Intern Emerg Med DOI 10.1007/s11739-015-1197-5
IM - ORIGINAL
Anemia in elderly hospitalized patients: prevalence and clinical impact Margherita Migone De Amicis • Erika Poggiali • Irene Motta Francesca Minonzio • Giovanna Fabio • Cinzia Hu • Maria Domenica Cappellini
•
Received: 18 October 2014 / Accepted: 14 January 2015 Ó SIMI 2015
Abstract Anemia is a common finding in elderly individuals. Several studies haveshown a strong relationship between anemia, morbidity and mortality, suggestinganemia as a significant independent predictor of adverse outcome in elderlyhospitalized patients. The pathophisiology of anemia in the elderly is not yet completelyunderstood. Several mechanisms are involved. Weinvestigated the prevalence of anemia in a cohort of 193 elderly patients admitted tothe Internal Medicine Ward of Ca’Granda Policlinico Hospital along 6 months, and itsrelationship to comorbidities and to the length of hospitalization. Anemia was classifiedaccording to the WHO criteria. The majority of patients (48 %) had a mildmoderate,normocytic anemia; severe anemia was found in 8 out of 92 anemicpatients. In a subgroup of patients erythropoietin was tested and resulted statisticallyhigher if compared to non-anemic controls (p = 0.003). Considering the most commoncause of anemia, nutritional deficiency, chronic renal disease and anemia of chronicdisease were found respectively in 36, 15 and 25 % of cases. Unexplained anemiawas diagnosed in 24 % of patients, according to the literature. Anemia wasindependently associated with increased length of hospital stay. Our studyconfirmed a high prevalence of anemia in
M. Migone De Amicis (&) E. Poggiali I. Motta F. Minonzio G. Fabio C. Hu M. D. Cappellini Department of Internal Medicine, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy e-mail: [email protected]; [email protected] E. Poggiali G. Fabio M. D. Cappellini Dipartimento di Scienze Cliniche e di Comunita`, Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Milan, Italy
elderly patients, and its association with ahigher number of comorbidities and a longer stay. A correct clinical approach toanemia in elderly hospitalized patients is essential, considering its negative impact onpatients’ quality of life, and its social burden in term of healthcare needs and costs. Keywords Anemia Elderly Hemoglobin Morbidity Mortality Hospitalization
Introduction A mild degree of anemia is very common in the elderly population. It occurs in more than 10 % of individuals who are older than 65 years [1], increases rapidly with age, reaching more than 50 % in individuals older than 80 years of age [2]. The reason why the prevalence of anemia is so high in the elderly population is still not completely clear. Several large-scale epidemiological studies have been conducted to describe the prevalence and the impact of anemia in the elderly. The National Health and Nutrition Examination Survey III (NHANES III) study shows that in one-third of elderly anemic individuals, the cause of anemia is due to nutritional defects, mainly iron deficiency, whereas the other two-thirds are affected by ‘‘the anemia of chronic disease,’’ (ACD) and ‘‘unexplained anemia’’ [1]. Tettamanti et al. have recently demonstrated that the prevalence of anemia increases with the age, and that it is typically mild, with a prevalence of severe anemia lower than 0.5 % [2]. In the elderly population, anemia is associated with many diseases and conditions, such as malignancies, bone marrow failure, chronic kidney disease, chronic inflammatory diseases, congestive heart failure, nutritional deficiencies, and malnutrition [3]. Although
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anemia is generally mild, and the patients are asymptomatic, several large studies of healthy community-dwelling individuals demonstrate that anemia is an independent predictor of morbidity and mortality in elderly patients with a mechanism not yet fully understood [4–6]. It seems that anemia is a marker of other biological pathways that affect the health and survival of the elderly population. In particular, one hypothesis in the pathogenesis of nonnutritional anemia in the elderly is the role of inflammation, either as the ACD through interleukin-6 pathway, or as iron-independent anemia through tumor necrosis factor and NFkB [7]. The pathophysiology of ACD is complex and multifactorial, and several other factors, including blood loss, hemolysis, treatment-associated adverse events or vitamin deficiencies can aggravate and influence the development of anemia [8]. However, most of the abnormalities of iron metabolism observed in ACD can be explained by the effect of hepcidin upregulation, which influences the iron-deficient hematopoiesis in the presence of adequate iron stores [9]. In addition, in a recent study by Nathavitharana et al., anemia independently predicts for a prolonged hospital stay, increased mortality and shorter time to readmission [10]. Moreover, a recent systematic review based on published data from the past 30 years shows a possible association between anemia in the elderly and cognitive performances, in the domain of executive functions, enhancing the importance of a correct diagnosis and management of anemia in individuals aged 65 years and over [11]. A reduced erythropoietin (EPO) response to anemia has also been demonstrated in elderly patients with normocytic anemia compared to younger patients with normocytic anemia, or patients of all ages with irondeficiency anemia (IDA) [12]. The Baltimore Longitudinal Study on Aging documents that EPO levels increase with age in healthy, non-anemic subjects [13, 14], supporting the idea that anemia in the elderly may occur as a failure of a normal compensatory increase in EPO levels required to maintain a normal hemoglobin level in the elderly subjects. To explain the increased EPO demand, two mechanisms have been proposed: an EPO resistance secondary to the increased inflammatory pathways [15–17], and a cell-intrinsic change in hemopoietic stem cells with increased age characterized by decreased erythroid colony-forming activity, and a shift toward myeloid maturation, which leads to a frequent occurrence of myeloid dysplasia or malignancies in the elderly [18]. On the basis of the information derived from all the large epidemiologic studies, and the observation that the number of elderly individuals is expected to significantly increase during time with a consequent relevant impact on healthcare needs and costs, we investigated the prevalence
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and the impact of anemia in a selected cohort of elderly inpatients admitted to an internal medicine unit, to identify the main causes of anemia, and to study the relationship between anemia, comorbidities and the length of hospitalization.
