Position statement - Japijapi.org/june_2017/09_ps_icp_anemia_in_metabolic.pdf · 2020-01-30 · 60 fi V 65 fi June 2017 Indian College of Physicians Position Statement on Anemia in

Journal of The Association of Physicians of India ■ Vol. 65 ■ June 201760

Indian College of Physicians Position Statement on Anemia in Metabolic SyndromeManisha Sahay1, Sanjay Kalra2, Mangesh Tiwaskar3, Sujoy Ghosh4, Rajesh Badani5, Ganapathi Bantwal6, AK Das7, Bharti Dhorepatil8, Tarun Jeloka5, Deepak Khandelwal9, Milind Y Nadkar10, Banshi Saboo11, Rakesh Sahay1, AG Unnikrishnan12, Sameer Aggarwal13, Navneet Agrawal14, Sarita Bajaj15, Manash P Baruah16, Manoj Chadha17, Sambit Das18, Puneet Dhamija19, Sandeep Julka20, Prashant Mehta21, Siddharth N Shah22, Balram Sharma23, A Muruganathan24

1Osmania Medical college, Hyderabad, Telangana; 2Bharti Hospital, Karnal, Haryana; 3Asian Heart Institute and Research Centre, Mumbai, Maharashtra; 4IGPGMER, Kolkata, West Bengal; 5Aditya Birla Memorial Hospital, Pune, Maharashtra; 6St Johns Medical College and Hospital, Bengaluru, Karnataka; 7Pondicherry Institute of Medical Sciences, Puducherry; 8Shree Hospital, Pune, Maharashtra; 9Maharaja Agrasen Hospital, Punjabi Bagh, Delhi; 10Seth G.S. Medical College and KEM Hospital, Mumbai, Maharashtra; 11Dia Care - Diabetes Care and Hormone Clinic, Ambawadi, Ahmedabad, Gujarat; 12Chellaram Diabetes Institute, Pune, Maharashtra; 13Post Graduate Institute of Medical Sciences, Rohtak, Haryana; 14Diabetes Obesity and Thyroid Centre, Gwalior, Madhya Pradesh; 15MLN Medical College, Allahabad, India; 16Excel Centre Hospitals, Guwahati, Assam; 17 Hinduja Hospital, Mumbai, Maharashtra; 18Apollo Hospitals, Bhubaneshwar, Orissa; 19AIIMS, Rishikesh, Uttarakhand; 20Radiance - The Hormone Health Clinic, Indore, Madhya Pradesh; 21Asian Hospital, Faridabad, Haryana; 22Bhatia Hospital, Tardeo; 23SMS Medical College and Hospital, Jaipur, Rajasthan; 24Coimbatore, Tamil NaduReceived: 06.05.2017; Accepted: 12.05.2017

P o s i t i o n s t a t e m e n t

Executive SummaryPreamble

• Anemiaiscommoninmetabolicsyndromeanditscomponentdisorders• ManagementofanemiaimprovesoutcomesinmetabolicsyndromeanditscomponentdisordersClinical Presentation

• Anemiaworsensglycemiaanditscomplications• Anemia/iron deficiencyworsens heart failure;may be associatedwith stroke and peripheral vascular

disease;andworsenstheoutcomeofdiabeticfoot• Renalimpairmentcausesanemia,andanemiacontributestoworseningofrenalimpairmentAssociated Conditions

• Anemiaand irondeficiencyarecommon inobesityandnonalcoholic fatty liverdisease (NAFLD). Ironoverloadisequallydetrimental,andhasshowntobeassociatedwithhigherriskofNAFLD.

• Ironoverloadmaybeassociatedwithpolycysticovarysyndrome• AnemiaandironoverloadareriskfactorsfordevelopmentofgestationaldiabetesmellitusTherapeutic Significance

• Anemiamayinterferewithdiagnosticandmonitoringtestsofglycemia• Overcorrectionofanemia (Hb>13g/dl) in renal impairment isassociatedwithadversecardiovascular

outcomes• Certaindrugsusedformanagementofmetabolicconditionsmaycauseanemia*orincreasehematocrit†Screening and Diagnosis

• Allpersonswithmetabolicsyndromeoritscomponentconditionsmustbescreenedforanemia.• Screeningmustincludeclinicalassessment,completebloodcountandperipheralbloodfilm.• Apragmaticclinical,biochemicalandhematologicalworkupshouldprecedemanagementofanemia.

Journal of The Association of Physicians of India ■ Vol. 65 ■ June 2017 61

Summary

ThisIndianCollegeofPhysicians(ICP) position statement on

anemia andmetabolic syndromeprovides c l inical insights andrecommendations on screening,evaluation and management ofanemiawithmetabolic syndromeanditscomponentdisorders.

IntroductionThe metabol ic syndrome is

a cong lomera t i on o f s eve ra li n t e r r e l a t e d r i s k f a c t o r s o fcardiovascular disease and type2 diabetes mellitus (T2DM) thatincludes glucose intolerance orinsulinresistance,increasedbloodpressure,obesityanddyslipidemia.According to the InternationalDiabetes Federat ion ( IDF) , anindividualwithmetabolicsyndromemusthavecentralobesityplusanytwooffouradditionalfactorssuchas raised triglyceride (TG) level(≥150mg/dL),reducedhighdensitylipoprotein(HDL)-cholesterol(<40mg/dL inmen and <50mg/dL inwomen), raised blood pressure(systolic BP ≥130 or diastolic BP≤85 mm Hg) or raised fast ingplasma glucose (≥100 mg/dL orpreviouslydiagnosedT2DM).1Theworldwideprevalenceofmetabolicsyndrome ranges between 10%and 84% and varies based on theethnicity, age and gender; IDFestimates that one-fourth of theworld’s population suffers frommetabolic syndrome.2 In India, itis considered as one of themajor

public health problem and theprevalenceinurbanregionofIndiaranges between 25% and 45%3,4and in rural India, a prevalenceof26.6%(95%CI:24.6–28.8%)hasbeenreported.5Anemia const i tutes another

major g lobal hea l th problem,whichisoftenlinkedwithchronicmetabolic conditions. TheWorldHea l th Organ i za t i on (WHO)defines anemia as a condition inwhichthenumberofredbloodcells(RBC) or their oxygen-carryingcapacity is insufficient to meetphysiologicneedsanditisthoughtto vary by age, gender, altitude,smoking, and pregnancy status.Globally,anemiaaffects1.62billionpeople(95%CI:1.50–1.74billion),whichisapproximatelyone-fourthof the population.6According totherecentNationalFamilyHealthSurvey(NFHS-4for2015-16),morethanhalfthewomenandonefourthof themen across states in Indiaareanemic.7

Anemia is often reported inpatientswithmetabolicsyndrome;however, the coexistence of thesemodifiable risk factors are oftendisregarded.Metabolic syndromeis associated with 5-fold risk ofdeve lop ing d iabe tes mel l i tusand 3- fold r isk of developingcardiovascular disease such asstroke or heart attack and 2-foldrisk of cardiovascular disease-re l a t ed mor ta l i ty . 8 However ,associated anemia can furtheramplify the riskofmorbidityandmortality,andcanadverselyaffect

theoverallqualityoflife.9-11Thus,devising treatment strategies foranemiainpatientswithmetabolicsyndromeisimperativetoimprovethe overall clinical outcome. Thepurposeofthispositionstatementis toprovide clinical insights andevidence-based recommendationsformanaginganemiainmetabolicsyndrome and i t s componentdisorders.

