PROPORTION OF NORMOCYTIC-NORMOCHROMIC AMONG ANEMIC OUTPATIENTS AT RSUPN DR. CIPTO MANGUNKUSUMO AND ITS ASSOCIATION WITH AGE AND GENDER

Dimas Tri Prasetyo1, Ina S. Timan2

1International Class Program, Faculty of Medicine Universitas Indonesia 2Department of Clinical Pathology, Faculty of Medicine Universitas Indonesia – RSUPN Dr. Cipto Mangunkusumo

Abstrak Anemia adalah masalah kesehatan yang umum terjadi di masyarakat. Anemia normositik- normokromik adalah salah satu jenis anemia yang umum terjadi pada penderita penyakit kronis. Anemia jenis ini ditandai dengan penurunan nilai (Hb) di bawah batas normal tetapi nilai mean cell volume (MCV) dan mean cell hemoglobin (MCH) dalam batas normal. Penelitian ini memiliki desain cross-sectional dan bertujuan untuk mencari proporsi anemia normositik-normokromik pada pasien anemia yang menjalani pengobatan rawat jalan di RSUPN Dr. Cipto Mangunkusumo dan hubungannya dengan usia dan jenis kelamin. Data sekunder tentang profil hematologi pasien rawat jalan bulan Maret 2011 diambil dari Laboratory Information System di RSUPN Dr. Cipto Mangunkusumo. Statistik deskriptif digunakan untuk menentukan prevalensi. Signifikansi perbedaan proporsi pada kategori umur yang berbeda pada pasien anemia normostik-normokromik dibandingkan dan diuji dengan uji chi-square, begitu pula dengan perbedaan proporsi pada wanita dan laki-laki juga diuji dengan uji chi-square. Studi ini menemukan bahwa proporsi pasien anemia normositik- normokromik dibandingkan dengan anemia jenis lain adalah sebesar 48.1%. Kategori umur II (15 – 59 tahun) merupakan kategori umur dengan presentase penderita anemia normositik- normokromik tertinggi (71.8%) dan wanita memiliki persentase lebih tinggi dibandingkan pria (62.8%) sebagai penderita anemia normositik-normokromik. Kata kunci: anemia; normositik-normokromik; usia; jenis kelamin.

Abstract Anemia is a serious public health problem. One of the types of anemia based on its morphology is normocytic-normochromic anemia. This anemia usually occurs in individuals with chronic diseases. To date, there are limited studies investigating the prevalence of normocytic-normochromic anemia. Most of these studies investigated the underlying conditions of normocytic-normochromic anemia. This study is a cross-sectional study that aims to investigate the proportion of normocytic-normochromic anemia among anemic outpatients at RSUPN Dr. Cipto Mangunkusumo and its association with age and gender by using data from laboratory results of outpatients who had their blood checked at RSUPN Dr. Cipto Mangunkusumo in March 2011. Descriptive statistical analysis was performed to determine prevalence. Then, statistical significance was tested with Chi-Square Test for gender and age. Our result showed that normocytic-normochromic anemia accounts for 48.1% among all anemic outpatients. Age group II had the highest percentage for normocytic- normochromic anemia (71.8%) and female seemed to be more prevalent than male (62.8%). Keywords: anemia; normocytic-normochromic; age; gender.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Introduction Anemia is a very common condition, which affects people of all ages.(1) It can be present as an independent disease, for example resulting from iron deficiency as in iron deficiency anemia (IDA), or may be a result of other conditions, one example is in chronic disease (rheumatoid arthritis, severe trauma, heart disease, or diabetes mellitus), when there is primarily a decreased availability of iron, relatively decreased levels of erythropoietin, and a mild decrease in the lifespan of red blood cells (RBCs).(2,3)

According to the World Health Organization (WHO), anemia affected 1.62 billion individuals or 24.8% of the global population. From 1.62 billion individuals affected, the highest proportion was in preschool-age children and that women were more prevalent than men. Furthermore, WHO made estimation of anemia from three population groups: preschool-age children, pregnant women and non-pregnant women, and found that Africa had the highest proportion of individuals affected (47.5 – 67.6%) while South-East Asia had the greatest number of people affected with anemia (315 million individuals).(1)

