Hepatic Resection-Related Hypophosphatemia Is of Renal Origin as Manifested by Isolated Hyperphosphaturia

Abstract

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.

Hypophosphatemia after major hepatic resection is a well described and ill-understood event of substantial metabolic significance. In 20 patients we studied, it was apparent that the transient isolated hyperphosphaturia uniformly occurs after hepatic parenchymal excision and regeneration. Because all patients developed hypophosphatemia despite calibrated exogenous replacement, the phenomenon is a renal rather than hepatic event. Our studies indicate that the renal phosphate leak associated with loss of hepatic parenchymal function reflects either increased production or decreased degradation of an as yet unidentified circulating phosphaturic factor.

George et al¹ described their experience with 44 patients undergoing major hepatic resection. They reported that all patients developed a fall in their serum inorganic phosphate. The mean decrease was 1.91 mg/dL. On average, this began on the second postoperative day, (range, days 1–3) and ended on the fifth postoperative day (range, days 2–9). The authors note that patients receiving aluminum-based antacids had a greater drop in serum phosphate (2.09 vs. 1.65 mg/dL). They cite glucose administration, postoperative respiratory alkalosis, and the use of phosphate-binding antacids as the cause of moderate transient hypophosphatemia. They speculated that the hypophosphatemia after major hepatic resection, which is more than that typically seen after other large abdominal surgeries, was the result of the increased metabolic and synthetic demands of the regenerating liver. However, no mention of renal phosphate handling was given.

Findling et al² described hypophosphatemia in a 20-month-old child after major hepatic resection for a mesenchymal hamartoma. This patient was found to have hyperphosphaturia in the setting of hypophosphatemia during postoperative days 1 through 7. The hyperphosphaturia and hypophosphatemia then resolved.

Pomposelli et al³ found that severe hypophosphatemia was universal in presumably healthy partial liver donors. They noted that the nadir serum phosphate was typically on postoperative day 2 and averaged a level of 1.1 mg/dL in those who were not given high-dose parenteral phosphate. Interestingly, hypophosphatemia was not noted in the recipients. The authors do not comment on renal phosphate handling.

Postoperative hypophosphatemia has been described and studied after other surgical procedures, including colorectal surgery,^4,5 aortic bypass grafting,⁶ and cardiothoracic surgery.⁷

This study was designed to evaluate renal phosphate handling in patients undergoing hepatic resection in an attempt to clarify the cause of postoperative hypophosphatemia.

MATERIALS AND METHODS

Between January 2001 and February 2002, 20 consecutive patients who underwent hepatic resection involving at least 2 hepatic segments, according to the classification of Couinaud,⁸ were enrolled. The number of segments resected and the disease processes are outlined in Table 1. No patients had a preoperative history of renal or endocrine disease, disturbances of electrolyte balance, or severe malnutrition. After obtaining approval from the Yale University Human Investigation Committee, serum was collected immediately preoperatively and postoperatively on a daily basis. Estimation of serum phosphate and creatinine were carried out in addition to the routine postoperative assays. Spot urine collections for phosphate and creatinine were carried out also daily until discharge. Using the values from these tests, the fractional excretion of phosphate was calculated using the formula (spot urinary phosphate/serum phosphate)/(spot urinary creatinine/serum creatinine) × 100. Twenty-four-hour urinary collections for phosphate and creatinine and spot urine for amino acid assay were obtained on 1 patient who developed profound hypophosphatemia in the setting of substantial hyperphosphaturia. Intact parathyroid hormone (PTH) estimations, 1–25 and 25 vitamin D₃ estimations were carried out on 2 patients. In 4 patients, evaluation of fibroblast growth factor (FGF-23) was carried out. For this, serum was collected immediately preoperatively and again approximately 48 hours postoperatively. The serum was stored at −70°C until all 4 were completed. FGF-23 was measured by a c-terminal assay.

