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ANEMIA OF CHRONIC DISEASE
&ANEMIA OF CANCER
Dr Manal Bessa,
MD Hematology
Alexandria University
ANEMIA
Definition : Decreased RBC mass and HB concentration
Anemia is classified in three groups: (1) Decreased production of red cells, (2) Increased destruction of red cells, (3) Acute blood loss.
Erythrocyte production requires the presence
of bone marrow stem cells, erythropoietin
(EPO), elemental iron, vitamins, cytokines,
and a suitable marrow microenvironment.
Deficiency or unavailability of any of these
key components may lead to the
underproduction of erythrocytes and result in
anemia.
ANEMIA OF CHRONIC DISEASE (ACD)
Classical definition
ACD, or anemia of inflammation, is the
term used to describe the
hypoproliferative anemia seen in response
to systemic illness or inflammation.
ACD is not due to marrow replacement by
tumor, or due to bleeding or hemolysis.
Means RT Jun, Krantz SB. Blood 1992; 80(7): 1639-1647
5
EPIDEMIOLOGY
The ACD is extremely common
Second most prevalent after anemia caused by
iron deficiency.
Most common cause of anemia in hospitalized
patients.
CAUSES OF ACD
PATHOGENESIS
The mechanisms that produce ACD include:
1. Altered iron homeostasis and iron-restricted
erythropoiesis,
2. impaired production of erythropoietin (EPO),
3. blunted marrow erythroid response to EPO,
4. and a diminished pool of EPO-responsive
cells.
ALTERED IRON HOMEOSTASIS
The mechanism of this include retention of iron
within the mononuclear phagocytic system with
subsequent development of hypoferremia, along
with a limited availability of iron for erythroid
progenitor cells.
This diversion of iron traffic is induced by
regulatory effects of pro-inflammatory cytokines
(IL-1,IL-6, TNF-α) on iron (uptake and release by
macrophages) that is mediated via hepcidin.
HEPCIDIN
MASTER REGULATOR OF IRON HOMEOSTASIS
25 AA peptide with antimicrobial potential,
Expression induced by iron in the liver,
Acute phase protein stimulated also by LPS and IL-6
by an iron independent pathway and blocked by TNF-
a.
Hepcidin over-expression leads to iron-deficient
anemia and hepcidin knock-out to iron overload
HEPCIDIN
Mechanism of action:
Hepcidin affects cellular iron homeostasis after
binding to the only known iron export protein
ferroportin, resulting in its degradation and
blockage of iron transfer from monocytes/
macrophages and hepatocytes to the circulation.
Also, Hepcidin inhibits duodenal iron absorption.
Fe3+
Fe2+
Luminal Baso-lateral
Enterocyte
Fe2+ Fe2+
DcytBHeph
DMT1
Tf Fe3+
Fe +
HO-1
Fe2+
HCP-1?
Heme
Fpn1
Fe2+
Hep
h
Tf Fe3+
Fp
n1
Macrophage
Fe2+
HO-1
-
Tf-Fe+3
Inflammation (IL-6, LPS)+Hepcidin
Hepcidin
Tf-Fe+3
-
-+
LiverSlide courtesy of Dr. G. Weiss. Hentze MW, et al. Cell. 2010;142:24-28
Control of Body Iron Homeostasis by Hepcidin
HEPCIDIN-MEDIATED REGULATION OF IRON HOMEOSTASIS.
(A)Increased hepcidin expression by the liver results from inflammatory stimuli. High levels of hepcidin in the bloodstream result in the internalization and degradation of the iron exporter ferroportin. Loss of cell surface ferroportin results in macrophage iron loading, low plasma iron levels, and decreased erythropoiesis due to decreased transferrin-bound iron. The decreased erythropoiesis gives rise to the anemia of chronic disease.
(B) Normal hepcidin levels, in response to iron demand, regulate the level of iron import into plasma, normal transferrin saturation, and normal levels of erythropoiesis.
(C)Hemochromatosis, or iron overload, results from insufficient hepcidin levels, causing increased iron import into plasma, high transferrin saturation, and excess iron deposition in the liver.
HEPCIDIN
Regulation of hepcidin production occurs through recognition of
iron levels and erythropoietic activity.
Thus iron excess stimulates hepcidin production,
Conversely, in iron deficiency, hepcidin production is suppressed,
Similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and
IL-6, and IL-1 has been shown to be a potent inducer of hepcidin
via signal transducer and activator of transcription-3 (STAT-3)
signalling. Parallel processes can be seen in malignant conditions.
