E. Andrès et al. / European Journal of Internal Medicine 19 (2008) 488–493 489Table 1 as anemia of chronic inflammation; and unexplained anemiaEtiology of anemia in 300 consecutive patients older than 65 years, hospitalized [1,8,10]. In the NHANES III study, 34% of all anemia in elderlyin the department of internal medicine in a tertiary reference center (personalcommunication in the French Congress of Internal Medicine, Aix-en-Provence, patients is caused by folate, vitamin B12, or iron deficiency,June 2001) alone or in combination (nutrient-deficiency anemia), 12% wasEtiology Prevalence (%) associated with renal insufficiency, 20% was due to chronic diseases, and in 34% the cause remained unexplained . AboutChronic inflammation (chronic disease) 23.0 60% of nutrient-deficiency anemias are associated with ironIron deficiency 18Renal failure 9 deficiency and most of those cases are the result of chronicLiver disease and endocrine disease (chronic disease) 7 blood loss from gastrointestinal lesions. The remaining cases ofPosthemorrhagic 7 nutrient-deficiency anemia are usually associated with vitaminFolate deficiency 6 B12 and/or folate deficiency and are easily treated. In Table 1,Myelodysplasia 5 we report our personal experience (retrospective study) of theVitamin B12 deficiency 4Unexplained causes 21 etiology of anemia in 300 hospitalized patients ≥ 65years old (personal communication in the French Congress of Internal Medicine, Aix-en-Provence, June 2001).increased susceptibility to anemia in the presence of hemato- Rare unknown causes of nutrient-deficiency anemia alsopoietic stress induced by an underlying disorder [3,5]. In include several other vitamin deficiencies, zinc or copperpractice, a Hb level b 10g/dL is considered as a trigger for the deficiencies.investigation and treatment of the cause of anemia . 6. Iron deficiency anemia in the elderly4. Prevalence of anemia in the elderly Iron deficiency anemia, the second most common cause of The prevalence of anemia increases with advancing age, anemia in the elderly , usually results from chronicespecially after age 60–65years, and rises sharply after the age gastrointestinal (GI) blood loss mainly caused by: esophagitis,of 80years [1,5]. Results from the third National Health and gastritis, ulcer, related or not related to nonsteroidal anti-Nutrition Examination Survey (NHANES III) carried out in the inflammatory drug intake and/or chronic Helicobacter pyloriUnited States indicate that the prevalence of anemia was 11% in infections, varices (portal hypertension), colorectal cancer orcommunity-dwelling men and 10.2% among women ≥ 65years pre-malignant polyps, or angiodysplasia [2,12]. GI blood loss isof age . Survey findings indicate further that most anemia often occult and is not ruled out by negative fecal blood tests. GIamong the elderly is mild; only 2.8% of women and 1.6% of tract abnormalities can be identified in the majority of patientsmen had a Hb b 11g/dL . Results from the Framingham with iron deficiency anemia . In 40 to 60% of patients, thecohort indicates a slightly lower prevalence of anemia among source is in the upper GI tract [2,14]. The blood loss is in theolder people living in the United States. In this group of 1016 colon in 15 to 30% of cases. The source is not found in thesubjects 67–96years of age, the prevalences of anemia in men remaining 10 to 40% of elderly patients with gastrointestinaland women are 6.1% and 10.5%, respectively . In the elderly, blood loss. Fortunately these patients do well with ironmuch of the variability in the reported prevalence of anemia replacement and repeat investigation is not often needed .reflects the heterogeneity of this population. Variables such as H. pylori infection and chronic gastritis, especially atrophicrace, living circumstances, and health status may all influence gastritis, are significantly associated with unexplained ironthe prevalence of anemia . deficiency anemia . Table 2 presents our experience of the5. Etiology of anemia in the elderly Table 2 Results of the evaluation of the gastrointestinal tract in 90 consecutive elderly Because elderly patients often have several associated co- patients (≥65 years) with chronic blood loss, hospitalized in the department ofmorbid conditions and are commonly taking a variety of medi- internal medicine in a tertiary reference center (personal communication in thecations, some of which may contribute to anemia, the etiology French Congress of Internal Medicine, Aix-en-Provence, June 2001)of anemia is frequently difficult to determine even after ex- Etiology Prevalence (%)tensive investigations, including bone marrow examination Esophagitis and Mallory Weiss syndrome 4.4. Examination of the etiology of anemia indicates that, in Gastritis, atrophic gastritis and ulcer related or 30most cases (approximately 80%), the etiology of anemia in the not related to NSAID use and/or Helicobacterelderly can be identified [3,11]. A significant proportion of pylori infectionelderly anemic patients (30–50%) are presumed to have mul- Varices related to portal hypertension 9 Angiodysplasia 2.25tiple causes for their anemia [2,10]. In the cases for which the Colon diverticula 4.5cause of anemia has not been established, patients may have Colorectal benign and pre-malignant polyps 5.5received an inadequate diagnostic work-up. Colorectal cancer 5.5 In elderly, causes of anemia are divided into three broad Inflammatory bowel disease 2.25groups: nutrient-deficiency anemia, most often iron deficiency Unexplained causes 36.6anemia; and/or anemia of chronic disease, perhaps better termed NSAID: Nonsteroidal anti-inflammatory drug.
