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Figure Caricature made by professor Stig Radner, Department of Internal Medicine, University Hospital of Lund, about 1980. Summary |
How we wish to be cited:
Cobalamin and folate for better and worse
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Figure Caricature made by professor Stig Radner, Department of Internal Medicine, University Hospital of Lund, about 1980. Summary |
Early history
Cobalamin turned a fatal illness, pernicious anemia, into a benign disorder
during the 1930´ies (1, 2). The interaction between folate and cobalamin in
macrocytic anemia was partly elucidated during the 1940´ies (1). The first
therapy for pernicious anemia was oral, raw liver, 200-300 gram daily. Later
therapy was parenteral, more or less crude liver extracts. Since these liver
extracts also contained folate and iron, the cobalamin effect was not blocked by
lack of folate or iron.
Documentation of oral B12 therapy
The Baltimore group of McIntyre (1960) was the first to demonstrate that 1
mg of cyanocobalamin daily is the optimal dose for safe and reliable oral
treatment of pernicious anemia in relapse (3). The experimental and clinical
works of the Berlin group started about 1960 in Eskilstuna, Örebro, and
Linköping (4). They began with 0.5 or 1.0 mg of oral cyanocobalamin daily.
However, some patients could not be maintained on 0.5 mg oral cyanocobalamin
daily. During the last three years of the study, all patients received 1 mg oral
cyanocobalamin daily.
The Berlins (1968) concluded that 1 mg of oral cyanocobalamin is a safe and reliable treatment for B12-deficiency anemia, both in the stage of remission treatment and in the stage of maintenance treatment (4). However, by that time B12 therapy was parenteral in clinical practice; the doctors hesitated to accept oral high-dose cobalamin. As a last appeasement to remaining anxiety, the Berlin group suggested that remission treatment could start with oral cyanocobalamin, 2 mg twice daily, for one month.
A single oral dose of 2 mg does not significantly exceed the capacity of transcobalamin and haptocorrin to carry cobalamin from bowel to tissues; larger doses produce a spill of cobalamin into urine, analogous to the spill in parenteral therapy. An oral single dose of 100 mg was non-toxic; the pharmacokinetics were akin to that of a one mg intramuscular injection (4). Ten years later, the Berlins verified that oral cyanocobalamin, 1 mg daily, fills the body stores as adequately as conventional injection therapy (5).
The Norwegian confirmation
The last classical study of vitamin B12 for pernicious anemia is that of the
Norwegian Erik Magnus (6) – a macrocytic anemia defined by hemoglobin,
hematocrit, or number of red cells in a patient with histamine-refractory
achylia. Magnus compared oral cyanocobalamin, 1 mg daily for 200 days, with two
modes of parenteral therapy. The oral treatment represented half the calculated
body stores of vitamin B12 in saturated patients. After each treatment period,
the patients were left without maintenance treatment until clinical symptoms
reappeared. Twenty-six patients completed 1-3 periods of oral treatment, which
was as satisfactory as parenteral treatment. The Magnus study provides precious
basic research on the natural history, course, pathogenesis, and individual
variation of B12 deficiency. It cannot be repeated nowadays due to the influence
of modern Ethical Committees.
Oral vitamin B12 in neuropathy
Now and then, it is suggested that the neuropathy of B12 deficiency may become
permanent, if not treated rapidly. Obviously, it is a matter of professional
honor to detect deficiency states at an early stage and give adequate therapy.
Nevertheless, the evidence for permanent nerve lesions due to B12 deficiency is
poor. Erik Magnus noted that one third of his patients started with neurologic
symptoms and relapsed with neurologic symptoms (6). This finding is now
generally accepted (7).
Some patients with neuropathy respond to treatment within days or weeks. It is reasonable to assume that the early responses reflect lack of transmittors in the nervous system due to B12 deficiency. I have seen at least two patients with severe disturbance of gait and foot sensitivity. Both of them, one with oral cyanocobalamom 1 mg daily, recovered within 2-3 years. The healing was accompanied by severe pain in the legs. It is reasonable to assume that such a course reflects the repair of lesions in nerve sheaths. The pain of healing is a signal of hope, not to be misinterpreted by patient and doctor.
Modern treatment of B12 deficiency
"In good old days, the patients were worse." Nowadays, the
incidence of pernicious anemia has fallen (7); in Sweden, the incidence is
thought to be about one case/100,000 residents a year. In early stages of
vitamin B12 deficiency, measurable improvement is quick. If the homocysteine
value is above 20 micromoles/L, it is reasonable to expect improvement of
symptoms, neurological symptoms included, within two months (8). An adequate
therapy is for example oral cyanocobalamin, 1 mg daily, and oral folic acid, 5
mg daily (8). Present prescription of cobalamin in Sweden, less than 300,000
patient years with doses corresponding to oral cyanocobalamin 1 mg daily (9, 10)
among 1.2 million of residents aged 70 and over, falls within the frames set by
epidemiological studies of deficiency prevalence (11).
Bo Norberg
References
Published July 5, 2004