The role of hepcidin in the pathogenesis of
human ACD is supported by the finding that:
1. Hepcidin levels are significantly increased in
patients with ACD.
2. Hepcidin level are correlated to iron retention
in monocytes/macrophages.
3. In vivo by the observation that administration
of anti-hepcidin antibodies ameliorates the
therapy of anemia in mice suffering from
brucellosis.
Erythropoietin
• Glycoprotein of 34 kDa
• Produced in kidney and liver; trace amounts in brain
• Stimulates survival and differentiation of erythroid progenitors
PHYSIOLOGY OF ERYTHROPOIETIN
Recombinant
Erythropoietin
THE PHYSIOLOGICAL ROLE OF ERYTHROPOIETIN IN THE HEALTHY
ADULT
Decreased oxygen delivery to the kidneys
Peritubular interstitial cells detect low oxygen levels in the blood
Pro-erythroblasts in red bone marrow mature more
quickly into reticulocytes
More reticulocytes enter circulating blood
Larger number of red blood cells (RBC)in circulation
Increased oxygen delivery to tissues
Return to homeostasis when response brings oxygen delivery to kidneys back to normal
EPO
Peritubular interstitial cells secrete
erythropoietin (EPO) into the blood
Macrophage
+Epo
-Epo
EPO PREVENTS APOPTOSIS OF ERYTHROID PROGENITORS
CFU-E
Regulation of Erythropoietin
Hypoxia Inflammatory (HIF-1 ) cytokines
-+Erythropoietin
Ludwig (1998); Lacombe (1999)HIF-1 = hypoxia-induced factor-1
Hb
leve
l (g/
dL)
Erythropoietin (plasma U)
104103102101
3
12
15
18
6
9
Hillman (1992)
Normal Erythropoietin Productionand Hb Levels
EPO AND ACDREDUCED EPO PRODUCTION
In chronic inflammatory conditions the EPO
response is blunted, leading to inadequate
levels of EPO for the degree of anemia.
This is thought to be mediated via
inflammatory cytokines such as IL-1 and TNF-
α.
However, other studies have shown conflicting
results, so blunted EPO response may not be
universal in ACD
REDUCED ERYTHROID RESPONSIVENESS
In ACD, the proliferation and differentiation of erythroid
progenitor cells is reduced.
Early studies showed that macrophages would suppress
erythroid colony formation in vitro.
Subsequent studies showed this effect to be due to inhibitory
effects of inflammatory cytokines, esp interferon-γ, on
growth of BFU-E and CFU-E, and this effect could be
overcome by addition of high concentrations of EPO to the
culture systems.
Hepcidin itself has an inhibitory effect on erythropoiesis in
vitro at low EPO concentrations .
REDUCED RED CELL SURVIVAL
Early studies suggested that red cell survival is shortened in ACD
(Cartwright, 1966) .
More recently, red cell survival is confirmed to be modestly
shortened in patients with rheumatoid arthritis and anemic
hospital inpatients (Mitlyng et al, 2006) and may be a
contributory factor in ACD.
No direct studies of the mechanisms involved: these may include
increased erythrophagocytosis induced by inflammatory
cytokines and oxidative damage to erythrocytes, causing
reduced
survival.
Effects of inflammation on erythropoiesis and iron metabolism. Key: + = stimulatory effect; - = inhibitory effect;
DIAGNOSTIC ISSUES IN ACD
Typically the anemia is mild to moderate
Normochromic and normocytic (although anemia may
become microcytic as disease progresses)
The reticulocyte count is low, reflecting the
hypoproliferative nature of the anemia.
Inflammation may be inferred from other features of
the such as neutrophilia, monocytosis or
thrombocytosis, and through measurement of non-
specific inflammatory markers, such as CRP or ESR.
Exclusion of IDA is very important in the work-up of patients
with ACD.
Typically, serum iron and transferrin saturation are both
decreased in ACD and iron deficiency, indicating limited iron
supply to the erythron, but transferrin levels are increased in
IDA, whereas in ACD they are normal or decreased.
Measurement of serum ferritin is frequently of little value, as
ferritin is an acute phase protein, and levels will be increased in
inflammation.
The gold standard for assessment of iron stores remains a Perl’s
stained bone marrow aspirate though it is invasive procedure.
NON-INVASIVE TOOLS FOR MEASUREMENT OF IRON SUPPLY.
