Case of the weekCase of the weekJagdish KJagdish K

Prof. A. Gowrishankar’s unitProf. A. Gowrishankar’s unit

25yr old male presented to us for getting 25yr old male presented to us for getting evaluated for anemia.evaluated for anemia.

He was apparently normal 10yrs ago, He was apparently normal 10yrs ago, following which he developed fever for following which he developed fever for two days.two days.

He went to a practitioner and diagnosed He went to a practitioner and diagnosed to have low Hb and was transfused two to have low Hb and was transfused two units of blood.units of blood.

Neither Hb value nor indication for Neither Hb value nor indication for transfusion was known.transfusion was known.

Patient’s Hb is on the lower side for the Patient’s Hb is on the lower side for the past 5yrs.past 5yrs.

No h/oNo h/o Chest painChest pain PalpitationPalpitation Giddiness Giddiness DizzinessDizziness SyncopeSyncope PresyncopePresyncope Undue fatiguabilityUndue fatiguability

No h/oNo h/o Abdominal painAbdominal pain Nausea / vomitingNausea / vomiting Altered bowel habitsAltered bowel habits Hematemesis / melena / hematocheziaHematemesis / melena / hematochezia

No h/oNo h/o DiplopiaDiplopia DysphagiaDysphagia DysarthriaDysarthria Motor / sensory deficitsMotor / sensory deficits Involuntary movementsInvoluntary movements Altered sensoriumAltered sensorium

No h/oNo h/o Bleeding tendanciesBleeding tendancies Chronic blood lossChronic blood loss Recurrent infectionsRecurrent infections

Not a k/c/o DM, HT, TB, Not a k/c/o DM, HT, TB,

Works as a software consultant.Works as a software consultant.

ExaminationExamination

Well oriented, conscious, afebrileWell oriented, conscious, afebrile Vitals : normalVitals : normal Pallor +vePallor +ve No icterus / cyanosis/ clubbing/ No icterus / cyanosis/ clubbing/

lymphadenopathy/ pedal edemalymphadenopathy/ pedal edema No evidence of facial dysmorphismNo evidence of facial dysmorphism Head to toe examination unremarkableHead to toe examination unremarkable

CVS : S1S2 +, no added soundsCVS : S1S2 +, no added sounds RS: NVBS +RS: NVBS + P/A : P/A :

Liver palpable 3cm below the costal marginLiver palpable 3cm below the costal margin Spleen palpable 4cm below the costal Spleen palpable 4cm below the costal

marginmargin No free fluidNo free fluid

CNS : NormalCNS : Normal

Patient was followed up on op Patient was followed up on op basis as requested.basis as requested.

ProblemsProblems

Anemia since childhoodAnemia since childhood

Hepatosplenomegaly Hepatosplenomegaly

InvestigationsInvestigations

CBC:CBC: Hb: 8 gm/dlHb: 8 gm/dl PCV: 24 %PCV: 24 % MCV: 62MCV: 62 MCH: 25MCH: 25 MCHC: 28MCHC: 28 Platelet: 2 lacsPlatelet: 2 lacs ESR: 10/15 ESR: 10/15 RDW: 15%RDW: 15%

Peripheral smear :Peripheral smear : microcytic hypochromic blood picture with microcytic hypochromic blood picture with

anisopoikilocytosisanisopoikilocytosis

Corrected reticulocyte count : 2.13Corrected reticulocyte count : 2.13

CXR : NormalCXR : Normal

ECG : sinus tachycardiaECG : sinus tachycardia

LFTLFT Tot Bil : 1.5Tot Bil : 1.5 Dir Bil : 0.2Dir Bil : 0.2 SGOT: 20SGOT: 20 SGPT: 22SGPT: 22 ALP: 120ALP: 120 Tot Protein: 6.2Tot Protein: 6.2 Albumin : 3.8Albumin : 3.8

RFT: RFT: Urea : 22Urea : 22 Creatinine: 0.6Creatinine: 0.6 RBS: 98RBS: 98 Electrolytes : normalElectrolytes : normal

Urine routine : normalUrine routine : normal Stool for occult blood / ova, cyst : Stool for occult blood / ova, cyst :

negativenegative

ANA:ANA: dsDNAdsDNA DCTDCT IDCTIDCT TIBC : 365TIBC : 365 S. Ferritin : 500S. Ferritin : 500 LDH -130LDH -130