Physiology of Iron Metabolism and HomeostasisTh e ma i n t e n a n c e o f i r o n

homeostasis involves regulationof iron absorption, utilization,t r a n spo r t a t i on , s t o r a g e a ndreut i l izat ion (Figure 1) . 12 Thenonheme iron, available inmanyfood sources, ismainly absorbedfromtheduodenumafterreductiontoferrous(Fe2+)byferrireductasein the enterocytes ; i t i s thentransportedthroughcellmembraneby divalent metal t ransporter1 (DMT1). The cytosolic iron isexported into circulation by theiron exporter ferroportin (Fpn),following oxidation of Fe2+ toferric (Fe3+) by the ferroxidasehephaes t in . The Fe3+ i n theplasma binds to transferrin (Tf )fortransportationanditisacquiredby cells via transferrin receptor(TfR1). Iron from dietary sourcesi s predominant ly u t i l i zed byerythropoietic bonemarrow cellsforerythropoiesis;whiletheexcessortheunusedironinthecirculation

Iron Management

• Variousoralironpreparationswithdifferentpropertiesareavailable.Ferrousascorbateandfumaratearepreferredoptions.

• Newergenerationintravenousironpreparations‡aresafeandeffective.Intravenousironshouldbeusedinsevereanemia,anemiarequiringrapidresponse,andiforalironisfoundto,orexpectedto,beineffective,poorlytolerated,ornotadheredto.

• Irontherapyshouldbemonitoredatregularintervalstoavoidoverload.Adjuvant Management

• Non-pharmacologicalmeasures(diet)mustbeinstitutedtoimprovehemoglobin• Alltreatablecausesofanemia,includingvitaminB12andfolicaciddeficiency,mustbeaddressed.• Irondeficiency should be corrected prior to use of erythropoiesis –stimulating agents (erythropoietin,

darbopoietin),inmanagementofanemiaofchronickidneydisease.*pioglitazone, metformin and renin-angiotensin blockers; †DPP4 inhibitors, SGLT2 inhibitors; ‡iron

carboxymaltose,ironsucrose


isstoredintheliverhepatocytesormacrophages,mainlyintheformofferritin.Anothersourceofironforerythropoiesisisfromreutilizationfrommacrophages, particularlysplenicmacrophages. Iron is alsofoundtobeaccumulatedintissuessuchasheartandpancreasinironoverloaddisorders.A systemic iron homeostasis

i s ma i n t a i n ed b y h ep c i d i n ,a circulating peptide hormonep r edominan t l y p roduced byl iver , in a nega t ive - feedbackmechanism. The hepcidin levelsare regulated in response to ironoverload, inflammation, hypoxia,irondeficiencyanderythropoieticactivity.Typically,hepcidinbindstoironexporterFpnanddecreasestheserumironlevelsbyinhibitingthe iron absorption in duodenalenterocytes and the release frommacrophagesandhepatocytes.12

Anemia and Diabetes MellitusAnemiaisacommonlyobserved

c o nd i t i o n i n p a t i e n t s w i t hdiabetes and it contributes to theprogression of diabetes-relatedcomplications.13Theprevalenceofanemiarangesfrom13%to45%inpatientswithdiabetes,dependingupon theethnicityanddiagnosticcriteriaused14-16anditisespeciallyhighwhen associatedwith renalimpairment.17Inaddition,theriskof anemia increaseswith severityof renal impairment in patientswith diabetes and they aremorelikely to developmacrovascularcomplications.17Itisalsoobservedthat diabetes patients who havepoorglycemiccontrolareathigherriskofanemia(oddsratio:3.71;95%CI:1.09;12.56)thanthosepatientswith good glycemic control, andthe likelihood to develop anemiais evengreater inpatientshavingrenal insufficiency (odds ratio:5.78; 95% CI: 1.34; 24.92).18 Thepathophysiology linking anemiaanddiabetesmellitus(bothtype1andtype2)ismultifaceted(Figure2).

Type 1 diabetes mellitus

Anemiaintype1diabetesmellitus(T1DM) i s ma in ly assoc ia tedwith autoimmune disorders suchas au to immune gas t r i t i s andperniciousanemia.Theprevalenceoftheseautoimmunedisordersis3to5-foldhigher inT1DMpatientsthan in genera l popula t ion . 19Iron deficiency anemia (IDA) isa frequent f inding in patientswithautoimmunegastritis,withaprevalencerangingfrom20%-40%,and i t o f t en deve lops be foreperniciousanemiaorattimesbothmay coexist. Pernicious anemiaduetovitaminB12deficiencymayoccur in 15%-25%of patients anditisconsideredasanend-stageofautoimmune gastritis.19 Patientswith T1DM having autoimmunegastritisharborantibodiestogastricparietal cells. Progressive loss ofH+/K+ATPase containing parietalcells results in decreased gastricacid secretion (hypochlorhydriaor ach lorhydr ia ) , which mayreduce the availability of iron forabsorption, leading to IDA. The

Fig. 1: Influence of metabolic syndrome and its component disorders on iron homeostasis


destruction of intrinsic factor-secretingparietalcellsmayleadtofailureintheproductionofintrinsicfactorandpreventtheformationofthe vitamin B12-intrinsic factorcomplex,causingmalabsorptionofvitaminB12inperniciousanemia.On the other hand,Helicobacter pyloriinfectionsmayplayaroleinthe pathogenesis of autoimmunegastritisandperniciousanemiabyinducingautoantibodiestoparietalcells.19Patientswith T1DMhave been

associated with malabsorptivedisorderlikeceliacdisease,whichis a chronic immune-mediateddisordercharacterizedbymucosalinflammationandvillousatrophydue to dietary gluten intake.20,21I r on de f i c i ency and v i t aminB12 def ic iency are commonlyreported in this condition due toimpairedabsorptionorbloodlossdue to gastrointestinal bleeding.Thyroidi t is i s a lso f requent lyobserved in T1DM patients andalmost20%to60%ofpatientswithhypothyroidism are reported tohave anemia. Inadequate thyroidl eve l s may resu l t in reducedproduction of erythropoietin andsubsequentlyleadstobonemarrowrepression.22