Serum transferrin receptor (sTFR) and
sTFR/ferritin ratio.
Red cell indices, the reticulocyte haemoglobin
content (CHr) and the percentage
hypochromic red cells (%HYPO).
Hepcidin assays
Growth differentiation factor 15
The transferrin receptor is found on virtually all cells
and at high levels on erythroid progenitors .
sTFR, the truncated fragment of the membrane
receptor, a possible tool for differentiating between
ACD and IDA..
sTFR levels increase in IDA as the availability of iron
for erythropoiesis decreases
Whereas in ACD levels may not differ as transferrin
receptor expression is negatively affected by
inflammatory cytokines.
SERUM TRANSFERRIN RECEPTOR (STFR)
STFR/FERRITIN RATIO.
The ratio of sTFR to the log of the serum
ferritin is a useful tool in the diagnosis of
ACD, and particularly in differentiating ACD
from IDA.
A ratio <1 makes ACD likely, whereas ratios
>2 suggest that iron stores are deficient,
with or without ACD.
HOWEVER,
In practice, interpretation of this assay in
differentiating IDA from ACD has proved more difficult,
and the assay has not been standardized.
RED CELL INDICES
new red cell indices that may be useful in the
evaluation of different forms of anemia. CHr :
1. measure of hemoglobin in the most recently formed erythrocytes, acute evaluation (48 h) of recent BM activity,
2. Useful tool in the detection of early iron deficiency, as well as in monitoring early response to iron therapy
%HYPO:1. indicates the percentage of cells with hemoglobin
content of <280 g/l.2. gives a time-averaged picture for the anemia(20–
120 d)
HEPCIDIN SERUM LEVEL
Elevated level was observed in a variety of inflammatory diseases,e.g RA, IBD, infections, MM, NHL and critical illness.
However, it may not be elevated in patients with co-existent ACD/IDA as the inflammation induced increase in hepcidin production will be opposed by the effects of iron deficiency.
Therefore, hepcidin level be more useful in distinguishing patients with pure ACD from combined ACD and IDA, and this may be of therapeutic value.
Further standardization is probably required before come into routine and widespread clinical
GROWTH DIFFERENTIATION FACTOR 15 (GDF15)
GDF15 is an erythropoiesis derived hormone that
is markedly increased in β-thalassaemia and
congenital dyserythropoietic anemia, and inhibits
hepcidin expression, contributing to the iron
overload seen in these anemias.
Subjects with both ACD and ACD/IDA showed
significantly higher levels of GDF15 than patients
with IDA,
MESSAGE ……
Currently, no uniform peripheral blood laboratory criteria for the reliable diagnosis of ACD .
Therefore, it is necessary to assess several laboratory parameters in making the diagnosis.
Use of laboratory investigations in the differential diagnosis of ACD.
Possible algorithm for the differential diagnosis of IDA, ACD and ACD/IDA (modified from Weiss & Goodnough, 2005, with permission from the Massachusetts Medical Society 2005).
MANAGEMENT OF ACD
Treatment of the underlying inflammatory or malignant process associated with ACD ….. not always be possible
The anemia in ACD is frequently mild, and correction may not always be necessary.
However, correction needed:1. cardiac patient to avoid deleterious effect2. to improve the quality of life3. Improve disease prognosis ???? Debate
Correction of as many contributory factors as possible is also desirable, e.g correction of nutritional deficiencies
BLOOD TRANSFUSION
Pros :1. a simple means of treating patients with
moderate to severe anemia Cons:
1. Risks of viral transmission, iron overload and alloimmunization.
Transfusion should therefore be reserved for patients with severe or life-threatening
anemia in the context of ACD
ERYTHROPOIESIS-STIMULATING AGENTS (ESA)
The rationale for the use of ESA in ACD is based on:
1. blunted EPO response in ACD,
2. lower serum levels of EPO for the observed degree
of anemia,
3. reduced sensitivity of erythroid progenitors to
endogenous EPO in ACD.
4. limited data to suggest that EPO may reverse
cytokine-mediated inhibition of erythropoiesis
ESAS
Several different rHuEPOs are currently available or in development:
Epoetin -α (Procrit; Ortho Biotech, Bridgewater, NJ, USA; Epogen; Amgen, Thousand Oaks, CA,
USA; Eprex; Janssen-Cilag, Cologno Monzese, Milan, Italy),
Epoetin-β (NeoRecormon, F.Hoffmann-La Roche, Basel, Switzerland)
Epoetin-δ, biosimilar epoetins (Retacrit; Hospira, Alemere, the Netherlands; Binocrit; Sandoz
Limited, Frimley, UK; Eporatio; Ratiopharm, Bristol, UK),
Darbepoietin-α (Aranesp; Amgen),
Continuous erythropoietin receptor activator (CERA) (Mircera;
F.Hoffmann-La Roche).
