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Anemia in Clinical Practice. Definition and classifica-

tion. Does Hb change with aging?
M. Domenica Cappellini MD, Irene Motta MD

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DOI: http://dx.doi.org/10.1053/j.seminhematol.2015.07.006
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 Seminars in Hematology: Anemia in clinical practice
Anemia in Clinical Practice. Definition and classification. Does Hb

change with aging?

M. Domenica Cappellini, MD1,2 and Irene Motta, MD1,2

1
Department of Medicine, IRCCS Fondazione C Granda Ospedale Maggiore Policlinico ,

Milan, Italy
2
Department of Clinical Science and Community Health, Universit degli Studi di Milano,

Milan, Italy

Via F. Sforza 35

Padiglione Granelli

20122 Milano

Tel +390250320288

Fax +390250320296

Email: maria.cappellini@unimi.it

Length of the manuscript: 2252 words

Abstract

Anemia is a global public health problem affecting both developing and developed

countries at all ages. According to WHO, anemia is defined as hemoglobin (Hb) levels

<12.0 g/dl in women and <13.0 g/dl in men. However, normal Hb distribution varies not

only with sex, but also with ethnicity and physiological status. New lower limits of normal
Hb values have been proposed, according to ethnicity, gender and age. Anemia is often

multifactorial and is not an independent phenomenon. For the classification and diagnosis

the hematological parameters,the underlying pathological mechanism and patient history

should be taken into account. The aging of population, especially in Western Countries,

causes an increase of anemia in elderly people. In this population, anemia, recently

defined by levels of Hb < 12 g/dL in both sexes, is mostly of mild degree (10-12 g/dl).

Understanding the pathophysiology of anemia in this population is important because it

contributes to morbidity and mortality. In one-third of the patients anemia is due to

nutritional deficiency, including iron, folate or vitamin B12 deficiency; moreover anemia of

chronic disease accounts for about another third of the cases. However, in one third of

patients anemia cannot be explained by an underlying disease or by a specific

pathological process, and for this reason it is defined unexplained anemia. Unexplained

anemia might be due to the progressive resistance of bone marrow erythroid progenitors

to erythropoietin, and a chronic subclinical pro-inflammatory state.

Introduction

Anemia is a global public health problem affecting both developing and developed

countries at all ages, with major consequences for human health as well as social and

economic burden1. According to WHO, anemia is defined as hemoglobin (Hb) levels <12.0

g/dl in women and <13.0 g/dl in men (Table 1)2. However, normal Hb distribution varies not

only with sex, but also with ethnicity, physiological status, e.g., with high altitude3 and

during pregnancy4. The decrease of Hb levels during pregnancy is often multifactorial; it is

partially due to physiological hemodilution for the increase in plasma volume, which is

maximal during 2024 weeks of gestation and is defined as pseudoanemia4.

Since the WHO definition of anemia was formulated over 40 years ago in a very small

population sample, without documentation of methodology, these thresholds have some

limitations5. Several papers have been published since then with consistent cut-off and

similar limitations (Table 2).

Evaluating data from two relatively recent databases on the American population (the

Scripps-Kaiser study and the NHANES-III study) (Table 3), Beutler suggested new lower

limits of normal Hb values (Table 4) taking into account ethnicity, gender and age.

Classification and diagnosis of anemia

Anemia is a condition that may recognize several pathophysiological mechanisms and

often is multifactorial. For practical purposes it could be classified on the basis of either the

mean cellular volume (MCV) (Table 5), or the underlying pathological mechanism

(hypoproliferative/maturation abnormalities/increased destruction of red cells) (Table 6) or

on the patient clinical history (acquired or congenital, acute or chronic). The

pathophysiology of several forms of anemia will be presented in detail in other chapters of

this issue.
To evaluate the underlying pathological mechanism, reticulocyte count, a marker of red

blood cell production, together with other hematological parameters provides useful

information and directs initial investigations. Reticulocytes are usually expressed as

percentage of RBC or as absolute number, but the most appropriate parameter is

reticulocytes index, that is corrected for the severity of anemia.

Reticulocyte Index (RI) is calculated as follows:

Reticulocytes percentage(%) x Ht (%)

RI =
Normal Ht(%)*

*(45% is usually used as a normal hematocrit).

Thus, a low RI reflects a marrow unable to compensate for anemia while a high RI reflects

a marrow that is attempting to compensate for red cell destruction, or recovering from

anemia. Based on RI anemias can be classified as in Table 6.

