This article is not intended to medical or healthcare advice. You should seek the care and guidance from your M.D. or primary care physician before embarking on any healthcare regimen.
There are many small corners in the world of chronic illness, and those who are low in Magnesium, Vitamin D, Zinc, and or phosphorous is another one of these corners.
If you find yourself chronically low in magnesium, or vitamin D despite supplementing, please read on, and if you have tested high on Organic Acids with high levels of Phosphoric Acid (>3000), please read on.....And finally, if you have done an Oligoscan test and have low phosphorous, low magnesium, low vitamin d, low Zinc, and or lowish B6.....read on.
There are 3 key genes in the body that regulate phosphorous levels in our body: FGF23, PHEX, SLC34A3
FGF23 - Fiber Growth Fibrobalst 23
The FGF23 gene provides instructions for making a protein called fibroblast growth factor 23, which is produced in bone cells. Fibroblast growth factor 23 (FGF23) is primarily synthesized in bone cells, and appears to inhibit phosphate reabsorption, and block the synthesis of the active form of vitamin D O25 from the inactive form Vitamin D3. This protein is necessary in regulating the phosphate levels within the body (phosphate homeostasis). FGF23, senses how much phosphorous and Vitamin D is in the blood, and when one or both are high, FGF23 increases, and begins to dump phosphorous, vitamin d, magnesium, and vitamin b6. This is also linked to the parathryoid, so you can see how this can begin to dysregulate the calcium magnesium balance managed by the parathyroid. Excessive supplementation of vitamin d can trigger this, as well as a diet high in phosphorous (beans, oats, cured meats, cheese, dairy, to name a few). With these folks, i often see significant mutations in FGF23 as well. If this is the case, stopping Vit D supplementation, a diet low in phosphorous, niacinamide (500mg 2x / day), and baking soda (.125-.25 teaspoons) with meals has provided substantial benefit of stopping the release of FGF23 and the balancing of phosphorous, D, B6, and Magnesium. Lab Corp offers a simple blood test for FGF23 levels to check this out too.
"Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. At physiological concentrations of the hormone, the endocrine actions of FGF23 in the kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the presence of the co-receptor αKlotho on target cells. It is well established that excessive concentrations of intact FGF23 in the blood lead to phosphate wasting in patients with normal kidney function. Based on the importance of diseases associated with gain of FGF23 function such as phosphate-wasting diseases and chronic kidney disease, a large body of literature has focused on the pathophysiological consequences of FGF23 excess. Less emphasis has been put on the role of FGF23 in normal physiology. Nevertheless, during recent years, lessons we have learned from loss-of-function models have shown that besides the paramount physiological roles of FGF23 in the control of 1α-hydroxylase expression and of apical membrane expression of sodium-phosphate co-transporters in proximal renal tubules, FGF23 also is an important stimulator of calcium and sodium reabsorption in distal renal tubules. In addition, there is an emerging role of FGF23 as an auto-/paracrine regulator of alkaline phosphatase expression and mineralization in bone. In contrast to the renal actions of FGF23, the FGF23-mediated suppression of alkaline phosphatase in bone is αKlotho-independent. Moreover, FGF23 may be a physiological suppressor of differentiation of hematopoietic stem cells into the erythroid lineage in the bone microenvironment."[1]
"This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC)"[2]
"Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis."[3]
PHEX
Another gene, PHEX is responsible for phosphorous re-uptake in the kidneys. This gene is zinc dependent. When folks are low in zinc, and or there are mutations in this gene, this is usually the trouble spot for high phosphorous - and the solution has been conistently simple, zinc supplementation - the form dependent on other issues. Phosphate regulating endopeptidase, encoded by PHEX, is a zinc-dependent enzyme that appears to be involved in the mineralization of bones and dentin, and phosphate reabsorption in the kidneys.
"Predicted to enable metalloendopeptidase activity. Acts upstream of or within bone mineralization; odontogenesis; and organophosphate metabolic process. Located in Golgi apparatus; endoplasmic reticulum; and perinuclear region of cytoplasm. Is expressed in several structures, including chondrocranium; epidermis; limb; liver; and tooth. Used to study X-linked dominant hypophosphatemic rickets and otitis media. Human ortholog(s) of this gene implicated in X-linked dominant hypophosphatemic rickets. Orthologous to human PHEX (phosphate regulating endopeptidase homolog X-linked)."[4]
"Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies..... PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP (Tubular Phosphate Re absorption) and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity." [5]
SLC34A3
SLC34A3 mediates the sodium-dependent transport of phosphate into cells and maintains phosphate concentrations in the kidney. When i see mutations in this gene, often folks can be low in sodium, and to date, sodium supplementation has provided relief of phosphorous wasting for several.
"Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis."[6]
References:
[1] Physiological Actions of Fibroblast Growth Factor-23. Reinhold G. Erben*Front. Endocrinol., 28 May 2018. Sec. Molecular and Structural Endocrinology. Volume 9 - 2018 | https://doi.org/10.3389/fendo.2018.00267
[2] NIH: November 23, 2023
[3] REGULATION AND FUNCTION OF THE FGF23/KLOTHO ENDOCRINE PATHWAYS
Aline Martin, Valentin David, and L. Darryl Quarles. Physiol Rev. Author manuscript; available in PMC 2012 Mar 16. PMCID: PMC3306265. NIHMSID: NIHMS354126. PMID: 22298654
Published in final edited form as: Physiol Rev. 2012 Jan; 92(1): 131–155.
[4] NIH: November 23, 2023
[5] Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: Tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type.
[6] SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Clemens Bergwitz 1, Nicole M Roslin, et. al. Am J Hum Genetetics . 2006 Feb;78(2):179-92. doi: 10.1086/499409.Epub 2005 Dec 9.Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. cbergwitz@partners.org. PMID: 16358214. PMCID: PMC1380228. DOI: 10.1086/499409