This is the first study to report the impact of parenteral nutrition on outcomes in biliary atresia patients with end-stage liver disease. Institution of PN in malnourished biliary atresia patients restores many patients to the same nutritional status observed in those patients managed with enteral nutrition alone. Outcomes after liver transplantation were similar in the two groups, despite more advanced liver disease at the time of transplant in the PN group. These data suggest that the beneficial effects of PN on nutritional status may have contributed to better outcomes following liver transplantation than would have been expected had the patients remained in their severely compromised nutritional state.
Malnutrition, a significant problem for children with biliary atresia, can be difficult to assess as ascites, organomegaly, and peripheral edema may confound interpretation of their weight and weight/length measurements.(2
) Weight z-scores and weight/length percentiles have been shown to overestimate nutritional status in patients with biliary atresia. MAC (a measure of muscle mass) and TSF (a measure of adipose stores) more accurately assess the state of malnutrition in these patients and were utilized as the primary markers of nutritional status in this study.(2
Decreased oral intake, early satiety, fat malabsorption, and increased energy expenditure due to a hypermetabolic state all likely contribute to malnutrition in biliary atresia patients.(17
) As mean energy intake (111 kcal/kg/day) in the PN groups was well below estimated caloric needs (131 kcal/kg/day), with signs of progressive malnutrition (lower MAC and TSF z-scores), parenteral nutrition was initiated to improve nutritional status while the patients awaited liver transplantation.(3
) Within the PN group, 64% had already failed to show improved nutritional status following the initiation of NG tube feeding supplementation, thus PN was considered the only viable option. With the addition of PN, the total energy intake was maintained in the PN group at the same level as the non-PN group at clinical endpoint. PN administration reversed the trend of falling TSF z-scores in the PN group and restored values to those observed in the non-PN group by the time of the clinical endpoint. At transplant listing and time of the clinical endpoint, although total energy intake was similar in both groups, MAC and TSF z-scores had improved only in the PN group. It is likely that the PN group would have had continued deterioration of nutritional status following transplant listing had PN not been instituted.
At transplant listing, albumin levels and platelet counts were significantly lower in the PN compared to the non-PN group, reflecting malnutrition and more severe liver disease. Among patients receiving PN, albumin levels stabilized or improved after listing. Platelet counts, however, continued to fall, and serum bilirubin and prothrombin time rose after transplant listing in the PN group, suggesting progression of chronic liver failure and portal hypertension. Moreover, at clinical endpoint the serum bilirubin and prothrombin time were higher and platelet counts significantly lower in the PN vs. non-PN group. Thus, despite worsening liver function, PN administration was successful in improving or stabilizing nutritional status in these infants with end-stage biliary atresia.
Malnourished biliary atresia patients are at higher risk of poor pre-transplant outcomes.(5
) Length and weight z-scores >-2 are associated with better outcomes in biliary atresia patients.(5
) Once listed for liver transplant, malnutrition (length or weight z-scores <-2) is associated with increased need for intensive care unit monitoring pre- transplant and mortality.(16
) Decreasing weight and length z-scores and serum albumin are also risk factors for death pre- transplant.(6
) In our PN group, TSF, MAC and albumin levels were decreasing prior to PN administration, and stabilized/increased following PN. Prior to transplant, the PN group had a higher incidence of GI bleeding and ascites compared with the non-PN group. Although this most likely represents more advanced liver disease and portal hypertension in the PN group, parenteral nutrition, with subsequent expansion of vascular volume, may have also contributed. The administration of PN was not, however, associated with increased bacteremia or pre-transplant mortality. In summary, based on expected worse pre-transplant
outcomes in BA patients who are severely malnourished,(5
) we speculate that the pre-transplant complications of liver disease would have been even worse in the PN group had they not achieved improved nutritional status provided by PN administration.
Malnourished biliary atresia patients are also at increased risk for significant post-transplant complications. Growth failure at the time of liver transplantation confers increased risk for graft failure and post-transplant death.(6
) In our study, PN improved MAC and TSF z-scores to > -2 at clinical endpoint. Although weight z-scores also improved, these findings are difficult to interpret given the frequency of ascites and fluid retention in this population. Following transplant, both PN and non-PN groups had similar clinical outcomes (days in ICU post-transplant, need for re-transplant, graft and patient survival). We postulate that without PN driven improvements in nutritional status, this group would have had poorer post-transplant
outcomes compared to the non-PN group.(6
Although this study addresses the importance of nutrition in biliary atresia, there are several limitations. The retrospective nature of this study resulted in incomplete nutritional data at all time points for some subjects (e.g., those that were breast fed). Although bacteremia rates were similar, we were unable to normalize bacteremia events to number of days with intravenous catheters in place because of inadequate documentation of line removal dates in the medical record. In addition, although pre-transplant mortality was similar between the PN and non-PN group, the possibility of a Type 2 error exists. We acknowledge that the PN and non-PN groups were not clinically equivalent (the PN group had more advanced disease and more severe portal hypertension), thus limiting to some extent the comparison of outcomes of these two groups. However, the more advanced liver disease in the PN group would have biased this group towards worse clinical outcomes, which were not observed.
It should be noted that, despite improved nutritional status in patients receiving PN, their liver disease appeared to progress more rapidly after PN initiation (based on higher bilirubin, lower platelets, longer prothrombin time, and higher calculated PELD) in the setting of a significantly lower GGT, compared to the non-PN group. PN-associated liver disease is well-documented in premature infants and infants with intestinal failure requiring PN supplementation(19
) but has not been described in BA patients. Our PN patients received doses of soy-based intravenous lipids in the range implicated in the pathogenesis of liver injury in infants with intestinal failure.(20
) Thus, it is possible that PN may have contributed to the more rapid progression of cholestasis in the PN group. Lipid sparing techniques and use of omega-3 fatty acid-based intravenous lipid preparations, shown to reverse PN-associated cholestasis(20
), might be considered for BA patients in the future to minimize this possibility.
In conclusion, malnutrition is a serious clinical problem in patients with biliary atresia awaiting liver transplantation. This study provides evidence that PN can be effectively utilized in biliary atresia patients with advanced liver disease and portal hypertension to improve nutritional status while awaiting liver transplantation. These data also suggest that PN may stabilize or improve the clinical outcomes both pre- and post-liver transplant by virtue of improvement in nutritional status. The potential effect of PN on the pace of liver function worsening in BA patients requires additional investigation. Based on the outcomes documented in this study, we suggest that PN should be considered a useful option for infants and children with end-stage liver disease and severe malnutrition awaiting liver transplantation.