Anemia of chronic disease

Normocytic/normochromic anemia to mildly hypochromic/microcytic anemia of variable severity associated with acute and chronic infections of many types. These include: Chronic inflammatory disorders (especially connective tissue) and autoimmune disorders: rheumatoid arthritis, systemic lupus erythematosus, inflammatory intestinal tract disorder ali!nancy "ypometabolic states (thyroid or pituitary disorders) #enal insufficiency Chronic re$ection of solid%or!an transplants
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&atophysiolo!y
'ive basic processes involved in AC( Inflammatory cytokines: )nflammatory cyto*ines appear to play a central role in the anemia of chronic disease, particularly )+% ,, TN', and the interferons . All of these suppress erythropoiesis by the marrow and may also decrease erythropoietin production by the *idney. Decreased erythrocyte survival: There is usually a modest decrease in #-C survival. &art of this may be due to the deposition of immune comple.es on erythrocytes, leadin! to pha!ocytosis by macropha!es of the reticuloendothelial system.
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 Decreased erythro oietin roduction: /rythropoietin production by the *idneys is impaired. /rythropoietin levels are usually increased but less than anticipated for the de!ree of anemia. Decreased marro! res onse: The marrow fails to respond appropriately to the anemia. This may be due in part to decreased erythropoietin levels, but the marrow response to erythropoietin also appears to be blunted. "lockage in iron transfer: &atients with anemia of chronic disease usually have ade0uate or increased iron stores, unless the primary illness also causes blood loss or there is some other condition causin! iron deficiency."owever, the serum iron is decreased, and transfer of iron to developin! erythrocytes is bloc*ed.
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&ato!enesis
hypoferremia, hyperferritinemia, decreased delivery of iron to developin! erythrocytes, and se0uestration of iron in stora!e cells . mediated lar!ely by the effects of hepcidin, 1pre!ulation of hepcidin synthesis mediated by )+%2 and the )+%2/hepcidin se0uence accounts for the ferro*inetic abnormalities AC(. the e.pression of transferrin receptors on the surface of erythroid precursors and the rate of iron transported into developin! erythrocytes is partly re!ulated by erythropoietin$
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 Thus, in patients with impaired renal function or decreased renal mass, decreased production of erythropoietin may contribute to anemia due to decreased erythropoietin bindin! to receptors on C'1, -'1%/ and C'1%/, which are precursors of erythropoiesis. Alto!ether, these abnormalities result in functional )( of developin! erythroid cells3. TN', )+%,, and 4% and 5%interferon from T%lymphocytes also decrease erythropoietin production in many conditions associated with anemia of chronic disorders.

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 reflects deran!ed iron metabolism produced by a host of conditions that include infections such as tuberculosis, autoimmune disorders such as rheumatoid arthritis, and cancers. AC( is characteri6ed by abnormal iron distribution, decreased red cell life span, and impaired erythropoietin response. AC( is the second most common anemia The characteristic combination of decreased serum iron, decreased serum transferrin!, and normal or increased serum ferritin distin!uishes it from )(A.
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 AC( is not a sin!le entity but a collection of syndromes that fracture the iron metabolism support networ*. The primary location of the rent in the net, its e.tent, and ultimate impact on iron metabolism vary dependin! on the nature of the primary process.

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 A basic phenomenon in the pathophysiolo!y of AC( is iron redistribution into macropha!e stores and reduced iron availability for hemo!lobin synthesis. This iron redistribution is reflected by a reduced serum iron concentration . A decrease in the serum iron concentration causes the iron saturation of transferrin to decrease in both AC( and )(A. Althou!h iron saturation of transferrin has become a widely used laboratory measure of iron status, in the dia!nosis of AC(and )(A, it only provides dia!nostic efficiency comparable to that of the C7 value alone
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#/( -+88( C/++ 8#&"8+89: AN( T#A()T)8NA+ C+A;;)')CAT)8N 8' AN/ )A; 8N T"/ -A;); 8' C7
)n AC( peripheral blood cell morpholo!y the elevated /;# can be morpholo!ically visuali6ed as the characteristic rouleau. formation of red blood cells. in neutrophils, which may be hyper!ranular in association with bacterial infections. All in all, traditionally considered to be a normocytic anemia but AC( may well be microcytic the chan!es are nonspecific the definitive dia!nosis must be based on other findin!s and tests.
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ferritin
'erritin macromolecule that consists of a protein shell (apoferritin with <= subunits) and an iron core. )n !eneral, ferritin synthesis and serum concentrations are > as a result of > iron in the reticuloendothelial system. Apoferritin synthesis is induced by iron and it is characteristic for serum ferritin that it reflects the amount of iron stores ran!in! all the way from diminished stores to e.cess of iron. serum ferritin measurements are useful in evaluation of iron deficiency and identification of patients with hemochromatosis or transfusional iron overload.

