Severe hypophosphataemia following oral bisphosphonate treatment in a patient with osteoporosis.

A 76-year-old woman was treated with oral bisphosphonate, alendronate, for osteoporosis in an outpatient clinic. Routine blood tests 4 months after alendronate prescription surprisingly revealed severe hypophosphataemia. The patient was hospitalised and treated with intravenous and oral phosphate supplements. Alendronate was later reintroduced as treatment for osteoporosis and the patient once again presented with severe hypophosphataemia in subsequent routine blood tests. The patient had only presented with lower extremity pain, muscle weakness and difficulty walking. Blood tests in the emergency department both times reconfirmed severe hypophosphataemia. Plasma (p-)ionised calcium levels were normal or slightly elevated and p-parathyroid hormone levels were normal or slightly suppressed. The p-25-hydroxyvitamin-D and p-creatine were in the normal range. Critical illness, malabsorption, nutritional issues and genetics were reviewed as potential causes but considered unlikely. Phosphate levels were quickly restored each time on replacement therapy and the case was interpreted as bisphosphonate-induced severe hypophosphataemia.

[Diagnosis and treatment of hypophosphatemia]. / Que faire de l'hypophosphatémie†?

Phosphate is widely spread in the human body, filling many roles across various tissues, both in the intra- and extracellular space. Serum phosphorus makes up only a slight fraction of the total body stocks but acts as an exchange between the different compartments. Hypophosphatemia is commonly found among hospitalized patients, especially those in an intensive care unit. Clinical manifestations associated with hypophosphatemia are mainly respiratory, neuromuscular, cardiac and hematologic, all of which are more common in the presence of severe hypophosphatemia. Interventional evidence on the benefit of correcting hypophosphatemia is lacking. Currently available recommendations vary and are based on weak evidence.

Le phosphate a un rôle physiologique essentiel dans l'organisme humain, il est ubiquitaire, tant en intracellulaire qu'en extracellulaire. La phosphatémie ne représente qu'une faible proportion du contenu corporel total de phosphate, mais joue un rôle important dans les échanges entre les différents compartiments de l'organisme. L'hypophosphatémie est fréquente chez les patients hospitalisés, en particulier aux soins intensifs. Des manifestations respiratoires, cardiologiques, neuromusculaires et hématologiques peuvent y être associées, pouvant même être à l'origine d'une surmortalité si elle est sévère. A ce jour, il n'existe pas d'évidence du bénéfice de corriger l'hypophosphatémie. Les recommandations pour la correction d'une hypophosphatémie varient et sont basées sur des évidences faibles.

X-linked hypophosphatemia: Management and treatment prospects.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.

Refeeding syndrome: relevance for the critically ill patient.

PURPOSE OF REVIEW: To provide an overview of recent findings concerning refeeding syndrome (RFS) among critically ill patients and recommendations for daily practice. RECENT FINDINGS: Recent literature shows that RFS is common among critically ill ventilated patients. Usual risk factors for non-ICU patients addressed on ICU admission do not identify patients developing RFS. A marked drop of phosphate levels (>0.16 mmol/l) from normal levels within 72 h of commencement of feeding, selects patients that benefit from hypocaloric or restricted caloric intake for at least 48 h resulting in lower long-term mortality. SUMMARY: RFS is a potentially life-threatening condition induced by initiation of feeding after a period of starvation. Although a uniform definition is lacking, most definitions comprise a complex constellation of laboratory markers (i.e. hypophosphatemia, hypokalemia, hypomagnesemia) or clinical symptoms, including cardiac and pulmonary failure. Recent studies show that low caloric intake results in lower mortality rates in critically ill RFS patients compared with RFS patients on full nutritional support. Therefore, standard monitoring of RFS-markers (especially serum phosphate) and caloric restriction when RFS is diagnosed should be considered. Furthermore, standard therapy with thiamin and electrolyte supplementation is essential.

Clinical features of hypophosphatemic osteomalacia induced by long-term low-dose adefovir dipivoxil.

