iron deficiency anemia rakhi naik, md, mhs assistant professor of medicine & oncology, division...

IRON DEFICIENCY ANEMIA

Rakhi Naik, MD, MHS

Assistant Professor of Medicine & Oncology,

Division of Hematology

Disclosures

None

Objectives

• Understand the basic physiology of iron absorption, transport and storage

• Understand the causes of iron deficiency and the compensatory responses seen in clinical lab tests

• Understand modalities of treatment of iron deficiency and anemia

Global Burden of Anemia

KASSEBAUM et al BLOOD, 30 JANUARY 2014 x VOLUME 123, NUMBER 5

KASSEBAUM et al BLOOD, 30 JANUARY 2014 x VOLUME 123, NUMBER 5

KASSEBAUM et al BLOOD, 30 JANUARY 2014 x VOLUME 123, NUMBER 5

Iron Distribution

Adult male has ~4g total body

iron stores

Andrews NEJM, 23 DEC 1999 x VOLUME 341, Number 26

Hemoglobin in RBC

Schechter BLOOD, 15 NOVEMBER 2008 VOLUME 112, NUMBER 10

Heme is a porphyrin

ring containing an iron atom

Each Hgb molecule can bind 4

oxygen molecules

at heme site

Schechter BLOOD, 15 NOVEMBER 2008 VOLUME 112, NUMBER 10

Iron Absorption• Food sources supply: 10 - 25 mg / day• Absorbed in the brush border of the upper small intestine

• Enhanced by gastric acid• Inhibited by tannins, systemic inflammation

• Most dietary iron is nonheme form, <5% bioavailability• < 10% dietary iron is heme form, >25% bioavailability

Iron absorption from food

Iron Absorption (% of dose)

0 5 10 15 20 25

Veal muscle

HemoglobinFish muscle

Veal liverFerritin

Soy beansWheat

LettuceCorn

Black beansSpinach

Rice

Non-hemeiron

Hemeiron

• Transferrin – plasma iron transporter protein. Carries less than 1% of total body iron

• Ferritin – intracellular storage of iron

• Hemosiderin – long term iron storage pool

Iron Storage

• Ferritin• multi-subunit protein• primarily intracellular• some in plasma

• Hemosiderin• insoluble form of ferritin

• visible microscopically

The iron cycle

Pietrangelo, NEJM 2004:350:2383

Iron Losses• Iron is closely conserved in humans

<0.05% of iron is lost per day normally

1. Very small amounts in urine, bile and sweat2. Cells shed from skin, intestinal and urinary tracts3. Menstrual blood loss4. Pregnancy and lactation• Humans have NO other physiologic means to excrete excess iron

Pathogenesis of Iron Deficiency

• Blood loss• Occult or overt GI losses, traumatic or surgical losses

• Failure to meet increased requirements• Rapid growth in infancy and adolescence• Menstruation, pregnancy

• Inadequate iron absorption • Diet low in heme iron• Gastrointestinal disease or surgery• Excessive cow’s milk intake in infants

Andrews NEJM, 23 DEC 1999 x VOLUME 341, Number 26

Features of Iron Deficiency Anemia

•Depends on the degree and the rate of

development of anemia

•Symptoms common to all anemias:

• pallor, fatigability, weakness, dizziness,

irritability

Other features of IDA• Pagophagia - craving ice• Pica - craving of nonfood substances

• e.g., dirt, clay, laundry starch

• Glossitis - smooth tongue• Restless Legs• angular stomatitis - cracking of corners of mouth• Koilonychia - thin, brittle, spoon-shaped fingernails

Tests for Iron Deficiency•Peripheral blood smear•Red cell indices (MCV, MCH)•Serum ferritin•Serum iron / transferrin = iron saturation•Bone marrow iron stain (Prussian blue)

