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The role of enteral nutrition in the reversal of parenteral nutrition–associated liver dysfunction in infants
Journal of Pediatric Surgery (2005) 40, 1015 – 1018
www.elsevier.com/locate/jpedsurg
The role of enteral nutrition in the reversal of parenteral nutrition–associated liver dysfunction in infants Patrick J. Javida, Sharon Collier b, Denise Richardsonb, Julie Iglesiasa, Kathleen Gurac, Clifford Lob, Heung Bae Kima, Christopher P. Dugganb, Tom Jaksica,* a
Department of Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA Department of Medicine, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA c Department of Pharmacy, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA b
Index words: Short bowel syndrome; Parenteral nutrition; Enteral nutrition; Bilirubin; Cholestasis
Abstract Background: Liver dysfunction in children dependent on parenteral nutrition (PN) is well established, and the extent of hyperbilirubinemia has been shown to correlate with morbidity and mortality. The aim of this study was to assess whether increasing provisions of enteral nutrition can improve PN-associated hyperbilirubinemia over time. Methods: A retrospective review was conducted on infants in our institution’s Short Bowel Syndrome Clinic from 1999 to 2004. Inclusion criteria included PN duration more than 1 month, serum direct bilirubin more than 3 mg/dL while on PN, and tolerance of full enteral nutrition with eventual discontinuation of PN. Paired t tests were used for statistical analyses. Results: Twelve infants were identified with a PN duration of 5 F 1 months. Five patients underwent liver biopsy while on PN, and histological evidence of cholestasis was found on all specimens. Peak total and direct bilirubin levels were 10.5 F 1.9 and 7.0 F 1.6 mg/dL, respectively, and occurred at time of PN discontinuation. Only 2 patients had improvement in serum bilirubin levels before initiation of full enteral nutrition. After initiation of full enteral nutrition and discontinuation of PN, all patients achieved permanent normalization of bilirubin levels by 4 months ( P b .05) after a 1-month plateau phase. Alkaline phosphatase levels approached reference range within this time but were not significant. Conclusion: These data demonstrate for the first time that although PN-dependent infants can achieve normalization of marked hyperbilirubinemia with enteral nutrition, the improvement in liver function usually begins only after full enteral nutrition is tolerated and PN is withdrawn. These findings support the aggressive weaning of PN to enteral nutrition in infants with short bowel syndrome. D 2005 Elsevier Inc. All rights reserved.
Presented at the 56th Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 8-10, 2004. T Corresponding author. Tel.: +1 617 355 8097. E-mail address: [email protected] (T. Jaksic). 0022-3468/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2005.03.019
The administration of parenteral nutrition (PN) is an important adjunct in the treatment of pediatric short bowel syndrome. In infants with insufficient bowel length and function, PN remains a life-saving modality that allows for growth and development until the process of intestinal adaptation permits the transition of parenteral to full enteral feedings.
1016
P.J. Javid et al.
Table 1 Primary etiologies of short bowel syndrome in the study population Primary diagnosis of short bowel syndrome
No. of patients
Gastroschisis 2 Hirschsprung disease with associated volvulus 1 Intestinal atresia 2 Midgut volvulus 1 Necrotizing enterocolitis 5 Omphalocele (giant) 1
Unfortunately, liver dysfunction associated with prolonged PN provision complicates its use in pediatric short bowel syndrome. The cause of PN-associated liver dysfunction remains unresolved, and although more prevalent in neonates, all patients dependent on PN are at risk for the development of this condition. The liver dysfunction is characterized by hepatic cholestasis with ensuing elevations in serum liver function tests and eventual fibrosis of liver parenchyma [1,2]. Recently, the extent of total and direct hyperbilirubinemia has been shown to correlate with the overall mortality and morbidity of these patients [3]. It is also known that alterations in liver function associated with PN may improve over time as increasing provisions of enteral nutrition are tolerated by the patient and the nutritional intake from PN is withdrawn. Surgical interventions, such as gastrostomy tube feeding and bowel lengthening procedures, are now routinely used in the treatment of short bowel syndrome to facilitate the transition from parenteral to enteral nutrition. However, at present, there is little objective data to define the exact temporal
relationship between increasing enteral intake and recovery from PN-associated liver dysfunction. Therefore, this study specifically sought to measure the effects of increasing provisions of enteral nutrition upon recovery from PN-associated hyperbilirubinemia in children younger than 12 months and to elucidate the pattern of such a recovery over time. Ultimately, it was hoped that information garnered from this study would allow clinicians to predict the juncture at which improvement from reversible PN-associated hyperbilirubinemia may be anticipated.