Type 2 diabetes mellitus

Both erythropoietin deficiencyand hyporespons iveness maycontr ibute to ear ly anemia inpatients with diabetes mellitus,particularly those having kidneydisease or even mild decline inrenal function.11,23 Sympatheticdenervat ion of k idney due toautonomicneuropathyandchronichyperg lycemia are impor tantfactors that potentiate hypoxia inthe renal interstitium, leading toimpairederythropoietinproductionby pe r i tubu l a r f i b rob l a s t s . 24Hype rg l y c em i a wo r s en s t h efunct ion of hypoxia- induciblefactor1(HIF-1),akeyregulatoroferythropoietin production duringhypoxia, which is also involvedin vasculogenesis and cellularme t abo l i sm . Reduced a c t i onof HIF-1 may cause interstitialf ibrosis and generate hypoxia,which ult imately decrease theability of peritubular fibroblastt o p r o du c e e r y t h r o p o i e t i n .Severalotherfactorsthatpromote

e ry th ropo i e t in s t r e s s due t ohypoxiaarediabeticnephropathy,neuropathy,chronicinflammation,increased advanced glycated endproducts , use o f ant id iabet i cmed i ca t i ons l i k e me t fo rmin ,and tes tosterone def ic iency. 24Additional contributing factorsincludedecreasedlifespanofRBC,abnormal RBC and occult bloodloss.I nadequa t e e ry th ropo i e t i n

responseislinkedtoerythropoietindeficiency, reduced functionale r y t h r o p o i e t i n , i n c r e a s e dglycosylation, and erythropoietinresistance due to glycat ion oferythropoietin receptors. Thesefactorsmayinturncausehypoxiaand lead to overstimulation andproductionoferythropoietin,whichmayultimatelyresultinapoptosisofperitubularcells.Increasedlevelsof pro-inflammatory cytokinessuch as interleukin (IL)-1, IL-6,tumor necrosis factor (TNF-α),transforminggrowthfactor(TGF-β)andinterferons(IFNs)alsocausesapoptosis of erythroid progenitorc e l l s . M o r e o v e r , a d va n c e dg l y c a t i on end p roduc t s andchronichyperglycemiamayreducedeformabi l i ty and l i fespan oferythrocytesandcausesreductioninhemoglobin(Hb)levels.24

A d d i t i o n a l l y , t h ed ipep ty lpep t ida se - 4 (DPP -4 )enzyme has been found to beinvolved in the hematopoiesis,by regulating hematopoietic stemcells, hematopoietic progenitorcells and supportive cells of bonemarrow throughmodification ofcertaincytokines,chemokines,andgrowth-modulating factors.25 Inpresence of a pathophysiologicalstate or modified physiologicalhomeostasis , a l terat ion in thefunc t iona l ac t iv i ty o f co lonystimulatingfactors,erythropoietinand IL-3by theDPP-4mayaffectthehematopoiesis.25,26

IDA is anothermajor cause ofanemia in CKD and may occurin patientswith diabetesmellitusdue to restricted dietary intake,impaired iron absorpt ion andincreased loss of blood due togastrointestinalbleeding.Impairediron absorption is probably dueto the increased level of hepcidinin response to inflammation. In

pat ients with diabet ic k idneydisease, hemodialysis procedure,uremia-related gastrointestinalulcers are the common causes ofanemia secondary to blood loss.Hemolyticanemiaduetoglucose-6 - pho spha t e d ehyd rog ena s e(G6PD) deficiency is also beenassociated with T2DM patients,especiallyinAfrican,ChineseandIndian populations. In a diabeticstate, reduced activity of G6PDresults from phosphorylation ofG6PDthroughactivationofproteinkinaseA.27

T h i a m i n e r e s p o n s i v emega lob la t i c anemia (TRMA)o the rwi se known a s Roge r ’ ssyndrome,isanautosomalrecessivedisorder, usually associatedwithear ly onset diabetes mel l i tus ,anemiaanddeafness.ItoccursduetomutationsinthegeneSLC19A2encoding thiamine transporterprotein. The resulting ineffectiveresponse of thiamine in severaltissues, including pancreatic βcells,causesdiabetesmellitus.Theonsetofanemiaisusuallybetweeninfancy and adolescence.28 TRMAis rareoutsideof consanguineouspairings and few caseshavebeenreported in countr ies such asBrazil,Japan,Italy,Iran,OmanandPakistanandinethnicpopulationssuch as Israeli Arab, Lebanese,AfricanAmericans, andKashmirifamiliesinGreatBritain.

Anemia and Diabetes-Related Microvascular ComplicationsDiabetic Nephropathy

The risk of developing anemiain patientswith diabetesmellitushaving associated kidney diseaseis2to10-foldgreaterthaninthosepatients having kidney diseaseof other causes.11 In addition, theonsetofanemiaisearlierandtendtobemoresevereinpatientswithdiabetickidneydiseasethaninthosehaving similar degree of kidneydiseasewithoutdiabetes.29Anemiacaused due to diabetic kidneydisease can further accelerate theprogression of kidney disease ina viciousmanner.23 There are noevidencesofdirectactionofanemiaindiabeticnephropathy,however,


hypoxia and ox idat ive s t ressarisingfromanemiatogetherwithreducederythropoietinproductionare the mechanisms involvedin the microvascular damage inkidney,resultinginend-stagerenaldisease.Additionally, increase inrenal sympathetic nerve activitydue to anemia may resu l t inincreased glomerular pressureand proteinuria, which furtherintensif ies the worsening.23 Inpatientswithdiabeteshavingearlystagesofkidneydisease,anincreasein i ron excret ion is observed.Urinary loss of transferrin anderythropoietin usually occurs innephroticsyndromeandresultsinironanderythropoietindeficiency.Thereisalsoincreasedtransferrinc a t a b o l i s m a n d d e c r e a s e derythropoietin production andresponse, which contributes toanemia.11

Diabetic Retinopathy

PatientswithlowlevelsofHb(<12g/dL)aretwiceaslikelytodevelopdiabetic retinopathy; however,the propensity increaseswith theseverity of anemia, particularlywhenthelevelsofHbdropbelow6g/dL.LowHb isalsoassociatedwith a 5-fold risk of proliferativeretinopathy.30,31Thecommonocularmanifestations related to anemiaare conjunctival pallor, retinalhemorrhages,venousandarteriolartortuosity,cottonwoolspots,andpapilledema.32Retinalhypoxiaduetoreducedcapillarybloodflowandcapillary occlusion, is consideredas a crucial component involvedinthepathogenesisofretinopathy.I t promotes the production ofva s cu l a r endo the l i a l g rowthfactor and stimulates vascularpermeability, neovascularization,r e t i n a l e d ema a nd e x ud a t eformation.23 Erythropoietic stressdue to diabetic kidney diseaseis also known to be associatedwith the progression of diabeticretinopathy.33Diabetic neuropathy

Anemia is common in patientswith neuropathy, particularly inthose having autonomic failure.Diabetic autonomic neuropathycan cause anemia and decreasein erythropoie t in leve ls evenwhen the kidney functions have

no t de t e r i o r a t ed . Anemia i near ly diabet ic nephropathy iscausedmainly due to ineffectiveresponse of erythropoietin to lowHb levels because of impairedsensingmechanismassociatedwithdiabetic autonomic neuropathy.Furthermore, in these patients,lossofappropriateerythropoietinproductioniscausedduetoefferentsympathetic denervation of thekidney.34

