Hypophosphatemia associated with coma.

In three cases of severe hypophosphatemia profound coma was associated. Although the occurrence of hypophosphatemia appeared to coincide with a high rate of intravenous administration of glucose and water, two of the three patients had liver disease and the other had hypothermia. In two instances the neurologic status improved with intravenous phosphate therapy. These case reports emphasize the importance of early recognition and treatment of profound hypophosphatemia in critically ill patients.     

Hypophosphatemia: A Practical Guide to Evaluation and Management

Phosphate plays a critical and diverse role in human physiology. In addition to its importance in skeletal mineralization, it is essential for energy homeostasis, enzyme function, and cell membrane integrity. These diverse functions of phosphate provide an explanation for the range of symptoms and clinical manifestations observed in patients with both acute and chronic causes of hypophosphatemia. Normal phosphate homeostasis involves several major systems, including the gastrointestinal tract, bones, and kidneys. Phosphate balance is maintained directly and indirectly by 1α,25-dihydroxyvitamin D₃, parathyroid hormone, and the osteocyte-derived phosphatonin fibroblast growth factor 23. This review discusses normal phosphate homeostasis, the clinical manifestations and causes of hypophosphatemia, and an approach to establish a diagnosis and appropriate management.     

Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency

A deficiency of vitamin D results in muscle weakness as well as rickets in children and osteomalacia in the adult. To study the basis for this weakness, severe vitamin D deficiency was produced in rats as revealed by a low level or absence of 25-hydroxyvitamin D₃ in the serum. Vitamin D deficiency was achieved by feeding purified diets to weanlings for 16 weeks. Muscle force, peak contraction (P), time-to-half contraction (T_1/2), time-to-peak contraction (T_P), and time-to-half recovery (T_1/2r) were measured. A significant reduction in muscle force was found when vitamin D deficiency was accompanied by hypophosphatemia. Within 2 days of correcting the hypophosphatemia, muscle strength was normalized. When serum calcium and serum phosphorus were maintained in the normal range in vitamin D-deficient rats, muscle weakness did not develop. Further, hypocalcemia together with vitamin D deficiency did not produce muscle weakness. These results strongly suggest that muscle weakness noted in rachitic patients is the result of the hypophosphatemia of vitamin D deficiency.     

Antibody-Mediated Activation of FGFR1 Induces FGF23 Production and Hypophosphatemia

The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.     

Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO

FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P_i). When TgHMW mice were fed a high P_i diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na⁺/P_i co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P_i wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P_i homeostatic axis.     

MEPE-Derived ASARM Peptide Inhibits Odontogenic Differentiation of Dental Pulp Stem Cells and Impairs Mineralization in Tooth Models of X-Linked Hypophosphatemia

Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) cause X-linked familial hypophosphatemic rickets (XLH), a disorder having severe bone and tooth dentin mineralization defects. The absence of functional PHEX leads to abnormal accumulation of ASARM (acidic serine- and aspartate-rich motif) peptide − a substrate for PHEX and a strong inhibitor of mineralization − derived from MEPE (matrix extracellular phosphoglycoprotein) and other matrix proteins. MEPE-derived ASARM peptide accumulates in tooth dentin of XLH patients where it may impair dentinogenesis. Here, we investigated the effects of ASARM peptides in vitro and in vivo on odontoblast differentiation and matrix mineralization. Dental pulp stem cells from human exfoliated deciduous teeth (SHEDs) were seeded into a 3D collagen scaffold, and induced towards odontogenic differentiation. Cultures were treated with synthetic ASARM peptides (phosphorylated and nonphosphorylated) derived from the human MEPE sequence. Phosphorylated ASARM peptide inhibited SHED differentiation in vitro, with no mineralized nodule formation, decreased odontoblast marker expression, and upregulated MEPE expression. Phosphorylated ASARM peptide implanted in a rat molar pulp injury model impaired reparative dentin formation and mineralization, with increased MEPE immunohistochemical staining. In conclusion, using complementary models to study tooth dentin defects observed in XLH, we demonstrate that the MEPE-derived ASARM peptide inhibits both odontogenic differentiation and matrix mineralization, while increasing MEPE expression. These results contribute to a partial mechanistic explanation of XLH pathogenesis: direct inhibition of mineralization by ASARM peptide leads to the mineralization defects in XLH teeth. This process appears to be positively reinforced by the increased MEPE expression induced by ASARM. The MEPE-ASARM system can therefore be considered as a potential therapeutic target.     