Negative

Serum iron: Male 65–177 : Male 65–177 μμg/dL ;g/dL ; Female 50–170 Female 50–170 μμg/dL g/dL TIBC: 250–370 TIBC: 250–370 μμg/dL g/dL Transferrin saturation: Male 20–50%; : Male 20–50%; Female 15–50%Female 15–50% Serum ferritin: Male 20-250 Serum ferritin: Male 20-250 μμg/L, Female g/L, Female

15-150 15-150 μμg/Lg/L[6

Hb electrophoresis:Hb electrophoresis: A : 9%A : 9% A2: 6%A2: 6% F : 85%F : 85% S : 0S : 0Reported as thalassemia minorReported as thalassemia minor

Bone marrow aspiration:Bone marrow aspiration: Marked erythroid hyperplasiaMarked erythroid hyperplasia Otherwise normalOtherwise normal

Hb A – Hb A – αα 2 2 ββ 2 2

Hb A 2 - Hb A 2 - αα 2 2 δδ 2 2

Hb F - - Hb F - - αα 2 2 γγ 2 2

THAL MAJOR THAL MINOR THAL INTERMEDIA

< 2 yrs; asymptomatic variable

Transfusion dependent asymptomtic variable

Hb 2-3 g at presentation

Rarely < 9 variable

Hb F > A2 > A Hb F < 5 % Same as major

Florid clinical manifestations

asymptomatic variable

Diagnosis Diagnosis

Probably thalassemia intermediaProbably thalassemia intermedia

HemoglobinHemoglobin

Heme + GlobinHeme + Globin

Globin chain : Globin chain : 4 subunits4 subunits α, α, ββ, , γγ, , δδ, , εε chains chains

Thalassemia is a condition in which one Thalassemia is a condition in which one more of the globin chain is not more of the globin chain is not synthesised.synthesised.

ThalassemiaThalassemia

Described by Described by CooleyCooley & & LeeLee in 1925 in 1925

Initially coined as thalassic anemia Initially coined as thalassic anemia

Later termed as thalassemia Later termed as thalassemia

Thalassic Thalassic sea sea

ββ thalassemia thalassemia

αα tetramer tetramer αα44

α with α with γγ HbF HbF

α with α with δδ Hb A2 Hb A2

Protection of HbFProtection of HbF

αα chain cross linked chain cross linked

Homo tetramer

Precipitates in RBC

Destroyed in marrow

Not soluble

Destroyed in spleen

Ineffective erythropoiesis Extravascular hemolysis

αα thalassemia thalassemia

αα part of fetal Hb and adult Hb part of fetal Hb and adult Hb (affected in utero & (affected in utero & continues even after patient is born)continues even after patient is born)

ββ44 tetramers relatively soluble. So no ineffective tetramers relatively soluble. So no ineffective erythropoiesis but only extravascular hemolysis erythropoiesis but only extravascular hemolysis (HbH)(HbH)

γγ 4 4 in utero is in utero is Barts HbBarts Hb

Anemia & thalassemiaAnemia & thalassemia

Ineffective erythropoiesisIneffective erythropoiesis

Extrvascular hemolysisExtrvascular hemolysis

Decreased synthesis of globin Decreased synthesis of globin decreased Hb decreased Hb

IntermediaIntermedia

Major ----- Homozygous β0 / β0

Minor ----- heterozygous β0/ n or β+/n

Beta thalessemia

Homozygous ---- β+/ β+

Heterozygous ---- β+/β0

Compound heterozygous --- β+/ β0δ0

Difference between them is strictly clinicalDifference between them is strictly clinical

Needless to do genotypingNeedless to do genotyping

Same genotype can be there for all the Same genotype can be there for all the three.three.

Variable presentation for the same Variable presentation for the same genotypegenotype

Endless mutations Endless mutations listless deletions…listless deletions…

PathophysiologyPathophysiology

Symptoms and signsSymptoms and signs

Anemia and hemolysisAnemia and hemolysis

Medullary expansionMedullary expansion Coarse faciesCoarse facies OsteoporosisOsteoporosis OsteopeniaOsteopenia

Extramedullary hematopoiesisExtramedullary hematopoiesis HepatomegalyHepatomegaly SplenomegalySplenomegaly Nerve compressionsNerve compressions

Features of iron overloadFeatures of iron overload

Complications Complications

Organ failureOrgan failure MC cause of death : cardiac failureMC cause of death : cardiac failure

