Etiology of anemia in patients older than 65 years (n = 300), hospitalized in an internal medicine department (tertiary reference center) .
In this chapter, we report and discuss the current literature of nutrient-deficiency anemia, also called nutritional anemia, in elderly patients in developed countries. For this purpose, a review of medical literatures was conducted searching PubMed, textbooks of hematology, internal medicine and geriatrics, and information collected from international meetings were also included. The term nutrient deficiency or nutritional anemia covers any anemia, defined by a hemoglobin level <13 g/dL (<130 g/L) in men and <12 g/dL (<120 g/L) in women, resulting from a deficiency of materials essential for erythropoiesis. Patients with nutritional anemia often have mild to moderate anemia, with hemoglobin levels between 8 and 10 g/dL (80 and 100 g/L). In practice, nutritional anemia represents one-third of all anemia in elderly patients. About two-third of nutritional anemia is associated with iron deficiency and most of those cases are the result of chronic blood loss from gastrointestinal lesions. The remaining cases of nutritional anemia are usually associated with vitamin B12 (cobalamin), most frequently related to food-cobalamin malabsorption (especially in case of atrophic gastritis), and Biermer’s disease (pernicious anemia); and/or vitamin B9 (folate) deficiency, most frequently related to inadequate dietary intake or malnutrition, several drugs (as methotrexate, cotrimoxazole) and chronic alcohol intake. In clinical practice, recognition of these disorders and deficiencies is essential for optimal treatment (nutrient-deficiency replacement).
- nutritional anemia
- nutrient-deficiency anemia
- iron deficiency
- vitamin B12 deficiency
- cobalamin deficiency
- vitamin B9 deficiency
- folate deficiency
Anemia is a common condition, especially in elderly patients (≥75 years) and its prevalence increases with age . Anemia affects quality of life in all elderly patients. It also affects cognitive and physical function, especially in frailty patients, and be a factor of aggravation or poor prognosis of chronic diseases, e.g., chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic renal failure, cerebrovascular disorders [2, 3]. Anemia is even associated with a risk of death. Thus, it should not be accepted as an unavoidable condition or a consequence of aging.
In the elderly, many underlying conditions can lead to anemia such as chronic diseases, renal failure, myelodysplastic syndromes, cancer, and unexplained anemia. However, the most common nutrient deficiencies are iron, vitamin B9 (folic acid), and vitamin B12 (cobalamin) deficiency . In clinical practice, recognition of these disorders and deficiencies is essential for optimal treatment.
In this chapter, we report and discuss the current literatures of nutrient-deficiency anemia, also called nutritional anemia, in elderly patients in developed countries.
2. Bibliographic search strategy
A review of the medical literatures was conducted to identify original studies and review articles concerning nutrient-deficiency anemia in elderly patients. In March 2017, PubMed was searched for English- and French-language articles. The terms used for online bibliographic search included “nutrient-deficiency anemia,” “nutritional anemia,” “iron deficiency,” “vitamin B9 deficiency,” “folate deficiency,” “vitamin B12 deficiency” or “cobalamin deficiency,” and “elderly patients.” A total of more than 500 abstracts related to clinical trial and reviews were identified between the years 2007 and 2017. All of the abstracts were reviewed by at least two senior researchers. Only 245 publications were eventually retained and 39 publications were used for this review. These publications have been selected because of the quality or the originality of the text, the excellence of the adopted methodology, and the reputation of the authors.
Textbooks of hematology, internal medicine and geriatrics, and information collected from international meetings were also included.
3. Definition of nutritional anemia
Although low hemoglobin levels (approximately 1 g/dL lower than the
In clinical practice, an Hb level <10 g/dL is often considered to be a cut off level where investigation in the elderly (“
Nutrient-deficiency or nutritional anemia refers to types of anemia that can be directly attributed to “
4. Prevalence of nutritional anemia
The prevalence of anemia increases with advancing age, especially after age 60–65 years, and rises sharply after the age of 80 years [2, 6]. Currently, anemia in this population represents a public health problem in developed countries.
In the United States (US), results from the third
In the US, results from the Framingham cohort indicate a lower prevalence of anemia among 1016 subjects within 67–96 years of age. In this group, the prevalence of anemia in men and women was 6.1 and 10.5%, respectively . In this study, in addition to anemia of inflammation and of renal failure, nutritional anemia was also a major cause of anemia.
