Hypophosphatemia in Living Liver Donors

ORGAN DONATION

Hypophosphatemia in Living Liver Donors L. Filik, H. Karakayalı, A. Dalgıç, R. Emirog˘lu, and M. Haberal ABSTRACT Background and aim. Some patients who undergo donor hepatectomy for adult living donor liver transplantation develop hypophosphatemia postoperatively. Since this imbalance appears to be a factor in postoperative complications, some authors advocate routine supratherapeutic phosphorus repletion. The purpose of this study was to determine the frequency of hypophosphatemia after elective donor lobectomy for liver transplantation and to assess whether phosphorus repletion is necessary in this patient group. Methods. The cases of 26 patients who donated 19 right lobe and seven left lateral lobe grafts between August 2004 and March 2005 were evaluated. Postoperative phosphorus levels and other relevant data were obtained from our institution’s transplant database. Presence/severity of hypophosphatemia was categorized as follows: normal (⬎2.5 mg/dL), mild (1.5 to 2.5 mg/dL), moderate (1.1 to 1.5 mg/dL), and profound (⬍1.0 mg/dL). Results. No patients undergoing donor hepatectomy suffered profound or life-threatening hypophosphatemia and no donor required hyperalimentation for phosphate repletion. Twenty one donors (80.7%) did not have postoperative hypophosphatemia. In addition there appears to be no increased morbidity related to hypophosphatemia. A left lateral segment donor (3.8%) had moderate hypophosphatemia that alleviated with oral intake gradually. Four patients (15.5%; three of right lobe donor, one of left lateral segment donor) had mild hypophosphatemia. We also appropriately corrected the hypophosphatemia with encouragement of normal oral intake. By postoperative day 5, essentially all donor phosphorus levels were corrected to normal range. Conclusions. The results suggest that hypophosphatemia after donor hepatectomy is not as common as previously reported. We find that appropriate early oral intake postoperatively effectively prevents/minimizes hypophosphatemia in patients who undergo donor hepatectomy.

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IVING DONOR LIVER transplantation is now being performed successfully, but there is still significant morbidity and mortality risk for both donor and recipient.1– 4 Postoperative follow-up of the donor must be as thorough as the preoperative evaluation. Hypophosphatemia after donor hepatectomy can cause various forms of morbidity, including cerebral dysfunction, anorexia, hemolysis, platelet dysfunction, and even myocardial suppression if serum phosphorus drops below 1 mg/dL.5–12 When a major portion of liver is resected, a precipitous decline in serum phosphorus can follow. One of the possible reasons © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 559 –561 (2006)

for this is a large flux of phosphorus into the remaining hepatic tissue as part of the body’s attempt to rapidly regenerate the liver.1,3 A number of recent reports have identified this marked drop in serum phosphorus after donor hepatectomy as a significant source of morbidity. Consequently, some

From the Departments of Gastroenterology and Surgery, Bas¸kent University, Faculty of Medicine, Ankara, Turkey. Address reprint requests to Levent Filik, MD, Bas¸kent University, Faculty of Medicine, Ankara, Turkey. E-mail: leventfilik@ yahoo.co.uk 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2005.12.046 559

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authors have advocated routine use of supratherapeutic doses of phosphorus or hyperalimentation to guard against lifethreatening hypophosphatemia after donor hepatectomy.1,3,13 Hyperalimentation is not innocuous; this procedure carries risks of infection, hemopneumothorax, air emboli, and other catheter-related complications.14 Phosphorus metabolism and homeostasis is a complex process that involves the kidneys, liver, gastrointestinal tract, and skeletal system. Normal serum concentrations range from 0.8 to 1.6 mmol/L, or 2.5 to 5 mg/dL (0.032 mmol phosphate ⫽ 1 mg). The recommended daily intake of phosphorus for the healthy population is approximately 1000 mg.15 The purpose of this study was to determine the frequency of hypophosphatemia in patients who undergo elective donor lobectomy for liver transplantation. We also investigated whether encouraging early oral food intake postoperatively is adequate for preventing hypophosphatemia in this patient group. PATIENTS AND METHODS From August 2004 through March 2005, a total of 26 individuals underwent living donor liver transplantation at our institution. Nineteen of the donors underwent right lobe hepatectomy and seven underwent left lateral segmentectomy. We reviewed our database, which was collected prospectively, to check these patients’ postoperative phosphorus levels and assess relevant supporting information. The ages of the donors ranged from 23 to 55 years (mean, 36.5 years). All potential liver donors at our center undergo a full four-stage preoperative workup that includes anatomical, medical, and histopathological assessments and psychological counseling. Data collected for each accepted donor, including demographics, operative information, postoperative laboratory values, examination findings, and complications, are entered in a transplant database. The donors are routinely cared for in the transplantation surgery ward. No donor receives routine parenteral nutrition, and oral nutrition is encouraged once bowel activity returns. Once the donor is on an oral diet again, he or she receives 1500 to 1600 mg of dietary phosphorus per day. Serum inorganic phosphorus levels are routinely measured as part of the preoperative workup for each donor and are also measured each morning of the hospital stay until the patient is stable on an oral diet. These levels are measured by calorimetric analysis with a commercially available phosphorus assay (Johnson & Johnson, New York, NY, USA). For this study, we categorized patients according to presence/severity of hypophosphatemia as follows: normal (⬎2.5 mg/dL), mild (1.5 to 2.5 mg/dL), moderate (1.1 to 1.5 mg/dL), and profound (⬍1.0 mg/dL).