Hypophosphatemia Induced by Dietary Aluminium Hydroxide Supplementation in Pigs: Effects on growth,blood variables,organ weights and renal morphology

Twenty-four pigs, 13-14 weeks of age, were studied during an experimental period of 10 weeks. The pigs were randomly divided into 3 groups. Two groups were fed a commercial feed supplemented either with a suspension of aluminium hydroxide (Al(OH)3) or aluminium phosphate (A1PO4). The third group served as a control. The same total amount of aluminium was given to each of the 2 experimental groups. After three weeks the Al(OH)3-pigs developed severe hypophosphatemia, with an average decrease in serum phosphate of 60%, a decreased growth rate and a lower concentration of 2,3-diphosphoglycerate in the erythrocytes as compared to controls. Intense hypercalcemia developed in the Al(OH)3-group during the first 6 weeks, whereas the AlPO4-pigs and the control group developed neither hypophosphatemia nor hypercalcemia. At necropsy, the consequence of the long lasting hypophosphatemia was found to be increased relative kidney weights with morphological signs of tubular damage and dyscalcification. No similar changes were observed in the AlPO4-groups and there were no organ weight deviations compared to the control group.     

Hypophosphatemia Induced by Dietary Aluminium Hydroxide Supplementation in Growing Pigs: Effects on Erythrocytes,Myocardium, Skeletal Muscle and Liver

Three groups of pigs were studied during and after 10 weeks of treatment with either Al(OH)3 (Al[OH]3-group, n=8) to induce hypophosphatemia, A1P04 (AlP04-group, n=8, aluminium control without hypophosphatemia) or no addition to the feed (control group, n=8). Blood samples were taken at the start of the experiment and after 3, 6 and 10 weeks and were analyzed for phosphate, calcium and 2,3-diphosphoglycerate (2,3-DPG). Samples from myocardium, skeletal muscle and liver were obtained in connection with exsanguination and analyzed for glycogen, adenosine-tri-phosphate (ATP), creatine phosphate (CP), glucose-6-phosphate (G-6-P) and lactate. The Al(OH)3-group became hypophosphatemic and hypercalcémie with low levels of 2,3-DPG in erythrocytes within 3 weeks and showed a retarded growth rate. After 10 weeks the Al(OH)3-group had low levels of ATP in myocardium as compared with the control-group and low levels of G-6-P as compared with the AlP04-group. No disturbances on electro-cardiograms registered at rest could be documented. G-6-P concentration was low in the biceps muscle in the Al(OH)3-group as compared with the AlP04-group and in the liver low G-6-P concentration was seen in addition to high lactate concentration. The fibre type composition in M. Longissimus did not differ between groups, but the Al(OH)3-group had, due to retardation in growth, smaller mean fibre-areas than pigs in the AlP04-group. Hypophosphatemia gave rise to high serum calcium levels, low concentration of 2,3-DPG in erythrocytes and influenced G-6-P concentration in skeletal muscle, G-6-P and ATP in myocardium, G-6-P and lactate in liver. Retarded growth was one serious consequence of hypophosphatemia and the disturbed energy metabolism.     

A Patient With Hypophosphatemia,a Femoral Fracture,and Recurrent Kidney Stones: Report of a Novel Mutation in SLC34A3

ObjectiveTo determine if there was a genetic contribution to our patient’s unusual clinical presentation of nephrolithiasis and nonhealing stress fracture.MethodsWe describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient’s clinical course and results from radiographic and biochemical analyses are described. Analysis of the SLC34A3 gene was performed using genomic DNA samples from the patient and his family members.ResultsBefore referral to the Yale Bone Center, the patient was treated with calcitriol, ergocalciferol, and phosphate. Changing therapy to phosphate alone led to clinical improvement. Genetic analysis revealed that the patient is a compound heterozygote for mutations in the SLC34A3 gene. On 1 allele, he has a previously described missense mutation in exon 7: c.575C > T (p.Ser192Leu). The other allele carries a novel nonsense mutation in exon 3: c.145C > T (p.Gln49X). One unaffected sibling is a carrier of the missense mutation and 1 sister with a history of flank pain is a carrier of the novel mutation.ConclusionsHereditary hypophosphatemic rickets with hypercalciuria is a rare metabolic disorder associated with mutations in SLC34A3, the gene that encodes the renal sodium phosphate cotransporter NaPi-IIc. Although hypercalciuria is a distinguishing feature of the disease, nephrolithiasis is rarely described. The patient’s atypical clinical presentation illustrates that both environmental and genetic factors potentially affect phenotypic expression of SLC34A3 mutations. (Endocr Pract. 2008;14:869-874)