490 E. Andrès et al. / European Journal of Internal Medicine 19 (2008) 488–493 jejunum. Folate deficiency usually develops as a result of inadequate dietary intake [2,7]. The body stores very little folate, only enough to last 4 to 6months. Patients usually have a history of weight loss, poor weight gain and weakness. In addition several drugs (methotrexate, cotrimoxazole, sulfasalazine, anticonvulsants…) and alcohol may cause deficiency of folate. 8. Vitamin B12 deficiency anemia in the elderly Both vitamin B12 and folate deficiency are common among the elderly, each occurring in at least 5% of the patients . TheFig. 1. Etiologies of cobalamin deficiency in 172 elderly patients hospitalized in Framingham study demonstrated a prevalence of 12% amongthe University Hospital of Strasbourg, France. elderly people living in the community . In elderly patients, the etiologies of cobalamin deficiency are represented primarilyevaluation of the GI tract in 90 elderly patients with chronic by food-cobalamin malabsorption (FCM) and pernicious anemiablood loss (personal communication in the French Congress of and, more rarely, by intake deficiency and malabsorption . InInternal Medicine, Aix-en-Provence, June 2001). Chronic blood our work in which we followed more than 200 elderly patientsloss from genitourinary tract and chronic hemoptysis may result with a proven deficiency, FCM accounted for about 60% to 70%in iron deficiency but are much less common causes . of the etiologies of cobalamin deficiency, and pernicious anemiaBleeding disorders and particularly anticoagulants (vitamin K 15% to 25%. Fig. 1 presents the principal causes of cobalaminantagonists) may favor iron deficiency in elderly (around 20% deficiency in 172 elderly patients (median age: 70years)in our experience). hospitalized in the University Hospital of Strasbourg, France . Older persons may also become iron deficient because of Initially described by Carmel in the 1990s, the FCM isinadequate dietary intake or inadequate absorption or bioavail- characterized by the inability to release cobalamin from foodability of iron (with anti acids) . Heme iron from animal and/or intestinal transport proteins, particularly in the case ofsources is better absorbed than non-heme iron from plant hypochlorhydria, where the absorption of “unbound” cobalaminsources. Vitamin C in food enhances iron absorption from non- is normal . As we have recently indicated, this syndrome isheme sources. The tannins and polyphenols in tea and coffee defined by cobalamin deficiency despite sufficient food-can inhibit iron absorption. Any elderly subject whose dietary cobalamin intake and a normal Schilling test, where the latterintake is poor, has recent unexplained weight loss is a candidate rules out malabsorption or pernicious anemia . FCM isfor increasing attention. Nevertheless, iron deficiency anemia is caused primarily by atrophic gastritis. Over 40% of patientsrarely the result of dietary deficiency in industrialized countries older than 80years of age have gastric atrophy that might or. Without blood loss, anemia takes several years to develop. might not be related to H. pylori infection . Other factors that commonly contribute to FCM in elderly people include7. Folate deficiency anemia in the elderly chronic carriage of H. pylori and intestinal microbial prolifera- tion (in which case cobalamin deficiency can be corrected by A regular diet contains 500 to 700µg of folate. On average, 50 antibiotic treatment); long-term ingestion of antacids, includingto 60% of dietary folate is absorbed in the duodenum and H2-receptor antagonists and proton-pump inhibitors, andTable 3Manifestations related to vitamin B12 deficiency (with the exception of hematological manifestations)Neuro-psychiatric manifestations Digestive manifestations Other manifestations– Frequent: polyneurites (especially sensitive ones), – Classic: Hunters glossitis, jaundice, – Under study: atrophy of the vaginal ataxia, Babinskis phenomenon LDH and bilirubin elevation (“intramedullary mucosa and chronic vaginal and urinary destruction”) infections(especially mycosis), venous thromboembolic disease, angina (hyperhomocysteinemia)– Classic: combined sclerosis of the spinal cord – Debatable: abdominal pain, dyspepsia, nausea, vomiting, diarrhea, disturbances in intestinal functioning– Rare: cerebellar syndromes affecting the cranial – Rare: resistant and recurring mucocutaneous nerves including optic neuritis, optic atrophy, urinary ulcers cobalamin deficiency and/or fecal incontinence– Under study: changes in the higher functions, even dementia, stroke and atherosclerosis (hyperhomocysteinemia), parkinsonian syndromes, depression, multiple sclerosis
