Development Of Parenteral Nutrition-associated Liver Disease Research Articles

Incidence of Parenteral Nutrition-Associated Liver Disease in Infants on Prolonged Parenteral Nutrition with a Soybean-Based Lipid Emulsion: A 7-Year Experience

Parenteral nutrition associated liver disease (PNALD) is a significant complication in infants receiving long-term parenteral nutrition (PN). Chronic administration of PN has been associated with its development. Our purpose is to characterize our incidence of PNALD over an extended period and identify risk factors for its development, including administration of soybean-based injectable lipid emulsions (ILEs) as we transit to novel ILEs in our practice. Infants receiving 30 days or more of PN were included. PNALD was defined as a direct bilirubin ≥ 2 mg/dL. Data collected included: patient demographics, clinical and enteral feeding characteristics. Macronutrient intake was recorded using these cut-offs: glucose infusion rate (GIR) of ≤14 mg/kg/min or above, protein doses of ≤3 g/kg/day or above and lipid doses of ≤2 g/kg/day or above. A total of 349 infants were included, with an annual incidence of PNALD ranging between 34% - 54%. Infants with PNALD were younger by gestation (27 vs. 29.5 weeks) and smaller by birthweight (900 vs. 1248 grams). Sepsis, GI disease including necrotizing enterocolitis and bowel resection were significantly associated with an increased risk for development of PNALD. PNALD infants received lower protein doses (3.0 vs 3.3 g/kg/day, p = 0.014) while receiving higher GIR (11.4 vs 10.7 mg/kg/min, p = 0.012) compared to non-PNALD infants. Low birth weight, sepsis and bowel resection remain strong indicators of risk for PNALD. No single macronutrient increased our infants’ risk for PNALD. The use of newer ILEs when available should be evaluated for their impact on PNALD development.

Nutritional Risk Factors in the Pathogenesis of Parenteral Nutrition-Associated Liver Disease

Parenteral nutrition has been a lifesaving therapy for individuals who cannot sustain adequate oral or enteral nutrient intake to maintain fluid, electrolyte, and nutrient balance. Nonetheless, parenteral nutrition can lead to an increased risk of complications, such as parenteral nutrition-associated liver disease (PNALD). The pathogenesis of PNALD has been associated with multiple risk factors, such as longer duration, reduced small bowel length, decreased enteral intake, and bacterial infections. Nutritional risk factors also play an important role in the development of PNALD. This review presents several nutrient deficiencies and excesses that have been associated with PNALD. Deficiencies in certain nutrients (amino acids, essential fatty acids, enteral intake), excesses of certain nutrients (calories, carbohydrates, lipids), types of lipid emulsions, and mineral toxicities (aluminum, copper, manganese) have been associated with PNALD. Strategies to address PNALD require correction of these risk factors. The use of newer mixed lipid emulsions (including soybean, medium-chain triglycerides, olive oil, and fish oil) may also have less hepatotoxicity than traditional soybean oil-based lipid emulsions. Knowledge of nutritional risk factors for PNALD will help the clinician in the systematic evaluation and treatment of these specific risk factors. Moreover, an understanding of their effects guides the balance between addressing the patient’s nutritional needs and reducing the risk of PNALD.

Lipid management in pediatric intestinal failure.

Lipids are a crucial component in parenteral nutrition but their prolonged use can be associated with parenteral nutrition-associated liver disease (PNALD), which may lead to significant morbidity and mortality. The purpose of this review is to discuss the current state of lipid management in pediatric intestinal failure, especially as it relates to the prevention of PNALD. Lipid restriction has emerged as a successful strategy in both the treatment and prevention of PNALD in parenteral nutrition-dependent children. There is concern, however, that lipid restriction can lead to essential fatty acid deficiency. This, in turn, may affect neurodevelopmental outcomes. A wide variety of lipid emulsion formulations is available throughout the world although only one, a soybean-based product, is Food and Drug Administration-approved for use in the pediatric population. To date, there are no definitive data favoring one lipid emulsion composition over another. Pediatric intestinal failure patients are at high risk for the development of PNALD. Although this may be managed, and even prevented, with lipid restrictive strategies, the development of essential fatty acid deficiency in this setting remains a concern. Further studies are needed to determine the ideal lipid emulsion and dose to be used in parenteral nutrition-dependent children.

Hepatic Overexpression of GRP94 in a Rabbit Model of Parenteral Nutrition-Associated Liver Disease.

Objective. To use a rabbit model of parenteral nutrition-associated liver disease (PNALD) to study changes of the endoplasmic reticulum stress (ERS) marker glucose regulatory protein 94 (GRP94) and determine its role in the pathogenesis of PNALD. Methods. A rabbit PNALD model total parenteral nutrition (TPN) group was established. A corresponding control group received breast-feeding for one week. Serum biochemical parameters were measured and liver histological examinations were performed. The level of GRP94 mRNA and protein were measured. Results. The results showed that the serum TBIL, DBIL, and γ-GT levels in the TPN group were significantly higher than those in the control group, while levels of serum ALB in TPN group were significantly lower than those in the control group. The immunohistochemistry results showed that the protein expression level of GRP94 in the liver of TPN group was significantly increased compared with the control group. The RT-PCR results showed that the level of GRP94 mRNA in the liver of the TPN group was significantly higher compared with the control group. Conclusions. The mRNA and protein levels of GRP94 in the TPN group were both significantly increased, indicating that ERS may be directly related to the occurrence and development of PNALD.

Intravenous fish oil lipid emulsion promotes a shift toward anti-inflammatory proresolving lipid mediators

Parenteral nutrition (PN)-associated liver disease (PNALD) is a life-threatening complication of the administration of PN. The development of PNALD may be partly due to the composition of the lipid emulsion administered with PN: soybean oil-based lipid emulsions (SOLE) are associated with liver disease, while fish oil-based lipid emulsions (FOLE) are associated with prevention and improvement of liver disease. The objective of this study was to determine how the choice of lipid emulsion modified the production of bioactive lipid mediators (LMs). We utilized a mouse model of steatosis to study the differential effect of FOLE and SOLE. We subsequently validated these results in serum samples from a small cohort of human infants transitioning from SOLE to FOLE. In mice, FOLE was associated with production of anti-inflammatory, proresolving LMs; SOLE was associated with increased production of inflammatory LMs. In human infants, the transition from SOLE to FOLE was associated with a shift toward a proresolving lipidome. Together, these results demonstrate that the composition of the lipid emulsion directly modifies inflammatory homeostasis.

The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical infants

PurposeSurgical infants requiring long-term parenteral nutrition (PN) are at risk for parenteral nutrition-associated liver disease (PNALD). The purpose of this study was to determine the effect of a lipid restricted PN regimen in preventing the development of PNALD in surgical infants. MethodsIn 2009, we implemented a lipid restricted strategy in surgical infants expected to be on long-term PN using a soy-based lipid emulsion at a goal provision of 1g/kg/day throughout a patient's entire PN course. An experimental cohort of surgical infants treated with lipid restriction from 2009 to 2011 (n=82) was retrospectively compared to a control cohort of infants from 2005 to 2008 receiving standard intravenous lipid dosing (n=132). A multivariable relative risk regression model was constructed analyzing the association between lipid restriction and PNALD. ResultsPatients admitted during the lipid restriction era had reduced daily lipid provisions compared to the control group (p<0.001). There were no significant differences in demographic or measured clinical characteristics between the two groups. A significant reduction in the incidence of PNALD was demonstrated in the lipid restricted group compared to the control group (22% vs. 43%, p=0.002). On multivariable relative risk regression, patients treated with standard lipid provisions were 1.77 times more likely to develop PNALD than patients who were lipid restricted (95% CI: 1.2–2.7; p=0.007). ConclusionRestriction of intravenous soy-based lipid in PN-fed surgical infants is associated with a reduction in the incidence of liver disease. Early lipid restriction should be considered in all surgical infants who require PN as a preventative measure against PNALD.

719 The Effect of a Fish-Oil-Based Lipid Emulsion on the Parenteral Nutrition-Associated Liver Disease in Very Low Birth Weight Infants

Background and AimsProlonged parenteral nutrition (PN) can cause parenteral nutrition-associated liver disease (PNALD) in very low birth weight infants (VLBWIs). Evidence has suggested soybean-oil-based lipid emulsion (SOLE) is a contributing...

Incidence and risk factors of parenteral nutrition‐associated liver disease in newborn infants

The aim of the present study was to determine the incidence and risk factors of parenteral nutrition-associated liver disease (PNALD) in neonates. A 1 year prospective cohort study was carried out at the neonatal intensive care unit and sick neonatal wards, Chiang Mai University Hospital. Newborns >1000 g, receiving >7 days of parenteral nutrition (PN), were enrolled. Liver function tests were done by the end of first, second, and fourth week, and then every 4 weeks until the PN was discontinued and the jaundice resolved. The diagnosis of PNALD relied on a history of PN, direct bilirubin >2 mg/dL, and exclusion of other causes of neonatal cholestasis. Selected patient factors and PN compositions were analyzed to determine the risks for development of PNALD. A total of 24 infants with a mean gestational age and birthweight of 32.5 weeks and 1840 g were enrolled. Eight of the 24 developed PNALD. Compared to those without PNALD, gastrointestinal surgery, duration of enteral starvation, duration of PN, maximum PN caloric intake, and maximum carbohydrate intake were significantly associated with the development of liver disease. Despite the lack of statistical significance, there was a trend towards cholestasis in patients with sepsis. Elevation of direct bilirubin was the earliest biochemical change, observed in the first week after PN, followed by increased transaminases. Gastrointestinal surgery, duration of enteral starvation, duration of PN, maximum caloric and carbohydrate intake in PN were significant risks of PNALD in newborn infants.

