FOSFATHENRY:

Konsentrasi fosfat dalam tubuh manusia dewasa dalam keadaan normal sejumlah 700-800 g. sekitar 80%-85% terdapat dalam tulang, serta sisanya tersimpan didalam extra celluler fosfat dalam bentuk inorganic fosfat dan juga tersimpan didalam sel jaringan lunak berupa phosfolipid asam nukleat, triphosphate (ATP), tulang berisi inorganic phosphate yang didominasi oleh bentuk sebagai hydroxyapatite, dan kalsium phosphate.Didalam darah organic fosfat terbanyak didapatkan dalam eritrosit sedangkan didalam plasma sebagian besar berisi inorganic fosfat, 2/3 dari jumlah fosfat didalam tubuh berupa dalam bentuk organic fosfat sedangkan sekitar 3-4 mg/dL dari total jumlah fosfat dalam tubuh sebesar 12 mg/dL terdapat dalam bentuk inorganic fosfat. Inorganic fosfat didalam serum dalam bentuk divalent(HPO42-) dan monovalent (H2PO4-) fosfat anion, keduanya merupakan bahan penting sabagai buffer. Perbandingan konsentrasi antara HPO42- : H2PO4- di dalam serum tergantung pada derajat keasaman sekitar 1 : 1 pada keadaan asam, 1 : 4 dalam pH. 7,4 dan 1 : 9 dalam keadaan basa. 10% dari fosfat dalam serum terikat dengan protein, 35% berikatan dengan kalsium, natrium dan magnesium, sedangkan sisanya sebanyak 55% berada bebas tanpa ikatan. Hanya fosfat inorganic saja yang dihitung dalam pemeriksaan fosfat di klinik.Fungsi fisiologis

Fosfat paling dominan berperan dalam tulang baik secara intra dan ekstraseluler. Fosfat merupakan bahan yang sangat penting bagi asam nukleat dimana pada kedua bantuknya yaitu RNA dan DNA yang tersusun dalam bentuk kompleks fosfodi-ester. setiap penambahan fosfat selalu berisi fosfolipid an fosfoprotein. Dan dalam bentuk ini merupakan campuran dari senyawa energy tinggi (ATP) dan merupakan ko-faktor dari Nicotinamide Adenine Dinucleotide Phosphate (NADP) dan terlibat sebagai penghubung dalam metabolisme dan berbagai sistem enzinm (adenyl siklase). Fosfat sangat berhubungan dengan kontrasi otot, fungsi saraf, transport elektrolit, dan membawa oksigen dengan Hb (2.3-diphosphoglycerate)Hemostasis fosfat