Severe anemia & sequelaeSevere anemia & sequelae

Growth retardation in childrenGrowth retardation in children

Tumour like nerve compressionTumour like nerve compression

Chronic hypoxia & high output stateChronic hypoxia & high output state

ComplicationsComplications

Hypercoagulable statesHypercoagulable states Why?Why? Pulmonary embolismPulmonary embolism CVACVA TIATIA PHTPHT Moya MoyaMoya Moya

RaceRace

AgeAge

SexSex

Lab diagnosisLab diagnosis

CBC CBC Peripheral smearPeripheral smear Hb electrophoresis: Hb electrophoresis:

normal -adultsnormal -adults A :95-98%A :95-98% A2: 2-3%A2: 2-3% F: <2%F: <2% S: 0S: 0

New born:New born: HbF: 50-80%HbF: 50-80%

6months:6months: HbF: 8%HbF: 8%

>6months>6months HbF: 1-2%HbF: 1-2%

In thalassemia intermediaIn thalassemia intermedia HbF: 20-100%HbF: 20-100% HbA2 : upto 7%HbA2 : upto 7% HbA: 0-80%HbA: 0-80%

Serum iron studiesSerum iron studies

Endocrine profile for iron overload complicationsEndocrine profile for iron overload complications

LFTLFT

MRIMRI Liver Liver good correlation with hepatic iron good correlation with hepatic iron

concentration, not with ferritinconcentration, not with ferritin Cardiac: correlation poorCardiac: correlation poor

Genotyping: Genotyping: usually not neededusually not needed Done only for antenatal cases and terminationDone only for antenatal cases and termination

Superconducting Quantum Interference Device Superconducting Quantum Interference Device ((SQUIDSQUID))

Non invasiveNon invasive

CostlyCostly

Good relaibilityGood relaibility

Little inferior to biopsyLittle inferior to biopsy

Uses very low power magnetc fieldUses very low power magnetc field

Will a patient diagnosed as Will a patient diagnosed as thalassemia intermedia thalassemia intermedia progress to thalassemia progress to thalassemia

major…?!?major…?!?

Medical careMedical care

Monitoring Monitoring

TransfusionTransfusion To maintain Hb >7 ( leucocyte depleted)To maintain Hb >7 ( leucocyte depleted)

SplenectomySplenectomy If no response to transfusionIf no response to transfusion Profound pancytopeniaProfound pancytopenia

Chelation Chelation ( when to start?)( when to start?)

LIC 1.5mg/gm of liver tissueLIC 1.5mg/gm of liver tissue

Or simply ferritin > 1gmOr simply ferritin > 1gm

Chelating agentsChelating agents

Desferroxamine s/c infusion 8-12hrs 5/7Desferroxamine s/c infusion 8-12hrs 5/7

DeferiproneDeferiprone

Defarisirox : Defarisirox : oral oral OD doseOD dose Highly efficientHighly efficient Already hit the market and running successfullyAlready hit the market and running successfully

NutritionNutrition Folic acidFolic acid Vitamin CVitamin C

When to give? When not?When to give? When not?

Bone marrow transplant if progression to majorBone marrow transplant if progression to major

Yersinia enterocolitis is a common complication in Yersinia enterocolitis is a common complication in iron overload. ( Septran for diarrhoea)iron overload. ( Septran for diarrhoea)

Take home messagesTake home messages

Difference between three types is strictly clinicalDifference between three types is strictly clinical

In Trait Hb rarely <9, totally asymptomaticIn Trait Hb rarely <9, totally asymptomatic

Major – first or second yr of life – transfusion Major – first or second yr of life – transfusion dependentdependent

Intermedia ------ inbetweenIntermedia ------ inbetween

Take home messagesTake home messages

Diagnosed by Hb electrophoresisDiagnosed by Hb electrophoresis

Genotyping is unnecessary except for prenatal Genotyping is unnecessary except for prenatal diagnosis. diagnosis.

Can have hypercoagulable statesCan have hypercoagulable states

Iron overload with or without transfusionIron overload with or without transfusion

Take home messagesTake home messages

SQUID – best noninvasive mode of assessing LICSQUID – best noninvasive mode of assessing LIC

Defarisirox– long acting, OD, highly effectiveDefarisirox– long acting, OD, highly effective

When in doubt treat as thalassemia majorWhen in doubt treat as thalassemia major

Thank you!!!Thank you!!!