Anemia in Elderly: A Review

Transcription

1 Review Article Anemia in Elderly: A Review Shaurya Mehta 1, Laxmi Kant Goyal 2, Ramkesh Parmar 3, Girdhari Lal Dhayal 4, Gunja Jain 5 Abstract Anemia is common among elderly and is associated with increased morbidity and mortality in this vulnerable age group. Anaemia hampers functional capacity and cognition, increases risk for frequent falls, frailty, dementia, hospitalization, mortality and mobility and ultimately affects the quality of life. Anemia in elderly is divided in three major types: nutritional deficiency, anemia of chronic disease including chronic renal disease and unexplained anemia. A high index of suspicion is required to manage anemia in elders. The symptoms (easy fatigue, decrease appetite, pallor) are usually taken as consequences of advance age. The onset of signs and symptoms are insidious and elders adjust their routine activities to the remaining physical capabilities and physiological adaptations. Anemia may present as worsening of associated disorder like worsening congestive heart failure, cognitive impairment, dizziness and apathy. The evaluation of anemia in elderly involves complete history including dietary, medical illness and medication history and through physical examination to detect any sign suggestive of etiology followed by further investigations accordingly. The treatment of anemia depends on its etiology and severity. In severe anemia, red cell transfusion is required along with treatment of underlying etiology. In unexplained anemia, erythropoietin replacement in higher dose than usual may be needed due to blunted response to erythropoietin. Anabolic steroid supplementation is also beneficial in elderly with anemia. (Journal of The Indian Academy of Geriatrics, 2018; 14: 74-78) Introduction Anemia is common among elderly and is associated with increased morbidity and mortality in this vulnerable age group. Anemia hampers functional capacity, mobility and ultimately the quality of life. 1,2 The symptoms are usually taken as consequences of advance age. The onset of signs and symptoms are insidious and elders adjust their 1. Senior Resident, Department of Medicine, 2. Assistant Professor, Geriatric Medicine, 3. Senior Resident, Department of Medicine, 4 & 5. Assistant Professor, Department of Medicine; Corresponding Author: Dr Girdhari Lal Dhayal, Assistant Professor, Department of Medicine, SMS Medical College, JLN Marg, Jaipur dr.dhayal@gmail.com routine activities to the remaining physical capabilities and physiological adaptations. 1 The causes of anemia also differ from younger population and may be the related to polypharmacy and comorbidities. A high index of suspicion is required to manage anemia in this segment of population. This review will highlight the clinicians approach towards anemia in the elderly. Prevalence Recent population-based surveys have renewed the debate and ascertained the rising prevalence of anaemia in elderly to be a public health crisis. 3 The prevalence of anemia among elderly varies between community studies and institutionalised persons. Using World Health Organization criteria for anemia (hemoglobin <12