OBJECTIVE: To investigate the predictors of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) and to monitor for early detection. PATIENTS AND METHODS: Hospitalized patients who were diagnosed with ADV-related hypo-phosphatemic osteomalacia were recruited and retrospectively analyzed in our hospital from January 2012 to December 2016. A telephone interview was conducted at 1, 3, 6, 9, 12, and 24 months after cessation of ADV. RESULTS: In the 8 patients enrolled in the study, the hypophosphatemic osteomalacia symptoms developed at an average of 5.14 (4-7) years since ADV treatment (10 mg/d). The average alkaline phosphatase (ALP) level was 279.50 (137-548) U/L, which was significantly higher than the normal level (45-125 U/L). The serum phosphorus level was an average of 0.59 (0.43-0.69) mmol/L, which was lower than the normal range (2.06-2.60 mmol/L). Serum calcium levels of the enrolled patients remained within normal limits. Reduced estimated glomerular filtration rate (eGFR <29 mL/min/1.73 m2) was seen in 4 cases. The clinical manifestations were mainly progressive systemic bone and joint pain, frequent fractures, trouble in walking, height reduction (4-6 cm), and so on. After cessation of ADV, symptoms like bone pain resolved gradually. Serum phosphorus level restored to normal in 4.5 months after the withdrawal of ADV. However, in 4 patients, renal function failed to return to normal in 24 months. CONCLUSION: More attention should be paid to the duration of ADV treatment. The level of serum phosphorus and ALP, as well as renal function, should be monitored for early detection of potential adverse drug reactions.

Iron-induced hypophosphatemia: an emerging complication.

PURPOSE OF REVIEW: Iron-induced hypophosphatemia is a well documented side-effect but associated complications are largely neglected, because the results from single dosing studies suggest that transient decreases in plasma phosphate concentrations are asymptomatic and fully reversible. However, an increasing number of case reports and case series suggest that some patients develop severe and symptomatic hypophosphatemia. Long-term complications from hypophosphatemia include osteomalacia and bone fractures, which can result from repeated intravenous administration of certain high-dose iron preparations. RECENT FINDINGS: Results from clinical trials suggest that the highest risk for the development of hypophosphatemia is associated with ferric carboxymaltose, iron polymaltose, and saccharated iron oxide. Clinical studies show that renal phosphate wasting mediated by increased fibroblast growth factor 23 causes hypophosphatemia after iron therapy. Impaired renal function therefore protects from hypophosphatemia, whereas the highest incidences and most severe manifestations have been reported in patients in whom the underlying cause of iron deficiency cannot be corrected. SUMMARY: Diagnosis of iron-induced hypophosphatemia requires clinical suspicion. Treatment is guided by the severity of hypophosphatemia, and most patients will require oral or intravenous phosphate substitution. Future treatment options could involve therapeutic anti-FGF23 antibody (KRN23). Prevention and correction of vitamin D deficiency represents a supportive treatment option.

Using phosphate supplementation to reverse hypophosphatemia and phosphate depletion in neurological disease and disturbance.

Hypophosphatemia (HP) with or without intracellular depletion of inorganic phosphate (Pi) and adenosine triphosphate has been associated with central and peripheral nervous system complications and can be observed in various diseases and conditions related to respiratory alkalosis, alcoholism (alcohol withdrawal), diabetic ketoacidosis, malnutrition, obesity, and parenteral and enteral nutrition. In addition, HP may explain serious muscular, neurological, and haematological disorders and may cause peripheral neuropathy with paresthesias and metabolic encephalopathy, resulting in confusion and seizures. The neuropathy may be improved quickly after proper phosphate replacement. Phosphate depletion has been corrected using potassium-phosphate infusion, a treatment that can restore consciousness. In severe ataxia and tetra paresis, complete recovery can occur after adequate replacement of phosphate. Patients with multiple risk factors, often with a chronic disease and severe HP that contribute to phosphate depletion, are at risk for neurologic alterations. To predict both risk and optimal phosphate replenishment requires assessing the nutritional status and risk for re-feeding hypophosphatemia. The strategy for correcting HP depends on the severity of the underlying disease and the goal for re-establishing a phosphate balance to limit the consequences of phosphate depletion.

Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature.

Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.

Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation.

INTRODUCTION: Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients. MATERIALS AND METHODS: We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23. RESULTS: Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024). CONCLUSIONS: Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss.

Approach to treatment of hypophosphatemia.

Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole.

Refeeding syndrome in children in developing countries who have celiac disease.

OBJECTIVES: The clinical presentations of celiac crisis and refeeding syndrome in celiac disease are almost similar, but information about refeeding syndrome is scarce. We are reporting for the first time 5 cases of refeeding syndrome in children with celiac disease that could have otherwise been labeled as celiac crisis. METHODS: From January to December 2010, a chart review of hospital records of all celiac disease cases was performed, and refeeding syndrome was ascribed in those celiac patients who deteriorated clinically after initiation of a gluten-free diet and had biochemical parameters suggestive of refeeding syndrome such as hypophosphatemia, hypokalemia, hypocalcemia, and hypoalbuminemia. RESULTS: Of the total 35 celiac disease patients, 5 (median age 6.5 [range 2.2-10] years, 3 boys) were identified as having refeeding syndrome. All 5 children were severely malnourished (body mass index <14 kg/m) and all of them had anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and hypocalcemia, meaning that they had the perfect setting for developing refeeding syndrome. At the same time, their clinical features fulfilled the criteria for celiac crisis except that their symptoms have worsened after the introduction of a gluten-free diet. Nevertheless, instead of using steroids, they were managed as refeeding syndrome in terms of correction of electrolytes and gradual feeding, and that led to a successful outcome in all of them. CONCLUSIONS: Severely malnourished patients with celiac disease are at risk of developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. Early recognition and appropriate treatment are the keys to a successful outcome.