An essential tool to evaluate the origin of anemia is the blood smear examination, that in

some cases can suggest the diagnosis (e.g. folate and B12 deficiency, iron deficiency

anemia, microangiopathic anemia, hemoglobinopathies, membrane abnormalities, malaria,

acute leukemia, and so on). Currently, due to th use of sophisticated automated blood cell

count, the value of blood smear in the prompt and complete comprehension of anemia is

frequently underestimated especially by young hematologists6.

A simple work up to classify and diagnose different forms of anemia based on RI is

represented in figure 1.

Prevalence of anemia

According to WHO data, anemia affects 1.62 billion people (95% CI: 1.501.74 billion),

which corresponds to 24.8% of the world population (95% CI: 22.926.7%)1; however
global data cannot describe the real burden of the problem because anemia has different

prevalence7 and causes in different settings. The highest prevalence of anemia is

recorded in children younger than 4 years1.

Recently Kassebaum et al. published a study about global anemia burden from 1990 to

20108. In this study they observed that the prevalence of anemia decreased from 40.2% to

32% over the two decades. The reduction of prevalence was more pronounced in males,

due to not well specified reasons, widening the gender gap. Therefore females still remain

at higher prevalence compared to males in all regions, but especially in sub-Saharan

Africa starting by age of 15 years and continuing through adulthood8. The most frequent

causes of anemia in women remain poor dietary iron intake together with reproductive

causes, such as pregnancy and lactation.

It is clear that the scenario varies according to the geographical area and consequently the

economic status of different countries. Notably, prevalence is higher in people with low

socioeconomic status, undernutrition, and in women who have recently given birth9. In

lower-income countries top causes of anemia remain infections, such as malaria,

hookworms, schistosomiasis8, and iron-related etiologies. Conversely, in high-income

regions the most frequent causes are cancer, gastrointestinal hemorrhage and chronic

kidney disease (CKD), that are also highly prevalent in elderly patients7. In some countries

(e.g. in Africa, India, Middle East and Mediterranean area) hereditary forms of anemia

such as thalassemia or Sickle Cell Disease are endemic and represent a significant socio-

economic burden; however migration are changing the epidemiology of these anemias that

are becoming a challenge for physicians and health systems all over the world.
Anemia and aging

The aging of population, especially in Western Countries, is unveiling the burden of

anemia in elderly people. In this population anemia, recently defined by levels of Hb < 12

g/dL in both sexes10, is mostly of mild degree (10-12 g/dl)11, 12 and increases with age11.

Prevalence in subjects older than 65 years varies from 11 to 60%, as shown in table 7,

according to the evaluated population. Understanding the pathophysiology of anemia in

this population is important because anemia contributes to morbidity13, 14

, including

decreased physical performance15, increased number of falls16, frailty17, dementia18,

hospitalization19 and mortality13, 14.

Data from the NHANES-II database show that in the north-American population older than

65 years, anemia prevalence in community-dwelling men and women was respectively

11% and 10.2%11. However, analyzing this group for race and ethnicity, data showed that

non-Hispanic whites have the lowest overall prevalence (9.0%), with a dramatically higher

rate in non-Hispanic blacks (27.8%)11. It is important to note that the higher prevalence in

older men than women might be due to the WHO sex-specific cut-point for men that is

<13.0 g/dl at all ages.

Consistently, the InCHIANTI study20 shows that the overall prevalence of anemia in a

representative Italian population aged >65 years was 11%21. Prevalence increases

dramatically in hospitalized patients, ranging between 48-60%22, 23

, supporting the idea

that anemia is not an independent phenomenon, but is the expression of different systemic

pathophysiological mechanisms including aging.

Notably, in elderly patients many factors can contribute to anemia: cancer, inflammation,

bleeding or nutrients deficiency, and it is often multifactorial21. In several studies it seems

that in one-third of the patients anemia is due to nutritional deficiency, including iron, folate

or vitamin B12 deficiency; moreover anemia of chronic disease (ACD) accounts for about

another third of the cases11, 12

. However, in a proportion of patients anemia cannot be
explained by an underlying disease or by a specific pathological process5, 24 and for this

reason almost one third of anemia in the elderly is defined unexplained anemia (UA). UA

is usually a hypoproliferative normocytic anemia25. Several age-related physiological

changes may contribute to either a decline in red blood cell production or shortened red

blood cell survival and these taken together could account for UA25.