Materials and methods A consecutive prospective observational cohort study of non-elective admissions to the Internal Medicine Ward of Ca’ Granda Policlinico Hospital, Department of Clinical Sciences and Community Health, Milan, Italy, was conducted for 6 months, from October 2010 to April 2011, to investigate the prevalence of anemia in the enrolled population, and its relationship to comorbidities and to the length of hospital stay. All the patients aged 65 years and over at admission were evaluated. For each patient, demographic data and medical history were collected. Patients with hematological malignancies and congenital hemoglobinopathies were excluded. Anemia was defined according to the World Health Organization (WHO) criteria (Hb \13 g/dL for males; Hb \12 g/dL for females). Anemia was defined as severe for Hb levels \8 g/dL, moderate for Hb levels between 8 and 10 g/dL and mild for Hb level [10 g/dL. To investigate the anemia, blood tests were performed, including complete blood count (CBC), reticulocyte number, iron status (serum ferritin, iron and transferrin), folate and vitamin B12 levels, hemolysis indices (LDH, haptoglobin and bilirubin) and inflammation (C reactive protein, CRP). Hepatic and renal functions were also evaluated, and eGFR was calculated according to the MDRD formula [GFR (mL/min/1.73 m2) = 175 9 (Scr)-1.154 9 (age)-0.203 9 (0.742 if female) 9 (1.212, if African American)] that has been validated in elderly patients [19]. EPO was measured in a subgroup of selected anemic patients, and matched for age and sex with normal controls. Routine blood parameters were determined by standard methods. Diagnostic tests to identify the pathogenesis of the anemia and the blood transfusions consumption during the hospitalization were also reported. All the participants gave their consent to be interviewed as required for admitted patients by our institution. Statistical analysis Data are presented as absolute numbers, mean ± standard deviation (SD), median or percentage. Comparisons of study variables was performed by Chi square and t Student tests. All p values were two-sided with the level of significance set at 0.05.
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Fig. 1 Hemoglobin levels in enrolled patients according to age and sex. Hb hemoglobin, M males (in black), F females (in white)
Results We enrolled 276 patients, 33 (12 %) of whom were excluded because they were affected by onco-hematologic disorders or congenital hemoglobinopathies; in the remaining 243 patients (88 %), the presence of anemia was looked for, and if anemia was found, it was classified according to the WHO criteria. One hundred ninety-three patients (89 %) were aged [65 years. According to the WHO classification, 92 of 193 (48 %) patients were anemic. Among the anemic patients, the mean age was 80.9 ± 7.6 years; 53 anemic patients (58 %) were aged over 80 years. Anemia was more prevalent in females than males, with no statistical significance (respectively, 58 versus 42 %, p \ 0.26). Mean Hb value was 10.1 ± 1.4 g/dL, with Hb levels higher in men than in women (respectively, 10.3 versus 9.8 g/dL), with no statistical significance. The same observations can also be
made when considering patients divided into three different groups according to the age (65–74, 75–84, and C85 years) (Fig. 1). The characteristics of anemic patients are reported in Table 1. In 60 patients (65 %), the anemia was mild to moderate (mean Hb value 11.2 ± 1.3 g/dL) and normocytic (MCV 87.9 ± 3.6 fL), as reported in Table 1. Patients were mainly women (39/60, 65 %), with a mean age of 81.4 ± 7.1 years. Most of them (85 %) also presented increased levels of CRP or increased white blood cell counts (22 %), suggesting the presence of a chronic inflammatory disease (ACD). Ten patients (11 %) (5 males, 5 females), with mean age 80.5 ± 7.4 years, had a microcytic moderate anemia (Hb 9.3 ± 1.5 g/dL, MCV 71.6 ± 4.3 fL). Eight of them (80 %) presented iron deficiency (transferrin saturation \15 % and low serum iron; three of them presented low serum ferritin levels, while in the remaining cases, serum ferritin was increased and associated with elevated RCP values (respectively, 290 ± 259 ng/mL and 12.8 ± 10.0 mg/dL). Twenty-two patients (24 %) had a moderate macrocytic anemia (Hb 10.0 ± 1.2 g/dL, MCV 98.1 ± 3.5 fL). In 18 patients, vitamin B12 and folate levels were tested, showing folate deficiency in 5 (28 %), and vitamin B12 deficiency in 5 (28 %) patients; only 1 (5 %) showed a combined vitamin deficiency. In the remaining cases, vitamin levels were normal. Severe anemia (Hb \8 g/dL) was only found in 8 of 92 (9 %) patients (2 males, 6 females), with mean age 81.4 ± 3.2 years. Mean Hb was 7.4 ± 0.9 g/dL, and mean MCV was 87.9 ± 8.8 fL. Five of them showed iron deficiency with normal values of folate and vitamin B12.
