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Home , Vitamin B12 deficiency

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Emmanuel Andrès, MD, B12 deficiency: A look beyond Laure Federici, MD, Stéphan Affenberger, MD pernicious Department of Internal Medicine, and Metabolic Diseases, Food-B12 —not pernicious anemia—is the Hôpitaux Universitaires de Strasbourg, leading cause of B12 malabsorption. It’s also very subtle Strasbourg, France emmanuel.andres @chru-strasbourg.fr Practice recommendations such as its link to Helicobacter pylori • Mild, preclinical B deficiency infection and long-term antacid and bi- Josep Vidal-Alaball, MD 12 Department of General is associated with food-B12 guanide use. It also requires that you Practice, Cardiff University,

malabsorption more often than consider not only a patient’s serum B12 with pernicious anemia. (C) ® Dowdenlevels, but his Health Media and meth - Noureddine Henoun Loukili, PhD • The classic treatment for B ylmalonic acid levels, since they are con- 12 Department of Hygiene and deficiency—particularly when the sidered more sensitive indicators of co- 6 Fight against Nosocomial cause is not a dietaryCopyright deficiency—isFor personalbalamin deficiency. use Keyingonly in on these Infections, Hôpital Calmette, 100 to 1000 mcg per month of indicators early will ensure prompt treat- CHRU de Lille, Lille, France , IM. (B) ment, which typically includes intramus- cular injections of the vitamin, but which Jacques Zimmer, MD, PhD • Oral crystalline cyanocobalamin could revolve around a more convenient Laboratoire is an effective treatment for food- d’Immunogénétique- option: oral B12. Allergologie, Centre de B12 malabsorption, though it’s Recherche Public de la Santé effectiveness in the long term has (CRP-Santé) de Luxembourg, not been demonstrated. (B) z A common problem that Luxembourg Georges Kaltenbach, MD comes in many shades Department of Internal f an image of an elderly patient with B12 deficiency is common in elderly pa- Medicine and Geriatrics, pernicious anemia is the first thing tients7 and its incidence increases with Hôpitaux Universitaires that comes to mind when you think age.7,8 The Framingham study revealed a de Strasbourg, I Strasbourg, France of B12 deficiency, take note: That image prevalence of 12% among elderly people could obfuscate a more common case of living in the community.8 Other studies

B12 deficiency—one caused by food-B12 focusing on those who are in institutions malabsorption. or who are sick and malnourished, have In this Article Food-B12 malabsorption, character- suggested a higher prevalence of 30% to ized by the inability to release B from 40%.3,9 z 12 Oral therapy is food or its binding proteins, is actually The clinical manifestations of B 12 a well-kept secret the leading cause of B12 malabsorption, deficiency are highly polymorphic and especially in elderly patients.1–4 And un- of varying severity ranging from milder Page 541 like pernicious anemia, it’s more likely to conditions such as the common senso-

be associated with mild, preclinical B12 ry neuropathy and isolated anomalies deficiency.1,5 of and hypersegmenta-

Spotting this form of B12 deficiency tion of neutrophils, to severe disorders, requires that you focus on its nuances, including combined sclerosis of the

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table 1 1,5,6,10–13 Clinical features of B12 deficiency

Hematologic Neuropsychiatric Frequent* Classic Macrocytosis Combined sclerosis of the spinal cord Hypersegmentation of the neutrophils Frequent* Aregenerative macrocytary anemia Polyneurites (especially sensitive ones) Medullary megaloblastosis (“blue spinal cord”) Rare Babinski’s phenomenon Isolated thrombocytopenia and neutropenia Rare Cerebellar syndromes affecting the cranial nerves including Hemolytic anemia optic neuritis, optic atrophy, urinary or fecal incontinence Thrombotic microangiopathy (presence of schistocytes) Possible Cognitive impairment digestive Stroke and atherosclerosis () Classic Parkinsonian syndromes Hunter’s Multiple sclerosis Jaundice other LDH and bilirubin elevation Possible Rare Atrophy of the vaginal mucosa Resistant and recurring mucocutaneous ulcers Chronic vaginal and urinary infections (especially mycosis) Hypofertility and repeated miscarriages Venous thromboembolic disease Angina (hyperhomocysteinemia) * Reported in practice and recent literature.

spinal cord, hemolytic anemia and even teine and methyl malonic acid—2 com- pancytopenia (Table 1).1,5,6,10–13 ponents of the cobalamin metabolic path-

