DISORDERS OF IRON KINETICS & HEME METABOLISM

Iron is consumed in the diet primarily in which oxidation state?

Ferric iron (Fe³⁺)

In the stomach, which substance reduces Fe³⁺ to Fe²⁺?

Hydrochloric acid (HCl)

Why is ferric iron (Fe³⁺) not directly absorbed by enterocytes?

Because Fe³⁺ cannot pass through the cell membranes of enterocytes

Which part of the gastrointestinal tract is the primary site for iron absorption?

Duodenum (and upper jejunum)

What receptor in the intestine facilitates the uptake of ferrous iron?

Divalent Metal Transporter 1 (DMT1) receptor

After absorption, what protein exports iron from enterocytes into circulation?

Ferroportin

Which enzyme converts ferrous iron (Fe²⁺) back to ferric iron (Fe³⁺) for transport?

Hephaestin

In plasma, Fe³⁺ binds to which molecule to form the iron carrier?

Apotransferrin, forming transferrin

Through which receptor does transferrin deliver iron into cells?

Transferrin receptor 1 (TR1)

Once inside cells, into what vital molecule is iron incorporated?

Hemoglobin in red blood cells (RBCs)

How are senescent red blood cells processed to recycle iron?

They are phagocytosed by macrophages in the reticuloendothelial system (RES)

In macrophages, in what form is recycled iron primarily stored?

Ferritin

Besides macrophages, which other cells have ferroportin to salvage iron?

Hepatocytes (liver cells) and other cells like enterocytes

What is the role of hepatocytes in the regulation of iron absorption?

They release hepcidin, which reduces ferroportin receptors, thereby regulating iron absorption and recycling

How does hepcidin affect ferroportin under high iron conditions?

Increased hepcidin leads to decreased ferroportin, reducing iron absorption and recycling

How does hepcidin affect ferroportin under low iron conditions?

Decreased hepcidin leads to increased ferroportin, enhancing iron absorption and recycling

What is the significance of the low pH in gastric juice regarding iron?

It helps to solubilize and reduce iron from dietary sources, making it available for absorption

What is the approximate absorption percentage of dietary iron from a daily intake of 10-20 mg?

Approximately 5% to 10%

What role does vitamin B6 (pyridoxine or pyridoxal) play in heme synthesis?

It is essential for the initial condensation of succinyl-CoA with glycine to form 5-aminolevulinic acid

Where does the initial step of heme synthesis occur?

In the mitochondria

What is the first product formed in the heme synthesis pathway?

5-Aminolevulinic acid (ALA)

Which tissues are the primary sites for heme (porphyrin) production?

Red bone marrow and the liver

What happens after the cytoplasmic production of coproporphyrinogen III in heme synthesis?

It reenters the mitochondrion for the final steps of heme formation

How is iron incorporated into the porphyrin ring to form heme?

In the final mitochondrial enzymatic steps, iron is inserted into protoporphyrin IX

What can defects in the synthesis of protoporphyrin IX lead to?

Sideroblastic anemia

What condition can result from problems in globin synthesis during heme formation?

Thalassemia

IRON STUDIES Overview: What types of anemia are typically hypochromic and microcytic?

They include Anemia of Chronic Inflammation, Thalassemia, Iron Deficiency Anemia, and Sideroblastic Anemia.

Serum Ferritin: What does serum ferritin reflect in the body?

It reflects the iron stores in the body.

What is the typical reference range for serum ferritin?

Approximately 15–200 µg/L. (rodaks: 40-400 ng/mL)

In which condition is serum ferritin decreased?

Only in iron deficiency anemia (IDA).

What additional characteristic of ferritin should be noted regarding inflammation?

Ferritin is an acute phase reactant and may be falsely elevated in chronic inflammation or infection.

Free Erythrocyte Protoporphyrin (FEP)/Zinc Protoporphyrin (ZPP): What accumulates in red blood cells when iron is not incorporated into heme?

Protoporphyrin IX accumulates, and zinc binds to it, forming zinc protoporphyrin.

What enzyme normally catalyzes the addition of iron to protoporphyrin IX?

Ferrochelatase catalyzes the conversion of protoporphyrin IX + iron into heme.

What happens to protoporphyrin IX levels when iron is missing?

Protoporphyrin IX levels increase.

Serum Iron: What is a key limitation of using serum iron levels for diagnosis?

It has limited utility due to variability and is affected by sample collection factors.

How should the serum iron sample be collected for optimal accuracy?

The sample should be fasting and collected early in the morning.

Total Iron-Binding Capacity (TIBC): What does TIBC indirectly measure?

It indirectly measures transferrin by representing all available iron-binding sites.

