A STUDY OF LIPID PROFILE IN ANAEMIA by Dr. Zayed Abdulla Dissertation Submitted to the Rajiv Gandhi University Of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of Doctor of Medicine in General Medicine Under the guidance of Professor Chikkalingaiah. M.D. Department of General Medicine Kempegowda Institute of Medical Sciences V.V. Puram, Bangalore 2005 IIRajiv Gandhi University Of Health Sciences, Karnataka, Bangalore DECLARATION BY THE CANDIDATE IherebydeclarethatthisdissertationentitledAStudyofLipidProfilein Anaemiaisabonafideandgenuineresearchworkcarriedoutbymeunderthe guidance of Dr. Chikkalingaiah M.D., Professor of Medicine, Kempegowda Institute of MedicalSciences,BangaloreandDr.MahadevappaPhD,ProfessorofBiochemistry, Kempegowda Institute of Medical Sciences, Bangalore. Signature of the Candidate Name: Dr. Zayed Abdulla Date:Place : Bangalore IIICERTIFICATE BY THE GUIDE ThisistocertifythatthedissertationentitledAStudyofLipidProfilein AnaemiaisabonafideresearchworkdonebyDr.ZayedAbdullainpartial fulfillment of the requirement for the degree of Doctor of Medicine. Date:Place : Bangalore Signature of the Guide Name: Dr. Chikkalingaiah. M.D. Professor of Medicine, Department of Medicine, Kempegowda Institute ofMedical Sciences, Bangalore. IVCERTIFICATE BY THE CO-GUIDE ThisistocertifythatthedissertationentitledAStudyofLipidProfilein AnaemiaisabonafideresearchworkdonebyDr.ZayedAbdullainpartial fulfillment of the requirement for the degree of Doctor of Medicine. Date:Place : Bangalore Signature of the Co-Guide Name: Dr K.L. Mahadevappa, Ph.D. Professor of Biochemistry, Department of Biochemistry, Kempegowda Institute ofMedical Sciences, Bangalore. V ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION ThisistocertifythatthedissertationentitledAStudyofLipidProfilein Anaemia is a bonafide research work done by Dr. Zayed Abdulla under the guidance ofDr.ChikkalingaiahM.D.,ProfessorofMedicine,KempegowdaInstituteofMedical Sciences, Bangalore. Seal & Signature of the Principal Name: Dr. M. K. Sudarshan. M.D., Principal, Kempegowda Institute of Medical Sciences, Bangalore. Date: Place : BangaloreDate : Place:BangaloreSeal & Signature of the HoD Name: Dr. V. Channaraya. M.D., DNB, F.I.C.C., Professor & HoD, Department of Medicine, Kempegowda Institute of Medical Sciences, Bangalore. VICOPYRIGHT Declaration by the Candidate IherebydeclarethattheRajivGandhiUniversityofHealthSciences,Karnatakashall havetherightstopreserve,useanddisseminatethisdissertation/thesisinprintor electronic format for academic / research purpose.

Rajiv Gandhi University of Health Sciences, Karnataka Date:Place : BangaloreSignature of the Candidate Name: Dr. Zayed Abdulla VIIACKNOWLEDGEMENT I would like to take this opportunity to express my deep sense of gratitude towards Dr.Chikkalingaiah.M.D.,ProfessorofMedicine,KempegowdaInstituteofMedical Sciences,Bangalore,forhisinvaluableguidance,constantencouragement,andexpert suggestions, in spite of his busy schedule, which was most crucial in overcoming various difficulties. IwouldnothavebeenabletocompletethisundertakingwithoutDr.K.L. MahadevappaPhD,ProfessorofBiochemistry,whoseguidanceandsuggestionswereof utmost help. I am deeply indebted to Dr. V. Channaraya. M.D., DNB, F.I.C.C., Professor and HoD, Department of Medicine for his invaluable suggestions and insight. IamextremelygratefultoDr.M.VPoornachandra.M.D.,Professorandformer HoD,DepartmentofMedicineforhissupervisionandkeeninterestinacademic activities. I am grateful to Dr. Gowri Shankar M.D., Dr. H.V. Nataraju M.D., Dr. R. Manjunath M.D.,andDr.ShivalingaiahM.D.,ProfessorsofMedicine,fortheirguidanceandtimely help. IamindebtedtoDr.N.C.SrinivasPrabhuM.D.,Dr.K.P.BalrajM.D.,Dr.G.N. NageshM.D.andDr.R.SrinivasM.D.,AssociateProfessorsofMedicinefortheir encouragement, valuable suggestions and healthy criticisms.VIII IsincerelythankDr.R.VedavathiM.D.andDr.K.C.ChannappaM.D.,Assistant ProfessorsofMedicinefortheirguidanceandhelpgiventomeinthisstudy.Iam gratefultoDr.H.D.RamachandraPrabhuM.D.andDr.C.JagadishM.D.,Lecturersin Medicine, and Dr. H. Rajeev M.D., Dr. N. Venkataswamy M.D. and Dr. Ramakrishna M.D., Senior Residents in Medicine for their moral support during my study period. IamindebtedtoDr.K.M.GovindarajuM.S.,MedicalSuperintendent,KIMS Hospital, Dr. J. Ramachandra M.S., Administrative Medical Officer, KIMS Hospital, Dr. M.K. Sudarshan M.D., Principal, KIMS, Dr L. Krishna M.D., former Principal, KIMS and Dr. Vasantha Kumar.S. M.D., D.G.O., Vice Principal, KIMS, for permitting me to carry out this work. MythanksareduetothestaffoftheDepartmentsofPathologyandBiochemistry forhelpingmecarryouttherequiredinvestigations.IamindebtedtoMr.K.PSuresh, Statistician,NationalInstituteofAnimalNutritionandPhysiology,Bangaloreforhis generous help. I am grateful to all my friends and colleagues for their untiring support. I thank all others who have assisted me in some form or the other in the preparation of this work. Last but not the least, I am grateful to all those patients who were the subjects for this study, without whose co-operation this work would not have been possible.

