Eileen Cowan

Treatment of Parenteral Nutrition-Associated Liver Disease: The Role of Lipid Emulsions

Parenteral nutrition is a life-saving therapy for infants with intestinal failure. However, long-term parenteral nutrition carries the risk of progressive liver disease. Substantial data has implicated components of parenteral soybean oil in the pathogenesis of parenteral nutrition-associated liver disease (PNALD). Elevated serum concentrations of phytosterols, an abundance of omega-6 polyunsaturated fatty acids, and a relative paucity of α-tocopherol have been associated with the risk of cholestasis and hepatic injury observed in PNALD. Currently available treatment strategies include the reduction of the dose of administered parenteral soybean oil and/or the replacement of parenteral soybean oil with alternative parenteral lipid emulsions. The purpose of this review is to provide an overview of the pathogenetic mechanisms associated with the development of PNALD and the data evaluating currently available treatment strategies.

The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy.

OBJECTIVE To determine the natural history of cirrhosis from parenteral nutrition-associated liver disease (PNALD) after resolution of cholestasis with fish oil (FO) therapy. BACKGROUND Historically, cirrhosis from PNALD resulted in end-stage liver disease, often requiring transplantation for survival. With FO therapy, most children now experience resolution of cholestasis and rarely progress to end-stage liver disease. However, outcomes for cirrhosis after resolution of cholestasis are unknown and patients continue to be considered for liver/multivisceral transplantation. METHODS Prospectively collected data were reviewed for children with cirrhosis because of PNALD who had resolution of cholestasis after treatment with FO from 2004 to 2012. Outcomes evaluated included need for liver/multivisceral transplantation, mortality, and the clinical progression of liver disease. RESULTS Fifty-one patients with cirrhosis from PNALD were identified, with 76% demonstrating resolution of cholestasis after FO therapy. The mean direct bilirubin decreased from 6.4 ± 4 mg/dL to 0.2 ± 0.1 mg/dL (P < 0.001) 12 months after resolution of cholestasis, with a mean time to resolution of 74 days. None of the patients required transplantation or died from end-stage liver disease. Pediatric End-Stage Liver Disease scores decreased from 16 ± 4.6 to -1.2 ± 4.6, 12 months after resolution of cholestasis (P < 0.001). In children who remained PN-dependent, the Pediatric End-Stage Liver Disease score remained normal throughout the follow-up period. CONCLUSIONS Cirrhosis from PNALD may be stable rather than progressive once cholestasis resolves with FO therapy. Furthermore, these patients may not require transplantation and show no clinical evidence of liver disease progression, even when persistently PN-dependent.

Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease

Parenteral nutrition (PN) can be life saving for infants unable to adequately absorb enteral nutrients due to intestinal failure from inadequate bowel length or function. However, long-term PN carries significant morbidity and mortality, with 30 to 60% of patients developing progressive liver dysfunction. The etiology of PN-associated liver disease (PNALD) is poorly understood, however the involvement of lipid emulsions in its pathogenesis has been clearly established, with new emphasis emerging on the role of omega-6 polyunsaturated fatty acids and omega-3 polyunsaturated fatty acids. Recent studies evaluating the use of parenteral fish oil lipid emulsions instead of soybean oil lipid emulsions have demonstrated marked improvements in cholestasis, morbidity, and mortality in patients with PNALD treated with fish oil. This review provides an overview of the role of lipid emulsions in the pathogenesis of PNALD and the proposed mechanisms by which parenteral fish oil lipid emulsions may be exerting their beneficial effects.

Fish oil-based lipid emulsion in the treatment of parenteral nutrition-associated liver disease.

Purpose of review Parenteral nutrition-associated liver disease (PNALD) is a major cause of morbidity and mortality in the parenteral nutrition-dependent population. Here, we review the most recent literature involving a fish oil-based lipid emulsion (FOLE) and its effects on PNALD. Recent findings Vegetable oil-based lipid emulsions (VBLEs) contribute to PNALD. This may be due to parenteral phytosterols and/or the presence of pro-inflammatory mediators. Whereas a small reduction in the dose of VBLE does not appear to prevent PNALD, a significant reduction in the dose may reverse PNALD; however, it carries the risk of essential fatty acid deficiency. Furthermore, the impact of extreme lipid restriction on subsequent neurodevelopment is unknown. Combination lipid emulsions containing fish oil are associated with decreased bilirubin levels, though no studies compare these emulsions with the outcomes with FOLE alone. The utility of FOLE in the reversal of PNALD has been demonstrated and its administration does not lead to essential fatty acid deficiency. Furthermore, there is evidence that FOLE may prevent PNALD. Conclusion FOLE appears to be an efficacious treatment to reverse PNALD. However, more studies are necessary to determine if FOLE might also be beneficial in the prevention of PNALD. Future studies should additionally focus on the preterm infant population, as they represent a major population requiring parenteral nutrition support for survival.