RESULTS

The 26 donor preoperative serum phosphorus levels were all in the normal range. None of the patients suffered profound or life-threatening hypophosphatemia, and no donor required hyperalimentation for phosphate repletion. Twenty-one (80.8%) of the donors had normal phosphorous levels postoperatively. The phosphorus levels in the first 5 days after donor hepatectomy ranged from 1.2 mg/dL to 4.9 mg/dL. The respective mean levels on days 1, 2, 3 and

FILIK, KARAKAYALI, DALGIÇ ET AL

4 were 2.9, 2.7, 2.7, and 3.0 mg/dL. By postoperative day 5, all the donor phosphorus levels were in the normal range. The case data also revealed no morbidity related to hypophosphatemia. One of the left lateral segment donors (3.8% of the 26 donors) developed moderate hypophosphatemia that gradually resolved with oral intake. Four patients (three right lobe donors and one left lateral segment donor; 15.4% of total) developed mild hypophosphatemia. These cases were also corrected with encouragement of normal oral intake. All donors were discharged in good health within 7 days of surgery. DISCUSSION

Development of hypophosphatemia after donor hepatectomy involves complex events that can be driven by a number of factors. There may be hepatic influx of phosphate during the regeneration response and for energy metabolism, and there may be movement of phosphorus into skeletal muscle induced by release of stress-related hormones (eg, insulin, glucagon) and endogenous cytokines (eg, tumor necrosis factor, interleukin-1, and interleukin-6).3,16 Administration of parenteral dextrose solutions devoid of phosphorus can also lead to hypophosphatemia associated with an increased flux of phosphorus into skeletal muscle.17,18 Research has also shown that hypophosphatemia can occur after prolonged glucose infusion.5–7 It is postulated that the renal tubules increase phosphate excretion in response to the higher glucose load that results from administration of intravenous fluids containing glucose. In patients who develop hypophosphatemia for any reason, this condition usually does not become clinically apparent because of the body’s efficient buffering system and large phosphorus reserve. Research indicates that preexisting cellular injury is required in order for a patient to show clinical signs of hypophosphatemic syndrome.1,3 There are many well-known causes of serum phosphorus decline to the point of severe hypophosphatemia. These include chronic alcoholism, malnourishment, alcoholic pancreatitis, gram-negative sepsis, changes during recovery from diabetic ketoacidosis, respiratory alkalosis, total parenteral nutrition with inadequate phosphorus supplementation, glucose loading, and antacid use. Such clinical scenarios are relatively common among patients in surgical intensive care, and there is a high prevalence of hypophosphatemia in the acute-care setting.1,7 However, healthy living liver donors do not exhibit this abnormality preoperatively. In a recent study, Salem and Tray hypothesized that posthepatectomy hypophosphatemia reflects a derangement of normal hepatorenal messaging.19 Their theory is that serum phosphorus levels drop due to disruption of renal phosphate handling caused by aberrations in the metabolism of an as-yet-unrecognized chemical messenger(s) responsible for tubular phosphate homeostasis. The authors also stated that elevated levels of novel circulating phosphaturic factors, such as fibroblast growth factor 23,

