Volume 13, Issue 3 pp. 519-527
REVIEW ARTICLE
Full Access

Anemia in elderly patients: New insight into an old disorder

Emmanuel Andrès

Corresponding Author

Emmanuel Andrès

Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France

Competence Center of Autoimmune Cytopenias in Adults, University Hospital of Strasbourg, Strasbourg, France

Correspondence: Professor Emmanuel Andrès MD PhD, Service de Médecine Interne, Diabète et Maladies Métaboliques, Clinique Médicale B, Hôpital Civil – Hôpitaux Universitaires de Strasbourg, 1 porte de l'Hôpital, 67091 Strasbourg Cedex, France. Email: emmanuel.andres@chru-strasbourg.frSearch for more papers by this author
Khalid Serraj

Khalid Serraj

Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France

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Laure Federici

Laure Federici

Department of Internal Medicine, University Hospital of Oujda, Oujda, Morocco

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Thomas Vogel

Thomas Vogel

Department of Geriatrics and Internal Medicine, University Hospital of Strasbourg, Strasbourg, France

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Georges Kaltenbach

Georges Kaltenbach

Department of Geriatrics and Internal Medicine, University Hospital of Strasbourg, Strasbourg, France

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First published: 17 December 2012
Citations: 75

Abstract

Anemia is an important healthcare concern among the elderly. In these patients, the anemia is often mild, with a hemoglobin level >10 g/dL. It is usually well tolerated, but might be responsible for several proteiform and/or atypical presenting complaints. In the elderly, anemia is usually of multifactorial origin, including chronic inflammation, chronic kidney disease, nutrient deficiencies and iron deficiency (approximately two-thirds of all cases). The remaining cases are unexplained (unknown etiology). In the elderly, the classic diagnosis of anemia, which is based on the mean corpuscular volume associated with a low hemoglobin level, might not be accurate. A predefined standardized diagnostic procedure should be followed. In the common case of frail elderly patients, all investigations should be carefully considered and invasive examinations undertaken where justified (risk–benefit balance). Nevertheless, most cases of anemia require further investigation and the underlying cause should be identified and treated whenever possible. Geriatr Gerontol Int 2013; 13: 519–527.

Introduction

Anemia is a common condition in elderly patients. Its prevalence increases with age.1 Anemia affects quality of life (QOL), and cognitive and physical function.2 It is a comorbid condition that affects other diseases (e.g. heart disease, cerebrovascular disorders) and is even associated with a risk of death.2 Thus, anemia should not be accepted as an unavoidable consequence of aging.

In the elderly, many underlying conditions can lead to anemia, but the most common are chronic inflammation, chronic renal failure and nutrient-deficiencies, especially iron deficiency.3 In clinical practice, recognition of these disorders and deficiencies is essential for optimal treatment.

In the present paper, we report our findings and discuss the current literature in the light of our experience of anemia in elderly patients, with a focus on nutrient-deficiency anemia.

Bibliographic search strategy

A review of the medical literature from the past 10 years was carried out to identify original studies and reviews regarding anemia in elderly patients. In March 2007, PubMed was searched for English and French language articles. Textbooks on hematology, internal medicine and geriatrics were consulted, and information gleaned from international meetings was also used.

Additional data from our research group on anemia (Groupe de Recherche sur les Anémies en Médecine Interne [GRAMI], Paris, France) and nutrient deficiency, especially cobalamin deficiency (CAREnce en vitamine B12 [CARE B12], Strasbourg, France) were also included in the present review, including data presented at international or national meetings.

Definitions of anemia in the elderly

The World Health Organization (WHO) defines anemia in the adult or elderly population, as hemoglobin (Hb) concentration <12 g/dL for non-pregnant women and <13 g/dL for men.4 In elderly patients, the “accepted” values for these parameters vary between countries, regions and laboratories.1, 5 However, to our knowledge, a Hb concentration <12 g/dL is commonly considered as indicating “established” anemia in this population, regardless of the sex of the patient4).

