Anemia in the elderly: current understanding and emerging concepts.

Anemia is currently defined by the World Health Organization (WHO) as a hemoglobin (Hb) level <13 g/dL in men and <12 g/dL in women. While estimates vary widely, nearly one quarter of community-based octagenerians and one half of the chronically ill elderly have Hb levels that satisfy a diagnosis of anemia according to these criteria. A growing body of evidence has linked adverse events with even "mild" anemia or low-normal Hb in the elderly. Recent studies suggest strongly that aging is associated with dysregulation of pro-inflammatory cytokines, most notably interleukin-6 (IL-6), which may negatively impact hematopoiesis, either by inhibition of erythropoietin (EPO) production or interaction with EPO receptors. Anemia in older individuals is associated with a very wide range of complications, including increased risk for mortality, cardiovascular disease, cognitive dysfunction, longer hospitalization for elective procedures and comorbid conditions, reduced bone density, and falls and fractures. Not surprisingly, anemia also has a significant effect on quality of life (QOL) in the elderly. Most anemia in older individuals results from iron deficiency, chronic inflammation, or chronic kidney disease, or it may be unexplained. Future research on anemia in the elderly should focus on the age-related physiologic changes underlying this condition and whether anemia correction can reduce anemia-associated risks, and improve QOL.

[1]  S. Bandinelli,et al.  Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[2]  A. Teppo,et al.  Successful treatment of the anemia of rheumatoid arthritis with subcutaneously administered recombinant human erythropoietin. Slower response in patients with more severe inflammation. , 1993, Scandinavian journal of rheumatology.

[3]  D. Fergusson,et al.  Mechanisms of Unexplained Anemia in the Nursing Home , 2004, Journal of the American Geriatrics Society.

[4]  E. Keller,et al.  Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. , 2000, Annual review of medicine.

[5]  H. Krumholz,et al.  Blood transfusion in elderly patients with acute myocardial infarction. , 2001, The New England journal of medicine.

[6]  T. Pincus,et al.  Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies. , 1989, Arthritis and rheumatism.

[7]  D. Lipschitz Medical and Functional Consequences of Anemia in the Elderly , 2003, Journal of the American Geriatrics Society.

[8]  S. Bandinelli,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC only. TRIALS The , 2004 .

[9]  B. Saka,et al.  Soluble transferrin receptor and soluble transferrin receptor-ferritin index for evaluation of the iron status in elderly patients. , 2004, The Tohoku journal of experimental medicine.

[10]  A. Konijn,et al.  Serum ferritin in an elderly population. , 1979, Journal of gerontology.

[11]  M. Cazzola,et al.  Use of recombinant human erythropoietin outside the setting of uremia. , 1997, Blood.

[12]  S. Rantapää-Dahlqvist,et al.  Availability of iron and degree of inflammation modifies the response to recombinant human erythropoietin when treating anemia of chronic disease in patients with rheumatoid arthritis , 1997, Rheumatology International.

[13]  S. Aronoff,et al.  The prevalence of anemia in patients with chronic kidney disease , 2004, Current medical research and opinion.

[14]  M. Shlipak,et al.  Association of anemia with diastolic dysfunction among patients with coronary artery disease in the Heart and Soul Study. , 2005, The American journal of cardiology.

[15]  R. Carmel,et al.  Anemia and aging: an overview of clinical, diagnostic and biological issues. , 2001, Blood reviews.

[16]  Gaël Nicolas,et al.  The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. , 2002, The Journal of clinical investigation.

[17]  B. Badhe,et al.  IS ADULT DEFINITION OF ANEMIA APPLICABLE TO A GERIATRIC POPULATION? STUDY OF ERYTHROCYTE PARAMETERS IN INDIAN GERIATRIC INPATIENTS , 2004, Journal of the American Geriatrics Society.

[18]  K. Fahrbach,et al.  The effect of anemia treatment on selected health-related quality-of-life domains: a systematic review. , 2003, Clinical therapeutics.

[19]  T. Quinn,et al.  Serum immunoreactive erythropoietin in HIV-infected patients. , 1989, JAMA.

[20]  Balducci,et al.  Anemia of Aging: A Model of Erythropoiesis in Cancer Patients. , 1998, Cancer control : journal of the Moffitt Cancer Center.