Diabetic foot ulcers

Anemia has been reported inabout49%to60%ofpatientswithdiabetic foot ulcers.35,36 Patientswi th anemia are a t increasedrisk of diabetic foot ulcer-relatedlower extremity amputat ions ,subsequenthighlevelamputationsand prolonged hospital izationfollowingsurgery.35,37,38Itisknowntoworsen the ischemic state anddelay the wound healing due toreducedoxygenavailability,whichresultsfromlowHblevels,reducedcapillary blood flow, increasedb lood v i s cos i ty and reducedperipheral perfusion.23 ImpairedH IF - 1 f un c t i on and ch r on i cinf lammation also contributesto the delayedwound healing indiabeticfootulcers.39

Anemia and its Influence on Glycated HemoglobinThe g l y c a t ed h emog l o b i n

(HbA1c) is a widely acceptedindicator of long-term glycemiclevelsanditisusedformonitoringthe glycemic changes in responsetodietandmedicationinadditionto diagnosing diabetesmellitus.40However , the use of this tooli s l imi t ed in ce r t a in c l in i ca lcondit ions that may inf luencethe factors involved in HbA1cmeasurement.Any condition thatincreases the erythrocyte survivalor decreases the RBC turnoverresults in erroneously elevatedHbA1c – eg. IDA, vitamin B12deficiency and asplenia.41,42 AnelevatedHbA1cisalsoobservedinclinical scenarios such as uremia,s eve r e hype r t r i g l y c e r id emia(>1750mg/dL),hyperbilirubinemia(>20mg/dL) and chronic alcoholc o n s ump t i o n d u e t o o t h e rmechanisms. The conditions thatare associated with decreased

erythrocyte survival or increasedRBC turnover results in lowerHbA1c levels – eg. anemia dueto acute or chronic blood loss,hemolyticanemia,chronicanemiaassociated with end-stage renaldisease, and use of vitamin E,ribavirin,andinterferon-alpha.41,43Duringpregnancy,uptothesecondtrimester,HbA1clevelsarefalselyloweredandhenceitislessreliablefor diagnosing or monitor inggestationaldiabetes.44,45TheHbA1cmeasurement is also unreliablein pa t i en ts wi th Hb var iants(hemoglobinopathies).46,47 Thereare several variants identif iedworldwide, however, the mostcommon are HbS and HbC. Themost prevalent variant in South-eastAsiancountries isHbE.48ThelevelsofHbA1cmaybefalselyhighor lowdependingupon the assaymethodused.46In these cl inical condit ions,

a l t e r n a t i v e t o o l s l i k efructosamine, glycated albumin,1,5-anhydroglucitrol (1,5-AG) canbe utilized to measure glycemicstatus.49 The continuous glucosemonitoring can be used as anadjunctinmeasuringtheglycemiclevels.Fructosamineandglycatedalbuminmayindicatetheaverageglycemic level over 2 to 3weeks.However, in patients with lowlevelsofserumproteinoralbumin(nephrotic syndrome or severeliver disease), fructosamine assaymaynotberecommended.Plasma1,5-AGmay reflect the averageglycemic levels over 48 hours to2weeksandcanbeusedtodetectpost-prandial hyperglycemia andglycemic variability. However,the results should be interpretedwith caut ion in pat ients withkidney disease and gestationaldiabetes.45 Thus, in renal failurepatients, HbA1c assessed usingthiobarbituricacidmethodisusefulasitismorelikelytoreflectaccuratelevels.50Ingestationdiabetes,75gor 100 g oral glucose tolerancetest(OGTT)canbeconsideredforscreeningordiagnosis.51

Anemia and Cardiovascular DiseaseAnemia is commonly observed

in patients with cardiovascular


d i s e a s e s u ch a s myo c a rd i a li n f a r c t i on , s t r oke and hea r tfailure.52-54Nearly10%-20%patientswi th coronary ar tery d i sease(CAD)55andone-thirdofthosewithcongestiveheartfailure(CHF)haveanemia.56,57Thepresenceofanemiacanworsen cardiac complicationsand is often correlatedwith pooroutcomes, including increasedhospitalizationrateandmortality,decreased physical function, andpoorqualityoflife.58

Congestive Heart Failure

The p r eva l ence o f anemiaincreases with severity of heartfailure(basedonNewYorkHeartAssociation [NYHA] functionalclassification)andwiththepresenceofchronickidneydisease.59,60Factorsthat lead to the development ofanemiainheartfailureencompasscomorbid chronic kidney disease,d im i n i s h e d e r y t h r o p o i e t i nproduction,hemodilution,aspirin-inducedgastrointestinalbloodloss,cytokine-mediated inflammation,gutmalabsorption,irondeficiency,reducedglomerular filtrationrateand plasma flow, decreased bonemarrow perfus ion and use ofangiotensinreceptorblockersand(ACE)inhibitors.59

Conversely, anemia can alsoaggravate the progress ion o fheart failure.Tissuehypoxiawithrelease of nitrous oxide causesarterialvasodilationanddecreasedperipheral vascular resistance.This in turn causes act ivat ionof sympathetic system, causingincreased heart rate and strokevolume, and reduced renal bloodflowandglomerularfiltrationrate.These changes trigger the renin–angiotensin system (RAAS) alongwithantidiuretichormone,causingfluid retention, increased plasmavolume and ultimately culminatein left ventricular hypertrophyand dilation, and worsening ofheart fai lure. 61 Cardiovascularremodelingisalsolinkedtoalteredactivity of sympathetic nervoussystemandRAAS,alongwiththeerythropoietindeficiency.59

Stroke

Various types of anemia havebeen associated with increasedr i sk for i schemic s t roke , andincreased mortality. In a recent

meta-analysis, a prevalence rateof nearly 22% of anemia amongstroke patientswas reported.62Asignificantly higher risk of strokewas observed in patients withchronickidneydisease,particularlyinthepresenceofanemia,63whichmaybeattributable to thedeclinein e ry thropoie t in product ionin conjunction with creatinineclearance.64,65Anemiamayinducehyperkinetic

state and influence endothelialadhesionmolecule genes, whichmay cause thrombus formation.Turbulenceandriseinbloodflowmayleadtomigrationofthrombusa n d c a u s e a r t e r y - t o - a r t e r yembolism. The IDA can result insecondaryreactivethrombocytosis.In addition, impaired erythrocytedeformability, through changesin oxygen capacity or blood flowabnormalities, may reduce tissueoxygen de l ive ry . In hypox i cstate, endothelial dysfunction viainflammatory pathway can causeischemic brain t issue damage.InflammatorymarkerssuchasIL-6,TNF-α andC-reactive protein arealsoelevatedinanemicpatientsandcouldpossiblyimpacttheprognosisafter stroke. In addition to thesemechanism,anemiaassociatedwithacute bleeding can increase theriskofthrombusformationduetoincreasedplateletadhesivenessanddecreasedfibrinolyticactivity.66,67

Anticoagulantsandantiplateletdrugs used for management ofs t roke may a l so cause occul tgastrointestinal bleeding leadingto IDA.Thus, timely interventionandquick treatmentdecisions forstroke patients with anemia areconsidered crucial to reduce therisk of life-threatening adverseoutcomes.62