TABLE 1. Pathology, Extent of Hepatic Resection, and Amount of Intravenous Phosphate Administered

All hepatic resections were done under low central venous pressure; all patients were extubated at the end of the procedure. The majority of patients were then transferred to a surgical intensive-care unit for 24 hours. All tumors were resected with negative margins and no patients had evidence of extrahepatic metastasis. Laboratory evaluations were carried out as necessary to monitor postoperative progress as well for the study requirements. No patients received enteral or parenteral nutrition and were advanced to a regular diet as tolerated. Patients were not given oral aluminum-, calcium-, or magnesium-based antacids and did not routinely receive diuretics. Intravenous phosphate using either potassium phosphate or sodium phosphate at a concentration of 15 mmol/dL was typically administered over a 4-hour period in an attempt to maintain serum phosphate at >2.2 mg/dL.

RESULTS

All patients had normal or low-normal serum phosphate preoperatively and on the day of surgery. Postoperative serum phosphate began to fall on postoperative day 1, typically reaching a nadir (mean, 1.86 mg/dL; range, 1.0–2.2 mg/dL) on postoperative day 2. This represented a 47% average drop in serum phosphate despite intravenous phosphate administration.

By postoperative day 4, serum phosphate in most patients was improving and phosphate supplementation requirements were declining. Mean serum phosphate on day 4 was 2.8 mg/dL. Mean phosphate requirements were 31 mmol on day 2 and 10 mmol on day 4. Total phosphate requirements in the postoperative period was 15–321 mmol (mean, 107 mmol) (Figs. 1 and 2).

FIGURE 1. Postoperative serum phosphate concentration.

FIGURE 2. Daily amount of phosphate administered postoperatively.

Associated with this fall in serum phosphate, patients developed profound hyperphosphaturia resulting in a markedly elevated fractional excretion of phosphate. This peaked typically on postoperative day 2 and gradually declined as shown in Figure 3. Mean fractional excretion of phosphate was 45 ± 5.2% on day 2 and 13.1 ± 3.2% on day 4. Serum phosphate was lowest at the times of highest fractional excretion of phosphate.

FIGURE 3. Postoperative fractional excretion of phosphate and serum phosphate.

Three patients had a fractional excretion of phosphate measured immediately preoperatively (days 9, 14, and 15) and these were 0.2%, 7%, and 6%, respectively. These patients, like the others in whom we did not collect urine preoperatively, became phosphaturic postoperatively with fractional excretion of phosphate of 31%, 53%, and 35%.

There was no obvious correlation between the number of hepatic segments resected and the degree of hypophosphatemia, and there was no correlation with the disease process or whether the tumors were primary or metastatic (Table 1).

Intact PTH, 1–25 and 25 vitamin D₃ estimations were within normal limits on the 2 patients who were evaluated. The patient who underwent urinary amino acid assay showed normal levels of aminoaciduria. Twenty-four-hour urinary estimation of phosphate in 1 patient was greater than 1 g on 2 occasions.

In the 4 patients who underwent estimations of FGF-23, no consistent change was found.

DISCUSSION

The relationship between hepatic function and renal homeostasis is well recognized but poorly understood, as exemplified by the concepts embodied within the global framework of the “hepatorenal” syndromes, a series of well-described but poorly mechanistically defined clinicopathologic scenarios. Major hypophosphatemia has previously been ascribed to nonspecific, postsurgical metabolic events or the metabolic demands of “regenerating hepatocytes,” although no rigorous data exist to provide a valid scientific basis for such assumptions, and such interpretations therefore remain based on speculation. Recently, evidence has accumulated to suggest the existence of a number of putative plasma phosphaturic agents and their role in the genesis of hypophosphatemia. These observations appear more plausible than excessive hepatic consumption of phosphate (for which there is no evidence) and provide a rational basis to consider the mechanism of alterations in renal function posthepatectomy. Indeed, our studies that demonstrate obvious evidence of renal wastage of phosphate in the face of replacement are consistent with a renally mediated event as opposed to putative hepatic consumption. Whether this reflects excessive production of a factor consequent on hepatic trauma or failure of the damaged liver to adequately degrade a circulating factor is as yet unclear. Nevertheless, despite the fact that the precise mechanism remains to be elucidated in a separate series of studies, the observation is novel and borne out by the clinical experimental data. Thus, posthepatic hypophosphatemia and its concomitant renal phosphate leak may well reflect the action of an as yet unidentified circulating agent responsible for phosphate homeostasis.