1. Methods After approval was obtained from the Children’s Hospital Boston Committee on Clinical Investigation (#M04 04- 085), a retrospective data collection was performed on patients who attended our institution’s Short Bowel Syndrome Clinic from January 1999 to March 2004. The review was limited to infants younger than 12 months only. For inclusion in this study, all subjects had to meet the following criteria: (1) total duration of PN administration more than 1 month, (2) serum direct bilirubin more than 3 mg/dL while on PN, and (3) ability to take full enteral nutrition with permanent discontinuation of PN. Collected data included patient characteristics and medical history, pathology results from liver biopsy, duration of PN administration, detailed composition of the nutritional regimen from dietary analysis, and serum liver function tests performed while on PN and after PN discontinuation. All serological liver function tests were
Fig. 1 Serum bilirubin patterns with increasing provisions of enteral nutrition are presented. Whereas enteral nutrition was increased from 60% to 100% of total caloric intake, there were no significant reductions in serum bilirubin concentration. Liver function, as measured by serum bilirubin, only improved after the initiation of full enteral nutrition and the discontinuation of PN. All patients completely and permanently normalized their bilirubin levels within 4 months of full enteral nutrition. Asterisk denotes P b .05 for comparison between levels of bilirubin at time of PN discontinuation and at each subsequent month.
The role of enteral nutrition in the reversal of parenteral nutrition performed in the chemistry laboratory at Children’s Hospital Boston. Liver function tests were performed on a weekly basis for inpatients and at each clinic visit for outpatients. Nutritional assessments and calculations were performed by a dedicated short bowel syndrome dietician who followed up all short bowel patients in the hospital and clinic settings. Full enteral nutrition was defined as a nutritional regimen administered through the gastrointestinal tract that provided the complete allotment of the patient’s nutrient and energy requirements. All patients were treated with ursodiol as standard therapy for PN-associated liver dysfunction. For statistical analyses, paired t tests were used for comparison, and P b .05 was deemed statistically significant. Unless otherwise stated, all data are presented as mean and SEM. Statistical calculations were performed using SPSS software (SPSS, Inc, Chicago, Ill).
2. Results Of the 70 patients who attended the Short Bowel Syndrome Clinic during the study period, 12 infants fulfilled study inclusion criteria. All subjects were diagnosed with short bowel syndrome as neonates. The mean bowel length for subjects at the initial operation was 76 F 7 (range 45-105) cm; 3 of the 12 subjects did not have bowel lengths recorded. The primary diagnoses for this cohort are listed in Table 1. The average duration of PN administration in these subjects was 5 F 1 months for a total of 56 patientmonths on PN. The indication for discontinuation of PN in all subjects was the ability to tolerate complete macronutrient and energy provisions by the enteral route.
1017
The changes in serum bilirubin associated with increasing allotments of enteral nutrition are illustrated in Fig. 1. Peak serum levels of total and direct bilirubin were 10.5 F 1.9 and 7.0 F 1.6 mg/dL, respectively, and are listed in Table 2. In 10 of the 12 patients, the maximum values for total and direct bilirubin occurred at the time of initiation of full enteral nutrition. Only 2 subjects demonstrated improvement in serum bilirubin before full enteral nutrition and PN discontinuation; 1 of the 2 subjects underwent a successful bowel lengthening operation immediately before the improvement in bilirubin levels. In all subjects, hyperbilirubinemia permanently normalized within 4 months after the start of full enteral nutrition and discontinuation of PN ( P b .05). Values for total and direct bilirubin were significantly reduced at 2, 3, and 4 months after initiation of full enteral nutrition and PN discontinuation ( P b .05). An initial 1-month plateau phase, during which the average total and direct bilirubin levels were not significantly different from the peak levels despite full enteral nutrition, was noted (Fig. 1, P = not significant). There were no recurrences of hyperbilirubinemia once full enteral nutrition was started and PN was permanently discontinued. Serum levels of alkaline phosphatase and alanine aminotransferase were elevated in all subjects during PN administration and approached reference range at the 4- month interval after PN discontinuation, although changes in these values were not statistically significant. Five of the 12 subjects underwent liver biopsy for clinical indications while on PN. All liver biopsy specimens demonstrated evidence of histological cholestasis on pathological examination.
