CME Geriatric medicine

Causes of anaemia in older people Geriatric medicine Most older people with anaemia have an identifiable pathological cause. Although Edited by Graham Mulley DM FRCP, Developmental Professor of Elderly intrinsic ageing can contribute to a low Medicine, St James’s University Hospital, Leeds and haemoglobin, it should not be accepted as the primary cause even in very elderly Peter Crome MD PhD FRCP FFPM, Professor of Geriatric Medicine, Keele subjects. Multiple causes of anaemia may University School of Medicine, University Hospital of North Staffordshire, coexist in the same patient. The most Stoke-on-Trent common causes in older people are the anaemia of chronic disease followed closely by iron deficiency (Table 1). results varying according to race, health Anaemia in elderly status and setting. Anaemia of chronic disease Anaemia is more common in hospi- patients talised and nursing home residents than Anaemia of chronic disease is typically in old people living at home. Large normocytic and normochromic but it epidemiological cohorts have reported can occasionally be microcytic. It is asso- Lesley McCormick BSc MBChB MRCP(UK), anaemia in around 6–12% of commu- ciated with chronic inflammatory disor- Senior House Officer in Geiatric Medicine nity dwelling older people.2 ders, renal impairment, chronic David J Stott MBChB MD FRCP(Glas) The symptoms usually associated with infections and malignancy.7 There is FRCP(Edin), David Cargill Professor of anaemia include breathlessness, palpita- reduced release of iron from bone Geriatric Medicine tions, tiredness and lethargy. However, in marrow despite adequate iron stores and Academic Section of Geriatric Medicine, older people anaemia is also associated Glasgow Royal infirmary an inadequate erythropoietin (EPO) with increased falls, impaired cognition, response to anaemia, resulting in reduced muscle strength and physical reduced erythropoiesis and shortened Clin Med 2007;7:501–4 function, and impaired quality of life.3,4 red cell survival. A reduction in haemoglobin is not a The main differential diagnosis of the Anaemia is defined by the World Health normal physiological part of the ageing anaemia of chronic disease is iron defi- Organization (WHO) as a haemoglobin process nor is it clinically benign – ciency. The single most helpful blood test concentration below 12 g/dl in women reduced haemoglobin is independently to discriminate between these is serum and 13 g/dl in men.1 The prevalence of associated with increased mortality ferritin.6 In the anaemia of chronic dis- anaemia in elderly subjects varies widely in elderly people, even at levels currently ease, serum ferritin is typically elevated; in different populations because of the considered to be within the lower end iron deficiency is unlikely if levels are heterogeneity of study populations, of normal.5 over 100 µg/l. Anaemia of chronic disease should be Key Points suspected if there is evidence of a chronic inflammatory process. Clinically, this could include: Anaemia is independently associated with mortality and loss of physical function in elderly subjects, even with haemoglobin levels currently considered to be within • a pressure sore or skin ulceration the lower end of the normal range

Chronic disease and iron deficiency anaemia are the most common causes of anaemia in older people Table 1. Prevalence of types of anaemia in older people. Reprinted with permission 6 A ferritin level below 45 µg/l should be used as a cut-off for diagnosing iron from Elsevier. deficiency in elderly people, but should be considered as a possibility with Type of anaemia Prevalence (%) ferritin levels up to 100 µg/l Anaemia of chronic disease 44 Patients with iron deficiency anaemia should be investigated for chronic gastrointestinal blood loss by and regardless of faecal Iron deficiency 36 occult blood test results Megaloblastic 8 Myeloma 2 should be considered in elderly patients with unexplained anaemia due to iron or folate deficiency Sideroblastic 1 Myelodysplasia 1 KEY WORDS: aged, anaemia, anaemia of chronic disease, folic acid, iron deficiency, Other 8 vitamin B12