The Addition of Medium-Chain Triglycerides to a Purified Fish Oil Based Diet Alters Inflammatory Profiles in Mice

OBJECTIVE Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. MATERIALS/METHODS Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. RESULTS All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. CONCLUSION These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation.

Neonatal intestinal physiology and failure

The neonatal intestine is a complex organ that regulates the absorption of nutrients essential for growth and development. Intestinal failure results from insufficient or functionally inadequate bowel and can lead to failure of neonatal growth and development. Current literature on neonatal intestinal physiology and failure was reviewed and summarized. A homeostatic interplay of electrolytes, enzymes, and hormonal regulators is essential to achieve the physiologic balance needed for adequate intestinal performance. Physiologic consequences of intestinal failure are dependent on the length and anatomic location of the diseased or surgically resected bowel. Intestinal failure leads to disruption of normal intestinal physiology and may have long-term consequences for growth and development if inadequately treated. Parenteral nutrition remains the mainstay of treatment for neonatal intestinal failure.

Role of parenteral lipid emulsions in the preterm infant

Parenteral nutrition (PN) is necessary for infants unable to receive adequate calories enterally due to prematurity, decreased bowel length, or functional intestinal disorders. While PN can be life saving, its use is associated with significant risks of sepsis from catheter-associated infections and progressive liver dysfunction from prolonged use. The preterm infant population is at highest risk for these complications due to the presence of multiple comorbidities and immaturity of the biliary system. Strong data has implicated parenteral lipids in the multifactorial pathogenesis of PN-associated liver disease (PNALD). However, lipids are essential in early infant development, particularly in the neurocognitive development of preterm infants. Substitution of the lipid source from soybean oil to fish oil has emerged as a safe and efficacious treatment of PNALD, with marked improvements in morbidity and mortality. Knowledge of the developmental needs and physiologic limitations of preterm infants is crucial to optimizing parenteral lipid administration to nurture growth, and minimize and treat associated complications. The purpose of this review is to provide an overview of lipid requirements of the preterm infant and discuss the role of parenteral lipid emulsions in the management of PNALD and other diseases of prematurity.

Challenging the 48-Hour Rule-Out for Central Line–Associated Bloodstream Infections in the Pediatric Intestinal Failure Population A Retrospective Pilot Study

INTRODUCTION While parenteral nutrition (PN) has revolutionized the management of patients with intestinal failure (IF), central line-associated bloodstream infections (CLABSIs) remain a leading cause of mortality and morbidity in this population. The objective of this study is to characterize the presentation of CLABSIs in pediatric IF and to determine the time to positivity of blood cultures. METHODS A retrospective cohort study of children with IF who presented to our institution for evaluation of a possible CLABSI from January 1, 2012, to December 31, 2012, was performed. RESULTS Sixty patients with IF were identified. There were 33 cases of CLABSI in 16 patients, with a rate of 1.5 infections per 1000 catheter days. There were no significant differences in age, growth parameters, or catheter days between patients with or without CLABSI. Fever was documented in 85% of patients with CLABSI. These patients demonstrated an increased percentage of neutrophils and higher C-reactive protein levels compared with patients without CLABSI. The mean time to culture positivity was 13.2 hours, and 97% of cultures were positive within 24 hours. CONCLUSION Our data suggest that most pediatric patients with IF who have CLABSI develop positive cultures within 24 hours, and the absence of fever and leukocytosis does not necessarily indicate the absence of infection. These findings may support clinical practice guidelines in favor of shorter hospital stay when CLABSI is suspected; however, a prospective analysis of CLABSI in this population is recommended to determine the safety and appropriate setting prior to any practice change.

Elevated Alkaline Phosphatase in Infants With Parenteral Nutrition-Associated Liver Disease Reflects Bone Rather Than Liver Disease.

BACKGROUND Elevated serum alkaline phosphatase (ALP) in infants with intestinal failure (IF) can be due to parenteral nutrition-associated liver disease (PNALD) or metabolic bone disease (MBD). The purpose of the study was to determine the utility of serum ALP in the diagnostic criteria for PNALD by measuring tissue-specific levels in infants with IF and PNALD. METHODS A retrospective review of patient data for 15 infants diagnosed with PNALD between December 2012 and August 2013 was performed. PNALD was defined as the presence of 2 consecutive direct bilirubin (DB) levels >2 mg/dL. Fractionated serum alkaline phosphatase was measured in each patient, while the DB was >2 mg/dL. Parathyroid hormone (PTH), vitamin D3, calcium, and phosphate levels were recorded where available. RESULTS In 15 infants with PNALD, elevation in total ALP was due to marked elevations in bone-specific ALP. The median liver-specific ALP remained within the normal range. PTH, vitamin D3, calcium, and phosphate levels were within normal limits. CONCLUSION While elevated ALP can reflect biliary stasis, the ALP elevation observed in infants with IF and PNALD is predominantly of bone rather than hepatic origin. An elevated unfractionated ALP in infants with PNALD should therefore raise suspicion of underlying bone disease, rather than being attributed to liver disease alone.