3. Discussion Table 2 Peak total and direct serum bilirubin concentrations for the cohort of 12 infants with short bowel syndrome Subject
Peak total bilirubin (mg/dL)
Peak direct bilirubin (mg/dL)
Enteral intake at time of peak bilirubin (%)
1 2 3 4 5 6 7 8 9 10 11 12
18.1 22.1 6.8 7.4 28.8 15.4 4.8 10.7 6.2 13.3 7.5 17.3
11.4 13.8 5.2 5.2 15.6 8.8 3.3 7.6 4.5 8.3 5.6 12.2
100 100 100 100 100 100 100 100 0* 100 100 63*
Ten of the 12 patients had peak bilirubin concentrations at the initiation of full enteral nutrition and did not show any improvement in serum bilirubin with increasing provisions of enteral intake. The remaining 2 subjects as marked (*) demonstrated resolution of hyperbilirubinemia before full enteral nutrition.
Despite years of focused investigation, the etiology and treatment of PN-associated liver dysfunction remain unclear. All children dependent on PN are at risk to develop this condition, although neonates appear to be particularly susceptible [2,4,5]. PN-associated liver dysfunction continues to be one of the major causes of mortality and morbidity in infants with short bowel syndrome [3,5]. The severity of PN-associated liver dysfunction is commonly thought to be alleviated by the provision of enteral nutrition, and surgical as well as medical therapy is aimed at facilitating the transition from parenteral to enteral feedings. In the present study, we hypothesized that increasing provisions of enteral nutrition would correlate with a decrease in hyperbilirubinemia in a cohort of PN-dependent infants with short bowel syndrome. An additional aim of the study was to determine the temporal pattern of this amelioration. For the purpose of measuring liver function, we retrospectively reviewed the serum liver function tests of infants as they received increasing provisions of enteral nutrition and subsequent reductions in PN. Numerous studies have demonstrated that the
1018 cholestatic liver injury associated with PN results in elevations of total and direct bilirubin [6,7], and recent data have shown that the extent of hyperbilirubinemia correlates with morbidity and mortality in this population [3]. Interestingly, the data indicate that the provision of enteral nutrition can indeed result in the complete resolution of marked hyperbilirubinemia in patients with PN-associated liver dysfunction (Fig. 1, P b .05). However, in all but 2 of 12 subjects in this series, the improvement only transpired after full enteral nutrition had been established and PN withdrawn. Moreover, the improvement in hyperbilirubinemia occurred only after a 1-month plateau phase after the initiation of full enteral nutrition; in total, complete normalization of bilirubin values took 4 months on average (Fig. 1). In addition, and equally important, children who fully weaned from PN to enteral nutrition demonstrated no recrudescence of hyperbilirubinemia. The study did identify 2 children who demonstrated improvements in their serum bilirubin indices before full enteral nutrition. Subject 9 was diagnosed with gastroschisis and an associated ileal atresia at birth and developed a rapid onset of hyperbilirubinemia within 3 weeks of PN administration at 1 month of age. His liver function tests gradually improved before the start of enteral feedings and had nearly normalized by the initiation of full enteral nutrition. Subject 12 was an 8 - month-old boy with neonatal volvulus and Hirschsprung disease who presented to us with severe total and direct hyperbilirubinemia and had been listed for liver transplantation. His bilirubin levels rapidly normalized as enteral feeds were advanced after a gastrostomy and serial transverse enteroplasty operation, although PN could not be discontinued for several months because of growth concerns. The reason that these 2 individuals had a more rapid response to the initiation of enteral feeds than others is unclear from this study. It is intriguing that the majority of patients did not show any evidence of improvement in hyperbilirubinemia until the PN was fully withdrawn, despite a steady increase in enteral feeding provisions, and then only after a 1 - month plateau phase. Whether the impetus for bilirubin normalization is the establishment of full enteral nutrition, the discontinuation of PN, or a combination of both remains unresolved. Nonetheless, these data help to define the natural history of PN-associated liver dysfunction in infants. In general, if elevations in total and direct
P.J. Javid et al. bilirubin are to resolve in PN-dependent infants, the changes tend to occur only after full enteral nutrition has been initiated and PN fully withdrawn. Once these nutritional benchmarks have been reached, the data suggest that full resolution of hyperbilirubinemia can be achieved in patients within a 4 -month time span. Beyond this duration, patients with persistent hyperbilirubinemia despite full enteral provisions may require a further diagnostic workup to seek an additional cause of hepatic impairment or the presence of irreversible hepatic injury. Finally, although the resolution of hyperbilirubinemia in these patients is encouraging, children with a history of PN-associated liver dysfunction still require careful longterm follow-up to safeguard against future problems related to hepatic physiology. Thus, the pattern identified here of bilirubin normalization with nutritional advancement in children with PN-associated liver dysfunction will likely be useful to clinicians who treat children dependent on PN. The information may also contribute to the counseling of families as to the prognosis and duration of PN-associated hyperbilirubinemia. Given the benefits associated with full enteral nutrition and the discontinuation of PN, the present study ultimately provides additional support for aggressive therapeutic techniques to achieve an early transition from parenteral to enteral nutrition in patients with short bowel syndrome.