Anemia is also a public health concern in Indonesia. A study in Indonesia stated that the prevalence of anemia among adolescent females was 57.1%, higher than two other groups observed: fertile-age females and pregnant women, which were 27.9% and 40.1%, respectively. Another study conducted by Timan et al found that the proportion of among adolescent females in five areas in Jakarta was 44.6%. The then Departemen Kesehatan Republik Indonesia (Department of Health of the Republic of Indonesia)-now Kementrian Kesehatan Republik Indonesia (Ministry of Health of the Republic of Indonesia) published a report in 1999 regarding the prevalence of anemia in Indonesia and found that its prevalence among 10 – 14 year-old males was 45.8%, and 58.3% among 15 – 44 year-old males.(4)

Anemia of chronic disease is the second most prevalent anemia after IDA. It usually occurs in patients with acute or chronic immune activation. Despite being a public health burden and relatively common, there is still not many research being conducted on normocytic- normochromic anemia, especially regarding the proportion among certain ages and genders. Based on this fact, the researcher felt the necesity to bring this topic regarding the proportion of normocytic-normochromic anemia among anemic outpatients at RSUPN Dr. Cipto Mangunkusumo, and its association to certain ages and in between male and female.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Literature Review Anemia is defined as a reduction in the hemoglobin concentration of the blood (7,8,9). This, however, varies between different laboratories or institution, although typical values would be less than 13.5 g/dL in adult males and less than 11.5 g/dL in adult females.(2)

Anemia is one of the most common clinical problems presenting in general practice, hospitals and in medical examinations. Usually characteristic symptoms and signs prompt a blood count to confirm the diagnosis but on occasion, an unexpectedly low hemoglobin estimation precedes the clinical consultation.(5)

A logical approach to anemia demands a clear understanding of both its possible causes and its clinical and laboratory features.

Howard et al divided anemia into two major classifications: morphological and etiological, in which both are best used together.(5)

Morphological Classification The morphological classification is based on a correlation between red cell indices, that will be explained later, and the underlying cause of anemia. The most important measurements are of red cell size (mean cell volume or MCV) and red cell hemoglobin concentration (mean cell hemoglobin (MCH) or mean cell hemoglobin concentration (MCHC)). with raised, normal and reduced value of MCV are termed macrocytic, normocytic and microcytic respectively. Anemias associated with a reduced hemoglobin concentration within red cells are termed hypochromic and those with a normal MCH are termed normochromic. Table 1 illustrates the types of anemia based on morphological classification as well as their possible underlying causes.(5,6)

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Table 1. Classification of anemia based on morphology (6) Anemia Types Microcytic- Normocytic- Macrocytic Hypochromic Normochromic MCV value MCV < 80 fL MCV 80 – 95 fL MCV > 95 fL MCH value MCH < 27 pg MCH > 27 pg

Possible causes Iron deficiency, , Vitamin B12 or folate , anemia anemia of chronic deficiency, liver of chronic disease disease (some cases), disease, (some cases), lead acute blood loss, myelodysplasia, poisoning, renal disease, mixed deficiencies (some cases)

Etiologic Classification Etiological classification is important in illuminating the pathogenesis of anemia. The basic fundamental of this classification is between excessive loss or destruction of mature red cells and inadequate production of red cells by the marrow. Loss of red cells occurs in hemorrhage and excessive destruction in hemolysis. A normal bone marrow will respond by increasing red cell production with accelerated discharge of young red cells (reticulocytes) into the blood. Inadequate red cell production may result from insufficient erythropoiesis, which is a quantitative lack of red cell precursors or ineffective erythropoiesis, which is the destruction of defective erythrocytes in the marrow.(6)

Complete Blood Count A routine (CBC) is required as part of the evaluation and includes the hemoglobin, hematocrit, and red cell indices: MCV in femtoliters, MCH in picograms/cell, and MCHC in grams/liter (non-SI: grams/deciliter). A number of physiologic factors affect the CBC including age, sex, pregnancy, smoking, and altitude. High-normal hemoglobin values may be seen in men and women who live at altitude or smoke heavily.(7)

Red cell indices examination is the most useful diagnostic tool in diagnosing anemia and determining its type. The diagnosis of microcytic, normocytic and can be made by examining the MCV. The MCH and MCHC reflect defects in hemoglobin synthesis (hypochromia). As well as suggesting the nature of the primary defect, this approach may also

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 indicate an underlying abnormality before overt anemia has developed.(6) The reference values for Hemoglobin, MCV and MCH at RSUPN Dr. Cipto Mangunkusumo is listed in Table 2.