UA is a diagnosis of exclusion, when the other causes of anemia have been ruled out.

Vitamin B12 and folate and iron pattern should be tested first. Particularly a low RI in

presence of low transferrin saturation (<15%) and low serum ferritin define an iron

deficiency anemia. Since gastro-intestinal diseases are the most common causes of IDA in

elderly, evaluated the risk-benefit ratio and the prognostic implications, the diagnostic

work-up should include endoscopic procedures26.

Conversely, a low transferrin saturation with high ferritin (>100 ng/ml) is peculiar of

anemia of chronic disease (ACD)27. Frequently these two entities coexist, presenting with

low transferrin saturation and a moderate increase in serum ferritin (Table 8). Of note,

normal cut-off value of serum ferritin in adults (1215 ng/mL) are stringent in elderly

patients26. Moreover the MCV, that usually directs the diagnostic work up, is not helpful in

elderly due to the overlap of different disorders such as iron deficiency and folate or B12

deficiency.

Soluble transferrin receptor (sTfR) reflects erythropoietic activity and inversely correlates

with the amount of iron available for erythropoiesis. Its levels do not increase with age and

are not affected by the presence of inflammation28. The sTfFR to the log of serum ferritin

ratio is useful in the diagnosis of ACD associated to IDA29 (Table 8); however, the use of

sTfR is limited in clinical practice and limited to clinical studies.

Stem Cell aging and erythropoietin response

Similarly to most organs and tissues, the hematopoietic system shows evidence of aging

accompanied by the progressive loss of hematopoietic stem cell (HSC) activity30.

Consistently, data from the National Marrow Donor Program (NMDP) registry show that in

allogenic bone marrow transplant, advanced donor age was significantly associated with

overall decreased disease-free survival of transplant recipients31.

Several pathophysiological changes, due to loss of homeostatic control, occur in the

hematopoietic system. Among them the decreased competence of the adaptive immune

system32, the increased incidence of myeloid diseases including leukemias33, and the

onset of anemia in the elderly34 (see chapter by Santini about anemia in MDS).

Moreover erythropoietin (EPO) production in elderly healthy non anemic subjects is

increased compared to young controls35,36, mainly for an impaired EPO responsiveness

of the hematopoietic stem cell35. Conversely, elderly anemic patients have lower EPO

concentration compared to young subjects with the same level of anemia35, as a sort of

failure to compensate anemia. However the inadequate EPO response mechanism still

remains to be determined. The InCHIANTI study showed that patients with UA had serum

EPO levels even lower than the non-anemic controls or subjects with ACD. Only subjects

with iron deficiency anemia, accounting for most of the cases of severe anemia, showed

clearly high compensatory EPO levels21.

Gene sets associated with inflammation seem to be increased in aged HSCs37, 38

. Young

and aged HSCs differ in epigenetic regulation; particularly, aged HSCs show general

hypermethylation39, while in most tissues aging is associated with hypomethylation40.

Expression of Inflammatory Markers

The underlying pathological mechanism of UA remains controversial. Most of the studies

considered small populations in different settings and give inconsistent results. Data from
the InCHIANTI study described the association between pro-inflammatory mediators, such

as IL-6, TNF-alpha and CRP, and UA in elderly subjects. The UA cohort (36% of all the

anemic population) was found to have lower levels of pro-inflammatory markers compared

to non-anemic controls and any other type of anemia group. This led the authors to

conclude that the blunted EPO response associated with UA was not associated with

increased levels of inflammation41.

In a more recent study on a very small population of elderly in the United States, it seems

that UA is the result of a low grade of inflammation, characterized by iron restriction and

blunted erythropoietin production42.

The Val Borbera study(VBS)43 and the Nijmegen biomedical studies (NBS)44, investigated

serum hepcidin levels in elderly. Both studies showed that before the menopause hepcidin

levels in women are nearly 50% lower than in males of corresponding ages. After the

menopause, hepcidin levels tend to be similar in both sexes, with a slight decrease in the

eldest groups. This was evident in both sexes in the VBS but only in males in the NBS.

These studies tended to exclude a sustained increase of hepcidin in elderly. Accordingly,

two studies in elderly anemic patients have failed to detect increased hepcidin levels in

urine45 and in serum26, 46.