References [1] Freund HR. Abnormalities of liver function and hepatic damage associated with total parenteral nutrition. Nutrition 1991;7:1 - 5. [2] Teitelbaum DH, Tracy T. Parenteral nutrition – associated cholestasis. Semin Pediatr Surg 2001;10:72 - 80. [3] Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr 2001;139:27 - 33. [4] Moss RL, Amii LA. New approaches to understanding the etiology and treatment of total parenteral nutrition – associated cholestasis. Semin Pediatr Surg 1999;8:140 - 7. [5] Meehan JJ, Georgeson KE. Prevention of liver failure in parenteral nutrition – dependent children with short bowel syndrome. J Pediatr Surg 1997;32:473 - 5. [6] Lindor KD, Fleming CR, Abrams A, et al. Liver function values in adults receiving total parenteral nutrition. JAMA 1979;241:2398 - 400. [7] Vileisis RA, Inwood RJ, Hunt CE. Laboratory monitoring of parenteral nutrition – associated hepatic dysfunction in infants. JPEN J Parenter Enteral Nutr 1981;5:67 - 9.
www.elsevier.com/locate/jpedsurg
The role of enteral nutrition in the reversal of parenteral nutrition–associated liver dysfunction in infants Patrick J. Javida, Sharon Collier b, Denise Richardsonb, Julie Iglesiasa, Kathleen Gurac, Clifford Lob, Heung Bae Kima, Christopher P. Dugganb, Tom Jaksica,* a
Department of Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA Department of Medicine, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA c Department of Pharmacy, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA b
Index words: Short bowel syndrome; Parenteral nutrition; Enteral nutrition; Bilirubin; Cholestasis
Abstract Background: Liver dysfunction in children dependent on parenteral nutrition (PN) is well established, and the extent of hyperbilirubinemia has been shown to correlate with morbidity and mortality. The aim of this study was to assess whether increasing provisions of enteral nutrition can improve PN-associated hyperbilirubinemia over time. Methods: A retrospective review was conducted on infants in our institution’s Short Bowel Syndrome Clinic from 1999 to 2004. Inclusion criteria included PN duration more than 1 month, serum direct bilirubin more than 3 mg/dL while on PN, and tolerance of full enteral nutrition with eventual discontinuation of PN. Paired t tests were used for statistical analyses. Results: Twelve infants were identified with a PN duration of 5 F 1 months. Five patients underwent liver biopsy while on PN, and histological evidence of cholestasis was found on all specimens. Peak total and direct bilirubin levels were 10.5 F 1.9 and 7.0 F 1.6 mg/dL, respectively, and occurred at time of PN discontinuation. Only 2 patients had improvement in serum bilirubin levels before initiation of full enteral nutrition. After initiation of full enteral nutrition and discontinuation of PN, all patients achieved permanent normalization of bilirubin levels by 4 months ( P b .05) after a 1-month plateau phase. Alkaline phosphatase levels approached reference range within this time but were not significant. Conclusion: These data demonstrate for the first time that although PN-dependent infants can achieve normalization of marked hyperbilirubinemia with enteral nutrition, the improvement in liver function usually begins only after full enteral nutrition is tolerated and PN is withdrawn. These findings support the aggressive weaning of PN to enteral nutrition in infants with short bowel syndrome. D 2005 Elsevier Inc. All rights reserved.
