IRON METABOLISM DISORDERS

ANEMIAANEMIADefinition

• Decrease in the number of circulating ec ease t e u be o c cu at gred blood cells

• Most common hematologic disorder by farfar

ANEMIAANEMIACauses

Blood loss• Blood loss• Decreased production of red blood cells

(Marrow failure)(Marrow failure)• Increased destruction of red blood cells

Hemolysis– Hemolysis

• Distinguished by reticulocyte count– Decreased in states of decreased production– Decreased in states of decreased production– Increased in destruction of red blood cells

ANEMIAANEMIACauses - Decreased Production

• Cytoplasmic production of protein– Usually normocytic (MCV 80-100 fl) or

microcytic (MCV < 80 fl)

• Nuclear division/maturation– Usually macrocytic (MCV > 100 fl)

ANEMIAANEMIACauses - Cytoplasmic Protein Production

D d h l bi th i• Decreased hemoglobin synthesis– Disorders of globin synthesis– Disorders of heme synthesis

• Heme synthesis– Decreased Iron– Iron not in utilizable form– Decreased heme synthesis

IRON DEFICIENCY ANEMIAIRON DEFICIENCY ANEMIAPrevalence

Country Men (%) Women(%)

PregnantWomen (%)

S I di 6 35 56S. India 6 35 56N. India 64 80Latin America 4 17 38Latin America 4 17 38Israel 14 29 47Poland 22Sweden 7USA 1 13

IRON

• Functions as electron transporter; vital for life• Must be in ferrous (Fe+2) state for activity• Must be in ferrous (Fe+2) state for activity• In anaerobic conditions, easy to maintain

ferrous stateferrous state• Iron readily donates electrons to oxygen,

superoxide radicals, H2O2, OH• radicalssuperoxide radicals, H2O2, OH radicals• Ferric (Fe+3) ions cannot transport electrons or

O22

• Organisms able to limit exposure to iron had major survival advantage

IRONBody Compartments 75 kg manBody Compartments - 75 kg man

StoresStores1000 mg

Tissue170 mg 4 mg

Absorption < 1 mg/day

Excretion < 1 mg/dayg

Red Cells2400 mgg

IRON CYCLE

CIRCULATING RBCs

Fe FeFe Fe

ptor

CIRCULATING RBCsMONONUCLEARPHAGOCYTES

Fe FeFeFe FerritinFe

e

Fe

Fe Fe

Ferritin Ferritinerrin

Rec

ep

Fe

Fe

Hemosiderinslow

Fe

Fe Ferritin

Tran

sfe

RBC PRECURSORRBC PRECURSOR

Fe Fe

TRANSFERRIN

INTRACELLULAR IRON TRANSPORTFe+2

Transferrin

Transferrin receptor

H+H+

LH+H+

Lysosome Fe+2

IRONCauses of Iron Deficiency

• Blood Loss– Gastrointestinal Tract– Gastrointestinal Tract– Menstrual Blood Loss– Urinary Blood Loss (Rare)– Blood in Sputum (Rarer)

• Increased Iron Utilization– Pregnancy– Infancy

Adolescence– Adolescence– Polycythemia Vera

• Malabsorption– Tropical SprueTropical Sprue– Gastrectomy– Chronic atrophic gastritis

• Dietary inadequacy (almost never sole cause)C bi i f b• Combinations of above

DAILY IRON REQUIREMENTSDAILY IRON REQUIREMENTSPregnancies

2

2.5

ay)

1

1.5

2

orbe

d Ir

on

men

t (m

g/da

0

0.5

1

Abs

oR

equi

rem

0 2

10 14 20 27 29 32 34 40 49 55 65

Males

0

Age

Males Females

IRON ABSORPTION

12

1416

)

810

12

mg/

day)

2

46

Iron

(

0

2

Iron in Diet IronSolubilized

Iron Uptake Iron Absorbed

GI ABSORPTION OF IRON

FERRITIN/TRANSFERRIN REGULATION

IRON ABSORPTION

100

1

10Iron

Absorbed (mg/day)

0.01

0.1(mg/day)

0 1 1 8 10 20 80 100 2000.1 1 8 10 20 80 100 200Iron Ingested (mg/day)

IRON DEFICIENCY ANEMIAProgression of Findings

St i bl I B M A i t• Stainable Iron, Bone Marrow Aspirate• Serum Ferritin - Low in Iron Deficiency• Desaturation of transferrin• Serum Iron dropsp• Transferrin (Iron Binding Capacity) Increases• Blood Smear - Microcytic Hypochromic;• Blood Smear - Microcytic, Hypochromic;

Aniso- & Poikilocytosis• Anemia• Anemia

IRON STORESI D fi i A iIron Deficiency Anemia

StoresStores0 mg

Tissue170 mg 3 mg

Absorption 2-10 mg/day

Excretion Dependent on Cause170 mg

Red Cells1500 mg

IRON DEFICIENCYIRON DEFICIENCYSymptoms

F ti S ti t f ti• Fatigue - Sometimes out of proportion to anemia

• Atrophic glossitis• Pica• Koilonychia (Nail spooning)• Esophageal Web• Esophageal Web

IRONCauses of Iron Deficiency

• Blood Loss– Gastrointestinal Tract– Gastrointestinal Tract– Menstrual Blood Loss– Urinary Blood Loss (Rare)– Blood in Sputum (Rarer)