Table 1 Characteristics of anemic elderly patients enrolled in the study Overall anemic elderly patients (N = 92)
65–74 years (N = 21)
75–84 years (N = 40)
C85 years (N = 31)
Sex (M/F)
39/53
14/7
15/25
10/21
Age (years)
80.9 ± 7.6
70.0 ± 3.0
80.4 ± 2.8
89.0 ± 2.8
Hb (g/dL)
10.1 ± 1.4
10.8 ± 1.5
9.6 ± 1.5
10.2 ± 1.0
MCV (fL)
88.6 ± 8.2
89.3 ± 8.0
88.6 ± 9.2
88.2 ± 6.9
Reticulocyte (106/mL)
0.08 ± 0.2
0.07 ± 0.08
0.06 ± 0.04
0.11 ± 0.33
eGFR (mL/min/1.73 m2)
62.1 ± 32.6
78.0 ± 35.3
60.5 ± 28.6
53.4 ± 32.6
Iron (lg/dL)
47.8 ± 31.8
55.9 ± 31.7
45.6 ± 32.4
45.2 ± 31.2
Ferritin (ng/mL)
396.8 ± 735.5 (219)
645.6 ± 1,088.0 (309)
250.9 ± 250.8 (169)
416.6 ± 835.5 (238)
Transferrin (mg/dL)
207.6 ± 113.8
189.5 ± 57.4
222.6 ± 156.5
200.5 ± 68.9
Transferrin saturation (%)
19.0 ± 16.2
24.2 ± 19.6
18.0 ± 17.4
16.7 ± 11.0
CRP (mg/dL)
5.95 ± 7.46 (2.9)
4.8 ± 6.6 (2.0)
6.3 ± 8.6 (2.1)
6.3 ± 6.5 (3.3)
Overall anemic patients and grouped according to the age. eGFR is calculated according to MDRD formula. Parameters are expressed as mean value ± standard deviation. Median value is reported in brackets for ferritin and CRP N number, Hb hemoglobin, MCV mean corpuscular volume, CRP C reactive protein
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Intern Emerg Med Table 2 Classification of anemia according to MCV value in the anemic elderly patients
Parameters are expressed as mean value ± standard deviation. Median value is reported in brackets for ferritin and CRP. Normal values: Folate: 4.6–18.7 ng/mL; Vitamin B12: 191–663 pg/mL; CRP \0.58 mg/dL N number; Hb hemoglobin, MCV mean corpuscular volume, RCP C reactive protein
Microcytic Anemia (MCV \80 fL) (N = 10)
Normocytic Anemia (MCV C80 and B94 fL) (N = 60)
Macrocytic Anemia (MCV [94 fL) (N = 22) 79.5 ± 8.9
Age (years)
80.5 ± 7.4
81.4 ± 7.1
Sex (M/F)
5/5
21/39
13/9
Hb (g/dL) MCV (fL)
9.3 ± 1.5 71.6 ± 4.3
10.2 ± 1.4 88.0 ± 3.6
10.0 ± 1.2 98.2 ± 3.5
Iron (lg/dL)
33.5 ± 28.6
43.0 ± 28.2
67.6 ± 35.0
Ferritin (ng/mL)
129.3 ± 202.0 (48)
445.4 ± 880.5 (219)
359.0 ± 321.3 (338)
Transferrin (mg/dL)
246.3 ± 105.9
194.3 ± 71.6
226.3 ± 188.1
Transferrin saturation (%)
13.3 ± 14.6
16.7 ± 12.9
27.7 ± 21.7
Folate (ng/mL)
6.7 ± 3.1
6.8 ± 3.5
6.9 ± 3.9
Vitamin B12 (pg/mL)
834.9 ± 675.2
605.4 ± 377.8
406.7 ± 288.4
CRP (mg/dL)
5.8 ± 8.5 (2.1)
6.9 ± 8.1 (4.1)
3.5 ± 3.9 (1.4)
The reticulocyte index was available in 75 of 92 (81 %) anemic patients, and it was lower than 1 in 48 (64 %) patients, suggesting hypogenerative anemia (Table 2). During recovery, 31 patients (33 %) required blood transfusions. In a group of anemic patients (32 patients), EPO was measured and compared to non-anemic controls (46 patients) matched for sex and age. Mean EPO values were statistically higher in anemic patients (28.4 ± 13.5 mU/ mL) compared to non-anemic (18.7 ± 13.5 mU/mL; normal value 4.2–27.8 mU/mL; p = 0.003). We investigated the causes of anemia in all the cases. The prevalence of the different causes is reported in Figs. 2 and 3. About one-third of the patients presented ‘‘nutritional deficiency,’’ considered as iron, folate or vitamin B12 deficiency. Iron deficiency and folate deficiency are more frequent, 19 and 16 % respectively, increasing with age. Seven out of 92 patients (8 %) present a combined deficit of iron, folate or vitamin B12. With regard to the causes of iron deficiency, 17/18 patients with IDA underwent endoscopic tests (gastroscopy or colonoscopy), which were positive in 9/17 (53 %) patients. Helicobacter pylori infection was excluded by gastric biopsy. Chronic kidney disease (CKD) anemia, related to an eGFR \ 30 mL/min/ 1.73 m2, was discovered in 14 out of 92 patients (15 %). Twenty-five out 92 patients (25 %) had ACD, defined according to CRP levels, or concomitant chronic diseases, including solid neoplasms, immunologic or rheumatologic diseases. Only one patient presented hemolytic component, related to a mechanical prosthetic valve. A precise etiology of anemia was unable to be determined in 22 out of 92 patients (24 %). We classify these cases as ‘‘unexplained anemia,’’ according to literature definitions [1]. Comorbidities were evaluated in all anemic patients, grouped as: hypertension, heart diseases, diabetes, liver diseases, CKD and solid tumors, and are reported in Fig. 4.
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Fig. 2 Different causes of anemia in the enrolled population (N = 92). CKD chronic kidney disease, ACD anemia of chronic disease
Fig. 3 Nutritional deficiency in anemic patients (N = 33)
Hypertension was present in 70 % of patients; the prevalence of heart diseases increased with age, while liver disease and solid tumors were more frequent in the 65–74year-old group. Diabetes had a lower prevalence among anemic patients aged 85 and over. Comparing anemic and non-anemic elderly patients, we observed more comorbidities (considered as number of comordibities for single patient), in the anemic group; in
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Fig. 4 Comorbidities in anemic and non-anemic elderly patients. CKD (Chronic Kidney Disease) for eGFR \30 mL/min/1.73 m2. For non-anemic patients CKD was based on clinical medical history
particular, there was a higher prevalence of diabetes, liver diseases and CKD in the anemic patients. In addition, we observed that anemia was independently associated with an increased length of hospital stay (13.4 ± 7.8 versus 10.0 ± 6.0 days in non-anemic patients; p \ 0.001).
