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Review Article Asia Pac J Clin Nutr 2020;29(Suppl 1):S41-S54 S41 Review Article Non-nutritional and disease-related anemia in Indonesia: A systematic review Agussalim Bukhari MD, MMed, PhD1, Firdaus Hamid MD, PhD2, Rahmawati Minhajat MD, PhD3,4, Nathania Sheryl Sutisna MD1, Caroline Prisilia Marsella MD1 1Department of Nutrition, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia 2Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia 3Division of Hematology and Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia 4Department of Histology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia Non-nutritional anemia, the second most common type of anemia worldwide after nutritional anemia, includes the anemia of inflammation (AI) and that due to helminthiasis. In this review, we examine the contribution that non-nutritional anemia makes to incidence in Indonesia. Anemia due to helminthiasis is a common problem in Indonesia and contributes to prevalence, particularly in children under 5 years. We conducted a systematic litera- ture review based on Google Scholar and Pubmed for non-nutritional anemia. We supplemented this with hemo- globin and chronic disease data in Makassar where prevalence and type of anemia were available. To effectively reduce anemia prevalence in Indonesia, interventions should address both nutritional and non-nutritional contrib- uting factors, including infection and genetic predisposition. Key Words: anemia of inflammation, helminthiasis, non-nutritional anemia, chronic disease, iatrogenic anemia BACKGROUND bolic syndrome, type 2 DM (T2DM) and CVD are also Anemia is a major public health problem in Indonesia.1-3 associated with anemia. In addition, Anemia is also a key Despite the various efforts of the Indonesian government, feature of chronic kidney disease (CKD), itself a serious such as providing iron and folic acid supplements to complication of T2DM and hypertension. pregnant women and food fortification, anemia preva- Helminthiasis is endemic disease in Indonesia (particu- lence has remained high.4 Anemia typically presents as a larly in <5-year-old children), and contributes to anemia. symptom of a disease caused by various factors, including Therefore, for comprehensive anemia management, the that that are nutritional and non-nutritional.5 The primary health authorities, systems and workers must identify and causes of nutritional anemia include low nutrient intake mitigate the underlying non-nutritional factors. Intersec- but may also be nutritionally responsive and secondary.6 toral and eco-nutritional approaches are needed to resolve The secondary causes include impaired absorption, blood persistent anemia in Indonesia.1 transport, metabolism, and storage of nutrients. Because This systematic review discusses AI pathomechanisms genetic factors underlie the secondary causes, their and prevalence in Indonesia and globally. Several Indo- pathomechanisms are increasingly being delineated nesian studies, not only of anemia in infectious, chronic, through nutrigenomics. For instance, gene polymor- and metabolic disease, but also in helminthiasis are con- phisms affect nutrient metabolism, causing variations in sidered. The genetic variations contributory to nutrient the nutritional requirements for erythrocyte formation. absorption, transport, metabolism, and storage and to Therefore, to prevent anemia, individuals with such gene erythropoiesis are considered. variants are required to consume certain nutrients at lev- els higher than the recommended daily allowance. Anemia of inflammation (AI) and iron deficiency (ID) anemia (IDA), the two most common forms of anemia worldwide, often coexist in developing countries where the prevalence of malnutrition and infectious disease is Corresponding Author: Dr Agussalim Bukhari, Faculty of 7 Medicine, Universitas Hasanuddin, Jl. Perintis Kemerdekaan typically high. AI is a frequently reported anemia in hos- Km. 10 Tamalanrea, Makassar 90245, Indonesia. pitalized patients and those with chronic, metabolic, or Tel: +62411591236 infectious disease. AI prevalence typically increases Email: [email protected] along with that of its associated diseases including diabe- Manuscript received and initial review completed 19 December tes mellitus (DM), CVD, cancer, tuberculosis (TB), ma- 2020. Revision accepted 24 December 2020. laria8 and HIV infection in Indonesia. Obesity, the meta- doi: 10.6133/apjcn.202012_29(S1).05 S42 A Bukhari, F Hamid, R Minhajat, NS Sutisna and CP Marsella METHODS Pathophysiology We searched the PubMed databases as well as Google Inflammation that occurs in both infectious and noninfec- Scholar and Google search engines for relevant literature tious diseases can lead