Marked hypochromasia,

microcytosis

Serum

Bone Marrow

N

N

N

Circulation

Reticulocyte

Erythrocyte

Spleen

Macrophage

Low Hgb

Low Serum Fe/TS Low sFt/Liver Fe

Iron Deficiency

High sTfR

ErythroblastTfR+

Fe

Transferrin

Sequential Changes in IDA

NORMALDEPLETED

IRONSTORES

IRONDEFICIENCY

IRONDEFICIENCY

ANEMIA

FERRITIN

IRON SATURATION

MCV & Hb & Hct

Differential for low serum ferritin1. Iron Deficiency

2. Iron Deficiency

CBC in Iron Deficiency Anemia

Lab values in severe IDA

Differential Diagnosis of IDA

•Thalassemia trait (low MCV, normal RDW)• Imbalance of globin chain production

•Anemia of inflammation• Decreased iron utilization in the face of

adequate iron stores

• Low ferritin / serum transferrin receptor

IDA vs. Inflammation

Ferritin

IDA Inflammation

Serum Iron

Transferrin sat

sfTR / log Ferr

Marrow Iron No D

Punnonen, K, Blood 1997; 89:1052

TfR-ferritin index <1.0 suggests the

diagnosis of ACD, while an index >2.0 suggests either IDA

or the combination of IDA and ACD

Iron stain of bone marrow

Iron Deficient MarrowPrussian Blue Stain

Normal MarrowPrussian Blue Stain

Treatment

• Most patients are treated initally with oral iron unless there is an absorptive problem.

• Dietary sources + FeSo4 BID. • TID is very constipating and causes gastric distress; commonest cause for noncompliance

• Iv iron is no longer ‘dangerous’. The newer formulations such as iron sucrose, lmw iron dextran and ferric gluconate have minimal risks of infusion reactions

• In very severe cases, RBC transfusion

Oral Therapy of Iron Deficiency

• Carbonyl iron (elemental), heme-iron polypeptide (extracted

from porcine RBC), polysaccharide-iron complex

• Ascorbic acid increases oral iron absorption but dose is usually

not in significant quantity to make a difference

• Phytates (cereal grains), tannins (tea) and antacid therapy

inhibit oral iron absorption

Price Matters!

Journal of

Family Practic

e JUNE 2002

VOL.51,

NO.6

Response to oral Iron Therapy

•Peak reticulocyte count 7 - 10 d.

• Increased Hb and Hct 14 - 21 d.

•Normal Hb and Hct 2 months

•Normal iron stores 4 - 5 months

Hgb response and MCV response parall

el each other after iron

replacement

Indications for iv iron• Severe symptomatic anemia requiring accelerated

erythropoesis• Failure of oral iron from g.i intolerance • Failure of oral iron due to absorption issues

H pylori infection, autoimmune gastritis, celiac disease, gastric bypass surgery, inflammatory bowel disease

• Cancer and chemotherapy associated anemia• Anemia with chronic renal disease (with or without[?] dialysis

dependance) • Heavy ongoing g.i or menstrual blood losses

Bastit et al JCO 26: 1511-1618 2008 Henry et al The Oncologist 2007;12:231–242

Intravenous Iron formulations• High molecular weight Iron Dextran is not routinely used

anymore due to a much poorer safety profile (anaphalyctoid reactions) in comparison to newer iron preparations

• Hemoglobin iron deficit (mg) = Body Wt x (14 - Hgb) x (2.145)

• (formula dose not account for repletion of body stores)

Lmw Iron Dextran

Iron Sucrose

Ferric Gluconate

Ferumoxytol Ferric Carboxy maltose

Administered Dosage

100mg 200 mg 125 mg 510mg 750mg

Total Dose Infusion

1000 mg no no 1020 mg 3d apart

1500mg 7d apart

Cost Inexpensive Inexpensive Inexpensive Expensive Expensive

Indication IDA IDA in CKD IDA in CKD/HD

+epo

IDA in CKD IDA +

IDA in CKD

Test dose Yes none none None None

Administration Iv (preferred) or im

Iv push or 15m

infusion

i.v push or 1hr infusion

17s i.v push or 15 m infusion

7.5 m iv push or 15 m infusion

Iv iron for fatigued nonanemic women with serum ferritin <15mg/dl

BLOOD, 22 SEPTEMBER 2011 VOLUME 118, NUMBER 12

In Conclusion….

• IDA is a highly prevalent, but easily treatable condition• Oral iron therapies are mostly equivalent in efficacy• Infusion reaction rates are very low in iv iron products other than HMW dextran

• Costs and indication for therapy are important to help decide the best iv iron replacement product for a patient.

Iron studies in inflammation and CKD• There is no established goal as to what lab parameters are

considered iron deficiency• Functional iron deficiency is where iron stores are present in the

body but not usable due to Hepcidin• Usually normocytic but microcytic anemia in severe cases

Iron deficiency in inflammation and CKD

Transferrin sats % Ferritin

Inflammation <20% <100

CKD <20% <100

ESRD <30% <500

Questionsrakhi@jhmi.edu