In iron deficiency anemia, what happens to TIBC?

TIBC is increased because transferrin levels are higher when total body iron is low.

In anemia of chronic disorders, how does TIBC usually present?

TIBC is usually normal or decreased.

Percent Transferrin Saturation: What does percent transferrin saturation reflect?

It reflects the degree of availability of transferrin for iron transport.

How is percent transferrin saturation calculated?

% Transferrin Saturation = (Serum Iron / TIBC) × 100.

Soluble Transferrin Receptor (sTfR): What does an increased sTfR level indicate?

It indicates that iron is low or that cells have an increased demand for iron, often seen in iron deficiency.

How does sTfR behave in anemia of chronic inflammation?

sTfR levels are typically normal in anemia of chronic inflammation.

Mnemonic for Microcytic, Hypochromic Anemias: What mnemonic can help recall these conditions?

ATIS: Anemia of Chronic Inflammation/Acute Blood Loss, Thalassemia, Iron Deficiency Anemia, Sideroblastic Anemia.

Hemoglobin Formation: What are the two main components of hemoglobin?

Heme and globin.

What test is performed to identify abnormal hemoglobin?

Hemoglobin electrophoresis.

Laboratory Assays: What is the typical serum iron level for adults and what does it indicate?

50–160 µg/dL; it indicates the amount of available transport iron.

What is the reference interval for serum transferrin (TIBC) and what does it represent?

250–400 µg/dL; it indirectly indicates iron stores via available binding sites.

What is the normal range for transferrin saturation and what does it indicate?

20%–55%; it reflects iron stores with transport iron.

What is the normal range for serum ferritin levels in adults?

40–400 ng/dL; it indicates the level of iron stores in the body.

What is the role of bone marrow or liver biopsy with Prussian blue staining in iron studies?

It provides a visual qualitative assessment of tissue iron stores.

What is the normal range for soluble transferrin receptor (sTfR) levels and its diagnostic significance?

1.15–2.75 mg/L; it indicates the amount of functional iron available in cells.

What is the sTfR/log ferritin index range and what does it indicate?

0.63–1.8; it reflects the functional iron available in cells.

What is the normal level for RBC zinc protoporphyrin, and why is it important?

<80 µg/dL of RBCs; it indicates the functional iron available in cells.

What is the normal hemoglobin content of reticulocytes, and what does it assess?

27–34 pg/cell; it indicates the functional iron available in developing red blood cells.

What is the daily replacement need for iron in an adult male?

Approximately 1 mg/day

How can inadequate iron intake lead to IDA?

When dietary iron consistently falls below the 1 mg/day replacement need, the body’s iron stores are gradually depleted

Which conditions can cause absorption issues leading to IDA?

Decreased gastric acidity (from aging, gastrectomy, or acid reducer medications), matriptase 2 mutation, autoimmune gastritis, celiac disease, and H. pylori infection

What physiological states increase the requirements for iron?

Pregnancy, nursing, infancy, and growth spurts in childhood and adolescence

How does chronic blood loss contribute to IDA?

Repeated loss (e.g., from GI bleeding, heavy menstruation, or urogenital bleeding) exceeds iron intake, depleting iron stores

Name parasitic infections that can cause iron deficiency anemia.

Hookworm, Trichuris trichiura, Schistosoma mansoni, and Schistosoma haematobium

What are common non-specific clinical manifestations of IDA?

Fatigue, weakness, shortness of breath on exertion, and pallor

What severe clinical signs may appear in advanced IDA?

Glossitis (sore tongue), angular cheilitis (cracked mouth corners), koilonychia (spoon-shaped nails), and pica (craving non-food items)

What characterizes Stage 1 (Storage Iron Depletion) of iron deficiency?

A progressive loss of iron stores with normal hemoglobin and no overt symptoms (latent stage)

What changes occur in Stage 2 (Transport Iron Depletion)?

Exhaustion of the storage pool, increased cell surface and soluble transferrin receptors, and reduced iron available for erythropoiesis while hemoglobin may still be normal

How is Stage 3 (Functional Iron Depletion) defined?

It is marked by frank anemia with a microcytic, hypochromic blood picture and the appearance of severe clinical signs

Which complete blood count (CBC) findings suggest iron deficiency anemia?

Microcytosis, hypochromia, decreased MCV, MCH, MCHC, decreased RBC count/hematocrit, and an elevated RDW (anisocytosis)

What are the key biochemical diagnostic tests for IDA?

Serum iron (decreased), TIBC (increased), transferrin saturation (decreased), and serum ferritin (decreased)

What specialized tests can further assess iron deficiency?

