Question

1- Explain how lead inhibits heme synthesis.

2- Explain the difference in the chemical composition of hemosiderin and ferritin.

3- How is sideroblastic anemia confirmed by laboratory analysis? Explain your answer.

4- Differentiate primary and secondary hemochromatosis?

5- Explain the absorption and assimilation of non-heme iron into hemoglobin in the RBC.

Answer 1

1. Lead interacts with zinc cofactors for ALA dehydratase and ferrochelatase leading to inhibition of these two enzymes in the biochemical biosynthetic pathway of heme. This inhibition leads to mostly ALA and some protoporphyrin IX accumulating in urine. Symptoms include abdominal pain, vomiting, fatigue irritability and developmental disability in children.

2.Haemosiderin : It is the storage form of iron in reticuloendothelial cells of bone marrow and liver.

It is the aggregate of hundreds and thousands of ferritin particles along with amorphous proteins and lipids.

Ferritin : It is made up of a globulin apoferritin plus iron.

Ferritin is water soluble and is present in all cells and extracellular fluids.

3. Following lab finding help in diagnosis of sideroblastic anaemia :

Decreased haemoglobin Decreased red cell indices Peripheral smear shows coarse basophilic stippling microcytic hypochromic. Iron status: serum and serum ferritin is increased Total iron binding capacity is decreased serum transferrin saturation is increased

4. PRIMARY HEMOCHROMATOSIS

Primary hemochromatosis is caused by a defect in the genes that control how much iron you absorb from food. This form of the disease sometimes is called hereditary or classical hemochromatosis. Primary hemochromatosis is more common than the secondary form of the disease.

The genes usually involved in primary hemochromatosis are called HFE genes. Faulty HFE genes cause the body to absorb too much iron. If you inherit two copies of the faulty HFE gene (one from each parent), you're at risk for iron overload and signs and symptoms of hemochromatosis.

If you inherit one faulty HFE gene and one normal HFE gene, you're a hemochromatosis "carrier." Carriers usually don't develop the disease. However, they can pass the faulty gene on to their children. Estimates suggest that about 1 in 10 people in the United States are hemochromatosis carriers.

If two parents are carriers of the faulty HFE gene, then each of their children has a 1 in 4 chance of inheriting two faulty HFE genes.

Although less common, other faulty genes also can cause hemochromatosis. Researchers continue to study what changes to normal genes may cause the disease.

SECONDARY HEMOCHROMATOSIS

Secondary hemochromatosis usually is the result of another disease or condition that causes iron overload. Examples of such diseases and conditions include:

• Certain types of anemia, such as thalassemia and sideroblastic anemia
• Atransferrinemia and aceruloplasminemia—both are rare, inherited diseases
• Chronic liver diseases, such as chronic hepatitis C infection, alcoholic liver disease, or nonalcoholic steatohepatitis

Other factors also can cause secondary hemochromatosis, including:

• Blood transfusion
• Oral iron pills or iron injections, with or without very high vitamin C intake (vitamin C helps your body absorb iron)
• Long-term kidney dialysis.   

5. Human enterocytes contain apical membrane-bound enzymes whose activity can be regulated and which function to reduce insoluble ferric (Fe3+) to absorbable ferrous (Fe2+) ion.

The absorption of most dietary iron occurs in the duodenum and proximal jejunum and depends heavily on the physical state of the iron atom. At physiological pH, iron exists in the oxidized, ferric (Fe3+) state. To be absorbed, iron must be in the ferrous (Fe2+) state or bound by a protein such as heme. The low pH of gastric acid in the proximal duodenum allows a ferric reductase enzyme, duodenal cytochrome B (Dcytb), on the brush border of the enterocytes to convert the insoluble ferric (Fe3+) to absorbable ferrous (Fe2+) ions. The gastric acid production plays a key role in plasma iron homeostasis. When proton-pump inhibiting drugs such as omeprazole are used, iron absorption is greatly reduced. Once ferric iron is reduced to ferrous iron in the intestinal lumen, a protein on the apical membrane of enterocytes called divalent metal cation transporter 1 (DMT1) transports iron across the apical membrane and into the cell.

Once inside the enterocyte, iron can be stored as ferritin or transported through the basolateral membrane and into circulation bound to ferroportin. (Ferritin that is not bound to iron is called apoferritin, which has an intrinsic catalytic activity that oxidizes ferrous iron into ferric iron so that it can be bound and stored as ferritin.)

Hepcidin binds ferroportin, resulting in its internalization and degradation and effectively shunting cellular iron into ferritin stores and preventing its absorption into the blood. Thereby, hepcidin also potentiates the excretion of iron through the sloughing of enterocytes (and their ferritin stores) into the feces and out of the body.