E. Andrès et al. / European Journal of Internal Medicine 19 (2008) 488–493 491Table 4 10. Clinical presentation in the elderlyHematological manifestations of vitamin B12 deficiency in 201 patients withdocumented cobalamin deficiency, followed in the department of internalmedicine in a tertiary reference center  Fatigue, dispend, and other typical symptoms often occur less severe anemia in elderly patients than would be expectedParameters Values with younger adults. The onset of symptoms is usuallyHemoglobin level (g/dL) 10.3 ± 0.4 (4.9–15.1) insidious, and many elderly patients adjust their activities. InMean erythrocyte cell volume (fL) 98.9 ± 25.6 (76–142) elderly, these symptoms of anemia are likely to be overlooked.Reticulocyte count (%) 15.2 (1–32)White cell count (/mm3) 6200 ± 4100 (500–20,000) In this situation, pallor can be helpful but hard to detect . ThePlatelet count (103/mm3) 146 ± 42 (27–580) symptoms of other diseases may be exacerbating if anemia isAnemia with Hb level b12 g/dL 37% also present. Therefore anemia should be considered whenAnemia with Hb level b6 g/dL 2.5% patients present worsening of heart or lung disease. Anemia canAnemia and macrocytosis (MECV N 100 fL) 33.8% also contribute to problems, such as decreased mobility,Isolated macrocytosis (VGM N 100 fL) 17%Microcytosis (VGM b 80 fL) 5% dizziness, cognitive impairment, and even depression .White cell count b4000/mm3 14% Moreover, symptoms related to nutrient deficiency (iron,Neutrophile count b1000/mm3 3% vitamin B12 and folate) may be present, outside the hematologicalThrombopenia (b150 × 103/mm3) 10% sphere. Table 3 presents features related to vitamin B12 deficiencyNeutrophile hypersegmentation 32% in elderly patients . It should be noted that vitamin B12Megaloblastosis 60%Life threatening manifestations 9% deficiency may be present even in the absence of anemia. The symptoms of folate deficiency are nearly indistinguishable from those of cobalamin deficiency. Iron deficiency is responsible for changes in hair, nails, mucosa and tongue as pruritus, chronicallybiguanides (metformin); chronic alcoholism; surgery or gastric sustained inflammation, dermatitis herpetiformis, photodermati-reconstruction (e.g. bypass surgery for obesity); partial and tis, and Plummers syndrome .pancreatic exocrine failure . Nutrient-deficiency anemia in elderly is generally hypor- egenerative and represents the consequence of the older he-9. Rare causes of nutrient-deficiency anemia in the elderly matopoietic system to replace the peripheral blood loss [2,3]. Elderly patients with nutrient-deficiency anemia often have In elderly patient, often malnourished, rare unknown causes mild to moderate anemia with Hb levels between 8 and 10g/dL.of nutrient-deficiency anemia also include: 1) several vitamin In practice, because of the multifactorial etiologies of anemia indeficiencies: vitamin A, vitamin E, vitamin B2 (riboflavin), elderly, the erythrocytes are frequently normocytic: meanvitamin B3 (in pellagra), vitamin B6 (pyridoxine) and vitamin C erythrocyte cell volume (MECV) between 80 and 100fL. In(in scurvy); and 2) several mineral deficiency as zinc or copper anemia of exclusive iron deficiency, the erythrocytes are usuallydeficiencies. microcytic (MECV b 80fL). In anemia of exclusive folate and/Table 5Personal experience on oral cobalamin therapy: results on hematological manifestations Study characteristics (number of patients) Therapeutic modalities ResultsOpen prospective study of well-documented Oral crystalline cyanocobalamin: 650 µg – Normalization of serum vitamin B12 levels vitamin B12 deficiency related to food- per day, during at least 3 months in 80% of the patients cobalamin malabsorption (n = 10) – Significant increase of Hb levels (mean of 1.9 g/dL) and decrease of MECV (mean of 7.8 fL)Open prospective study of low vitamin B12 Oral crystalline cyanocobalamin: 1000 µg – Normalization of serum vitamin B12 levels in levels not related to pernicious anemia (n = 20) per day during at least 1 week 85% of the patientsOpen prospective study of well-documented Oral crystalline