02: Iron Deficiency/Overload & Anemia of Chronic Inflammation

Question 1

Components of total body iron

Answer 1

• Total body iron = 3.5 g
• Loss: 1-2 mg/day via menstruation, desquamation of epithelial cells of GI tract
• Absorption: 1-2mg/day via duodenum
• Storage:
  
  • RBC hemoglobin: 2,300 mg (2/3rds total body iron)
  • Macrophages: 500 mg
  • Muscle fibers: 350 mg
  • Liver: 200 mg
  • Bone marrow: 150 mg

Question 2

Causes of anemia

Answer 2

• Intrinsic to RBC
  
  • Hgb synthesis
    
    • Nutrient deficiency (iron, folate, B12)
    • Hemoglobinopathy/thalassemia
    • Porphyrias
  • RBC membrane disorder
  • RBC enzyme disorder

NB: Iron deficiency > sickle cell/thalassemia > hookworm > malaria

Question 3

Iron absorption

Answer 3

1. Most food iron is in ferric [Fe3+] form; cannot be absorbed, so reduced to ferrous [Fe2+] form by ferric reductase on apical side of duodenal enterocyte.
2. Iron enters cell via duodenal divalent metal transporter (DMT-1); can be stored in cell by ferritin.
3. Iron exits into bloodstream via channel called ferroportin (FPN).
4. Iron re-oxidized to ferric form by ferroxidase.
5. Two ferric iron atoms bind to transport protein transferrin.
6. The di-ferric transferrin is transported to the site of use or storage.

Question 4

Transferrin

Answer 4

• Clinically measured as total iron binding capacity (TIBC).
• Serum Fe/TIBC = “transferrin saturation”
  
  • Normal = 20-50%

Question 5

Iron transport

Answer 5

• Di-ferric transferrin carries iron to hepatocyte/macrophage/erythropoeitic cell.
• Binds to transferrin receptor (TFR1 or **TFR2)**.
• Entire molecule internalized for intracellular usage –> stored as ferritin.

Question 6

Iron deficiency Sx in children

Answer 6

Impaired growth, impaired cognitive development (irreversible!)

Question 7

Iron deficiency anemia:
PRESENTATION

Answer 7

• Lethargy, irritability, pallor.
• Sx may precede anemia.
• History of poor Fe intake, blood loss (heavy menses, blood in stool, epistaxis [nosebleed]).
• Fe malabsoprtion from gut suggests celiac disease, autoimmune gastritis

Question 8

Iron deficiency anemia:
DIAGNOSIS

Answer 8

• Dietary/GI history
• Hx of blood loss (test stool for occult blood)
• PEX
• Labs

Question 9

Stages of iron deficiency

Answer 9

1. Depletion of iron stores
   
   • ↓Fe in bone marrow
   • ↓serum ferritin
2. Decreased transport iron
   
   • ↓serum iron
   • ↑TIBC (transferrin attempts to absorb more Fe)
3. Anemia
   
   • ↓MCV, Hgb, HCT
   • ↓reticulocyte count
   • Smear: hypochromia, microcytosis, anisocytosis (unequal sized RBC), poikilocytosis

Question 10

Early age hematocrit

Answer 10

• Newborn: 135 mL RBC
• 1 year: 270 mL RBC
  
  • Requires an additional 135 mg Fe!
  • Thus, Fe essential early in life

Question 11

Fe absorption enhancers

Answer 11

Vitamin C, sugar, acid, ethanol

Question 12

Non-hematologic manifestations of iron deficiency

Answer 12

• Aerobic energy production: less endurance
• Behavioral manifestations
• Pica (geophagia, pagophagia)
• Spoon nails
• Blue sclera
• Carotenemia (yellow pigmentation)
• Intestinal changes, (+) guaiac: blood in stool
• Esophageal web

Question 13

Iron deficiency anemia:
DDX

Answer 13

• Thalassemia
  
  • Microcytosis unresponsive to iron
  • Nearly normal Hgb and RDW (RBC distribution width [poikilocytosis]) in Thal trait
  • Normal iron studies
• Anemia of chronic disease
  
  • Usually normocytic
  • Iron-deprived erythropoiesis may be microcytic

Question 14

Iron deficiency anemia:
TREATMENT

Answer 14

• Dietary counseling (avoid XS cow’s milk)
• ID and treat sources of blood loss
• Oral Fe supplementation

Question 15

Hepcidin

Answer 15

• Small peptide hormone central to iron regulation in the body
• Member of Liver-Excreted Antimicrobrial Proteins (LEAP) family
• Circulates in serum, excreted in urine
• Regulates **ferroportin **(which controls iron egress from cell)
  
  • ↑plasma Fe –> hepcidin induced in liver via **HFE, TRF2 **& HJV –> hepcidin causes internalization & degradation of ferroportin –> Fe absorption & relase from stores ceases
• Production controlled at level of transcription (responsive to hypoxia, iron stores, erythropoiesis and inflammation)
• ↓heparin expression –> **hemochromatosis **(iron overload)

Question 16

Serum ferritin

Answer 16

• Measured as indicator of body iron stores.
• Goes up with iron overload/hemochromatosis.
• Also goes up as “acute phase reactant” with tissue injury.
• With iron overload, complexes to form hemosiderin in cells.

Question 17

Genetic hemochromatosis

Answer 17

• Due to disruption of hepcidin/ferroportin balance
• Autosomal recessive mutations:
  
  • HFE C282Y/C282Y (most common)
    
    • Variable penetrance (diet plays role)
  • TfR2
  • Hemojuvelin (HJV)
  • Hepcidin
• Autosomal dominant mutations:
  
  • Ferroportin (hepcidin resistance)

Question 18

Hemochromatosis:
PHENOTYPE

Answer 18

• Vertigo
• Hair loss
• Memory loss
• Heart degeneration
• Hepatomegaly
• Eleveated liver enzymes
• Cirrhosis
• DM2
• Testicular atrophy
• Bronze skin
• Arthritis

Tx: regular phlebotomy

Question 19

Transfusion-related hemochromatosis

Answer 19

• Common in conditions requiring chronic transfusion (Beta Thalassemia Major) –> iron overload
• Inappropriately low hepcidin from ineffective erythropoiesis (RBCs being produced, but not released –> low Hepcidin:RBC ratio)

Question 20

Anemia of Chronic Disease:
INFLAMMATION

Answer 20

• Inflammatory states –> IL6 –> ↑hepcidin synthesis
• Causes ↓Fe in blood 2/2 ferroportin degradation
• Evolved to starve pathogens of iron needed to multiply!

Question 21

Anemia of Chronic Inflammation

Answer 21

• Most common cause of anemia in hospital inpatients
• Associated w/ multiple inflammatory conditions
  
  • Rheumatologic, infectious, malignant
• Usually normocytic
• Iron-deprived erythropoiesis may be microcytic
• May require parenteral iron to bypass decreased iron absorption