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HEMATOLOGY -ONCOLOGY Div. Child Health Depart.- School of Medicine University of Sumatera Utara

AnemiaDefinition: reduction in red cell mass or blood hemoglobin concentration below 2 standard deviations (SD)

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Table 1.Normal red blood cell values in childrenHemoglobin(g/dl)MCV(fl)AgeMean -2SD Mean -2SDBirth (cord blood)16.5 13.5 108 981-3 days(capillary)18.5 14.5 108 95 1 week17.5 13.5 107 882 week16.5 12.5 105 861 month14.0 10.0 104 852 month11.5 9.0 96 773-6 month11.5 9.5 91 740.5-2 years12.0 10.5 78 702-6 years12.5 11.5 81 756-12 years13.5 11.5 86 7712-18 years, female14.0 12.0 90 7812-18 years, male14.5 13.0 88 7818-49 years, female14.0 12.0 90 8018-49 years, male15.5 13.5 90 80

Caroline Hasting,2002

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Anemia(WHO,1976):- 6 month

*IRON DEFICIENCY ANEMIA

Definition : Anemia resulting from lack of sufficient iron for synthesis of hemoglobin.

Prevalence :The most common cause of anemia worlwideAn estimated 30% of the worlds population :4.5 billion anemic500 600 million Iron def. anemia

...Prevalence

North American (1970) : 30 - 75% of child 1 2 years of ageIsraelli : 25% females (aged 16 - 17 yrs) Indonesia : 25 35% (aged 5 yrs)

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*PrevalenceAnemia Developed countries0-4 tahun : 20.1%5-14 tahun: 5.9%Developing countries0-4 tahun: 39.0%5-14 tahun: 48.1%

WHO, 2001

*Prevalence of ID & IDA

USA: 1-2 years ID 9%; IDA 3%adolescent girls ID 9%; IDA 2%UK Infants: Asian IDA 39% Afro-Caribbean 20% White 16%

Developing countriesAdolescent girls 21-35%Indonesia (SKRT 2001):

*Etiology of iron deficiency

ETIOLOGY

I. Deficiency intake :Dietary (milk 0,5-1.5 mg iron/L)

II. Increased demand :Growth (low birth weight, premarurity, low-birth-weight twins or multiple births, adolescence, pregnancy)Cyanotic Congenital heart disease

III. Blood loss :A. Perinatal1. Placental Transplacental bleeding into maternal circulationRetroplacental (e.g,premature placental separatio )IntraplacentalFetal blood loss or before birth (e.g, placenta previa)Fetofetal bleeding in monochrorionic twinsPlacental abnormalities*

. 2.Umbilicus - Ruptured umbilical cord (e.g, vasa previa) and other umbilical cord abnormalities- Inadequate cord tying- Postexchange transfusionB. Postnatal 1.Gastrointestinal tract- Primary iron deficiency anemia resulting in gut alteration with blood loss agravating existing iron deficiency - Hypersensitivity to whole cows milk? - Anatomic gut lesions, exudative enteropathy caused by undelying bowel disease- Gastritis from aspirin, adrenocortical steroids, indomethacin, phenylbutazone- Intestinal parasites( e.g, hookworm /Necator Americanus)- Henoch-Scholein Purpura *

2. Hepatobililiary system: hematobilia3. Lung: Pulmonary hemosiderosis, Goodpasture sydrome, defective iron mobilization with IgA deficiency4. Nose: recurrent epistaxis5. Uterus: menstrual loss6. Heart: intracardiac myxomata, valvular prostheses or patches7. Kidney: microangiopathic hemolytic anemia, hematuria, nephrotic syndrome,hemosiderinurias-chronic intravascular hemolysis8. Extracorporeal: hemodialysis, trauma

IV. Imparied absorption Malabsorption syndrome, celiac disease, severe prolonged diarrhea, postgastrectomy, inflammatory bowel disease, Helicobacter pylori infection associated chronic gastritis