To summarize UA in elderly might be due to the progressive resistance of bone marrow

erythroid progenitors to erythropoietin (EPO), and a chronic subclinical pro-inflammatory

state47.

Future perspective

Currently many laboratory are working to find the secret of rejuvenation, that has been

the dream in many cultures. The attention is focused on the TGF-b superfamily member

Growth Differentiation Factor 11 (GDF11). Few years ago studies on skeletal muscle

showed through proteomic analysis that in older mice GDF11 was low compared to young
mice and GDF11 was capable of reversing age-related hypertrophy48. On the contrary,

more recently it has been published that GDF11 serum levels increase during aging49;

moreover systemic injection of GDF11 impairs satellite cell expansion and differentiation,

leading to decreased regenerative capacity. Members of the TGF- family, such as

activins, grow differentiation factors, and bone morphogenetic proteins, are key regulators

of human hematopoiesis, modulating proliferation, differentiation, migration and apoptosis.

Moreover GDF11 has recently been identified as a cytokine that blocks terminal erythroid

maturation in thalassemia and its effect seems to be reversed by activing receptor ligand

trap drugs50. The role of GDF11 in aging remains controversial; thus more studies are

needed to identify the potential role of GDF11 in aging and hematopoiesis.

Treatment of anemia in the elderly

Currently, no specific guidelines exist for the management of anemia in the elderly;

whenever possible, any underlying cause should be identified and treated51, 52.

Symptomatic treatment, such as transfusion, should be prescribed in elderly patients with

clinical symptoms such as exertion dyspnea, fatigue and tachycardia. Laboratory cut off

have been proposed11, 51, 52

, however decisions, especially in complex patients with

cardiac dysfunction, should be driven by a comprehensive clinical evaluation.

In nutritional deficiency anemias the cause, including the nutritional habit and lifestyle, has

to be considered, in order to define the most adequate nutrient support. When iron

deficiency is clearly proven, iron supplementation should be started in association with the

treatment of the underlying cause of bleeding if present, and according to the general

conditions of the patient. Standard therapy for iron deficiency is oral administration, with

the aim of correcting both anemia and iron stores. Divalent compounds like ferrous sulfate

or gluconate are preferred because of their superior bioavailability53 and a better cost-
effective ratio, compared to parenteral iron administration26. Iron replacement should be

continued for 3 months after correction of anemia to replenish iron stores. The time

needed may be even longer in elderly patients, because of slower bone marrow response.

This reduces the compliance, particularly when the patient has to take a huge number of

pills per day and it provokes abdominal discomfort. Intravenous iron replacement,

particularly with the new formulation (Fe(III)-hydroxide carbohydrate) can be considered in

patients that fail to respond to oral replacement10, 53

. In elderly patients, cobalamin

deficiency anemia and folate deficiency might be treated by i.m. vitamin B12 and oral

folate supplementation.

Conclusions

In conclusion, anemia is an important healthcare problem all over the world at all ages with

different impact in developed and developing countries. Recent migrations, that are

changing the epidemiology of hereditary anemias, and the significant increase in average

life expectancy are modifying the anemia scenario, becoming an important healthcare

problem and a challenging condition for physicians54. Importantly, in one third of anemic

elderly patients, anemia remains unexplained, thus larger and more comprehensive

studies are necessary for a better definition and treatment of UA. Moreover, in frail

patients, all investigations, especially the invasive examinations, should be carefully

evaluated according to the riskbenefit ratio in order to avoid useless tests that cannot

have an impact on patients health and quality of life.

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Figure Legends

Figure1. Diagnostic work-up for anemia.

Tables

Table 1. Hemoglobin thresholds to define anemia2.

Age or gender group Hemoglobin threshold (g/dL)

Children (0.504.99 yrs) 11.0

Children (5.0011.99 yrs) 11.5

Children (12.0014.99 yrs) 12.0

Non-pregnant women (15.00 yrs) 12.0

Pregnant women 11.0

Men (15.00 yrs) 13.0

Table 2. Cut-off to define anemia5.

Source Men, Women, Effect of race

g/dL g/dL

WHO (Blanc et al)2 13 12 Not provided

Jandl 14.2 12.2 Discussed

Williams (Beutler et al)59 14 12.3 Not provided

Wintrobe (Lee et al)60 13.2 11.6 Not provided

Rapaport61 14 12 Not provided

Goyette62 13.2 11.7 Blacks hemoglobin

0.5 g/dl lower

Tietz63 13.2 11.7 Not provided

Hoffman et al 13.5 12 Not provided

 Table 3. Lower limits of normal hemoglobin concentration in blood in younger and older

white and black adults in g/dL5.