HYPOPHOSPHATEMIA IN LIVING LIVER DONORS

are responsible for phosphate wasting. Their findings suggest that transient isolated hyperphosphaturia after hepatic resection is responsible for hypophosphatemia in these patients rather than increased uptake of phosphate by regenerating liver tissue. Pomposelli et al suggested that hypophosphatemia is a “universal event” after donor hepatectomy, and reported that five of eight liver donors they studied had profound or severe hypophosphatemia at 2 days postsurgery even though they were receiving slightly more than the daily recommended phosphorus intake.3 In our study, only 5 (19.2%) of the 26 donors had hypophosphatemia and most of these cases were mild phosphorus depletion. The reason for the discrepancy between our findings and those of Pomposelli and colleagues is not clear. All our donors were healthy at the time of surgery, and we presume the same was true for the smaller group investigated by Pomposelli et al. In our study group, we administered Isolyte S (which contains 1 mEq/L phosphate) intraoperatively and this might have prevented or minimized serum phosphorus decline in our patients. Also, liver donors at our center are routinely started on an oral diet the first day after surgery, and dextrose-containing intravenous crystalloid solution is discontinued once the patient is eating well. The diet these patients receive is rich in phosphorus, and this could also have helped prevent or correct hypophosphatemia in our donors after hepatectomy. Our observations of postoperative phosphorus homeostasis in our subgroup of right-lobe donors (19 of the 26 total) were similar to those reported by Tan et al.1 None of the 26 donors in our study developed profound or life-threatening hypophosphatemia after lobectomy, none required hyperalimentation for metabolic derangements, and all were able to start oral feeding promptly after surgery. We consider patient safety during and after donor hepatectomy to be of paramount importance. It is critical to monitor the postoperative course of all liver donors with the utmost care. Profound or life-threatening hypophosphatemia is not a frequent problem in this patient group, and we do not endorse routine administration of hyperalimentation because of the potential morbidity with this approach. Our data indicate that hypophosphatemia is not as frequent as previously reported in patients who undergo donor hepatectomy, and we have found that appropriate

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early oral intake is sufficient for preventing/minimizing hypophosphatemia in this patient group.

REFERENCES 1. Tan HP, Madeb R, Kovach SJ, et al: Hypophosphatemia after 95 right-lobe living-donor hepatectomies for liver transplantation is not a significant source of morbidity. Transplantation 76:1085, 2003 2. United Network of Organ Sharing: United Network of Organ Sharing (UNOS) 2001 Data Registry. Available at: http:// www.unos.org. Accessed February, 2003 3. Pomposelli JJ, Pomfret EA, Burns DL, et al: Life-threatening hypophosphatemia after right hepatic lobectomy for live donor adult liver transplantation. Liver Transpl 7:637, 2001 4. Burak KW, Rosen CB, Fidler JL, et al: Hypophosphatemia after right hepatectomy for living donor liver transplantation. Can J Gastroenterol 18:729, 2004 5. Yu GC, Lee DB: Clinical disorders of phosphorus metabolism. West J Med 147:569, 1987 6. Subramanian R, Khardori R: Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment. Medicine 79:1, 2000 7. Knochel JP: Hypophosphatemia. West J Med 134:15, 1981 8. Smyrniotis V, Kostopanagiotou G, Katsarelias D, et al: Changes of serum phosphorus levels in hepatic resections and implications on patients’ outcomes. Int Surg 88:100, 2003 9. Buell JF, Berger AC, Plotkin JS, et al: The clinical implications of hypophosphatemia following major hepatic resection or cryosurgery. Arch Surg 133:757, 1998 10. Findling R, Foreman JW, Krummel TM: Hypophosphatemia in a pediatric patient after major hepatic resection. J Pediatr Surg 24:1165, 1989 11. Keushkerian S, Wade T: Hypophosphatemia after major hepatic resection. Curr Surg 41:12, 1984 12. George R, Shiu MH: Hypophosphatemia after major hepatic resection. Surgery 111:281, 1992 13. Pomposelli JJ, Burns DL: Hypophosphatemia and the live liver donor. Transplantation 78:305, 2004 14. Knochel JP: Complications of total parenteral nutrition. Kidney Int 27:489, 1985 15. Reference Values for Nutrition Labeling: Available at: http://www.newtrition.net. Accessed May, 2005 16. Kotani G, Usami M, Kasahara H, et al: The relationship of IL-6 to hormonal mediators, fuel utilization, and systemic hypermetabolism after surgical trauma. Kobe J Med Sci 42:187, 1996 17. Tan HP, Marcos A: Hypophosphatemia and the live liver donor. Transplantation 79:27, 2005 18. Rasmussen A, Kimose HH, Hessov I: Severity of postoperative hypophosphatemia in relation to glucose administration and renal handling of phosphate. Acta Chir Scand 154:617, 1998 19. Salem RR, Tray K: Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Ann Surg 241:343, 2005