Date:Place : BangaloreSignature of the Candidate Name: Dr. Zayed Abdulla IXLIST OF ABBREVIATIONS USED (in alphabetical order) 2,3-BPG2,3-biphosphoglycerate AIDSAcquired immune deficiency syndrome ApoApolipoprotein BMIBody mass index CETPCholesteryl ester transfer protein CHDCoronary heart disease CoACoenzyme A DMDimorphic anaemia DNADeoxyribo nucleic acid FADH Reduced flavin adenine dinucleotide FBSFasting blood sugar FHFamilial hypercholesterolemia G6PDGlucose 6 phosphate dehydrogenaseGITGastrointestinal tract GM-CSFGranulocyte-macrophage colony stimulating factor GPEGeneral physical examination HbHaemoglobin HCLHairy cell leukemia HDLHigh density lipoprotein HMG CoA3-hydroxy-3-methylglutaryl coenzyme A HMPHexose monophosphate XHSPGHeparan sulphate proteoglycans IDLIntermediate density lipoproteins JVPJugular venous pulse KIMSKempegowda Institute of Medical Sciences LCATLecithin:Cholesterol acyl transferase LDLLow density lipoprotein LP(a)Lipoprotein a LPLLipoprotein lipase LRPLow density lipoprotein receptor related protein MCHMean corpuscular haemoglobin MCHCMean corpuscular haemoglobin concentration MCP-1Monocyte chemoattractant protein 1 MCVMean corpuscular volume MHMicrocytic hypochromic anaemia MPDMyeloproliferative disorder MTPMicrosomal transfer protein NADH Reduced nicotinamide adenine dinucleotide NCEPNational cholesterol education program NHNormocytic hypochromic anaemia NNNormocytic normochromic blood picture PPBSPost prandial blood sugar RBCRed blood cell RBSRandom blood sugar XISAPSerum alkaline phosphatase SDStandard deviation SGOTSerum glutamate oxaloacetate aminotranferase SGPTSerum glutamate pyruvate aminotransferaseT3 3,5,3-Triiodothyronine T4 Thyroxine TSHThyroid stimulating hormone VLDLVery low density lipoprotein XIIABSTRACT Background&Objectives:Anaemiaisreportedtobeassociatedwithloweringinall lipidsubfractions.Thisstudywasconductedtostudytheclinicalfeaturesofanaemia, effectofanaemiaonlipidprofile,andeffectofseverityandtypeofanaemiaonlipid profile Methods:ThedataforthisstudywascollectedfrompatientswhopresentedtoKIMS hospitalfromJunetoJune2005.100anaemiccasesand100nonanaemicageandsex matchedcontrolsunderwentclinicalassessmentandrelevantinvestigations,including lipid profile estimation. Results:Casesyoungerthan50yearswerefoundtobemorelikelytohavesevere anaemia.Fatigueandpallorwerethemostcommonclinicalfeatures.Clinicalfeatures were more common among cases with severe anaemia. The mean total cholesterol (132.2 29.0vs173.420.3,P 250 U/L 15. TSH > 7.0 U/ml or TSH < 0.3 U/ml Clinical evaluation Adetailedhistorywasobtainedfromthesubjectsofthestudy,withspecial emphasis on age, sex and occupation; non specific symptoms of anaemia like fatigability, dyspnoea, giddiness, palpitations and angina; symptoms suggestive of a specific cause for anaemialikepica,dysphagia,abdominalpainpain,bonypain,fever,lossofappetite, weightloss,jaundice,bleeding,malaena,haemoglobinuria,menorrhagia,pregnancyand postmenopausalbleeding.Pasthistoryofdisordersassociatedwithdyslipidemiaor anaemia was obtained, including diabetes mellitus, hypertension, ischemic heart disease, cerebrovascularaccident,AIDS,recentbloodlossandgallstones.Dietaryhabitsand habitslikealcoholismandtobaccosmokingwasascertained.Historyofintakeofdrugs affectinglipidlevels,suchasoralcontraceptives,betablockers,diuretics,steroidsand 67NSAIDswasobtained.Familyhistoryofanaemia,jaundiceandgallstoneswasalso obtained. Each patient was subjected to a detailed general physical examination, with special emphasisonpallor,koilonychias,icterus,pedaledema,lymphadenopathy,glossitis, angularstomatitis,petechiae,haemolyticfacies,ankleulcers,perioralpigmentationand knucklepigmentation.Pulse,bloodpressure,weight,heightandbodymassindexwas measured. Thoroughsystematicexaminationwasmadeofthecardiovascularsystemtolook for the presence of elevated JVP, venous hum, cardiomegaly, S3 and flow murmur. The respiratorysystemwasexaminedtolookforevidenceofpulmonaryoedema.Abdomen wasexaminedtolookfororganomegaly.Thecentralnervoussystemwasexaminedfor confusion, muscular weakness, deep tendon reflexes, vibration sense, position sense and rombergs sign. Investigations Venousbloodwasdrawnforinvestigationslikecompletehaemogram,random bloodsugar,bloodurea,serumcreatinine,liverfunctiontests,andthyroidstimulating hormone levels. A urine sample was obtained for urine analysis, including albumin, sugar andmicroscopy.Fastingvenousbloodsample(>12hours)wasobtainedforestimation of lipid profile. T3 and T4 levels, fasting and post prandial (two hours after an oral dose of 75gms of glucose) blood sugar levels, and bone marrow aspiration cytology was done in selected cases based on clinical assessment. 