Clinical aspects of cobalamin deficiency in elderly patients - Comment
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What's going to be covered in this presentation slides: 1. This article was published in an Elsevier journal. The attached copy is furnished to the author for non-commercial research and education use, including for instruction at the author’s institution, sharing with colleagues and providing to institution administration. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright 2. Author's personal copy European Journal of Internal Medicine 18 (2007) 456 – 462 www.elsevier.com/locate/ejim Review article Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy ☆ Emmanuel Andrès a,⁎, Josep Vidal-Alaball b,f , Laure Federici a , Noureddine Henoun Loukili c , Jacques Zimmer d , Georges Kaltenbach e a Department of Internal Medicine, Diabetes and Metabolic Diseases, Hôpitaux Universitaires de Strasbourg, France b National Public Health Service for Wales, UK c Department of Infection Control Management, Hôpital Calmette, CHRU de Lille, France d Laboratoire d'Immunogénétique-Allergologie, Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg e Department of Internal Medicine and Geriatrics, Hôpitaux Universitaires de Strasbourg, France f Department of General Practice, Cardiff University, UK Received 21 July 2006; received in revised form 3 November 2006; accepted 22 February 2007 Abstract The aim of this work was to review the literature concerning cobalamin deficiency in elderly patients. Articles were identified through searches of PubMed–MEDLINE (January 1990 to June 2006), restricted to: English and French language, human subjects, elderly patients (N 65 years), clinical trial, review and guidelines. Additional unpublished data from our cohort with cobalamin deficiency at the University Hospital of Strasbourg, France, were also considered. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study. In elderly people, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. The recently identified food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or from its binding proteins. This syndrome is usually the consequence of atrophic gastritis, related or not to Helicobacter pylori infection, and of the long-term ingestion of antacids and biguanides (in around 60% of the patients). Management of cobalamin deficiency has been well established with the use of cobalamin injections. However, new routes of cobalamin administration (oral and nasal) are currently being developed, especially the use of oral cobalamin therapy to treat food-cobalamin malabsorption. © 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Cobalamin; Cobalamin deficiency; Elderly patients; Food-cobalamin malabsorption; Oral cobalamin therapy Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 2. Definition of cobalamin deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 3. Epidemiology of cobalamin deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 4. Cobalamin metabolism and functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 5. Causes of cobalamin deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 6. Food-cobalamin malabsorption syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 ☆ Funding: The research on cobalamin deficiency was supported by a grant from the Fondation de France (Prix Robert et Jacqueline Zittoun 2004). ⁎ Corresponding author. Service de Médecine Interne, Diabète et Maladies Métaboliques, Clinique Médicale B, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, 67 091 STRASBOURG cedex, France. Tel.: +33 3 88 11 62 59; fax: +33 3 88 11 62 62. E-mail address: emmanuel.andres@chru-strasbourg.fr (E. Andrès). 0953-6205/$ - see front matter © 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2007.02.013 3. Author's personal copy E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 457 7. Clinical manifestations of cobalamin deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 8. Classical treatment of cobalamin deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460 9. Oral cobalamin therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460 10. Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Appendix A. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 1. Introduction to date, little and conflicting evidence is available about the effectiveness of these new tests in real life clinical practice and Cobalamin, or vitamin B12, deficiency is frequent in elderly in elderly patients [10]. patients [1], but it is often unrecognized or not investigated because the clinical manifestations are subtle. However, 3. Epidemiology of cobalamin deficiency because of the potential seriousness of the complications, particularly neuropsychiatric and hematological [1–4], inves- Epidemiological studies have shown a prevalence of tigation of all patients who present with vitamin or nutritional cobalamin deficiency of around 20% in the elderly population deficiency is required. Classic disorders, such as pernicious of industrialized countries (between 50% and 60%, depending anemia, are the cause of cobalamin deficiency in only a limited on the definition of cobalamin deficiency used in the study). proportion of elderly patients [4]. The main cause of cobalamin The Framingham study demonstrated a prevalence of 12% deficiency is food-cobalamin malabsorption, a disorder among elderly people living in the community [11]. Other characterized by the inability to release vitamin B12 from studies focusing on elderly people, particularly those who are in food or from its binding proteins [4]. institutions or who are sick, have suggested a higher prevalence We summarize here the current state of knowledge on of 30–40% [12,13]. Using a stringent definition (Table 1), we clinical aspects of cobalamin deficiency in the elderly, with a have found a prevalence of 5% in a group of patients followed special focus on food-cobalamin malabsorption and partic- or hospitalized in a tertiary reference hospital in France [8]. ularly on oral cobalamin therapy. 4. Cobalamin metabolism and functions 2. Definition of cobalamin deficiency Cobalamin metabolism is complex and requires many In the recent literature, several definitions of cobalamin processes, any one of which, if not present, may lead to deficiency in elderly patients have emerged, depending mainly cobalamin deficiency [4,14–16]. The different stages of on the populations studied and on the particular test assay kits cobalamin metabolism and corresponding causes of cobalamin used [5–7]. Varying test sensitivities and specificities have deficiency are shown in Table 2 [14,16]. Once metabolized, resulted from this lack of a precise ‘gold standard’, especially cobalamin is a cofactor and coenzyme in many biochemical in elderly patients. The definitions of cobalamin deficiency reactions, including DNA synthesis, methionine synthesis used in this review are shown in Table 1 [7,8]. Currently, from homocysteine, and conversion of propionyl into succinyl cobalamin deficiency is often defined in terms of the value of coenzyme A from methyl malonate [4,9]. serum cobalamin and of homocysteine and methyl malonic A typical Western diet contributes 3–30 μg of cobalamin acid, two components of the cobalamin metabolic pathway. In per day to the estimated daily requirement of between 2 and the future, new serum cobalamin assay kits, such as 5 μg, according to the U.S. Food and Drug Administration holotranscobalamin, may replace older assay kits and become [17]. It has been estimated that there is a delay of between 5 the standard for testing for cobalamin deficiency [9]. However, and 10 years between the onset of cobalamin deficiency and the development of clinical illness, and this is a direct result Table 1 of the hepatic stores (N 1.5 mg) and the enterohepatic cycle Definitions of cobalamin (vitamin B12) deficiency [7,8] [4,14]. Between 1% and 5% of free cobalamin (or crystalline Definitions of cobalamin deficiency cobalamin) is absorbed along the entire intestine by passive Serum cobalamin level b150 pmol/l (b200 pg/ml) and clinical features diffusion, and this is the mechanism underlying the and/or hematological anomalies related to cobalamin deficiency effectiveness of oral cobalamin as a treatment for cobalamin Serum cobalamin level b150 pmol/l (b200 pg/ml) at two different times deficiencies [18,19]. Serum cobalamin level b150 pmol/l (b200 pg/ml) and total serum homocysteine level N13 μmol/l or methylmalonic acid levels N0.4 μmol/l a 5. Causes of cobalamin deficiency Low serum holotranscobalamin level a This definition is useful only in the absence of renal failure and folate Fig. 1 presents the principal causes of cobalamin deficiency and vitamin B6 deficiency because homocysteine and methylmalonic acid in 172 elderly patients (median age 70 years) hospitalized in the levels are dependent on these factors. University Hospital of