Anemia and Peripheral Vascular DiseaseIn pat ients with per ipheral

artery disease (PAD), anemia isassociatedwith an increased riskofacutemyocardialinfarctionanditisconsideredasanindependentrisk factor for mortality or limbampu t a t i o n i n h o sp i t a l i z e dpatients.Inamulticentreregistry,anemiawasfoundtobepresentinalmost50%ofpatientshospitalized

for PAD. These patients also hadcomorbidities such as diabetes,CAD, CHF and chronic kidneydisease.68 Chronic anemia mayexacerbate lower limb ischemiaduedecreasedsupplyorincreaseddemand for oxygen, particularlyin patientswith underlying CHForCAD. In addition, vitaminB12deficiencyand increased levelsofproinflammatory cytokines mayhavearoleinlimbischemia.68,69

Role of Medications in AnemiaU s e o f c e r t a i n a n t i -

hyperglycemicagents(AHAs)likemetforminandthiazolidinediones,andantihypertensivemedicationslikeangiotensin receptorblockers(ARBs)andangiotensinconvertinge n z y m e ( A C E ) i n h i b i t o r sare associated with the risk ofdeveloping anemia. Long-termuse of metformin is known tocausemegaloblasticanemiaduetoalterationsinsmallbowelmotility,which can s t imulate bacter ia lovergrowth,competitiveinhibitionor inactivation of B12 absorption,a l tera t ions in in tr ins ic fac torlevels,interactionwiththecubilinendocytic receptor and inhibitionof calcium-dependent absorptionof the vitamin B12-IF complex attheterminalileum.70Typically,theclinicalsymptomsbecomeevidentaf ter 5-10 years of t reatment ,depending upon the metformindose , bu t the impa i rment o fvitaminB12absorptionmaybeginwithinfourmonthsaftertreatmentinitiation.71Thiazolidinedioneusemayresult inanemiadueto fluidretention, and fat accumulationin thebonemarrow.72 In fewcasestudies,useofsulphonylureashavebeen associated with haemolyticanemia . 73 ,74 Use o f ARBs andACE inhibitors may precipitateanemia by direct b lockade ofthe pro-erythropoietic effects ofangiotensinIIonredcellprecursors,degradat ion o f phys io log ica linhibitors of hematopoiesis andsuppressionofinsulin-likegrowthfactor(IGF)-I.75-77

Interestingly, use of certainAHAs like DPP-4 inhibitors andsodium glucose co-transportertype 2 (SGLT2) inhibitors have


beenidentifiedtoshowbeneficialeffects in anemia.78-80 It has beenspeculated that DPP4 inhibitorsmay enhance the erythropoietinlevels through anti-inflammatoryac t ion , improvement in bonemarrow function, and inhibitionof impaired activity of DPP4 onerythropoietin.79 Certain DPP-4inhibitorshavebeenassociatedwithreductioninthedoserequirementof erythropoie t in s t imulat ingagents (ESA) in T2DM patientsundergoing hemodialysis.80,81 TheSGLT2 inhibitors, through theirrenoprotective effects, have beenfoundtoenhancetheerythropoietinproduct ion by improving thetubulointerst i t ial hypoxia andoxidative stress. It improves thereticulocyte count, followed byincrease in Hb and hematocritlevels.78

Anemia and ObesityIron deficiency and IDA are

the common observations in bothmenandwomenatvariousstagesof obesity.82 Several studies havereported low serum iron levelsand serum transferrin saturationpercentages (TSAT) in patientswith high BMI compared withpatientshavinglowBMI.83Besidespoor nutrition and increased ironrequirement, high prevalence ofirondeficiencyinobesepatientsismainlyattributedtoreduceddietaryiron absorption from duodenumdue to increased hepcidin level.I n c r e a s e d h e p a t i c h e p c i d i nproduction is primarily inducedbyinflammatorycytokinesduetochronic low-grade inflammationin obese condition.83 In addition,visceralandsubcutaneousadiposet i s su e s i n ob e s i t y may a l s osecrete hepcidin and contributeto the c irculat ing levels . Pro-inflammatorycytokinessuchasIL-6andTNF-αsecreted fromadiposetissuesarealsoknowntointerferewitherythropoietinproductionandimpair the response of erythroidprecursors,thuscausinganemiainobesepatients.84

Bariatricsurgeriesareindicatedinmorbidlyobesepatients,butoftenresultsindiminishedabsorptionofnutrients from intestine, reducedgastricacidsecretionor intestinal

b l e e d i n g . 8 5 T h e c ommo n l yperformed procedures such asRoux-en Y gastric bypass (RYGB)surgery,adjustablegastricbanding,andsleevegastrostomyare foundtobeassociatedwith incidenceofirondeficiencyorIDA.82

Anemia and Non-Alcoholic Fatty Liver DiseaseNon-alcoholicfattyliverdisease

(NAFLD) is a common disorderamong patients with metabolicdisorders such as obesity andT2DM and it is known to affectironhomeostasisinamultifariousmanner.Ithasbeenobservedthatapproximately one third of adultNAFLDpatientswereirondeficient(defined by TSAT <20%) due toincreased hepcidin levels in thepresenceofobesity-relatedchronicinflammation.86Anotherone-thirdo f NAFLD p a t i e n t s h a v i n gmetabolic syndrome componentsis associated with iron overloadcondition, called dysmetaboliciron overload syndrome (DIOS),which is characterised by normalTSAT l eve l bu t h igh f e r r i t inlevels.87,88 Themechanism of ironoverload inNAFLD isnot clearlyestablished, however, it has beenhypothesizedthat irondepositionmight result from impaired ironexpor t f rom hepatocytes andmesenchymalKupffercellsduetodownregulation of Fpn 1, whichis cause by low-grade systemicin f lammat ion . In response tointrahepatic iron accumulation,hepcidin production is increased,resulting in decreased duodenalexpression of Fpn 1. However,decreased l iver express ion ofFpn 1 continues to retain hepaticiron.89 In addition, low copperbioavailability contributes to ironaccumulationinNAFLD.Elevatedlevelsofhepcidin inurine,serumandliverwereobservedinpatientswithNALFDhavingDIOSthaninnormal individuals, patientswithNAFLDwithout iron overload orpatientswithhemochromatosis.90,91Although there is an increasedleve ls o f hepc idin , i t may beineffective for iron regulation.92Interestingly,inNAFLDassociatedwithobesity,both irondeficiencyand DIOS are associated with

increased hepcidin concentration,whichisassociatedwithdecreasediron absorption from duodenumand impaired iron transport fromthe reticuloendothelial system tobonemarrow. InDIOS, increasedhepcidin concentrat ion is dueto increased hepatic iron stores,howeve r i n i r on de f i c i en cy ,inc reased hepc id in i s l inkedwith low grade inf lammation(increased levelsof IL-6).Limitedevidences suggest that excessiron may further aggravate theprogression of NAFLD towardsnon-alcoholic steatohepatitis andhepaticfibrosis.87

