THE JOURNAL OF FAMILY PRACTICE Emmanuel Andrès, MD, B12 deficiency: A look beyond Laure Federici, MD, Stéphan Affenberger, MD pernicious anemia Department of Internal Medicine, Diabetes and Metabolic Diseases, Food-B12 malabsorption—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 United Kingdom with pernicious anemia. (C) ® Dowdenlevels, but his Health homocysteine Media and meth - Noureddine Henoun ylmalonic acid levels, since they are con- Loukili, PhD • The classic treatment for B 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 cyanocobalamin, 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. ( ) Luxembourg B z A common problem that 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 macrocytosis 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 www.jfponline.com VOL 56, NO 7 / JULY 2007 537 For mass reproduction, content licensing and permissions contact Dowden Health Media. THE JOURNAL OF FAMILY PRACTICE 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”) Ataxia Rare Babinski’s phenomenon Isolated thrombocytopenia and neutropenia Rare Pancytopenia 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 (hyperhomocysteinemia) Classic Parkinsonian syndromes Hunter’s glossitis 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 dementia.14 acid levels >0.4 µmol/L (in the absence Further muddying the waters is the of renal failure and folate 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 intrinsic factor, 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 Schilling test 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 gastrectomy 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 pancreatitis (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 atrophic gastritis.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.