1. Anemia of chronic disease
혈액종양내과 이정옥

2. Definitions (1) Anemia of Chronic Disease (ACD)
mild to moderately severe anemia (Hgb 7 to 12 g/dL) associated with
chronic infections and inflammatory disorders and some malignancies
Anemia of critical illness
acutely (within days) in intensive care settings where the effects of
infection or inflammation are exacerbated by disease-related or
iatrogenic blood loss or red cell destruction, which by themselves are
not sufficiently severe to cause anemia
Anemia of Inflammation (AI)
include not only ACD, but anemia of critical illness, a condition that
develops within days of the onset of illness

3. Definitions (2) Anemia of aging
diagnosed in the older when a normocytic normochromic anemia
with low serum iron and preserved iron stores develops without an
identified underlying disease
typically have an elevated ESR and/or CRP, a high plasma IL-6
concentration, and frailty
Anemia of CKD
presents similarly to AI 
relative EPO deficiency
systemic inflammation, true iron deficiency, ↓clearance of hepcidin

4. Relationship between hematocrit (Hct) and creatinine clearance in patients with CKD

5. Common conditions associated with AI
Infection
AIDS/HIV, tuberculosis, malaria, osteomyelitis, chronic abscesses, sepsis
Inflammation
RA, other rheumatologic disorders, inflammatory bowel disease, systemic inflammatory response syndrome
Malignancy
carcinomas, multiple myeloma, lymphomas
Cytokine dysregulation
Anemia of aging

6. Pathogenesis Red cell destruction
Suppressive effects of inflammation on erythropoietic precursors
Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability

7. Pathogenesis Red cell destruction
: transfused normal erythrocytes have a decreased life span in AI recipients.
:  is caused by the activation of hosts factors such as macrophages that
prematurely remove aging erythrocytes from the bloodstream
: Whether extrinsic factors, such as bacterial toxins and medications, or host-
derived antibodies or complement contribute to this process is unknown.
Suppressive effects of inflammation on erythropoietic precursors
Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability

8. Pathogenesis Red cell destruction
Suppressive effects of inflammation on erythropoietic precursors
: tumor necrosis factor (TNF)-α, IL-1, and the interferons, exert a suppressive
effect on erythroid colony formation
Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability

9. Pathogenesis Red cell destruction
Suppressive effects of inflammation on erythropoietic precursors
Inadequate erythropoietin secretion and resistance to erythropoietin
: relative EPO deficiency is often a major contributor to anemia of CKD
: Inflammation induces a state of relative resistance to EPO
Erythropoiesis restriction as a result of iron unavailability

10. Pathogenesis Red cell destruction
Suppressive effects of inflammation on erythropoietic precursors
Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability

11. Erythropoiesis restriction as a result of iron unavailability
Hypoferremia
one of the defining features of AI, develops within hours of the onset of inflammation.
dependent on IL-6 which induces the iron-regulatory hormone, hepcidin
IL-6–hepcidin axis now appears to be responsible for the induction of
hypoferremia during inflammation
Erythropoiesis in Anemia of Inflammation Is Limited by Iron
Inhibition of Intestinal Absorption of Iron and Other Factors Leading to Systemic Iron Deficiency
IL-6 is a potent and direct inducer of hepcidin and neither IL-1 nor TNF-α share this activity. 

12. Effect of inflammation on iron concentrations in plasma
During inflammation
the release of iron from MΦ and probably also from liver stores is markedly inhibited.
MΦ recycling of senescent erythrocytes + hepatocyte iron stores
hepcidin inhibits iron flow into the plasma transferrin compartment -
- binding to cell membrane-
associated ferroportin
(conduits for iron export)
- inducing ferroportin
internalization and degradation
20 to 25 mg of iron that daily enters the plasma iron/transferrin pool comes from macrophage recycling of senescent erythrocytes and from hepatocyte iron stores;
only approximately 1 to 2 mg come from dietary iron.
Only approximately 2 to 4 mg of iron is bound to transferrin but the entire daily iron flow transits through this compartment;
thus, the iron in this pool turns over every few hours.

13. N Engl J Med 2005;352:1011

14. Laboratory features (1)
MCV/MCH
usually normocytic and normochromic but,
with increasing severity or duration, can sometimes become hypochromic
and eventually microcytic
Reticulocyte
absolute reticulocyte count is normal or slightly elevated

15. Laboratory features (2)
Hypoferremia & decreased serum transferrin
Increased serum ferritin
Increased soluble transferrin receptor (sTfR) levels
Elevated hepcidin level

16. Distribution of serum ferritin measurements in patients with iron-deficiency anemia (IDA), ACD
Iron deficiency should be suspected if ferritin <60 mcg/L

17. Laboratory Studies of Iron Metabolism in IDA & ACD
IDA (n = 48)
AI (n = 58)
COMBI (N=17)
Hemoglobin, g/L
93 ± 16 (96)
102 ± 12 (103)
88 ± 20 (90)
MCV, fL
75 ± 9 (75)
90 ± 7 (91)
78 ± 9 (79)
Iron, μmol/L (10–40)
8 ± 11 (4)
10 ± 6 (9)
6 ± 3 (6)
Transferrin, g/L
(2.1–3.4 m, 2.0–3.1 f)
3.3 ± 0.4 (3.3)
1.9 ± 0.5 (1.8)
2.6 ± 0.6 (2.4)
Transferrin saturation, %
12 ± 17 (5.7)
23 ± 13 (21)
12 ± 7 (8)
Ferritin, μg/L
(15–306 m, 5–103 f)
21 ± 55 (11)
342 ± 385 (195)
87 ± 167 (23)
TfR, mg/L (0.85–3.05)
6.2 ± 3.5 (5.0)
1.8 ± 0.6 (1.8)
5.1 ± 2.0 (4.7)
TfR/log ferritin
6.8 ± 6.5 (5.4)
0.8 ± 0.3 (0.8)
3.8 ± 1.9 (3.2)

