1-13-10 Chronic Disease Anemia mechanisms, concepts, example 1. Define the kinetics of the anemias.

The kinetics of a patient without anemia can be summarized as rbc production rbc destruction! Conse"uentl#, anemia in$ol$es an imbalance of this e"uilibrium in either direction, and %b&%ct fall until a new e"uilibrium is reached! The kinetics of anemias are measured b# retic ct, indirect bili, and 'D%! Decreased production( reduced retic ct, reduced indirect bili, reduced 'D% %emol#sis( increased retic ct, increased indirect bili, increased 'D% )neffecti$e er#thropoeisis( reduced retic ct, increased indirect bili, *reatl# increased 'D% Acute blood loss( increased retic ct, low to normal indirect bili, low 'D% +hat can cause decreased production, Thalassemia minor )ron deficienc# anemia Anemias of chronic inflammation/disease (ACD)* 'ead poisonin* and other sideroblastic anemias -bc aplasia .acute or chronic/ 0+hat diseases are considered ACD, 1! chronic infections( *ranulomatous diseases like T1, histoplasmosis, coccidiom#cosis, osteom#elitis, pulmonar# abscess 2! non-infectious inflammation( rheumatoid arthritis, s#stemic lupus er#thematosus .both are autoimmune/, burns, sterile abscesses 3! mali*nanc#( carcinoma, sarcoma 2. Describe the pathophysiology common to the anemias of chronic disease. 1/ increases in pro-inflammator# c#tokines( upre*ulated macropha*es and splenic function .macropha*es in spleen/ lead to erythrophagocytosis! Conse"uence( shortened rbc sur$i$al b# 10-20 da#s, which re"uires a sli*ht increase in er#thropoeisis to maintain balance! )f this tri$ial er#thropoeitic response does not occur, anemia results 2/ fault# iron reutilization( lactoferrin is released b# 345s and binds iron in circulation more a$idl# than transferrin, deli$erin* 6e to macropha*es! %epcidin0 is released b# the li$er .$ia D4T1 upre*ulation/ resultin* in iron retention b# macrapha*es! Downre*ulation of ferroportin leads to decreased iron absorption in the plasma $illous endothelial cells! Conse"uence( di$ersion of iron from the plasma circulation to macropha*e stora*e as ferritin&hemosiderin! The resultin* low serum iron le$els cause decreased er#thropoeisis! 3/ 1lunted 738 response( )'-1 and T56-alpha directl# inhibit 738 m-5A b# releasin* -89:s that destro# 738 producin* cells! Conse"uence( hi*her 738 doses are re"uired to form C6;-7 in cell culture

</ c#tokine inhibition of marrow er#thropoiesis( )65-*amma and )'-1 directl# inhibit C6;-7 colon# *rowth, while T56-alpha is increased in patients with rheumatoid arthritis and is associated with decreased stem cell colon# *rowth .C6;-=4 and 16;-7/ and with anemia! Treatment with an antibod# to T56 impro$es the anemia! Conse"uence( anemia> ?minor features@ common to all ACD( A/ time to de$elop anemia is about 2 months, since there is partial replacement of circulatin* rbc mass B/ anemia fluctuates with disease acti$it# and impro$es with resolution of ACD C/ low 4CD due to fault# ?internal@ 6e2E deficienc# F/ de*ree of anemia and microc#tosis correlate with disease se$erit# *Hepcidin is the principle re*ulator of iron homeostasis! )ts s#nthesis increases with iron loadin*&excess and decreases with iron deficienc#&h#poxia! )t is also increased with inflammation or infection by IL-1 and IL-6! )t acts b# bindin* to ferroportin and inducin* its internalization and de*radation! %epcidin and ferroportin are found in hepatoc#tes, enteroc#tes, and macropha*es .but li$er release is what causes the ACD s#mptoms/! . !dentify the feat"res specific to each gro"p of disorders. Three t#pes of %b s#nthesis defects leadin* to microc#tic anemia( Defect in iron incorporation into heme( iron deficienc#, chronic inflammation, mali*nanc# Defect in protoporph#rin incorporation into heme( sideroblastic anemia Defect in *lobin incorporation into heme( thalassemias Anemia of chronic renal disease( e$ident when renal function is half normal, as measured b# creatinine clearance! 5on-specific inflammation features( altered 6e kinetics, reduced rbc sur$i$al, suppression of er#thropoeisis 9pecific features( $er# ob$ious underproduction of 738, will see renal insufficienc#, deficiencies in 6e, folic acid, protein, and caloriesG will see b"rr cells due to acid p%, responds to recombinant 738 in dose dependent fassion Anemia of chronic li#er disease( 5on-specific inflammation features( altered 6e kinetics, reduced rbc sur$i$al, suppression of er#thropoeisis 9pecific features( increased plasma $olume dilutes rbc mass .will also see ascites/, altered lipid metabolism causes mild macroc#tosis .4CD 10A, 5 F0-100/, h#persplenism&splenome*al# from portal h#pertension, bleedin* from esopha*eal $arices due to acute&chronic 6e deficienc# H!$ infection( 5on-specific inflammation features( altered 6e kinetics, reduced rbc sur$i$al, suppression of er#thropoeisis

9pecific features( 3ure rbc aplasia( caused b# par$o$irus 11H and dru*s .will see inclusion bodies in pronormoblast/ 4#elophthisis .displacement of the marrow into the 31/( caused b# metastasis resultin* in marrow in$asion %l"mbism .lead poisonin*/( in*estion of lead-based paint, automobile exhaust .tetraeth#l lead/, and inhalation from industrial sources 9pecific features( Shortened rbc life span )nhibition of steps in protoporph#rin metabolism includin* delta-aminole$ulinic acid deh#drase, heme s#nthetase .ferrochelatase/, coprophorph#rino*en oxidaseresults in ALA and coproporphyrin in urine -esults in microcytic hypochromic anemia resemblin* thalassemia minor Basophilic stippling due to inhibition of p#rimidien A: nucleotidase 9ide note( basophilic stipplin* is seen in plumbism, beta thalassemia, and sideroblastic anemia Ringed siderblasts in the bone marrow due to inhibition of heme s#nthetase Accumulation in tissues such a brain, bones, *um line( causes abdominal colic, *out, reduction in )I, reduction in *rowth&de$elopment, lead line on J-ra# %regnancy( increase of 20K in rbc mass combined with <AK increase in plasma $olume dilution! 8ccurs mainl# in the 3rd trimester

&. '(plain iron kinetics in chronic inflammation. 9ee obLecti$e 2, fault# iron reutilization ). Disting"ish iron deficient anemia from the anemias of chronic inflammation. '(plain the ser"m iron/!*C and ferritin changes in inflammation #s iron deficiency. )ron deficienc# anemia and ACD both ha$e microcytosis, low serum Fe !, and low saturation! +a#s to distin*uish( +er"m ferritin could be used to distin*uish between the two! %owe$er, ferritin can be ele$ated b# underl#in* disease since it is an acute phase reactant! Direct assessment of ,e2- stores b# 14 biops#( this is the *old standard for dia*nosis of iron deficienc#! +ol"ble ser"m transferrin (.f) receptor( Tf receptor le$el is proportional to the marrow er#throid mass .or M of er#throid precursors/! )n cases of uncomplicated iron deficienc#, Tf *oes up! )n contrast, durin* chronic inflammation Tf receptor le$els drop .due to blunted 738 and c#tokine inhibition/! /. !nterpret the bone marro0 iron stain.