Iron Hemostasis Porphyrin Metabolism Flashcards
How is Iron Deficiency Anemia diagnosed?
Low Serum Iron
High Total Iron Binding Capacity (TIBC)
What is the normal iron intake in the Western diet?
Who has higher than normal requirements?
10-20 mg per day (Adequate)
Require Higher than Normal: Children and Menstruating/Pregnant Women
What two forms does iron exist in in the body?
Which form is most iron found in?
Functional and Storage forms
Most iron is found in the Functional form
Functional Form of Iron
- Where is it found?
***Actively Participating in Metabolic Processes***
- About 80% is found in hemoglobin
- Smaller in myoglobin, cytochromes, or Fe-containing enzymes
Also, another small pool is bound to Transferrin for transport in the blood
Storage Form of Iron
- Where is it found?
***Sequestered in particles and biologically inactive***
Two modes exist:
- Ferritin-bound: dynamic molecule, from which iron can be released according to demand
-
Hemosiderin-bound: degenerated iron-protein complex that cannot be mobilized
- Hemosiderin granules in tissues is a sign of iron overload
Describe the uptake and storage of Iron
- Iron is taken up by enterocytes and is bound in the plasma by transferrin
- Plasma iron is taken up by erythroid precursor cells in the bone marrow and incorporated into RBCs
- After phagocytosis of RBCs by splenic macrophages, iron is stored as ferritin
- Macrophage ferritin can be released into the plasma, where it is bound to transferrin
***Plasma iron (bound to transferrin) is exchanged with liver iron stores (bound to ferritin)***
What are the main two ways that iron is lost?
Shedding of epithelial cells** (particularly enterocytes) and **blood loss
***About 1-2 mg***
How is iron hemostasis regulated?
Iron hemostasis can be regulated only** by adjusting the **uptake from the diet (i.e. the absorption by the epithelial cells in the proximal duodenum)
***Only way iron leaves the body is by sloughing off of duodenal/other epithelal cells
Uptake of Heme vs. Non-Heme iron
Heme iron uptake: taken up efficiently (~25%) through Heme Carrier Protein HCP1
Non-Heme iron uptake: non heme (Fe3+) is first reduced to Fe2+ by duodenal cytochrome p450 then is taken up by the Divalent Metal Transporter DMT1 (Less efficient ~5%)
What happens to the action of enterocytes when iron stores are full?
Uptake into enterocytes is still active, as it is not regulated by body iron requirements
What are the two options that enterocytes have after taking up as much dietary iron as possible?
- Fe2+ can be stored in the enterocyte as mucosal ferritin; this oute leads to EXCRETION of iron, as enterocytes are quickly turned over and sloughed off in the intestine
- Fe2+ can be released into the plasma through ferroportin
What is the key regulatory protein in the enterocyte?
Hepcidin: regulates the export of iron from the enterocyte by inhibiting Fe2+ release through ferroportin on the basal surface of enterocytes
***This prevents the dissemination of iron through the body***
(Once released, Fe2+ is oxidized to Fe3+ and binds to transferrin in the plasma)
What effect does iron overload have on enterocyte function?
NO EFFECT
- Enterocytes (lifespan 5-6 days) do not function as an iron reservoir
- Iron deposits are merely a ***short-term buffer***
What is the function of Transferrin?
Transferring binds iron –> iron-Transferrin binds Transferrin Receptor and is taken up in clathrin-coated pits –> taken into endosome where ATPase acidifies the environment (now a lysosome) –> Fe3+ is released from transferrin and is reduced in the acidic environment to Fe2+ –> DMT1 transports Fe2+ into the cytoplasm
Where is iron stored in the cytoplasm?
In Ferritin (Soluble and mobilized easily)
Hemosiderin forms when ferritin particles accumulate and denature (Insoluble and does not release iron as easily)
Where are the highest concentrations of Ferritin-bound iron found?
Liver (to synthesize cytochrome__s)
Spleen (from phagocytosis of RBCs)
Bone Marrow (because of RBC synthesis)
What is one of the first signs of iron overload?
Appearance of hemosiderin inside macrophages
How does hepcidin function and what are the two physiological consequences of this?
Function: Hepcidin inhibits iron transport protein Ferroportin
Physiological Consequences:
- Enterocytes do not release iron into blood; instead stored and lost during epithelial cell turnover
- Macrophages do not release iron into blood; instead, macrophages accumulate iron stores in the form of ferritin** and **hemosiderin
What regulates iron uptake and what do high concentrations of this molecule do?
Hepcidin
High concentrations reduce iron uptake
Describe the post transcriptional regulation of Ferritin
- The 5’ UTR of ferritin contains an Iron Response Element (IRE) that forms a stemloop strucutre
- Iron regulatory proteins (IRPs) normally bind the IRE and block translation; however, free iron in the cytoplasm will bind the IRP and displace it, allowing for translation of Ferritin to begin quickly
How is post-transcriptional regulation of D-ALA synthase done?