Discussion Anemia is very common in elderly individuals, and is associated with numerous health consequences, representing a significant economic burden for society [20]. Data reported in the literature clearly show that in hospitalized elderly patients, anemia is linked with increased length of hospitalization, mortality and hospital readmission [10]. Our observational cohort study confirms a high prevalence of anemia (48 %) in hospitalized elderly patients, which is higher than in community-resident elderly people as reported in other studies [1, 2, 21], but is similar to data reported for nursing home residents and hospitalized patients (48–60 %) [17, 22]. Most of the enrolled patients presented with a mild-moderate normocytic anemia, with mean hemoglobin level lower than reported in literature studies, mostly related to the different population analyzed (community or nursing home resident versus hospitalized patients). Considering the etiology of anemia, it is well recognized that anemia in the elderly can be mainly divided into three groups: (1) due to nutritional deficiency (iron, folate, vitamin B12); (2) related to chronic inflammation (ACD); and (3) unexplained anemia. In our study, we find that one-third of patients have a nutritional deficit, including iron, folate or vitamin B12 deficiency as reported by Guralnik et al. [1]. In 9 out of 18 patients with IDA, gastrointestinal blood losses were detected, whereas in all the other patients, the IDA can be considered a nutritional deficiency, related to hyporexia or real malnutrition, quite common in elderly patients. Similar
data have been collected in American studies, which is also considering a community population (NHANES III study); a different prevalence is reported in the Italian study, from a community population analyzed by Tettamanti et al. [2], but the results can be explained from the different characteristics of the study population. In addition, in 14 out 92 patients (12 %), a chronic renal failure is documented as a possible cause of the chronic anemia. These data are reported in the literature, and renal diseases should be investigated in patients with ACD [1]. Several factors can contribute to the pathogenesis of anemia in the elderly. The real challenge for clinicians is to understand the underlying causes and contributing factors that result in anemia in these patients to decide the correct management. Inflammation plays a central role in the development of anemia in the elderly, and ACD still remains the most complex form of anemia to treat. The role of inflammation in interfering with erythropoiesis and renal function is well known: patients with ACD have decreased red cell survival, disorders of erythropoiesis, low EPO levels compared to the degree of anemia, and progressive EPO resistance of erythroid progenitors [23]. In our study, EPO levels are higher in anemic patients, compared to nonanemic. According to the literature, a group of patients (24 %) did not present a precise cause of the anemia, which remained ‘‘unexplained,’’ confirming the prevalence observed in the Italian study by Tettamanti et al. [2]. The social impact of anemia is profound, considering that the number of elderly individuals is expected to increase significantly in the future. Even if anemia is generally mild, it cannot be considered only a common laboratory finding without clinical relevance or impact on an elderly patient’s life. As demonstrated in several studies, anemia correlates with increased disability, and morbidity and mortality in the anemic elderly [10]. In our study, anemic patients compared to non-anemic elderly patients present an increased number of comorbidities and a longer hospital stay, confirming the data reported in the literature and stressing the central role of anemia.
Conclusions Our data, derived from patients admitted to internal medicine ward for different reasons, confirmed the great importance of a comprehensive hematologic evaluation to diagnose anemia in the elderly. Based on our results, we strongly believe that anemia in the elderly cannot be considered as a normal consequence of aging, and a correct therapeutic management has to be taken into account according to the cause so as to have a positive impact on the quality of life and social burdens. The
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understanding of the pathophysiology of anemia in the elderly still represents a clue for a correct diagnostic and therapeutic approach. Treatment undertaken for anemia should always have a personalized approach for each patient, considering not only the cause of anemia, but also the underlying conditions and the comorbidities of the patient. In particular, considering the ACD and the central role of inflammation in the anemia of the elderly affecting iron metabolism, the manipulation of the hepcidin pathway may in the near future represent a therapeutic strategy, especially in patients with EPO resistance that limits the response to erytropoiesis-stimulating agents (ESAs), with or without high-dose intravenous iron, or if the use of ESAs can have negative consequences, such as increased blood pressure and thromboembolism [24, 25]. In conclusion, we are aware that a clear and complete knowledge of the pathophysiology of anemia in the elderly still remains the central clue in the design of a rational and targeted therapy for each patient. We strongly suggest an individualized clinical approach in the management of anemia in the elderly considering not only the negative impact of anemia on patients’ performance and quality of life, but also its social impacts in term of healthcare needs and costs. Conflict of interest
None.