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• limb girdle stiffness consistent with deficiency should be considered with Assessment for source of polymyalgia rheumatica ferritin levels up to 100 µg/l; iron chronic blood loss enlarged lymph nodes deficiency is unlikely with ferritin above • this level, even in the presence of coexis- In a patient with IDA it is highly likely abdominal masses suggestive of • tent chronic inflammatory disease.7 that there will be underlying chronic tumour. Iron deficiency is typically associated blood loss, particularly from the 10,11 A basic investigative screen is essential. with a low serum iron and an elevated gastrointestinal (GI) tract. Dietary Abnormal results that may point towards total iron-binding capacity, but this rise insufficiency is an uncommon cause, and an underlying cause of anaemia of is attenuated in older people and in the in older populations there is no associa- chronic disease include: presence of coexistent chronic inflamma- tion between iron intake and anaemia. elevated serum urea and creatinine tion. In practice, measurement of Therefore, even when the diet appears • poor, this cannot be assumed to be the increased erythrocyte sedimentation transferrin saturation adds little to the • cause of anaemia. rate (ESR) interpretation of serum ferritin. The first step in determining possible • abnormal function tests chronic blood loss is the history. The Serum transferrin receptor. A useful low serum albumin use of non-steroidal anti-inflammatory • additional blood test may be serum tumour on chest X-ray. drugs (perhaps bought over the counter) • transferrin receptor (sTfR). sTfR is and antiplatelet agents should be estab- The treatment of anaemia of chronic expressed on most cells and has a major lished. Enquiry should also be made disease in the older patient is primarily role in internalisation of iron. It is over- about blood in vomit, stool or urine, or directed at the underlying disorder. For expressed on the cell membrane when black stool colour. example, successful healing of a pressure iron stores are deficient, so levels of sTfR However, non-specific symptoms such sore, drainage of an abscess or resolution are inversely correlated with tissue iron as dyspepsia or change in bowel habit do of polymyalgia rheumatica with steroids stores. It is not an acute-phase reactant not associate strongly with an underlying may all result in a rise in haemoglobin. and can be an alternative method for source of chronic blood loss. Even in the EPO treatment should be considered for assessment of iron status; it may be par- absence of symptoms, up to 44% of severe anaemia due to renal failure. ticularly useful in differentiating between adults with iron deficiency will have a GI IDA and the anaemia of chronic disease. Iron deficiency anaemia lesion capable of causing blood loss. The ratio of sTfR to the log serum fer- Similarly faecal occult blood (FOB) ritin level is known as the sTfR index. Laboratory investigations testing is not helpful. This may be sensitive and specific in Patients with a series of negative Iron deficiency anaemia (IDA) is detection of iron deficiency and can be a results can still have an important treat- typically associated with a microcytic, valuable tool in differentiating between able cause of GI blood loss, so the results hypochromic blood film, with poikilocy- IDA and anaemia of chronic disease. tosis, anisocytosis and target cells. However, the diagnostic utility of the However, these findings are insensitive sTfR has yet to be proven in older people. and some patients are normochromic Table 2. Causes of iron deficiency anaemia and normocytic.8 (IDA) in elderly patients (n=96), revealed Oral iron replacement. In cases where at upper gastrointestinal endoscopy and serum ferritin is equivocal (45–100 µg/l), colonoscopy. Reprinted with permission Serum ferritin. The single most useful from S Karger AG, Basel.9 investigation in establishing iron a therapeutic trial of oral iron replace- deficiency is measurement of serum ment can help confirm the diagnosis. Cause of IDA %* With correction of iron deficiency (con- ferritin. However, ferritin rises both with Gastric or duodenal ulcer 26 ageing and with chronic inflammation; firmed by a rise in ferritin) there will be Gastric erosions/oesophagitis 24 cut-off levels for diagnosis of likely iron an early reticulocytosis and rise in red Gastric or oesophageal cancer 7 deficiency in older people are higher cell distribution width, followed by a rise Gastric polyp 3 than those used by many laboratories. in mean cell volume and haemoglobin. The WHO recommends a ferritin Colon cancer 8 below 12 µg/l as the cut-off for diagnosis Stainable bone marrow iron. The Colonic adenoma/polyp 6 of iron deficiency. This has a high definitive test for diagnosis of IDA is Diverticula 3 specificity but low sensitivity and most absence of stainable bone marrow iron. Vascular malformation 2 elderly patients with IDA have a serum Bone marrow aspiration is an invasive Colitis 2 ferritin above this level. In older people a test that can be associated with signifi- Haemorrhoids 6 serum ferritin level below 45 µg/l has a cant discomfort. In general, it is per- No lesion found 16 sensitivity of 85% and a specificity of 92% formed only when there is doubt about for diagnosing bone marrow iron the diagnosis after all non-invasive *Percentages total more than 100 as some patients had more than one lesion. deficiency.9 The possibility of iron options have been explored.