In clinical practice, a Hb level < 10 g/dL is often considered to be a cut-off level where investigation and treatment should be carried out (“anemia to explore”; Table 1).3, 4 Indeed, at this Hb level, several recent studies have shown a benefit from investigating the anemia.6

Table 1. Semantics and definitions of anemia in elderly patients
● “Established” anemia: anemia with a Hb level < 12 g/dL
● “Anemia to explore”: anemia with a Hb level < 10 g/dL
● “Life-threatening” anemia: anemia with a Hb level < 6 g/dL, especially in cases with multiple comorbidities (frail patient, history of cardiac disease)
● “Anemia of chronic disease and/or inflammation”: anemia related to chronic diseases, including chronic kidney disease, chronic heart failure and chronic inflammation (infections, malignancy, autoimmune and inflammatory disorders)
● “Unexplained anemia” (epidemiological view) better termed as “unexplored” or “underexplored anemia” (clinical view): anemia with no detected underlying disorders (including e.g. myelodysplasia) and/or due to the absence of any systematic invasive exploration of anemia
  • Hb, hemoglobin.

Furthermore, even though anemia usually develops gradually in the elderly, allowing the body to adapt, its effects can be life-threatening – particularly because of the many comorbidities. In our experience, any elderly patient with a Hb level < 6 g/dL (“life-threatening anemia”) should be managed in an intensive care unit and rapidly transfused (with a target Hb level of at least >8 g/dL), especially in cases with cardiac disease. Such patients represent approximately 4% of the elderly referred to our department (university referral center) for anemia (personal data). It should be noted that there is no correlation between the severity of anemia and its underlying cause.

In practice, although low Hb levels are often seen with advancing age, anemia should not be considered simply as a normal consequence of aging.1, 5 Age might be associated with compromised hematopoietic reserve and consequently with an increased susceptibility to anemia in the presence of hematopoietic stress induced by an underlying disorder (e.g. infections, surgery, trauma, stress).2

Prevalence of anemia in the elderly

The prevalence of anemia increases with advancing age, especially after 60–65 years-of-age, and rises sharply after the age of 80 years.7-10 Results from the Third National Health and Nutrition Examination Survey (NHANES III) carried out in the USA show that the prevalence of anemia among men and women aged 65 years or older who lived in towns was 11% for men and 10.2% for women.7

Results from the Framingham cohort show a slightly lower prevalence of anemia among older men living in the USA. In this group of 1016 participants aged 67–96 years, the prevalence of anemia in men and women were 6.1% and 10.5%, respectively.8

In a French nationwide study of 1351 patients hospitalized in departments of internal medicine, anemia was present in 874 (65%) patients according to the WHO definition, and 573 (42%) patients had Hb levels < 11 g/dL.10

Survey findings also show that most cases of anemia among the elderly are mild; just 2.8% of women and 1.6% of men had a Hb <11 g/dL.9 Although typically mild with Hb levels remaining above 10 or 11 g/dL in most cases, anemia in the elderly is frequently associated with negative outcomes with regards to mortality, morbidity and decreased QOL (see the next section).1, 6

In the elderly, much of the variability in the reported prevalence of anemia reflects the heterogeneity of this population. Variables such as race, living circumstances and health status (e.g. heart failure, chronic kidney disease, cancer) might all influence the prevalence of anemia.1

The health status of frail older patients (“frail elderly”) results in a state of vulnerability that carries an increased risk of poor outcomes in older adults.11 In our experience, the prevalence of anemia in frail elderly patients is higher than in otherwise healthy elderly patients (38% vs 52% in a study of 252 hospitalized older patients; personal data).

