Iron Deficiency Anemia and Hemochromatosis Quiz

Plasma Iron

• Iron concentration changes throughout the day, highest in the morning.
• During the menstrual cycle, serum iron levels are lower than before the cycle.
• Women lose 104 to 3.4 mg of iron per day during their menstrual cycle.
• 50% of women lose 1.4 mg/day, 25% lose 1.7 mg per day, and another 25% lose 3.2 mg per day
• Elevated plasma iron in pregnant women is a normal occurrence.

Plasma Iron Calculations

• Transferrin = 0.7 x TIBC (µg/dL)
• TIBC = 1.43 x Transferrin (mg/dL)
• Transferrin saturation = 100 x (serum iron / TIBC)
• TIBC stands for Total Iron Binding Capacity

Iron Storage - Ferritin

• Ferritin stores iron in the liver and other cells.
• Molecular weight (MW) is 460,000.
• The outer shell of ferritin (apoferritin) consists of 22 protein subunits.
• An iron-phosphate-hydroxide core is at the center of the molecule.
• Ferritin contains 20% iron by weight and can bind up to 4,500 iron atoms per molecule.
• Only a small fraction of ferritin is found in the bloodstream (less than 1% of serum iron).
• Iron is stored and released in a controlled way by ferritin.

Plasma Ferritin

• Plasma ferritin is an iron storage protein.
• It contains iron and apo-ferritin.
• Apo-ferritin has 24 subunits.
• Ferritin molecules have 4000 iron atoms each.
• Measuring plasma ferritin levels is essential for diagnosing iron-related conditions, especially low or high iron levels in patients.
• This is also useful for diagnosing patients with anemia resulting from infections or those with elevated plasma iron.

Ferritin Measurement

• Ferritin levels reflect stored iron.
• Low ferritin levels indicate iron deficiency, a highly reliable finding.
• Elevated ferritin levels can indicate iron overload.
• Ferritin levels can be raised by the release of ferritin from damaged tissues, like in hepatitis, leukemia, or lymphoma.
• Acute phase reactions (caused by infection, tissue damage, and cancer) can also cause increased ferritin.

Iron Release from Cells

• Ferroportin is a protein on the cell surface that releases iron.
• Ferroportin is located on gut cells, liver cells, and macrophages.
• A cofactor is needed to oxidize iron to allow binding to transferrin.
• Hephaestin is in the gut, and caeruloplasmin is in other cells helping with iron release.
• Hepcidin prevents iron release from cells, and this is linked to chronic disease anemia.

Iron Uptake by Cells

• Transferrin, carrying iron, binds to receptors on hepatocytes and erythrocytes.
• The transferrin-receptor complex is internalized into the cell.
• Transferrin releases iron into the mitochondria, where it's used in heme synthesis.
• Ferritin absorbs released iron for enzyme and other protein synthesis.
• The transferrin receptor is then released from the cell.

Transferrin Receptors

• Transferrin receptors collect iron from transferrin.
• They recognize and bind to transferrin before internalization into the cells.
• Iron is released inside the cell using the Iron transporter DMT1.
• The receptor returns to the cell surface, and transferrin is released.

Solvable Transferrin Receptors

• Soluble transferrin receptors are truncated forms of cell-surface receptors found circulating in the blood.
• High levels are indicative of iron deficiency, while low levels often accompany iron overload.
• They might aid in diagnosing iron deficiency, particularly in inflammatory conditions.
• They aren't routinely used for testing now.

Intracellular Movement of Iron

• Fe-apotransferrin binds to transferrin receptors on cell membranes.
• Transferrin and the receptor form a complex (Tf-receptor).
• The binding constant (Ka) for this complex is 10^-7.

Internalization Cycle of Transferrin

• Transferrin binds to the receptor.
• Transferrin is internalized into the cell.
• Iron is released from transferrin.
• Transferrin-apotransferrin is exocytosed from the cell and returns to the plasma.
• Apotransferrin is released from the receptor to transport to the intestine. Iron can be brought to the mitochondria.
• Some iron enters ferritin for storage.

Hepcidin

• Hepcidin is a 25 amino acid peptide.
• Identified in 2000.
• It has antimicrobial activity and is produced by the liver.
• Hepcidin is a master iron regulatory hormone.
• Hepcidin deactivates ferroportin, thus reducing iron release from cells.
• Low hepcidin levels can increase iron absorption in the gut, and this often leads to high levels of iron in the body.
• High hepcidin levels can decrease iron absorption.

Heme Synthesis

• Heme biosynthesis involves a series of enzymatic reactions.
• Amino-levulinic acid (ALA) is a crucial starting material.
• It leads to the production of porphyrinogens from multiple steps until the final step where protoporphyrin combines with iron to form heme.

Related Publications and Articles

• Various articles and publications related to aluminum/chromium toxicity, their effects on heme synthesis, and protein synthesis and plasma iron have been referenced.