Sebagian besar fosfat didapat dari diet, namun beberapa dihasilkan dari hasil metabolism dari tulang. Fosfat tersedia pada makanan olahan. Kebutuhan tubuh manusia terhadap fosfat dalam sehari sekitar 800 mg sampai 1400 mg yang sebaian besat didapat dari makanan berupa sereal, telur dan daging. Sebanyak 60% sampai 80% dari fosfat yang telah dicerna diserap dalam usus secara transport pasif. Tetapi selain transport pasif juga terdapat suatu energy aktif yang distimulasi oleh 1,25(OH)2D3. Antara serum kalsium dan fosfat terdapat suatu proses yang timbal balik. Fosfat difiltrasi secara bebas dalam glomerulus, lebih dari 80% dari hasil filtrasi glomerulus akan direabsorbsi kembali di tubulus proximal dan sebagian kecil lainnya di tubulus distalis. Reabsorbsi di tubulus proximal benrlangsung secara pasif transport bersama natrium (na-P-co-transport). Mekanisme regukasi co-transport terutama dipengaruhi oleh intake fosfat dan parathormon (PTH). Retriksi fosfat dapat meningkatkan reabsorbsi fosfat dan menenurunkan intake. PTH menginduksi terjadinya fosfaturia dengan menghambat proses Na-P-co-transport. Dimana proses yang terjadi yair=tu pada tubulus proximal. Hormone berikatan dengan spesifik redeptor pada basolateral membrane, dan menghasilkan aktivasi dari kedua jalur, adenyl cyclase / cyclic Adenosine monophosphste / protein kinase A dan phospholipida C / calcium / protein kinase C systemkedanya menghambat Na-P-co-transport (bellorin-font, 1990).Meskipun PTH menurunkan fosfat serum, kadar fosfat serum akan meningkat dengan keberadaan vitamin D dan growth hormone, vitamin D akan meningkatkan absorbs fosfat di usus dan diginjal, growth hormone berperan penting pada pertumbuhan tulang, keberadaannya di dalam aliran darah akan mengurangi ekskresi fosfat dalam ginjal yang kemudian akan berakibat meningkatnya kadar fosfat dalam serum.Sementara itu regulasi yang berhubungan dengan hormone, fibroblast growth hormone faktor 23 (FGF-23), enzyme [phosphate-regulating-gene with homologies to endopeptide (PHEX)] diduga juga terlibat dalam metabolism FGF-23, dan protein [Matrix Extracelluler Glycoprotein (MEPE)] telah menjelaskan tentang metabolism ini (quarles, 2003). Proses kaskade tersebut diperkirakan terlibat dalam proses homestasis fosfat tapi ada beberapahal yang masih belum dapat dipahmi mekanismenya. FGF-23 secara normal diproduksi oleh osteosit da osteoblas, juga diproduksi di perisit sumsum tulang, timus dan lemfenode, namun beberapa data menunjukkan bahwa FGF-23 dikeluakan terbanyak melalui tulang (Lu, 2007) dan juga memberikan bukti pertama tentang regulasi bebes hormonal terhadap kadar fosfat. Pengingkatan Kdadar FGF-23 menyebabkan hyperfosfaturia, secara primer menghambat Na-P-co-transport resorpsi chanel, FGF-23 juga menghambat absorpsi fosfat di usus dengan menghambat 25OH-vitamin D, 1--hydroxylase di tubulus proximal ginjal (LU, 2007). Mutasi yang berkaitan dengan FGF-23, PHEX dan MEPE berimplikasi terhadap pembuangan fosfat oleh ginjal dan juga berkaitan dengan abnormalitas mineral lain (Quarles, 2003).Teknik analitikMetode yangdigunakan dalam pengukuran fosfat adalah dengan memeriksa inorganic fosfat, berdasarkan reaksi antara inorganic fosfat dengan ammonium molybdate yang kemudian membentuk complex phosphomolybdate. Kompleks phosphomolybdate yang tidak tereduksi tidak berwarna dan digunakan sinar ultraviolet dengan panjang gelombang 340 nm, sebagaimana yang dikemukakan oleh Daly dan Ertinghausen 1972, dan juga banyak digunakan dalam pemeriksaan automatis analiser. Beberapa alternative metode pemeriksaan yang lain adalah dengan mereduksi kompleks phosphomolybdate dengan beberapa agen (ascorbic acid, ferrous sulfat, aminophtholsulfonic acid, methyl-p-aminophenol sulphate) untuk menghasilkan bentukan molybdenum blue yang dapat di periksa oleh sinar dengan panjang gelombang 600-700 nm. Bentuk phosphomolybdate sangat tergantung pH, dan juga dipengaruhi oleh kensentrasi protein, pemeriksaan dengan tidak mereduksi kompleks molybdate memiliki beberapa keuntungan antara lain: Simple, Cepat, stabil.Metode pemeriksaan fosfat yang lain secara reaksi enzymatic dimana fosfat mengalami beberapa reaksi enzimatk yang berurutan dengan dikatalisa oleh glycogen phosphorylase, phosphoglucomutase dan glucose-6-phosphat dehydrogenase (G6PD). NADPH dapat dihitung secara kuantitatif baik secara fluorometrically atau spectrofotometri. Reaksi ini terjadi dalam suasana pH netral, kemudian hal tersebut membolehkan pengukuran fosfat inorganic dalam organic fosfat yang tidak stabil.sampel yang dianjurkan adalah serum karena semua antikoagulan kecuali heparin dapat mempengaruhi hasil yang false low. Hasil pemeriksaan fosfat dapat meningkat apabila sampel dibiarkan terlalu lama dalam suhu kamar. Sampel yang hemolisis tidak diterima karena eritrosit mengandung organic ester yang tinggi, yang kemudian akan dihidrolisa menjadi inorganic fosfatselama penyimpanan, hel tersebut bertanggungjawab terhadap peningkatan kadar fosfat.Refferen Interval

Normal dewasa: 2,8 mg/dL 4,5 mg/dL (0,89 mmol/L 1,44 mmol/L) konsentrasi normal yang tinggi ditemukan pada anak usia pertumbuhan 4-7 mg/dL (1,29 2,26 mmol/L) Untuk hasil yang baik maka serum yang diambil harus dari orang yang berpuasa dan diambil pagi hari karena adanya efek diurnal dari fosfat dengan hasil yang lebih tinggi ditemukan pada sore hari dan malam hari serta pada saat sesaat setelah makan, kadar fosfat akan meningkat padakeadaan diet fosfat, makan, dan olahraga.Inorganic fosfat, orthophosphate, atau organic, seperti glucose-6- fosfat, asam nukleat, fosfoprotein, dan seterusnya. Sebagian besar fosfat dalam serum dalam bentuk inorganic fosfat, organic fosfat terutama terdapat dalam intraseluler. Phosphoric acid adalah tribasik acid, dan bentuk utama fosfat pada pH darah adalah H2PO42- dan HPO42- . pemeriksaan kadar total inorganic fosfat metode yang biasa digunakan adalah dengan fosfomolybdate dimana ammonium molybdate akan bereaksi dengan inorganic fosfat membentuk ammonium-fosfomolybdate kompleks (endress, 1999). Bentukan yang tidak tereduksi dari ammonium-fosfomolybdate kompleks dapat dengan mudah diketahui peningkatannya dengan melihat absorbance pada panjang gelombang 340 nm. pH harus dalam keadaan asam karena kondisi basa dapat menyebabkan kompleks fosfomolybdate tereduksi. Namun pada kenyataannya reduksi yang terjadi pada kompleks ini menghasilkan warna biru yang mana absorben dapat dihitung pada panjang gelombang 600-700 nm (fiske-subbarow method). Bahan-bahan pereduksi yang digunakan adalah asam askorbat, stannous chloride, ferrous ammonium sulfat, 1-amino-2-naphtol-4-sulfonic acid dan beberapa yang lainnya. Sebagian besar metode menggunakan sinar dengan panjang gelombang 340 nm karena kecepatan dan hanya dilakukan dalam satu langkah.Phosphate

Fisiologi fosfat

Ditemukan dalam sel-sel hidup, fosfsat merupakan salah satu bahan pembentuk sel yang sangat penting pada beberapa proses bahan-bahan biokemikal. Bahan-bahan pembentuk DND dan RNA juga merupakan kompleks dari fosfodiester. Sebagian ko-enzyme merupakan ester dari phosphorik atau phosphophoric acid. Bahan biokemikal yang sangat penting sebagai energy adalah ATP, kreatinin fosfat dan phosphoenolpyruvat. Penurunan kadar fosfat merupakan salah satu pengyebab dari kekurangan ATP, yang pada akhirnya bertanggungjawab terhadap timbulnya gejala-gejala klinis terhadap hipofosfatemia.Perubahan konsentrasi dari 2,3-biphodphogycerate (2,3-BPG) pada sel darah merah mamberikan efek terhadap afinitas hemoglobin terhadap oxygen dalam jaringan dan berkurangnya ikatan Hb yang tersedia. Dengan mempengaruhi formasi dari 2,3-BPG, konsentrasi dari inorganic fosfat secara tidak langsung mempengruhi pelepasan oxygen dari hemoglobin.Untuk mengetahui perubahan yang terjadi pada fosfat dalam darah sangat sulit karena adanya perubahan konsentrasi fosfat menuju area transeluler merupakan penyebab utana terjadinya hipofosfatemia dalam darah. Demikian juga apabila terjadi peningkatan perubahan fosfat menuju intrasel maka akan mengosongkan fosfst dari dalam darah. Manakala fosfat banyak digunakan oleh sel, maka sisanya akan digunakan untuk memebentuk sintesa ikatan phosphorylated.Regulasi fosfat

Fosfat dalam darah berasal dari absorbsi fosfat oleh usus yang berasan dari makanan yang dimakan sehari-hari, juga merupakan hasil pelepasan fosfat dari dalam sel menuju darah serta pelepasan dari tulang. Pada individu yang sehat semua berlangsung dengan konstan dan dapat dengan mudah diregulasi oleh ginjal baik dalam ekskresi maupun reabsorsi dari fosfat.Semua gangguan yang terjadi dalam proses ini dapat menyebabkan perubahan dari konsentrasi fosfat dalam darah, namun demikian yang paling berpengaruh terhadap konsentrasi fosfat adalah gagalnya fungsi ginjal. Meskipun faktor-faktor lain juga dapat berpengaruh antara lain vitamin D, calsitonin, growth hormone dan status asam-basa, yang dapat mempengaruhi ginjal dalam meregulasi fosfat, dan faktor yang penting juga adalah Parathormon (PTH), dimana keseluruhan itu menurunkan konsentrasi dalam darah dengan meningkatnya ekskresi melalui ginjal.Vitamin D meningkatkan fosfat dalam darah dengan jalan meningkatkan absorbsi fosfat dalam usus dan juga meningkatkan reabsorbsi fosfat dalam ginjal.Growth hormone yang bekerja dalam regulasi tulang yang juga dapat berdampak terhdap konsentrasi fosfat. Pada kasus meningkatnya growth hormone yang berlebih menyebabkan paningkatan fosfat dalam darah karena adanya pengaruh terhadap penurunan ekskresi fosfat oleh ginjal.