Complications of anemia in the elderly

Anemia in older individuals is associated with a wide range of complications, including increased risk of mortality and cardiovascular disease. Anemia has been reported to worsen angina and congestive heart failure, as well as cognitive dysfunction related to cerebrovascular pathology. Anemia also increases the duration of hospital stay for elective procedures and comorbid conditions, and is associated with a decrease in mobility and reduced bone density, with more reported falls and fractures (Fig. 1).6, 12 In the recent Leiden 85-plus study, anemia appeared to be an independent predictor of mortality.13

figure

Complications of anemia in elderly patients.

Not surprisingly, anemia also has a significant effect on QOL in the elderly, with fatigue, alteration of cognitive function, depression and decreased muscle strength.1, 5, 12 Notably, these detrimental effects are observed not only in elderly individuals with severely lowered Hb levels, but also in those with mild anemia or low-normal Hb levels.1, 3

In the elderly, anemia is often associated with several underlying disorders, related or not to the anemia itself, which might also have an impact on health and QOL in elderly patients. For example, in our experience (internal medicine department), anemia is associated with cancer, hematological disorders, renal failure, inflammatory syndromes and diabetes mellitus in at least three-quarters of patients (personal data).

Clinical presentations of anemia in the elderly

In the elderly population, anemia frequently presents in the absence of other symptoms and is often an early sign of disease.1, 5 Fatigue and other typical symptoms often occur less severely in elderly patients than would be expected with younger adults.14 The onset of symptoms is usually insidious, and many elderly patients simply adjust their daily activities. In the elderly, complaints caused by anemia are likely to be overlooked. In this situation, pallor can be helpful, but is difficult to detect.2 The signs and symptoms of anemia often only become apparent once the anemia has become severe. Symptoms of comorbid illness might also mask the early signs and symptoms of anemia.5, 14 As aforementioned, the symptoms of other diseases might be exacerbated if anemia is present; for example, angina and congestive heart failure are worsened.12, 13

Clinical signs related to the underlying cause of the anemia might also be present, outside the hematological sphere. For example, in anemia as a result of iron deficiency, several symptoms and signs might be reported, such as changes in hair, nails, mucosa and tongue; pruritus; chronically sustained inflammation; dermatitis herpetiformis; photodermatitis; and Plummer's syndrome.15

The presentation of vitamin B12 deficiency is often multisystemic in nature and can vary greatly in severity (known as the great mimic). Hematological and neurological features usually predominate the clinical picture, in addition to symptoms related to epithelial cell involvement.16 The symptoms of folate (vitamin B9) deficiency are almost indistinguishable from those of cobalamin deficiency. It should be note that vitamin B deficiencies might be present in the elderly even in the absence of anemia, and might be responsible for several other hematological manifestations, such as neutropenia, thrombocytopenia, pancytopenia, hemolysis and pseudo-microangiopathy.17

Etiology of anemia in the elderly

Because elderly patients often have several associated comorbid conditions and underlying disorders, and are commonly taking a variety of medications, the etiology of anemia is frequently difficult to determine, even after extensive investigations including bone marrow biopsy.1, 18 Nevertheless, in most cases (approximately 80%), the cause of the anemia can be identified.2, 5, 10

However, in routine investigation of anemia, 20–30% of cases are of “unknown” etiology (Table 1).5 Indeed, in the elderly, and particularly the very elderly population, invasive and full investigation of anemia is not always possible or even desirable.5 Thus, in this fragile population (frail patients) any explorations, especially if they are invasive such as endoscopies and bone marrow examination, should always be considered in light of the risk–benefit balance.

