Download Anemia of Inflammation

Anemia of chronic disease
2017.3.5
혈액종양내과 이정옥
Definitions (1)
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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
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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
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Anemia of Inflammation (AI)
include not only ACD, but anemia of critical illness, a condition that
develops within days of the onset of illness
Definitions (2)
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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
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Anemia of CKD
• presents similarly to AI
• relative EPO deficiency
• systemic inflammation, true iron deficiency, ↓clearance of hepcidin
Relationship between hematocrit (Hct) and
creatinine clearance in patients with CKD
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
Pathogenesis
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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
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 hostderived antibodies or complement contribute to this process is unknown.
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Suppressive effects of inflammation on erythropoietic precursors
Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability
Pathogenesis
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Red cell destruction
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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
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Inadequate erythropoietin secretion and resistance to erythropoietin
Erythropoiesis restriction as a result of iron unavailability
Pathogenesis
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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
Pathogenesis
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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
Erythropoiesis restriction
as a result of iron unavailability
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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
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.
hepcidin inhibits iron flow into the
plasma transferrin compartment - binding to cell membraneassociated ferroportin
(conduits for iron export)
- inducing ferroportin
internalization and degradation
MΦ recycling of senescent erythrocytes
+ hepatocyte iron stores
N Engl J Med 2005;352:1011
Laboratory features (1)
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MCV/MCH
usually normocytic and normochromic but,
with increasing severity or duration, can sometimes become hypochromic
and eventually microcytic
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Reticulocyte
absolute reticulocyte count is normal or slightly elevated
Laboratory features (2)
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Hypoferremia & decreased serum transferrin
Increased serum ferritin
Increased soluble transferrin receptor (sTfR) levels
Elevated hepcidin level
Distribution of serum ferritin measurements in
patients with iron-deficiency anemia (IDA), ACD
Iron deficiency should be
suspected if ferritin <60 mcg/L
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)
N Engl J Med 2005;352:1011
Differential diagnosis
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Drug-induced marrow suppression or drug-induced hemolysis
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Chronic blood loss depletes iron stores and decreases serum iron and
serum ferritin but increases transferrin
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Endocrine disorders, including hypothyroidism and hyperthyroidism,
testicular failure, and diabetes mellitus
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Anemia resulting from metastatic invasion of the marrow by tumors
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Thalassemia minor
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Dilutional anemia is seen in pregnancy and in patients with severely
increased plasma protein levels as a result of multiple myeloma or
macroglobulinemia
Differential diagnosis
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Drug-induced marrow suppression or drug-induced hemolysis
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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.
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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
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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.
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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
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.
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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
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
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Thalassemia minor
: microcytosis is a life-long condition and usually is more severe in this
group of disorders than in AI.
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Dilutional anemia is seen in pregnancy and in patients with severely
increased plasma protein levels as a result of multiple myeloma or
macroglobulinemia
Before treatment
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rule out reversible and potentially more threatening causes, such as
occult hemorrhage; iron, vitamin B12, and folate deficiencies; hemolysis;
and drug reaction
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effective treatment of the underlying disease resolves the anemia
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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
Treatment (1)
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
•Hgb <10 g/dL
•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
Treatment (2)
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
Erythropoietin
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Erythropoietin-α
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Erythropoietin-β
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Darbepoetin-α
동일한 아미노산 배열을 가지고 당 사슬의 탄수화물 구성성분
이 다르나 약효 면에서는 유사
: Erythropoietin-α에 탄수화물 체인을 결합시킨 Erythropoietin 유사체
: 탄수화물 체인에 있는 시알산(sialic acid)에 의해 간에서의 대사가 지연되어
작용지속시간이 긴 특징
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Methoxy polyethylene glycol-epoetin-β
: 월 1회 투여 가능
경청해 주셔서 감사합니다.