Table 2. Reference values for Hemoglobin, MCV and MCH at RSUPN Dr. Cipto Mangunkusumo (8)

No. Type of Examination Units Age Gender Reference Value 1 Hemoglobin g/dL 0 – 1 day 14.5 – 22.5 2 – 31 days 10.0 – 18.0 1 month – 6 years 11.5 – 15.5 7 – 13 years Female 12.0 – 16.0 Male 13.0 – 16.0 Adults Female 12.0 – 14.0 Male 13.0 – 16.0 2 MCV fL 0 – 1 day 95.0 – 121.0

2 days – 2 years 70.0 – 86.0 3 – 12 years 77.0 – 95.0

Adults 82.0 – 92.0

3 MCH g/dL 0 – 1 day 31.0 – 37.0 2 – 31 days 28.0 – 40.0 1 month – 6 years 23.0 – 31.0 1 – 13 years 25.0 – 33.0 6 – 12 years 25.0 – 35.0 Adults 27.0 – 31.0

Other important laboratory tests include the reticulocyte count and measurements of iron supply, which include serum iron, total iron-binding capacity (TIBC; an indirect measure of the transferrin level), and serum ferritin. The peripheral blood smear is also important as it provides important information about defects in red cell production.(6)

Normocytic-Normochromic Anemia A mild normochromic, is a common finding and usually a consequence of other diseases, including anemia of chronic disease, associated with chronic infection, all

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 forms of inflammatory diseases, and malignant disease, in which exact mechanism still unknown but likely to involve multiple factors; typically leads to a reduction in the serum iron concentration with concurrent reduction in the level of transferrin, hence saturation of the iron binding capacity is usually normal or only slightly reduced. Normocytic-normochromic anemia can also be caused by other disorders, including renal failure, hypothyroidism, hypopituitarism, marrow failure (aplastic anemia, infiltration, pure red-cell aplasia), acute blood loss, and polymyalgia rheumatic.(9)

In anemia of chronic kidney disease, males have a 30% greater risk of developing anemia as compared to females. One factor that contributes to this fact is that, although males have higher hemoglobin values, they also have higher rates of advanced chronic kidney disease.(10)

Anemia is common in patients with chronic kidney disease. The landmark study by Obrador et al showed that among predialysis patients, 68% of those with advanced chronic kidney disease who required renal replacement therapy had a hematocrit less than 30 mg/dL; of these, 51% of patients had a hematocrit less than 28 mg/dL. Furthermore, although anemia is not as common in earlier stages of chronic kidney disease, patients with stage III disease have a prevalence of concurrent anemia of 5.2%, whereas those with stage IV disease have a prevalence of concurrent anemia of 44.1%.(11) However, whether the results of this study correlate with the prevalence of normocytic-normochromic anemia needs further investigation.

There is also a greater prevalence of anemia of chronic kidney disease in those older than 60 years, as compared to those aged between 46 and 60 years. This is probably secondary to the greater rate of chronic kidney disease in older individuals, as well as the lower estimated glomerular filtration rates (GFRs) that are associated with aging.(12)

The pathogenesis, epidemiological and clinical characteristics of normocytic-normochromic anemia are not well established.(13)

Wall and Street classified normocytic-normochromic anemia into two types based on the result of reticulocyte count: those with increased reticulocyte count and those with normal or decreased reticulocyte count. The first group includes acute blood loss and hemolytic anemias, while those with normal or reduced reticulocyte count includes anemia of chronic disease, renal anemia, hypersplenism, endocrine diseases (e.g., hypothyroidism, hyperthyroidism,

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 hypoadrenalism), primary bone marrow diseases (e.g., aplastic anemia, bone marrow infiltration or replacement by malignancy), myelosuppression due to drugs or alcohol, and physiological anemia of pregnancy. (14)

