anemia in chronic disease and cancer

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.