Presented at the 56th Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 8-10, 2004. T Corresponding author. Tel.: +1 617 355 8097. E-mail address: [email protected] (T. Jaksic). 0022-3468/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2005.03.019
The administration of parenteral nutrition (PN) is an important adjunct in the treatment of pediatric short bowel syndrome. In infants with insufficient bowel length and function, PN remains a life-saving modality that allows for growth and development until the process of intestinal adaptation permits the transition of parenteral to full enteral feedings.
1016
P.J. Javid et al.
Table 1 Primary etiologies of short bowel syndrome in the study population Primary diagnosis of short bowel syndrome
No. of patients
Gastroschisis 2 Hirschsprung disease with associated volvulus 1 Intestinal atresia 2 Midgut volvulus 1 Necrotizing enterocolitis 5 Omphalocele (giant) 1
Unfortunately, liver dysfunction associated with prolonged PN provision complicates its use in pediatric short bowel syndrome. The cause of PN-associated liver dysfunction remains unresolved, and although more prevalent in neonates, all patients dependent on PN are at risk for the development of this condition. The liver dysfunction is characterized by hepatic cholestasis with ensuing elevations in serum liver function tests and eventual fibrosis of liver parenchyma [1,2]. Recently, the extent of total and direct hyperbilirubinemia has been shown to correlate with the overall mortality and morbidity of these patients [3]. It is also known that alterations in liver function associated with PN may improve over time as increasing provisions of enteral nutrition are tolerated by the patient and the nutritional intake from PN is withdrawn. Surgical interventions, such as gastrostomy tube feeding and bowel lengthening procedures, are now routinely used in the treatment of short bowel syndrome to facilitate the transition from parenteral to enteral nutrition. However, at present, there is little objective data to define the exact temporal
relationship between increasing enteral intake and recovery from PN-associated liver dysfunction. Therefore, this study specifically sought to measure the effects of increasing provisions of enteral nutrition upon recovery from PN-associated hyperbilirubinemia in children younger than 12 months and to elucidate the pattern of such a recovery over time. Ultimately, it was hoped that information garnered from this study would allow clinicians to predict the juncture at which improvement from reversible PN-associated hyperbilirubinemia may be anticipated.
1. Methods After approval was obtained from the Children’s Hospital Boston Committee on Clinical Investigation (#M04 04- 085), a retrospective data collection was performed on patients who attended our institution’s Short Bowel Syndrome Clinic from January 1999 to March 2004. The review was limited to infants younger than 12 months only. For inclusion in this study, all subjects had to meet the following criteria: (1) total duration of PN administration more than 1 month, (2) serum direct bilirubin more than 3 mg/dL while on PN, and (3) ability to take full enteral nutrition with permanent discontinuation of PN. Collected data included patient characteristics and medical history, pathology results from liver biopsy, duration of PN administration, detailed composition of the nutritional regimen from dietary analysis, and serum liver function tests performed while on PN and after PN discontinuation. All serological liver function tests were
Fig. 1 Serum bilirubin patterns with increasing provisions of enteral nutrition are presented. Whereas enteral nutrition was increased from 60% to 100% of total caloric intake, there were no significant reductions in serum bilirubin concentration. Liver function, as measured by serum bilirubin, only improved after the initiation of full enteral nutrition and the discontinuation of PN. All patients completely and permanently normalized their bilirubin levels within 4 months of full enteral nutrition. Asterisk denotes P b .05 for comparison between levels of bilirubin at time of PN discontinuation and at each subsequent month.
The role of enteral nutrition in the reversal of parenteral nutrition performed in the chemistry laboratory at Children’s Hospital Boston. Liver function tests were performed on a weekly basis for inpatients and at each clinic visit for outpatients. Nutritional assessments and calculations were performed by a dedicated short bowel syndrome dietician who followed up all short bowel patients in the hospital and clinic settings. Full enteral nutrition was defined as a nutritional regimen administered through the gastrointestinal tract that provided the complete allotment of the patient’s nutrient and energy requirements. All patients were treated with ursodiol as standard therapy for PN-associated liver dysfunction. For statistical analyses, paired t tests were used for comparison, and P b .05 was deemed statistically significant. Unless otherwise stated, all data are presented as mean and SEM. Statistical calculations were performed using SPSS software (SPSS, Inc, Chicago, Ill).