Lanzkowsky,2005

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*Key Functional of Iron

*Iron Status in Human Body

*Iron cycle

BLUE OCEAN **

BLUE OCEAN

BLUE OCEAN **

BLUE OCEAN

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Pathophysiology

Stages Iron Deficiency

*Diagnostic ApproachAnamnesisPhysical examination findingsLaboratory examination

Korones D, 1999 Glader B, 2007

History takingPallor,floppiness :time of onsetFatigue,lethargyPoor feedingIrritabilityAbdominal painHeadache ,dizzinessShortness of breathArthralgia*

Clinical Manifestation

Pallor ,jaundiceTachycardia,postural hypotensionAnorexia Angular stomatitis GlossitisSpoon nailPica (pagophagia)Effect on neurologic and intellectual function: attention span, allertness,learning

Nathan Oski,2003Lanzkowsky P,2005 Glader B, 2007*

CLINICAL MANIFESTATIONSConsequences of anemia :Mild moderate iron def. ( Hb 6-10 g/dl) compensatory mechanism (+)Severe iron deficiency (Hb < 5 g/dl) :Fatigue, listlessness, irritability, anorexia, tachycardia, cardiac dilatation & systolic murmurs.Advanced iron deficiency : Pale, plump, & petulant .*

*Nonhematologic consequence :Pica :Phagophagia (compulsive eating of ice)Geophagia : interest in dirt consumption risk for parasitic infestation & lead poisoning)Ephitelial changes : Koilonychia, atrophy of lingual papilExercise intoleranceBehavioral changesAbnormal thermogenesisAltered host response

Miller Rd,Baehner RL,edisi ke 7CLINICAL MANIFESTATIONS

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*LABORATORIUM FINDINGS

Hemoglobin(Hb) is below the acceptable level for ageRed cell indices : - / normal MCV,MCHC and MCHC for age - RDW Blood smear : - Red cells : hypochromic, microcytic with anisocytosis and poikilocytosis Hb concentration

Reticulocyte count: N/slightly increasedPleated count : Thrombocytopenia, thrombocytosisFree erythrocyte protoporphyrin: > 100 g/dl

Lab.finding

Consentration Ferritin < 12 mg/dlSerum iron and iron saturation percentage iron metabolism :Serum iron : TIBC : Transferrin sat. (ratio SI : TIBC) : Serum transferrin receptor levels ( STfR ) Red blood cell zinc protoporphyrin/ heme ratio - Bone marrow iron is insufficient to support heme synthesis- Zinc protoporphrin relative to heme increases- Zinc substituses for iron in protoporphyrin IX

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The diagnosis of microcitic anemia using MCV and RDWMCV

Low

RDW

NarrowWide

Hb elektroforesisFEP* MCV on Parents Ferritin Trial of Iron*Also elevated in lead poisonin. Do serum lead level (if clinical indicated) *

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*PoikylocytosisAnisocytosis

*DIFFERENTIAL DIAGNOSIS1.Thalassemia trait2.Anemia of chronic diseases 3.Lead poisoning

*Diffrential Diagnosis Hypochrom Microcytic AnemiaLab findings IDA Thalassemia Minor Anemia chronic disease

MCV N/Serum ironN TIBCN Transferrin saturationN N/FEPN Serum ferritinN Lukens,1995

*DIAGNOSIS

Criteria of IDA by WHO :Hb concentration < normal (age dependent)Hematocrit < 31% ( N: 32 - 35%)Serum iron < 50 Ug/dl (N: 80-180 ug/dl)Transferrin sat. < 15 (N: 20-50%)

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Diagnostic Criteia of IDA (Cook dan Monsen):

Hypochrom microcytic anemiaTransferrin saturation 100 ug/dLSerum ferritin

*...Diagnosis Alternative way to determine IDA: Trial of iron supplementation

Important to know subclinical IDA with monitor hemoglobin respons (increased hemoglobin level).This procedure is very practical, sensitive dan economical especially for children at high risk of IDAIf with iron supplementation 3 mg iron/kgBW/day, 3-4 weeks, Hb level is increased 1-2 g/dL it is confirmed for IDA.