68 CompletehaemogramwasperformedusingtheSysmaxautomatedanalyzer. Haemoglobinlevelswereconfirmedbythecolorimetricmethod.Differentialcountand peripheral smear was done manually using Leishmanns stain by a qualified pathologist. Urine albumin and sugar was estimated by dipstick method. Urine microscopy was done manuallybyaqualifiedpathologist.Biochemicalanalysesweredoneusingthefully automated Technicon RA-XT system by Bayer. TSH, T4 and T3 were estimated using the chemiluminescence method on the fully automated ADVIA Centaur system by Bayer. Estimationoftotalcholesterol,HDLandtriglycerideswasdonewiththe commerciallyavailableAutopakcholesterolkitonTechniconRA-XTsystem.VLDL wascalculatedusingtheformula,VLDL=Triglyceride/5.LDLcholesterolwas calculated using the Friedewalds equation. LDL = Total cholesterol [(Triglycerides/5) + HDL] mg/dl. Controls One hundred non anemic age and sex matched subjects were selected and screened for compliance with the exclusion criteria. Complete haemogram, lipid profile and other investigations were performed on them. Statistical Methods80,81

Studentttesthasbeenusedtotestthehomogeneityofagebetweencaseand control.Chi-squaretesthasbeenusedtofindthehomogeneityofsexbetweencaseand control.StudentttesthasbeenusedtofindthesignificanceofLipidprofilesbetween 69caseandcontrols.AnalysisofVariancehasbeenusedtofindthesignificanceofmean lipid profiles when there are more than 2 groups. Mann Whitney U test has been carried tofindthesignificancebetweencaseandcontrolforTC/HDLandLDL/HDLratio. KruskalWallistesthasbeenusedtofindsignificanceofTC/HDLandLDL/HDLratio when there are more than 2 groups. Effect Size due to Cohen d has been computed to find the extent of effect of anemia on Lipid profiles. 0< d< 0.20 No effect 0.20 < d < 0.50Mild Effect 0.50 < d < 0.80Moderate effect 0.80 < d < 1.20Large effect d > 1.20 Very Large effect Statistical softwareThe statistical software used for the analysis of the data was SPSS 11.0 and Systat 8.0. Microsoft Word and Excel have been used to generate figures and tables.705. Results Study DesignA case - control study consisting of 100 anaemic cases and 100 normal subjects was undertaken to study the clinical presentation of anaemic cases and also to investigate the relationship between anaemia and lipid profile. Age Thecasesandcontrolswerematchedforage.Majorityofthecasesweremiddle aged (30-60). The youngest case was 14 years old. The oldest was 75 years old. Table 1 Age distribution with Haemoglobin levels in cases and controls Case Haemoglobin levels (in gm/dl) Age in years < 6 (n=23) 6-9 (n=40) > 9 (n=37) Total (n=100) Control (n=100) 20 3 (13.0) 3 (7.5) 2 (5.40) 88 21-30 6 (26.1) 10 (25.0) 3 (8.1) 1919 31-40 4 (17.4) 11 (27.5) 7 (18.9) 2222 41-50 4 (17.4) 6 (15.0) 3 (8.1) 1313 51-60 2 (8.7) 4 (10.0) 17 (45.9) 2323 61-70 3 (13.0) 5 (12.5) 3 (8.1) 1111 >70 1 (4.3) 1 (2.5) 2 (5.4) 44 Inference Samples are age matched (P>0.05). Anaemic cases < 50 years of age are 2.42 times more likely to have Hb levels < 6 gm/dl (p=0.107) and Anaemic cases > 50 years of age are 4.31 times more likely to have > 9 Hb gm/dl (P70Age (i n years)Age and Hb levelHb > 9 gm/dlHb 6-9 gm/dl Hb < 6 gm/dl72Sex The cases and controls were matched for sex. The cases consisted of 48 males and 52 females. Sex was not associated with haemoglobin levels. Table 2 Sex distribution between case and controls Case Haemoglobin levels(in gm/dl) Sex < 6 (n=23) 6-9 (n=40) > 9 (n=37) Total (n=100) Control (n=100) Male 10 (43.5) 19 (47.5) 19 (51.4) 4848 Female 13 (56.5) 21 (52.5) 18 (48.6) 5252 Inference Samplesaresexmatched(P>0.05).Sexisnotstatistically associated with haemoglobin levels (P>0.05) Figures in parenthesis are percentages Figure 3 Sex distribution in cases and controls Mal e48%Femal e52%Case Mal e48%Femal e52%Control73Distribution of cases according to type and severity of Anaemia Atotalof100caseswereincludedinthisstudy.40caseshaddimorphicanaemia (DM)accordingtoperipheralsmear,25caseshadmicrocytichypochromicanaemia (MH),18caseshadnormocytichypochromicanaemia(NH)and10caseshada normocyticnormochromicbloodpicture(NN).Outofthe7casesgroupedtogetheras othersforthepurposeofanalysis,3caseshadmegaloblasticanaemia,2caseshad pancytopenia,andonecaseeachhadchronicmyeloidleukemiaandleukoerythroblastic bloodpicture.Atotalof23caseshadhaemoglobinlessthan6gm/dl,40caseshad haemoglobin between 6 and 9 gm/dl, and 37 cases had haemoglobin more than 9 gm/dl. Table 3 Distribution of cases according to type and severity of Anaemia Type of Anaemia Hb (in gm/dl) DMMHNHNNOthersTotal < 6145--423 6-921152-240 > 9551610137 Total402518107100 74Symptoms The most common presenting symptom was easy fatigability, which was present in 51 cases. The next common symptoms were dyspnoea (29 cases), palpitations (27 cases) and giddiness (24 cases). Other symptoms were loss of appetite (9 cases), fever (7 cases), weight loss (5 cases), angina, dysphagia, jaundice and menorrhagia (3 cases each), bony pain and bleeding (1 case) each. Not seen in the study group were pica, abdominal pain, malaena, haemoglobinuria and pregnancy. Figure 4 Symptoms 0102030405060No of casesA B C D E F G H I J K L MSymptomsA: Fati gueB: DyspnoeaC: Gi ddi nessD: Pal pi tati onsE: AnginaF: Dysphagi aG: Bony pai nH: Fever I : Loss of appeti teJ: Wei ght l ossK: Jaundi ceL: Bleedi ngM: Menorrhagi a75Symptoms and severity