[21]  L. Ferrucci,et al.  Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[22]  L. Ferrucci,et al.  Anemia in older adults , 2005, Current opinion in hematology.

[23]  E. Norkus,et al.  Mild anemia and the risk of falls in older adults from nursing homes and the community. , 2004, Journal of the American Medical Directors Association.

[24]  N. Casadevall,et al.  Decreased erythropoietin responsiveness to iron deficiency anemia in the elderly , 1993, American journal of hematology.

[25]  D Grillot,et al.  Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. , 1996, Blood.

[26]  Sabbatini The Relationship between Anemia and Quality of Life in Cancer Patients. , 2000, The oncologist.

[27]  H. Tilg,et al.  Role of IL-10 for Induction of Anemia During Inflammation1 , 2002, The Journal of Immunology.

[28]  M. Passeri,et al.  Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes , 2001, Experimental Gerontology.

[29]  B. Löwenberg,et al.  Anaemia of chronic disease in rheumatoid arthritis , 1990, Rheumatology International.

[30]  Brigden Ml Clinical utility of serum tests for iron deficiency in hospitalized patients. , 1990 .

[31]  K. Punnonen,et al.  Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. , 1997, Blood.

[32]  B. Seifert,et al.  Prediction of iron deficiency in chronic inflammatory rheumatic disease anaemia , 1995, British journal of haematology.

[33]  E. Nečas,et al.  Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin. , 2004, Blood.

[34]  R. Kurzrock The role of cytokines in cancer‐related fatigue , 2001, Cancer.

[35]  R. D'Agostino,et al.  Iron status of the free-living, elderly Framingham Heart Study cohort: an iron-replete population with a high prevalence of elevated iron stores. , 2001, The American journal of clinical nutrition.

[36]  G. Enzi,et al.  Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: Some results of an italian multicentric study , 1994, Aging.

[37]  T. Schnitzer,et al.  Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. , 1990, The American journal of medicine.

[38]  M. Fischl,et al.  Recombinant human erythropoietin for patients with AIDS treated with zidovudine. , 1990, The New England journal of medicine.

[39]  M. Cesari,et al.  Anemia and cognitive performance in hospitalized older patients: results from the GIFA study , 2006, International journal of geriatric psychiatry.

[40]  P. Poole‐Wilson,et al.  Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial , 2004 .

[41]  J. Spivak The anaemia of cancer: death by a thousand cuts , 2005, Nature Reviews Cancer.

[42]  L. Fried,et al.  Looking at the Relationship Between Hemoglobin Concentration and Prevalent Mobility Difficulty in Older Women. Should the Criteria Currently Used to Define Anemia in Older People be Reevaluated? , 2002, Journal of the American Geriatrics Society.

[43]  J. Zuckerman,et al.  The Relationship Between Admission Hemoglobin Level and Outcome After Hip Fracture , 2002, Journal of orthopaedic trauma.

[44]  L. Ferrucci,et al.  Anemia and decline in physical performance among older persons. , 2003, The American journal of medicine.

[45]  N. E. Hansen,et al.  Serum ferritin and the assessment of iron deficiency in rheumatoid arthritis. , 1983, Scandinavian journal of rheumatology.

[46]  Á. Remacha,et al.  Erythroid abnormalities in rheumatoid arthritis: the role of erythropoietin. , 1992, The Journal of rheumatology.

[47]  M. Jongen‐Lavrencic,et al.  Elevated levels of inflammatory cytokines in bone marrow of patients with rheumatoid arthritis and anemia of chronic disease. , 1997, The Journal of rheumatology.

[48]  Elizabeta Nemeth,et al.  Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. , 2003, Blood.

[49]  W. McIlroy,et al.  Laboratory diagnosis of iron-deficiency anemia , 1992, Journal of General Internal Medicine.

[50]  D. Knook,et al.  The definition of anemia in older persons. , 1999, JAMA.

[51]  Helle Bruunsgaard,et al.  Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. , 2003, European cytokine network.

[52]  L. Ferrucci,et al.  Serum Erythropoietin and Aging: A Longitudinal Analysis , 2005, Journal of the American Geriatrics Society.

