It is important to recognize that enzyme inhibitors do not turn off all copies of the enzyme, but rather slow down pathways at specific points. This causes accumulation of precursors immediately upstream of the site where the inhibitors act. An analogy is driving on a highway with two lane reductions between the departure and destination locations. Before each lane reduction, there will be a buildup of cars. After each lane reduction there will still be some cars on the road. Compared to the same highway without lane reductions, there will overall be less cars arriving at the destination over any given period of time.
Lead (a heavy metal) inhibits ALA dehydratase (ALAD, aka porphobilinogen synthetase) and ferrochelatase. Lead inhibits ALAD by displacing its zinc moiety and results in accumulation of delta-aminolevulinic acid (d-ALA) and decreased porphobilinogen. Lead also inhibits the physiologic activity of ferrochelatase. Under physiologic conditions, ferrochelatase catalyzes the incorporation of Fe2+ to the substrate protoporphyrin IX to create a heme product. In lead poisoning, Zn2+ is incorporated into protoporphyrin IX to form zinc protoporphyrin (ZPP). The diagnostic workup begins with a positive environmental or occupational history in children (e.g. lead paint ingestion) or adults (inhalation of lead-containing compounds). Serum lead levels will be elevated. The second step is to measure the non-heme protophyrin levels, either ZPP or free protophyrins in erythrocytes. UpToDate mentions that some labs report ZPP levels as FEP (Free Erythrocyte Protophyrins). Both are elevated in lead poisoning. Other lab tests will be used to assess the severity of effects (e.g. CBC may show microcytic anemia, renal function tests (Cr, BUN, urinalysis) may show renal damage). Abdominal Xrays may be ordered in children to confirm the source (e,g, radioopaque lead paint chips in the GI system suggesting ingestion.)
Sideroblastic anemias are a type of microcytic anemia caused by pathologic ring sideroblasts in the bone marrow. In one type, there is a defect in 5-aminolevulinic acid synthase (ASAS) that converts succinyl CoA from the TCA cycle to d-ALA that is used in heme synthesis. If protoporphyrin levels are measured (ZPP or FEP), they will be decreased due to the upstream defect in the heme synthesis pathway and no downstream defects (e.g. ferrochelatase deficiency). The diagnostic workup begins with anemia detected on a CBC. The mean corpuscular volume (MCV) will be low (<80 fL). Iron studies will show normal to high iron and ferritin as less iron will be incorporated into heme. A smear of a bone marrow aspirate will show sideroblasts, which are the hallmark of these diseases. A further workup will be needed to determine the type of sideroblastic anemia, but rarely includes protoporphyrin levels.
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