of anaemia Caseswithmoresevereanaemiawerefoundtobemorelikelytohavesymptoms. All cases with haemoglobin less than 6 gm/dl had at least one symptom, while out of 39 caseswithhaemoglobinmorethan9gm/dl,only12cases(30.8%)hadatleastone symptom.Mostsymptomswerefoundmorefrequentlyincaseswithmoresevere anaemia.100%ofcaseswithhaemoglobinlessthan6gm/dlcomplainedoffatigue, compared to just 13.5 % of cases with haemoglobin more than 9 gm/dl. Fever, bony pain andbleedingweretheonlysymptomswhichwerefoundmorefrequentlyincaseswith lesssevereanaemia.Caseswithsevereanaemiaalsohadmorenumberofsymptoms. Cases with haemoglobin less than 6 gm/dl had an average of 3.7 symptoms, compared to cases with haemoglobin more than 9 gm/dl, who had only an average of 0.6 symptoms. Symptoms and type of anaemia Nonspecificsymptomssuchasfatigue,dyspnoea,giddiness,palpitations,fever, lossofappetiteandlossofweightwereequallyfrequentinthedifferenttypesof anaemia,exceptnormocytichypochromicanaemiaandcaseswithnormocytic normochromicbloodpicture.Thisispossiblyduetothefactthatthesecaseshadless severeanaemia.Symptomslikeangina,dysphagiaandmenorrhagiawereseenonlyin patientswithdimorphicanaemiaandmicrocytichypochromicanaemia.Bonypainand bleeding was seen only in one patient with chronic myeloid leukemia. 76Table 4 Symptoms and severity of Anaemia Haemoglobin levels in cases (in gm/dl)Presenting Illness Total (n=100) < 6 (n=23) 6-9 (n=40) > 9 (n=37) Fatigue51 23 (100.0) 23 (57.5) 5 (13.5) Dyspnoea29 19 (82.6) 10 (25.0) - Giddiness24 10 (43.5) 11 (27.5) 3 (8.1) Palpitation27 14 (60.9) 9 (22.5) 4 (10.8) Angina3 3 (13.0) -- Pica---- Dysphagia3 3 (13.0) -- Abd pain---- Bony pain1-- 1 (2.7) Fever7 1 (4.3) 2 (5.0) 4 (10.8) Loss of appetite9 4 (17.4) 2 (5.0) 3 (8.1) Wt loss5 4 (17.4) 1 (2.5) - Jaundice3 2 (8.7) 1 (2.5) - Bleeding1-- 1 (2.7) Malaena---- Haemoglobinuria---- Menorrhagia3 2 (8.7) 1 (2.5) - Pregnancy---- Post menopausal bleed ---- Figures in parenthesis are percentages 77Table 5 Symptoms and type of Anaemia Types of AnaemiaSymptoms DM (n=40) MH (n=25) NH (n=18) NN (n=10) Others (n=7) Fatigue 31 (77.5) 14 (56.0) 1 (5.6) - 5 (71.4) Dyspnoea 15 (37.5) 9 (36.0) 1 (5.6) - 4 (57.1) Giddiness 13 (32.5) 6 (24.0) 2 (11.1) 1 (10.0) 2 (28.6) Palpitation 14 (35.0) 8 (32.0) 3 (16.7) - 2 (28.6) Angina 2 (5.0) 1 (4.0) --- Pica----- Dysphagia 1 (2.5) 2 (8.0) --- Abd pain----- Bony pain---- 1 (14.3) Fever 1 (2.5) 2 (8.0) 2 (11.1) 1 (10.0) 1 (14.3) Loss of appetite 3 (7.5) 2 (8.0) 2 (11.1) - 2 (28.6) Wt loss 1 (2.5) 3 (12.0) -- 1 (14.3) Jaundice 1 (2.5) 1 (4.0) -- 1 (14.3) Bleeding---- 1 (14.3) Malaena----- Haemoglobinuria----- Menorrhagia 2 (5.0) 1 (4.0) --- Pregnancy----- Post menopausal bleed ----- Figures in parenthesis are percentages 78Past history Noneofthecaseswasaknowncaseofdiabetesmellitus,hypertension,ischaemic heart disease or AIDS. None of the cases had a past history of cerebrovascular accident, recent blood loss or gall stones. Personal history 19 cases were vegetarian. 34.8% (8 cases out of 23) of all cases with haemoglobin lessthan6gm/dlwerevegetarian,comparedto15.8%(6casesoutof38)ofallcases withhaemoglobinmorethan9gm/dl.Vegetariansweremorelikelytohavedimorphic anaemia(55.6%)comparedto the other types of anaemia (5.6% to 22.2%). None of the cases had a history of alcohol use or tobacco smoking. Drug History Noneofthecaseshadahistoryofintakeoforalcontraceptives,betablockers, diuretics, steroids or non steroidal anti inflammatory drugs. Family history Fourcaseshadafamilyhistoryofanaemia,outofwhomthreehadmicrocytic hypochromic anaemia. Five cases had a family history of jaundice, out of whom four had dimorphic anaemia. 79General physical examination The most common finding on general physical examination was pallor, which was presentin67cases.Alsoseenwereglossitis(20cases),koilonychia(11cases),angular stomatitis(9cases),knucklepigmentation(7cases),pedaloedema(6cases),icterus(3 cases),lymphadenopathy(1case)andperioralpigmentation(1case).Noneofthecases had petechiae, haemolytic facies or ankle ulcers. Figure 5 General physical examination 010203040506070No of casesA B C D E F G H I J K LGeneralphysi calexami nati onA: PallorB: KoilonychiaC: IcterusD: Pedal oedemaE: LymphadenopathyF: GlossitisG: Angular stomatitisH: Petechiae I : Haemolytic faciesJ: Ankle ulcersK: Perioral pigmentationL: Knuckle pigmentation80General physical examination and severity of anaemia Cases with more severe anaemia were found to be more likely to have findings on general physical examination. All cases with haemoglobin less than 6 gm/dl had at least onesign,whileoutof39caseswithhaemoglobinmorethan9gm/dl,only8cases (21.6%)hadatleastonesign. All signs were found more frequently in cases with more severeanaemia.100%ofcaseswithhaemoglobinlessthan6gm/dlhadpallorand 56.5%hadglossitis,comparedtojust21.6%and0%incaseswithhaemoglobinmore than9gm/dl.Caseswithsevereanaemiaalsohadmorenumberofsignsongeneral physicalexamination.Caseswithhaemoglobinlessthan6gm/dlhadanaverageof2.8 signs, compared to cases with haemoglobin more than 9 gm/dl, who had only an average of 0.2 signs. General physical examination and type of anaemia Pallorwasequallyfrequentinthedifferenttypesofanaemia,exceptnormocytic hypochromicanaemiaandcaseswithnormocyticnormochromicbloodpicture.Thisis possiblyduetothefactthatthesecaseshadlesssevereanaemia.Koilonychia, lymphadenopathy,glossitisandangularstomatitiswereseenonlyincaseswith dimorphicanaemiaandmicrocytichypochromicanaemia.Knucklepigmentationand preioral pigmentation was seen only in cases with megaloblastic anaemia and dimorphic anaemia. 