cyanocobalamin: between – Normalization of serum vitamin B12 levels in 87% vitamin B12 deficiency related to food- 1000 and 250 µg per day, during 1 month of the patients cobalamin malabsorption (n = 30) – Significant increase of Hb levels (mean of 0.6 g/dL) and decrease of MECV (mean of 3 fL); normalization of Hb levels and ECV in 54% and 100% of the patients, respectively – Dose effect — effectiveness dose of vitamin B12 ≥500 µg per dayOpen prospective study of low vitamin B12 Oral crystalline cyanocobalamin: between 1000 – Normalization of serum vitamin B12 levels in all levels not related to pernicious anemia (n = 30) and 125 µg per day during at least 1 week patients with at least a dose of vitamin ≥250 µg per day – Dose effect — effectiveness dose of vitamin B12 ≥500 µg per dayOpen prospective study of low vitamin B12 Oral crystalline cyanocobalamin: 1000 µg – Significant increase of serum vitamin B12 levels in levels related to pernicious anemia (n = 10) per day, during at least 3 months 90% of the patients (mean of 117.4 pg/mL) – Significant increase of Hb levels (mean of 2.45 g/dL) and decrease of MECV (mean of 10.4 fL)Hb: hemoglobin. MECV: mean erythrocyte cell volume.
492 E. Andrès et al. / European Journal of Internal Medicine 19 (2008) 488–493or vitamin B12 deficiency, the erythrocytes are usually macro- 13. Conclusioncytic (MECV N 120fL). Other hematological manifestationsmay be associated as presented in Table 4, with the example In conclusion, nutrient-deficiency anemia represents aroundof cobalamin deficiency . A low serum iron level, an in- one third of all anemias in elderly patients. About two thirds ofcreased total iron-binding capacity, and a low serum ferritin nutrient-deficiency anemias are associated with iron deficiencylevel (b 15ng/mL) accompany iron deficiency anemia [2,15]. and most of those cases are the result of chronic blood lossIn cobalamin deficiency, serum vitamin B12 level is low from gastrointestinal lesions. The remaining cases of nutrient-(b 200pg/mL), serum methylmalonic acid and homocysteine deficiency anemia are usually associated with vitamin B12,levels are increased . In folate deficiency, the red cell most frequently related to food-cobalamin malabsorption, and/folate concentration is more reliable than the serum level and or folate deficiency. All these nutrient-anemias are easily treatedshould be considered. with nutrient-deficiency replacement.11. Complications of anemia in the elderly 14. Learning points Anemia in older individuals is associated with a very wide • Nutrient-deficiency anemia represents one third of all ane-range of complications, including increased risk for mortality, mias in elderly patients.cardiovascular disease — anemia has been reported to worsen • About two thirds of nutrient-deficiency anemias are as-angina and congestive heart failure, cognitive dysfunction related sociated with iron deficiency and most of those cases are theto cerebrovascular insufficient, longer hospitalization for elective result of chronic blood loss from gastrointestinal lesions.procedures and comorbid conditions, reduced bone density, and • The remaining cases of nutrient-deficiency anemia arefalls and fractures [1,5,24]. Not surprisingly, anemia also has a usually associated with vitamin B12, most frequently relatedsignificant effect on quality of life (QOL) in the elderly. Notably, to food-cobalamin malabsorption, and/or folate deficiency.these detrimental effects are observed not only in elderly • Treatment of nutrient-deficiency anemia is easy withindividuals with severe reductions in Hb, but also in those with nutrient-deficiency replacement but requires particularmild anemia or low–normal Hb levels . Nutrient deficiency attention to discerning the cause.usually may be associated with several manifestations that alsomay have an impact on health and QOL in elderly patients. References12. Treatment of nutrient-deficiency anemia  Eisenstaedt R, Penninx BW, Woodman RC. Anemia in the elderly: current understanding and emerging concepts. Blood Rev 2006;20:213–26. Food sources of nutrients are best for prevention of nutrient-  Carmel R. Anemia and aging: an overview of clinical, diagnostic anddeficiency anemia, but often supplementation is necessary, biological issues. Blood Rev 2001;15:9–18.especially for very old . Vitamin C enhances iron absorption.  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