The initial description of hypophosphatemia after hepatic resection was by Keushkerian and Wade⁹ who studied 9 patients who had elective resection of at least 50% of their hepatic mass. Postoperative hypophosphatemia was demonstrated. Although their study was small, they suggested a relationship between the degree of hypophosphatemia and the extent of hepatic resection; they suggested, as have others, that the hypophosphatemia was associated with intravenous glucose infusion by causing increased transport of glucose into liver and skeletal muscle.

George and Shiu reported marked hypophosphatemia after right and extended right hepatic lobectomy in 44 patients.¹ Hypophosphatemia of less then 1.0 mg/dL was associated with a significantly increased incidence of postoperative complications. This was thought to be aggravated by aluminum-containing antacids and was considered to be the result of the increased phosphate demands of the regenerating liver. Pomposelli et al³ similarly showed that significant hypophosphatemia occurred in liver donors undergoing right hepatectomy; they found that patients receiving 35 mmol per day of phosphate often developed life-threatening hypophosphatemia (serum phosphate <1 mg/dL) and that this could be avoided in part by increasing the daily phosphate administration to 60 mg per day. They too demonstrated that profound hypophosphatemia was associated with increased postoperative complications. They too attributed the hypophosphatemia to the increased regenerative and metabolic demands of the regenerating liver. Interestingly, the recipients who would also presumably be undergoing hepatic regeneration did not develop hypophosphatemia. Buell et al¹⁰ report hypophosphatemia associated with both hepatectomy and cryotherapy, also demonstrating a higher complication rate in hypophosphatemic patients. The only report of posthepatectomy hypophosphatemia being attributed to hyperphosphaturia is a solitary case report by Findling et al of an infant who developed transient renal wasting of phosphate.² To date, no study has evaluated renal handling of phosphate in a series of patients posthepatectomy.

Our study has demonstrated profound hyperphosphaturia with high fractional excretion of phosphate to be the cause of posthepatectomy hypophosphatemia. As previously reported by others, hypophosphatemia occurred on postoperative day 1, reaching a nadir on postoperative day 2. None of our patients received oral antacid therapy and none were placed on parenteral nutrition. In our patients, fractional excretion of phosphate was also found to be highest on postoperative day 2 and then fell in concert with the rise in serum phosphate. Judicious administration of phosphate in an attempt to keep the serum phosphate above 2.2 mg/dL was generally successful in avoiding severe hypophosphatemia, although 1 patient on a solitary occasion did drop her serum phosphate to 1.0 mg/dL. Severe, life-threatening hypophosphatemia with serum phosphate <1.0 mg/dL was not seen with this regimen. Phosphate requirements to attain this goal varied considerably, and although our sample size was small, we did not find a correlation between the extent of the hepatic resection and the postoperative phosphate requirements.

Hypophosphatemia is caused by 1 or a combination of 3 basic pathophysiological processes: movement of phosphate into cells, decreased intestinal absorption of phosphate, or increased renal phosphate excretion.

Movement of Phosphate Into Cells

Movement of phosphate into cells as seen in the treatment of diabetic ketoacidosis, refeeding syndromes, acute respiratory alkalosis, and the hungry bone syndrome after parathyroidectomy should all be associated with low urinary phosphate excretion. Although arterial blood gases were not checked routinely in our patients to rule out respiratory alkalosis, it has been well described that in response to hypophosphatemia from respiratory alkalosis, urinary phosphate excretion will approach zero.¹¹ Therefore, it is unlikely that respiratory alkalosis could be responsible for the hypophosphatemia and hyperphosphaturia noted in our patients. It is also unlikely that refeeding played a role. First, our patients were not malnourished. Second, there was no use of enteral or parenteral nutritional supplements beyond the diet that could be tolerated postoperatively.

The suggested pathophysiology of hypophosphatemia being the result of the increased demand of the regenerating liver did not appear to be the case in our patients as evidenced by dramatic phosphate wasting with hyperphosphaturia and profoundly increased fractional excretion of phosphate. Dramatic urinary phosphate wasting would not be present if increased hepatic demand was the primary derangement. Also given the large urinary losses of phosphate (greater than 1 g in 24 hours in 1 patient) and the relatively small extracellular pool of inorganic phosphate, it seems likely that the phosphaturia alone was responsible for the majority of the fall in serum inorganic phosphate.