In the opposite case of the otherwise healthy elderly patient, where the cause of anemia has not yet been established, patients might have undergone inadequate diagnostic tests. In a recent study carried out by our group using a standardized diagnostic procedure (predefined protocol, 95 elderly patients), we were able to identify at least one cause of anemia in more than 91% of cases.18

Anemia is a provisional diagnosis and, in the elderly, is always secondary to other pathologies that must be identified if treatment is to be effective. A significant proportion of elderly anemic patients (30–50%) are presumed to have multiple causes of their anemia.2, 10 In a recent study by Petrosyan et al., anemia was found to be due to more than one cause in 43.5% of the 95 elderly patients investigated.18

In the elderly, causes of anemia are divided into several broad groups including: nutrient-deficiency anemia, most often iron deficiency anemia; and/or anemia of chronic disease, perhaps better termed as “anemia of chronic inflammation”; anemia related to chronic kidney disease (CKD); and unexplained anemia.1, 9, 18 It should be noted that there is no correlation between the severity of anemia and its underlying cause. In the aforementioned NHANES III study, 34% of all anemia in elderly patients was caused by iron, folate or vitamin B12 deficiency, alone or in combination (nutritient-deficiency anemia); 20% was due to chronic diseases; 12% was associated with renal insufficiency; and in the remaining 34% the cause remained unexplained.7

In a study by Petrosyan et al. including 95 patients with a mean age of 79.7 years (range 66–101 years), the five most prominent causes of anemia were: inflammation (62.1%), iron deficiency (30.5%), folic acid deficiency (21%), chronic renal failure (17.9%) and cobalamin deficiency (11.6%).18 In this population, at least one cause of anemia was diagnosed in 87 of the 95 (91.6%) patients, and the anemia was multifactorial in 44 of the 95 (46.3%) cases.

In a French nationwide study, which included a younger population of 696 anemic patients (mean age 63 years), the causes of anemia were: inflammatory disorders (33%), hematological disorders (27%), bleeding (23%), iron/vitamin deficiency (21%) and renal failure (21%).10

In a recent Italian population-based study carried out in residents aged 65 years or older, chronic disease anemia, thalassemia and renal insufficiency were reported as the most frequent types of “mild” anemia (defined as Hb concentration of 10.0–11.9 g/dL in women and 10.0–12.9 g/dL in men).19 In this population, the underlying cause of mild anemia remained unexplained in 26.4% of cases, almost one-third of which might be accounted for by myelodysplastic syndromes.

Iron deficiency anemia in the elderly

As aforementioned, iron deficiency anemia is the second most common cause of anemia in the elderly.7, 15, 18 It usually results from chronic gastrointestinal (GI) blood loss, mainly caused by: esophagitis; gastritis; ulcers – related or not-related to non-steroidal anti-inflammatory drug intake and/or chronic Helicobacter pylori infections; varices (portal hypertension); colorectal cancer or premalignant polyps; or angiodysplasia.3, 5

In the elderly, GI blood loss is most often occult and is not ruled out by negative fecal blood tests.20 GI tract abnormalities can be identified in the majority of patients with iron deficiency anemia.3, 5, 15 These days, the GI tract can be particularly well explored by endoscopy – gastroscopy and colonoscopy have become almost routine procedures. A video capsule can also be used as a second-line investigation.6, 21, 22 In this population, clinicians must keep in mind that such explorations should always be discussed in light of the risk–benefit balance.6 However, in our opinion, iron supplementation without exploration must be reserved for very old frail patients or patients with other life-threatening comorbidities or underlying diseases.

In 40–60% of patients, the source of the bleeding is in the upper GI tract.6, 20 The blood loss is in the colon in 15–30% of cases. The source is not found in the remaining 10–40% of elderly patients with GI blood loss. Fortunately, these patients frequently do well with iron replacement and repeat investigation is not often required.23 For several authors, H. pylori infection and chronic gastritis, especially atrophic gastritis, and more rarely celiac's disease, are significantly associated with this unexplained iron deficiency anemia.24, 25

Chronic blood loss from the genitourinary tract and chronic hemoptysis might result in an iron deficiency, but are much less common causes.15, 26 Bleeding disorders and particularly anticoagulants (vitamin K antagonists) might cause iron deficiency in the elderly (approximately 20% in our experience).