Distribusi

Meskipun konsentrasi fosfat dalam darah sekitar 12 mg/dL (3,9 mmol/L), sebagian besar adalah organic fosfat dan hanya 3-4 mg/dL berupa inorganic fosfat. Fosfat predominan berada dalam intrasel anion, dengan konsentrasi yang bervariasi, tergantung dari tipe sel tertentu. 80% dari keseluruhan fosfat terkumpul di tulang, 20% pada jaringan lunak dan kurang lebih 1% bebes dalam serum atau plasma.Aplikasi klinis

Hipofosfatemia tedapat pada 1-5% pasien di rumah sakit, insidennya akan meningkat 20-40% pada pasien-pasien dengan ketoasidosis, ppok, asthma, malignancy, terapi nutrisi parenteral jangka panjang (TPN) inflammatory bowel disease, anoreksia nervosa, alcoholism. Dan akan meningkat 60-80% lagi pada pasien sepsis di ICU. Dan hipofosfatemia dikarenakan adanya peningkatan ekskresi oleh ginjal serta penurunan absorbsi fosfat oleh usus dikarenakan defisiensi vitamin D dan penggunaan antacid yang berlebih. Meskipun kasus yang terjadi moderat dan jarang menyebabkan masalah, hypofosfatemia yang berat < 1,0 mg/dL atau 0,3 mmol/L membutuhkan perhatian dan pemberian terapi penambahan fosfat. Terdapat 30% kematian pada pasien dengan hipofosfatemia berat dan 15% kematian pada pasien dengan normal fosfatemia dan hipofosfatemia ringan.Hyperfosfatemia

Pasien yang beresiko terjadi hyperfosfatemia adalah mereka yang mengalami akut atau kronik gagal ginjal. Peningkatan intake fosfat dan peningkatan fosfat oleh pelepasan sel dapat menyebabkan hiperfosfatemia. Dikarenakan belum terbentuknya PTH yang matur dan metabolism vitamin D pada neonatus rentan terhadap hiperfosfatemia karena peningkatan intake fosfat dari pemberian susu sapi atau laxative. Peningkatan penghancuran dari sel dapat berakibat hiperfosfatemia sebagaimana juga adanya infeksi yang berat, latihan olahraga yang berat, gangguan neoplastik, atau hemolisis intravaskuler. Pada immature limfoblas memiliki kadar fosfat 4 kali lebih banyak dari pada limfosit matur, pasien dengan limfoblastik leukemia sangat rentan terhadap hiperfosfatemia.

Pemeriksaan Inorganik fosfat

Specimen: serum atau plasma dengan lithium heparin untuk analisis fosfat. Oxsalat dan EDTA serta sitrat tidak dapat digunakan karena akan menjadi interfere terhadap metode analisis. Dihindari adanya sampel yang hemolisis karena kadar fosfat yang tinggi dari dalam sel darah merah, sirkulasi fosfat dalam tubuh juga dipengaruhi oleh efek sirkandian dengan konsentrasi fosfat yang tinggi pada akhir pagi dan kadar paling rendah pada sore atau malam hari. Analisa fosfat urin dibutuhkan urin tampung 24 jam karena untuk menghindari efek diurnal.

Metode yang digunakan adalah ammonium phosphomolybdate kompleks dengan asorbsi ultraviolet dengan panjang gelombang 340 nm, atau dengan mereduksi kompleks diatas dengan asam dan membentuk molybdate blue untuk kemudian disinari dengan panjang gelombang 600-700 nm.

Reffernce range

Nilai fosfat dipengaruhi oleh usia:

Neonates: 1,45-2,91 mmol/L (4,5-9 mg/dL)Anak

: 1,45-1,78 mmol/L (4,5-55 mg/dL)Dewasa

: 0,87-1,45 mmol/L 2,7-4,5 mg/dL)

Urine (24 jam): 13-42 mmol/hari (0,4-1,3 g/hari)

pproximately 60-70% of dietary phosphate, 1000-1500 mg/day, is absorbed in the small intestine. Although vitamin D can enhance the absorption, especially under conditions of dietary phosphate depletion, intestinal phosphate absorption does not require the presence of active vitamin D. Specifically, high serum phosphate and high dietary phosphate intake do not significantly impair intestinal uptake. The movement of phosphate in and out of bone, the reservoir containing most of the total body phosphate, is generally balanced. Renal excretion of excess dietary phosphate intake ensures maintenance of phosphate homeostasis, maintaining serum phosphate at a level of approximately 3-4 mg/dL in the serum.

The vast majority of filtered phosphate is reabsorbed by type 2a sodium phosphate cotransporters located on the apical membrane of the renal proximal tubule. The expression of these cotransporters is increased by low dietary phosphate intake and several growth factors to enhance phosphate absorption. The expression is decreased by high dietary phosphate intake, parathyroid hormone (PTH), FGF23, and dopamine. Phosphate absorption in the remainder of the nephron is generally mediated by type 3 sodium phosphate cotransporters. No direct evidence has been found related to the regulation of these transporters in renal cells under physiologic conditions. The absorption in the proximal tubule is regulated such that the final excretion matches the dietary excess in order to maintain homeostasis

Hyperphosphatemia inhibits 1-alpha hydroxylase in the proximal tubule directly and indirectly through stimulation of FGF23, thus inhibiting the conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3. FGF23 additionally increases the expression of 24-hydroxylase, leading to inactivation of active 1,25 dihydroxyvitamin D3. The decrease in active vitamin D production with high phosphate is somewhat offset by the ability of hyperphosphatemia to stimulate the secretion of parathyroid hormone (PTH), which will increase the activity of 1-alpha hydroxylase. The result is generally a neutral effect on intestinal phosphate absorption. Hyperphosphatemia-stimulated PTH secretion is mediated through an as yet unidentified pathway. With normal renal function, the transient increase in PTH and decrease in vitamin D serve to inhibit renal and intestinal absorption of phosphate, resulting in resolution of the hyperphosphatemia. In contrast, under conditions of renal failure, sustained hyperphosphatemia results in sustained hyperparathyroidism. The hyperparathyroidism enhances renal phosphate excretion but also enhances bone resorption, releasing more phosphate into the serum. As renal failure progresses and the ability of the kidney to excrete phosphate continues to diminish, the action of PTH on the bone can exacerbate the already present hyperphosphatemia.

Systemic phosphate balance in an adult human. On the basis of Figure 2 from a review by Berndt and Kumar, modified and used with permission.1

Overlay of the systemic phosphate homeostasis with the major players in the phosphate regulatory network and their functional interactions. ( stimulation; inhibition). Modified from Figure 3 by Rowe,36 with permission.

Phosphate regulation by klotho: Hypotheses. The first arrow starts from the intestine, where a reduced dietary phosphate intake diminishes serum phosphate concentration and leads to a decrease in PTH secretion, which physiologically reduces urinary phosphate excretion. In addition, to save phosphate, the renal action of FGF23 will decrease facilitating tubular phosphate reabsorption by the stimulation of sodium-dependent phosphate cotransporters (NPT2a and NPT2c). It will also facilitate the synthesis of 1,25(OH)2D3 in spite of low PTH levels. The increase in calcitriol levels stimulates sodium-dependent phosphate cotransporter type IIb expression and intestinal phosphate absorption. Then, to counteract the activation of these three phosphate-saving mechanisms and to avoid hyperphosphatemia, the renal synthesis of klotho is increased. This increase in renal klotho will facilitate the phosphaturic action of FGF23. Klotho binds to FGFR1(IIIc) and forms the specific FGF23 receptor. Furthermore, klotho negatively regulates the synthesis of 1,25(OH)2D3 by enabling FGF23 binding to its receptor and thereby its inhibitory effect on 1--hydroxylase activity. At the bone level, klotho could stimulate bone resorption and phosphate release by acting on TRPV5, which is a recently identified osteoclast function modulator. The increased levels of 1,25(OH)2D3 could also stimulate osteoclast differentiation and bone resorption and thereby phosphate release. It could also stimulate skeletal FGF23 synthesis to control further, at the renal level, any excessive increase in serum phosphate resulting from the activation of the prophosphatemic mechanisms. Abbreviations: PTH, parathyroid hormone; FGF23, fibroblast growth factor-23; TRPV5, epithelial calcium channel TRPV5 (transient receptor potential vallinoid-5).

Figure 1. Synthesis and metabolism of vitamin D in the regulation of calcium, phosphorus, and bone metabolism. During exposure to solar UVB radiation, 7-dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to vitamin D3 in a heat-dependent process. Excessive exposure to sunlight degrades previtamin D3 and vitamin D3 into inactive photoproducts. Vitamin D2 and vitamin D3 from dietary sources are incorporated into chylomicrons and transported by the lymphatic system into the venous circulation. Vitamin D (hereafter, D represents D2 or D3) made in the skin or ingested in the diet can be stored in and then released from fat cells. Vitamin D in the circulation is bound to the vitamin Dbinding protein, which transports it to the liver, where vitamin D is converted by vitamin D-25-hydroxylase to 25(OH)D. This is the major circulating form of vitamin D that is used by clinicians to determine vitamin D status. (Although most laboratories report the normal range to be 20 to 100 ng/mL [50 to 250 nmol/L], the preferred range is 30 to 60 ng/mL [75 to 150 nmol/L].) This form of vitamin D is biologically inactive and must be converted in the kidneys by 25-hydroxyvitamin D-1-hydroxylase (1-OHase) to the biologically active form 1,25(OH)2D. Serum phosphorus, calcium, fibroblast growth factor 23 (FGF-23), and other factors can either increase (+) or decrease () the renal production of 1,25(OH)2D. 1,25(OH)2D decreases its own synthesis through negative feedback and decreases the synthesis and secretion of PTH by the parathyroid glands. 1,25(OH)2D increases the expression of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D to the water-soluble, Figure 1 (Continued). biologically inactive calcitroic acid, which is excreted in the bile. 1,25(OH)2D enhances intestinal calcium absorption in the small intestine by interacting with the vitamin D receptorretinoic acid x-receptor complex (VDR-RXR) to enhance the expression of the epithelial calcium channel (transient receptor potential cation channel, subfamily V, member 6 [TRPV6]) and calbindin 9K, a calcium-binding protein (CaBP). 1,25(OH)2D is recognized by its receptor in osteoblasts, causing an increase in the expression of the receptor activator of RANKL. RANK, the receptor for RANKL on preosteoclasts, binds RANKL, which induces preosteoclasts to become mature osteoclasts. Mature osteoclasts remove calcium and phosphorus from the bone, maintaining calcium and phosphorus levels in the blood. Adequate Ca2+ and phosphorus (HPO42) levels promote the mineralization of the skeleton. Reproduced with permission from Holick M. Vitamin D deficiency. N Engl J Med. 2007;357:266281. Copyright 2007 Massachusetts Medical Society. All rights reserved.

P Metabolsm

Phosphorus Metabolism

Although 85% of the ~600 g of body phosphorus is present in bone mineral, phosphorus is also a major intracellular constituent, both as the free anion(s) and as a component of numerous organophosphate compounds including structural proteins, enzymes, transcription factors, carbohydrate and lipid intermediates, high-energy stores (ATP, creatine phosphate), and nucleic acids. Unlike calcium, phosphorus exists intracellularly at concentrations close to those present in ECF (e.g., 12 mmol/L). In cells and in the ECF, phosphorus exists in several forms, predominantly as H2PO4 or NaHPO4, with perhaps 10% as HPO42. This mixture of anions will be referred to here as "phosphate." In serum, about 12% of phosphorus is bound to proteins. Concentrations of phosphates in blood and ECF are generally expressed in terms of elemental phosphorus, the normal range in adults being 0.751.45 mmol/L (2.54.5 mg/dL). Because the volume of the intracellular fluid compartment is twice that of the ECF, measurements of ECF phosphate may not accurately reflect phosphate availability within cells that follows even modest shifts of phosphate from one compartment to the other.

Phosphate is widely available in foods and is efficiently absorbed (65%) by the small intestine, even in the absence of vitamin D. On the other hand, phosphate absorptive efficiency may be further enhanced (to 8590%) via active transport mechanisms that are stimulated by 1,25(OH)2D. These involve activation of Na+/PO42 co-transporters that move phosphate into intestinal cells against an unfavorable electrochemical gradient. Daily net intestinal phosphate absorption varies widely according to the composition of the diet but is generally in the range of 5001000 mg/d. Phosphate absorption can be inhibited by large doses of calcium salts or by sevelamer hydrochloride (Renagel), strategies commonly used to control levels of serum phosphate in renal failure. Aluminum hydroxide antacids also reduce phosphate absorption but are less commonly used because of the potential for aluminum toxicity. Low serum phosphate directly stimulates renal proximal tubular synthesis of 1,25(OH)2D.

Serum phosphate levels vary by as much as 50% on a normal day. This reflects the effect of food intake but also an underlying circadian rhythm that produces a nadir between 7 and 10 A.M. Carbohydrate administration, especially as IV dextrose solutions in fasting subjects, can decrease serum phosphate by >0.7 mmol/L (2 mg/dL) due to rapid uptake into, and utilization by, cells. A similar response is observed in the treatment of diabetic ketoacidosis and during metabolic or respiratory alkalosis. Because of this wide variation in serum phosphate, it is best to perform measurements in the basal, fasting state.

Control of serum phosphate is determined mainly by the rate of renal tubular reabsorption of the filtered load, which is ~46 g/d. Because intestinal phosphate absorption is highly efficient, urinary excretion is not constant but varies directly with dietary intake. The fractional excretion of phosphate (ratio of phosphate to creatinine clearance) is generally in the range of 1015%. The proximal tubule is the principal site at which renal phosphate reabsorption is regulated. This is accomplished by changes in the apical expression and activity of a specific Na+/PO42 co-transporter (NaPi-2) in the proximal tubule. Apical expression of NaPi-2 is rapidly reduced by PTH, the major known hormonal regulator of renal phosphate excretion. FGF23 can dramatically impair phosphate reabsorption (see below). Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, this molecule also leads to reduced synthesis of 1,25(OH)2D, which may worsen the resulting hypophosphatemia by lowering intestinal phosphate absorption. Renal reabsorption of phosphate is responsive to changes in dietary intake, such that experimental dietary phosphate restriction leads to a dramatic lowering of urinary phosphate within hours, preceding any decline in serum phosphate (e.g., filtered load). This physiologic renal adaptation to changes in dietary phosphate availability occurs independently of PTH. Findings in FGF23-knockout mice suggest that FGF23 normally acts to lower blood phosphate and 1,25(OH)2D levels. In turn, elevations of blood phosphate increases blood levels of FGF23.

Renal phosphate reabsorption is impaired by hypocalcemia, hypomagnesemia, and severe hypophosphatemia. Phosphate clearance is enhanced by ECF volume expansion and impaired by dehydration. Phosphate retention is an important pathophysiologic feature of renal insufficiency (Chap. 274).

Hypophosphatemia

Causes

Hypophosphatemia can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, or (3) rapid redistribution of phosphate from the ECF into bone or soft tissue (Table 346-1). Because phosphate is so abundant in foods, inadequate intestinal absorption is almost never observed now that aluminum hydroxide antacids, which bind phosphate in the gut, are no longer commonly used. Fasting or starvation, however, may result in depletion of body phosphate and predispose to subsequent hypophosphatemia during refeeding, especially if this is accomplished with IV glucose alone.

Table 346-1 Causes of Hypophosphatemia

I. Reduced renal tubular phosphate reabsorption

A. PTH/PTHrP-dependent

1. Primary hyperparathyroidism

2. Secondary hyperparathyroidism

a. Vitamin D deficiency/resistance

b. Calcium starvation/malabsorption

c. Bartter syndrome

d. Autosomal recessive renal hypercalciuria with hypomagnesemia

3. PTHrP-dependent hypercalcemia of malignancy

4. Familial hypocalciuric hypercalcemia

B. PTH/PTHrP-independent

1. Genetic hypophosphatemia

a. X-linked hypophosphatemic rickets

b. Dent disease

c. Autosomal dominant hypophosphatemic rickets

d. Fanconi syndrome(s)

e. Cystinosis

f. Wilson disease

g. McCune-Albright syndrome (fibrous dysplasia

h. Idiopathic hypercalciuria (absorptive subtype)

i. Hereditary hypophosphatemia with hypercalciuria (Bedouins)

2. Tumor-induced osteomalacia

3. Other systemic disorders

a. Poorly controlled diabetes mellitus

b. Alcoholism

c. Hyperaldosteronism

d. Hypomagnesemia

e. Amyloidosis

f. Hemolytic uremic syndrome

g. Renal transplantation or partial liver resection

h. Rewarming or induced hyperthermia

4. Drugs or toxins

a. Ethanol

b. Acetazolamide, other diuretics

c. High-dose estrogens or glucocorticoids

d. Heavy metals (lead, cadmium)

e. Toluene, N-methyl formamide

f. Cisplatin, ifosfamide, foscarnet, rapamycin

g. Calcitonin, pamidronate

II. Impaired intestinal phosphate absorption

A. Aluminum-containing antacids

B. Sevalamer

III. Shifts of extracellular phosphate into cells

A. Intravenous glucose

B. Insulin therapy of prolonged hyperglycemia or diabetic ketoacidosis

C. Catecholamines (epinephrine, dopamine, albuterol)

D. Acute respiratory alkalosis

E. Gram-negative sepsis, toxic shock syndrome

F. Recovery from starvation or acidosis

G. Rapid cellular proliferation

1. Leukemic blast crisis

2. Intensive erythropoetin, other CSF therapy

IV. Accelerated net bone formation

A. Following parathyroidectomy

B. Treatment of vitamin D deficiency, Paget disease

C. Osteoblastic metastases

Note: CSF, cerebrospinal fluid.

Chronic hypophosphatemia usually signifies a persistent renal tubular phosphate-wasting disorder. Excessive activation of PTH/PTHrP receptors in the proximal tubule, because of primary or secondary hyperparathyroidism or because of the PTHrP-mediated hypercalcemia syndrome in malignancy (Chap. 347), is among the more common causes of renal hypophosphatemia, especially because of the high prevalence of vitamin D deficiency in older Americans. Familial hypocalciuric hypercalcemia and Jansen's chondrodystrophy are rare examples of genetic disorders in this category (Chap. 347).