[53]  Risk factors associated with hospitalization for unintentional falls: Wisconsin hospital discharge data for patients aged 65 and over. , 2003, WMJ : official publication of the State Medical Society of Wisconsin.

[54]  R. Abels Erythropoietin for anaemia in cancer patients. , 1993, European journal of cancer.

[55]  A. Collins,et al.  Chronic kidney disease and cardiovascular disease in the Medicare population. , 2003, Kidney international. Supplement.

[56]  E. Rimon,et al.  Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index. , 2002, Archives of internal medicine.

[57]  S. Piantadosi,et al.  Decreased erythropoietin response in patients with the anemia of cancer. , 1990, The New England journal of medicine.

[58]  W. McIlroy,et al.  Laboratory diagnosis of iron-deficiency Anemia: An overview , 1992, Journal of General Internal Medicine.

[59]  Elizabeta Nemeth,et al.  IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. , 2004, The Journal of clinical investigation.

[60]  D. Rockey,et al.  Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. , 1993, The New England journal of medicine.

[61]  D. Silverberg,et al.  The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? , 2004, Journal of nephrology.

[62]  L. Ferrucci,et al.  Renal function, erythropoietin, and anemia of older persons: the InCHIANTI study. , 2005, Archives of internal medicine.

[63]  J. Krause,et al.  Comparison of stainable iron in aspirated and needle-biopsy specimens of bone marrow. , 1979, American journal of clinical pathology.

[64]  S. Bandinelli,et al.  Circulating Erythropoietin (EPO) and Pro-Inflammatory Markers in Elderly (>/=65) Persons with and without Anemia. , 2004 .

[65]  J. van Pelt,et al.  Measurements of serum ferritin used to predict concentrations of iron in bone marrow in anemia of chronic disease. , 1991, Clinical chemistry.

[66]  W. Ershler Biological Interactions of Aging and Anemia: A Focus on Cytokines , 2003, Journal of the American Geriatrics Society.

[67]  T. Ganz,et al.  Hepcidin in iron overload disorders. , 2005, Blood.

[68]  J. Spivak The blood in systemic disorders , 2000, The Lancet.

[69]  C. Lionis,et al.  In what extent anemia coexists with cognitive impairment in elderly: a cross-sectional study in Greece , 2001, BMC family practice.

[70]  J. Cook,et al.  Serum transferrin receptor: a quantitative measure of tissue iron deficiency. , 1990, Blood.

[71]  E. Hertrampf,et al.  Prevalence of anemia in elderly subjects living at home: role of micronutrient deficiency and inflammation , 2000, European Journal of Clinical Nutrition.

[72]  D. Witte Can serum ferritin be effectively interpreted in the presence of the acute-phase response? , 1991, Clinical chemistry.

[73]  K. Kario,et al.  Serum erythropoietin levels in the elderly. , 1991, Gerontology.

[74]  M. Schroll,et al.  Iron status in 358 apparently healthy 80-year-old Danish men and women: relation to food composition and dietary and supplemental iron intake , 2004, Annals of Hematology.

[75]  K. Kario,et al.  Reduced erythropoietin secretion in senile anemia , 1992, American journal of hematology.

[76]  Tomas Ganz,et al.  Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. , 2003, Blood.

[77]  M. Loda,et al.  Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. , 2002, Blood.

[78]  M. Worwood,et al.  Ferritin in serum. Clinical and biochemical implications. , 1975, The New England journal of medicine.

[79]  D. Norfolk,et al.  Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia , 1992, European journal of haematology.

[80]  C. Patterson,et al.  Assessment of Iron Stores in Anemic Geriatric Patients , 1985, Journal of the American Geriatrics Society.

[81]  C. Taylor,et al.  Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  T. Möttönen,et al.  Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia. , 2000, Arthritis and rheumatism.

[83]  S. Rubin,et al.  Inflammatory markers and cognition in well-functioning African-American and white elders , 2003, Neurology.

[84]  M. Jongen‐Lavrencic,et al.  Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial. , 1996, Annals of the rheumatic diseases.

[85]  M. Goldberg,et al.  EFFECT OF INFLAMMATORY CYTOKINES ON HYPOXIA-INDUCED ERYTHROPOIETIN PRODUCTION , 1992 .