Older persons might also become iron deficient because of inadequate dietary intake or inadequate absorption or bioavailability of iron (with anti-acids).26 The tannins and polyphenols in tea and coffee can inhibit iron absorption, whereas vitamin C enhances it. Any elderly patient 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.27 Without blood loss, anemia takes several years to develop.

Vitamin B deficiency anemia in the elderly

Both vitamin B12 and folate deficiency are common among the elderly, each occurring in at least 5% of anemic patients.16 The Framingham study showed an incidence of 12% among elderly people living in the community.28 In our experience, at least 25% of the elderly patients hospitalized in our department have a documented (symptomatic or not) vitamin B deficiency.25

In the elderly, folate deficiency usually develops as a result of inadequate dietary intake.6, 7 The body stores very little folate, only enough to last 4–6 months. Elderly patients are sometimes malnourished. In this context, patients usually have a history of weight loss, poor weight gain and weakness. In addition, several drugs (e.g. methotrexate, cotrimoxazole, sulfasalazine, anticonvulsants) and alcohol can cause folate deficiency.25

In elderly patients, the etiology of cobalamin deficiency is primarily food-cobalamin malabsorption (FCM) and pernicious anemia. More rarely, inadequate intake (and malabsorption) are responsible.16 In our experience, based on more than 300 elderly patients with a proven deficiency, FCM accounted for approximately 50–60% of cobalamin deficiency, and pernicious anemia accounted for 20–30%.29, 30

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.31 In clinical practice, this syndrome is characterized by cobalamin deficiency despite sufficient cobalamin intake from food and a normal Schilling test, where the latter rules out malabsorption or pernicious anemia.29 Nevertheless, to date, diagnosis of FCM is primarily, in our experience, a diagnosis of exclusion, partly because Schilling's test is no longer available.30

FCM is caused primarily in the elderly by atrophic gastritis.29-31 Over 40% of patients aged older than 80 years have gastric atrophy that may or may not be related to H. pylori infection.32 Other factors that commonly contribute to FCM in elderly people include chronic carriage of H. pylori and intestinal microbial proliferation (in which case cobalamin deficiency can be corrected by antibiotic treatment); long-term ingestion of antacids, including H2-receptor antagonists and proton-pump inhibitors; and biguanides (metformin).29, 30

Other common etiologies of anemia in the elderly

For completeness, three other types of anemia are worth discussing in the context of this general review, particularly because of their frequency: (i) anemia related to chronic disease (anemia related to CKD or severe chronic heart failure); (ii) anemia related to inflammation; and (iii) “unexplained anemia”.6, 33 To our knowledge, several excellent recent reviews have been devoted to these disorders.1, 5, 6, 12, 22 Thus, below we discuss only a few of these points, which in our opinion are the most relevant for the present review.

CKD is an important cause of anemia in the elderly population, especially considering that renal function declines with age.33, 34 Reduced renal erythropoietin production is the primary factor leading to anemia in CKD. However, the precise degree of renal dysfunction sufficient to cause anemia in the elderly remains controversial (a minimum creatinine clearance of under 30 mL/min).34, 35

In our experience, chronic heart failure is also a common, but not so well-known, cause of anemia in elderly patients, especially if the heart failure is severe and advanced (personal data). In this situation, there are often multiple mechanisms behind the anemia, including: hemodilution; absolute and functional iron deficiency; associated functional or organic renal failure (with decreased erythropoietin production); low levels of chronic inflammation with the detrimental role of cytokines (e.g. interleukin-6); and tumor necrosis factor (TNF).36 It should be remembered, as aforementioned, that anemia can be exacerbated by chronic heart failure.6

Anemia related to inflammation usually develops in the presence of disorders such as chronic infections, malignancy, autoimmune and inflammatory disorders.6, 10 These disorders are particularly frequent in the elderly. Inflammation inhibits erythropoiesis through a combination of cytokine release and the recently discovered hepcidin pathway.18, 37