In a French nationwide study of 1351 patients hospitalized in several departments of Internal Medicine, anemia was present in 874 (65%) patients according to the
5. Etiology of anemia with a focus on nutritional anemia
Because elderly patients often have several associated co-morbid conditions and are commonly taking a variety of medications, some of which may contribute to anemia, the precise etiology of anemia is frequently difficult to determine, even after extensive investigations, including bone marrow biopsy [3, 13]. Thus, according to the literatures and in our own experience, the etiology of anemia can be identified in only approximately 80% of the cases, in spite of the use of new tools such as video capsule [7, 14]. Moreover, a significant proportion of elderly anemic patients, around 30–50%, are presumed to have multiple causes for their anemia [14, 15]. In cases where the causes of anemia have not been established, an inadequate diagnostic work-up for the patient could be suspected.
In the elderly, causes of anemia are divided into three main broad groups: (1) “nutrient-deficiency or nutritional anemia,” mainly in relation with iron deficiency anemia; (2) “anemia of chronic disease,” including anemia related to renal failure, chronic inflammation, chronic heart failure; and (3) “unexplained anemia” [2, 3, 9]. In the aforementioned
About 60% of nutritional anemia is associated with iron deficiency and most of those cases are the result of chronic blood loss from gastrointestinal lesions in developed countries . The remaining cases of nutrient-deficiency anemia are usually associated with vitamin B12 and/or vitamin B9 deficiency and are easily treated. In Table 1, we report our personal experience (retrospective study) of the etiology of anemia in 300 hospitalized patients of ≥65 years old [4, 7].
|Chronic inflammation (chronic disease)||23.0|
|Liver disease and endocrine disease (chronic disease)||7|
|Vitamin B12 deficiency||4|
Rare unknown causes of nutrient-deficiency anemia include several other vitamin deficiencies (e.g., vitamins A, B2, B3, C, and E), selenium, zinc, or cooper . These later etiologies are nevertheless not well-studied in the literature, and to date, few not well-documented data are available, except for the theoretical and pathological aspects of anemia.
6. Iron deficiency anemia in the elderly
Iron deficiency anemia, the most common cause of anemia in the elderly , results usually from chronic gastrointestinal (GI) blood loss mainly caused by esophagitis, gastritis, ulcer, related or not related to nonsteroidal anti-inflammatory drug intake, and/or chronic
It is important to keep in mind that GI blood loss is often occult and is not ruled out by negative fecal blood tests. In elderly, GI tract abnormalities can be identified with appropriate investigations (mainly invasive and require general anesthesia) in the majority of patients with iron deficiency anemia . In 40–60% of patients, the source is in the upper GI tract and the identified cause of GI blood loss is benign [18, 19]. In 15–30% of patients, the source of GI blood loss is in the colon, here also with mainly benign lesions. Table 2 presents our experience of the evaluation of the GI tract in 90 patients with chronic blood loss during their follow-up in an internal medicine department (in a referral center) .
|Esophagitis and Mallory Weiss syndrome||4.4|
|Gastritis, atrophic gastritis and ulcer related or not related to NSAID use and/or ||30|
|Varices related to portal hypertension||9|
|Colorectal benign and pre-malignant polyps||5.5|
|Inflammatory bowel disease||2.25|
The source of bleeding is not found in the remaining 10–40% of patients with GI blood loss. Fortunately, these patients do well with iron replacement and repeated investigation may be only proposed in “
Chronic blood loss from the genitourinary tract and exceptionally from chronic hemoptysis may result in iron deficiency . In this situation, bleeding disorders and particularly anticoagulant and antiplatelet medications may promote the development of iron deficiency in the elderly (around 20% in our experience) [7, 14].
7. Vitamin B9 and vitamin B12 deficiency anemia in the elderly
Both vitamin B9 and B12 deficiencies are common among elderly, each occurring in at least 5% of the patients . The Framingham study demonstrated an incidence of 12% among elderly people living in the community .
Vitamin B9 deficiency usually develops as a result of inadequate dietary intake and malnutrition, quiet frequent in elderly patients of malabsorption, as in coeliac disease [1, 15]. In fact, a regular diet contains 500–700 μg of vitamin B9 and the body contains very little vitamin B9 with stocks expected to last 4–6 months. The affected patients usually have a history of weight loss, poor weight gain, and weakness. This is particularly the case in Alzheimer’s patient or in patients with advanced dementia. In addition, several drugs (methotrexate, cotrimoxazole, sulfasalazine, anticonvulsants) and alcohol—even in elderly—may cause deficiency of folic acid .