502 Clinical Medicine Vol 7 No 5 October 2007 CME Geriatric medicine of FOB testing should not influence the an option in investigation of the GI tract inability to cleave the vitamin from decision to investigate further. in frail elderly patients. Evidence is lim- dietary protein to allow absorption.18 ited; results to date show limited sensi- This food-cobalamin is tivity for detection of clinically significant primarily caused by atrophic gastritis Investigation of the 13 in iron colonic tumours. Other developing tech- and hypochlorhydria. The problem is deficiency anaemia niques such as magnetic resonance therefore inability to release B12 from colonography cannot be recommended food, despite adequate intake and the Investigation of both the upper and for routine use at present. ability to absorb free B12. lower GI tract will often be required. Pernicious anaemia is often assumed When a benign lesion is found at one end Coeliac disease to be the cause for B12 deficiency, but of the bowel it should not be assumed accounts for only 15–20% of cases in that this is the only cause of the anaemia, The prevalence of coeliac disease in the older people. Pernicious anaemia is an so investigation should include both UK is high (about 1 in 100). Typical mal- autoimmune disorder. Parietal cell anti- upper and lower GI tract. absorption symptoms including diar- bodies, present in the serum of about rhoea are uncommon; chronic iron or 90% of patients with pernicious Endoscopy and colonoscopy folate deficiency with anaemia may be anaemia, are also found in many elderly the only presenting feature. patients with gastric atrophy; specificity Endoscopy is the mainstay of investiga- Serology using human recombinant is therefore low. anti- tion for IDA. It is usually preferred to tissue transglutaminase antibody has bodies have a higher specificity but sensi- radiological imaging; it has higher high sensitivity and specificity (93% and tivity is low (about 50%). diagnostic sensitivity and the opportu- >98%, respectively) and is a useful Other causes of B12 deficiency are nity for tissue diagnosis if a lesion is seen. screening tool for coeliac disease.14 relatively rare. Occasional patients have Upper GI endoscopy is better tolerated Histological changes on distal duodenal primary dietary deficiency. Surgical than barium meal in older patients. biopsy remain the standard for removal of the terminal ileum will The yield from upper GI endoscopy diagnosis; in patients undergoing inevitably result in B12 deficiency if plus colonoscopy is substantial, with endoscopy for IDA, duodenal biopsies replacement is not given. Metformin can benign lesions in up to 60% and malig- should be taken if no other cause for cause B12 deficiency. nancies, polyps or adenomas (premalig- anaemia is found. nancies) in around 25% (Table 2). If colonoscopy is not available, barium Schilling test for absorption of enema is a reasonable alternative, Anaemia due to vitamin B12 vitamin B12 detecting around 95% of the lesions deficiency The Schilling test can be used to measure found at colonoscopy. Both colonoscopy is common in B12 absorption. The standard test and barium enema require good bowel elderly patients.15 In the Framingham involves first assessing absorption of preparation, with pretreatment with study,16 12% of community dwelling radiolabelled vitamin B12. If excretion in laxatives to empty the bowel. Neither older people had evidence of B12 defi- the urine is low, the patient then pro- of these tests is practicable in frail ciency, while studies in institutional care ceeds to the second part of the test in immobile patients. have shown a prevalence of up to 40%. which absorption of radiolabelled vit- amin B12 is assessed when given with Computed tomographic A low serum vitamin B12 level is usu- intrinsic factor. In pernicious anaemia, colonography ally associated with altered erythro- poiesis. Typically, severe B12 deficiency the expected result is reduced B12 A newer radiological technique, less causes macrocytosis with a megaloblastic absorption when given alone in part 1, invasive than colonoscopy and better bone marrow, but abnormalities may be corrected by the addition of intrinsic tolerated by patients, is computed tomo- subtle with a modest rise in mean cell factor in part 2 of the test. graphic (CT) colonography. It does not volume within the accepted reference However, this test is of no value in require sedation, though necessitates full range.17 Macrocytosis can also be masked detecting food-cobalamin malabsorp- bowel preparation and air insufflation. A by concomitant iron deficiency. It is tion. In addition, a falsely low result meta-analysis of published studies con- therefore important to screen all anaemic may occur if the 24-hour urine collection cluded that CT colonography is less elderly patients for both B12 and iron is incomplete or renal function is accurate than colonoscopy for detection deficiency with measurement of serum impaired – often the case in elderly of polyps or other small lesions.12 CT vitamin B12 and ferritin levels. patients. The treatment of food-cobal- colonography may be more accurate amin malabsorption and pernicious than air contrast barium enema. Causes of vitamin B12 deficiency anaemia is the same, with replenishment Minimal preparation CT avoids the of vitamin B12. need for bowel preparation or intravenous The most common cause of vitamin B12 The result of the Schilling test does not contrast and is non-invasive. It is therefore deficiency in older people (60–70%) is affect clinical management, so it is not