References 1. Guralnik JM et al (2004) Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 104(8):2263–2268 2. Tettamanti M et al (2010) Prevalence, incidence and types of mild anemia in the elderly: the ‘‘health and anemia’’ populationbased study. Haematologica 95(11):1849–1856 3. Penninx BW et al (2006) Anemia in old age is associated with increased mortality and hospitalization. J Gerontol A Biol Sci Med Sci 61(5):474–479 4. Woodman R, Ferrucci L, Guralnik J (2005) Anemia in older adults. Curr Opin Hematol 12(2):123–128 5. Kikuchi M, Inagaki T, Shinagawa N (2001) Five-year survival of older people with anemia: variation with hemoglobin concentration. J Am Geriatr Soc 49(9):1226–1228
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6. Guralnik JM et al (2005) Anemia in the elderly: a public health crisis in hematology. Hematology Am Soc Hematol Educ Program 2005:528–532 7. Berliner N (2013) Anemia in the elderly. Trans Am Clin Climatol Assoc 124:230–237 8. Poggiali E, Migone De Amicis M, Motta I (2014) Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Intern Med 25(1):12–17 9. Weiss G, Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352(10):1011–1023 10. Nathavitharana RL et al (2012) Anaemia is highly prevalent among unselected internal medicine inpatients and is associated with increased mortality, earlier readmission and more prolonged hospital stay: an observational retrospective cohort study. Intern Med J 42(6):683–691 11. Andro M et al (2013) Anaemia and cognitive performances in the elderly: a systematic review. Eur J Neurol 20(9):1234–1240 12. Carpenter MA et al (1992) Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia. Eur J Haematol 49(3):119–121 13. Kario K, Matsuo T, Nakao K (1991) Serum erythropoietin levels in the elderly. Gerontology 37(6):345–348 14. Ershler WB et al (2005) Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc 53(8):1360–1365 15. Bruunsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23(1):15–39 16. Ferrucci L et al (2005) The origins of age-related proinflammatory state. Blood 105(6):2294–2299 17. Artz AS et al (2004) Mechanisms of unexplained anemia in the nursing home. J Am Geriatr Soc 52(3):423–427 18. Pang WW et al (2011) Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci USA 108(50):20012–20017 19. National Kidney Foundation (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39(2 Suppl 1):S1–S266 20. Ershler WB et al (2005) Economic burden of patients with anemia in selected diseases. Value Health 8(6):629–638 21. Ferrucci L et al (2007) Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of proinflammatory markers. Br J Haematol 136(6):849–855 22. Robinson B et al (2007) Prevalence of anemia in the nursing home: contribution of chronic kidney disease. J Am Geriatr Soc 55(10):1566–1570 23. Roy CN (2010) Anemia of inflammation. Hematology Am Soc Hematol Educ Program 2010:276–280 24. Macdougall IC, Cooper AC (2002) Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant 17(Suppl 11):39–43 25. Horl WH (2007) Clinical aspects of iron use in the anemia of kidney disease. J Am Soc Nephrol 18(2):382–393
IM - ORIGINAL
Anemia in elderly hospitalized patients: prevalence and clinical impact Margherita Migone De Amicis • Erika Poggiali • Irene Motta Francesca Minonzio • Giovanna Fabio • Cinzia Hu • Maria Domenica Cappellini
•
Received: 18 October 2014 / Accepted: 14 January 2015 Ó SIMI 2015
Abstract Anemia is a common finding in elderly individuals. Several studies haveshown a strong relationship between anemia, morbidity and mortality, suggestinganemia as a significant independent predictor of adverse outcome in elderlyhospitalized patients. The pathophisiology of anemia in the elderly is not yet completelyunderstood. Several mechanisms are involved. Weinvestigated the prevalence of anemia in a cohort of 193 elderly patients admitted tothe Internal Medicine Ward of Ca’Granda Policlinico Hospital along 6 months, and itsrelationship to comorbidities and to the length of hospitalization. Anemia was classifiedaccording to the WHO criteria. The majority of patients (48 %) had a mildmoderate,normocytic anemia; severe anemia was found in 8 out of 92 anemicpatients. In a subgroup of patients erythropoietin was tested and resulted statisticallyhigher if compared to non-anemic controls (p = 0.003). Considering the most commoncause of anemia, nutritional deficiency, chronic renal disease and anemia of chronicdisease were found respectively in 36, 15 and 25 % of cases. Unexplained anemiawas diagnosed in 24 % of patients, according to the literature. Anemia wasindependently associated with increased length of hospital stay. Our studyconfirmed a high prevalence of anemia in
M. Migone De Amicis (&) E. Poggiali I. Motta F. Minonzio G. Fabio C. Hu M. D. Cappellini Department of Internal Medicine, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy e-mail: [email protected]; [email protected] E. Poggiali G. Fabio M. D. Cappellini Dipartimento di Scienze Cliniche e di Comunita`, Ca’ Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Milan, Italy
elderly patients, and its association with ahigher number of comorbidities and a longer stay. A correct clinical approach toanemia in elderly hospitalized patients is essential, considering its negative impact onpatients’ quality of life, and its social burden in term of healthcare needs and costs. Keywords Anemia Elderly Hemoglobin Morbidity Mortality Hospitalization
Introduction A mild degree of anemia is very common in the elderly population. It occurs in more than 10 % of individuals who are older than 65 years [1], increases rapidly with age, reaching more than 50 % in individuals older than 80 years of age [2]. The reason why the prevalence of anemia is so high in the elderly population is still not completely clear. Several large-scale epidemiological studies have been conducted to describe the prevalence and the impact of anemia in the elderly. The National Health and Nutrition Examination Survey III (NHANES III) study shows that in one-third of elderly anemic individuals, the cause of anemia is due to nutritional defects, mainly iron deficiency, whereas the other two-thirds are affected by ‘‘the anemia of chronic disease,’’ (ACD) and ‘‘unexplained anemia’’ [1]. Tettamanti et al. have recently demonstrated that the prevalence of anemia increases with the age, and that it is typically mild, with a prevalence of severe anemia lower than 0.5 % [2]. In the elderly population, anemia is associated with many diseases and conditions, such as malignancies, bone marrow failure, chronic kidney disease, chronic inflammatory diseases, congestive heart failure, nutritional deficiencies, and malnutrition [3]. Although
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anemia is generally mild, and the patients are asymptomatic, several large studies of healthy community-dwelling individuals demonstrate that anemia is an independent predictor of morbidity and mortality in elderly patients with a mechanism not yet fully understood [4–6]. It seems that anemia is a marker of other biological pathways that affect the health and survival of the elderly population. In particular, one hypothesis in the pathogenesis of nonnutritional anemia in the elderly is the role of inflammation, either as the ACD through interleukin-6 pathway, or as iron-independent anemia through tumor necrosis factor and NFkB [7]. The pathophysiology of ACD is complex and multifactorial, and several other factors, including blood loss, hemolysis, treatment-associated adverse events or vitamin deficiencies can aggravate and influence the development of anemia [8]. However, most of the abnormalities of iron metabolism observed in ACD can be explained by the effect of hepcidin upregulation, which influences the iron-deficient hematopoiesis in the presence of adequate iron stores [9]. In addition, in a recent study by Nathavitharana et al., anemia independently predicts for a prolonged hospital stay, increased mortality and shorter time to readmission [10]. Moreover, a recent systematic review based on published data from the past 30 years shows a possible association between anemia in the elderly and cognitive performances, in the domain of executive functions, enhancing the importance of a correct diagnosis and management of anemia in individuals aged 65 years and over [11]. A reduced erythropoietin (EPO) response to anemia has also been demonstrated in elderly patients with normocytic anemia compared to younger patients with normocytic anemia, or patients of all ages with irondeficiency anemia (IDA) [12]. The Baltimore Longitudinal Study on Aging documents that EPO levels increase with age in healthy, non-anemic subjects [13, 14], supporting the idea that anemia in the elderly may occur as a failure of a normal compensatory increase in EPO levels required to maintain a normal hemoglobin level in the elderly subjects. To explain the increased EPO demand, two mechanisms have been proposed: an EPO resistance secondary to the increased inflammatory pathways [15–17], and a cell-intrinsic change in hemopoietic stem cells with increased age characterized by decreased erythroid colony-forming activity, and a shift toward myeloid maturation, which leads to a frequent occurrence of myeloid dysplasia or malignancies in the elderly [18]. On the basis of the information derived from all the large epidemiologic studies, and the observation that the number of elderly individuals is expected to significantly increase during time with a consequent relevant impact on healthcare needs and costs, we investigated the prevalence
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and the impact of anemia in a selected cohort of elderly inpatients admitted to an internal medicine unit, to identify the main causes of anemia, and to study the relationship between anemia, comorbidities and the length of hospitalization.
