Hepatic surgery-related hypophosphatemia

Clinica Chimica Acta 380 (2007) 13 – 23 www.elsevier.com/locate/clinchim

Invited critical review

Hepatic surgery-related hypophosphatemia Harish K. Datta a,b,⁎, Mahdi Malik a , R. Dermot G. Neely a,c a

b

Department of Clinical Biochemistry and Metabolism, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK School of Clinical and Laboratory Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK c School of Clinical Medical Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK Received 5 September 2006; received in revised form 7 January 2007; accepted 21 January 2007 Available online 2 February 2007

Abstract This review describes pathophysiology of post-surgical hypophosphatemia (HP), which has particularly high incidence following liver transplantation. HP remains poorly understood; and there is a lack of universally accepted guidelines for its investigation and management. The pathogenesis of HP following major liver surgery has been hypothesized as being due either to excessive utilization by regenerating liver or increased urinary losses of phosphate. This review provides evidence that excessive urinary loss rather than increased Pi uptake by the liver is the most likely mechanism, and this may be mediated by recently described phosphaturic factors, known as phosphatonins. Until recently blood Pi homeostasis had been explained solely in terms of classical hormones, i.e., vitamin D and PTH. It is however increasingly recognized that phosphatonins may play a critical role in the post-operative HP, but the exact mechanism and candidate phosphaturic factor has not yet been identified. In this review, we have described likely mechanisms and suggest candidate phosphatonins that may mediate urinary Pi loss following liver transplantation. We also discuss the biochemical consequences of cellular Pi depletion, which exposes some gaps in the utilization of established knowledge and therefore in the management of HP. The main aspects of pathophysiology of HP and cellular Pi depletion are presented to provide rational for novel biochemical investigations, which are likely to improve monitoring of HP associated metabolic stress as well as extent of severity of HP, and thereby enhance management of these patients. © 2007 Elsevier B.V. All rights reserved. Keywords: Hypophosphatemia; Liver; Phosphatonins; Metabolic stress; Nucleotide metabolism

Contents 1. 2.

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of plasma Pi homeostasis. . . . . . . . . . . . . . . . . 2.1. Fibroblast growth factor 23 (FGF-23) . . . . . . . . . . . . . 2.1.1. FGF-23 structure and distribution . . . . . . . . . . 2.1.2. FGF-23 as counter-regulatory phosphaturic hormone 2.1.3. Mechanism of FGF-23 action . . . . . . . . . . . . 2.1.4. Processing of FGF-23 . . . . . . . . . . . . . . . . 2.1.5. FGF-23 and kidney disease . . . . . . . . . . . . . 2.2. Secreted frizzled-related protein-4 (sFRP-4) . . . . . . . . . . 2.2.1. sFRP-4 isolation and distribution. . . . . . . . . . .

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Abbreviations: ADHR, Autosomal-dominant hypophosphatemic rickets; ASARM, acidic serine-aspartate-rich MEPE-associated motif; FGF, Fibroblast growth factor receptor; sFRP-4, Secreted frizzled related protein-4; HP, Hypophosphatemia; MEPE, Matrix extracellular phosphoglycoprotein; PHEX, Phosphate-regulating gene with homologies to endopeptidases on the X chromosome; Pi, Inorganic phosphate; SIBLING, Small integrin-binding ligand-interacting protein; TC, Familial tumoral calcinosis; TIO, Tumor-induced osteomalacia; XLH, X-linked hypophosphatemic rickets. ⁎ Corresponding author. School of Clinical and Laboratory Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Tel.: +44 191 222 6759; fax: +44 191 222 6227. E-mail address: [email protected] (H.K. Datta). 0009-8981/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2007.01.027

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2.2.2. sFRP-4 and serum Pi regulation . . . . . Matrix extracellular phosphoglycoprotein (MEPE) . 2.3.1. MEPE isolation and characterization . . . 2.3.2. MEPE structure . . . . . . . . . . . . . . 2.3.3. MEPE as a phosphatonins candidate . . . 3. Post-liver transplantation hypophosphatemia . . . . . . . 4. Pathophysiology of hypophosphatemia . . . . . . . . . . 4.1. Metabolic consequence of cellular Pi depletion . . 5. Management of hypophosphatemia . . . . . . . . . . . . 6. Concluding remarks . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.