Hepatectomy-related hypophosphatemia may predict donor liver dysfunction in live-donor liver transplantation.

BACKGROUND: Hypophosphatemia after living-donor liver donation was recently reported to not be linked to donor morbidity. However, few studies have examined the relationship between hypophosphatemia and hepatic function after hepatectomy in live liver donors. In this study, we investigated the relationship between postoperative hypophosphatemia and hepatic function in living donors after hepatectomy. METHODS: We collected data from 102 live-donor hemihepatectomy cases. The severity of hypophosphatemia was categorized as mild (1.5-2.5 mg/dL), moderate (1.1-1.5 mg/dL), or severe (<1.0 mg/dL). We compared complications among the groups and factors possibly related to the postoperative nadir phosphorus levels. RESULTS: One hundred cases (98%) developed mild (n = 56), moderate (n = 25), or severe (n = 19), hypophosphatemia. Serum phosphate levels began to fall on postoperative day (POD) 2, reaching a nadir (1.89 ± 0.72 mg/dL) on POD 3. There was a significant difference in the incidence of postoperative liver dysfunction among the 3 groups (P = .027). Moreover, a correlation was identified between the incidence and the hypophosphatemia severity (r = 0.549; P = .023). The nadir phosphorous level significantly and negatively correlated with the peak of total bilirubin (P = .001) and international normalized ratio (P = .004). Patients with intravenous phosphorus replacement showed better hepatic function and a lower incidence of hepatic dysfunction among the severely hypophosphatemic group. CONCLUSION: Hypophosphatemia was predictive of hepatic dysfunction after hepatectomy in living donors. Phosphorus replacement may improve recovery of hepatic function among living liver donors.

Hypophosphatemic effect of niacin in patients without renal failure: a randomized trial.

BACKGROUND AND OBJECTIVES: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268). RESULTS: Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of -0.13 mmol/L (-0.15 to -0.13 mmol/L; -0.41 mg/dl [-0.46 to -0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or > or =60 ml/min per 1.73 m(2), a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus < or =1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use. CONCLUSIONS: We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to > or =90 ml/min per 1.73 m(2) (i.e., stages 1 through 3 chronic kidney disease).

Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II.

Vitamin D-dependent rickets type II (VDDR-type II) is a rare disorder caused by mutations in the vitamin D receptor (VDR) gene. Here, we describe a patient with VDDR-type II with severe alopecia and rickets. She had hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated serum alkaline phosphatase and 1,25-dihydroxyvitamin D(3). Sequence analysis of the lymphocyte VDR cDNA revealed deletion mutation c.716delA. Sequence analysis of her genomic DNA fragment amplified from exon 6 of the VDR gene incorporating this mutation confirmed the presence of the mutation in homozygous form. This frameshift mutation in the ligand binding domain (LBD) resulted in premature termination (p.Lys240Argfs) of the VDR protein. The mutant protein contained 246 amino acids, with 239 normal amino acids at the N terminus, followed by seven changed amino acids resulting in complete loss of its LBD. The mutant VDR protein showed evidence of 50% reduced binding with VDR response elements on electrophoretic mobility assay in comparison to the wild-type VDR protein. She was treated with high-dose calcium infusion and oral phosphate. After 18 months of treatment, she gained 6 cm of height, serum calcium and phosphorus improved, alkaline phosphatase levels decreased, and intact PTH normalized. Radiologically, there were signs of healing of rickets. Her parents and one of her siblings had the same c.716delA mutation in heterozygous form. Despite the complete absence of LBD, the rickets showed signs of healing with intravenous calcium.

Fibroblast growth factor 23 (FGF23) and the kidney.

Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTh), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders - tumor-induced osteomalacia (TIo), autosomal dominant hypophosphatemic rickets (ADhr) and X-linked hypophosphatemic rickets (XLh) - has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. fibroblast growth factor-23 (fGf-23) is the most extensively studied ''phosphatonin''. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.

Disorders of calcium, phosphorus and magnesium metabolism.