Materials and methods A consecutive prospective observational cohort study of non-elective admissions to the Internal Medicine Ward of Ca’ Granda Policlinico Hospital, Department of Clinical Sciences and Community Health, Milan, Italy, was conducted for 6 months, from October 2010 to April 2011, to investigate the prevalence of anemia in the enrolled population, and its relationship to comorbidities and to the length of hospital stay. All the patients aged 65 years and over at admission were evaluated. For each patient, demographic data and medical history were collected. Patients with hematological malignancies and congenital hemoglobinopathies were excluded. Anemia was defined according to the World Health Organization (WHO) criteria (Hb \13 g/dL for males; Hb \12 g/dL for females). Anemia was defined as severe for Hb levels \8 g/dL, moderate for Hb levels between 8 and 10 g/dL and mild for Hb level [10 g/dL. To investigate the anemia, blood tests were performed, including complete blood count (CBC), reticulocyte number, iron status (serum ferritin, iron and transferrin), folate and vitamin B12 levels, hemolysis indices (LDH, haptoglobin and bilirubin) and inflammation (C reactive protein, CRP). Hepatic and renal functions were also evaluated, and eGFR was calculated according to the MDRD formula [GFR (mL/min/1.73 m2) = 175 9 (Scr)-1.154 9 (age)-0.203 9 (0.742 if female) 9 (1.212, if African American)] that has been validated in elderly patients [19]. EPO was measured in a subgroup of selected anemic patients, and matched for age and sex with normal controls. Routine blood parameters were determined by standard methods. Diagnostic tests to identify the pathogenesis of the anemia and the blood transfusions consumption during the hospitalization were also reported. All the participants gave their consent to be interviewed as required for admitted patients by our institution. Statistical analysis Data are presented as absolute numbers, mean ± standard deviation (SD), median or percentage. Comparisons of study variables was performed by Chi square and t Student tests. All p values were two-sided with the level of significance set at 0.05.
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Fig. 1 Hemoglobin levels in enrolled patients according to age and sex. Hb hemoglobin, M males (in black), F females (in white)
Results We enrolled 276 patients, 33 (12 %) of whom were excluded because they were affected by onco-hematologic disorders or congenital hemoglobinopathies; in the remaining 243 patients (88 %), the presence of anemia was looked for, and if anemia was found, it was classified according to the WHO criteria. One hundred ninety-three patients (89 %) were aged [65 years. According to the WHO classification, 92 of 193 (48 %) patients were anemic. Among the anemic patients, the mean age was 80.9 ± 7.6 years; 53 anemic patients (58 %) were aged over 80 years. Anemia was more prevalent in females than males, with no statistical significance (respectively, 58 versus 42 %, p \ 0.26). Mean Hb value was 10.1 ± 1.4 g/dL, with Hb levels higher in men than in women (respectively, 10.3 versus 9.8 g/dL), with no statistical significance. The same observations can also be
made when considering patients divided into three different groups according to the age (65–74, 75–84, and C85 years) (Fig. 1). The characteristics of anemic patients are reported in Table 1. In 60 patients (65 %), the anemia was mild to moderate (mean Hb value 11.2 ± 1.3 g/dL) and normocytic (MCV 87.9 ± 3.6 fL), as reported in Table 1. Patients were mainly women (39/60, 65 %), with a mean age of 81.4 ± 7.1 years. Most of them (85 %) also presented increased levels of CRP or increased white blood cell counts (22 %), suggesting the presence of a chronic inflammatory disease (ACD). Ten patients (11 %) (5 males, 5 females), with mean age 80.5 ± 7.4 years, had a microcytic moderate anemia (Hb 9.3 ± 1.5 g/dL, MCV 71.6 ± 4.3 fL). Eight of them (80 %) presented iron deficiency (transferrin saturation \15 % and low serum iron; three of them presented low serum ferritin levels, while in the remaining cases, serum ferritin was increased and associated with elevated RCP values (respectively, 290 ± 259 ng/mL and 12.8 ± 10.0 mg/dL). Twenty-two patients (24 %) had a moderate macrocytic anemia (Hb 10.0 ± 1.2 g/dL, MCV 98.1 ± 3.5 fL). In 18 patients, vitamin B12 and folate levels were tested, showing folate deficiency in 5 (28 %), and vitamin B12 deficiency in 5 (28 %) patients; only 1 (5 %) showed a combined vitamin deficiency. In the remaining cases, vitamin levels were normal. Severe anemia (Hb \8 g/dL) was only found in 8 of 92 (9 %) patients (2 males, 6 females), with mean age 81.4 ± 3.2 years. Mean Hb was 7.4 ± 0.9 g/dL, and mean MCV was 87.9 ± 8.8 fL. Five of them showed iron deficiency with normal values of folate and vitamin B12.
