Disorders of Iron Kinetics and Heme Metabolism

What is the most abundant heavy metal in the body?

iron

2/3 or more of total body iron in _______________.

RBCs

Each mL of RBC contains 1 mg of iron

Distribution of iron ~4000 mg total

Iron intake pattern:

Increases in first few years of life untill teen life. Female adults stay ~18 mg while male adults ~8 mg. Older adult females ~8mg.

iron in Bone Marrow:

~300 mg

iron in Duodenum:

~1-2 mg

Iron in liver:

~1000 mg

iron in myoglobin:

carries and stores oxygen for muscle contraction

~200 mg

iron in transferrin:

~4 mg

it binds to iron and shuttles it to tissues

iron in macrophages:

~600 mg

iron in RBC:

~2500 mg of Ferris 2+

What type of iron is in the blood?

Ferris 2+

how much iron do you usually lose a day?

*What are some causes of loss?

1-2 mg per day

*Sloughed cells

*menstruation

How is iron absorbed?

- Transferrin is secreted by enterocytes into the lumen of the small intestine

- Transferrin binds iron (Fe3+)

- Transferrin-iron complex binds receptor

- Fe3+ transformed to Fe2+ is Taken into cells by receptor-mediated endocytosis

- Some iron is stored in enterocytes as ferritin

- Some iron is transported into blood: bound to transferrin

Ferrous Iron

Fe2+

Ferric Iron

Fe3+

when iron levels are high, what is released?

Hepicidin

**shuts down ferroportin channel reducing iron release to the body-holds iron in storage form in cells

**produced in the liver

What is the ferroportin chanel?

Transports iron(Fe2+) to the body

What is ferritin?

storage form of iron

What converts Fe3+ to Fe2+ on an enterocyte?

duodenal cytochrome B (Dcytb)

**ferric reductase enzyme on border of enterocyte

What channel allows Fe2+ to enter the enterocyte?

DMT 1

In a RBC, how is Fe3+ converted to Fe2+?

Steap 3

AKA a ferreductase

Iron Deficiency Anemia Etiology

-Inadequate intake

-Increased need (pregnancy)

-Impaired absorption (celiac disease)

-Chronic blood loss

Iron Deficiency Anemia 3 stages:

Stage 1—progressive loss of storage iron

Stage 2—exhaustion of iron storage pool

Stage 3—frank anemia

Stage 1 IDA:

RBC development normal

Patient is asymptomatic

Serum ferritin is low

Latent, subclinical

Stage 2 IDA:

-Hgb content of retics decreaase Hgb on hemogram/CBC is normal

-RDW may be increased

-Serum iron and ferritin decreased

-Total Iron Binding Capacity increased

-sTR’s increase

-Prussian blue stain of BM is negative

-Iron deficient erythropoiesis

-Hepcidin decreased

Stage 3 IDA:

-Frank Anemia

-H/H decreased

-Hypo/micro

-FEP and sTR increase

-Ferritin decreased (more iron distribution)

-Hepcidin decreased

-Serum iron decreased

-TIBC increased

-Patient is symptomatic

Some symptoms of stage 3 IDA:

Fatigue

Weakness

pallor

glossitis

koilonychia

pica

Groups more at risk for IDA:

•Menstruating women

•Adolescent females

•Pregnant and nursing women

Factors increasing risk of IDA

•Socioeconomics

•Iron absorption

Iron Deficiency Levels:

Serum Ferritin:

Serum iron:

TIBC:

transferrin saturation:

BM Iron:

Serum Ferritin: decreased

Serum iron: decreased/normal

TIBC: increased

transferrin saturation: decreased

BM Iron: no stainable iron

Thalassemia Minor Levels:

Serum Ferritin:

Serum iron:

TIBC:

transferrin saturation:

BM Iron:

Serum Ferritin: increased/normal

Serum iron: increased/normal

TIBC: none

transferrin saturation: increased/normal

BM Iron: increased/normal

Anemia of Chronic Inflammation Levels:

Serum Ferritin:

Serum iron:

TIBC:

transferrin saturation:

BM Iron:

Serum Ferritin: increased/normal

Serum iron: decreased

TIBC: decreased

transferrin saturation: decreased/normal

BM Iron: increased/normal

Sideroblastic Anemia Levels:

Serum Ferritin:

Serum iron:

TIBC:

transferrin saturation:

BM Iron:

Serum Ferritin: increased

Serum iron: increased

TIBC: decreased/normal

transferrin saturation: increased

BM Iron: increased

What kind of cells would you expect to find on the peripheral blood smear of someone with IDA?

Shistocytes

PLT

ovalocyte

helmet cell

target cell

tear drop cell

In a patient with IDA, how would an erythroblast present on a Bone marrow smear?

