Electronic letters to:

Review:
Emmanuel Andrès, Noureddine Henoun Loukili, Esther Noel, Georges Kaltenbach, Maher Ben Abdelgheni, Anne Elisabeth Perrin, Marie Noblet-Dick, Frédéric Maloisel, Jean-Louis Schlienger, and Jean-Frédéric Blicklé
Vitamin B12 (cobalamin) deficiency in elderly patients
CMAJ 2004; 171: 251-259 [Abstract] [Full text] [PDF]
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Electronic letters published:

[Read eLetter] Food-cobalamin malabsorption syndrome requires supplemental hydrochloric acid and pepsin
Jonathan E. Prousky   (20 August 2004)
[Read eLetter] Diagnosing vitamin B12 deficiency in Canada
Joel G Ray   (17 August 2004)
[Read eLetter] The classic treatment of B12 deficiency is oral
S Peter Wetterberg   (16 August 2004)

Food-cobalamin malabsorption syndrome requires supplemental hydrochloric acid and pepsin 20 August 2004
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Jonathan E. Prousky
The Canadian College of Naturopathic Medicine

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Re: Food-cobalamin malabsorption syndrome requires supplemental hydrochloric acid and pepsin

jprousky{at}ccnm.edu Jonathan E. Prousky

In a recent review article[1], parenteral and/or oral administration of cobalamin were recommended as the treatment of choice for food- cobalamin malabsorption syndrome. The authors’ did mention hypochlorhydria as a factor in this problem, but they did not recommend hydrochloric acid (HCl) and pepsin therapy as a potential treatment.

In a study of 5 patients with hypochlorhydria, all the patients had decreased urinary excretion of protein-bound cobalamin[2]. After receiving supplemental HCl, pepsin, gastric intrinsic factor, or some combination of these, 4 of the 5 patients showed improvement in protein-bound cobalamin absorption. Another study examined the ability of water, cranberry juice, or a 0.1 N HCl solution upon the absorption of protein-bound cobalamin in elderly subjects[3]. The omeprazole-treated subjects had the greatest increase in cobalamin absorption following the ingestion of the dilute HCl solution (p < 0.001).

Maintaining an adequate gastric pH ensures a sufficient sterilizing barrier against enteric pathogens, allows for proper micronutrient absorption, preserves normal intestinal permeability, and prevents hypergastrinemia[4,5]. A high gastric pH (as occurs in atrophic gastritis) is also associated with the development of gastric malignant tumors[6]; therefore, maintaining an adequate gastric pH might be preventative. Supplemental HCl has been shown to reduce (acidify) gastric pH in subjects with simulated hypochlorhydria[7]. Its method of administration has been described by several investigators[5,8-10]. Patients usually start with one 5-10 grain (325-650 mg) capsule of betaine or glutamic acid hydrochloride and pepsin with each meal. Patients are instructed to increase the dosage by one 5-10 grain capsule with each meal, sometimes working up to 60-80 grains with every meal. Patients are advised against this therapy if they are concurrently on nonsteroidal anti-inflammatory medications or corticosteroids, if they have active peptic ulcer disease, if they have abdominal pain, or if they develop abdominal pain or burning from using this treatment. Patients are also informed to use fewer capsules with smaller meals and more capsules at larger meals.

Jonathan E. Prousky, Associate Dean of Clinical Education, Chief Naturopathic Medical Officer, The Canadian College of Naturopathic Medicine, Toronto, Ont.

References

1. Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;171(3):251-9.

2. King CE, Leibach J, Toskes PP. Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12. Dig Dis Sci 1979;24(5):397-402.

3. Saltzman JR, Kemp JA, Golner BB, Pedrosa MC, Dallal GE, Russell RM. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr 1994;13(6):544-5.

4. Kassarjian Z, Russell RM. Hypochlorhydria: a factor in nutrition. Amm Rev Nutr 1989;9:271-85.

5. Kelly GS. Hydrochloric acid: physiological functions and clinical implications. Altern Med Rev 1997;2(2):116-27.

6. Cheli R, Ciancemeria SG, Canciani G. A clinical and statistical follow-up study of atrophic gastritis. Dig Dis 1973;18(12):1061-6.

7. Knapp MJ, Berardi RR, Dressman JB, Rider JM, Carver PL. Modification of gastric pH with oral glutamic acid hydrochloride. Clin Pharm 1991;10(11):866-9.

8. Wright JV. Dr. Wright’s Guide to Healing Through Nutrition. Emmaus: Rodale Press; 1984. p.35-8.

9. Wright JV, Lenard L. Why Stomach Acid Is Good For You. New York: M. Evans and Company, Inc; 2001. p.138-40.

10. Plummer N. The unseen epidemic: the linked syndromes of achlorhydria and atrophic gastritis. Towsend Lett Doctors Patients 2004;252:89-94.

Conflict of Interest:

Jonathan E. Prousky, N.D., FRSH is a consultant for Swiss Herbal Remedies, Ltd., a company that sells nutritional supplements.
Diagnosing vitamin B12 deficiency in Canada 17 August 2004
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Joel G Ray
Department of Medicine, St. Michael’s Hospital, University of Toronto

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Re: Diagnosing vitamin B12 deficiency in Canada

rayj{at}smh.toronto.on.ca Joel G Ray

Dear Editor

Emmanuel Andrès and colleagues have written a comprehensive review of the diagnosis and treatment of vitamin B12 (cobalamin) deficiency <1>. However, we feel that their article fails to consider two elements relevant to the Canadian experience.

First, Canada's flour supply has been fortified with folic acid under a mandatory programme effective since January 1998 <2>. As a consequence, plasma homocysteine, whose main determinant is folate status, is a much less effective test in the diagnostic work-up of suspected cobalamin deficiency <3> in this country. In a large population-based study conducted in 1999, we established the test properties of a total plasma homocysteine for the diagnosis of cobalamin deficiency among 692 adult Ontarians, after exclusion of persons with renal impairment or folate deficiency (red cell folate less than 215 nmol/L) <2>. A homocysteine value greater than or equal to 15 umol/L did not discriminate between cobalamin concentrations below versus those above 120 pmol/L (positive and negative predictive values 7.4% and 97.2%, respectively), nor did it discriminate “indeterminate” cobalamin levels between 120 and 150 pmol/L (positive and negative predictive values 6.3% and 94.0%, respectively) <2>.

Second, the diagnostic algorithm for cobalamin deficiency that Andres et al propose (Figure 3 of their paper) is unnecessarily complex to apply, especially among seniors, in whom cobalamin malabsorption is commonly found due to age-related atrophic gastritis <4>. We accept that serum methylmalonic acid (MMA) might have some place in a diagnostic algorithm, but this indicator of cobalamin insufficiency is falsely elevated in the presence of modest renal impairment <5>, a condition that is increasingly prevalent with advanced age. Serum MMA is commonly elevated in North American seniors <6>, but its lowering through vitamin B12 supplementation does not appear to impact on blood hemoglobin concentration, neurological disability score or quality of life <7>. Like homocysteine, MMA not been fully validated as a routine clinical test of cobalamin deficiency <8>, especially in the face of increased folate fortification <2>, and is not routinely available in Canadian centres and community laboratories.

We propose a simpler and more direct diagnostic approach in the elderly (Figure). We suggest two options for serum cobalamin concentrations in the "grey zone" of 150 to 200 pmol/L (see Figure: http://www.cmaj.ca/pdfs/eletter_aug1704.pdf). Option A considers serum holotranscobalamin -- the complex formed by cobalamin and its transport protein, transcobalamin -- the physiologically active form of vitamin B12 that is transported into cells <9>. This inexpensive, simple radioimmunoassay-based test will become more readily available in Canada, and in at least one previous study, displayed a sensitivity of 100% and a specificity of 89% for cobalamin deficiency <9>. Option B is to initially treat with parenteral cobalamin by the dosing schedule outlined by Andres <1>, and assess the clinical response in 3 months (Figure). High-dose oral cobamalmin (e.g., 1000 ug per day) can be used thereafter, as described by Andres <1>. A therapeutic response validates not only the diagnosis, but also the treatment, which is otherwise safe and inexpensive. Sincerely,

Joel G Ray, MD, MSc, FRCPC Assistant Professor, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario

David E C Cole, MD, FRCPC, PhD Professor, Department of Pathology, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario

References

<1> Andres E, Loukili NH, Noel E, et al. Vitamin B(12) (cobalamin) deficiency in elderly patients. CMAJ 2004; 171: 251-9.

<2> Ray JG, Cole DE, Boss SC. An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise?. Clin Biochem 2000; 33: 337-43.

<3> Joosten E, Pelemans W, Devos P, et al. Cobalamin absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin. Eur J Haematol 1993; 51: 25–30.

<4> Sipponen P, Laxen F, Huotari K, Harkonen M. Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection. Scand J Gastroenterol 2003; 38: 1209-16.

<5> Schneede J, Ueland PM, Kjaerstad SI. Routine determination of serum methylmalonic acid and plasma total homocysteine in Norway. Scand J Clin Lab Invest 2003; 63: 355-67.

<6> Morris MS, Jacques PF, Rosenberg IH, Selhub J. Elevated serum methylmalonic acid concentrations are common among elderly Americans. J Nutr 2002; 132: 2799-803.

<7> Hvas AM, Juul S, Nexo E, Ellegaard J. Vitamin B-12 treatment has limited effect on health-related quality of life among individuals with elevated plasma methylmalonic acid: a randomized placebo-controlled study. J Intern Med 2003; 253: 146-52.

<8> Hvas AM, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001; 161: 1534-41.

<9> Hvas AM, Nexo E. Holotranscobalamin as a predictor of vitamin B12 status. Clin Chem Lab Med 2003; 41: 1489-92.

Thank you, Joel Ray

Conflict of Interest:

None declared
The classic treatment of B12 deficiency is oral 16 August 2004
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S Peter Wetterberg
Consultant geriatrician, Medi 3 AS

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Re: The classic treatment of B12 deficiency is oral

peterwet{at}start.no S Peter Wetterberg

The authors state that the classic treament for B12 deficiency is injections of crystalline B12, and that "in recent years", an oral treatment has been devised. However, oral treatment of pernicious anemia was described already in 1926 by George Minot and William Murphy. Indeed, they received the Nobel Prize in 1934 together with George Whipple for their work. Not until 1948 did Karl Folkers and coworkers at Merck succeed in purifying crystalline B12.

Conflict of Interest:

None declared