81Table 6 GPE and severity of Anaemia Haemoglobin levels in cases (in gm/dl) GPETotal (n=100) < 6 (n=23) 6-9 (n=40) > 9 (n=37) Pallor67 23 (100.0) 36 (90.0) 8 (21.6) Koilonychia11 9 (39.1) 2 (5.0) - Icterus3 2 (8.7) 1 (2.5) - Pedal oedema6 6 (26.1) -- Lymphadenopathy1- 1 (2.5) - Glossitis20 13 (56.5) 7 (17.5) - Angular stomatitis9 7 (30.4) 2 (5.0) - Petechiae---- Haemolytis facies---- Ankle ulcers---- Peri oral pigmentation 1- 1 (2.5) - Knuckle pigmentation 7 5 (21.7) 2 (5.0) - Figures in parenthesis are percentages 82Table 7 GPE and type of Anaemia Types of Anaemia SymptomsDM (n=40) MH (n=25) NH (n=18) NN (n=10) Others (n=7) Pallor 37 (92.5) 20 (80.0) 3 (16.7) - 7 (100.0) Koilonychia 5 (12.5) 6 (24.0) --- Icterus 1 (2.5) 1 (4.0) -- 1 (14.3) Pedal oedema 4 (10.0) --- 2 (28.6) Lymphadenopathy- 1 (4.0) --- Glossitis 12 (30.0) 8 (32.0) --- Angular stomatitis 4 (10.0) 5 (20.0) --- Petechiae----- Haemolytis facies----- Ankle ulcers----- Peri oral pigmentation ---- 1 (14.3) Knuckle pigmentation 5 (12.5) --- 2 (28.6) Figures in parenthesis are percentages 83Pulse Rate Themeanpulseratewas85.4/minuteincasesand83.7/minuteincontrols.The mean pulse rate was significantly increased (89.3/ minute) in cases with haemoglobin less than 6 gm/dl. There was no difference in mean pulse rate between the different types of anaemia except in the others group, in whom in was significantly raised (96.3/ minute). Blood Pressure The mean blood pressure was 121.2/ 76.3 mm of Hg in cases and 122.1/ 76.5mm ofHgincontrols.Itwaslessincaseswithhaemoglobinlessthan6gm/dl(118.7/75.2 mm of Hg), compared to cases with haemoglobin more than 9 gm/dl (122.7/ 77.3 mm of Hg). There was no significant difference in mean blood pressure in the different types of anaemia. Body Mass Index The mean body mass index was 21.5 kg/m2 in cases and 21.6 kg/m2 in controls. It wassignificantlydecreased(20.9kg/m2)incaseswithhaemoglobinlessthan6gm/dl. There was no significant difference of mean BMI among the various types of anaemia. 84Table 8 Pulse rate, Blood Pressure and BMI with severity of Anaemia Case Haemoglobin levels(in gm/dl) < 6 (n=23) 6-9 (n=40) > 9 (n=37) Total (n=100) Control (n=100) Mean pulse rate 89.3 12.883.6 9.884.9 7.585.4 10.083.7 16.9 Mean systolic blood pressure 118.7 9.7121.3 8.5122.7 10.4 121.2 9.6122.1 15.2 Mean diastolic blood pressure 75.2 7.976.1 7.777.3 9.076.3 8.276.5 8.4 Mean BMI20.9 1.522.0 1.721.4 1.621.5 1.721.6 1.6 Inference Increased mean pulse rate (p=0.082) as well as significantly decreased mean BMI (p0.05). Figure 6 Pulse rate 8081828384858687888990Mean ( /minute) Control s Cases Hb < 6gm/dlHb 6-9gm/dlHb > 9gm/dl85Figure 7 Blood Pressure Figure 8 Body Mass Index 2020.52121.52222.523kg/ m2 Control s Cases Hb < 6gm/dlHb 6-9gm/dlHb > 9gm/dl020406080100120140mm of HgControls Cases Hb < 6gm/dlHb 6-9gm/dlHb > 9gm/dlSystol i c BPDi ast ol i c BP86Table 9 Pulse rate, Blood Pressure and BMI with type of Anaemia Types of Anaemia DM (n=40) MH (n=25) NH (n=18) NN (n=10) Others (n=7) Mean Pulse rate85.0 8.582.3 12.087.0 7.584.1 5.296.3 14.9 Mean systolic blood pressure 120.1 9.8122.3 8.9118.9 8.3126 11.7122.9 9.5 Mean diastolic blood pressure 75.1 6.775.6 10.077.2 8.379.0 8.880.0 8.2 Mean BMI21.5 1.721.4 1.721.6 1.821.4 1.421.8 1.9 Inference Mean pulse rate significantly higher in the others group (P0.05). Mean BMI is not significantly different (P>0.05) Figure 9 Pulse, Blood pressure & BMI with types of Anaemia 020406080100120140DM MH NH NN OthersType of Anaemi aPulse (per mt)SBP (mm Hg)DBP (mm Hg)BMI (kg/m2)87Systemic examination Themostcommonfindingsonsystemicexaminationwerevenoushumandflow murmurs (9 cases each). Abdominal examination revealed 8 cases with splenomegaly and 5caseswithhepatomegaly.CNSfindingswereimpairmentofvibrationsense(4cases) andjointpositionsense(2cases),suggestiveofperipheralneuropathy.ElevatedJVP, cardiomegaly, and basal crepitations were seen in 2 cases each. Figure 10 Systemic Examination Systemic examination and severity of anaemia CardiovascularandrespiratoryfindingssuchaselevatedJVP,venoushum, cardiomegaly,flowmurmursandbasalcrepitationswerefoundonlyincaseswith haemoglobinlessthan6gm/dl,withtheexceptionofonecasewithhaemoglobin 012345678910No of casesA B C D E F G H I J K L M NSystemi c exami nati onA: JVPB: Venous HumC: CardiomegalyD: Gallop RhythmE: Flow murmersF: Basal CepitationsG: HepatomegalyH: Splenomegaly I : ConfusionJ: Motor WeaknessK: Abnormal DTRsL: Vibration SenseM: Joint Position SenseN: Romberg' s sign88between6and9gm/dl,whohadaflowmurmur.Impairmentofvibrationandjoint