Treatment Treatment is that of the underlying condition. For those in whom such reversals are not possible, such as patients with end-stage kidney disease, cancer, and chronic inflammatory diseases, symptomatic anemia requires treatment. The forms of treatment for theses conditions include transfusions and erythropoietic agents. Iron therapy for patients with anemia of chronic disease is controversial. Oral iron is poorly absorbed because of the down regulation of absorption in the duodenum. Only a fraction of the absorbed iron will reach the sites of erythropoiesis, owing to iron diversion mediated by cytokines, which directs iron into the reticuloendothelial system.(7)

Blood Transfusions Blood transfusions are widely used as a rapid and effective therapeutic intervention. Transfusions are particularly helpful in the context of either severe or life-threatening anemia, particularly when the condition is aggravated by complications that involve bleeding. Blood transfusion therapy has been associated with increased survival rates in anemic patients with myocardial infarction, but transfusion itself has also been associated with multi organ failure and increased mortality in patients who are in critical care. Whether blood transfusions modulate the immune system, causing clinically relevant adverse effects, remains undetermined.(15,16,17)

Erythropoietic Agents EPO is particularly useful in anemias in which endogenous EPO levels are inappropriately low, such as the hypoproliferative anemias. Iron status must be evaluated and iron repleted to obtain optimal effects from EPO. Once a target hemoglobin level is achieved, the EPO dose can be decreased. A fall in hemoglobin level occurring in the face of EPO therapy usually signifies the development of an infection or iron depletion. When an infection intervenes, it is best to interrupt the EPO therapy and rely on transfusion to correct the anemia until the infection is adequately treated.(7)

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013

Research Methodology This study utilizes cross-sectional method to find the proportion of normocytic-normochromic anemia among anemic outpatients at RSUPN Dr. Cipto Mangungkusumo. The results will be analyzed to find the association between normocytic-normochromic anemia and the patients’ age and gender.

This study is conducted from March 2011 – June 2013 in Jakarta, Indonesia. The data itself comprised of the patients’ data from 1 – 31 March 2011. The data is obtained from the Laboratory Information System at RSUPN Dr. Cipto Mangunkusumo, Jalan Diponegoro 71, Jakarta Pusat. This data is limited only from the results of peripheral blood examination obtained from patients of the Outpatient Polyclinics of RSUPN Dr. Cipto Mangunkusumo, Jalan Diponegoro 71, Jakarta Pusat. Other rest of the process is done at at Fakultas Kedokteran Universitas Indonesia, Jalan Salemba Raya 6, Jakarta Pusat.

The population of this study is the patients of Outpatient Polyclinics of RSUPN Dr. Cipto Mangunkusumo Hospital. The sample for this study is the outpatients who fulfill the inclusion and exclusion criteria provided below: a. Inclusion Criteria 1. Anemic outpatients of RSUPN Dr. Cipto Mangunkusumo who visit the polyclinics during the period of data collection. 2. Anemic outpatients whose laboratory results show a normocytic-normochromic anemia feature. b. Exclusion Criteria 1. Patients of Inpatient Wards of RSUPN Dr. Cipto Mangunkusumo. 2. Outpatients whose data do not include their age, gender, hemoglobin level, MCV and MCH results.

The formula used to calculate the minimum sample size is the formula to determine the proportion of health problem in the population. Minimum sampling size is calculated as below:

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 ! − ! !×!×(1 − !) ! = ! !! where, n= raw minimum sample size

(Z1-α) is already determined 1.96 for α=5% p= general proportion of normocytic-normochromic anemia among anemic patients, which is assumed to be 50% d= acceptable error of the researcher

Based on the formula above, the minimum number of subjects recruited for this study is:

1.96 !×50%×(1 − 50%) ! = 0.1! ! = 96.04 ≈ 96

Considering the possibility of unexpected occurrences that might cause a decrease of the amount of sample size during research, the total number of subjects must be added an additional 10%, which give a 106 number of subjects that are expected to participate in this study.(18)

Variable Identification The variables used in this study are listed in Table 3. Table 3. List of variables used in this study

Variable Name Variable Type Explanation Independent Age Categorical I, II and III Variable Gender Categorical Male and female. Normocytic- Categorical Normocytic- Dependent normochromic normochromic anemia Variable anemia status and non normocytic- normochromic anemia

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Data Processing The data obtained from the Laboratory Information System of RSUPN Dr. Cipto Mangunkusumo is collated into tables by Microsoft Excel. Then, the data is analyzed statistically by SPSS v20. Descriptive analysis is done for each variable. This study uses Chi- Square Test to find the influence of independent variable to the dependent variable. Data is interpreted to have association from independent towards dependent variables according to the significance of the respective tests. The significant result is denoted with p<0.05.