(Same as Ferritin)
Free iron increases** D-ALA synthase translation and **increases the synthesis of Heme
How is Transferrin Receptor post-transcriptionally regulated?
(Same as Ferritin, except…)
The regulation is inverted
Binding of the IRPs stabilizes the mRNA and increases translation. Free iron decreases transferring receptor translation and reduces iron uptake
Serum Iron Test
- Utility
- Used to diagnose iron poisoning/overload
***Little clinical value - does not inform about total iron stores in the body***
Total Iron Binding Capacity (TIBC)
(i. e. Transferrin Saturation)
1. Normal vs. Pathologic Values
Normal: About 30% saturated with iron
Below 15% points to iron deficiency
Serum Ferritin
- Utility
Serum Ferritin is considered to be the best measure for body iron stores, as it measures Ferritin, which is both the intracellular storage form of iron and is present in the serum
Red Cell Protoporphyrin
- Utility
Protoporphyrin is the iron-free pre-cursor of heme
- Elevated value indicates a shortage of iron to complete heme synthesis
Iron Deficiency Anemia
- Causes
1. ***Chronic Blood Loss- always assume this is the cause until proven otherwise, as this is the most common (caused by malignant growth or bleeding ulcers)
2. Chronic Disease- frequent cause in hospitalized patients ; inflammatory mediators (e.g. IL-6) stimulate the synthesis of hepcidin, which then REDUCES iron release from entrocytes
3. Poor Dietary Intake
4. Intestinal Parasites
5. Malabsorptive Disease (Celiac Disease)
What are the stages of development of Iron Deficiency Anemia? (3)
1. Iron Depletion (tissue iron stores become depleted and serum ferritin levels fall)
2. Deficient Erythropoiesis with NORMAL hemoglobin concentration (RBC production slows down due to slow synthesis of heme. Serum protoporphyrin levels rise. Increased production of transferrin leads to a drop in transferrin saturation)
3. Iron deficiency anemia (Hemoglobin production is inadequate, leading to hypochromic, microcytic anemia)
Treatment of Iron Deficiency Anemia
Establish cause - look for occult blood loss
Supplement iron orally or intramuscular
Iron deficiency can take six months to reverse
What conditions lead to Iron Overload? (4)
1. Chronic Blood Transfusions for treatment of hemolytic disorders. Iron stores accumulate in macrophages from the destruction of damaged RBCs
2. Inappropriate parenteral nutrition
3. Ineffective hematopoiesis (RENAL FAILURE)
4. Hereditary iron uptake disorder
Hemochromatosis
- Cause
- Mechanism of Disease
Cause: Common hereditary uptake disorder, caused by a mutation in the HFE gene, which leads to repression of hepcidin expression
MoD: low concentrations of hepcidin lead to an increase in iron release from enterocytes
***In hereditary hemochromatosis, there is little deposition of iron in enterocytes because of increase iron efflux through ferroportin
What is the committed/regulated step of Heme Synthesis?
Where does it take place?
What regulates this step, and thus, heme synthesis?
- Committed Step: The ALA SYNTHASE (Aminolevulini Acid Synthase) reaction that synthesizes aminolevulinic acid from succinyl-CoA** and **glycine
- This reaction occurs in the Mitochondria
- This reaction is regulated by 1) Iron Concentration (The ALA synthase mRNA has an IRE and high concentrations of iron activate translation), and 2) Heme (Oxidized (Fe3+) heme, hemin, represses Ala synthase activity)
What are Porphyrias?
How do they normally present?
Triggers?
The diseases of heme synthesis
Normally present as acute abdominal pain
Triggers:medications,alcohol(due to synthesis of cytochromes for the p450 enzymes of themicrosomal ethanol oxidizing sytems (MEOS) –> accumulation of porphyrin precurses in porphyria patients)
Acute Intermittent Prophyria (AIP)
- Cause
- Results of Disease
- Symptoms
Cause: deficiency in porphobilinogen deaminase
Result of Disease: ALA and PBG accumulate in circulation and urine, giving it a dark red color
Symptoms: Diffuse neurological; Confusion and Sharp Abdominal Pain
Porphyria Cutanea Tarda (PCT)
- Cause
- Results
- Symptoms
Cause: Deficiency of uroporphyrinogen decarboxylase
Results: Buildup of porphyrins (detected in the urine using UV light –> emits a pink fluorescence)
***Porphyrins are able to absorb visible and UV light***
Symptoms: Photosensitivity of the skin, leading to blistering of exposed areas
Lead Poisoning
- Impact on Heme Synthesis
- Symptoms
Inhibits porphobilinogen synthase and ferrochelatase
Impact on Heme Synthesis: Leads to the accumulation of ALA and other heme precursors in the heme-producing tissues
Symptoms: Similar to other porphyrias (e.g. confusion, abdominal pain)