Anemia and LipidsTheevidencesfortheassociation

betweenanemiaanddyslipidemiaareratherscanty.Increasedlevelsof cholesterol and triglycerideare occasionally observed amongpa t i en t s wi th anemia hav ingassociatedmetabolic disorders;93however, thedirect associationofdyslipidemia in ironmetabolismis not clearly understood. Fews tud i e s have po s tu l a t ed t h ecorrelation of increased hepcidinlevels (due tounderlyingobesity,other inf lammatory condit iono r compensa to ry mechan i smin over load) with low HDL.94In addit ion, a s trong posi t ivecorrelationwasobservedbetweenlipidparameters(totalcholesterol[TC, low densi ty l ipoproteinscholesterol [LDL-C] and TG) andserum ferritin.95 The iron-storageprotein,serumferritinisrecognizedas an acute phase marker o finf lammation such as chronickidneydiseaseandasadeterminantof metabolic syndrome, NAFLD,and hyperinsulinemia. Therefore,the association of ferrit in anddyslipidemia could represent acardiometabolicriskfactor.95

O n t h e o t h e r h a n d ,hypocholesterolemia has beenobservedinvariouschronicanemialikethalassemiamajor,thalassemiaintermediate, sickle cell disease,G6PD deficiency, spherocytosis,aplasticanemiaandmyelodysplasticsyndrome.96 The pathophysiologyof hypocholesterolemia resultingf rom anemia inc ludes plasmadilution, increased cholesterol


r e q u i r e m e n t a s s o c i a t e dw i t h e r y th ro id hype rp l a s i a ,proinflammatorycytokinerelease,increased cholesterol utilizationbythereticuloendotheliialsystem,or liver injury secondary to ironoverload.96

Anemia and Gestational Diabetes MellitusThe wor ldwide preva lence

of gestational diabetes mellitus(GDM) is found to be up to 28%among pregnantwomen97 and inIndia it ranges between 3.8% and17.8% 98 The common risk factorsof GDM include familial historyof diabetes, obesity, pregnancy-relatedweightgain,oldermaternalage , comorbidi ty o f essent ia lhypertension or polycystic ovarysyndrome(PCOS).ThepresenceofGDMincreasestheriskoffetalloss,preeclampsia,laterdevelopmentofT2DM,cardiovasculardiseasesandimminentadversemetaboliceffectsonthechild.99-101

Various studies have exploredtheassociationbetweenalteredHblevelsandriskofGDMandithasbeen found that pregnantwomenwithlowlevelsofHbislesslikelyto developGDM.A retrospectivecase-control study reported thereduced probability of GDM inpregnant women with IDA. Inthe samestudy, theprevalenceofGDMwas negatively correlatedwith severi ty and durat ion ofanemia.102 Further studies haveshown high maternal Hb wasassociatedwith the increasedriskof GDM. Hb level >13 g/dL inearly pregnancy is considered tobe an independent risk factor ofGDM.102Therelationshipbetweenvar ious serum b iomarkers o fi ron (serum iron, ferr i t in andhepcidin) and GDM was a lsoevaluated.103,104 Increased serumferritinandhepcidinwasfoundtobeassociatedwithGDM,however,findingsofstudiessuggestingtheassociationbetweenserumironandriskofGDMare inconsistent.105,106Itisfurtherpostulatedthatexcessironintakecouldbeassociatedwithincreased risk ofGDM.For every1mgofdietaryheme iron intake,thereisa51%increaseintheriskofGDM.107Anotherstudyshowedthat

non-anemicwomenwhohavehightotalironintakearetwicelikelytodevelopGDMthanthosewhohavelowironintake.108I n c r ea sed ox ida t i ve s t r e s s

due to excess iron and resultinggenerationofreactivefreeradicalsare proposed to be involved indevelopment of diabetesmellitusduringpregnancy.Irondepositionandoxidative stress inpancreaticβ cells may result in impairedinsulin synthesis and secretion.Excessironmayalsoinduceinsulinres is tance and cause reducedglucoseuptakebyadipocytesandmuscles, and increased hepaticglucoseproduction.109

Anemia and Polycystic Ovarian SyndromePCOSiscommonlyobservedin

premenopausal women and it ischaracterized by excess androgenlevels and ovarian dysfunction.110The metabolic risk factors likeobesity and insulin resistance areoften associated with PCOS andcontributestotheriskofT2DM.111Inaddition,amild ironoverload,characterizedbyhyperferritinemia,i s a l so been a s soc i a t ed wi thPCOS. 112 S tudies have shownincreased serum ferritin levels inpatientswithoverweightorobesepatientswithPCOS.113,114However,inasubsequentstudy,increaseinserumferritinlevelwasobservedinbothobeseandnon-obesepatients,suggesting an independent roleof PCOS.115 Increased serum iron,transferrin, TSAT and decreasedsoluble TfR (sTfR) concentrationshave also been noticed in PCOS,indicating iron overload.112 Themechanisms involved in mi ldiron overload and PCOS includereduced menstrual loss due tooligomenorrhea or amenorrheaanddecreasedhepcidinlevelsduetoinsulinresistanceandandrogenexcess,which results in increasedintestinalironabsorption.Themildiron overloadmay cause glucoseintolerance in PCOS through βcel l dysfunct ion secondary toiron deposition in pancreas andinsulinresistanceduetooxidatives t ress . Bes ides , in f lammatorycytokinesarealsoinvolvedinthispathogenesisofT2DMinPCOS.112

Iron Overload and Risk of DiabetesI r o n o ve r l o a d , o t h e rw i s e

known as hemochromatosis, canbe classified as primary (genetic)or secondary (acquired) form.T h e p r im a r y o r h e r e d i t a r yhemochromatosis i s a genet icd i so rder , i n wh i ch muta t ionof the genes that are involvedin iron homeostasis can causeinadequate hepcidin production,resulting in impaired regulationof iron absorption and increasedi ron retent ion. Depending onthe gene involved in mutation,the hereditary hemochromatosisis classified as type I (HFE genemutations – the most commonform) , type I IA (hemojuvel in[HJVorHFE2]mutation),typeIIB(hepcidin antimicrobial peptide[HAMP]orHFE2Bmutation),typeIII(TfR2orHFE3mutation),ortypeIV (ferroportin [SLC40A1] genemutation). In these conditions,e x c e s s i r o n a c c umu l a t e s i nparenchymal cells, particularly intheheart,liver,pancreas,endocrineglands like thyroid andpituitary,andsynovium.89,116In secondary (or acquired)

h emo c h r oma t o s i s , t h e i r o noverload occurs due to multipleb lood t ransfus ions in cer ta inanemic conditions (thalassemia,sideroblastic anemia, sickle celldisease,chronichemolyticanemia,aplastic anemia, pyruvate kinasedeficiency)orduetochronicliverdiseases (hepatitis C infection,NAFLD, a l coho l i c f a t ty l iverdisease),porphyriacutaneatarda,or other miscellaneous causes.In this type, iron accumulates inreticuloendothelialsysteminbonemarrow,spleen,Kupffercells,andlymphnodes.89,116Both hereditary and acquired

forms of hemochromatosis canaffect the progression of severalchronicmetabolic disorders suchas T2DM, obesity, NAFLD, andatherosclerosis. Recent evidenceshaveconfirmedthatironoverloads t a t u s , i r r e s p e c t i v e o f t h ecausative factors, is associatedwith increased risk of T2DM.116Although the pathogenesis ofT2DMmay vary among causes,


iron accumulation in β-cell, liver,muscles and adipose tissues andresulting oxidative stress are thekeymechanisms involved in theimpairment of glucose and lipidmetabolism.Excessirondecreasesinsulinsecretionduetodamageofpancreaticβcellsandcauseinsulinresistanceduetoabnormalinsulins ignal ing in muscles , adiposetissuesandliver.Impairedinsulinaction causes increased lipolysisand altered adiponectin secretionin adipose tissues, and reducedglucose uptake in both adiposetissuesandmuscles.Italsoimpairsthe insulin action on inhibitingthe hepatic glucose production,c au s ing hype rg ly c emia , andreduceshepatic insulin clearance,causinghyperinsulinemia.116