• Increased Iron Utilization– Pregnancy– Infancy

Adolescence– Adolescence– Polycythemia Vera

• Malabsorption– Tropical SprueTropical Sprue– Gastrectomy– Chronic atrophic gastritis

• Dietary inadequacy (almost never sole cause)C bi i f b• Combinations of above

IRON REPLACEMENT THERAPYResponse

U ll l ll 300 900 /d• Usually oral; usually 300-900 mg/day• Requires acid environment for

absorption• Poorly absorbedy

IRON THERAPYIRON THERAPYResponse

Initial response takes 7 14 days• Initial response takes 7-14 days• Modest reticulocytosis (7-10%)

C ti f i i 2 3 th• Correction of anemia requires 2-3 months• 6 months of therapy beyond correction of

anemia needed to eplete sto es ass minganemia needed to replete stores, assuming no further loss of blood/iron

• Parenteral iron possible but problematic due• Parenteral iron possible, but problematic due to allergic reactions

Hemochromatosis-1• Disease of excess iron uptake• Disease of excess iron uptake• 2% of population has hemochromatosis;

inherited as autosomal dominant• Exists worldwide, but

– Belt across Northern Europe with increased incidenceincidence

• Ireland, Scandinavia, Russia

• Defects can be in DMT-1, more commonly in HFE (genetic defects only really studied forHFE (genetic defects only really studied for northern Europeans)

• Can also have acquired hemochromatosis, f t f i f th illfrom transfusion for other illnesses

Hemochromatosis -2

D f t i HFE d d i• Defect in HFE causes decreased iron uptake by crypt enterocytes

• Leads to increased DMT-1, causing increased iron extraction from diet & increased iron delivery to tissues

• Once iron is absorbed, very difficult to , yremove

Hemochromatosis-3• Sequence of events:• Sequence of events:

– Increased ferritinIncreased transferrin saturation– Increased transferrin saturation• Normal c. 33%; if > 60%, often marker for

disease; if > 90-95%, can start to get free iron

• Increased iron binding to other transport proteins– Albumin

• Iron deposition in tissues, leading to:p , g

Hemochromatosis 4Hemochromatosis-4• Diseases

– Skin darkening• Due to iron deposition in skin causing increased

melanin productionmelanin production– Endocrinopathy

• Diabetes, hypothyroidism, hypopituitarism, yp y , yp p– Liver damage

• Can lead to cirrhosis, hepatocellular CA– Cardiac damage

• Cardiomyopathy leading to congestive heart failurefailure

Hemochromatosis-5

T t t• Treatment– Early recognition– Phlebotomy– Iron chelation – Generally reserved for

f i i d d h h itransfusion-induced hemochromatosis

ANEMIA OF CHRONIC DISEASEFindingsFindings

• Mild, non-progressive anemia (Hgb c. 10, Hct c. 30%30%

• Other counts normal• Normochromic/normocytic (30%• Normochromic/normocytic (30%

hypochromic/microcytic)• Mild aniso- & poikilocytosisp y• Somewhat shortened RBC survival• Normal reticulocyte count (Inappropriately low for y ( pp p y

degree of anemia)• Normal bilirubin• EPO levels increased but blunted for degree of

anemia

ANEMIA OF CHRONIC DISEASECauses

• Thyroid diseaseCollagen Vascular Disease• Collagen Vascular Disease– Rheumatoid Arthritis– Systemic Lupus Erythematosus

Polymyositis– Polymyositis– Polyarteritis Nodosa

• Inflammatory Bowel DiseaseUlcerative Colitis– Ulcerative Colitis

– Crohn’s Disease• Malignancy

Ch onic Infectio s Diseases• Chronic Infectious Diseases– Osteomyelitis– Tuberculosis

F ili l M dit F• Familial Mediterranean Fever

IRON STORESA i f Ch i DiAnemia of Chronic Disease

StoresStores2500 mg

Tissue170 mg 1 mg

Absorption < 1 mg/day

Excretion < 1 mg/day170 mg g

Red Cells1100 mg

IRON CYCLEAnemia of Chronic DiseaseAnemia of Chronic Disease

MONONUCLEARPHAGOCYTESFe Fe

or

CIRCULATING RBCs

Fe FeFeFe Ferritin

F

Fe Fe

F iti Ferritinrrin

Rec

epto

FeHemosiderin

slow

Fe Ferritin Ferritin

Tran

sfer

RBC PRECURSORRBC PRECURSORFe Fe

IL-1/TNF

TRANSFERRIN

IRON DEFICIENCY versus ACD

S I T f i F itiSerum Iron Transferrin Ferritin

Iron Deficiencyy

ACD

Soluble Transferrin Receptor• Measure of ferrokinetic activity• Measure of ferrokinetic activity• Elevated in iron deficiency

N ll l d i i f• Not usually elevated in anemia of chronic inflammation (not an acute phase reactant)phase reactant)

• Still not widely availableE i• Expensive

• May replace iron binding capacity &/or f itiferritin

SUMMARYSUMMARYIron Metabolism Disorders

• Most common form of anemia• Most common form of anemia• Symptom of pathologic process

P i if i i h l i• Primary manifestation is hematologic• Treatment requires:

– Replacement therapy– Correction of underlying cause (if possible)

• Iron excess more dangerous than iron deficiency