Scripps-Kaiser NHANES-III

Years No. 2.5% 2.5% 5% actual 5%normal No. 2.5% 2.5% 5% actual 5%normal

actual normal distribution actual normal distribution

distribution distribution

White men 20-59 6709 13.4 13.4 13.7 13.7 1456 13.4 13.4 13.8 13.7

60+ 5515 12.8 12.8 13.2 13.2 934 12.2 12.4 12.8 12.7

White women 20-49 2966 11.9 11.9 12.2 12.2 1045 12.0 11.9 12.2 12.1

50+ 8313 11.9 11.9 12.2 12.2 1395 11.5 11.6 12.0 11.9

Black men 20-59 434 12.6 12.5 12.9 12.9 1253 12.3 12.4 12.8 12.8

60+ 135 - 12.4 - 12.7 235 11.4 11.9 11.8 12.2

Black women 20-49 205 11.2 11.2 11.5 11.5 904 10.9 10.8 11.3 11.1

50+ 255 11.2 11.2 11.5 11.5 442 11.0 10.9 11.3 11.2

Legend: - indicates insufficient number to determine

Table 4. Proposed lower limits of normal for hemoglobin concentration of the blood for

white and black adults5.

Group Hemoglobin, g/dl

White men, y

20-59 13.7

60+ 13.2

White women, y

20-49 12.2

50+ 12.2

Black men, y

20-59 12.9

60+ 12.7

Black women, y

20-49 11.5

50+ 11.5

Based on Scripps-Kaiser data for the 5th percentiles (see Table 3).
Table 5. Classification of anemia according to the MCV.

Low MCV (<80 fl) Normal MCV (80-99 fl) High MCV (>100 fl)

Thalassemic syndromes* ACD Folate or vitamin B12

IDA Anemia of CKD deficiency

IRIDA Sickle cell disease Alcohol

Sideroblastic anemia Myelodysplasia Chronic liver disease

Combined deficiency (for MDS

example iron + folate) Reticulocytosis

Legend: ACD: Anemia of chronic disease; CKD: Chronic Kidney Disease; IDA: Iron

deficiency anemia; IRIDA: Iron Refractory Iron Deficiency Anemia; MDS: myelodislpastic

syndromes; *- and -thalassemia, HbE, Hb Lepore

Table 6. Classification of anemia according to the Reticulocyte Index.

RI < 1% R < 1% R > 1%*

Hypoproliferative anemias Maturation abnormalities

ACD Vitamin B12 deficiency Immune Hemolytic anemias

Anemia CKD Folate deficiency Infectious causes of

IDA MDS hemolysis

Congenital Sideroblastic anemia Membrane abnormalities

dyserythropoietic anemias Mechanical hemolysis

Drugs or toxins Hemoglobinopathies

Endocrine anemias Red blood cell enzyme

Marrow replacement abnormalities

Legend: ACD: Anemia of chronic disease; CKD: Chronic Kidney Disease;IDA: Iron

deficiency anemia; MDS: myelodislpastic syndromes; *Appropriate response to increased

RBCs destruction, blood loss, nutritional supplementation.

Table 7. Anemia prevalence in elderly.

Study Age Population Prevalence

(Years) (%)

Guralnik et al (2004)11 65 Community-dwelling 10.6

elderly Americans

Ferrucci et al (2007)21 >70 Community-dwelling 11

elderly Americans

Denny et al (2007)55 71 Community-dwelling 24

Joosten et al (1992)56 65 Hospitalized 24

Artz et al (2004)57 Most 65 Nursing-home 48

Robinson et al (2007)23 65 Nursing-home 59.6

MIgone de Amicis et al (2014)22 65 Hospitalized 48

Table 8. Serum parameters in differential diagnosis of ACD, IDA and both conditions65.

ACD IDA ACD associated to

IDA

Iron

Transferrin /N

Transferrin

saturation

Ferritin N/ /N

sTR N N/

STR/logFerritin (<1) (>2) (>2)

Cytokine lebels N

sTr: soluble transferrin receptor; ACD: anemia of chronic disease; IDA: iron deficiency

anemia; N: normal