Assays for free erythrocyte protoporphyrin (FEP, often measured as zinc protoporphyrin) and soluble transferrin receptor (sTfR) levels

What is the primary treatment strategy for IDA?

Address the underlying cause (e.g., bleeding, parasitic infection) and provide dietary iron supplementation, commonly oral ferrous sulfate

Which groups are epidemiologically at higher risk for IDA?

Menstruating women, growing children, infants (especially if fed cow’s milk without supplementation), pregnant/nursing women, and the elderly

Why is cow’s milk considered a poor iron source for infants?

It contains low levels of iron and can interfere with the absorption of iron, necessitating iron-supplemented formulas by about 6 months of age

How does the body normally maintain iron balance?

By conserving nearly all iron from senescent cells and replacing approximately 1 mg/day lost from skin desquamation and sloughed intestinal epithelium

How does decreased gastric acidity impair iron absorption?

It limits the conversion of dietary ferric iron (Fe³⁺) to the absorbable ferrous form (Fe²⁺)

What role does a matriptase 2 mutation play in iron deficiency?

It causes persistent hepcidin production, which inactivates ferroportin, thereby reducing intestinal iron absorption

How does chronic blood loss eventually lead to IDA?

When the loss of iron through bleeding exceeds dietary intake, the iron storage becomes exhausted and RBC production is impaired

What is the significance of an elevated RDW in IDA?

It reflects increased anisocytosis (variation in RBC size), serving as an early indicator of iron deficiency

How do transferrin receptor levels change in iron deficiency?

They increase on the surface of iron-starved cells (and as soluble receptors in serum) to capture more iron

Why is iron essential for erythropoiesis?

Iron is a critical component of heme, necessary for hemoglobin synthesis and oxygen transport

What might happen if iron deficiency anemia remains untreated?

Progressive decline in hemoglobin, impaired oxygen delivery, worsening fatigue, and other severe clinical manifestations

How do reticulocyte parameters aid in the diagnosis of IDA?

A decreased hemoglobin content in reticulocytes indicates iron-restricted erythropoiesis even before mature RBC indices change

How are laboratory findings used to stage iron deficiency anemia?

Stage 1 shows normal hemoglobin with declining ferritin; Stage 2 shows subtle CBC changes and abnormal iron studies; Stage 3 presents with overt anemia and marked lab abnormalities

What is the formula for calculating transferrin saturation?

(Serum iron (µg/dL) x 100) ÷ TIBC (µg/dL)

What characterizes Anemia of Chronic Inflammation (AOI)?

It is an acquired anemia with abundant iron stores, yet the iron cannot be readily incorporated into serum or red blood cells.

What causes the iron to be unavailable for use in AOI?

Increases in acute phase reactants during inflammation slow down iron release needed by developing cells.

Which protein is primarily responsible for decreasing iron release from macrophages and hepatocytes in AOI?

Hepcidin.

What additional role does hepcidin play in iron homeostasis?

It regulates the absorption of iron in the intestine.

How does lactoferrin contribute to the pathophysiology of AOI?

It competes with transferrin for plasma iron, limiting iron availability.

Do red blood cells (RBCs) have lactoferrin receptors?

No, RBCs lack lactoferrin receptors.

What is the role of ferritin in AOI?

Ferritin binds iron, sequestering it away from erythroid precursors.

Do developing red blood cells have receptors for ferritin?

No, they do not have ferritin receptors.

What is the first mechanism (MECHANISM 1) of AOI involving hepcidin?

Increased hepcidin levels decrease iron absorption from the intestine and trap iron in macrophages and hepatocytes.

What is the second mechanism (MECHANISM 2) related to lactoferrin in AOI?

Lactoferrin competes with transferrin for plasma iron, reducing its availability to developing RBCs.

What is the third mechanism (MECHANISM 3) in AOI involving ferritin?

Ferritin binds and stores iron, keeping it sequestered in macrophages, while erythroblasts lack receptors to access it.

What does “iron-restricted erythropoiesis” mean in the context of AOI?

Despite normal or high iron stores, developing red blood cells cannot access iron, impairing effective erythropoiesis.

Which screening test is commonly used to initially evaluate AOI?

Complete Blood Count (CBC).

What CBC findings might be seen in AOI?

Leukocytosis, thrombocytosis, and a blood picture that is typically normocytic/normochromic; sometimes microcytic/hypochromic if iron deficiency coexists.

What does a decreased Reticulocyte Production Index (RPI) indicate in AOI?

It suggests ineffective erythropoiesis.

In iron studies for AOI, what happens to serum iron levels?

Serum iron levels are decreased.

How is the Total Iron-Binding Capacity (TIBC) affected in AOI?

TIBC is decreased.