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1. Background Over the past two decades there has been a steady increase in liver transplantation; and as a consequence the incidence of hepatic surgery-related hypophosphatemia (HP) has been rising [1–5]. But the detection, management and prevention of post-surgical HP have been ineffective due diverse number of reasons [6–9]. The main reason being that the homeostatic regulation of plasma inorganic phosphate (Pi) is not well understood, therefore its possible contribution to metabolic derangement has been often overlooked, hence the term ‘forgotten anion’. Many of the early post-operative complications, such as respiratory and renal failure, refractory arrhythmias, pancytopenia causing sepsis, and metabolic acidosis, are similar to clinical manifestations of HP, as a consequence creating further diagnostic problems. An additional factor contributing to this neglect is that unlike for other critical analytes, such as glucose, blood gases and calcium, there has been a lack of parallel advances in ‘near patients testing’ technology for Pi. A further difficulty is created by an absence of universally accepted definition of HP, it is described as being mild (2.2– 2.8 mg/dL, or 0.70–0.90 mmol/L), moderate (1.5–2.2 mg/L, or 0.50–0.69 mmol/L) and severe (0.90–1.20 mg/dL, or 0.30– 0.49 mmol/L) respectively [6–8]. A sole reliance on the plasma concentration of inorganic phosphate (Pi) as an indicator of cellular and the body status of the anion can be misleading, since plasma Pi does not always reflect cellular or total body status of the anion. The purpose of the review is to provide current update on the understanding of Pi physiology and pathophysiology and in light of that suggest improved approach towards investigation and management of HP in patients undergoing hepatic transplantation. 2. Physiology of plasma Pi homeostasis Pi has many diverse and critical roles, such as energy storage and transfer, intracellular signalling and bone mineralization. The endocrine factors involved in Pi homeostasis act in a complex manner, by modulating fractional absorption in intestine, altering renal tubular excretion, and affecting exchange with skeletal or intracellular pools [10–14]. Classical understanding, which assigns regulatory role to PTH and 1α,25 (OH)2D3 is generally accepted as being incomplete since it cannot explain underlying derangement in serum Pi and

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mineralization in a number of rare disease states, such as Xlinked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), McCune–Albright syndrome and tumor-induced osteomalacia (TIO) [15–19]. The pathogenesis of HP in these diseases is inconsistent with the notion of vitamin D and PTH being the sole endocrine regulator of Pi. In these patients there is a derangement in counterregulatory response to HP; i.e., renal tubular reabsorption of Pi is suppressed and the concentration of 1α,25(OH)2D3 instead of being elevated are often normal and may even be suppressed [17–19]. Recently, phosphaturic factors known as “phosphatonins” have been identified and are believed to mediate excessive Pi urinary excretion, a hallmark of some HP disorders [17,18,20]. The mode of action of phosphatonins itself has once again emphasized a central role of the kidney in regulating Pi homeostasis, which involves modulation of tubular reabsorption of filtered Pi in proximal convoluted tubules [20–23]. Therefore, regulation Pi tubular reabsorption involves phosphatonins as well as classical factors. Fig. 1 summarizes the current understanding of complex interaction between phosphatonins and other key components of Pi homeostatic regulation. 2.1. Fibroblast growth factor 23 (FGF-23) 2.1.1. FGF-23 structure and distribution Fibroblast growth factor 23 (FGF-23), generally accepted as being an archetypal phosphatonin, is a 32-kDa circulating peptide [24–28]. FGF-23 was identified as the gene for ADHR by employing positional cloning and was localized to 12p13.5 region of the chromosome [24,25]. Independently, FGF-23 was cloned from TIO, and was shown to be causative factor for osteomalacia and was over-expressed in majority of TIO tumors [26–28]. The human FGF-23 mRNA, which is 3018 bp in length and has predicted protein sequence of 251 amino acids, is highly expressed in bone but shows relatively low levels in heart, intestine, thyroid, and skeletal muscles [25,26]. However, Northern blot and RT-PCR analysis of cancers shows that the presence of 3 and 1.3 kb mRNA transcripts; most tumors express one of the transcripts while some express both [25,26]. 2.1.2. FGF-23 as counter-regulatory phosphaturic hormone Fibroblast growth factor FGF-23 is emerging as a counterregulatory phosphaturic hormone that acts as an endocrine

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Fig. 1. Illustration of normal renal regulation of phosphate by classical hormones, i.e., vitamin D and PTH, and recently described phosphaturic factors (phosphatonins). A possible mechanism of hypophosphatemia following major hepatic surgery is proposed, and may involve excessive production of sFRP-4 (2) or release of proteases, such as cathepsin B, which then activates phosphatonin precursors (3).

regulator of phosphate and of vitamin D metabolism. Serum FGF-23 is mainly derived from cells derived from the osteoblast lineage [29] and it acts in kidney [30,31]. It maintains serum Pi homeostasis and vitamin D metabolism [32,33] by regulating the sodium phosphate co-transporter and the key renal vitamin D-metabolizing enzymes CYP27B1 and CYP24A1 [34]. Dietary phosphate is a key regulator of circulating FGF-23 levels in humans and mice [35–37]. Dietary phosphate restriction decreases FGF-23 and loading increases FGF-23 significantly [38]. Normalization of serum phosphate by diet in VDR(−/−) mice increases FGF-23; suggesting that FGF-23 is independently regulated by phosphate and by vitamin D [39]. Dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in FGF-23 gene expression in bone [40]. FGF23 is emerging as a physiological regulator of serum phosphate [39–47]. The Fgf23(−/−) mice have significantly high serum phosphate with increased renal phosphate reabsorption than the wild type [42]. FGF-23 may regulate Pi homeostasis in response to dietary phosphate changes, independent of PHEX function [40]. It is unclear whether the phosphaturic effect of FGF-23 is diminished in the absence of PTH or a PTH effect [36,46]. FGF-23 has also been shown to regulate 1α,25(OH)2D3 [39,40,42,44–47]. Fgf23(−/−) mice have elevated serum 1,25 (OH)2D due to the enhanced expression of renal 25-hydroxyvitamin D-1α-hydroxylase (1alpha-OHase) [42]. FGF-23 reduces renal 1 α-OHase activity, and Pi transport, by a mechanism that is independent of the VDR [45]. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1α,25(OH)2D3 levels induced by FGF-23 are dependent on the VDR [45].

1α,25(OH)2D3 is an important regulator of FGF-23 production by osteoblasts in bone [44,47,48]. Administration of 1α,25(OH)2D3 to mice rapidly increases serum FGF-23 concentrations and increases FGF-23 transcripts in bone, the predominate site of FGF-23 expression [44,48]. Furthermore, studies VDR null mice and thyroparathyroidectomized rats show that both serum 1α,25(OH)2D3 and Pi regulate circulating FGF-23 independent of each other [49]. This has led to proposal that there was a feedback loop existing among serum Pi, 1α,25 (OH)2D3, and FGF-23, in which the novel phosphate-regulating bone-kidney axis integrated with the parathyroid hormonevitamin D(3) axis in regulating phosphate homeostasis [49]. The physiologic role of FGF-23 may therefore be to act as a counter-regulatory phosphaturic hormone to maintain phosphate homeostasis in response to vitamin D [44,47]. 2.1.3. Mechanism of FGF-23 action FGF-23 is the only known endocrine member of fibroblast growth factor (FGF) family; it possesses FGF-like domain in its N-terminal and therefore was classified as a member of the FGF family [25]. The FGF-23 receptor has not yet been described, but it appears to be distinct from the known FGF receptors [30]. The functional relationship between FGF-23 and Klotho had been suggested by the fact that defective Klotho expression in mice causes phenotypic traits, such as decreased bone mineral density and ectopic calcification, which are also observed in FGF-23 null mice [50,51]. It has now been shown that the membrane protein Klotho directly binds FGF-23 and determines the ligand specificity of FGF receptor 1 (FGFR1) [52].

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FGF-23 requires highly sulfated glycosaminoglycan (GAG) to exert its activity, highly sulfated GAGs may act as cofactors for FGF-23 activity or facilitate circulation from bone to the kidney without being trapped by heparin sulfate [50] The importance of carbohydrate moiety is further highlighted by the fact that recessive loss-of-function mutations in UDP-N-acetylalpha-D-galactosamine-polypeptide N-acetylgalactos-aminyltransferase produces familial tumoral calcinosis (TC) [53]. TC, a heritable disorder characterized by hyperphosphatemia and often severe ectopic calcifications, had been shown to arise from recessive mutations in FGF-23 [53–56]. FGF-23 induces tyrosine phosphorylation and inhibits sodium-phosphate cotransporter NPT2a mRNA expression in a model kidney proximal tubule opossum cell line [50]. FGF-23 reduces intestinal sodium-dependent Pi transport activity and the amount of type IIb sodium-dependent Pi cotransporter (type IIb NaPi) protein in the brush border membrane vesicles by a mechanism that is dependent on VDR [57]. XLH is caused by inactivating mutations in PHEX (phosphateregulating gene with homologies to endopeptidases on the X chromosome) [58]. XLH is an X-linked dominant renal Pi wasting disorder, which presents with hypophosphatemia with normocalcemia, and inappropriately normal or low 1α,25 (OH)2D3 concentrations. PHEX encodes a protein that is a member of the membrane-bound metalloproteases; other members include neutral endopeptidase and endothelin converting enzymes [58,59]. Although XLH is a renal Pi wasting disorder, PHEX shows the highest expression in bone cells, low expression in the lung, brain, parathyroid glands and skeletal muscle, but there is no expression in kidney [60,61]. XLH phenotype, PHEX protein homology and tissue distribution has led to the hypothesis that PHEX interacts with small, circulating factors outside of the kidney to directly or indirectly control renal Pi homeostasis. PHEX deficiency is necessary but not sufficient for increased FGF-23 expression in the osteoblast lineage, it seems that additional factors are necessary for PHEX deficiency to stimulate FGF-23 gene transcription in bone [62,63]. HYP males lacking both FGF-23 alleles were indistinguishable from Fgf-23/−/ mice, both in terms of serum phosphate levels and skeletal changes, suggesting that FGF-23 is upstream PHEX and that the increased plasma FGF-23 levels in HYP mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder [62,63]. 2.1.4. Processing of FGF-23 FGF-23 is processed at the C-terminus between amino acids 179 and 180, and the cleavage site is mutated in ADHR, preventing processing of FGF-23 [64–66]. Inactivating mutations of the PHEX, the disease-causing gene in XLH, and ectopic production in TIO result in increased FGF-23. FGF-23 is involved in the pathogenesis of these three hypophosphatemic disorders and directly link PHEX and FGF-23 within the same biochemical pathway [65]. This has led to speculation that FGF-23 is a substrate of PHEX, but studies have been inconclusive so far [47,67]. However, there is evidence against cleavage of intact FGF-23 as well as of N- and C-terminal fragments by the endopeptidase PHEX; instead, it has been

shown that FGF-23 is likely to be cleaved by subtilisin-like proprotein convertases, that are widely expressed and are also present in osteoblasts [67]. 2.1.5. FGF-23 and kidney disease Serum Pi, calcium, and PTH may be regulators of FGF-23 levels in uremic patients; in these patients pre-treatment serum FGF-23 levels were a good indicator in predicting the response to calcitriol therapy [68,69]. FGF-23 levels increase early in chronic kidney disease before the development of serum mineral abnormalities and were independently associated with serum phosphate and calcitriol deficiency [62]. Therefore, the measurement of serum FGF-23 levels, together with PTH, may provide better management of secondary hyperparathyroidism [62,68,69]. Hypophosphatemia is one of the common complications of renal transplantation, and tends to persist even after PTH concentrations normalize [70,71]. Hypophosphatemia, together with elevated PTH and suppressed calcitriol concentrations are seen even following functional renal transplantation, suggesting involvement of PTH-independent mechanisms. In chronic renal failure, circulating FGF-23 has been shown to increase with decreasing creatinine clearance rates and increasing Pi concentrations; and post-transplantation there was rapid decline, suggesting FGF-23 is perhaps cleared by the kidney [70,71]. Residual FGF-23 may contribute to the hypophosphatemia in post-transplant patients [70]. Excessive FGF-23 exposure in the early post-transplant period appears to be strongly associated with post-transplant hypophosphatemia [71]. 2.2. Secreted frizzled-related protein-4 (sFRP-4) 2.2.1. sFRP-4 isolation and distribution sFRP-4, a member of secreted Frizzled protein family, has a cysteine-rich ligand-binding and a hydrophilic C-terminal region; and it shares homology with the extracellular region of the Wnt receptors [72,73]. sFRP-4 is an unlikely candidate for phosphatonins, since Wnt pathways are involved in the regulation of differentiation and are more typically found at the plasma membrane [72,74]. Most of the FRPs act as soluble decoyreceptors and inhibit Wnt signaling through direct association with Wnt proteins [72,74]. The gene for sFRP-4, which is located on chromosome 7p14.1, has six axons and encodes a protein that has 346 amino acids. sFRP-4, which was identified in serial analysis of gene expression of TIO in a group of hemangiopericytomas, is present in normal human serum and is increased in the serum in TIO [75,76]. sFRP-4 , which is ubiquitously expressed , and circulates as a 48-kDa protein that is detectable in the circulation of healthy individuals [75,76]. 2.2.2. sFRP-4 and serum Pi regulation Recently evidence has been presented for the possible role of sFRP-4 as a phosphatonin, and for its involvement in the pathogenesis of phosphaturia in TIO and other hypophosphatemic disorders [76–80]. sFRP-4, like FGF-23, inhibits sodiumdependent phosphate cotransport, carried out by NTP-2a present in renal proximal tubule cells, which mediate the majority of Pi

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transport across these cells [76,80]. This inhibition was demonstrated in cultured opossum renal epithelial cells, and indicates a possible direct action of sFRP-4 on proximal tubular phosphate transport. Further evidence is provided by fact that the systemic administration of recombinant sFRP-4 to normal rats produces phosphatruria but without stimulating 1α-hydroxylase activity in the kidney [76]. In parathyroidectomized mice, intravenous sFRP-4 caused hypophosphatemia due to an increase in the fractional excretion of Pi, indicating that FRP-4 inhibits renal Pi reabsorption, at least in part, by PTH-independent mechanisms [76]. FRP-4 failed to decrease serum 1α,25(OH)2D3, although an expected reciprocal increase in response to hypophosphatemia was blunted. 2.3. Matrix extracellular phosphoglycoprotein (MEPE) 2.3.1. MEPE isolation and characterization TIO is characterized by phosphaturia, hypophosphatemia, and suppression of serum 1α,25(OH)2D3. The fact that successful resection of TIO tumors results in remission of the symptoms suggested an involvement of a circulating phosphaturic factor. MEPE (matrix extracellular phosphoglycoprotein), also known as osteoblast/osteocyte factor 45 (OF45), was cloned from TIO tissue as a candidate tumor-secreted phosphaturic factor [81,82]. Human MEPE is 525 residues in length with an N-terminal sixteen amino acid signal peptide; the murine homologue of MEPE is a protein of 433 amino acids, 92 amino acids shorter than human MEPE [81,82]. MEPE is expressed in bone, salivary gland and dental tissue, and is highly expressed in tumors that cause oncogenic hypophosphatemic osteomalacia; and normal tissue expression was found in bone marrow and brain with very-low-level expression found in lung, kidney, and human placenta [81–87]. 2.3.2. MEPE structure MEPE has major similarities to a group of bone-tooth mineral matrix phospho-glycoproteins, i.e., osteopontin, dentin sialo phosphoprotein, dentin matrix protein 1, bone sialoprotein II, and bone morphogenetic proteins [77,81,82]. MEPE and proteins contain arginine-glycine-aspartic acid (RGD) sequence motifs and the genes encoding these proteins map to a defined region in chromosome 4q21.1 [88]. All these extracellular matrix proteins (ECM) are involved in bone-tooth matrix mineralization a member of the small integrin-binding ligandinteracting protein (SIBLING) family. The C-terminal eighteen amino acids of MEPE, and other SIBLING family of integrinbinding phosphoglycoproteins, constitute the ASARM (acidic serine-aspartate-rich MEPE-associated) motif [81]. ASARM, a small 2-kDa carboxy-terminal MEPE peptide protease-resistant fragment has been shown to inhibit calcium phosphate precipitation in saliva, prevents calcification of the urinary tract, and impairs skeletal mineralization [89–93]. 2.3.3. MEPE as a phosphatonins candidate The role of MEPE in XLH etiology was suggested as circulating MEPE levels were found to elevated in XLH patients and the HYP mice, homologue of XLH [94,95]. The fact that