Operational Definition Anemia is defined as a reduction of hemoglobin or red cell concentration in the blood below normal value. Table 4 illustrates the reference value at RSUPN Dr. Cipto Mangunkusumo.

Table 4. Reference value for anemia at RSUPN Dr. Cipto Mangunkusumo (8) Age Group Sex Definition Anemia Less than 7 years Male and female Hb < 11.5 g/dL old 7 – 13 years old Male Hb < 13 g/dL Female Hb < 12 g/dL More than 13 years Male Hb < 13 g/dL old Female Hb <12 g/dL

Mean cell volume (MCV) represents average size. Table 5 illustrates the normal reference value of MCV at RSUPN Dr. Cipto Mangunkusumo.

Table 5. Reference value for normocytic (normal MCV) at RSUPN Dr. Cipto Mangunkusumo (8) Age Group Sex Normal Value Normocytic Less than 3 years Male and female MCV 70.0 – 86.0 fL old 3 – 12 years old Male and female MCV 77.0 – 95.0 fL More than 12 years Male and female MCV 82.0 – 92.0 fL old

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Mean cell hemoglobin (MCH) represents hemoglobin amount per red blood cell.

Table 6. Reference value for normochromic (normal MCH) at RSUPN Dr. Cipto Mangunkusumo (8) Age Group Sex Normal Value Normochromic Less than 6 years Male and 23.0 – 31.0 pg old female 6 – 12 years old Male and 25.0 – 33.0 pg female 13 – 18 years old Male and 25.0 – 35.0 pg female More than 18 Male and 27.0 – 31.0 pg years old female

Normocytic – normochromic anemia a subtype of anemia based on its morphological value with normal MCV and normal MCH.

Age Group I is those patients, who, at the time of the study, are below 15 years old.

Age Group II is those patients, who, at the time of the study, belong to 15 – 59 years old range.

Age Group III is those patients, who, at the time of the study, are minimum 60 years old.

Results and Discussion

Study Population Characteristics Among all 3799 eligible subjects recruited, it was found that 1766 patients were anemic and 2033 were not. From 1766 patients that were anemic, gender distribution showed that the percentage of female patients that were anemic was higher than males (65.3% for females and 34.7% for males). The results of gender distribution among anemic and non-anemic patients can be seen in Table 7.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Table 7. Gender distribution of the outpatients between anemia and non-anemia

Gender Anemic Non-Anemic Female Frequency 1153 (65.3%) 1105 (54.4%) (% within all female) Male Frequency 613 (34.7%) 928 (45.6%) (% within all male) Total 1766 (100%) 2033 (100%)

In this study, age was categorized into three groups as has already been explained in Chapter II. Group I comprises those <15 years of age. Group II consists of outpatients whose ages were between 15 – 60 during the time of the study. The last group consists of those aged 60 and above. Table 8 shows the proportion of each age group among anemic and non-anemic outpatients.

Table 8. Proportion of anemic and non-anemic outpatients in different age groups Age Group Anemia Non-Anemia Frequency Percentage within Frequency Percentage within Non- Anemia Anemia I (<15) 55 3.1% 62 3.0% II (15 – 59) 1340 75.9% 1588 78.1% III (60 and 371 21.0% 383 18.8% above) Total 1766 100% 2033 100%

It was found that there was 55 anemic patients from age group I, 1340 anemic patients from age group II and 371 anemic patients from age group III. Age group II has the highest percentage of patient within all anemic outpatients. Similar to that, 78.1% of non-anemic outpatients were from age group II with total number of patients of 1588.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Proportion of Normocytic-Normochromic Anemia among Anemic Outpatients The proportion of normocytic-normochromic anemia among all anemic outpatients was calculated. The result showed that from the total 1766 outpatients who had anemia, 48.1% of which had normocytic-normochromic anemia, with the total number of patients affected as many as 849 patients. The results can be seen in Table 9.