Table 1 Characteristics of anemic elderly patients enrolled in the study Overall anemic elderly patients (N = 92)
65–74 years (N = 21)
75–84 years (N = 40)
C85 years (N = 31)
Sex (M/F)
39/53
14/7
15/25
10/21
Age (years)
80.9 ± 7.6
70.0 ± 3.0
80.4 ± 2.8
89.0 ± 2.8
Hb (g/dL)
10.1 ± 1.4
10.8 ± 1.5
9.6 ± 1.5
10.2 ± 1.0
MCV (fL)
88.6 ± 8.2
89.3 ± 8.0
88.6 ± 9.2
88.2 ± 6.9
Reticulocyte (106/mL)
0.08 ± 0.2
0.07 ± 0.08
0.06 ± 0.04
0.11 ± 0.33
eGFR (mL/min/1.73 m2)
62.1 ± 32.6
78.0 ± 35.3
60.5 ± 28.6
53.4 ± 32.6
Iron (lg/dL)
47.8 ± 31.8
55.9 ± 31.7
45.6 ± 32.4
45.2 ± 31.2
Ferritin (ng/mL)
396.8 ± 735.5 (219)
645.6 ± 1,088.0 (309)
250.9 ± 250.8 (169)
416.6 ± 835.5 (238)
Transferrin (mg/dL)
207.6 ± 113.8
189.5 ± 57.4
222.6 ± 156.5
200.5 ± 68.9
Transferrin saturation (%)
19.0 ± 16.2
24.2 ± 19.6
18.0 ± 17.4
16.7 ± 11.0
CRP (mg/dL)
5.95 ± 7.46 (2.9)
4.8 ± 6.6 (2.0)
6.3 ± 8.6 (2.1)
6.3 ± 6.5 (3.3)
Overall anemic patients and grouped according to the age. eGFR is calculated according to MDRD formula. Parameters are expressed as mean value ± standard deviation. Median value is reported in brackets for ferritin and CRP N number, Hb hemoglobin, MCV mean corpuscular volume, CRP C reactive protein
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Intern Emerg Med Table 2 Classification of anemia according to MCV value in the anemic elderly patients
Parameters are expressed as mean value ± standard deviation. Median value is reported in brackets for ferritin and CRP. Normal values: Folate: 4.6–18.7 ng/mL; Vitamin B12: 191–663 pg/mL; CRP \0.58 mg/dL N number; Hb hemoglobin, MCV mean corpuscular volume, RCP C reactive protein
Microcytic Anemia (MCV \80 fL) (N = 10)
Normocytic Anemia (MCV C80 and B94 fL) (N = 60)
Macrocytic Anemia (MCV [94 fL) (N = 22) 79.5 ± 8.9
Age (years)
80.5 ± 7.4
81.4 ± 7.1
Sex (M/F)
5/5
21/39
13/9
Hb (g/dL) MCV (fL)
9.3 ± 1.5 71.6 ± 4.3
10.2 ± 1.4 88.0 ± 3.6
10.0 ± 1.2 98.2 ± 3.5
Iron (lg/dL)
33.5 ± 28.6
43.0 ± 28.2
67.6 ± 35.0
Ferritin (ng/mL)
129.3 ± 202.0 (48)
445.4 ± 880.5 (219)
359.0 ± 321.3 (338)
Transferrin (mg/dL)
246.3 ± 105.9
194.3 ± 71.6
226.3 ± 188.1
Transferrin saturation (%)
13.3 ± 14.6
16.7 ± 12.9
27.7 ± 21.7
Folate (ng/mL)
6.7 ± 3.1
6.8 ± 3.5
6.9 ± 3.9
Vitamin B12 (pg/mL)
834.9 ± 675.2
605.4 ± 377.8
406.7 ± 288.4
CRP (mg/dL)
5.8 ± 8.5 (2.1)
6.9 ± 8.1 (4.1)
3.5 ± 3.9 (1.4)
The reticulocyte index was available in 75 of 92 (81 %) anemic patients, and it was lower than 1 in 48 (64 %) patients, suggesting hypogenerative anemia (Table 2). During recovery, 31 patients (33 %) required blood transfusions. In a group of anemic patients (32 patients), EPO was measured and compared to non-anemic controls (46 patients) matched for sex and age. Mean EPO values were statistically higher in anemic patients (28.4 ± 13.5 mU/ mL) compared to non-anemic (18.7 ± 13.5 mU/mL; normal value 4.2–27.8 mU/mL; p = 0.003). We investigated the causes of anemia in all the cases. The prevalence of the different causes is reported in Figs. 2 and 3. About one-third of the patients presented ‘‘nutritional deficiency,’’ considered as iron, folate or vitamin B12 deficiency. Iron deficiency and folate deficiency are more frequent, 19 and 16 % respectively, increasing with age. Seven out of 92 patients (8 %) present a combined deficit of iron, folate or vitamin B12. With regard to the causes of iron deficiency, 17/18 patients with IDA underwent endoscopic tests (gastroscopy or colonoscopy), which were positive in 9/17 (53 %) patients. Helicobacter pylori infection was excluded by gastric biopsy. Chronic kidney disease (CKD) anemia, related to an eGFR \ 30 mL/min/ 1.73 m2, was discovered in 14 out of 92 patients (15 %). Twenty-five out 92 patients (25 %) had ACD, defined according to CRP levels, or concomitant chronic diseases, including solid neoplasms, immunologic or rheumatologic diseases. Only one patient presented hemolytic component, related to a mechanical prosthetic valve. A precise etiology of anemia was unable to be determined in 22 out of 92 patients (24 %). We classify these cases as ‘‘unexplained anemia,’’ according to literature definitions [1]. Comorbidities were evaluated in all anemic patients, grouped as: hypertension, heart diseases, diabetes, liver diseases, CKD and solid tumors, and are reported in Fig. 4.