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MEPE amino acid sequence had revealed a potential PHEX cleavage site led to MEPE being proposed as a phosphatonins candidate, since mutant PHEX would allow unhindered MEPE associated renal Pi wasting and defective mineralization [81]. However, in vitro studies failed to show PHEX-dependent hydrolysis of recombinant human MEPE [96]; instead, PHEX inhibited cleavage of MEPE by endogenous cathepsin-like enzyme activity present in membrane. The C-terminal domain of PHEX was required for inhibition of MEPE cleavage; however, it did not require PHEX enzymatic activity. ASARM cleavage from MEPE by cathepsin-B has been demonstrated in an in vitro study; and the involvement of cathepsin-like enzyme has been supported by observation that cathepsin C gene mutation, which is likely to be associated the lack of ASARM, may account for ectopic calcification in Papillon–Lefevre syndrome [97,98]. Surface plasmon resonance studies have shown that MEP binds PHEX via ASARM motif, therefore PHEX can interfere with function of other SIBLINGS and actions of other enzymes that degrade extracellular matrix proteins [99]. This has led to suggestion that in XLH loss of PHEX activity may cause elevation in circulating ASARM, and ASARM inhibits bone mineralization and promotes phosphaturia [95,99]. The role of MEPE in systemic regulation of serum Pi and vitamin D metabolism has been also been explored. In healthy individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD) [100,95]; and elevated circulating MEPE levels were reported in XLH patients [94] and in Hyp mice [95], MEPE inhibited sodium-dependent Pi uptake in proximal tubule cells in a dose-dependent manner [97]; and elevated serum levels of ASARM occur in HYP/hyp and they accumulate in kidneys [95,100]. Intra-peritoneal MEP injections induce hypophosphatemia secondary to increased renal Pi clearance. However, disparate experimental evidence suggests that MEPE may not be a direct regulator of Pi and vitamin D metabolism. MEPE null mice, despite having an increased skeletal formation and bone mass [101], have normal serum Pi and vitamin D; and Phex/Mepe double null mice experimental indicate that MEPE is most likely not the phosphaturic factor present in Hyp mice [94]. Chinese hamster ovary (CHO) cells over-expressing MEPE when injected into nude mice did not lead to expected renal phosphate wasting. In healthy human subjects on a high-Pi diet exhibited a concomitant reduction of circulating MEPE, instead of an expected compensatory increase [102]. It seem that MEPE, though is highly expressed in tumors that cause TIO and inhibit skeletal mineralization, may only have a minor role in the systemic levels of serum Pi or vitamin D. It is apparent that classical hormones as well as phosphatonins is involved in blood Pi homeostasis, but the precise interaction and relative importance of these factors in HP pathogenesis is still emerging (Fig. 1). 3. Post-liver transplantation hypophosphatemia The pathogenesis of liver transplantation-related HP is unknown and the likely mechanisms involved are discussed

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here. One of the explanations that is generally forwarded is that post-surgically liver recovers rapidly and therefore utilizes large amount of Pi, and in the absence of adequate replacement it leads to acute fall in circulating Pi. However, simple calculations based on the rate of recovery of liver mass, intracellular and plasma Pi concentrations show that this explanation is seriously flawed, as the rate of Pi uptake required by rapidly recovering liver following surgery cannot account for the observed severity of HP [2–5,104]. Instead, it is excessive renal loss of Pi that produces ‘regenerating liver syndrome’ HP resulting in ‘phosphate diabetes’ [103]. However, the underlying factors for increased Pi urinary losses in patients following hepatic surgery remain unexplained, and possible increase in circulatory phosphatonins has been suggested. To date, at least one study has excluded the involvement of FGF-23, but possible involvement of MEPE and sFRP-4 has not been investigated [104]. However, these findings should be interpreted with caution as the investigations was carried out in only four patients; and employed a C-terminal assay. It has been postulated that cathepsin B may play a critical role in the activation of MEPE [96–98]. In this context it is interesting to note that liver has high cathepsin B content and liver injury is associated with the leak of the enzyme into circulation [105]. We propose that acute damage to liver, direct or indirect, which results in the release of large and sustained increase of the enzymes cathepsin B, will lead to the digestion of MEPE and/or other phosphatonins precursors. The digestion of MEPE by cathepsin B may release ASARM (acidic serine-aspartate-rich MEPE-associated motif) which

acts directly on renal tubule and increases Pi loss due to diminution in NaPi2 expression [81,97,98]. It is however entirely possible that acutely damaged liver may also release other proteolytic enzymes that activate phosphaturic hormones other than MEPE. 4. Pathophysiology of hypophosphatemia It is only the depletion of intracellular rather than plasma Pi concentrations, which is associated with cellular dysfunction and eventual multi-organ failure [106–114]. The signs and symptoms characterizing clinical manifestations of severe HP are due to consequent depletion of intracellular ATP as well as other nucleotide triphosphates, and decreased erythrocyte 2,3diphosphoglycerate (2,3-DPG) (Fig. 2) [106,111,114]. A decrease in 2,3-DPG in red cells leads to increased affinity for oxygen and therefore tissue hypoxia occurs, and fall in the availability of energy-rich phosphate compounds compromises all cell functions [112]. A considerable morbidity and mortality that often follows major post-operative surgery have complications that overlap with signs and symptoms of prolonged HP [111]. An isolated episode of even a severe HP will not always lead to clinical symptoms, since it may not always be accompanied by depletion of the intracellular Pi store. Indeed, in many cases HP may develop due to acute transcellular shift of Pi into the cell so that in fact intracellular Pi is replenished; such conditions occur as in acute insulin and glucose infusion or respiratory alkalosis, HP produced as a result in fact increases intracellular

Fig. 2. Schematic diagram of mechanisms involved in hypophosphatemic-related cellular stress leading to metabolic acidosis and depletion of cellular 2,3-DPG and intracellular energy-rich phosphate compound, leading to multi-organ failure [106–110,114–117].