As discussed earlier, the cause of approxiamtely one-third of cases of anemia in the elderly remains unexplained.6 In these cases, there is usually only a mild decrease in Hb level. Possible mechanisms for this “unexplained anemia” include a blunted erythropoietic response related to iron deficiency, higher circulating levels of pro-inflammatory cytokines, decreased androgen levels, and a decrease in the proliferative and regenerative capacity of bone marrow stem cells.6, 9, 10

Furthermore, myelodysplasia, which is more common in elderly people, is likely to be included in the group of “unexplained” causes of anemia. Thus, in general practice, myelodysplasia is often disregarded, not documented or remains undiscovered in these often very frail patients as a result of the absence of invasive systematic investigations (e.g. bone marrow with karyotype examination) carried out in this population.10

Laboratory evaluation of anemia in the elderly

Anemia in the elderly is generally hyporegenerative and is often mild to moderate, with Hb levels between 8 and 10 g/dL.6, 10 Table 2 presents the main characteristics of anemia in 95 hospitalized patients aged 65 years and older.18

Table 2. Main characteristics of anemia in 95 hospitalized patients aged 65 years and older18
Hematological parameters Mean values
Hemoglobin (g/L) 103 (60–129)
Hemoglobin (g/L) > 100 58 (61.1)
n (%)
Hemoglobin (g/L): 80–100 32 (33.7)
n (%)
Hemoglobin (g/L) < 80 5 (5.2)
n (%)
MCV (fL) 90.2 (62.1–110)
Microcytic anemia 9 (9.5)
MCV < 80 fL n (%)
Macrocytic anemia 8 (8.4)
MCV > 100 fL
n (%)
Normocytic anemia 78 (82.1)
MCV 80–100 fL
n (%)
Reticulocytes < 120 000/mm3 92 (96.8)
n (%)
  • MCV, mean corpuscular volume.

Numerous algorithms have been proposed for investigation of anemia in the elderly. The most widely used are based on the size of red blood cells.5, 6, 18 In practice and pragmatically, because of the mutifactorial etiology of anemia in these patients, the erythrocytes are frequently normocytic: mean corpuscular volume (MCV) between 80–100 fL.1, 5, 6, 10 This is also the case for anemia related to CKD or chronic heart failure35, 36 and unexplained anemia.5, 6, 10, 19 In anemia exclusively due to iron deficiency15, 38 and/or chronic inflammation,5, 6, 12 the erythrocytes are usually microcytic (MCV < 80 fL). In anemia exclusively due to folate and/or vitamin B12 deficiency, the erythrocytes are usually macrocytic (MCV > 120 fL).12

In our experience, diagnosis based on the MCV does not appear to correlate well with etiologies in the elderly. In a recent study, microcytosis was present in just 27.5% of patients who had an iron deficiency, and macrocytosis was present in just 7.4% of patients who had a folic acid and/or cobalamin deficiency.18 Consequentially, we suggest that classical diagnosis that is based on the MCEV associated with anemia, might not be accurate in the elderly. Instead, diagnosis using a predefined protocol should be encouraged, as documented by our team.18

Nutrient-deficiency anemia, a low serum iron level, an increased total iron-binding capacity and low serum ferritin levels (<15 ng/mL) accompany iron deficiency anemia.15, 38 In cases associated with inflammation, the transferrin receptor–ferritin index is the most appropriate parameter to measure.39, 40

In cobalamin deficiency, serum vitamin B12 levels are low (<200 pg/mL), and the holotranscobalamin, serum methylmalonic acid and homocysteine levels are increased.19 In folate deficiency, the red cell folate concentration is more reliable than the serum level and therefore should be measured.