Interference of Metal Ions with Heme Synthesis

• Aluminum interferes with iron uptake by hepatocytes and erythrocytes leading to anemia.
• Cadmium also interferes with iron uptake by hepatocytes.
• Lead (Pb) can disrupt heme synthesis.
• Toxicity from chromium and zinc also contribute to anemia.

Hemoglobins

• Hemoglobin structure/ types are noted, along with their percentage presence in the body.

Hemoglobins (Continued)

• Other types of hemoglobin are listed

Iron Scavenging

• Intravascular hemolysis is the breakdown of red blood cells within the blood vessels.
• Free hemoglobin combines with haptoglobins in the blood.
• The complex is taken up by the liver.
• Free haem combines with hemopexin.
• Haemopexin-bound haem is taken up by the liver.
• Haem passing through the kidneys is reabsorbed.
• These mechanisms help to maintain iron balance in the body, particularly in pathological situations.

Iron Re-use

• Old red blood cells are broken down in macrophages, located in the spleen and other organs
• Recovered iron is transported to the liver and other storage sites.
• Iron from old red blood cells is re-used.
• Very little iron is lost via routine metabolism.

Bilirubin

• Hemoglobin is broken down to iron and protoporphyrin.
• Protoporphyrin is converted into biliverdin.
• Biliverdin is further converted into bilirubin.
• Bilirubin binds to albumin.
• Bilirubin is processed in the liver and then eliminated via the bile.

Iron Deficiency

• Iron deficiency can arise from decreased iron intake, increased iron loss, or increased iron demand.
• Iron stores are depleted before signs of deficiency are noticeable.
• Conditions causing iron deficiency must be addressed first before diagnosing iron deficiency.
• Biochemical parameters include high TIBC, low ferritin, and low plasma iron levels.

Iron Deficiency (Continued)

• Iron deficiency is common but not a diagnosis in itself.
• The underlying reason(s), such as low intake, malabsorption, or blood loss, needs to be investigated.
• This can relate to obstetric causes, inflammatory bowel disease, or bowel issues.

Iron Deficiency (continued)

• Laboratory findings for iron deficiency show low iron, low ferritin, elevated transferrin, and low transferrin saturation.

Iron Overload

• Iron overload can result from high iron intake, intravenous injections, or hemochromatosis.
• High plasma iron levels are accompanied by high transferrin saturation and high plasma ferritin levels.

Hemochromatosis

• Hemochromatosis is a rare disease.
• Excessive iron absorption is a characteristic feature.
• Hemosiderin appears in the skin.
• Liver damage, pancreatic dysfunction, diabetes, and heart problems can occur.

Genetic Hemochromatosis

• Genetic hemochromatosis is an iron overload disease.
• Caused by increased iron absorption.
• This condition may lead to progressive liver damage (cirrhosis) and eventually affect other organs.

Genetic Hemochromatosis (continued)

• The most common genetic hemochromatosis is caused by mutations in the HFE gene (C282Y).
• These mutations lead to low hepcidin levels and excessive ferroportin activity.
• Increased gut iron absorption also contributes to the condition.
• Other mechanisms, including DMT1 and DcytB activity, may also be involved. This type of hemochromatosis has a variable penetrance, meaning the expression of the disease can vary from person to person.

Genetic Hemochromatosis (continued)

• Different types of genetic hemochromatosis are related to different genes.

Anemia of Chronic Disease

• Anemia of chronic disease is associated with conditions like infection, inflammation, or cancer.
• Decreased iron absorption, low serum iron, and iron storage in cells are seen.
• Hepcidin, an acute-phase protein, is increased in the blood and impedes iron absorption by restricting the iron release from cells.

Anemia of Chronic Disease (continued)

• Anemia of chronic disease shares some symptoms with iron deficiency anemia, but the treatments differ significantly.
• Ferritin, iron, and transferrin levels can be misleading as they can be elevated, decreased, or normal in this type of anemia.

Other Tests Related to Iron Status

• Hemoglobin levels are commonly low in iron-deficient anemia.
• Mean cell volume (MCV) is usually low in iron deficiency.
• Liver iron levels are high in iron overload diseases and may be a better marker for detecting hereditary hemochromatosis than standard iron indices, especially when corrected for age.
• Bone marrow iron helps detect if iron is depleted in the person.

Future Possibilities

• Treatment with hepcidin could be effective in managing iron overload.
• Research is underway on methods to block hepcidin for conditions like anemia of chronic disease.
• Diagnostic tools based on hepcidin could offer more accurate and precise diagnoses.

Conclusions

• Iron-related diseases are common and clinically important.
• Recent advances have significantly improved iron-related disease understanding, diagnosis, and management.
• Iron studies are crucial initial assessments.
• New techniques and therapeutics will likely evolve based on these improvements.