to increased levels of cytokines, using the following keywords: “anemia,” “hemoglobin,” particularly tumor necrosis factor (TNF)-, interferon “inflammation,” “kidney,” “obesity,” “chronic disease,” (IFN)-, interleukin (IL)-1, and IL-6. IFN- elicits leuco- “heart failure,” “helminthiasis,” “tuberculosis,” “HIV,” cyte proliferation, thus activating macrophages to phago- and “Indonesia.” Original articles published in both inter- cytose erythrocytes and shortening the erythrocyte life; national and Indonesian journals, unpublished theses, and TNF- inhibits erythroid precursor proliferation; and IL-6 registry data were selected. In total, 39 Indonesian studies promotes liver hepcidin synthesis.11,12 Moreover, proin- from Indonesian journals (35 studies) and university the- flammatory cytokines suppress erythropoietin production; ses (4 studies) were finally included. Internationally pub- this natural mechanism reduces iron availability in the lished articles on AI in Indonesia were scant. The studies blood to inhibit the survival and reproduction of microor- were typically cross-sectional or descriptive, with some o ganisms that use iron. Although this adaptative mecha- only reporting the proportions or mean hemoglobin levels nism is beneficial in mitigating acute infections, its chron- without describing anemia type. Anemia in helminthiasis ic continuation in chronic infections can lead to AI and data were mostly observational, conducted in Indonesia disrupt metabolism.11 and published variously in international and Indonesian In plasma, iron binds to transferrin, which carries it to journals. The definitions of anemia varied with different the bone marrow for hemoglobin synthesis. Hepcidin is cutoff points for hemoglobin. an iron-regulating hormone that binds to ferroportin to We also obtained data for Makassar from patients of block the iron transfer from duodenal enterocyte cells, the Clinical Nutrition Department, Universitas Hasanud- macrophages, and liver cells to blood plasma. Under din affiliated to the Dr. Wahidin Sudirohusodo Hospital, normal conditions, hepcidin synthesis is regulated by the in Makassar, Indonesia from July 2019 to September number of iron stores and serum iron levels. However, in 2020. low-grade chronic inflammatory conditions such as those in obesity and anemia, increased hepcidin levels have INFLAMMATION been reported worldwide, including in Indonesia.13 Hep- AI most commonly presents as a mild-to-moderate cidin also worsens impaired renal function and is associ- normocytic normochromic anemia, which is caused by ated with inflammation.14 systemic inflammation that inhibits erythrocyte formation AI is typically normocytic and normochromic, which and survival. In AI, hemoglobin rarely drops below 8 means that AI exhibits normal erythrocyte size and nor- g/dL. In contrast to IDA, which is characterized by low mal hemoglobin content (Table 1). In some cases, par- serum iron and ferritin, AI exhibits low serum iron but ticularly those of chronic inflammation, AI may be mi- normal or high serum ferritin levels. This phenomenon crocytic (small erythrocyte size) and hypochromic (low may be due to the iron redistribution in AI shifting from hemoglobin content).7 the location of utilization to that of storage, particularly in the hepatic and splenic mononuclear phagocyte system.9 CHRONIC AND METABOLIC DISEASE AI is commonly found in patients with chronic system- Noncommunicable diseases (NCDs) or chronic diseases ic inflammatory conditions including both infectious and result from a combination of factors including those that noninfectious diseases. Thus, AI is typically associated are genetic, behavioral, and environmental. In Indonesia, with chronic systemic inflammatory diseases including hypertension and T2DM incidence is 84 and 20 per 1000 TB, malaria HIV, acquired immunodeficiency syndrome population, respectively.4 The prevalence of anemia in (AIDS), immune-mediated diseases (e.g., systemic lupus some chronic diseases among the patients from our de- erythematosus), cancerous and hematological malignan- partment is illustrated in Figure 1. cies, obesity, T2DM, anemia in elderly persons, anemia The prevalence of obesity, a major risk factor for met- in critical illness, congestive heart failure, CKD, and abolic syndrome, has also increased considerably in In- chronic pulmonary diseases.10 donesia (Table 2A). In adults, central obesity prevalence Tropical infectious diseases, which are typically acute (e.g., typhoid fever), are highly prevalent infectious dis- Table 1. Differences in IDA and AI biomarkers eases in Indonesia. The prevalence of other acute infec- tious diseases, such as diphtheria, pertussis, and morbilli, Iron deficiency
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