Treatment of anemia in the elderly

To our knowledge, there are currently no specific guidelines to help clinicians manage anemia in the elderly, with the exception of anemia associated with cancer and CKD.1, 5, 6, 35, 41 Furthermore, the choice of management is complicated by the fact that the underlying etiology of the anemia is unknown in up to one-third of patients.7 Nevertheless, it is clear that in the elderly, anemia should be investigated, and the underlying cause should be identified and treated whenever possible.5, 6

Transfusion or erythropoiesis-stimulating agents (e.g., epoetin alpha, epoetin beta and darbepoetin alpha) are used for anemia associated with chronic diseases and their treatments (e.g. cancer/chemotherapy and CKD).42 In the elderly, cost, concerns about safety and potential side-effects should always be considered. Iron overload is only a problem once patients receive more than 20 pints of blood and chelating therapy is therefore necessary.5, 6, 10

Symptomatic treatment, such as transfusion, should be routinely discussed and prescribed in elderly patients with a Hb level < 6 d/dL, especially if they are frail or with numerous comorbidities (e.g. ischemic heart disease).5, 6, 10 In our practice, these patients were managed in the intensive care unit and were quickly transfused (with target Hb level of at least >8 g/dL; personal data). Note that transfusing 2 units of red blood cells might be the optimum volume in elderly patients who have pre-existing cardiac dysfunction.43

Treatment of nutrient deficiency anemia requires particular attention in order to establish the correct cause.5, 12, 15 In iron deficiency anemia, iron supplementation should be initiated in association with treatment of the underlying cause of bleeding. Standard therapy for iron deficiency is oral administration of a 300-mg tablet of ferrous sulfate (60 mg of elemental iron).5, 6, 15 Intravenous iron replacement can be helpful in patients with iron deficiency that fails to respond to oral replacement. Parenteral iron might also be used when there is intolerance or non-compliance with oral preparations. Intravenous iron sucrose is reasonably well tolerated, even when administered in boluses.

In elderly patients, cobalamin deficiency anemia might be treated by vitamin B12 supplementation, both parenterally or orally.15, 25 Our team has developed an effective oral treatment for food-cobalamin malabsorption and pernicious anemia, using crystalline cyanocobalamin. The main results of our oral cobalamin treatment studies are summarized in Table 3.44-46 A systematic review carried out under the auspices of the Cochrane Metabolic and Endocrine Disorders Review Group supports the efficacy of oral cobalamin therapy, with a daily dose of 2000 μg initially and then 1000 μg weekly of vitamin B12.47

Table 3. Cohort studies of oral vitamin B12 treatment carried out at the University Hospital of Strasbourg, France44
Study characteristics (number of patients) and therapeutic modalities Results

Open prospective study of vitamin B12 deficiency related to food-cobalamin malabsorption (n = 10)

Oral crystalline cyanocobalamin: 650 μg per day, during at least 3 months

  • Normalization of serum vitamin B12 levels in 80% of the patients
  • Significant increase in Hb levels (mean of 1.9 g/dL) and decrease of MCV (mean of 7.8 fL)
  • Improvement of clinical abnormalities in 20% of the patients
  • No adverse effect

Open prospective study of low vitamin B12 levels not related to pernicious anemia (n = 20)

Oral crystalline cyanocobalamin: between 1000 μg/day during at least 1 week

  • Normalization of serum vitamin B12 levels in 85% of the patients
  • No adverse effect

Open prospective study of vitamin B12 deficiency related to food-cobalamin malabsorption (n = 30)

Oral crystalline cyanocobalamin: between 1000 and 250 μg per day, during 1 month

  • Normalization of serum vitamin B12 levels in 87% of the patients
  • Significant increase of Hb levels (mean of 0.6 g/dL) and decrease of MCV (mean of 3 fL); normalization of Hb levels and MCV in 54% and 100% of the patients, respectively
  • Dose effect – effectiveness dose of vitamin B12 ≥500 μg/day
  • No adverse effect

Open prospective study of low vitamin B12 levels not related to pernicious anemia (n = 30)

Oral crystalline cyanocobalamin: between 1000 and 125 μg per day during at least 1 week