Strasbourg, France [15]. Historically, in 4. Author's personal copy 458 E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 Table 2 Table 3 Stages of cobalamin metabolism and corresponding causes of cobalamin Food-cobalamin malabsorption syndrome [4,15,16] deficiency [14,16] Criteria for food-cobalamin Associated conditions or agents Stages and factors in Causes of malabsorption cobalamin metabolism cobalamin deficiency – Low serum cobalamin – Gastric disease: atrophic gastritis, Intake solely through food Strict vegetarianism (patients (vitamin B12) levels type A atrophic gastritis, gastric disease who are sick in institutions associated with Helicobacter pylori or in psychiatric hospitals) infection, partial gastrectomy, Digestion brings into play Gastrectomies; pernicious gastric by-pass, vagotomy haptocorrin, gastric secretions anemia; food-cobalamin – Normal results of Schilling test – Pancreatic insufficiency: alcohol (HCl and pepsin), intrinsic factor, malabsorption using free cyanocobalamin abuse pancreatic and biliary secretions, labeled with cobalt-58 or the enterohepatic cycle abnormal results of derived Absorption brings into play intrinsic Ileal resections; malabsorption; Schilling test a factors and cubilin pernicious anemia; – No anti-intrinsic factor – Gastric or intestinal bacterial food-cobalamin malabsorption antibodies overgrowth: achlorhydria, tropical Transport by transcobalamins Congenital deficiency in sprue, Ogylvie's syndrome, HIV transcobalamin II – No dietary cobalamin – Drugs: antacids (H2-receptor Intracellular metabolism based on various Congenital deficiency in deficiency antagonists and proton pump intracellular enzymes various intracellular enzymes inhibitors) or biguanides (metformin) – Sjögren's syndrome, systemic HCl = hydrochloric acid. sclerosis – Haptocorrine deficiency – Aging or idiopathic disorder a elderly patients, cobalamin deficiency was associated with Derived Schilling tests use food-bound cobalamin (e.g., egg yolk, pernicious anemia (or Biermer's or Addison's disease) [1,12]. chicken, and fish proteins). The principal characteristics of pernicious anemia have been reported in detail in several recent reviews [20–22]. Cobalamin malabsorption, especially in elderly patients [4,8,12,23]. In our deficiency caused by dietary deficiency or surgical resection is experience [15,24], food-cobalamin malabsorption has rare in the elderly. Dietary deficiency is limited to elderly accounted for 60–70% of cases of cobalamin deficiency in people who are already malnourished, such as elderly patients elderly patients, with pernicious anemia accounting for just living in institutions or in psychiatric hospitals [4,14]. Since the 15–25%. 1980s, malabsorption of cobalamin caused by surgery has become uncommon, owing mainly to the decreasing frequency 6. Food-cobalamin malabsorption syndrome of gastrectomy and surgical resection of the ileum [4,8,15]. Several other uncommon disorders in elderly people have been First described by Carmel in 1995 [23], food-cobalamin associated with cobalamin malabsorption: deficiency in the malabsorption is a syndrome characterized by the inability of exocrine function of the pancreas following chronic pancrea- the body to release cobalamin from food or intestinal transport titis (usually alcoholic), lymphomas or tuberculosis (intestine), proteins, particularly in the presence of hypochlorhydria, Crohn's disease, Whipple's disease, and celiac disease [12,16]. where the absorption of “unbound” cobalamin is normal. This The past 15 years have been marked by the recognition of food- syndrome is characterized by cobalamin deficiency in the cobalamin malabsorption as the leading cause of cobalamin presence of sufficient food-cobalamin intake and a normal Schilling test, ruling out malabsorption or pernicious anemia [15,23,24]. The principal characteristics of this syndrome are listed in Table 3. Authors supporting the existence of this syndrome have employed a modified Schilling test, which uses radioactive cobalamin bound to animal proteins (e.g., salmon, trout) and reveals malabsorption when the results of a standard Schilling test are normal [4,15,24]. Some authors have questioned the existence and significance of cobalamin deficiency related to food-cobalamin malabsorption [4] because many patients experience only mild clinical or hematological features. However, several of the patients we have described in a recently published study [15] had serious features classically associated with pernicious anemia, includ- ing polyneuropathy, confusion, dementia, medullar-combined sclerosis, anemia, and pancytopenia. Table 4 lists the principal features in the aforementioned series of 92 elderly patients with Fig. 1. Causes of cobalamin deficiency in 172 elderly patients [15]. food-cobalamin malabsorption [15]. Nevertheless, the partial 5. Author's personal copy E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 459 Table 4 pump inhibitors [27,28], particularly among patients with Clinical manifestations in 92 elderly patients with food-cobalamin Zollinger–Ellison syndrome [29], and biguanides (metfor- malabsorption [15] min) [30,31]; chronic alcoholism; surgery or gastric recon- Clinical manifestations struction (e.g., bypass surgery for obesity); partial pancreatic Epidemiological data The median (±SD) patient age is 76 ± 8 years; the exocrine failure [4,15]; and Sjögren's syndrome or systemic female/male ratio is 2. sclerosis [32] (Table 3). In a series of 92 elderly patients Clinical data – Clinical features are reported in 70% of all (mean age 76 years) with food-cobalamin malabsorption patients, with mild sensory polyneuropathy (45%), confusion or impaired mental functioning (23%), [15], we have reported at least one of these associated and physical asthenia (21%). conditions or agents in 60% of the patients. These conditions Biological and – The mean (±SD) serum cobalamin level is mainly include atrophic gastritis (± H. pylori infection) in hematological data 131 ± 38 pg/mL and the mean total 30% of the patients and long-term metformin or antacid serum homocysteine level is 22.1 ± 9.3 μmol/L. intake in 20% of the patients. –Hematological abnormalities are reported in 76% of all patients, with macrocytosis (mean erythrocyte cell volume N100 fL; 53%), anemia (hemoglobin 7. Clinical manifestations of cobalamin deficiency level b10 g:dL; 21%), leukopenia (white cells count b4 × 109/L; 11%), thrombopenia (platelets count The primary clinical manifestations of cobalamin deficiency b100 × 109/L; 9%), and pancytopenia (6.5%). in elderly patients are described in Table 5. They are highly – The mean (± SD) hemoglobin level is 10.9 ± 2.5 g/ dL and the mean erythrocyte cell volume is 95.7 ± polymorphic and of varying severity, ranging from milder 12.7 fL. conditions such as tiredness, common sensory neuropathy, and isolated anomalies of macrocytosis or hypersegmentation of neutrophils, to severe disorders, including combined sclerosis nature of this form of malabsorption may produce a more of the spinal cord, hemolytic anemia, and even pancytopenia slowly progressive depletion of cobalamin than does the more [2,15,33–35]. In the aforementioned series of 92 patients with complete malabsorption engendered by disruption of the food-cobalamin malabsorption [15], we found at least one intrinsic factor-mediated absorption. The slower progression of clinical or hematological abnormality in 70% and 76% of the depletion probably explains why mild, preclinical deficiency is patients, respectively (Table 4). Cobalamin deficiency appears more frequently associated with food-cobalamin malabsorp- to be more common among patients who have a variety of tion than with pernicious anemia [4,15]. chronic neurological conditions, such as dementia, Alzheimer's Food-cobalamin malabsorption is caused primarily by disease, stroke, Parkinson's disease, and depression, although it atrophic gastritis [15]. Over 40% of patients older than is unclear if there is a causal relationship [4,36]. In these 80 years have gastric atrophy, related or not to Helicobacter conditions, it is important to keep in mind that malnutrition is pylori infection [12,25]. Other factors that contribute to food- often an important factor. In our personal experience, the cobalamin malabsorption in the elderly include: intestinal administration of cobalamin to patients with dementia did not microbial proliferation (cobalamin deficiency that can be improve their neurological condition [8,15]. Other reported addressed by antibiotic treatment) [5,26]; long-term ingestion studies found similar results [19,37]. To date, the causal role of of antacids, including H2-receptor antagonists and proton cobalamin in these conditions remains unclear. Table 5 Main clinical features of cobalamin deficiency in elderly patients [2,4,15,16,33–35] Hematological manifestations Neuro-psychiatric manifestations Digestive