B12 deficiency is often unrecognized way. A deficiency exists if the patient’s or not investigated because the clini- blood work reveals the following:2,18

cal manifestations can be very subtle. • Serum B12 levels <150 pmol/L In fact, one of its manifestations—mild and either total serum homocysteine memory loss—can mimic the early stag- levels >13 µmol/L or methylmalonic es of .14 acid levels >0.4 µmol/L (in the absence Further muddying the waters is the of renal failure and and vitamin

fact that B12 deficiency appears to be B6 deficiencies). more common among patients who have • Low serum holotranscobalamin a variety of chronic neurologic condi- levels <35 pmol/L. tions such as stroke, Parkinson’s disease, dementia, Alzheimer’s disease, and de- pression—although it is unclear if these z The “classic” cause are causal relationships.1,15 In our own is not the most common

studies in which we administered B12 to The principal causes of B12 deficiency patients with dementia, we did not ob- include pernicious anemia, dietary defi- serve any improvement.2,5 Other studies ciency, postsurgical malabsorption, and 16,17 have had similar results. food-B12 malabsorption. Of note is the

B12 deficiency is typically defined in fact that there is typically a 5- to 10-

terms of the serum concentration of B12, year delay between the onset of B12 de- as well as the concentration of homocys- ficiency and the development of clinical

538 vol 56, No 7 / july 2007 The Journal of Family Practice t B12 deficiency

illness, in part because of hepatic stores z A form of malabsorption of cobalamin (>1.5 mg).1,19 that’s tough to spot

In elderly patients, B12 deficiency is Food-B12 malabsorption is a syndrome classically caused by pernicious anemia,3,7 characterized by the inability to release the principal characteristics of which B12 from food or intestinal transport have been reported in detail in several re- proteins, particularly in the presence views.20–22 The one thing, of course, that of hypochlorhydria, in which the ab- bears repeating is that this form of anemia sorption of “unbound” B12 is normal. is associated with a lack of , As various studies have shown,4,5,24 this which facilitates the absorption of B12. syndrome is defined by 12B deficiency in

B12 deficiency caused by dietary defi- the presence of sufficient food-B12 intake ciency is more rare. Dietary causes of de- and normal results, which ficiency are limited to elderly people who rules out pernicious anemia. In theory, are already malnourished, such as those indisputable evidence of food-B12 mal- living in institutions (they may consume absorption comes from using a modified inadequate amounts of foods containing Schilling test, which uses radioactive B12 1,19 vitamin B12) and strict vegetarians. (A bound to animal proteins (eg, salmon, typical Western diet contributes 3–30 mcg trout) and reveals malabsorption when of B12 per day towards the recommended the results of a standard Schilling test dietary allowance set by the Food and are normal.1,5,24 Nutrition Board of the Institute of Medi- Some authors have speculated about cine (US) of 2.4 mcg/day for adults and the significance of 12B deficiency related 2.6 to 2.8 mcg/day during pregnancy.23) to food-cobalamin malabsorption,1 Over the past 20 years, postsurgical because many patients have only mild malabsorption of B12 has been on the de- clinical or hematological features. Sev- cline, due in large part to the decreasing eral of our patients, however, have had frequency of and surgical re- significant features classically associated section of the terminal small intestine.1,2,5 with pernicious anemia, including poly- There are, however, several disorders com- neuropathy, confusion, dementia, me- fast track monly seen in gastroenterology practice dullar-combined sclerosis, anemia, and Food-B that may be associated with cobalamin pancytopenia.5 Nevertheless, the partial 12 malabsorption. These include deficiency nature of this form of malabsorption malabsorption in the exocrine function of the pancreas might produce a more slowly progres- accounts for after chronic (usually alco- sive depletion of B12 than does the more 60%–70% holic), lymphomas or tuberculosis (of the complete malabsorption engendered by of the cases intestine), Crohn’s disease, Whipple’s dis- disruption of intrinsic factor–mediated 3,13 ease, and occasionally celiac disease. absorption. The slower progression of of B12 deficiency Rounding out the list of causes of depletion probably explains why mild, in elderly patients

B12 deficiency is food-B12 malabsorption, preclinical deficiency is associated with which is the leading cause of B12 malab- food-B12 malabsorption more often than sorption—especially in elderly patients.1–4 with pernicious anemia.1,5 In our own studies in which we have followed more than 300 patients with a z documented B12 deficiency, food-B12 mal- H pylori, antacid use absorption accounts for about 60% to should raise suspicions