PEGylated synthetic dimeric peptide capable of binding to and
stimulating the EPO receptor, Hematide (Affymax, Palo Alto, CA, USA) is
undergoing clinical trials.
Responses may be reduced in ACD patients
with more with marked inflammation
Or if there is iron deficiency, especially in
patients with IBD,
highlighting both the importance of aiming
treatment at the underlying condition and of
ensuring replenishment of iron stores in
patients who are iron deficient.
FDA RECOMMENDATION OF ESAS
1. Prescribers should use the lowest dose of ESAs that would
gradually increase Hb concentration to a level that would
avoid the need for transfusion
2. Treatment with ESAs might increase the risk of serious
cardiovascular events and death when administered to
produce Hb levels >120 g/l.
3. ESAs should not be used in specific tumor types (breast,
head and neck, NSCLC), nor be administered to patients
with active malignancy not receiving chemo- or
radiotherapy.
IRON THERAPY
Rational based on ,
1. IDA frequently co-exists with ACD
2. functional iron deficiency
Oral iron supplements are often poorly tolerated, and patients
frequently exhibit poor compliance: in addition, high hepcidin
levels, expected to inhibit intestinal iron absorption.
However, oral iron is cheap, widely available, and easy to
administer,
Much of the literature concerning intravenous iron has come
from the field of renal medicine, where the parenteral iron found
to have superior effect, moreover, it improves the responses to
ESAs.
Safety issues also need to be considered when using intravenous
iron, particularly as older preparations.
POSSIBLE FUTURE DIRECTIONS
Anti-hepcidin antibodies
Indirect suppression of hepcidin
Dorsomorphin
Anti-IL-6 receptor antibodies, tocilizumab
Vitamin D.
Pentoxifylline. is a drug with anti-
inflammatory properties, and can suppress
production of TNF-a and IFN-γ.
ANEMIA IN CANCER,FACTS…
Anemia is a frequent finding in cancer patients,
occurring in >40% of cases. And in 90% in
patients treated with chemotherapy.
Anemia exerts a negative influence on the quality
of life.
It may contribute to cancer-induced fatigue.
Anemia has also been identified as an adverse
prognostic factor.
PATHOPHYSIOLOGY
can be grouped into 3 different categories:1. Blood loss2. Increased destruction of red blood cells3. Decreased production of functional red
blood cells.
ANEMIA IN CANCER PATIENTS, CAUSES Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Shortenedsurvival
FACTORS INVOLVED IN THE CAUSE AND DEVELOPMENT OF ANEMIA IN CANCER PATIENTS
Tumour cells
RBCs
Activatedimmune system
MacrophagesTNF
Anaemia
IFN-a,bIFN-gIFN-gIL-1IL-1IL-1TNFTNFTNF
a1-antitrypsin
ReducedImpairedSuppressedEPOironBFU-e
productionutilisationCFU-e
Nowrousian MR. Med Oncol 1998;15(Suppl. 1):S19–28
Erythrophagocytosis
Dyserythropoiesis
TNF = tumour necrosis factor; IFN = interferon; IL-1 = interleukin-1;BFU-e = erythroid burst-forming unit; CFU-e = erythroid colony-forming unit
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
BONE MARROW INVOLVEMENT
Follicular lymphoma
Neuroblastoma
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
PURE RED CELL APLASIA
In lymphoma, NSCLC, breast and gastric cancer.
Humoral and cellular events suppression of erythropoiesis.
Therapy of underlying cancer response in 30-50%
For others, may need immunosuppressive / cytotoxic therapy.
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Microangiopathic Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
ANEMIA IN CANCER PATIENTS Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
CONCLUSION:
ACD is common and contribute to morbidity for
millions of patients world wide
Marked expansion in our understanding of the
pathogenesis of ACD, particularly in the key role
played by hepcidin in mediating the functional iron
deficiency occurred .
Diagnostic tests should be done to differentiate ACD
and IDA.
Treatment of the underlying disease , ESAs and iron
supplement are the main stay of management.