Screening of AnemiaPa t i e n t s c a n b e i n i t i a l l y

diagnosedforanemiabasedontheWHO criteria (Hb level <13 g/dLformen,<12g/dLfornon-pregnantwomenand<11g/dLforpregnantwomen) 117 and eva lua ted fo rcomorbid conditions, medication

historyandclinical status.Asperthe Indian Council of MedicalResearch (ICMR) classification,the severi ty of anemia can bemild (Hb 8-11%), moderate (Hb5-8%)orsevere(Hb<5%).Inorderto evaluate the type of anemia,complete blood count (CBC) andgeneral blood picture must beassessed. The mean corpuscularvolume(MCV)candifferentiatethenormocytic(80-100fL),microcytic(<80fL)ormacrocytic(>100fL)typeofanemia.Megaloblasticanemiainmacrocytic typecanbeconfirmedbased on the peripheral bloodsmear or bonemarrow aspiration(if necessary). In megaloblasticanemia, thepossibilityofvitaminB12 or folate deficiency can befurther determined based on theserumvitaminB12orfolatelevels.In patients receiving long-termme t fo rmin t r e a tmen t , s e rumvi tamin B12 leve ls should beassessed periodically, especiallyinthosewithanemiaorperipheralneuropathy. Normocytic anemiacould be related to malignancy,a n em i a due t o h emor rhage ,hemolytic anemia (high bilirubin

level), or anemia due to chronicd i s e a s e o r r e n a l f a i l u r e . I nmicrocytic or normocytic anemia,furtherevaluationofserumferritinand TSAT is useful to determinethe IDA.Serum ferritin is an ironstorage protein and TSAT levelscould reflect iron available forerythropoiesis;serumferritinlevel<30 µg/mL andTSAT <20% couldindicate IDA. In chronic diseasessuch asCKD, orCHF, the IDA isindicated, if ferritin levels rangebetween 30-100 µg/mL and TSAT<20%.In CKD, the abso lu te i ron

deficiencyshouldbedistinguishedfromfunctionalirondeficiency.Inabsolute iron deficiency (serumferr i t in <100 ng/dL and TSAT<20%), iron levels are inadequatefor erythropoiesis. In functionaliron deficiency (serum ferritin>100µg/mLandTSAT<20%),ironlevelsareadequate;however,thereis poor bioavailability of iron forerythropoiesis.Inanemiaofchronicdisease, serum ferri t in rangesfrom 100-500 ng/mL and TSAT20-30%; however, the presenceof IDA can be ruled out with

Fig. 2: Mechanism of iron disorders in metabolic syndrome and its component disorders


solubletransferrinreceptor(sTfR)/log ferritin index. The sTfR <1 isobservedinanemiaduetochronicdiseaseanditis>2inIDA.118

Fur the r eva lua t i on can bec onduc t ed t o d e t e rm ine t h eunderlying causes: urine or stoolexamination,colonoscopyorupperendoscopy to determine ongoingbloodlossfromgastrointestinalorgenitourinary tract; non-invasivescreening to confirm atrophicg a s t r i t i s , c e l i a c d i s e a s e ; Hbelectrophoresisforsicklecelldiseaseor thalassemia; and C-reactiveprotein (CRP) for inflammatorycondit ions. Occasional ly bonemarrowaspirationmayberequiredfordetectingresistantanemia.

Management of AnemiaEv idence s c l e a r l y suppor t

appropriate treatment for anemiain metabolic disorders as i t isknown to improve the cl inicaloutcomes and overall quality ofl ife. 119 Treating the underlyingcauseshouldbethefirstapproach,f o l l owed by managemen t o fanemiausingvitaminB12orfolatesupplements, iron preparations(oral or parenteral ) , or ESAs.The treatment decision should bemadebasedonanindividualbasisdepending on the clinical status,associated disorders like CKD orCHF, and response to treatment(Figure3).Dietary management

The dietary sources of i roncan help to maintain the ironlevels,but it isunlikelytorepleteiron stores. Hence, it is alwaysadvised as an adjunct to i ronsupplementation.Takingmeat,fishand poultry products alongwithironsupplementationcanincreaseironabsorption.Inaddition,fruitsrich in vitamin C (gooseberriesalso known as amla), guava andothercitrusfruitscanimproveironabsorptionfromsupplementationsaswellasfromplantfoods(greenleafy vegetables, legumes anddry fruits) . 120 Cooking in ironpotsorvesselsarealsoadvisable.However, consumption of coffeeorteashouldbeavoidedasitcanpotentially reduce the absorptionofiron.

Oral or intravenous iron preparations

There are severa l ora l i ronpreparat ions ava i lab le in theform of ferrous salts (eg. ferrousascorbate,ferrousfumarate,ferrousgluconate,andferroussulphate),inthe form of ferric iron salts (eg.ferric citrate) or carbonyl iron(Table 1). Oral iron preparationsshould be cons idered in IDAwhen the intestinal absorptionis normal and if the Hb level isbetween 11-12 g/dL because ofslowrepletion.Adequaterepletioncan be achieved with the doserange of 100 to 200mg elementalironperday.Gastrointestinalsideeffectsarecommonwithoralironpreparationsandmayexhibitpoorcompliance; therefore, to improvethe tolerability and adherence,smallerdoses~60mgofelementaliron per day can be given. TheHb levels should be monitoredcarefullyduringthetreatmentandifthelevelsdonotincreaseby2g/dLwithin4or8weeks,treatmentshouldbechangedtointravenousiron depending on the cause andseverityofthecondition.Inaddition,theintravenousiron

preparations(Table1)arepreferredin anemia tha t requi re rap idcorrection,inconditionsassociatedwith diminished iron absorptionsuch as autoimmune gastri t is ,celiacdisease,obesityandbariatricsurgery, or in acute or chronicblood loss due to gastrointestinalbleeding, post-surgery, etc. InCKDpatientswhoarenon-dialysisdependent,oralorintravenousironpreparationcanbeuseddependingupontheclinicalprofile;however,in dialysis dependent patients,intravenousironispreferred.Conditions that require large

amountofironforrepletion,useofferriccarboxymaltose,ferumoxytoland iron isomaltoside could bebeneficial, as higherdoses can beadministeredperinfusionandalsoithasbetter tolerabilityprofile inCKD patients. The Hb level andotherserumironmarkers(ferritinand TSAT) should be carefullymonitoredevery2 to3months toavoid iron overload and patientswhodonotrespondtointravenousiron, treatment with ESAs alongwith intravenous iron should beconsidered as they are likely to

haveanemiaofchronicdisease.Erythropoietin and analogues

Severa l d i f f e ren t ESAs areavailable and can be classifiedinto first generation (Epoetin-alfaa n d E p o e t i n - b e t a ) , s e c o n dgenerat ion (darbepoet in-a l fa )and third generation (continuouserythropoietin receptor activator[CERA). These ESAs are widelyusedinthemanagementofanemiaassociated with chronic diseasesl ike CKD and diabet ic kidneydisease.TreatmentwithESAmustbeindividualizedbasedontheHblevels, previous responses to irontreatment,riskoftransfusion,risksrelated to ESAs, and symptomsattributedtoanemia(Table2).