In elderly patients, the etiologies of vitamin B12 deficiency are represented primarily by food-cobalamin malabsorption (FCM) and Biermer’s disease, also called pernicious anemia. The FCM is not a real malabsorption in view of physiopathology, but a maldigestion of vitamin B12 (linked to food). More rarely, the etiologies of vitamin B12 deficiency include intake deficiency and true malabsorption, related for example, to digestive tract surgery . In a study by our group (n = 200), FCM accounted for about 60–70% of the etiologies of vitamin B12 deficiency and about 15–25% in Biermer’s disease [26, 27]. Figure 1 presents the principal causes of vitamin B12 deficiency in 172 elderly patients (median age: 70 years) hospitalized in the University Hospital of Strasbourg, France .
FCM is characterized by the inability to release cobalamin from food and/or intestinal transport proteins, particularly in case of hypochlorhydria, where the absorption of “unbound” cobalamin is normal (“
Biermer’s disease is caused by impaired absorption of vitamin B12 due to the neutralization of intrinsic factor action in the setting of immune atrophic gastritis (loss of intrinsic factor in genetic form) [4, 25]. In practice, the diagnosis of Biermer’s disease is based on the presence of: (i) intrinsic factor antibodies in serum (specificity: >98%, sensibility: around 50%) and/or (ii) autoimmune atrophic gastritis (the presence of
8. Clinical presentation of nutritional anemia
In elderly patients, the onset of anemic symptoms (fatigue, asthenia) and signs (pallor, palpitations) is usually insidious because majority of these patients adjust their physical activities, stay at home, and take several drugs which mask the anemic symptomatology. Thus, these symptoms may be overlooked and undiagnosed. . In elderly, anemia may be revealed by the exacerbation of chronic-associated conditions or disorders, as dyspnea or edema of the legs related to worsening of cardiac failure. Anemia has also been reported to worsen angina, cognitive dysfunction related to cerebrovascular insufficiency .
Iron, vitamin B9, and vitamin B12 deficiencies may be associated with specific symptoms and clinical manifestations. Table 3 presents features related to vitamin B12 deficiency in elderly patients . The features of vitamin B9 deficiency are nearly indistinguishable from those of vitamin B12 deficiency, although the symptomatology is generally less severe. Iron deficiency is responsible for changes in hair (hair loss), nails (koilonychias), glossitis, dermatitis herpetiformis, photodermatitis, restless legs syndrome, and/or Plummer’s syndrome .
|Neuropsychiatric manifestations||Digestive manifestations||Other manifestations|
Under study: changes in the higher functions, even dementia, stroke and atherosclerosis (hyperhomocysteinemia), parkinsonian syndromes, depression, multiple sclerosis
9. Biological abnormalities related to nutritional anemia
Patients with nutritional anemia often have mild to moderate anemia, with Hb levels between 8 and 10 g/dL. This anemia is generally hyporegenerative, with a low reticulocyte count (<50 × 109/L). This represents the consequence of the reduced activity of the hematopoietic system to replace the peripheral blood loss or deficiency [12, 15].
In elderly, the anemia is frequently “normocytic,” with a mean erythrocyte cell volume (MECV) between 80 and 100 fL. This normocytic nature of the anemia is related to the multifactorial etiologies of anemia. In exclusive iron deficiency, the erythrocytes are usually “microcytic,” with a MECV <80 fL (main differential diagnoses: chronic inflammation, thalassemia). In exclusive vitamin B9 and/or vitamin B12 deficiency, the erythrocytes are usually “macrocytic,” with a MECV >120 fL (main differential diagnosis: alcohol, hypothyroidism, and myelodysplastic syndromes). Other hematological abnormalities and manifestations may also be associated with cobalamin deficiency as listed in Table 4 .