Shagged outer cytoplasm

The Thomas plot measures:

Hemoglobin content of retics against sTfR/log ferritin to measure iron status and deficiency

Screening tests for Diagnosing IDA:

•Abnormal complete blood count (CBC) results

•Blood smear abnormalities

Diagnostic testing for IDA:

•Serum iron

•Total iron-binding capacity (TIBC)

•Transferrin saturation

•Ferritin

•Reticulocyte Hb content

Specialized tests for Dx IDA:

•Evaluation of heme synthesis

•Free erythrocyte protoporphyrin

•Soluble transferrin receptors (sTfR)

•Bone marrow evaluation ? not necessary

treatment for IDA:

•Treat underlying cause

•Ferrous sulfate oral supplements

•Iron dextran parenteral administration

•Monoferric (FDA approved) given IV

•RBC transfusion

Measuring response to treatment for IDA

•Reticulocyte Hb content

•Relative and absolute reticulocyte counts

•Hb

•MCV

•Peripheral film smear evaluation

In which stage of IDA is the hemoglobin on CBC normal, serum iron decreased, ferritin decreased, sTfR increased, and TIBC increased?

Stage 2

Anemia of Chronic Inflammation Etiology

-Underlying condition

-Cell products involved

Pathophysiology of Anemia of Chronic Inflammation

-Impaired ferrokinetics

•Role of hepcidin

•Role of lactoferrin

•Role of ferritin

-Inflammatory cytokine production

Anemia of Chronic Inflammation

a type of anemia that affects people who have conditions that cause inflammation, such as infections, autoimmune diseases, cancer link, and chronic kidney disease

Laboratory diagnosis of Anemia of Chronic Inflammation

Hgb 8-10 g/dL

Absence of reticulocytosis

N/N ~ micro/hypo (a third of patients)

Low serum iron

Low TIBC

High ferritin

High FEP

•Failure to incorporate iron into heme molecule

How to Dx Iron deficient Anemia:

-decreased RBC

-Biochemical/clinical evidence of inflammation

-transferrin saturation

How to Dx anemia of inflammation

-decreased RBC

-Biochemical/clinical evidence of inflammation

-transferrin saturation

treatment for anemia of chronic inflammation

Erythropoietin

Ferrous sulfate

General features of Sideroblastic Anemias

Diverse group of diseases

Hereditary and acquired conditions

Iron deposits in mitochrondria of erythroblasts

Ringed sideroblasts ~ Hallmark

Hereditary Sideroblastic Anemias are

X linked or autosomal

Acquired Sideroblastic Anemias could be from

antitubercular drugs

chloramphenicol

alcohol

lead

chemo agents

Sideroblastic Anemia caused by lead poisoning

-Interferes in biosynthesis of heme

•Conversion of aminolevulinic acid (ALA) to porphobilinogen (PBG) by ALA dehydratase increasing aminolevulinic acid

•Incorporation of iron into protoporphyrin IX by heme synthase

-N/N ~ micro/hypo anemia

-Increased reticulocytes

-interferes with heme biosynthesis

-basophilic stippling

Porphyrias

-Impaired production of porphyrin component of heme

-When an enzyme in heme synthesis is missing the products from earlier stages in the pathway accumulate in cells and body tissues

Erythropoietic Porphyrias (EPP):

Enzyme affected:

Affected Gene:

Clinical features:

RBC:

Urine:

Feces:

Enzyme affected: Ferrochelatase deficiency

Affected Gene: FECH

Clinical features: photosensitivty, mild anemia

RBC(protoporphyrin): increased

Urine(porphobilinogen): normal

Feces(protoporphyrin): increased

Treatment for Erythropoietic Porphyrias (EPP):

Scenesse (FDA approved)

Iron Overload Etiology:

-Acquired

•Blood transfusions – transfusion-related hemosiderosis

-Hereditary

•Homozygous hemochromatosis (5 of 1000 northern Europeans)

•Heterozygous hemochromatosis (13%)

Hemochromatosis, Type 1 (HFE):

Affected gene:

Mutated protein:

normal function of affected protein:

Age of onset:

Affected gene: HFE

Mutated protein: hereditary hemochromatosis

normal function: inhibits TfR1, iron intake, regulates hepicidin

Age of onset: 30-40

Pathogenesis of Iron Overload

-In presence of oxygen ferrous iron initiates superoxide production which damages membranes

-Lysosomal enyzmes released

-Cell death

-"Bronzed diabetes"

*Tanning of the skin, joint pain

Laboratory diagnosis of Iron Overload

-Increased serum ferritin and transferrin saturation

-Genetic testing for mutation

Treatment for Iron Overload

-Hereditary hemochromatosis

•Therapeutic Phlebotomy

•Removal of ~ 500 mL blood per week

-Transfusion-related hemochromatosis

•Iron chelating drugs (e.g. Desferrioxamine)

In which iron disorder is the ferritin increased, serum iron increased, TIBC normal or decreased, FEP increased, and transferrin saturation increased?

Sideroblastic anemia