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Pi., in those situations cell ATP or 2,3-DPG concentration remains unaffected. Acute HP induced by insulin and glucose has been used as a model to investigate the consequence of HP on intracellular energy-rich phosphates, and these studies have wrongly concluded that Pi has no effect on the maintenance of cell ATP levels [109]. The conclusions derived from such studies are invalid as they are employing inappropriate model, where cellular Pi concentrations instead of showing decline are not only maintained but are also in fact increased [109]. A combination of severe HP and lack of availability of Pi from diet or from bone resorption may lead to metabolic acidosis [110,112–114]. The pathogenesis of metabolic acidosis in this situation is generally attributed to decreased tubular reabsorption of bicarbonate, depression of ammonia production and reduction of Pi excretion, leading to diminution of urinary excretion of hydrogen ions [110,112,113]. Therefore, in severe HP metabolic acidosis worsens the depletion of cellular Pi, and 2,3-DPG and intracellular energy-rich phosphate compounds [111,114]. 4.1. Metabolic consequence of cellular Pi depletion A substantial fall in intracellular Pi leads to decrease or even disruption of oxidative phosphorylation and failure of ATP as well other energy-rich nucleotide triphosphate generation. In this situation, cellular requirements for ATP are met by employing contingency pathways, which involve the generation of ATP utilizing ADP, i.e., by the transfer of high energy phosphate from one ADP to another ADP thus: ADP þ ADPYATP þ AMP: The above reaction, which can occur in Pi depleted cell, increases cellular AMP (nucleoside-5′-monophophate) [115]. Furthermore, post-operative stress per se would lead to cellular catabolism and nucleic acid break down, and the principal product of this breakdown is AMP. 5′ nucleosidase hydrolytically removes 5′-monophosphate, and generate adenosine and Pi; and adenosine is then converted to adenine and ribose-1phosphate. Removal of –NH2 from adenine and AMP produces inosine and IMP (inosine-5′-monophosphate), which are excreted [116]. In short, severe HP associated with substantially decreased intracellular Pi is associated with marked increase in the nucleotides, nucleosides, and oxypurines metabolite. The above considerations suggest that urinary excretion of nucleotide metabolites, estimated as a ratio of creatinine, may serve as an adjunct sensitive biochemical marker to assess the extent of metabolic stress in HP. HP has also been shown to be associated with acute changes in 2,3-DPG concentrations in erythrocytes, which can be readily calculated from blood gas [117]. We contend that the measurement of both 2,3-DPG and nucleotides breakdown products rather than individual metabolites is likely to provide better and more reliable index of HP-induced stress. The failure of normalization of these metabolites, i.e., 2,3DPG and nucleotide in a particular patient following treatment of HP would therefore suggest inadequate replenishment of cellular Pi, or existence of an alternative etiology of cellular stress.

19

5. Management of hypophosphatemia The patients undergoing surgery are often being treated with a number of known Pi lowering agents, such as bisphosphonates and antivirals, this together with inadequate Pi supplementation and catabolic state puts the patients at particular risk of body Pi depletion. Therefore, these and other likely risk factors should be identified, their plasma Pi concentrations as well as balance studies should be conducted prior to surgical intervention; and if indicated prophylactic Pi supplementation should be given. The prophylactic preoperative Pi therapy is critical, because the combination of above circumstances is likely to produce severe intra-operative HP, which can produce cascading effect leading to multiple organ failure and even death. However, prolonged preoperative excessive Pi supplementation should be avoided since it is likely to increase circulating FGF-23 levels [35–37]. Peri-operative HP may itself cause acidemia, this in turn may transiently restore serum Pi due to mobilization of intracellular Pi, but it is associated with the depletion of cellular Pi. In such situation the restoration of plasma Pi concentration may occur despite an inadequate Pi supplementation and continuing urinary loss of Pi; the role of phosphatonins in urinary loss in perioperative situation is unclear. Interestingly, metabolic acidosis and phosphate loading may protect against the progression disease because the harmful effects of acidosis may be counterbalanced [113]. Oral supplementation with a neutral Pi effectively corrects post-transplantation hypophosphatemia, increases muscular ATP and phosphodiester content without affecting mineral metabolism, and improves renal acid excretion and systemic acid/base status [112]. Presently, treatment of HP is reliant on the plasma levels of Pi, which as has been explained above is an unreliable indicator of Pi. In post-surgical patients, who tend to be acidemic and in a catabolic state the plasma concentration can be misleading. The assessment of Pi status therefore should not just be based solely on measurement of plasma Pi; it must also be supported by Pi balance studies. In the critically ill post-surgical patients, Pi retained can be calculated by measuring urinary losses (Pi retained = administered − urinary loss). In these situations, it may even be possible to estimate the distribution of retained (Pi retained = ∑PiECF + PiICF)