|Hemoglobin level (g/dL)||10.3 ± 0.4 (4.9–15.1)|
|Mean erythrocyte cell volume (fL)||98.9 ± 25.6 (76–142)|
|Reticulocyte count (%)||15.2 (1–32)|
|White cell count (/mm3)||6200 ± 4100 (500–20,000)|
|Platelet count (103/mm3)||146 ± 42 (27–580)|
|Anemia with Hb level < 12 g/dL||37%|
|Anemia with Hb level < 6 g/dL||2.5%|
|Anemia and macrocytosis (MECV >100 fL)||33.8%|
|Isolated macrocytosis (MECV >100 fL)||17%|
|Microcytosis (MECV <80 fL)||5%|
|White cell count <4000/mm3||14%|
|Neutrophil count <1000/mm3||3%|
|Thrombopenia (<150 × 103/mm3)||10%|
|Life threatening manifestations||9%|
Iron deficiency is documented by a low serum iron level, an increased total iron-binding capacity, and a low serum ferritin level (<15 ng/mL) . In cases associated with chronic inflammation, the transferrin receptor-ferritin index appears to be the most appropriate parameter to discriminate between the two disorders .
Vitamin B12 deficiency is usually documented by a low serum vitamin B12 level (<200 pg/mL). An increase of the serum methylmalonic acid or homocysteine levels should be established to exclude a false negative result for vitamin B12 . In vitamin B9 deficiency, the red cell vitamin B9 concentration is the recommended investigation .
10. Treatment of nutritional anemia
In iron deficiency anemia, iron supplementation should be initiated in association with the treatment of the underlying cause of bleeding. Treatment of nutritional anemia requires particular attention to establish the correct cause in all patients, particularly in elderly patients in a very good general condition of the body or mind . Standard therapy for iron deficiency is an oral administration of 200–300 mg of ferrous sulfate (60 mg of elemental iron) [34, 35]. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia because of its effectiveness and low cost. Vitamin C enhances iron absorption. Intravenous iron replacement may be reserved for patients with iron deficiency that fails to respond to oral replacement or in patients with documented malabsorption, inflammatory bowel diseases, malignancies, renal failure, and also perhaps in anemic patients with chronic heart failure. Parenteral iron supplementation may also be used when there is an intolerance or noncompliance with oral preparations. Intravenous iron sucrose is reasonably well tolerated, even when administered in boluses .
In elderly patients, vitamin B12 deficiency anemia may be treated by vitamin B12 supplementation, parenterally (commonly intramuscular) or orally [36, 37]. Our team (
|Study characteristics (number of patients)||Therapeutic modalities||Results|
|Open prospective study of well-documented vitamin B12 deficiency related to food-cobalamin malabsorption (n = 10)||Oral crystalline cyanocobalamin: 650 μg/day, during the condition and continue at least 3 months|
|Open prospective study of low vitamin B12 levels not related to pernicious anemia (n = 20)||Oral crystalline cyanocobalamin: 1000 μg/day during the condition and continue at least 1 week|
|Open prospective study of well-documented vitamin B12 deficiency related to food-cobalamin malabsorption (n = 30)||Oral crystalline cyanocobalamin: between 1000 and 250 μg/day, during the condition and continue at least 1 month|
|Open prospective study of low vitamin B12 levels not related to pernicious anemia (n = 30)||Oral crystalline cyanocobalamin: between 1000 and 125 μg/day during the condition and continue at least 1 week|
|Open prospective study of low vitamin B12 levels related to pernicious anemia (n = 10)||Oral crystalline cyanocobalamin: 1000 μg/day, during the condition and continue at least 3 months|
In vitamin B9 deficiency, therapeutic doses of vitamin B9 vary between 1 and 5 mg/day . Usually, supplementation is continued for at least 3–6 months, provided that the underlying causes of the deficiencies have been corrected.
Food sources of nutrients are best for prevention of nutritional anemia, but often supplementation is necessary, especially for the elderly . The
In elderly patients, nutritional anemia represents 30–40% of all anemia. About two-third of this nutritional anemia is related to iron deficiency. Iron deficiency anemia is mainly the result of chronic blood loss from gastrointestinal lesions (with benign lesions in two-third of the cases). The remaining cases of nutritional anemia are usually associated with vitamin B12 and/or vitamin B9 deficiency. In elderly patients, vitamin B12 deficiency is most frequently related to food-cobalamin malabsorption; vitamin B9 is related to inadequate dietary intake or malnutrition, several drugs (as methotrexate, cotrimoxazole) and chronic alcohol intake. Treatment of nutritional anemia is simple and involves replacement of the deficient nutrient but requires particular attention to discerning the cause.
Conflict of interest
None related to the content of the present chapter.