Isolated Orthotopic Liver Transplantation for Parenteral Nutrition–Associated Liver Injury
From the * Michael E. DeBakey Department of
Surgery, and Correspondence: John A. Goss, MD, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 1709 Dryden, Suite 1500, Houston, TX 77030. Electronic mail may be sent to jgoss{at}bcm.tmc.edu. Background: Mild liver dysfunction is common after prolonged use of parenteral nutrition (PN), but end-stage liver failure occurs only rarely. Few treatment options other than combined liver-intestine transplantation exist for patients with liver failure associated with PN use, however. Herein, we report the results of a cohort of patients undergoing isolated orthotopic liver transplantation (OLT) for PN-associated liver injury. Methods: A retrospective cohort study of 80 patients (73 pediatric patients and 7 adults) who have undergone isolated OLT for PN-associated liver injury as the primary indication for transplantation was performed. Results: At the time of OLT, the mean total serum bilirubin was 19.5 mg/dL and the mean serum albumin level was 2.9 mg/dL. Severe hepatic encephalopathy was seen in 5%, spontaneous bacterial peritonitis was seen in 6.3%, and respiratory failure requiring mechanical ventilation was seen in 14% of patients at the time of OLT. Overall 1- and 5-year survival rates were 72% and 52%, respectively, with infection being the most common cause of death after OLT. Retransplantation was required in 25% of patients, and the 5-year posttransplant patient survival rate only reached 35% in these cases. Conclusions: Patients with end-stage liver disease associated with PN administration often have very severe liver disease, multiple comorbidities, and poor prognosis by the time they are listed for OLT. Nonetheless, isolated OLT is associated with good long-term survival and should be considered for selected patients with combined intestine-liver failure. Parenteral nutrition (PN) has become an essential means of supporting patients who are be unable to sustain themselves on enteral feedings or intravenous (IV) carbohydrate solutions alone. Although lifesaving, PN is often associated with significant complications, including liver injury that can range from self-limited cholestasis to end-stage cirrhosis.1–5 Few good treatment options exist once cirrhosis has developed from long-term PN use. Perhaps the best option for those with PN-associated cirrhosis and continuing need for PN is a combined liver-intestine transplant, an option associated with 49%–55% long-term survival.6,7 Isolated orthotopic liver transplantation (OLT) exists as an option for selected patients, but in contrast to the combined liver-intestine procedure, the outcomes of OLT for PN-associated liver injury have only been described for single cases and single-institution series of no more than 10 patients.8–11 The current study was undertaken to estimate the long-term patient survival in pediatric and adult patients undergoing OLT for this rare indication.
Patients enrolled in this study were identified through the United Network for Organ Sharing (UNOS) Organ Procurement and Transplant Network liver transplant database. This database contains patient and graft outcome data for >62,000 patients who underwent OLT in the United States between January 1988 and December 31, 2003. Patients with a primary diagnosis of PN-associated liver injury were selected for study. Patients who had received previous small intestine transplants or simultaneous multiorgan transplant were excluded. Descriptive statistics for each cohort were calculated using all available pretransplant and peritransplant variables. Patient and allograft survival was assessed using Kaplan-Meier survival analysis, and survival rates of subgroups were compared with the log rank test. All statistical analyses were performed with SPSS version 11.0 (SPSS Corporation, Chicago, IL). A p value of < .05 was used to determine statistical significance.
Patient Characteristics Since 1988, a total of 80 patients have undergone isolated OLT, with PN-associated liver injury listed as the primary indication for transplantation. These patients were predominantly pediatric at the time of initial OLT. Specifically, 40 (50%) were <12 months of age, 24 (30%) were between 12 and 24 months of age, 8 (10%) were between 2 and 6 years of age, and 1 (1.3%) was between 6 and 10 years of age. None of the recipients were between 11 and 17 years of age. The ages of the 7 adult recipients (9% of the total cohort) ranged from 21 to 60 years of age, with a median 48 years of age. Thirty-four (42%) of the recipients were female patients and 46 (58%) were male patients. White patients composed 62% of the recipient cohort, black patients represented 18%, Hispanic patients represented 16%, and mixed-ethnicity patients represented 3.8%. At the time of OLT, the mean total serum bilirubin was 19.5 mg/dL (range, 0.6–54.0 mg/dL), the mean serum creatinine was 0.58 mg/dL (range, 0.10–9.0 mg/dL), and the mean serum albumin was 2.9 mg/dL (range, 1.9–4.5 mg/dL). Eleven patients (14%) required mechanical ventilation at the time of OLT, and at least 1 had required dialysis in the week before OLT. Four patients (5.0%) had a history of spontaneous bacterial peritonitis, and 5 patients (6.3%) had a history of grade III or IV hepatic encephalopathy. Twenty-three of the 73 pediatric recipients (32%) have been transplanted since the Pediatric End-Stage Liver Disease (PELD) model has been used to rank candidates awaiting OLT. Of these, 12 (52%) were listed as status 1 (high urgency, expected survival without transplantation of <7 days). The median PELD score of the remaining 11 patients was 27 points (corresponding to a predicted 90-day mortality of 9.6%).
Transplant and Allograft Characteristics
Post-transplant Patient Survival
A total of 20 deaths occurred in this cohort. The most common cause of death was infection, accounting for 6 deaths (30% of total deaths). Other causes of death included multiple-organ-system failure (3 deaths, or 15%), cardiovascular deaths (including heart failure and thromboembolism; 3 deaths, or 15%), respiratory failure (3 deaths, or 15%), liver allograft failure (3 deaths, or 15%), and posttransplant lymphoproliferative disease (1 death, or 5%). The cause of the 1 remaining death was unknown.
