched as markers for metabolic deficiency of cobalamin (MMA, Hcy) and folate (Hcy). The analyses are sensitive but not specific:

1. MMA is strongly influenced by kidney function, even within reference values of serum creatinine (3,4).
2. The variation coefficient of MMA is alarmingly high, 34% (5).
3. In a patient population with serum creatinine within reference range and elevated MMA and/or Hcy, about 15% had no sign of cobalamin malabsorption (6).
4. The results of Lindenbaum et al (7) suggests that homocysteine, much like MMA, is influenced by renal function.
5. Beside cobalamin/folate deficiency, several other factors increase plasma Hcy (8).

Current knowledge suggests that about 90% of cobalamin deficiency in patients not subjected to gastric or bowel surgery is caused by chronic atrophic gastritis (9). The main part of the rest is caused by celiac disease. Thus, it is suggested that a possible atrophic gastritis is diagnosed or excluded by pepsinogen A, combined with gastrin or pepsinogen C. In patients with renal impairment, the pepsinogens and gastrin may be increased due to reduced excretion; in such patients, gastroscopy should be performed. Celiac disease should be excluded by means of antibody tests against gliadine and transglutaminase (9).

Patients with gastrointestinal symptoms, especially loose stools, may generously be referred to a gastroenterologist. A serum Hcy below 15 micromol/L excludes deficiency of cobalamin and folate in patients with neurological or neuropsychiatric symptoms. An elevated Hcy has to be interpreted with caution.

It is suggested that the following patients are considered for prophylactic treatment:

1. Symptom-free patients with chronic atrophic gastritis.
2. Patients with previous surgical procedures in stomach or distal part of the small bowel.
3. Patients with Crohn´s disease in the small bowel.
4. Patients on long-term therapy (several years) with protone pump inhibitors, which interfere with the up-take of protein-bound cobalamin.
5. Patients on long-term therapy with metformin, which is reported to inhibit the calcium-mediated up-take of the B12-IF complex in the terminal part of ileum.

On a group level, oral cyanocobalamin, 1-2 mg daily, is at least as effective as parenteral cobalamin (10). It is a common knowledge among physicians that many patients on parenteral treatment require injections every one or two months; they complain of fatigue and mood changes otherwise. It is desirable that such a statement by a patient is taken seriously.

The classical concept is cobalamin monotherapy in case there is no evidence of folate deficiency. Conversely, the classical concept is that folate should be combined with cobalamin in order to avoid progression of neurological lesions due to cobalamin deficiency, covered by folate therapy; "it is an error of the art to treat a macrocytic anemia with folate only".

During the last six years, a Swedish manufakturer has marketed the combination preparation TrioBe (cobalamin 0.5 mg, folate 0.8 mg, pyridoxine 3 mg) in Sweden for all persons with homocysteine above 12-15 micromol/L. TrioBe is not registered and licenced for treatment of cobalamin deficiency, cardiovascular disease, or dementia. Homocysteine lowering has not been shown to decrease the morbidity and mortality of vascular disease (11-12). Thus, the indications for TrioBe have vanished in recent years.

1. 1.Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ 2002;324:1512-15.
2. Lindgren A. On the diagnosis of cobalamin malabsorption. Akademisk avhandling Göteborgs Universitet 1998.
3. Lindgren A. Elevated serum methylmalonic acid. How much comes from cobalamin deficiency and how much comes from the kidneys. Scand J Clin Invest 2002;62:15-20.
4. Hvas AM, Juul S, Gerdes LU, Nexø E. The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J Intern Med 2000;247:507-12.
5. Hvas AM, Ellegaard J, Nexø E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001;161:1534-41.
6. Lindgren A, Swolin B, Nilsson O, Johansson KW, Kilander AF. Serum methylmalonic acid and total homocysteine in patients with suspected cobalamin deficiency: a clinical study based on gastrointestinal histopathological findings. Am J Hematol1997;56:230-38.
7. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994:60:2-11.
8. Lindgren A. Mag-tarmstatus bästa diagnostikum vid misstänkt B12-brist. Läkartidningen 2000;97:3987-92.
9. Lindgren A, Lindstedt G, Kilander AF. Advantages of serum pepsinogen A combined with gastrin or pepsinogen C as first-line analytes in evaluation of suspected cobalamin deficiency:a study in patients previously not subjected to gastrointestinal surgery. J Intern Med 1998;244:341-9.
10. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191-98.
11. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ,Sides EG, Wang Chin-Hua, Stampfer M. Lowering Homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. The VISP randomized controlled trial. JAMA 2004;291:565-75.
12. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D´Agostino RB, Wilson PWF, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer´s disease. N Engl J Med 2002;346:476-83.

Published April 22, 2005