positionsensewerealsofoundonlyincaseswithsevereanaemia.Hepatomegalyand splenomegaly were found in all groups of cases equally. Table 10 Systemic examination and severity of Anaemia Haemoglobin levels in cases (in gm/dl) Systemic Examination Total (n=100) < 6 (n=23) 6-9 (n=40) > 9 (n=37) CVS JVP2 2 (8.7) -- Venous hum9 9 (39.1) -- Cardiomegaly2 2 (8.7) -- Gallop rhythm---- Flow murmur9 8 (34.8) 1 (2.5) - RS: Basal crepts 2 2 (8.7) -- P/A Hepatomegaly5 2 (8.7) 1 (2.5) 2 (5.4) Splenomegaly8 2 (8.7) 3 (7.5) 3 (8.1) CNS Confusion---- Power---- DTRs---- Vibration4 4 (17.4) -- Position2 2 (8.7) -- Romberg's---- Figures in parenthesis are percentages 89Systemic examination and type of anaemia ElevatedJVP,venoushum,cardiomegaly,flowmurmursandbasalcrepitations werenotfoundincaseswithnormocytichypochromicanaemiaandnormocytic normochromicbloodpicture.Thisispossiblyduetothefactthatthesecaseshadless severe anaemia. Hepatomegaly and splenomegaly was seen in all types of anaemia except caseswithnormocyticnormochromicbloodpicture.Impairmentofvibrationandjoint positionsensewasseenonlyincaseswithdimorphicanaemiaandmegaloblastic anaemia. Table 11 Systemic examination and type of Anaemia Types of Anaemia Symptoms DM (n=40) MH (n=25) NH (n=18) NN (n=10) Others (n=7) CVS JVP---- 2 (28.6) Venous hum 5 (12.5) 1 (4.0) -- 3 (42.6) Cardiomegaly---- 2 (28.6) Flow murmur 6 (15.0) 1 (4.0) -- 2 (28.6) RS- Basal crepts---- 2 (28.6) P/A Hepatomegaly 2 (5.0) 1 (4.0) 1 (5.6) - 1 (14.3) Splenomegaly 2 (5.0) 2 (8.0) 2 (11.1) - 2 (28.6) CNS Vibration 3 (7.5) --- 1 (14.3) Position 1 (2.5) --- 1 (14.3) Figures in parenthesis are percentages 90Anaemia and Lipid profile The mean serum total cholesterol levels were significantly lower (P 9114.226.4101.423.4126.632.4109.525.7114.00#p>0.05 < 64.00.74.41.0--3.90.4p>0.05K 6-94.10.84.90.93.70.6-4.21.5p>0.05K TC/ HDL > 94.30.74.61.14.60.84.40.54.60#p>0.05K < 62.40.62.71.0--1.90.6p>0.05K 6-92.50.62.90.71.90.5-2.51.2p>0.05K LDL/ HDL > 92.70.62.91.12.80.72.90.52.60#p>0.05K Inference There is no statistically significant difference in lipid fractions between different types of anemia (P>0.05) # - p value could not be computed as there was only one case. K - Kruskal Wallies Test 966. Discussion The observations made in 100 cases of anaemia and 100 non anaemic controls, who presentedtoDepartmentofMedicine,KempegowdaInstituteofMedicalSciences, Bangalore,fromJune2003toJune2005isdiscussedhereandresultshavebeen compared with other similar studies. Age Allcasesinthisstudywerebetween14and75years.Majorityofthecaseswere middleaged(30-60years).Anaemiccasesyoungerthan50yearsweremorelikelyto havemoresevereanaemia,ascomparedtocasesolderthan50years,whoweremore likely to have less severe anaemia. This is probably due to younger individuals having a higherriskofworminfestations,andalsotheonsetofmenopausewithcessationof menstrual blood loss after the age of 50 years. Sex The cases consisted of 48 males and 52 females. There was no correlation between sex and severity of anaemia. Type and severity of Anaemia Dimorphicanaemiawasthemostcommonlyseentypeofanaemiainthisstudy. Microcytic hypochromic anaemia was the second most common, followed by normocytic hypochromicanaemia,andthosewithnormocyticnormochromicbloodpicture.Onlya fewcasesofmegaloblasticanaemiaandpancytopenia,andonecaseofchronicmyeloid leukemiawereseen.Thisisconsistentwithstandardtextbooksofmedicine,which 97describe nutritional deficiencies, especially iron deficiency, to be the most common cause for anaemia25,26. Most cases had mild to moderate anaemia, as defined by a haemoglobin level above 6gm/dl.Noneofthecaseswithnormocytichypochromicanaemiaornormocytic normochromic blood picture had severe anaemia. Symptoms Casescommonlypresentedwithnonspecificsymptomsofanaemia,suchas fatigue,dyspnoea,palpitationsandgiddiness.Symptomssuggestiveofaspecificcause for anaemia were rarely seen. Cases with more severe anaemia were more likely to have symptoms and had more numberofsymptoms.Patientswithhaemoglobinmorethan10gm/dlwereusually asymptomatic,andincidentallydetectedtohaveonanaemiaonroutine evaluation. This isconsistentwithstandardtextbooksofmedicinewhichstatethatmildanaemiasof insidious onset are usually asymptomatic26. Nonspecificsymptomssuchasfatigue,dyspnoea,giddiness,palpitations,fever, lossofappetiteandlossofweightwereequallyfrequentinthedifferenttypesof anaemia,exceptnormocytichypochromicanaemiaandcaseswithnormocytic normochromicbloodpicture.Thisispossiblyduetothefactthatthesecaseshadless severe anaemia. 