What is Zinc protoporphyrin (ZPP)?
Zinc protoporphyrin (ZPP) is a normal metabolite that accumulates in trace amounts in erythrocytes (Red blood cells) during hemoglobin (=a protein in red blood cells that carries oxygen) synthesis (=the production of hemoglobin).
The final step in the heme pathway involves the enzyme ferrochelatase, which binds ferrous iron with protoporphyrin IX through a process called chelation. This reaction is crucial for the synthesis of heme, a compound that plays a vital role in various biological functions such as oxygen transport. However, in cases of iron deficiency or impaired iron utilization, an alternative metal substrate, zinc, can be used by ferrochelatase. On the other hand, lead toxicity can interfere with the transfer of iron within cells, leading to a condition similar to iron deficiency. Essentially, lead toxicity mimics the effects of iron deficiency by disrupting the normal functioning of intracellular iron transfer.
What does the ZPP test measure?
The test measures the concentration of zinc protoporphyrin (ZPP) in the blood. ZPP is present in blood in trace amounts and is formed during the production of heme. Concentrations of ZPP are increased in patients with lead poisoning and iron deficiency. Heme is an essential component of hemoglobin, the protein in red blood cells (RBCs) that carries oxygen from the lungs to the body’s tissues and cells. The formation of heme occurs in a series of reactions that conclude with the insertion of an iron into the center of a molecule called protoporphyrin. If there is not enough iron available, then protoporphyrin combines with zinc instead of iron to form zinc protoporphyrin (ZPP). ZPP serves no useful purpose in the red blood cells since it cannot transport oxygen around the body. Lead prevents iron (but not zinc) from attaching to protoporphyrin so zinc protoporphyrin will also be elevated in severe cases of lead poisoning.
Ogun AS, Joy NV, Valentine M. Biochemistry, Heme Synthesis. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537329/
Rivett ED, Heo L, Feig M, Hegg EL. Biosynthesis and trafficking of heme o and heme a: new structural insights and their implications for reaction mechanisms and prenylated heme transfer. Crit Rev Biochem Mol Biol. 2021 Dec;56(6):640-668. doi: 10.1080/10409238.2021.1957668. Epub 2021 Aug 25. PMID: 34428995; PMCID: PMC8877297.
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The ZPP concentration in blood is usually very low. An increase in ZPP indicates a disruption of normal heme production but is not specific as to its cause. The main reasons for increases in ZPP are iron deficiency and lead poisoning. It is important that ZPP concentrations be evaluated in the context of a patient’s history, clinical findings, and the results of other tests such as ferritin, lead, and a complete blood count (CBC). It is possible that the patient may have both iron deficiency and lead poisoning.
In cases of chronic lead exposure, ZPP reflects the average lead concentration over the previous 3-4 months. However, the amount of lead currently present in the blood and the burden of lead in the body (the amount in the organs and bones) cannot be determined with a ZPP test. Values for ZPP rise more slowly than the blood lead concentration following exposure, and they take longer to drop after exposure to lead has ceased.
ZPP levels must be evaluated in the context of your history, clinical findings, and the results of other tests such as ferritin, lead, and a complete blood count (CBC). You may have both iron deficiency and lead poisoning.
In cases of chronic lead exposure, ZPP reflects the average lead level over the previous three to four months. However, the amount of lead currently present in the blood and the amount in the organs and bones cannot be determined with a ZPP test. Values for ZPP rise more slowly than blood lead concentrations following exposure and take longer to drop after exposure to lead has ceased.
ZPP can also be elevated in anemia caused by chronic inflammatory diseases, infections, and cancer, but it is not generally used to monitor or diagnose these diseases.
Depending on the method used to test ZPP, high levels of other substances in the blood, such as bilirubin and riboflavin, can produce false-positive results. Falsely low values may occur if the sample is not protected from light before testing.
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