Table 1 Summary of the main types of treatment regimes for the treatment hypophosphatemia [6–8,118–120] Regime categories

Dose given

1. Fixed dose with varied duration Moderate (0.4–0.45 mmol) Severe (0.3–34) Moderate or severe with symptoms 2. Varied dose with varied duration Mild (65–79) Moderate (0.33–0.65) Severe (b0.32) 3. High graduated dose Mild (0.71–0.97) Moderate (0.51–0.73) Severe (b0.48

15–45 mmol

Duration (h) 4–12 2–6 2–3

0.08–0.16 mmol/kg 0.16–0.32 mmol/kg 0.24–0.64 mmol/kg

b6 N6 to b12 N12

0.16 mmol/kg 0.32 mmol/kg 0.64 mmol/kg

24–72 24–72 24–72

20

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provided cellular damage has not occurred; which can be excluded by such measurements as serial troponins. There is a variety of HP treatment regimes (Table 1) reflecting a lack of consensus due to inability to monitor and assess extent of Pi loss [5–8,118–120]. The recommended treatment regimes are based purely on the severity of HP rather than reliable index of Pi tissue depletion. We believe that the treatment regimes should be guided by the extent of Pi depletion and rate of urinary Pi loss as well as plasma Pi levels, rather than purely on the basis of severity of HP. Furthermore, the rate of replenishment of Pi should be adjusted according to the rate of Pi urinary losses before any surgical intervention. The majority of post-surgical patients suffer from metabolic academia, due to combination of factors, including catabolic state and chloride overload that usually worsens Pi tissue depletion. This however can be prevented by glucose–insulin–potassium therapy and hyperchloremia minimized by substitution of chloride anion [121–123]. This is vital since [Pi] supplementation or infusion in the presence of metabolic academia does not lead to tissue replenishment. Regarding the identity of phosphatonins as causal factors in the pathogenesis of post-operative HP, particularly following hepatic surgery, studies are required to determine possible involvement of sFRP-4 and MEPE and its digestion product. 6. Concluding remarks Post-surgical HP is an established complication, which is particularly severe and extremely common after following hepatic surgery. However, the management of peri-operative HP is haphazard due the lack of understanding of the precise physiology of Pi homeostasis, and the lack of advances in the detecting and managing of at risk patients. Over the last decade evidence has emerged that suggests that, in addition to vitamin D and PTH, circulating factors such as phosphatonins play a role in Pi and vitamin D homeostasis. FGF-23 is an archetypal phosphatonin, which circulates at elevated levels in patients with disorders of Pi homeostasis, such as ADHR, XLH, and TIO. sFRP-4 and MEPE, isolated from TIO tumours, may also have roles in Pi handling and mineral metabolism but the roles require further investigation. sFRP-4 inhibit sodium-dependent phosphate cotransporters in renal proximal tubule cells, however physiological role of sFRP-4 in Pi and in vitamin D metabolism is unclear. MEPE inhibits skeletal mineralization, but has less well defined role in serum Pi homeostasis and vitamin D metabolism. A better understanding of the involvement of phosphatonins in serum Pi and vitamins D regulations is likely to improve management of disorders of Pi homeostasis including post-operative HP. References [1] White SA, Al-Mukhtar A, Lodge JP, Pollard SG. Progress in living donor liver transplant. Transplant Proc 2004;36:2720–6. [2] George R, Shiu MH. Hypophosphataemia after major hepatic resection. Surgery 1992;111:281–6. [3] Cohen J, Kogan A, Sahar G, Lev S, Vidne B, Singer P. Hypophosphatemia following open heart surgery: incidence and consequences. Eur J Cardiothorac Surg 2004;26:306–10.

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