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 )(A serum ferritin concentrations are ? and in anemic patients the depletion of iron stores can be confirmed by a ferritin concentration that is below a certain limit. The use of conventional reference limits is complicated by the fact that serum ferritin concentration shows a se. difference in the reference ran!es, and it is 0uestionable whether the reference limits are appropriate for dia!nostic purposes
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 )n AC( > in serum ferritin and even if the condition is accompanied by severe iron deficiency, the concentration very seldom falls below <@ A!/+. in these patients, the proper decision limit for dia!nosis of iron depletion is considerably above the conventional lower reference limit (appro.imately ,@B,C A!/+) or the proposed health%related reference limit (<< A!/+)
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 )n the (( between AC( and combined AC( and iron deficiency, the optimal cut%off level for serum ferritin concentration has been estimated to be D =@B2@ A!/+ 8n the basis of meta%analysis, it has been even stated that a !ray 6one e.ists even between ,C and ,@@ A!/+, where iron deficiency can neither be disclosed nor ruled out on the basis of serum ferritin concentration
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Transferin
the transport protein for serum iron. The traditional statement is that the serum transferrin concentration > in )( and is therefore useful in dia!nosis. "owever, when considerin! the (( of )(A and AC(, the situation is complicated because transferrin is a ne!ative acute phase reactant.
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 patients who have AC( and an inflammatory condition have a reduction in transferrin synthesis due to the effects of the inflammatory cyto*ines

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sTf#
The surfaces of all cells e.press transferrin receptors in proportion to their need for iron. A truncated form of the e.tracellular domain of the receptor (serum or soluble transferrin receptor, ;Tf#) is produced by proteolytic cleava!e and is present in the plasma in direct proportion to the number of receptors e.pressed on the surfaces of all body tissues. As functional iron depletion occurs, more receptors appear on cell surfaces. The plasma soluble transferrin receptor level rises concomitantly.

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"ow to rule out coe.istin! )(A

Althou!h pure forms of both may be readily distin!uished, in an important number of cases both diseases coe.ist, ma*in! it difficult to ascertain whether the main cause of the anemia in a !iven patient is iron deficiency, mas*ed by an inflammatory, infectious or de!enerative state, or if the anemia is, in itself, due to this state.
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 whole%body iron status needs to be assessed, but the results of standard measures, such as the acute phase reactant ferritin, total iron% bindin! capacity and serum iron may be affected by the chronic disease state. sTf# is not correlated with inflammatory parameters li*e /;# and C#& sTf# will be elevated only if there is iron deficiency or increased red cell production as in haemolytic anaemia
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sTf#/lo! ferritin inde.

serum ferritin reflects the stora!e iron compartment and sTf# reflects the functional iron compartment, sTf#%' inde. based on these two values, has been su!!ested as a !ood estimate of body iron compared with the sTf#/ferritin ratio The sTf#/lo! ferritin inde. has an even hi!her specificity and sensitivity for )(A in AC( than sTf# alone the nonanemic sta!es of )( are readily detectable usin! this inde.

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 more dia!nostic efficacy than sTf# alone, as a parameter that combines into a ratio serum ferritin that reflects the stora!e iron compartment and sTf# as an indicator of functional iron compartment The sTf#/lo! ferritin ratio (Tf#%' )nde.) has been shown to distin!uish between iron% replete and iron%deplete anemic patients effectively
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 The Tf#%' )nde. can distin!uish stora!e iron depletion (sta!e )) from )(/ (sta!e ))), such that separate decision limits could be derived in the present study: a ratio of ,.E (F@G C), ,.CC to ,.FF) or !reater for stora!e iron depletion and <.< (F@G C), ,.E, to <.CH) or !reater for )(/