Clinical Medicine Vol 7 No 5 October 2007 503 recommended in routine clinical practice 2 Beghé C, Wilson A, Ershler WB. Prevalence et al. Prevalence of cobalamin deficiency in for older patients with B12 deficiency and outcomes of anemia in geriatrics: a the Framingham elderly population. Am J and anaemia. systematic review of the literature. Am J Clin Nutr 1994;60:2–14. Med 2004;116(Suppl 7A):3S–10S. 17 Stott DJ, Langhorne P, Hendry A et al. 3 Chaves PH, Carlson MC, Ferrucci L et al. Prevalence and haemopoietic effects of low Anaemia due to folate Association between mild anemia and serum vitamin B12 levels in geriatric executive function impairment in medical patients. Br J Nutr 1997;78:57–63. deficiency community-dwelling older women: the 18 Andres E, Affenberger S, Vinzio S et al. The predominant cause of folate defi- Women’s Health and Aging Study II. J Am Food-cobalamin malabsorption in elderly Geriatr Soc 2006;54:1429–35. patients: clinical manifestations and ciency is poor dietary intake. It may also 4 Chaves PH, Semba RD, Leng SX et al. treatment. Am J Med 2005;118:1154–9. occur with malabsorption, use of certain Impact of anemia and cardiovascular drugs or in medical conditions associ- disease on frailty status of community- ated with increased cell proliferation. dwelling older women: the Women’s Health Serum and red cell folate assays are and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 2005;60:729–35. readily available. Red cell folate is a better 5 Chaves PH, Xue QL, Guralnik JM et al. measure as it is more stable and not What constitutes normal hemoglobin affected by day-to-day changes in dietary concentration in community-dwelling folic acid intake. disabled older women? J Am Geriatr Soc The cause in most elderly patients is 2004;52:1811–6. 6 Guyatt GH, Patterson C, Ali M et al. nutritional and no further investigation Diagnosis of iron-deficiency anemia in the is necessary. Malabsorption should be elderly. Am J Med 1990;88:205–9. considered if there is unexplained weight 7 Cash JM, Sears DA. The anemia of chronic loss, steatorrhoea, low albumin or mul- disease: spectrum of associated diseases in tiple deficiencies of other vitamins and a series of unselected hospitalized patients. Am J Med 1989;87:638–44. minerals including iron, calcium and 8 McKay PJ, Stott DJ, Holyoake T et al. Use vitamins B12 and D. of the erythrogram in the diagnosis of iron deficiency in elderly patients. Acta Other causes of anaemia Haematol 1993;89:169–73. 9 Holyoake TL, Stott DJ, McKay PJ et al. Use Other causes of anaemia in the older of plasma ferritin level to diagnose iron patient are relatively rare. Myeloma deficiency in elderly patients. J Clin Pathol 1993;46:857–60. typically causes a high ESR. Further 10 Coban E, Timuragaoglu A, Meric M. Iron investigation includes plasma protein deficiency anemia in the elderly: prevalence electrophoresis and urine Bence-Jones and endoscopic evaluation of the protein. Myelodysplasia causes an ele- gastrointestinal tract in outpatients. Acta vated mean cell volume and should be Haematol 2003;110:25–8. 11 Joosten E, Ghesquiere B, Linthoudt H et al. considered if B12 or folate deficiency are Upper and lower gastrointestinal excluded. These rare causes of anaemia evaluation of elderly inpatients who are are likely to require specialist assessment iron deficient. Am J Med 1999;107:24–9. which may involve bone marrow 12 Rosman AS, Korsten MA. Meta-analysis examination. comparing CT colonography, air contrast barium enema, and colonoscopy. Review. Am J Med 2007;120:203–10. Conclusions 13 Kealey SM, Dodd JD, MacEneaney PM, Gibney RG, Malone DE. Minimal Anaemia is common in older people. preparation computed tomography instead Making an accurate diagnosis requires of barium enema/colonoscopy for careful interpretation of laboratory data suspected colon cancer in frail elderly including serum ferritin, vitamin B12 patients: an outcome analysis study. Clin Radiol 2004;59:44–52. and red cell folate. The most common 14 Lewis NR, Scott BB. Systematic review: the forms of anaemia in older people are the use of serology to exclude or diagnose anaemia of chronic disease and iron coeliac disease (a comparison of the deficiency. endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther 2006;24:47–54. References 15 Andres E, Loukili NH, Noel E et al. Vitamin B12 (cobalamin) deficiency in 1 World Health Organization. Nutritional elderly patients. Review. CMAJ anaemias. Report of a WHO scientific 2004;171:251–9. group. Technical Report Series no 405, 1968. 16 Lindenbaum J, Rosenberg IH, Wilson PWF

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