Chronic inflammation (chronic disease)
Liver disease and endocrine disease (chronic disease)
Vitamin B12 deficiency
As see below, rare unknown causes of nutrition-deficiency anemia also include several other vitamin deficiencies (vitamins A, B2, B3, C, and E), selenium, zinc, or copper . These later etiologies are nevertheless not well-studied in the literature, and to date, few not-well-documented date are available, except for the theoretical and pathological aspects of anemia.
Iron-Deficiency Anemia in Middle Age Patients and in the Elderly
Iron-deficiency anemia, the most common cause of anemia in middle age patient and 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 Helicobacter pylori infections, varices (portal hypertension), colorectal cancer or premalignant polyps, or angiodysplasia [15, 16]. GI blood loss is often occult and is not ruled out by negative fecal blood tests. GI tract abnormalities can be identified in the majority of patients with iron-deficiency anemia .
In 40–60% of patients, the source is in the upper GI tract [18, 19]. The blood loss is in the colon in 15–30% of cases. The source is not found in the remaining 10–40% of patients with GI blood loss . Fortunately, these patients do well with iron replacement and repeat investigation is not often needed, especially in frailty elderly and too sick elderly . In middle age patient, repeat GI investigation with upper and/or lower endoscopy and video capsule may be of interest, with the detection of the etiology of bleeding in an additional 20% of cases [19, 20]. It is important because one-third of the iron-deficiency anemia is related to GI malignancies. In young women, iron-deficiency anemia is often in relation with heavy menstrual bleeding, or meno-metrorrhagia .
Table 3.2 presents our experience of the evaluation of the GI tract in 90 patients with chronic blood loss, follow-up in an internal medicine department (in a referral center) . Bleeding disorders and particularly anticoagulants (vitamin K antagonists ) may cause iron deficiency in the elderly (around 20% in our experience) [7, 14].
Results of the evaluation of the gastrointestinal tract in elderly patients (≥65 years) with chronic blood loss (n = 90), hospitalized in an internal medicine department
Esophagitis and Mallory Weiss syndrome
Gastritis, atrophic gastritis and ulcer related or not related to NSAID use and/or Helicobacter pylori infection
Varices related to portal hypertension
Colorectal benign and pre-malignant polyps
Inflammatory bowel disease
H. pylori infection and chronic gastritis, especially atrophic gastritis, are significantly associated with unexplained iron-deficiency anemia, as celiac disease and rarely, large amount of tea (at least 2 L par day) and vegetarian diet . Older persons may also become iron deficient because of inadequate dietary intake or inadequate absorption or bioavailability of iron (with anti-acids) . Heme iron from animal sources is better absorbed than non-heme iron from plant sources. Vitamin C in food enhances iron absorption from non-heme sources. The tannins and polyphenols in tea and coffee can inhibit iron absorption. Any elderly subject whose dietary intake is poor and has recent unexplained weight loss is a candidate for increased medical surveillance. Nevertheless, iron-deficiency anemia is rarely the result of dietary deficiency in industrialized countries . Without blood loss, anemia takes several years to develop.
Chronic blood loss from the genitourinary tract and chronic hemoptysis may result in iron deficiency but are much less common causes .
Vitamin B9 Deficiency Anemia in Middle Age Patients and in the Elderly
A regular diet contains 500–700 μg of vitamin B9. On average, 50–60% of dietary folic acid is absorbed in the duodenum and jejunum. Vitamin B9 deficiency usually develops as a result of inadequate dietary intake, of malabsorption, as in celiac disease, or of malnutrition [1, 15]. The body contains very little vitamin B9, with stocks expected to last 4–6 months. Patients usually have a history of weight loss, poor weight gain, and weakness.
In addition, several drugs (methotrexate, cotrimoxazole, sulfasalazine, anticonvulsant) and alcohol may cause deficiency of folic acid . Pregnancy is also a common cause of vitamin B9 deficiency , but is generally prevented in industrialized countries by vitamin B9 supplementation.
Vitamin B12 Deficiency Anemia in Middle Age Patients and in the Elderly
Both vitamin B12 and folic acid deficiency are common among middle age patient and in the 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 .
In adult and elderly patients, the etiologies of cobalamin deficiency are represented primarily by food-cobalamin malabsorption (FCM) and pernicious anemia and, more rarely, by intake deficiency and malabsorption . In our study, in which we followed more than 200 elderly patients with a proven deficiency, FCM accounted for about 60–70% of the etiologies of cobalamin deficiency, and pernicious anemia 15–25%. Figure 3.1 presents the principal causes of cobalamin deficiency in 172 elderly patients (median age: 70 years) hospitalized in the university hospital of Strasbourg, France [26, 27].