manifestations Other manifestations – Frequent: macrocytosis, neutrophil – Frequent: polyneuritis (especially – Classic: Hunter's glossitis, – Frequent: tiredness, loss of appetite hypersegmentation, aregenerative sensitive), ataxia, Babinski's phenomenon jaundice, LDH and bilirubin macrocytary anemia, medullar elevation (“intramedullary megaloblastosis (“blue spinal cord”) destruction”) – Rare: isolated thrombocytopenia and – Classic: combined sclerosis of the – Debatable: abdominal pain, – Under study: atrophy of the vaginal neutropenia, pancytopenia spinal cord dyspepsia, nausea, vomiting, mucosa and chronic vaginal and diarrhea, disturbances in urinary infections (especially mycosis), intestinal functioning venous thromboembolic disease, angina (hyperhomocysteinemia) – Very rare: hemolytic anemia, – Rare: cerebellar syndromes affecting the – Rare: resistant and recurring thrombotic microangiopathy cranial nerves including optic neuritis, optic mucocutaneous ulcers (presence of schistocytes) atrophy, urinary and/or fecal incontinence – Under study: changes in the higher functions, dementia, stroke, angina and atherosclerosis (hyperhomocysteinemia), parkinsonian syndromes, depression, multiple sclerosis 6. Author's personal copy 460 E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 8. Classical treatment of cobalamin deficiency both food-cobalamin malabsorption [41–44] and pernicious anemia [47] using a crystalline cobalamin (cyanocobalamin). The standard treatment of cobalamin deficiency, particular- The main results of our oral cobalamin treatment studies (open, ly when the cause is not dietary deficiency, is parenteral not randomized) are summarized in Table 6 [41–44,47]. These administration – usually by intramuscular injection – of data confirmed the previously reported efficacy of oral cyanocobalamin or hydroxocobalamin [1,18,19,33]. In France, crystalline cyanocobalamin, especially in food-cobalamin the recommended practice to build up the body stores of the therapy [19,35,39]. All patients treated orally corrected their vitamin quickly and to correct serum cobalamin hypovitami- vitamin B12 levels and at least two-thirds their hematological nosis, particularly in the case of pernicious anemia, involves abnormalities [41–44,47]. Moreover, one-third experienced the administration of 1000 μg of cyanocobalamin per day for clinical improvement upon oral treatment. In most cases of 1 week, followed by 1000 μg/week for 1 month, and then by 1 food-cobalamin malabsorption, “low” cobalamin doses (i.e., injection of the same dose once a month, normally for the rest between 125 to 1000 μg of oral crystalline cyanocobalamin per of the patient's life [8,12,20]. In the UK, the regimen involves day) were used. These findings are consistent with the results the administration of intramuscular hydroxocobalamin, initial- of two prospective, randomized, controlled studies comparing ly 1000 μg 3 times a week for 2 weeks and then every 3 months oral cobalamin versus intramuscular cobalamin therapy in cases where there is no neurological involvement and [18,40]. Kuzminski et al. [18], in a prospective, randomized 1000 μg on alternate days until no further clinical improvement trial including 38 patients, reported improvement in hemato- and then every 2 months for the rest of the patient's life when logical parameters and cobalamin levels (mean value 907 pg/ there is neurological involvement [38]. mL) after 4 months of oral cobalamin therapy using a much higher dose (i.e., 2000 μg/day). Bolaman et al. [40], in a 9. Oral cobalamin therapy prospective randomized trial of 60 patients, also reported significant improvement in hematological parameters and In the absence of nutritional deficiency etiology, two cobalamin levels (mean improvement +140.9 pg/mL) after alternative routes of cobalamin administration have recently 3 months of 1000 μg daily of oral cyanocobalamin therapy. A been proposed: oral [18,19,39–44] and nasal [45,46]. Our systematic review conducted under the auspices of the working group has developed an effective oral treatment for Cochrane Metabolic and Endocrine Disorders Review Group Table 6 Oral cobalamin therapy for food-cobalamin malabsorption: main results of studies conducted mainly in the University Hospital of Strasbourg, France Study characteristics (number of patients) Therapeutic modalities Results Open prospective study of well-documented Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in [42] vitamin B12 deficiency related to 650 μg/ day for at least 3 months 80% of the patients food-cobalamin malabsorption (n = 10) – Significant increase in hemoglobin (Hb) levels (mean of 1.97 g/dL) and decrease in mean erythrocyte cell volume (ECV) (mean of 7.8 fL) – Improvement of clinical abnormalities in 20% of the patients – No adverse effect Open prospective study of low vitamin B12 Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in 85% [43] levels not related to pernicious anemia (n = 20) 1000 μg/day for at least 1 week of patients – No adverse effect Open prospective study of well-documented Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in 87% [41] vitamin B12 deficiency related to between 1000 and 250 μg/day of patients food-cobalamin malabsorption (n = 30) for 1 month – Significant increase in Hb levels (mean of 0.6 g/dL) and decrease in ECV (mean of 3 fL); normalization of Hb levels and ECV in 54% and 100% of patients, respectively – Dose effect — effectiveness dose of vitamin B12 ≥500 μg/day – No adverse effect Open prospective study of low vitamin B12 levels Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in all patients [44] not related to pernicious anemia (n = 30) between 1000 and 125 μg/day for with a dose of at least ≥250 μg/day at least 1 week – Dose effect — effectiveness dose of vitamin B12 ≥500 μg/ day – No adverse effect Open prospective study of low vitamin B12 levels Oral crystalline cyanocobalamin: – Significant increase in serum vitamin B12 levels in 90% of [47] related to pernicious anemia (n = 10) 1000 μg/day for at least 3 months patients (mean of 117.4 pg/mL – Significant increase in Hb levels (mean of 2.45 g/dL) and decrease in ECV (mean of 10.4 fL) – Improvement of clinical abnormalities in 30% of patients 7. Author's personal copy E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 461 supports the efficacy of oral cobalamin therapy, with a daily the search to human data, elderly patients (N65 years old), dose of 2000 and 1000 μg initially, and thereafter weekly, of clinical trial, review, and guidelines, and English and French vitamin B12 [48]. Vidal-Alaball et al. reported that serum languages. Additional references were localized through a vitamin B12 levels increased significantly in patients on oral review of textbooks on hematology and internal medicine, as vitamin B12, and both groups of patients receiving oral or well as information gleaned from international meetings. intramuscular treatment had neurological improvement. In a Additional unpublished data from our cohort with cobalamin recent randomized, parallel-group, double blind, dose-finding deficiency at the University Hospital of Strasbourg were also trial, Eussen et al. demonstrated that the lowest dose of oral considered. All of the papers and abstracts were reviewed by cyanocobalamin required to normalize mild cobalamin at least two senior researchers who selected the data used in deficiency (N 500 μg per day) is more than 200 times greater the study. than the recommended dietary allowance, which is approxi- mately 3 μg daily [49]. However, a standardized oral References cobalamin regimen has not been validated in pragmatic [1] Matthews JH. Cobalamin and folate deficiency in the elderly. clinical settings, and some doubts have been raised about the Bailliere's Clin Haematol 1995;54:245–53. efficacy of long-term oral treatment [50]. To date, as several [2] Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum authors have suggested, oral cobalamin therapy remains one of and diagnosis of cobalamin deficiency. Blood 1990;76:871–81. medicine's “best kept secret” [51,52]. Nevertheless, despite [3] Reynolds EH. Neurological aspects of folate and vitamin B12 the uncertainty, three different options regarding the use of oral metabolism. Clin Haematol 1976;5:661–96. [4] Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med cobalamin can be proposed: (1) ongoing cobalamin supple- 2000;51:357–75. mentation until the associated disorders are corrected (e.g., by [5] Snow C. Laboratory diagnosis of vitamin B12 and folate deficiency. A stopping the ingestion of the offending medication or by guide for the primary care physician. Arch Intern Med 1999;159:1289–98. treating H. pylori infection and pancreatic exocrine failure), [6] Zittoun J, Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. Sem Haematol 1999;36:35–46. 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