2 Anemia in Elderly: A Review 75 g/dl in women and <13 g/dl in men), the prevalence of anemia in the elderly reported as 8-44% among different studies. 4-6 Mild anemia (haemoglobin 10g/dl) was found in about 10% cases in a community dwelling elderly survey. 7 Various studies have demonstrated significant negative impact of mild anemia in elderly in terms of decreased physical performance and cognition along with increased association with frequent falls, frailty, dementia, hospitalization and mortality Etiopathogenesis of Anemia Anemia in older persons is divided in three major types according to cause and include nutritional deficiency, anemia of chronic disease including chronic renal disease and unexplained anemia. 7,11-12 Nutritional anemia The most common cause of nutritional anemia is iron deficiency anemia (IDA) worldwide. Vitamin B12 and folate deficiency alone or in combination with iron deficiency constitutes the remaining cohort. 7,13 Anemia of chronic disease (ACD) This is next common and include 1/3 rd cases of anemia in elderly. The ACD occurs in chronic inflammatory conditions i.e. chronic infection, malignancy, autoimmune disorder, chronic heart failure, chronic renal failure etc. ACD usually suspected in cases with anemia with underlying chronic disease without a clear etiology of anemia. 7 The anemia in ACD is normochromic normocytic to microcytic. The ACD is diagnosed when there is low circulating iron despite increased iron stores (normal or increased ferritin, increased transferrin saturation) along with reduced total iron binding capacity. The markers of inflammation remain elevated in ACD. Reticulocyte indices show low reticulocyte count. The pathogenetic mechanism of ACD involves many factors. The dysregulation of iron homeostesis is the chief mechanism behind ACD. 14 Chronic inflammation activates CD3 T lymphocytes and macrophages which release cytokines - IFN-γ, TNFα, IL-1 and IL Chronic inflammation also increases hepcidin. 17 Unexplained anemia (UA) The unexplained/unclassified anemia constitutes 25-33% cases of anemia in elderly and includes anemia that cannot be classified into any other categories. 7 These are usually hypoproliferative normocytic anemia. The possible mechanism of UA may include reduction of progenitor mass, blunted effect of erythropoietin on erythrocyte precursors, decreased intracellular oxygen utilization, alteration in sex hormones and sarcopenia. 18 Hepcidin and Anemia Hepcidin is a peptide hormone secreted by hepatocytes and a key regulator of iron homeostesis. It inhibits iron absorption from the duodenum and release of iron by the bone marrow macrophages via downregulating intestinal iron absorption and plasma iron concentration by its ability to degrade its receptor ferroportin Ferroportin is the only known transporter for the efflux of iron from cells. 13 Downregulation of Ferroportin by hepcidin in splenic or hepatic macrophages decreases the ability of macrophages to export the recycled iron from senescent RBCs. 20 In tissue cells, Hepdicin induces internalization and degradation of Ferroportin, resulting in decreased iron export with increased cellular iron retention Thus hepcidin reduction results in tissue iron overload and its elevation leads to hypoferremia and anemia of inflammation. 13 Hepcidin also decreases the erythropoietin synthesis and impairs its biological activity. 13 Hepcidin expression in human hepatocytes is increased by inflammation, IL-6 and lipopolisaccaride and are suppressed by TNF-α. 13 Stimulators of erythropoiesis (i.e hypoxia, erythropoietin administration, phlebotomy) suppresses hepcidin expression. 13 Cytokines and anemia Cytokines also plays important role in ACD as they inhibit erythropoiesis i.e. TNF- α, IFN-γ, IL-1, transforming growth factor-β etc. 22 IFN-γ is the most potent inhibitor of erythropoiesis. 22 It stimulates ferritin transcription and also inhibits transferrin receptor (TfR) mrna expression which ultimately results in decrease intestinal transport of iron from gut lumen to blood Cytokines also exert a direct toxic effect on progenitor cells by inducing the formation of free radicals by neighboring macrophage-like cells. 13 In ACD, erythropoietin production is inhibited by combined effect of raised hepcidin and direct inhibition of the EPO promoter gene through cytokine-induced toxic radicals. 27 The low response to erythropoietin replacement, blunted erythropoietin response, can also be partly explained by the combined effect of raised hepcidin and cytokines induced toxic free radicals

3 76 Journal of The Indian Academy of Geriatrics, Vol. 14, No. 2, June, 2018 Figure 1: Management of anemia in elderly1

4 Anemia in Elderly: A Review 77 Sex Hormones and Anemia Low testosterone levels are found to be associated with anemia in both elderly men and women. 30 Androgens (including testosterone and its derivatives nandrolone, oxandrolone, etc.) stimulate the hematopoietic system by various mechanisms. 13 In addition to their anabolic effect, they stimulate erythropoietin release and bone marrow activity and increases iron incorporation into erythron. 31 Studies had reported increment in haemoglobin upon addition of Testosterone/ Androgen in the treatment. 32 When elderly male patients on dialysis received Nandrolone, anemia improved in a similar manner to that observed with recombinant erythropoietin administration. 33 Clinical features The clinical symptoms of anemia including easy fatigue, decrease appetite, pallor are easily overlooked due to many reasons. The onset of symptoms and signs is usually insidious, and many elderly patients adjust their activities as they make physiologic adaptations for the condition. Typical symptoms of anemia, such as fatigue, weakness and dyspnea, are not specific and in elderly patients tend to be attributed to advancing age. Pallor can be hard to detect in the elderly. 1 In advance age, anemia may present as worsening of associated disorder like worsening congestive heart failure, cognitive impairment, dizziness and apathy. 1 Evaluation The evaluation of anemia in elderly involves complete history including dietary. Medical illness and medication history and thorough physical examination to detect any sign suggestive of etiology (i.e. brittle spoon shape nails in IDA, nuchal pigmentation in Vit B12 deficiency, neurological signs in Vit B12 deficiency, signs of liver disease etc). The investigations are ordered according to history and examination 1 (Figure 1). Management The treatment of anemia depends on its etiology and severity. In severe anemic, red cell transfusion is required along with treatment of underlying etiology. In IDA, oral or parenteral administration is required. In vitamin B12 or folate deficient elderly, parenteral supplementation may be required because of decreased gut absorption. In ACD, correction of the underlying cause is required. In UA, erythropoietin replacement in higher dose than usual may be needed due to blunted response to erythropoietin. Anabolic steroid supplementation is also beneficial in elderly anemic patients. References 1. Douglas L, Smith MD. Anemia in the Elderly. Am Fam Physician Oct 1;62(7): Ania Lafuente BJ, Fernandez-Burriel Tercero M, Suarez Almenara JL, et al. Anaemia and functional capacity at admission in a geriatric home. An Med Interna. 2001; 18(1): Guralnik JM, Ershler WB, Schrier SL, et al. Anaemia in the elderly: a public health crisis in hematology. Hematology Am Soc Hematol Educ. 2005: Ania BJ, Suman VJ, Fairbanks VF, Melton LJ III. Prevalence of anemia in medical practice: community versus referral patients. Mayo Clin Proc. 1994; 69: Salive ME, Cornoni-Huntley J, Guralnik JM, Phillips CL, Wallace RB, Ostfeld AM, et al. Anemia and hemoglobin levels in older persons: relationship with age, gender, and health status. J Am Geriatr Soc. 1992; 40: Daly MP. Anemia in the elderly. Am Fam Physician. 1989;39: Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004; 104: Zakai NA, Katz R, Hirsch C, et al. A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. Arch Intern Med. 2005; 165: Culleton BF, Manns BJ, Zhang J, Tonelli M, Klarenbach S, Hemmelgarn BR. Impact of anemia on hospitalization and mortality in older adults. Blood. 2006; 107: Hong CH, Falvey C, Harris TB, et al. Anemia and risk of dementia in older adults: Findings from the Health ABC study. Neurology. 2013; 81: Bhasin A, Rao MY. Characteristics of anemia in elderly: a hospital based study in South India. Indian J Hematol Blood Transfus 2011;21(1): Alwar V, Reethi K, Rameshkumar K. Geriatric Anemia: An Indian Perspective. Indian J Hematol Blood Transfus (Apr-June 2013) 29(2):