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sTf#/ferritin ratio
sTf#/ferritin ratio is inversely proportional to the body iron This ratio would also help in the differentiation of iron deficiency from the anaemia of chronic disease Accordin! to &ettersson et al, a hi!h Tf#/ferritin ratio indicated iron deficiency, with or without inflammation.
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+o! sTfr/ferritin
This ratio was si!nificantly different in each of the reco!ni6ed cate!ories of iron status (e.cept )(A and )(/) and was clearly different in normal, iron deficiency and A) +o!Tf#/'er ratio is a better criterion than either Tf# alone or the so%called Tf#%)nde. for definin! the iron status 1sin! a cut%off level of +o!Tf#/'er ratio I<,CC, non% anaemic children with mar!inal iron status who could not be identified usin! the conventional methods were identified as iron deficient
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 the ratio I<,CC is specific for pure iron deficiency the +o! Tf#/'er ratio J<,CC identifies both A) and combined )(A and A). the ratio clearly distin!uishes pure iron deficiency from A) and combined )(ADA) with a hi!her specificity than the conventional methods but it still cannot distin!uish between A) and combined )(ADA). )n cases of combined )(AD)A, the +o! Tf#/'er ratio will be decreased and will rise to levels dia!nostic of iron deficiency when the inflammation is cleared.
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;8+1-+/ T#AN;'/##)N #/C/&T8# AN( Tf#%' )N(/K )N T"/ ()''/#/NT)A+ ()A9N8;); 8' )(A AN( AC(

Tf# participates in the transport of ironBtransferrin comple.es from the e.tracellular space into the cell. ;mall amounts of Tf# are e.pressed on the surface of virtually every cell but the e.pression is by far most abundant in erythroid precursors in the bone marrow. sTf# is mostly derived from bone marrow erythroblasts, and the concentrations are elevated both by enhanced erythropoiesis and iron deficiency

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 ;oluble Tf# is released by cleava!e of membrane receptors between amino acids ,@@B,@, (Ar!B+ys) $ust above the cell membrane. )n serum, the truncated Tf# e.ists as a comple. with transferrin the predominant form of Tf# in serum is a dimeric Tf# in comple. with transferrin Circulatin! Tf# provides hi!h sensitivity and specificity for the dia!nosis of depleted iron stores provided that hemolysis and hematolo!ical mali!nancies can be e.cluded as causes of anemia

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 Tf# concentrations are not influenced by acute phase responses provides Tf# an essential benefit over the more conventional measurements of iron status. the interpretation of sTf# concentration is easier than that of serum ferritin concentration, because an elevation of Tf# above the upper reference limit indicates iron deficiency while in AC( the values stay within the reference limits )t is therefore important to reali6e that even sli!htly elevated Tf# concentrations have a biolo!ical bac*!round and are related either to iron deficiency or increased rate of erythropoiesis

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 dia!nostic efficiency of serum ferritin and Tf# measurements can be improved by the calculation of the Tf#%' )nde., which is the sTf#/lo! ferritin ratio Tf#%' )nde. has been reported to be useful in detection of functional iron deficiency irrespective of the concurrent iron status and it is also able to define the patients who can be e.pected to benefit from supplemental iron
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+imitation of sTf# ferritin indices

A calculated parameters attention for the proper cutt off (esirable to have both assay from the same manufacturer

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al!orithm for differential dia!nosis of )(A, AC(, and AC( with iron deficiency

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Treatment
the treatment of the underlyin! disease is thus the pivotal approach to treat AC(. "owever, a sufficient treatment of the underlyin! disease is not always possible, particulary in the case of patients with mali!nancies, chronic infections, or autoimmune disorders. Thus, specific therapeutic re!imen are warranted that include the application of transfusions, iron, and human recombinant erythropoietin

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 anta!onists of acute phase proteins such as hepcidin, to the use of cyto*ine/cyto*ine inhibitors such as )+%, receptor anta!onists or inhibitors of TN'%a activity, to the clinical application of modulators of iron homeostasis such as iron chelators that are able to increase endo!enous erythropoietin formation to the therapeutic use of hormones or recombinant !rowth factors such as )+%H or stem cell factor that could stimulate erythroid pro!enitor proliferation.
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&roposed interaction of the host immune response with the reticuloendothelial system, resultin! in decreased circulatin! iron and anemia.

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