Abnormalities of calcium, magnesium and phosphorus are common in hospitalized patients. Infrequently patients might present in the outpatient settings with non-specific symptoms that might be due to abnormalities of divalent cation (magnesium, calcium) or phosphorous metabolism. Several inherited disorders have been identified that result in renal or intestinal wasting of these elements. Physicians need to have a thorough understanding of the mechanism of calcium, magnesium and phosphorous metabolism and diagnoses disorders due to excess or deficiency of these elements. Prompt identification and treatment of the underlying disorders result in prevention of serious morbidity and mortality.

Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation.

BACKGROUND AND OBJECTIVES: In the first months after successful kidney transplantation, hypophosphatemia and renal phosphorus wasting are common and related to inappropriately high parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels. Little is known about the long-term natural history of renal phosphorus homeostasis in renal transplant recipients. DESIGN, SETTING, PARTICIPANTS: We prospectively followed parameters of mineral metabolism (including full-length PTH and FGF-23) in 50 renal transplant recipients at the time of transplantation (Tx), at month 3 (M3) and at month 12 (M12). Transplant recipients were (1:1) matched for estimated GFR with chronic kidney disease (CKD) patients. RESULTS: FGF-23 levels (Tx: 2816 [641 to 10665] versus M3: 73 [43 to 111] versus M12: 56 [34 to 78] ng/L, median [interquartile range]) and fractional phosphorus excretion (FE(phos); M3: 45 +/- 19% versus M12: 37 +/- 13%) significantly declined over time after renal transplantation. Levels 1 yr after transplantation were similar to those in CKD patients (FGF-23: 47 [34 to 77] ng/L; FE(phos) 35 +/- 16%). Calcium (9.1 +/- 0.5 versus 8.9 +/- 0.3 mg/dl) and PTH (27.2 [17.0 to 46.0] versus 17.5 [11.7 to 24.4] ng/L) levels were significantly higher, whereas phosphorus (3.0 +/- 0.6 versus 3.3 +/- 0.6 mg/dl) levels were significantly lower 1 yr after renal transplantation as compared with CKD patients. CONCLUSIONS: Data indicate that hyperphosphatoninism and renal phosphorus wasting regress by 1 yr after successful renal transplantation.

Disorders involving calcium, phosphorus, and magnesium.

Disorders of mineral metabolism are common in both the office and hospital setting. The diagnosis can be simplified by remembering the target organs involved--intestine, kidney, and bone--and by assessing the presence of kidney disease, levels of parathyroid hormone, and vitamin D status. Although the list of possible causes for these derangements is long, most patients who have hypercalcemia have hyperparathyroidism or malignancy; those who have hypocalcemia, hypophosphatemia, and hypomagnesemia have reduced gastrointestinal absorption, and those who have hyperphosphatemia and hypermagnesemia have increased intake in the setting of kidney disease.

Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia.

OBJECTIVE: The objective of this study was to elucidate and define the pathophysiological mechanism(s) responsible for the clinically relevant phenomenon of posthepatic resection hypophosphatemia. SUMMARY BACKGROUND DATA: Although biochemically significant hypophosphatemia has been described after major hepatic resection, no mechanism or validated scientific explanation exists. The phenomenon is of considerable clinical relevance because numerous patients, after hepatic resection, develop significant hypophosphatemia requiring large doses of phosphate replacement to maintain metabolic homeostasis. This event has previously been empirically ascribed to amplified phosphate utilization of regenerating hepatocytes, although no rigorous data attest to this postulate. Recent data identifying a novel mechanism of phosphaturia in X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and oncogenic osteomalacia demonstrate that elevated levels of novel circulating phosphaturic factors such as fibroblast growth factor 23 (FGF-23) and PHEX are responsible for phosphate wasting. We hypothesize that posthepatectomy hypophosphatemia reflects a derangement of normal hepatorenal messaging and is the result of a disruption of renal phosphate handling consequent on aberrations in the metabolism of an as yet unrecognized chemical messenger(s) responsible for tubular phosphate homeostasis. This postulate has not previously been proposed or examined. METHODS: Twenty patients undergoing hepatic resection were studied prospectively with respect to serum phosphate, phosphate requirements, as well as renal phosphate handling. Fractional excretion of phosphate was calculated on a daily basis. To confirm the relationship between phosphate loss and a circulating renal-targeted messenger, the plasma levels of the circulating phosphaturic factor FGF-23 were measured using a c-terminal assay both pre- and postoperatively. RESULTS: All patients developed hypophosphatemia with a nadir on postoperative day 2 (average drop of 47% despite phosphate administration). This phenomenon was associated with hyperphosphaturia (mean +/- standard error) with high fractional excretion of phosphate. A consistent change in FGF-23 was not identified. CONCLUSION: Hypophosphatemia after hepatic resection is a frequent occurrence. Transient isolated hyperphosphaturia and not increased phosphate utilization is the predominant cause of this phenomenon, although the identity of the agent involved remains to be identified.