  • Normalization of serum vitamin B12 levels in all patients with at least a dose of vitamin ≥250 μg per day
  • Dose effect – effectiveness dose of vitamin B12 ≥500 μg per day
  • No adverse effect

Open prospective study of low vitamin B12 levels related to food-cobalamin malabsorption and pernicious anemia (n = 31)

Oral crystalline cyanocobalamin: between 125 to 1000 μg per day, during at least 3 months

  • Significant increase of serum vitamin B12 levels in 90% of the patients (mean of 117.4 pg/mL
  • Significant increase of Hb levels (mean of 2.45 g/dL) and decrease of MCV (mean of 10.4 fL)
  • Improvement of clinical abnormalities in 30% of the patients

Retrospective study of low vitamin B12 levels mainly related to food-cobalamin malabsorption (n = 22)

Oral crystalline cyanocobalamin: 650 μg per day, during a median of 2.5 years

  • Significant increase of the serum cobalamin levels in all the patients, with a mean of +161,6 ± 79,3 pg/mL in the food-cobalamin malabsorption group and +136,7 ± 67,4 pg/mL in the pernicious anemia group
  • Normalization of hematological parameters in 90% of the patients, independently of the cause of the cobalamin deficiency

Cohort study of patients with cognitive alteration related to low vitamin B12 levels mainly related to food-cobalamin malabsorption (n = 10)

Oral crystalline cyanocobalamin: 1000 μg per day, during a week, then 1000 μg per week, during a month, and 1000 μg per month, during at least 3 months

  • Increase of MMSE score during the treatment (P < 0.06)
  • Hb, hemoglobin; MCV, mean corpuscular volume; MMSE, Mini-Mental State Examination.

In folate deficiency anemia, therapeutic doses vary between 1 to 5 mg per day.15, 48 Usually treatment is continued for at least 3–6 months, provided that the underlying cause has been corrected.

Conclusions

In conclusion, anemia is an important healthcare concern among the elderly, and remains a diagnostic and therapeutic challenge for clinicians.49 In these patients, the anemia is often mild with a hemoglobin level >10 g/dL. It is generally well tolerated and might be responsible for several proteiform and/or atypical presenting complaints.

In the elderly, anemia is usually of multifactorial origin; including chronic inflammation, chronic kidney disease and nutrient-deficiencies. In these patients, approximately two-thirds of nutrient deficiency anemia is associated with iron deficiency, and most cases are the result of chronic blood loss from the gastrointestinal tract. The remaining cases of nutrient deficiency anemia are usually associated with vitamin B12, most frequently related to food-cobalamin malabsorption and/or folate deficiency. The remaining cases are termed “unexplained” anemia (unknown etiology).

In the elderly, diagnosis is classically based on the MCV associated with anemia. This might not be accurate and therefore a predefined standardized diagnostic procedure should be followed. In the case of frail patients, all investigations should be carefully considered and invasive examinations justified (risk–benefit balance).

Nevertheless, most cases of anemia require thorough investigation, and the underlying cause should be identified and treated whenever possible. All cases of nutrient deficiency anemia are easily treated with replacement therapy.

Disclosure statement

Professor E Andres is a member of the Commission Nationale de Pharmacovigilance (National Commission of Pharmacovigilance). The data developed herein solely represent his personal opinion. He is responsible for the Centre de Compétences des Cytopénies Auto-Immunes de l'Adulte (Competence Centre of Autoimmune Cytopenia in Adults) at the CHRU of Strasbourg. He leads a working group on vitamin B12 deficiency at the University Hospital of Strasbourg (CARE B12) and is a member of GRAMI: Groupe de Recherche sur les Anémies en Médecine Interne (Research Group on Anemia in Internal Medicine). He is an expert consultant to several laboratories involved in hematology (AMGEN, ROCHE, CHUGAI, GSK, VIFOR, FERRING, BMS, SHERRING, GENZYME, ACTELION), and has participated in numerous international and national studies sponsored by these laboratories and academic works.

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