Several genetic and acquired diseases cause PTH/PTHrP-independent tubular phosphate wasting, with associated rickets and osteomalacia. All of these diseases manifest severe hypophosphatemia; renal phosphate wasting, sometimes accompanied by aminoaciduria; low blood levels of 1,25(OH)2D; low-normal serum levels of calcium; and evidence of impaired cartilage or bone mineralization. Analysis of these diseases has led to the discovery of a "new" hormone, FGF23, that is an important physiologic regulator of phosphate metabolism. FGF23 decreases phosphate reabsorption in the proximal tubule and also suppresses the 1-hydroxylase responsible for synthesis of 1,25(OH)2D. FGF23 is synthesized by cells of the osteoblast lineage. High-phosphate diets increase FGF23 levels, and low-phosphate diets decrease them. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease linked to abnormalities in FGF23. ADHR results from activating mutations in the gene encoding FGF23. The most common inherited cause of hypophosphatemia is X-linked hypophosphatemic rickets (XLHR), which results from inactivating mutations in an endopeptidase termed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is most abundantly expressed on the surface of mature osteoblasts. Patients with XLH usually have high FGF23 levels, and ablation of the FGF23 gene reverses the hypophosphatemia found in the mouse version of XLH. How inactivation of PHEX leads to increased levels of FGF23 has not yet been determined. A third hypophosphatemic disorder, tumor-induced osteomalacia (TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete molecules that induce renal phosphate wasting. The hypophosphatemic syndrome resolves completely within hours to days following successful resection of the responsible tumor. Such tumors express large amounts of FGF23 mRNA, and patients with TIO usually exhibit elevations of FGF23 in their blood.

Dent's disease is an X-linked recessive disorder caused by inactivating mutations in CLCN5, a chloride transporter expressed in endosomes of the proximal tubule; features include hypercalciuria, hypophosphatemia, and recurrent kidney stones. Renal phosphate wasting is common among poorly controlled diabetics and alcoholics, who therefore are at risk for iatrogenic hypophosphatemia when treated with insulin or IV glucose, respectively. Diuretics and certain other drugs and toxins can cause defective renal tubular phosphate reabsorption (Table 346-1).

In hospitalized patients, hypophosphatemia is often attributable to massive redistribution of phosphate from the ECF into cells. Insulin therapy of diabetic ketoacidosis is a paradigm for this phenomenon, in which the severity of the hypophosphatemia is related to the extent of antecedent depletion of phosphate and other electrolytes (Chap. 338). The hypophosphatemia is usually greatest at a point many hours after initiation of insulin therapy and is difficult to predict from baseline measurements of serum phosphate at the time of presentation, when prerenal azotemia can obscure significant phosphate depletion. Other factors that may contribute to such acute redistributive hypophosphatemia include antecedent starvation or malnutrition, administration of IV glucose without other nutrients, elevated blood catecholamines (endogenous or exogenous), respiratory alkalosis, and recovery from metabolic acidosis.

Hypophosphatemia can also occur transiently (over weeks to months) during the phase of accelerated net bone formation following parathyroidectomy for severe primary hyperparathyroidism or during treatment of vitamin D deficiency or lytic Paget's disease. This is usually most prominent in patients who preoperatively have evidence of high bone turnover (e.g., high serum levels of alkaline phosphatase). Osteoblastic metastases can also lead to this syndrome.

Clinical and Laboratory Findings

The clinical manifestations of severe hypophosphatemia reflect a generalized defect in cellular energy metabolism because of ATP depletion, a shift from oxidative phosphorylation toward glycolysis, and associated tissue or organ dysfunction. Acute, severe hypophosphatemia occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and preexisting phosphate depletion due to excessive urinary losses, severe malabsorption, or malnutrition. Chronic hypophosphatemia tends to be less severe, with a clinical presentation dominated by musculoskeletal complaints such as bone pain, pseudofractures, and proximal muscle weakness or, in children, rickets and short stature.

Neuromuscular manifestations of severe hypophosphatemia are variable but may include muscle weakness, lethargy, confusion, disorientation, hallucinations, dysarthria, dysphagia, oculomotor palsies, anisocoria, nystagmus, ataxia, cerebellar tremor, ballismus, hyporeflexia, impaired sphincter control, distal sensory deficits, paresthesia, hyperesthesia, generalized or Guillain Barrlike ascending paralysis, seizures, coma, and death. Serious sequelae such as paralysis, confusion, and seizures are likely only at phosphate concentrations