Fluoride is a clinically important electrolyte that is overshadowed by the other electrolytes routinely measured in the clinical chemistry laboratory. Most labs do not perform their own plasma/serum fluoride testing and it often is sent out to reference labs for analysis. Fluoride tests are useful for discovering long-term or short term ingestion of large amounts of fluoride, aiding in the diagnosis of skeletal fluorosis, and for monitoring patients taking voriconazole for Aspergillus infections (Aspergillosis).
Fluorine is naturally found the earth in in a variety of minerals existing in varying concentrations around the world. Fluoride, the anion F-, has been added to drinking water in the United States since the 1940’s to decrease the occurrence of dental cavities. Fluoride administered orally will replace demineralized hydroxyapatite with fluorapatite, which is more resistant to demineralization. In parts of the United States that fluoridate their drinking water, the water contains approximately 1 ppm fluoride. This was found to be a safe concentration to add to drinking water without causing any adverse effects. This is compared to adult toothpaste which contains more than 1000 times that amount of fluoride and is not safe to ingest. Over time excess fluoride can cause skeletal fluorosis, which can lead to periostitis, osteoporosis, and increased growth of dense, brittle bones that are more susceptible to fractures (1). Some parts of Asia have very high levels of fluoride ion in the groundwater, increasing the risk for skeletal fluorosis for inhabitants who have no access to alternative sources of drinking water (2).
High levels of fluoride in individuals in the United States have been documented originating from excessive tea consumption. In 2013 a 47-year-old woman acquired skeletal fluorosis due to years of drinking large amounts of strong-brewed tea (3). She reportedly drank a pitcher of tea a day brewed from 100-150 tea bags (estimated daily intake of fluoride > 20 mg/day) for 17 years. Black tea has long been known to contain high fluoride levels, but it requires years of strong tea drinking to reach the levels seen in this patient.
High fluoride levels can also been seen in patients taking long-term voriconazole. Voriconazole is a triazole antifungal medication that is primarily used for invasive Aspergillosis and Candidiasis, and it is often a lifelong therapy. It has been shown that prolonged voriconazole therapy can cause fluorosis with accompanying periostitis in some patients (4). The mechanism of which ‘voriconazole-induced periostitis’ occurs is not yet entirely understood, but it is said to be related to the three fluorine atoms contained within the voriconazole molecule itself. It is quite common for medications to contain fluorine atoms (5), but voriconazole in particular has been shown to cause fluorosis in some patients. Patients who acquire voriconazole-induced fluorosis are moved to other medications such as posaconazole, which does not contain any fluorine atoms (6).
Fluoride is usually detected using an ion-selective electrode (ISE). The fluoride ISE contains a lanthanum fluoride (LaF3) crystal doped with europium fluoride (EuF2) and works in a similar manner to a pH electrode where a potential difference across the membrane can be related to an ion concentration using the Nernst equation. Fluoride analysis uses an indirect potentiometric method similar to sodium, potassium, and chloride on a large chemistry analyzer, but instead of using a large dilution in order to keep the ionic strength constant, fluoride analysis requires the use of a total ionic strength adjustment buffer (TISAB).
There are some other important pieces of chemical information to know when performing fluoride testing in the clinical laboratory. It has long been known that glass tubes are unsuitable for fluoride analysis due to the fluoride ions being adsorbed onto the surface of the glass or bound to the lattice. Gray blood tubes that contain potassium oxalate/sodium fluoride to inhibit glycolysis are unacceptable for fluoride testing due to the fluoride additive and would give a falsely high result. The pH of the solution being measured is important as well, as a low pH can cause a falsely low fluoride reading due to H+ ions complexing with F-. Similarly, high pH levels can cause the OH- ions to interact with the ISE, causing falsely elevated levels.
- Sellami M, Riahi H, Maatallah K, Ferjani H, Bouaziz MC, Ladeb, MF. Skeletal fluorosis: don’t miss the diagnosis! Skeletal Radiology 2020;49:345-357
- Wei W, Pang S, Sun D. The Pathogenesis of Endemic Fluorosis: Research Progress in the Last 5 Years. J Cell Mol Med. 2019;23(4):2333-2342
- Kakumanu N, Rao SD. Skeletal Fluorosis Due to Excessive Tea Drinking. N Engl J Med. 2013;368:1140
- Wermers RA, Cooper K, Razonable RR, Deziel PJ, Whitford GM, Kremers WK, Moyer TP. Fluoride Excess and Periostitis in Transplant Patients Receiving Long-Term Voriconazole Therapy. Clinical Infectious Diseases 2011;52(5):604-611
- Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015;58(21):8315-8359
- Thompson III GR, Bays D, Cohen SH, Pappagianis D. Fluoride Excess in Coccidioidomycosis Patients Receiving Long-Term Antifungal Therapy: an Assessment of Currently Available Triazoles. Antimicrob Agents Chemother. 2012;56(1):563-564