* DiagnosisCriteria of IDA by Lanzkowsky :1. Peripheral smears : - Microcytic hypochromic - MCV, MCH, MCHC : - RDW > 17%2. FEP : 3. Serum ferritin : 4. Serum ferritin , TIBC , Transferrin sat. < 16%5. Response to iron preparation 6. Bone marrow : Iron (-) /

* Classification of Anemia

ScreeningHb CBC: MCV- MCHMicrocytic, hypochromicMCV

Clinical management DiagnosisAssessment of underlying cause: dietary history, birth history, presence of abnormal bleeding , family history , past medical/surgery historyInvestigation and treatmentof any underlying cause found : dietary advice ,endoscopyIron therapy*

Iron therapyOral therapy

Dose: 3 mg/kg/day (2 devided doses)max 180mgDuration: 6-8 weeks after Hb and the red cell indices return normalThe following preparations provide 3 mg of elemental iron: 15 mg of ferrous sulfate, 9 mg of ferrous fumarate, 26 mg of ferrous gluconate, 9 mg of ferrous succinate, 17 mg of ferrous glycine sulfate, 21 mg of sodium iron edetate*

Hematologic response:a. Reticulocyte increase within 5-10 days following initiation of iron therapyb. Hb concentration increase Failure to respond to oral iron :The following reasons should be considered:a. Poor complianceb. Inadequate iron dosec. Ineffective iron preparationd. Persistent or unrecognized blood losse. Incorrect diagnosisf. Coexistent disease (infection ,inflammatory bowel disease,malignant disease,hepatic or renal disease)g. Impaired GI absorption*

Parenteral Therapy1.IntramuscularIron dextran ( 50 mg elemental iron/ml) /im , with dose : Normal Hb - initial Hb x Blood volume(ml)x 3.4 x 1.5 100It is safe,effective ,well tolerated in infants with acute illnessIndications :- Noncompliance with oral of iron- Severe bowel disease(e.g,inflammatorybowel disease)- Chronic hemorrhage (e.g, hereditarytelangiectasia, menorrhagia)- Acute diarrheal disorder in under privilegedpopulations with iron deficiency anemia

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2.Intravenous .Sodium ferric gluconate (Ferrlecit).Iron(III) hydroxyde sucrose comple (Venofer)Anemia associated with renal failure and hemodialysisDose: 1 4 mg/Kg/week *

Transfusion therapy

Packed red cell Severe anemia (Hb < 5 g/dl) requiring correction more rapidly especially when signs of cardiac dysfunction are present

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Nutritional Counseling

Maintain breast feeding for at least 6 monthsiron fortified (6-12mg/L) infant formulas after weaning from the breast and in non-breast fed infants until 1 year of age Iron-fortified cereal from 6 months to 1 year Suplemental ironFacilitator of iron absorption: vitamin C-rich foods(citrus,tomatoes,potatoes),meat,fish,poultryEliminated inhibitors of iron absorption such tea,phosphate ,phytates common in vegetarian diets*

Iron Content of Infant Foods

Food Iron,mg Unit

Milk0.5-1.5 LiterEggs1.2 EachCereal,fortified 3.0-5.0 OunceVegetables(starched)Yellow0.1-0.3 OunceGreen0.3-0.4Meats(strained)Beef, lamb, liver 0.4-2.0 Ounce Pork, liver, bacon 6.6 OunceFruits(strained)0.2-0.4 Ounce

Lanzkowsky,2005*

Factors affecting iron absorption of nonheme iron from the gastrointestinal tractIncreased absorptionVit C: citrus, tomatoes, potatoes, SolutesSugarsmeat, fish,poultryHydrochloric acidDecreased absorptionAntacidsPancreatic secretionsHypochlorhydriaPhytatesPhosphatesBlackwell,2006*

Prevention1.Encouragement of breast feeding (BF)2.Use of iron-fortified infant formula after weaning BF or non-BF3.Delay in the introduction of whole cows milk to 1 year of age4.Use iron fortified infant cereals and ascorbic acid-rich food solid food are introduced at 6 months5.Supplemental iron

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..PreventionIron supplemental:

Exclusive breast feeding beyond 6 month : 1 mg/Kg/dLow birth weight infants:a. 1.5-2.0 kg: 2 mg/kg/dayb. 1.0-1.5 kg: 3 mg/kg/dayc.