98Personal history 19caseswerevegetarians.Vegetariansweremorelikelytohavemoresevere anaemiaandtohavedimorphicanaemia.Vegetariansarelikelytohavemoresevere anaemia as dietary iron of plant origin has less bioavailability. General physical examination Pallorwasthemostcommonfindingongeneralphysicalexamination.Caseswith more severe anaemia were found to be more likely to have findings on general physical examination. Signs were usually not seen in cases with haemoglobin less than 10 gm/dl. Koilonychia,lymphadenopathy,glossitisandangularstomatitiswereseenonlyincases withdimorphicanaemiaandmicrocytichypochromicanaemia.Knucklepigmentation andperioralpigmentationwasseenonlyincaseswithmegaloblasticanaemiaand dimorphicanaemia.Thisisconsistentwithdescriptionsgiveninstandardtextbooksof medicine25. Pulse Rate Themeanpulseratewashigherinanaemiccaseswhencomparedtononanaemic controls.Themeanpulseratewashigherincaseswithmoresevereanaemia.Thepulse ratehasbeendescribedtobehigherincaseofanaemia,instandardtextbooksof medicine. This is part of a compensatory mechanism to raise cardiac output and maintain tissue oxygenation34. 99Ickx,RigoletandLinden33,in2000,demonstratedthatanaemiacausesarisein pulse rate and stroke volume in patients whose haemoglobin was lowered from 13 gm/dl to 8 gm/dl. Blood Pressure Themeanbloodpressurewascomparableincasesandcontrols.Itwaslowerin caseswithmoresevereanaemia.Thisisduetoperipheralvasodilatation,another compensatory mechanism to raise cardiac output and maintain tissue oxygenation. DukeandAbelmann31,in1969,demonstratedthatredistributionofbloodvolume andvasodilatationplayedadominantroleinthehyperkineticcirculatoryresponseto chronic anaemia. Body Mass Index Themeanbodymassindexwascomparablein cases and controls. It was lower in cases with more severe anaemia. Systemic examination Themostcommonfindingsonsystemicexaminationwerevenoushumandflow murmurs.Featuressuggestiveofhyperdynamicstateofcirculationandcongestive cardiacfailurewereonlyseenincaseswithsevereanaemia.Featuressuggestiveof peripheral neuropathy were seen only in cases with megaloblastic anaemia and dimorphic anaemia. 100ThiswasconsistentwithastudydonebyGraettinger,ParsonsandCampbell35in 1983, which demonstrated that anaemia leads to significant haemodynamic changes only when it is severe. Anaemia and Lipid profile Theresultsofthisstudyconfirmthefindingsofpreviousinvestigatorsthatthe mean serum total cholesterol, HDL, LDL, VLDL and triglyceride levels are decreased in anaemia. The mean total cholesterol was found to be lower in anaemic cases when compared to controls. The decrease in mean serum cholesterol was not due to a specific lowering of any of the serum lipoprotein families; hypocholesterolemia was caused by a reduction in allthemajorlipoproteinfamilies,includingmeanHDL,LDL,VLDLandtriglycerides. TherewasaverylargedecreaseinmeantotalcholesterolandLDLlevels,andalarge decreaseinmeanHDLlevels,resultinginamildfallinmeanTC/HDLandLDL/HDL ratios. There was a mild decrease in mean VLDL and triglyceride levels. RifkindandGale4,5in1967showedthatanaemiawasassociatedwith hypocholesterolemiaandthedecreaseinserumcholesterolwasnotduetoaspecific loweringofanyoftheserumlipoproteinfamilies,andthathypocholesterolemiawas caused by a proportional reduction in all the major lipoprotein families. 101Elwood and Mahler6, in 1970, conducted a study 4,070 women, and demonstrated a significant difference in cholesterol between women with haemoglobin levels above and below 10.5g/dL. Severity of Anaemia and Lipid profile Patientswithmoresevereanaemiawerefoundtohavealargerfallinmeantotal cholesterolandallthelipidsubfractions.Thissuggeststhattheseverityofanaemiais responsible for the hypocholesterolemia seen in anaemia. A study conducted by Choi61 et al in 2001 showed that lipid levels in patients with iron deficiency anaemia were directly related to the hemoglobin levels. Type of Anaemia and Lipid Profile The type of anaemia did not have a significant effect on the mean lipid levels. This suggests that it is anaemia per se, and not the type of anaemia that is responsible for the lowering of lipid levels in anaemia. AstudybyWesterman7in1975examinedtherelationshipbetween hypocholesterolemiaandvarioustypesofanaemia,includingmegaloblasticanaemia, hereditaryspherocytosis,homozygoussicklecelldisease,aplasticanaemia,andliver associated anaemia. The study showed that the plasma cholesterol level is closely related to haematocrit levels, both initially and throughout the course of the anaemias associated withhypocholesterolemia.Thisassociationwasmaintainedregardlessofthecauseof 102changes in haematocrit levels. The authors concluded that low haematocrit, not the type of anaemia, is the cause of low cholesterol levels. SeipandSkrede56,in1967,foundanassociationbetweenserumcholesteroland haemoglobin in all cases, regardless of cause of anaemia. 1037. Conclusion 100casesofanaemiaand100controlswhopresentedtotheDepartmentof Medicine,KempegowdaInstituteofMedicalSciences,Bangalore,fromJune2003to June 2005 are presented here. They were studied regarding demographic characteristics, clinicalpresentationandbiochemicalchangeswithspecialreferencetolipidprofilein relation to severity and type of anaemia. The following conclusions were arrived at. 1)Majorityofcaseswithanaemiawereintheagegroupof30-60years.Younger cases were more likely to have more severe anaemia. 2)There was no relation between sex and severity of anaemia 3)Dimorphic anaemia was the most commonly seen type of anaemia. 4)Most cases had mild to moderate anaemia. 