5 78 Journal of The Indian Academy of Geriatrics, Vol. 14, No. 2, June, Bianchi V E.Anemia in the Elderly Population J Hematol. 2014;3(4): Madu AJ, Ughasoro M D. Anaemia of Chronic Disease: An In-Depth Review. Med Princ Pract. 2017;26(1): Moldawer LL, Marano MA, Wei H, et al: Cachectin/ tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J 1989; 3: McCranor BJ, Kim MJ, Cruz NM, et al: Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol Dis 2014; 52: Galushko EA: The clinical significance of hepcidin detection in the patients with anemia and rheumatoid arthritis (in Russian). Klin Med (Mosk) 2014; 92: Canestrari F, Buoncristiani U, Galli F, Giorgini A, Albertini MC, Carobi C, Pascucci M, et al. Redox state, antioxidative activity and lipid peroxidation in erythrocytes and plasma of chronic ambulatory peritoneal dialysis patients. Clin Chim Acta. 1995; 234(1-2): Ganz T, Nemeth E: Hepcidin and iron homeostasis. Biochim Biophys Acta 2012; 1823: Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest. 2013;123(6): Ramey G, Deschemin JC, Durel B, Canonne-Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica. 2010; 95(3): Means RT, Jr. Recent developments in the anemia of chronic disease. Curr Hematol Rep. 2003; 2(2): Wang CQ, Udupa KB, Lipschitz DA. Interferongamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol. 1995; 162(1): Lortz S, Schroter S, Stuckemann V, et al: Influence of cytokines on DMT1 iron transporter and ferritin expression in insulin-secreting cells. J Mol Endocrinol 2014; 52: Costa E, Fernandes J, Ribeiro S, et al: Aging is associated with impaired renal function, INF gamma induced inflammation and with alterations in iron regulatory proteins gene expression. Aging Dis 2014; 5: Kheansaard W, Mas-Oo-di S, Nilganuwong S, et al: Interferon-gamma induced nitric oxide mediated apoptosis of anemia of chronic disease in rheumatoid arthritis. Rheumatol Int 2013; 33: Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18(8): De Lurdes Agostinho Cabrita A, Pinho A, Malho A, et al: Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patient, stages 4 and 5. Int Urol Nephrol 2011; 43: Nazemian F, Karimi G, Moatamedi M, et al: Effect of silymarin administration on TNFalpha serum concentration in peritoneal dialysis patients. Phytother Res 2010; 24: Ferrucci L, Maggio M, Bandinelli S, Basaria S, Lauretani F, Ble A, Valenti G, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med. 2006; 166(13): Shahani S, Braga-Basaria M, Maggio M, Basaria S. Androgens and erythropoiesis: past and present. J Endocrinol Invest. 2009; 32(8): Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003;51(1): Adamu B, Ma'aji SM, Erwin PJ, Tleyjeh IM. Meta- Analysis of Randomized Controlled Trials on Androgens versus Erythropoietin for Anaemia of Chronic Kidney Disease: Implications for Developing Countries. Int J Nephrol. 2012; 2012: