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Elevated Methylmalonic Acid and Total Homocysteine Levels Show High Prevalence of Vitamin B12 Deficiency after Gastric Surgery

Anne E. Sumner, MD; Margaret M. Chin, PharmD; Janet L. Abrahm, MD; Gerard T. Berry, MD; Edward J. Gracely, PhD; Robert H. Allen, MD; and Sally P. Stabler, MD
[+] Article, Author, and Disclosure Information

From Philadelphia Veterans Affairs Medical Center, Medical College of Pennsylvania and Hahnemann University, Philadelphia College of Pharmacy and Science, and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and University of Colorado Health Sciences Center, Denver, Colorado. Grant Support: By Department of Health and Human Services research grants DK-21365(RHA), AG0983(SPS), and AG00532 (AES) from the National Institutes of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging and by The Howard Heinz Endowment to the Medical College of Pennsylvania. The University of Colorado and two of the authors, Robert H. Allen and Sally P. Stabler, have applied for patents covering various aspects of the assays for methylmalonic acid and homocysteine. Requests for Reprints: Anne E. Sumner, MD, Medical College of Pennsylvania, 3300 Henry Avenue, Philadelphia, PA 19129.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(5):469-476. doi:10.7326/0003-4819-124-5-199603010-00002
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Objective: To determine the prevalence of vitamin B12 deficiency in patients who have had gastric surgery.

Design: Cross-sectional study.

Setting: Philadelphia Veterans Affairs Medical Center.

Participants: 61 patients who had had gastric surgery and 107 controls.

Measurements: Serum levels of vitamin B12, folate, methylmalonic acid, and total homocysteine measured before and after treatment in participants with vitamin B12 deficiency. Vitamin B12 deficiency was defined as one of the following: 1) a serum vitamin B12 level less than 221 pmol/L and an elevated methylmalonic acid level; 2) a serum vitamin B12 level less than 221 pmol/L and an elevated total homocysteine level that decreased with vitamin B12 treatment; or 3) in patients unavailable for treatment, a serum vitamin B12 level less than 221 pmol/L, a folate level greater than 9 nmol/L, and an elevated total homocysteine level.

Results: Study patients and controls were similar in age, sex, and racial distribution. Nineteen patients (31%) and 2 controls (2%) had vitamin B12 deficiency (P < 0.001). Twelve (63%) of the 19 vitamin B12-deficient patients had elevated total homocysteine levels. In all participants with vitamin B12 deficiency who received treatment (15 of 21), methylmalonic acid and total homocysteine levels decreased substantially, confirming the deficiency before treatment.

Conclusion: Patients who have had gastric surgery have a high prevalence of vitamin B12 deficiency. Prompt recognition and treatment of the deficiency with resultant normalization of elevated total homocysteine and methylmalonic acid levels may prevent the development of cardiovascular, hematologic, and neurologic abnormalities. Our data support both frequent screening and vitamin B12 replacement therapy in patients who have had gastric surgery and have serum vitamin B12 levels less than 221 pmol/L.


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Figure 1.
The two vitamin B12-dependent enzymes, L-methylmalonyl-CoA mutase (left) and methionine synthase (right).1212

In vitamin B -deficient tissues, the excess methylmalonyl-CoA is hydrolyzed to methylmalonic acid, and serum and urine methylmalonic acid levels increase. With vitamin B or folate deficiency, serum total homocysteine levels increase because methionine synthase requires both cofactors.

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Figure 2.

Serum methylmalonic acid levels before and after treatment. The serum methylmalonic acid levels are shown for the 19 vitamin B -deficient patients (who had had gastric surgery) and the 2 vitamin B -deficient controls (who had not had surgery). Results after parenteral vitamin B therapy are shown for the 15 participants available for treatment. The solid lines represent the normal range, calculated as the mean ±SDs after log normalization to correct for skewing toward higher values as previously reported . The dashed line represents the mean ± 3 SDs. B. Serum total homocysteine levels before and after treatment. The serum total homocysteine levels are shown for the same participants described in panel A.

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