6 - Iron Homeostasis & Porphyrin Metabolism Flashcards Preview

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Flashcards in 6 - Iron Homeostasis & Porphyrin Metabolism Deck (26):

Properties of Iron

- Binding oxygen and transferring electrons
- Iron rusts (=oxidizes)
--- Oxygen can remove an electron and transform it from the useful Fe2+ to rather useless Fe3+
--- Reduced oxygen poses a problem (reactive oxygen species)
- Iron needs to be controlled at all times: no free Fe2+/3+ allowed
--- can't be excreted through kidney


Dietary Sources of Iron

About 10 - 20 mg/day in normal diet
- Usually sufficient (exception: growth, blood loss)


Plant iron

mostly Fe3+
- not bound to heme, heme
- hard to mobilize and take up
--- (only 5% taken up)


Animal iron

mostly heme-bound
--- (about 25% taken up)


Excretion of Iron

- No regulated loss through urine
--- Iron should is bound to protein
--- Iron homeostasis regulated through uptake only
- Blood loss
--- Can occur in intestine (cancer, ulcerations)
--- Intravascular hemolysis (hemoglobin in urine)
- Sloughing off of iron-containing cells in the intestine and kidney


Distribution of Iron in Man

80% is in active forms
--- Hemoglobin, myoglobin, cytochromes
--- Transport: Transferrin
20% is in inactive forms
--- Dynamic storage: Ferritin
--- Degenerated, long-term storage: Hemosiderin
-----> Hemosiderin granules can be sign of iron overload
-----> Hemosiderin can't be mobilized


Inside the Cell

- Iron binds to ferritin
--- water soluble
--- easy to mobilize
--- High concentrations in liver, spleen and bone marrow
- Ferritin particles slowly denature to hemosiderin granules
--- Water insoluble
--- Hard to mobilize
--- Sign of iron overload


The Role of Macrophages

- The life of red blood cells usually ends in splenic macrophages (extravascular)
--- Macrophages take up the iron
--- A hemolytic disorder leads to accumulation of ferritin and hemosiderin in macrophages


Regulation of Iron Homeostasis

- Iron uptake into body is regulated by release of iron from enterocytes
- Main regulator: The inhibitor hepcidin
- Upstream regulator, sometimes defective: HFE
--- Mutations in HFE cause low hepcidin expression



- main regulator of iron homeostasis
--- inhibits
- Low hepcidin = high uptake
- Hepcidin also regulates iron release from macrophages


Regulation of Intracellular Iron Storage

- Iron response element (IRE)
--- part of the RNA structure
- iron regulatory protein (aconitase)
--- sits on IRE


Iron Response Element

- Found on 5’ UTR (untranslated region) of RNAs of iron inducible genes:
--- Ferritin
--- d-ALA synthase
- Found on 3’ UTR of RNAs of iron repressible genes
--- Transferrin receptor
--- On this end the binding of the repressor protein prolongs the mRNA half-life
--- Iron speeds up mRNA degradation


Laboratory Tests

- Serum Iron Concentration
- Total Iron binding capacity (TIBC) or transferrin saturation
- Serum Ferritin
- Red Cell Protoporphyrin


Serum Iron Concentration

Limit: No information about body iron stores
- can diagnose acute iron poisoning


Total Iron binding capacity (TIBC) or transferrin saturation

- TIBC measures UNOCCUPIED transferrin. The higher the TIBC, the lower the iron stores
- Transferrin saturation measures OCCUPIED transferrin. The higher the saturation, the higher the iron stores


Serum Ferritin

A fraction of ferritin is present in serum
– best measure for body iron stores


Red Cell Protoporphyrin

- Protoporphyrin is Iron-free precursor of heme
- The lower the iron stores, the higher the protoporphyrin


causes of Iron Deficiency

Chronic blood loss
Chronic disease (hepcidin production)
Poor dietary intake (limited absorption of plant iron)
Intestinal parasites (compete for Iron)
Malabsorptive disease (Celiac)


iron deficiency leading to anemia

1. Iron depletion – serum ferritin falls
2. Deficient erythropoiesis – hemoglobin still normal, but protoporphyrin levels up, transferrin saturation falls
3. Iron deficiency anemia – hypochromic (low hemoglobin), microcytosis


Causes of Iron Overload

regulation of iron is very good so need a mutation somewhere or large stress
- Blood transfusions for treatment of hemolytic disease (iron (from own body) accumulates in macrophages)
- Slow erythropoiesis (renal failure)
- Hereditary hemochromatosis type 1 (HFE mutations, up to 10% of the population are carriers)


Symptoms of iron overload

presents with liver failure (ALT, AST increased)

- look for:
High transferrin saturation
Hemosiderin deposits


Heme Synthesis

- Aminolevulinic acid synthase synthesizes ALA from succinyl-CoA and glycine (regulated by heme).
- 2 molecules of ALA are joined to form porphobilinogen (PBG).
- Four molecules of PBG are joined to form uroporphyrinogen.
- Modifications of the side-chains generate coporphyrinogen and protoporphyrinogen.
- Ferrochelatase inserts a Fe2+ into the molecule to yield heme.


Heme Synthesis Disorders

Acute Intermittent Porphyria (AIP)
Porphyria Cutanea Tarda (PCT)
Lead Poisoning


Acute Intermittent Porphyria (AIP)

- Caused by a deficiency in porphobilinogen deaminase (PBGD).
- ALA and PBG accumulate in the circulation and in the urine, giving the urine a dark red color.
- AIP can be life-threatening and causes episodes of confusion and sharp abdominal pain.


Porphyria Cutanea Tarda (PCT)

- Results from a deficiency of uroporphyrinogen decarboxylase.
- Leads to a buildup of porphyrins (can be detected in the urine).
- Porphyrins are able to absorb visible and UV light.


Lead Poisoning

- Lead inhibits ALA dehydrase and ferrochelatase.
- Lead poisoning leads to the accumulation of ALA and other heme precursors in heme-producing tissues.
- Lead poisoning causes symptoms similar to the porphyrias.