Retransplantation
The outcomes of combined liver-intestine transplantation6,7 and sequential liver-intestine transplantation11 have been previously described, and this remains the best option for patients with liver failure and dependence on PN. In previous cases and case series, however, it has been noted that selected patients with intestine and liver failure achieve long-term survival and independence from PN after isolated OLT.8–11 Although the reason why an isolated liver graft alone suffices in these selected patients, it has been suggested that it may work by ameliorating many of the consequences of liver failure and portal hypertension that affect bowel function and appetite, including venous congestion of the bowel wall; anorexia and nausea; malabsorption secondary to luminal bile acid deficiency, gastrointestinal hemorrhage, and exudative enteropathy.10,12,13 Intestinal adaptation may also contribute to the ability of patients under the age of 4 to achieve independence from PN in spite of only having received an isolated OLT.10 The current study, based on 80 patients undergoing isolated OLT in the United States between 1991 and 2005, demonstrate that a 73.4% 1-year and 51.9% 5-year post-transplant survival rate can be achieved in select patients. The demographic data available revealed 2 important features of the patients undergoing isolated OLT for PN-associated liver injury. First, such patients are predominantly pediatric: approximately 91% of recipients were <11 years of age, and most of these patients were neonates. This should not be unexpected as it has long been known that small premature infants and neonates seem to be most susceptible to PN-associated liver injury.3 Age <12–24 months may be an independent risk factor for increased mortality after OLT,14,15 but many centers have shown that good posttransplant outcomes can be achieved in very small or very young infants.16–19 Second, these patients are quite ill at the time of transplantation. Of those pediatric patients added to the waiting list during the current era of transplantation (specifically, since the implementation of the PELD model for liver allograft allocation), half had an expected survival of less than a week, and the remaining half had a median expected 90-day mortality of 9.6%. Many of these patients also experienced many of the comorbidities associated with end-stage liver disease, including respiratory failure, spontaneous bacterial peritonitis, and severe hepatic encephalopathy. Together, these data demonstrate that these patients would not have survived long without having undergone isolated OLT and support the suggestion that isolated OLT be used in combined intestine-liver transplant candidates that acutely decompensate before an intestinal graft becomes available.11 The long-term survival of patients undergoing OLT for PN-associated liver disease is lower than that of adult and pediatric patients undergoing OLT for other indications, and the rate of retransplantation is higher than in patients with other indications. Isolated OLT should nonetheless be considered as among the best treatment options for patients with end-stage liver disease recalcitrant to medical management because (1) the likelihood of long-term survival of these patients without OLT is low; and (2) no currently existing treatment option other than OLT may help such patients achieve long-term survival. The median interval of 35 days between listing and OLT is notably brief, and it may be shorter than expected for clinicians unfamiliar with the allocation of donor livers for pediatric OLT candidates. Previously, the "status 1" condition was used by transplant centers to designate an OLT candidate who is expected to live <7 days without OLT, and candidates listed as status 1 were given the highest priority in the allocation of donor livers. Adult OLT candidates with acute liver failure can be listed as status 1, but patients with acute decompensation of chronic liver disease can only be listed as status 1b. Until very recently, however, pediatric OLT candidates with either acute liver failure or acute decompensation of chronic liver disease were allowed to be listed as status 1. Indeed, the lack of distinction between status 1 candidates with acute liver failure and chronic liver disease led to as many as 50% of pediatric candidates being listed as status 1 at some centers.18,20 Thus, acutely ill pediatric candidates were given very high priority for donor livers regardless of the etiology if their expected waitlist survival was <7 days. The laboratory values, prevalence of status 1 designation, and the PELD scores of the patients in this study cohort all suggest that they were very ill at the time of transplantation. If the severity of liver disease was not recognized or was underappreciated until an episode of acute decompensation occurred, it should not be surprising to have a median wait time of 35 days. The data used in this database are derived from a large US registry of OLT recipients, the creation of which was mandated the National Organ Transplant Act of 1984.21 This database contains numerous demographic, clinical, and survival data and is very complete as all US OLT centers are required to provide these data or risk loss of federal Medicare/Medicaid payments.22 Furthermore, analytical comparisons have demonstrated that the OLT recipient survival data in the UNOS database has been shown, in comparison to transplant recipient databases that incorporate the Social Security Death Master File, to be very accurate even in reporting long-term follow-up. Nonetheless, we should acknowledge that, in general, studies that make use of database-derived data do have some inherent limitations. Results of such studies can be affected by lack of standardization in collecting and reporting data, limitations in variables/parameters available for analysis, and missing data. This study in particular relied on the discharge diagnosis of PN-associated liver disease, and as a result the reliability of the data may be subject to errors in diagnosis. In addition, no data on posttransplant PN requirements are available. This has prevented estimates of how successful isolated OLT is in achieving independence from PN in these patients. In summary, patients undergoing isolated OLT for PN-associated liver disease are often young infants with severe liver disease, multiple comorbidities, and poor prognosis. In selected cases, isolated OLT should be considered in patients who have end-stage PN-associated liver disease, especially in patients who are refractory to medical management. Transplantation may contribute to long-term survival. The authors acknowledge the Methodist Foundation for financial support and the United Network for Organ Sharing for the data used in the study. Dr Beth Carter acknowledges the American Gastroenterological Association/Roche and the Baylor Child Health Research Center (National Institutes of Health, K12 HD41648) for research support. Received for publication January 16, 2006. Accepted for publication June 30, 2006.
Journal of Parenteral and Enteral Nutrition, Vol. 30, No. 6,
526-529 (2006)
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MATERIALS AND METHODS
RESULTS