2. Results Of the 70 patients who attended the Short Bowel Syndrome Clinic during the study period, 12 infants fulfilled study inclusion criteria. All subjects were diagnosed with short bowel syndrome as neonates. The mean bowel length for subjects at the initial operation was 76 F 7 (range 45-105) cm; 3 of the 12 subjects did not have bowel lengths recorded. The primary diagnoses for this cohort are listed in Table 1. The average duration of PN administration in these subjects was 5 F 1 months for a total of 56 patientmonths on PN. The indication for discontinuation of PN in all subjects was the ability to tolerate complete macronutrient and energy provisions by the enteral route.
1017
The changes in serum bilirubin associated with increasing allotments of enteral nutrition are illustrated in Fig. 1. Peak serum levels of total and direct bilirubin were 10.5 F 1.9 and 7.0 F 1.6 mg/dL, respectively, and are listed in Table 2. In 10 of the 12 patients, the maximum values for total and direct bilirubin occurred at the time of initiation of full enteral nutrition. Only 2 subjects demonstrated improvement in serum bilirubin before full enteral nutrition and PN discontinuation; 1 of the 2 subjects underwent a successful bowel lengthening operation immediately before the improvement in bilirubin levels. In all subjects, hyperbilirubinemia permanently normalized within 4 months after the start of full enteral nutrition and discontinuation of PN ( P b .05). Values for total and direct bilirubin were significantly reduced at 2, 3, and 4 months after initiation of full enteral nutrition and PN discontinuation ( P b .05). An initial 1-month plateau phase, during which the average total and direct bilirubin levels were not significantly different from the peak levels despite full enteral nutrition, was noted (Fig. 1, P = not significant). There were no recurrences of hyperbilirubinemia once full enteral nutrition was started and PN was permanently discontinued. Serum levels of alkaline phosphatase and alanine aminotransferase were elevated in all subjects during PN administration and approached reference range at the 4- month interval after PN discontinuation, although changes in these values were not statistically significant. Five of the 12 subjects underwent liver biopsy for clinical indications while on PN. All liver biopsy specimens demonstrated evidence of histological cholestasis on pathological examination.
3. Discussion Table 2 Peak total and direct serum bilirubin concentrations for the cohort of 12 infants with short bowel syndrome Subject
Peak total bilirubin (mg/dL)
Peak direct bilirubin (mg/dL)
Enteral intake at time of peak bilirubin (%)
1 2 3 4 5 6 7 8 9 10 11 12
18.1 22.1 6.8 7.4 28.8 15.4 4.8 10.7 6.2 13.3 7.5 17.3
11.4 13.8 5.2 5.2 15.6 8.8 3.3 7.6 4.5 8.3 5.6 12.2
100 100 100 100 100 100 100 100 0* 100 100 63*
Ten of the 12 patients had peak bilirubin concentrations at the initiation of full enteral nutrition and did not show any improvement in serum bilirubin with increasing provisions of enteral intake. The remaining 2 subjects as marked (*) demonstrated resolution of hyperbilirubinemia before full enteral nutrition.