*MEGALOBLASTIC ANEMIADefinition :Presences of megaloblasts in the bone marrow and macrocytes in the blood Abnormalities of red blood cell (RBC) morphology and maturationEtiology :Deficiency of folic acidDeficiency Vitamin B12 (Cobalamin)Inborn errors of metabolism (rarely)

Causes of MegaloblastosisVit B12 (Cobalamin) deficiencyFolate deficiencyMiscellaneousA. Congenital disorders in DNA synthesis 1. Orotic aciduria(uridine responsive) 2. Thiamine- responsive megaloblastic anemia 3. Congenital familial megaloblastic anemia requiring massive dose of vit B12 and folate 4. Associated with congenital dyserythropoietic anemia 5. Lesch-Nyhan syndrome (adenine responsive)B. Acquired defects in DNA synthesis 1. Liver disease 2. Sideroblastic anemias 3. Leukemia, especially acute myeloid leukemia 4. Aplastic anemia (constitutional/acquired) 5. Refractory megaloblastic anemiaC. Drug induced megaloblastosis 1. Purine analogues (e.g, 6 mercaptopurine, azathioprine and thioguanine) 2. Pyrimidine analogues 3. Inhibitor of ribonucleotide reductase (cytosine arabinoside, hydroxyurea)Lanzkwosky,2005*

*Megaloblastic anemia

*Nucleated RBC of megaloblastic anemia Reticulocytes

*FOLIC ACID DEFICIENCY

Folic acid : adsorbed in the small intestineMegaloblastic anemia : occurs after 2 3 mo on a folate- free diet.

Causes of Folic Acid DeficiencyI Inadequate intake A. Poverty, ignorance, faddism B. Method of cooking (sustained boiling loses 40% folate) C. Goats milk feeding (6g folate/ L) D. Malnutrition (marasmus, kwasiokor) E. Spesial diets for phenylketonuria or maple syrup urine disease F. Prematurity G. Post bone marrow transplantionII. Defective absorption A. Congenital, isolated defect of folate malabsorption B. Aquired1. Idiopathic steatorrhea2. Tropical sprue3. Partial or total gastrectomy4. Multiple diverticula of small intestine5. Jejunal resection6. Regional Ileitis

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7. Whipple disease8. Intestinal Lymphoma9. Broad spectrum antibiotics 10. Drugs associated with impaired absorption/utilization of folic acid (e.g, Dilantin, primidone, metformin, ethanol,barbiturates) 11. Post bone marrow transpntation ( total body irradiation, drugs, intestinal GVH disease)III. Increased requirementsA. Rapid growth (e.g, prematurity, pegnancy)B. Cronic hemolytic anemia ( thalassemia major)C. Dyserythropoietic anemiasD. Malignant disease(e.g, lymphoma, leukemia)E. Hypermetabolic states (e.g, infection, hyperthyroidism)D. Extensive skin disease (e.g, Dermatitis herpetiformis,psosiasis)G. CirrhosisH. Post bone marrow transplantation*

IV. Disorders of folic acid metabolismA. Congenital1. Methylenetetrahydrofolate reductase deficiency2. Glutamate formiminotransferase deficiency3. Fuctional N5- methyltetrahydrofolate: homocysteine methyltransferasedeficiency4. Dihydrofolate reductase deficiency5. Methenyl-tetrahydrofalate cyclohydrolase6. Primary methyl-tetrahydrofolate: homocysteine methyltransferase deficiency*

B. Acquired1. Impaired utilization of folate a. Folate antagonis (drugs that are dihydrofolate reductase inhibitors,e.g, methotrexate, pyrimethamine, trimethoprim, pentamidine) b. Vit B12 deficiency c. Alcoholism d. Liver disease (acute and cronic) e. Other drugsV. Increased excretion (e.g, chronic dialysis, vit B12 deficiency, liver disease, heart disease)

Lanzkowsky,2005

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*VITAMIN B12 DEFICIENCY ANEMIADerived from cobalamin in food (mainly animal sources) secondary toproduction by microorganism

Obtained primarily from :Animal proteins (ie, red meat, poultry, fish, eggs, and dairy)Plants and vegetables lack the vitamin unless they have been contaminated by soil microorganisms