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Fig. 2 Different causes of anemia in the enrolled population (N = 92). CKD chronic kidney disease, ACD anemia of chronic disease
Fig. 3 Nutritional deficiency in anemic patients (N = 33)
Hypertension was present in 70 % of patients; the prevalence of heart diseases increased with age, while liver disease and solid tumors were more frequent in the 65–74year-old group. Diabetes had a lower prevalence among anemic patients aged 85 and over. Comparing anemic and non-anemic elderly patients, we observed more comorbidities (considered as number of comordibities for single patient), in the anemic group; in
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Fig. 4 Comorbidities in anemic and non-anemic elderly patients. CKD (Chronic Kidney Disease) for eGFR \30 mL/min/1.73 m2. For non-anemic patients CKD was based on clinical medical history
particular, there was a higher prevalence of diabetes, liver diseases and CKD in the anemic patients. In addition, we observed that anemia was independently associated with an increased length of hospital stay (13.4 ± 7.8 versus 10.0 ± 6.0 days in non-anemic patients; p \ 0.001).
Discussion Anemia is very common in elderly individuals, and is associated with numerous health consequences, representing a significant economic burden for society [20]. Data reported in the literature clearly show that in hospitalized elderly patients, anemia is linked with increased length of hospitalization, mortality and hospital readmission [10]. Our observational cohort study confirms a high prevalence of anemia (48 %) in hospitalized elderly patients, which is higher than in community-resident elderly people as reported in other studies [1, 2, 21], but is similar to data reported for nursing home residents and hospitalized patients (48–60 %) [17, 22]. Most of the enrolled patients presented with a mild-moderate normocytic anemia, with mean hemoglobin level lower than reported in literature studies, mostly related to the different population analyzed (community or nursing home resident versus hospitalized patients). Considering the etiology of anemia, it is well recognized that anemia in the elderly can be mainly divided into three groups: (1) due to nutritional deficiency (iron, folate, vitamin B12); (2) related to chronic inflammation (ACD); and (3) unexplained anemia. In our study, we find that one-third of patients have a nutritional deficit, including iron, folate or vitamin B12 deficiency as reported by Guralnik et al. [1]. In 9 out of 18 patients with IDA, gastrointestinal blood losses were detected, whereas in all the other patients, the IDA can be considered a nutritional deficiency, related to hyporexia or real malnutrition, quite common in elderly patients. Similar
data have been collected in American studies, which is also considering a community population (NHANES III study); a different prevalence is reported in the Italian study, from a community population analyzed by Tettamanti et al. [2], but the results can be explained from the different characteristics of the study population. In addition, in 14 out 92 patients (12 %), a chronic renal failure is documented as a possible cause of the chronic anemia. These data are reported in the literature, and renal diseases should be investigated in patients with ACD [1]. Several factors can contribute to the pathogenesis of anemia in the elderly. The real challenge for clinicians is to understand the underlying causes and contributing factors that result in anemia in these patients to decide the correct management. Inflammation plays a central role in the development of anemia in the elderly, and ACD still remains the most complex form of anemia to treat. The role of inflammation in interfering with erythropoiesis and renal function is well known: patients with ACD have decreased red cell survival, disorders of erythropoiesis, low EPO levels compared to the degree of anemia, and progressive EPO resistance of erythroid progenitors [23]. In our study, EPO levels are higher in anemic patients, compared to nonanemic. According to the literature, a group of patients (24 %) did not present a precise cause of the anemia, which remained ‘‘unexplained,’’ confirming the prevalence observed in the Italian study by Tettamanti et al. [2]. The social impact of anemia is profound, considering that the number of elderly individuals is expected to increase significantly in the future. Even if anemia is generally mild, it cannot be considered only a common laboratory finding without clinical relevance or impact on an elderly patient’s life. As demonstrated in several studies, anemia correlates with increased disability, and morbidity and mortality in the anemic elderly [10]. In our study, anemic patients compared to non-anemic elderly patients present an increased number of comorbidities and a longer hospital stay, confirming the data reported in the literature and stressing the central role of anemia.
Conclusions Our data, derived from patients admitted to internal medicine ward for different reasons, confirmed the great importance of a comprehensive hematologic evaluation to diagnose anemia in the elderly. Based on our results, we strongly believe that anemia in the elderly cannot be considered as a normal consequence of aging, and a correct therapeutic management has to be taken into account according to the cause so as to have a positive impact on the quality of life and social burdens. The
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understanding of the pathophysiology of anemia in the elderly still represents a clue for a correct diagnostic and therapeutic approach. Treatment undertaken for anemia should always have a personalized approach for each patient, considering not only the cause of anemia, but also the underlying conditions and the comorbidities of the patient. In particular, considering the ACD and the central role of inflammation in the anemia of the elderly affecting iron metabolism, the manipulation of the hepcidin pathway may in the near future represent a therapeutic strategy, especially in patients with EPO resistance that limits the response to erytropoiesis-stimulating agents (ESAs), with or without high-dose intravenous iron, or if the use of ESAs can have negative consequences, such as increased blood pressure and thromboembolism [24, 25]. In conclusion, we are aware that a clear and complete knowledge of the pathophysiology of anemia in the elderly still remains the central clue in the design of a rational and targeted therapy for each patient. We strongly suggest an individualized clinical approach in the management of anemia in the elderly considering not only the negative impact of anemia on patients’ performance and quality of life, but also its social impacts in term of healthcare needs and costs. Conflict of interest
None.
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