18. N Engl J Med 2005;352:1011

19. Differential diagnosis
Drug-induced marrow suppression or drug-induced hemolysis 
Chronic blood loss depletes iron stores and decreases serum iron and serum ferritin but increases transferrin 
Endocrine disorders, including hypothyroidism and hyperthyroidism, testicular failure, and diabetes mellitus
Anemia resulting from metastatic invasion of the marrow by tumors 
Thalassemia minor
Dilutional anemia is seen in pregnancy and in patients with severely increased plasma protein levels as a result of multiple myeloma or macroglobulinemia 

20. Differential diagnosis
Drug-induced marrow suppression or drug-induced hemolysis 
Chronic blood loss depletes iron stores and decreases serum iron and serum ferritin but increases transferrin 
: Once this issue is addressed, a successful trial of iron repletion confirms the
diagnosis of iron deficiency complicating AI or anemia of CKD.
Endocrine disorders, including hypothyroidism and hyperthyroidism, testicular failure, and diabetes mellitus
Anemia resulting from metastatic invasion of the marrow by tumors 
Thalassemia minor
Dilutional anemia is seen in pregnancy and in patients with severely increased plasma protein levels as a result of multiple myeloma or macroglobulinemia 

21. Differential diagnosis
Drug-induced marrow suppression or drug-induced hemolysis 
Chronic blood loss depletes iron stores and decreases serum iron and serum ferritin but increases transferrin 
Endocrine disorders, including hypothyroidism and hyperthyroidism, testicular failure, and diabetes mellitus
: serum iron should be normal in these disorders.
Anemia resulting from metastatic invasion of the marrow by tumors 
Thalassemia minor
Dilutional anemia is seen in pregnancy and in patients with severely increased plasma protein levels as a result of multiple myeloma or macroglobulinemia 

22. Differential diagnosis
Drug-induced marrow suppression or drug-induced hemolysis 
Chronic blood loss depletes iron stores and decreases serum iron and serum ferritin but increases transferrin 
Endocrine disorders, including hypothyroidism and hyperthyroidism, testicular failure, and diabetes mellitus
Anemia resulting from metastatic invasion of the marrow by tumors 
: normal or increased serum iron
  : PBS- poikilocytes, teardrop-shaped red cells, normoblasts, or immature
myeloid cells
: Direct marrow examination is necessary to establish the diagnosis.
Thalassemia minor
Dilutional anemia is seen in pregnancy and in patients with severely increased plasma protein levels as a result of multiple myeloma or macroglobulinemia 

23. Differential diagnosis
Drug-induced marrow suppression or drug-induced hemolysis 
Chronic blood loss depletes iron stores and decreases serum iron and serum ferritin but increases transferrin 
Endocrine disorders, including hypothyroidism and hyperthyroidism, testicular failure, and diabetes mellitus
Anemia resulting from metastatic invasion of the marrow by tumors 
Thalassemia minor
: microcytosis is a life-long condition and usually is more severe in this
group of disorders than in AI.
Dilutional anemia is seen in pregnancy and in patients with severely increased plasma protein levels as a result of multiple myeloma or macroglobulinemia 

24. Before treatment
rule out reversible and potentially more threatening causes, such as occult hemorrhage; iron, vitamin B12, and folate deficiencies; hemolysis; and drug reaction
effective treatment of the underlying disease resolves the anemia
If treatment of the underlying disease is not effective and the patient has symptoms or medical complications attributable to anemia, one or more of the available anemia-specific treatment modalities should be considered 

25. Treatment (1) Transfusion Erythropoietin Iron (oral or parenteral)
Modality
Indications
Typical Setting
Transfusion
•Cardiac ischemia
•Lack of response to other modalities
•Hgb <10 g/dL
•Chest pain and electrocardiogram
changes
Erythropoietin
•Fatigue, exertional intolerance
•Anemia symptoms
•Balance against side effects in Hgb
10–12 g/dL
Iron (oral or parenteral)
•Coexisting iron deficiency
Resistance to erythropoietin
(investigational)
•Suspected or documented iron
deficiency

26. Treatment (2) Transfusion Erythropoietin Iron (oral or parenteral)
Modality
Risk and Side Effects
Specific Benefits
Transfusion
•Infections
•Volume overload
•Transfusion reaction
•Rapid correction of anemia
Erythropoietin
•Response takes several weeks
•Rare red cell aplasia with some forms
of erythropoietin
•May worsen outcome in some
cancers
•Increased thromboembolic events
•Expensive
•Usually well tolerated, relatively safe
Iron (oral or parenteral)
•Gastrointestinal side effects (oral)
•Systemic and local reactions
•May decrease resistance to
infections?
•Inexpensive, relatively safe

27. Erythropoietin Erythropoietin-α Erythropoietin-β Darbepoetin-α
: 탄수화물 체인에 있는 시알산(sialic acid)에 의해 간에서의 대사가 지연되어
작용지속시간이 긴 특징
Methoxy polyethylene glycol-epoetin-β
: 월 1회 투여 가능
동일한 아미노산 배열을 가지고 당 사슬의 탄수화물 구성성분
이 다르나 약효 면에서는 유사

28. 경청해 주셔서 감사합니다.