Despite years of focused investigation, the etiology and treatment of PN-associated liver dysfunction remain unclear. All children dependent on PN are at risk to develop this condition, although neonates appear to be particularly susceptible [2,4,5]. PN-associated liver dysfunction continues to be one of the major causes of mortality and morbidity in infants with short bowel syndrome [3,5]. The severity of PN-associated liver dysfunction is commonly thought to be alleviated by the provision of enteral nutrition, and surgical as well as medical therapy is aimed at facilitating the transition from parenteral to enteral feedings. In the present study, we hypothesized that increasing provisions of enteral nutrition would correlate with a decrease in hyperbilirubinemia in a cohort of PN-dependent infants with short bowel syndrome. An additional aim of the study was to determine the temporal pattern of this amelioration. For the purpose of measuring liver function, we retrospectively reviewed the serum liver function tests of infants as they received increasing provisions of enteral nutrition and subsequent reductions in PN. Numerous studies have demonstrated that the
1018 cholestatic liver injury associated with PN results in elevations of total and direct bilirubin [6,7], and recent data have shown that the extent of hyperbilirubinemia correlates with morbidity and mortality in this population [3]. Interestingly, the data indicate that the provision of enteral nutrition can indeed result in the complete resolution of marked hyperbilirubinemia in patients with PN-associated liver dysfunction (Fig. 1, P b .05). However, in all but 2 of 12 subjects in this series, the improvement only transpired after full enteral nutrition had been established and PN withdrawn. Moreover, the improvement in hyperbilirubinemia occurred only after a 1-month plateau phase after the initiation of full enteral nutrition; in total, complete normalization of bilirubin values took 4 months on average (Fig. 1). In addition, and equally important, children who fully weaned from PN to enteral nutrition demonstrated no recrudescence of hyperbilirubinemia. The study did identify 2 children who demonstrated improvements in their serum bilirubin indices before full enteral nutrition. Subject 9 was diagnosed with gastroschisis and an associated ileal atresia at birth and developed a rapid onset of hyperbilirubinemia within 3 weeks of PN administration at 1 month of age. His liver function tests gradually improved before the start of enteral feedings and had nearly normalized by the initiation of full enteral nutrition. Subject 12 was an 8 - month-old boy with neonatal volvulus and Hirschsprung disease who presented to us with severe total and direct hyperbilirubinemia and had been listed for liver transplantation. His bilirubin levels rapidly normalized as enteral feeds were advanced after a gastrostomy and serial transverse enteroplasty operation, although PN could not be discontinued for several months because of growth concerns. The reason that these 2 individuals had a more rapid response to the initiation of enteral feeds than others is unclear from this study. It is intriguing that the majority of patients did not show any evidence of improvement in hyperbilirubinemia until the PN was fully withdrawn, despite a steady increase in enteral feeding provisions, and then only after a 1 - month plateau phase. Whether the impetus for bilirubin normalization is the establishment of full enteral nutrition, the discontinuation of PN, or a combination of both remains unresolved. Nonetheless, these data help to define the natural history of PN-associated liver dysfunction in infants. In general, if elevations in total and direct
P.J. Javid et al. bilirubin are to resolve in PN-dependent infants, the changes tend to occur only after full enteral nutrition has been initiated and PN fully withdrawn. Once these nutritional benchmarks have been reached, the data suggest that full resolution of hyperbilirubinemia can be achieved in patients within a 4 -month time span. Beyond this duration, patients with persistent hyperbilirubinemia despite full enteral provisions may require a further diagnostic workup to seek an additional cause of hepatic impairment or the presence of irreversible hepatic injury. Finally, although the resolution of hyperbilirubinemia in these patients is encouraging, children with a history of PN-associated liver dysfunction still require careful longterm follow-up to safeguard against future problems related to hepatic physiology. Thus, the pattern identified here of bilirubin normalization with nutritional advancement in children with PN-associated liver dysfunction will likely be useful to clinicians who treat children dependent on PN. The information may also contribute to the counseling of families as to the prognosis and duration of PN-associated hyperbilirubinemia. Given the benefits associated with full enteral nutrition and the discontinuation of PN, the present study ultimately provides additional support for aggressive therapeutic techniques to achieve an early transition from parenteral to enteral nutrition in patients with short bowel syndrome.
References [1] Freund HR. Abnormalities of liver function and hepatic damage associated with total parenteral nutrition. Nutrition 1991;7:1 - 5. [2] Teitelbaum DH, Tracy T. Parenteral nutrition – associated cholestasis. Semin Pediatr Surg 2001;10:72 - 80. [3] Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr 2001;139:27 - 33. [4] Moss RL, Amii LA. New approaches to understanding the etiology and treatment of total parenteral nutrition – associated cholestasis. Semin Pediatr Surg 1999;8:140 - 7. [5] Meehan JJ, Georgeson KE. Prevention of liver failure in parenteral nutrition – dependent children with short bowel syndrome. J Pediatr Surg 1997;32:473 - 5. [6] Lindor KD, Fleming CR, Abrams A, et al. Liver function values in adults receiving total parenteral nutrition. JAMA 1979;241:2398 - 400. [7] Vileisis RA, Inwood RJ, Hunt CE. Laboratory monitoring of parenteral nutrition – associated hepatic dysfunction in infants. JPEN J Parenter Enteral Nutr 1981;5:67 - 9.