70% of the cases of B12 deficiency in el- Food-B12 malabsorption is caused pri- derly patients, whereas pernicious anemia marily by .5 More than accounts for only 15% to 25%.5,24 In our 40% of patients older than 80 years study of 172 hospitalized patients with have gastric atrophy that might (or

B12 deficiency (median age, 70), 53% had might not) be related to H pylori infec- 5 3,25 food-B12 malabsorption. tion. Other factors that contribute to

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table 2 38–41,45 French hospital findings support use of oral 12B treatment

Study characteristics (number of patients) Therapeutic modalities results

Open prospective study Oral crystalline cyanocobalamin: • Normalization of serum vitamin B12 levels in 80% of the patients of well-documented 650 mcg per day, for at least • Significant increase of hemoglobin (Hb) levels (mean of 1.9 g/dL)

vitamin B12 deficiency 3 months and decrease of mean erythrocyte cell volume (ECV) (mean of 7.8 fL)

related to food-B12 • Improvement of clinical abnormalities in 20% of the patients malabsorption (n=10)39 • No adverse effects

Open prospective study of Oral crystalline cyanocobalamin: • Normalization of serum vitamin B12 levels in 85% of the patients

low vitamin B12 levels not between 1000 mcg per day • No adverse effects related to pernicious for at least 1 week anemia (n=20)40

Open prospective study Oral crystalline cyanocobalamin: • Normalization of serum vitamin B12 levels in 87% of the patients of well-documented between 250 and 1000 mcg • Significant increase of Hb levels (mean of 0.6 g/dL) and decrease

vitamin B12 deficiency per day, for 1 month of ECV (mean of 3 fL); normalization of Hb levels and ECV in 54%

related to food-B12 and 100% of the patients, respectively 38 malabsorption (n=30) • Therapeutic dose of vitamin B12 ≥500 mcg per day • No adverse effects

Open prospective study Oral crystalline cyanocobalamin: • Normalization of serum vitamin B12 levels in all patients with

of low vitamin B12 levels between 125 and 1000 mcg at least a dose of vitamin ≥250 mcg per day

not related to pernicious per day for at least 1 week • Therapeutic dose of vitamin B12 ≥500 mcg per day anemia (n=30)41 • No adverse effects

Open prospective study Oral crystalline cyanocobalamin: • Significant increase of serum vitamin B12 levels in 90% of the

of low vitamin B12 levels 1000 mcg per day, for at least patients (mean of 117.4 pg/mL) related to pernicious 3 months • Significant increase of Hb levels (mean of 2.45 g/dL) anemia (n=10)45 and decrease of ECV (mean of 10.4 fL) • Improvement of clinical abnormalities in 30% of the patients

5 food-B12 malabsorption in elderly peo- food-B12 malabsorption, we found ple include: at least one of the associated condi- • Chronic carriage of H pylori and tions or agents listed at left in 60% of intestinal microbial proliferation (in the patients. These conditions mainly

which case B12 deficiency can be correct- included atrophic gastritis (H pylori ed by antibiotic treatment)25,26 infection) in 30% of the patients and • Long-term ingestion of antacids, long-term or antacid intake

including H2-receptor antagonists and in 20% of the elderly patients. proton-pump inhibitors,27,28 particularly among patients with Zollinger-Ellison syndrome29,30 z IM injection is customary, • Long-term ingestion of biguanides though dosages vary 31–33 (metformin) The classic treatment for B12 deficiency, • Chronic alcoholism particularly when the cause is not a di- • Surgery or gastric reconstruction etary deficiency, is parenteral adminis- (eg, bypass surgery for ) tration—usually by intramuscular injec- • Partial pancreatic exocrine failure1,5 tion—of cyanocobalamin (and in rare • Sjögren’s syndrome or systemic occasions, ).7,11,16,35 sclerosis34 In the US and UK, dosages range from In our research involving 92 elder- 100 to 1000 mcg per month (or every ly patients (mean age: 76 years) with 2–3 months when hydroxocobalamin is

540 vol 56, No 7 / july 2007 The Journal of Family Practice t B12 deficiency

given). The patient will receive this treat- and 2000 mcg given daily in the begin- ment for the rest of his life.1,35 ning, and then weekly.46 In this analysis,