When and how to start: BeforetreatmentwithESAs,othercausesof anemia should be ruled out ortreated (including IDA). The timefor initiating ESA therapy mayvary among patients. The ESA isinitiated in iron replete state—innon-dialysis patients when Hblevel <11 g/dL and in dialysispatientswhen<10g/dL—toreducetheneedforbloodtransfusion,riskofhospitalizationandmortality.Thefirst-generationESAs,which

has a shorter half - l i fe , can beadministeredup to 3 times/weektomaintain theHb levels inCKDpatients onhemodialysis. In non-dialysisCKDpatients,epoetin-alfacan be administered once aweekoronceevery2week.Thesecond-generation ESA, darbepoetin-alfahasalmost3timeslongerhalf-lifethan epoet in , and thus i t hasadvantages of reduced dosingfrequency and improved patientcompliancewhen comparedwithepoetin. Darbepoetin-alfa can beadministered once every 2weeks(dose equivalent to thrice-weeklyepoetin)atinitiation,howeveritcanbe administered onceweekly forpatientsondialysis.Subsequently,once monthly darbepoetin-alfacan be administered tomaintaintheadequateHblevels.Thethird-genera t i on ESA (CERA) a l sohas longer half-life and can beadministered up to once every 2weeksoroncemonthly.However,therearelimitedclinicalexperienceinpatientswithCKD.I n d i a l y s i s p a t i e n t s ,


intravenous ESAs are preferredover subcutaneous due to ease ofadministration; however, in non-dialysis patients and those onperitoneal dialysis, subcutaneousESAshavegreateradvantage.

How to monitor: TheHb levelsare monitored every week untilthe levels reach 11-12 g/dL andsubsequently everymonth.WhentheHblevelincreasesby1g/dLina2-weekperiodorifitis>12g/dL,thetreatmentshouldbesuspendedandreinitiatedwithreduceddose(25% below the previous dose)after Hb level declines to <11 g/dL.However,iftheincreaseinHblevelis≤1g/dLover4weeks,doseofESAdoseshouldbeincreasedby25%. If theHb is inappropriatelylowafter 4 to 6weeks, causes forESA hyporesponsiveness shouldbe de te rmined . The poss ib l ecauses are vitamin deficiency,hemolysis,infection,inflammation,ormalignancy; occult blood loss

or accumulation of aluminium.Targe t ing Hb >13g /dL i s no trecommended in patients withCKD and could increase the riskof stroke, vascular thrombosisandhypertension.11,121Inaddition,serum ferritin levels of >200 µg/land TSAT of >20% are requiredtobemaintained.Uponachievingthe target levels , maintenancedose of IV iron (once weekly ormonthly)isusuallygivenwithESAtherapytosupporterythropoiesis.Further,ESAsshouldberestrictedin patientswith CHF and shouldbe used if the benefit outweighsthe risk of adverse outcomes likestroke or hypertension. 121 TheESA therapy should be carefullymonitored foranyadverseeffectssuch as headache, shortness ofbreath,hypertension,tachycardia,hyperkalemia,nauseaorvomiting,diarrhea and hypersensi t ivi tyreactions such as rash or itching.E S A t r e a t m e n t s h o u l d b ediscontinued if patient developspureredcellaplasia(rareadversereaction associatedwith ESA) orsevereanaphylacticreactions.Blood transfusion for anemia

Thebloodtransfusionisgenerallyrestricted in order to minimizethe associated r isk . However ,i t can be considered if benefitoutweighs the risk in patientswho have severe life threateninganemia , a c t i ve b l eed ing andhemodynamicallyunstable,failureof other treatments, or anemiaassociated with cardiovascular

disease (Hb level: <7 g/dL).122,123Followingtransfusion,appropriatetreatment with intravenous ironor ESAs, should be considered inorder to correct andmaintain theHblevels,andtopreventtheneedforsubsequenttransfusions.Conclusions

The co-exis tence of anemiaand metabo l i c syndrome canbe de t r imenta l . Hence , ea r lydiagnosiswithappropriateclinicalevaluationandtimelymanagementare required to reduce the riskof morbidity andmortality, andto improve overal l qual i ty oflife.Available treatment optionssuch as oral or intravenous ironpreparations and ESAs for themanagementofanemiashouldbeconsidered based on the clinicalp ro f i l e , r i sk a s soc i a t ed wi thtreatment,tolerability,convenienceandcompliance.Excesscorrectionof anemia associated with ironoverload could lead to adverseoutcomes. Therefore, treatmentof anemia should be carefullymon i t o r ed a l ong w i th o the rmetabolicriskfactors.

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Table 1: Iron preparations for the management of anemia

Oral DosageFerrousascorbate 100-200mgof

elementaliron/dayFerroussulphateFerrousfumarateFerrousgluconateFerrousbisglycinateFerroussuccinateFerriccitrateCarbonylIron 100-200mg/dayParenteralFCM 15mgor20

mgiron/kg(IVadministration)or1000mgofiron(20mLFCM)

Ironisomaltoside 100-200mgIVbolusinjectionorupto20mgiron/kginfusion.

Ferumoxytol 510mgIVoveratleast15minutes

HMVdextran* Upto100mgofironIVat≤50mg/min

LMWdextran* Upto100mgofironIVat≤50mg/min

Sodiumferricgluconatecomplex

62.5-125mgIVduringdialysisorinfusionover1hour

Ironsucrose 100-200mgIVover2-5minutes

IV,intravenous,FCM,ferriccarboxymaltose;HMW,highmolecularweight;LMW,lowmolecularweight;*Testdoserequired.

Table 2: Various types of erythropoietin stimulating agents

ESAs DosageFirst generationEpoetin-alfa 50to100units/kgIV

orSC3timesaweekEpoetin-beta 50to100units/kgIV

orSC3timesaweekSecond generationDarbepoetin-alfa 0.45mcg/kg/wk

or0.75mcg/kg/fortnightlyIVorSC

Third generationContinuouserythropoietinreceptoractivator(CERA)

0.6mcg/kg/fortnightly

ESA,erythropoietinstimulatingagents;IV,intravenous;SC,subcutaneous.


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Position statement - Japijapi.org/june_2017/09_ps_icp_anemia_in_metabolic.pdf · 2020-01-30 · 60 fi V 65 fi June 2017 Indian College of Physicians Position Statement on Anemia in