*Absorption of vit. B12

Cause of vitamins B12 DeficiencyInadequate vitamins B12 intakeA. Dientary (

B. Failure of absorption in small intestine 1. Spesific vit B12 malabsorption a. Abnormal intrinsik factor b. Defective cobalamin transport by enterocytesc. Ingestion of chelating agents 2. Intestinal disease causing generalized malabsorption, including vit.B12 malabsorption :a. Intestinal resectionb. Crohnn diseasec. Tunerculosis of terminal ileumd. Lymphosarcoma of teminal ileume. Pancreatic insufficiencyf. Zollinger-Ellison syndromeg. Celiac disease, topical sprueh. Other less specific malabsorption syndromesi. HIV infectionj. Long standing medication that decreases gastric acidityk. Neonatal necrotizing enterocolitis 3. Competition for vit B12a. Small bowel bacterial overgrowthb. Diplyllobothrium latum, Giardia lamblia, Plasmodium falcifarum, Strongyloides stercoralis

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III. Defective vit.B12 transporta. Congenital TC II deficiencyb. Transient deficiency of TC IIc. Partial deficiency of TC IIIV. Disorders of vit.B12 metabolismA. Conenital1. Adenosylcobalamin Cb1A and Cb1B diseases2. Deficiency of methylmalonyl-CoA mutase3. Methylcobalamin deficiency Cb1E and Cb1G diseases4. Combined adenosylcobalamin and methylcobalamin deficienciesB. Acquired1. Liver diseases2.Protein malnutrition3. Drugs associated with impaired absorption and/or utilization of vitB12

Lanzkowsky,2005

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Clinical Features of cobalamin and folate deficiencyPallor, lethargy, fatigability, and anorexia; sore red tounge and glossitis; episodic or continous diarrheaHistory: similarly affected sibling or a sibling who died, maternal vit B12 deficiencyVit B12 deficiency: developmental delay, apathy, weakness, irritability, or evidance of neurodevelopmental delay, loss of developmental milestones, particulary motor achievements, hypotonia,loss reflexs,paresthesiasNeurologic complications are increased risk of vascular thrombosis due to hyperhomocysteinemiaMaternal folate deficiency: neural tube defects, prematurity, fetal growth retardation, fetal lossInborn errors of metabolism: failure to thrive, neurologic disorders, unexplained anemias, cytopenias

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Diagnosis1. Red cell changes:a. Hemoglobulin : reducedb. Red cell indices: MCV, MCHC normalc. RDW: d. Blood smear: macrocytes and macro ovalocytes, anisocytosis, poikilocytosis, Howell-Jolly bodies2. White bood cell count: 1500-4000/mm3, neutrophils large and hypersegmentation3. Platelet count: 50.000-180.000/mm34. Bone marrow : megaloblastic5. Serum vit.B12 level:

Vit.B12 deficiency suspected :

1. History dietary and previous surgery2. Schilling excretion test3. Schilling test is abnormal, repeat with commercial intrinsic factor.4. Gastric acidity after histamine stimulation5. Measure serum holo-transcobalamin II6. Investigated : Ileal disease7.Disorders of vitamin B12 metabolism

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Suspect folic acid deficiency :

1. Dietary and drugs (antibiotics,anticonvulsants), gastroenterologic symptoms (malabsorption,diarrhea,dietary history)2. Tests for malabsorption3. Upper gastrointestinal barium study and follow through4. Endoscopy and biopsy : upper gut ,jejunal5. Enzyme assays *

Treatment Folic acid deficiency

Folic acid : Initially corrected : 5 mg (100 g/Kg)daily for 4 months orally or parenteral Diagnostic test: smaller dose 0.1 mg/day for a week2. Underlying causative disorder3. Improvement of the diet (increase folate intake4. Prophylactic folic acid: children with severe hemolytic anemia5.Transfusion : severe anemia or child is very ill.6. N-5-formyl tetrahydrofolic acid : Hereditary dihydrofolate reductase deficiency *

TreatmentVitamin B12 deficiencyPreventionProphylactic vit B12 :total gastrectomy,Ileal resectionActive treatment- First treated : 6 series im or sc Hydroxocobalamin - Low doses of Cobalamin 10 g/day o 0.2 g/Kg sc for 2 days reticulocytosis- Maintenance :1000g Hydroxocobalamin every 3 months- Food supplemented with Cobalamin

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