In France, the recommended prac- serum B12 levels increased significantly in tice is to build up the tissue stores of the patients receiving oral vitamin B12 and vitamin quickly and correct serum B12 both groups of patients (receiving oral hypovitaminosis, particularly in the case and intramuscular treatment) had neuro- of pernicious anemia. The treatment in- logical improvement. volves administering 1000 mcg of cyano- In a randomized, parallel-group, dou- cobalamin per day for 1 week, followed ble-blind, dose-finding trial, Eussen et al by 1000 mcg per week for 1 month, fol- showed that the lowest dose of oral cya- lowed by 1000 mcg per month, normally nocobalamin required to normalize mild 2,3,20 for the rest of the patient’s life. B12 deficiency is more than 200 times the recommended dietary allowance of ap- proximately 3 mcg daily (ie, >500 mcg/ z 47 Oral therapy day). The procedure for oral B12 treat- is a well-kept secret ment has, however, not been completely

In cases of B12 deficiency that don’t in- validated yet in “real life,” particularly as volve nutritional deficiency, alternative it relates to long-term efficacy.48 Nonethe- routes of cobalamin administration, in- less, several authors suggest that oral B12 cluding the oral16,35–42 and nasal43,44 routes therapy remains one of medicine’s “best- have been used. These alternative routes kept secrets.”49 n offer patients a way to avoid the discom- Correspondence fort, inconvenience, and cost of an office Prof. E. Andrès, Service de Médecine Interne, Diabète visit for monthly injections. et Maladies Métaboliques, Clinique Médicale B, Hôpital Our research team has developed Civil – Hôpitaux Universitaires de Strasbourg, 1 porte de l’Hôpital, 67091 Strasbourg Cedex, France; emmanuel. an effective oral treatment of food-B12 [email protected] malabsorption38–41 and for pernicious anemia45 using crystalline cobalamin Acknowledgements We are indebted to Professor Marc Imler and jean- (cyanocobalamin). Our principal stud- Louis Schlienger who initiated this work and to Helen fast track ies of oral B treatment (open, not Fothergill who kindly edited the text for publication in 12 this English-language journal. All patients treated randomized studies) are described in 38–41,45 with oral therapy Table 2. Our data confirm the pre- Disclosure Emmanuel Andrès reports that his research on B defi- viously reported efficacy of oral crystal- 12 corrected their ciency was supported by a grant from the Fondation de line cyanocobalamin, especially in food- France (Prix Robert et Jacqueline Zittoun 2004). B levels and B therapy.6,16,36 All of our patients who 12 12 References at least two thirds received oral therapy corrected their B 12 1. Carmel R. Current concepts in cobalamin deficiency. levels and at least two thirds corrected Ann Rev Med 2000; 51:357–375. corrected their their hematological abnormalities.38–41,45 2. Andrès E, Perrin AE, Kraemer JP, et al. Anémies par hematological carence en vitamine B12 chez le sujet âgé de plus de Moreover, one third of patients expe- 75 ans: nouveaux concepts. A propos de 20 observa- abnormalities rienced a clinical improvement on oral tions. Rev Med Interne 2000; 21:946–955. treatment. In most cases of food-B 3. 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Andrès E, Kaltenbach G, Noblet-Dick M, et al. Hema- 25:556–561. tological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in 21. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. Oral B therapy  elderly patients. J Nutr Health Aging 2006; 10:3–6. 12 N Engl J Med 1997; 337:1441–1448. has not been 22. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo 42. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Clin Proc 1994; 69:144–150. Oral vitamin B12 versus intramuscular vitamin B12 completely for vitamin B12 deficiency: a systematic review 23. Institute of Medicine. Dietary reference intakes for of randomized controlled trials. Fam Pract 2006; thiamin, , niacin, , folate, vitamin 23:279-285. validated in “real B12, panthothenic acid, biotin and choline. Food and Nutrition Board, Washington, DC. National Academies 43. Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN. life,” though Press, 1998. 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Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jen-   B12 deficiency. Am J Med 2004; 116:358. sen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with 49. Graham ID, Jette N, Tetroe J, Robinson N, Milne S, Zollinger-Ellison syndrome. Am J Med 1998; 104:422– Mitchell SL. Oral cobalamin remains medicine’s best 430. kept secret. Arch Gerontol Geriatr 2007; 44:49–59.

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