Decreased Intestinal Absorption of Phosphate

It is unlikely that the hypophosphatemia noted as early as postoperative day 1 was caused by decreased intestinal absorption of phosphate with or without a phosphate-binding antacid. Lotz et al¹² described that in normal volunteers placed on a low-phosphate diet with antacid administration, urinary phosphate declined to 0 after 5 to 7 days. A negative phosphorous balance occurred after 14 to 21 days, and severe hypophosphatemia did not occur until after 75 to 100 days.

Increased Renal Phosphate Excretion

Postoperative hypophosphatemia in association with seemingly inappropriate phosphaturia has been elegantly described and studied after colorectal surgery.^4,5,13 These authors found that after patients undergoing colorectal surgery who were given dextrose-containing intravenous fluid developed hypophosphatemia, seemingly caused by phosphaturia in the absence of glucosuria. The authors state, “The cause of this postoperative hypophosphatemia is not known but seems to be mediated by the humoral response to the operative trauma.” Andersen et al described severe hypophosphatemia on postoperative day 2 after abdominal aortic bypass grafting. They found that urinary phosphate excretion was dramatically increased on postoperative days 1 and 2.⁶

As described here, our patients clearly had a significant, and initially unanticipated, phosphaturia given the degree of hypophosphatemia they experienced. Increased renal phosphate excretion is described in hyperparathyroidism, calcitriol deficiency, osmotic diuresis, use of proximal tubular diuretics, and the Fanconi syndrome. None of these were clinically apparent in our patients, and all of this was thoroughly excluded in our patient who exhibited the most profound phosphate depletion. The observed phenotype of isolated phosphaturia, albeit transient, is reminiscent of oncogenic osteomalacia, X-linked and autosomal-dominant hypophosphatemic rickets. These 3 syndromes are all characterized by hypophosphatemia, decreased renal phosphate reabsorption, inappropriately normal or low serum calcitriol concentrations, normal serum concentrations of calcium and parathyroid hormone, and defective skeletal mineralization. In the last 2 years, there has been an increase in our understanding of these disorders, as well as the elucidation of a previously anticipated but unidentified system of phosphate regulation through a soluble phosphaturic factor known as phosphatonin. It now appears that FGF-23 is a phosphatonin. Tumors from patients with oncogenic osteomalacia express FGF-23. Patients with X-linked hypophosphatemic rickets have a defect in the endopeptidase, PHEX, which may function to degrade native FGF-23. In autosomal-dominant hypophosphatemic rickets, a mutation in FGF-23 exists, which makes it resistant to cleavage.^14,15

We did not find a consistent change in serum FGF-23 as measured by the C-terminal assay. Native FGF-23 may be metabolized into inactive fragments.¹⁶ Therefore, circulating concentrations of FGF-23 analyzed with an intact FGF-23 assay, rather than the c-terminal assay, may be required to fully understand the role of FGF-23 after liver resection.

In conclusion, hypophosphatemia after hepatic resection is a frequent occurrence. Our study has attempted to elucidate the mechanism of posthepatectomy hypophosphatemia. It appears that the previously suggested mechanism of increased phosphate utilization by the regenerating liver was not the cause of hypophosphatemia in our patients; transient isolated phosphaturia seems to be the predominant etiology of this phenomenon.

A greater recognition of this phenomenon may prevent unappreciated potentially dangerous hypophosphatemia. The cause of postoperative phosphaturia remains elusive, and although profound after hepatic resection, it is not limited to hepatic surgery. As our understanding of phosphatonins increases, this physiology may become clearer. Further study of postoperative phosphaturia may provide insight into normal and pathologic phosphate homeostasis.

ACKNOWLEDGMENTS

The authors thank Drs. Econ and White for assistance with FGF-23 assay, Dr. Robert Reilly for his assistance during editing, Dr. Irvin Modlin for help with the manuscript, and Dr. Lloyd Cantly for use of his laboratory facilities.