Table 9. Proportion of normocytic-normochromic anemia among anemic outpatients

Anemia Status Frequency Percentage Normocytic- 849 48.1% normochromic Non 917 51.9% normocytic- normochromic Total 1766 100%

Based on the literature searching, there has been no study which directly investigated the proportion of normocytic-normochromic anemia among anemic population. Most studies directed towards the prevalence of conditions that may result in normocytic-normochromic anemia as their consequences. Furthermore, there are some underlying conditions for normocytic-normochromic anemia that may also cause different morphology other than normocytic and/or normochromic. Examples of those conditions are hemolytic anemia and anemia caused by hypothyroidism that may also be macrocytic, or anemia caused by hyperthyroidism that may also be microcytic. Although there are also some conditions that are usually non normocytic-normochromic but may be normocytic-normochromic in their early stages, such as iron deficiency (IDA usually presents as microcytic-) and anemia caused by vitamin B12 or folate deficiency (which usually presents as macrocytic anemia), these conditions cannot be used as a comparison for the proportion of normocytic - normochromic due to their non-exclusive red cell indices.

Association between Age and Normocytic–Normochromic Anemia A cross-tabulation was done to determine the frequency distribution of normocytic- normochromic anemia between each age group in anemic outpatients. After that, a Chi- Square Test was performed to obtain statistical values of these variables and their statistical

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 significance. Table 10 summarizes the results of association between age and normocytic- normochromic anemia.

Table 10. Association between age and normocytic-normochromic anemia Age Group Frequency Total

Normocytic- Non Normocytic- Normochromic Normochromic I (<15) 25 (2.9%) 38 63

II (15 – 59) 610 (71.8%) 722 1332

III (60 and 214 (25.2%) 157 371 above) Total 849 (100%)

p=0.000

Table 10 shows that there is an association between age and normocytic-normochromic anemia. Statistical analysis showed that the results generated was statistically significant (p<0.05). The results show that age group II had the highest proportion of normocytic- normochromic anemia compared to other age groups.

There are several studies investigating the prevalence of conditions are underlying normocytic-normochromic anemia and their association with age. In genetically acquired anemias (e.g., , thalassemia, Fanconi syndrome), children were more prevalent than adults.(19) As Hb declines slightly as people ages, anemia prevalence rises in men and women with advancing age.(20) One study showed anemia proportion was 8% among those aged 65 – 74 years, 13% for those aged 75 – 84 years, and 23% for those aged 85 years and older. The reason for increased anemia proportion with advancing age has not been established.(21) However, table 10 shows that age group II has the highest number of patients having normocytic-normochromic anemia. This might be due to the fact that the number of patients from that age group was the highest.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Association between Gender and Normocytic-Normochromic Anemia A cross-tabulation was done to determine the frequency distribution of normocytic- normochromic anemia between each gender in anemic outpatients. Then, a Chi-Square Test was performed to obtain statistical values of these variables and their statistical significance. Table 11 summarizes the association between gender and normocytic-normochromic anemia.

Table 11. Association between gender and normocytic-normochromic anemia Gender Frequency Total

Normocytic- Non Normocytic- Normochromic Normochromic Female 533 (62.8%) 620 1153

Male 316 (37.2%) 297 613

Total 849

p=0.033

Table 11 shows that there is an association between gender and normocytic-normochromic anemia. Statistical analysis showed that the results generated was statistically significant (p<0.05). The number of female outpatients who had normocytic-normochromic anemia was 533 patients or 62.8% of normocytic-normochromic patients.

This result regarding the association between gender and normocytic-normochromic anemia is similar to the results of other research studying the prevalence of anemia in general, in which females are more prevalent especially during childbearing age. On the other hand, this is different to the results of other researches studying the prevalence of possible underlying conditions for normocytic-normochromic anemia, e.g., anemia of chronic disease, in which males are more prevalent than females.(20,21) The results of these studies, however, could not be compared to this study because all of those studies did not directly investigate the prevalence of normocytic-normochromic anemia in their respective study population.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 Association between Age and Gender among Normocytic–Normochromic Anemia A cross-tabulation was done to determine the frequency distribution of normocytic- normochromic anemia between each age group and sex. After that, a Chi-Square Test was performed to obtain statistical values of these variables and their statistical significance. Table 12 summarizes the results of association between age and gender among normocytic- normochromic anemia patients.