[86]  M. Pirisi,et al.  Erythropoietin and the anemia of chronic diseases. , 1993, Clinical and experimental rheumatology.

[87]  Kathleen Koenig,et al.  Serum Interleukin‐6 and Hemoglobin as Physiological Correlates in the Geriatric Syndrome of Frailty: A Pilot Study , 2002, Journal of the American Geriatrics Society.

[88]  C. Salvarani,et al.  Recombinant human erythropoietin therapy in patients with rheumatoid arthritis with the anemia of chronic disease. , 1991, The Journal of rheumatology.

[89]  M. Siimes,et al.  Circulating transferrin receptor during erythropoietin medication of anemic patients with rheumatoid arthritis. , 1996, Scandinavian journal of rheumatology.

[90]  S. Schreiber,et al.  Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. , 1996, The New England journal of medicine.

[91]  L. Ferrucci,et al.  Anemia Is Associated with Disability and Decreased Physical Performance and Muscle Strength in the Elderly , 2004, Journal of the American Geriatrics Society.

[92]  G. Cartwright The anemia of chronic disorders. , 1966, Seminars in hematology.

[93]  I. Macdougall,et al.  Increased Expression of Erythropoiesis Inhibiting Cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T Cells in Patients Exhibiting a Poor Response to Erythropoietin Therapy , 2003 .

[94]  L. Ferrucci,et al.  What Constitutes Normal Hemoglobin Concentration in Community‐Dwelling Disabled Older Women? , 2004, Journal of the American Geriatrics Society.

[95]  J. Griffith,et al.  Hematocrit and left ventricular mass: the Framingham Heart study. , 2004, Journal of the American College of Cardiology.

[96]  Bruno Turlin,et al.  A New Mouse Liver-specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload* , 2001, The Journal of Biological Chemistry.

[97]  S. Bandinelli,et al.  Proinflammatory state and circulating erythropoietin in persons with and without anemia. , 2005, The American journal of medicine.

[98]  Mary Cushman,et al.  A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. , 2005, Archives of internal medicine.

[99]  Carol West,et al.  Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. , 2005, Blood.

[100]  L. Ferrucci,et al.  Inflammation, hormones, and body composition at a crossroad. , 2003, The American journal of medicine.

[101]  N. Papadopoulos,et al.  Correlation of interleukin-6 serum levels with bone density in postmenopausal women , 1997, Clinical Rheumatology.

[102]  Luigi Ferrucci,et al.  Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. , 2004, Blood.

[103]  J. Cook The measurement of serum transferrin receptor. , 1999, The American journal of the medical sciences.

[104]  D. Smith,et al.  Anemia in the elderly. , 2000, American family physician.

[105]  S. Krantz,et al.  Progress in understanding the pathogenesis of the anemia of chronic disease. , 1992, Blood.

[106]  M. Kikuchi,et al.  Five‐Year Survival of Older People with Anemia: Variation with Hemoglobin Concentration , 2001, Journal of the American Geriatrics Society.

[107]  S. Bandinelli,et al.  Bone density and hemoglobin levels in older persons: results from the InCHIANTI study , 2005, Osteoporosis International.

[108]  B. Astor,et al.  Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the Atherosclerosis Risk in Communities (ARIC) study. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[109]  J. Guralnik,et al.  Late‐Life Anemia Is Associated with Increased Risk of Recurrent Falls , 2005, Journal of the American Geriatrics Society.

[110]  L. Balducci Anemia, cancer, and aging. , 2003, Cancer control : journal of the Moffitt Cancer Center.

[111]  N. Andrews,et al.  2002 E. Mead Johnson Award for Research in Pediatrics Lecture: The Molecular Biology of the Anemia of Chronic Disease: A Hypothesis , 2003, Pediatric Research.

[112]  H. Papadaki,et al.  Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. , 2002, Blood.

[113]  E. Goldwasser,et al.  Blunted erythropoietin response to anaemia in rheumatoid arthritis , 1987, British journal of haematology.

[114]  W. Ershler,et al.  Recombinant Erythropoietin Treatment of Anemia in Older Adults , 2001, Journal of the American Geriatrics Society.

[115]  L. Goodnough,et al.  Anemia of chronic disease. , 2005, The New England journal of medicine.