Initially described by Carmel in the 1990s, the FCM is characterized by the inability to release cobalamin from food and/or intestinal transport proteins, particularly in the case of hypochlorhydria, where the absorption of “unbound” cobalamin is normal (“mal digestion” of the food-cobalamin) . As we have recently indicated, this syndrome is defined by cobalamin deficiency despite sufficient cobalamin intake from food and a normal Schilling test, where the latter rules out malabsorption or pernicious anemia .
FCM is caused primarily by atrophic gastritis. Over 40% of patients older than 80 years of age have gastric atrophy that might or might not be related to H. pylori infection . Other factors that commonly contribute to FCM in middle age patient and elderly people include: chronic carriage of H. pylori and intestinal microbial proliferation (in which case vitamin B12 deficiency can be corrected by antibiotic treatment); long-term ingestion of antacids, including h2-receptor antagonists and proton-pump inhibitors, and biguanides (metformin); chronic alcoholism; surgery or gastric reconstruction (e.g., bypass surgery for obesity); partial and pancreatic exocrine failure .
In our experience, the clinical manifestations of FCM are not very different from those of cobalamin deficiencies associated with other causes, e.g., Biermer’s disease . However, it should be emphasized that Carmel first believed that FCM was associated with moderate cobalamin deficiency , leading to only “subtle” clinical symptoms (“subtle cobalamin deficiency”) . Our published data contradict this assertion [26, 27].
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Clinical Presentation of Nutritional Anemia
The onset of symptoms is usually insidious, anemia settling in general over several weeks or months, and many patients adjust their activities. Fatigue, dispend, and other typical symptoms often occur gradually. In elderly, these symptoms of anemia are likely to be overlooked. In this situation, pallor can be helpful but hard to detect . The symptoms of other diseases may be exacerbating if anemia is also present.
Anemia in older individuals is associated with a very wide range of complications, including increased risk for mortality, cardiovascular disease—anemia has been reported to worsen angina and congestive heart failure, cognitive dysfunction related to cerebrovascular insufficient, longer hospitalization for elective procedures and comorbid conditions, reduced bone density, and falls and fractures [6, 31]. Not surprisingly, anemia also has a significant effect on quality of life in the elderly.
Moreover, symptoms related to nutrition-deficiency as iron, vitamin B12, and folic acid might be present outside the hematological sphere. Table 3.3 presents features related to vitamin B12 deficiency in elderly patients . It should be noted that vitamin B12 deficiency may be present even in the absence of anemia. The symptoms of vitamin B9 deficiency are nearly indistinguishable from those of cobalamin deficiency.
Manifestations related to vitamin B12 deficiency (with the exception of hematological manifestations)
Frequent: polyneurites (especially sensitive ones), ataxia, Babinski’s phenomenon
Classic: Hunter’s glossitis, jaundice, LDH, and bilirubin elevation (“intramedullary destruction”)
Under study: atrophy of the vaginal mucosa and chronic vaginal and urinary 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 nerves including optic neuritis, optic atrophy, urinary and/or fecal incontinence
Rare: resistant and recurring mucocutaneous ulcers cobalamin deficiency
Under study: changes in the higher functions, even dementia, stroke and atherosclerosis (hyperhomocysteinemia), parkinsonian syndromes, depression, multiple sclerosis
Iron deficiency is responsible for changes in hair, nails, mucosa and tongue as pruritus, chronically sustained inflammation, dermatitis herpetiformis, photodermatitis, and Plummer’s syndrome .
Nutritional anemia is generally hyporegenerative and represents the consequence of the hematopoietic system inability to replace the peripheral blood loss [12, 15]. Patients with nutritional anemia often have mild to moderate anemia, with Hb levels between 8 and 10 g/dL. In practice, because of the multifactorial etiologies of anemia, particularly in elderly, the erythrocytes are frequently normocytic: mean erythrocyte cell volume (MECV) between 80 and 100 fL in anemia of exclusive iron deficiency, the erythrocytes are usually microcytic (MECV <80 fL) in anemia of exclusive vitamin B9 and/or vitamin B12 deficiency, the erythrocytes are usually macrocytic (MECV >120 fL). Other hematological manifestations may be associated as presented in Table 3.4, with the example of cobalamin deficiency .
Hematological manifestations of vitamin B12 deficiency in patients with documented cobalamin deficiency (n = 201), hospitalized in an internal medicine department (tertiary reference center)