Table 12. Association between age and gender among normocytic-normochromic anemia patients Age Group Proportion Female Male Total I Frequency 8 17 25 Percentage within age 32.0% 68.0% 100% II Frequency 424 186 610 Percentage within age 69.5% 30.5% 100% III Frequency 101 113 214 Percentage within age 47.2% 52.8% 100% Total 849 917 1766 p=0.000 Table 12 shows that from age group I, male predominates the proportion of normocytic- normochromic anemia with 17 out of 25 patients in this age group were males (68.0%). However, in age group II, female predominates the proportion of normocytic-normochromic anemia with 69.5% patients of this group was female. In age group III, male again predominates the proportion of normocytic-normochromic anemia with 52.8% of the patients in this group was male, although the difference was not as big as in age group I. Statistical analysis showed that the results generated was statistically significant (p<0.05).

Since many conditions that underlie normocytic-normochromic anemia usually occurs in the latter decades of life, there are limited resources regarding their prevalence in younger ages, which in this study belong to age groups I and II. In age group II, female is more prevalent that male. This is similar to the findings in anemia in general, in which women of pre- menopausal ages are more prevalent to anemia. However, to link this with normocytic- normochromic anemia is too early as there are no previous studies discussing this issue. The minimal differentiation of subjects in this study also poses as a limitation. One example is that

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013 the age groups are divided into three groups and there is no information whether female subjects recruited were pregnant or in menstruation ages or not.

The result in age group III, on the other hand, corresponds to the findings in many studies investigating the epidemiology conditions underlying normocytic-normochromic anemia, such as in anemia of chronic disease. In those studies, there was a shift between male and female in the proportion of anemia, in which males predominate. One hypothesis is that males are more prone to diseases in the older ages compared to females.(22)

Conclusion 1. From 3799 outpatients recruited for this study, 1766 of which had anemia. From those with anemia, 917 patients (51.9% of the anemic outpatients) had normocytic- normochromic anemia and there was 849 patients (48.1% of the anemic outpatients) who had non-normocytic-normochromic anemia. 2. There is an association between age and normocytic-normochromic anemia in the outpatients of RSUPN Dr. Cipto Mangunkusumo. Statistical analysis showed that the association is statistically significant. 3. There is an association between gender and normocytic-normochromic anemia in the outpatients of RSUPN Dr. Cipto Mangunkusumo. Statistical analysis showed that the association is statistically significant.

Suggestions

For Academicians and Future Researchers This research can, hopefully, open to more research questions that interest academics and researchers to further investigate about normocytic-normochromic anemia. By conducting research on normocytic-normochromic anemia as an independent condition, more depth understanding regarding the pathophysiology of normocytic-normochromic anemia, which until now is still unclear, can be achieved and mechanisms that link all the underlying diseases that may give rise to normocytic-normochromic anemia may be established. Furthermore, by understanding more about normocytic-normochromic anemia, more effective treatment strategy can be formulated as well, especially for patients whose underlying conditions causing the occurrence of normocytic-normochromic anemia are not treatable. This will in turn, be very beneficial for clinicians.

Proportion of normocytic..., Dimas Tri Prasetyo, FK UI, 2013

For Clinicians Based on the result regarding the proportion of normocytic-normochromic anemia, it was found that the number of patients suffering from normocytic-normochromic anemia was more than half of the anemic outpatients at RSUPN Dr. Cipto Mangunkusumo. This means that normocytic-normochromic anemia is a common disease encountered in outpatient setting. Clinicians must be aware that normocytic-normochromic anemia does not stand alone, in a way that this condition is usually only a manifestation of more severe disease in the body. Therefore, clinicians should pay more attention to patients who are diagnosed with normocytic-normochromic anemia based on their red cell indices to look for possible underlying diseases.

For Institution Institution should take this issue regarding normocytic-normochromic anemia seriously. Standardization must be made in screening, diagnosing, managing, and rehabilitation of patients with normocytic-normochromic anemia. This is important because the management of underlying diseases of this type of anemia may be benefited by improving the anemia status or vice versa. By conducting thorough assessment, especially towards patients who have higher risk of having normocytic-normochromic anemia, such as patients with chronic renal disease or patients with malignant tumor, it will hopefully decrease the chance of misdiagnosis and mistreatment of anemia.

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