5)The most common presenting symptom was fatigue. Patients with severe anaemia were more likely to be symptomatic. 6)Vegetarians were more likely to have more severe anaemia. 7)Pallor was the most common finding on general physical examination. Cases with moresevereanaemiaweremorelikelytohavefindingsongeneralphysical examination. 1048)The mean pulse rate was higher in cases. The mean pulse rate was higher in cases with severe anaemia. The mean blood pressure and BMI were lower in cases with severe anaemia. 9)The most common findings on systemic examination were venous hum and flow murmurs. Features suggestive of hyperdynamic state of circulation and congestive cardiac failure were only seen in cases with severe anaemia. 10) The mean total cholesterol, HDL, LDL, VLDL and triglyceride levels, along with TC/HDL and LDL/HDL ratios were significantly decreased in cases compared to controls. 11) Therewasalargerreductioninmeantotalcholesterol,HDL,LDL,VLDLand triglyceridelevels,alongwithTC/HDLandLDL/HDLratioswithincreased severity of anaemia. 12) The type of anaemia did not have a significant effect on the mean lipid levels. 1058. Summary This study was done on 100 anaemic cases and 100 non anaemic controls to study the clinical presentation and effect on lipid profile of anaemia. Youngerindividualsaremorelikelytohavesevereanaemia.Caseswithsevere anaemiahavemoresymptoms.Theyhavehighermeanpulserate,lowermeanblood pressure and mean BMI. Vegetarians are more likely to have severe anaemia. Cases with severe anaemia also have more signs on examination. 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Proforma A Study of Lipid Profile in Anaemia Case/Control No: Matched with Case/Control No: Preliminary data of the Patient History of Presenting Illness: FatigueYes/ No DyspnoeaYes/ No GiddinessYes/ No PalpitationsYes/ No AnginaYes/ No PicaYes/ No DysphagiaYes/ No Abd painYes/ No Bony painYes/ No FeverYes/ No Loss of appetiteYes/ No Weight loss Yes/ No Name:Age:yearsSex:M / F Occupation: OP/IP No:Unit:Med Date: 116JaundiceYes/ No BleedingYes/ No MalaenaYes/ No HaemoglobinuriaYes/ No MenorrhagiaYes/ No PregnancyYes/ No Post menopausal bleedingYes/ No Past History: Diabetes MellitusYes/ No HypertensionYes/ No IHDYes/ No CVAYes/ No AIDSYes/ No Recent blood lossYes/ No Gall stonesYes/ No Personal History: Diet:Veg/ Non veg SmokingYes/ No AlcoholYes/ No Drug History: Oral ContraceptivesYes/ No 117Beta blockersYes/ No Diuretics Yes/ No SteroidsYes/ No NSAIDsYes/ No Family History AnaemiaYes/ No JaundiceYes/ No GallstonesYes/ No On Examination: PallorYes/ No KoilonychiaYes/ No Icterus Yes/ No Pedal edemaYes/ No LymphadenopathyYes/ No GlossitisYes/ No Angular stomatitisYes/ No PetechiaeYes/ No Haemolytic facies Yes/ No Ankle ulcersYes/ No Perioral pigmentation Yes/ No Knuckle pigmentation Yes/ No Pulse:/minRhythmVolume BP:mm of Hg 118Weight:kgs Height:cms Body Mass Index:kg/m2 Cardiovascular system JVPYes/ Nocms Venous humYes/ No CardiomegalyYes/ No S3Yes/ No Flow murmerYes/ No Respiratory system Basal crepitationsYes/ No Abdomen Hepatomegaly Yes/ No Splenomegaly Yes/ No Central nervous system ConfusionYes/ No Power DTRs VibrationNormal/ Impaired PositionNormal/ Impaired RombergsPresent/ Absent 119Investigations: 1. Complete Haemogram Hbg/dl PCV%, TC* 103 /mm3 DC%P%L%E%M%B, ESRmm/hr RBC*106 /mm3 MCVfL MCHpg MCHCg/dlPeripheral Smear: 2. Lipid Profile Total Cholesterolmg/dl HDLmg/dl LDLmg/dl VLDLmg/dl, Triglyceridesmg/dl TC/ HDL Ratio LDL/ HDL Ratio 1203. Urine Routine Albumin Sugar MicroscopyPC / HPF EPC / HPF RBC / HPF 4. Random Blood Sugarmg/dl 5. Blood Ureamg/dl 6. Serum Creatininemg/dl 7. Liver Function Tests Serum total bilirubinmg/dl Serum direct bilirubin mg/dl SGOTU/L SGPTU/L SAPU/L Serum total proteingm/dl, Serum albumingm/dl Albumin/ Globulin Ratio 1218. Thyroid Profile TSHU/ml T3 ng/dl T4 g/dl 9. FBSmg/dl PPBSmg/dl 10. Bone Marrow Aspiration Cytology 122II. Master Chart Key to Master Chart DMDiabetes mellitus HTNHypertension IHDIschemic heart disease CVACerebrovascular accident AIDSAcquired immunodeficiency syndrome OCsOral contraceptives BPBlood pressure WtWeight HtHeight BMIBody mass index CVSCardiovascular system JVPJugular venous pressure RSRespiratory system P/APer Abdomen CNSCentral nervous system DTRsDeep tendon reflexes Hb Haemoglobin PCVHaematocrit TCTotal count PPolymorphs LLymphocytes 123EEosinophils MMonocytes BBasophils ESRErythrocyte sedimentation rate MCVMean corpuscular volume MCHMean corpuscular haemoglobin MCHCMean corpuscular haemoglobin concentration STCSerum total cholesterol HDLHigh density lipoprotein LDLLow density lipoprotein VLDLVery low density lipoprotein TGTriglycerides PCsPus cells EPCsEpithelial cells RBCsRed blood cells RBSRandom blood sugar FBSFasting blood sugar PPBSPost prandial blood sugar STBSerum total bilirubin SDBSerum direct bilirubin SGOTSerum glutamate oxaloacetate aminotranferase SGPTSerum glutamate pyruvate aminotransferase SAPSerum alkaline phosphatase 124A/GAlbumin/ globulin ratio TSHThyroid stimulating hormone T33,5,3-Triiodothyronine T4Thyroxine