Intravenous Fat Emulsions Reduction for Patients with Parenteral Nutrition–Associated Liver Disease

To test the hypothesis that implementation of a marked reduction in intravenous fat will result in reversal of parenteral nutrition-associated liver disease (PNALD) in infants. Prospective study of intravenous fat emulsion reduction in parenteral nutrition to 1 g/kg/d 2 times per week in neonates diagnosed with PNALD. Primary outcome measure was total bilirubin levels compared with gestational age, birth weight, and diagnosis-matched historical controls receiving 3 g/kg/d of intravenous lipids. Intravenous fat emulsion reduction resulted in a significant decline in total bilirubin levels compared with controls. Comparison of growth in the 2 groups was similar. Mild essential fatty acid deficiency was detected in 8 of 31 infants and was reversed with additional days of lipid infusion. No significant adverse events were noted. An association between intravenous lipid emulsion administration and the development of PNALD seems probable. Use of intravenous fat emulsion reduction is a potential approach to reverse PNALD in young infants. Frequent monitoring of essential fatty acid deficiency is needed with the use of this regimen.

Risk Factors for Parenteral Nutrition–associated Liver Disease Following Surgical Therapy for Necrotizing Enterocolitis

The aim of the study was to prospectively determine risk factors for the development of parenteral nutrition-associated liver disease (PNALD) in infants who underwent surgery for necrotizing enterocolitis (NEC), the most common cause of intestinal failure in children. : From February 2004 to February 2007, we diagnosed 464 infants with NEC, of whom 180 had surgery. One hundred twenty-seven patients were available for full analysis. PNALD was defined as serum direct bilirubin ≥ 2 mg/dL or ALT ≥ 2 × the upper limit of normal in the absence of sepsis after ≥ 14 days of exposure to PN. Median gestational age was 26 weeks and 68% were boys. Seventy percent of the cohort developed PNALD and the incidence of PNALD varied significantly across the 6 study sites, ranging from 56% to 85% (P = 0.05). Multivariable logistic regression analysis identified small-bowel resection or creation of jejunostomy (odds ratio [OR] 4.96, 95% confidence interval [CI] 1.97-12.51, P = 0.0007) and duration of PN in weeks (OR 2.37, 95% CI 1.56-3.60, P < 0.0001) as independent risk factors for PNALD. Preoperative exposure to PN was also associated with the development of PNALD; the risk of PNALD was 2.6 (95% CI 1.5-4.7; P = 0.001) times greater in patients with ≥ 4 weeks of preoperative PN compared with those with less preoperative PN use. Breast milk feedings, episodes of infection, and gestational age were not related to the development of PNALD. The incidence of PNALD is high in infants with NEC undergoing surgical treatment. Risk factors for PNALD are related to signs of NEC severity, including the need for small-bowel resection or proximal jejunostomy, as well as longer exposure to PN. Identification of these and other risk factors can help in the design of clinical trials for the prevention and treatment of PNALD and for clinical assessment of patients with NEC and prolonged PN dependence.

Prevention of parenteral nutrition-associated liver disease: lipid minimization

The cause of parenteral nutrition-associated liver disease (PNALD) is unknown. Evidence over the past decade has suggested soybean oil-based intravenous emulsions are a contributing factor to the development of PNALD. This review details the historical and scientific rationale, which associates intravenous lipid emulsion administration and PNALD. The article then reviews our own group's experience with lipid restriction and the reversal of PNALD in neonates on long-term parenteral nutrition. Finally, a clinical approach to restricting soybean-based intravenous lipid emulsions in parenteral nutrition is given. An association between intravenous lipid emulsion administration and the development of PNALD seems probable. Strategies to reduce lipid emulsions or develop new, nonsoybean-based lipid emulsions should be considered.

Hepatic P-glycoprotein changes with total parenteral nutrition administration.

The mechanism(s) responsible for the development of parenteral nutrition-associated liver disease (PNALD) is unknown. Recently, a number of bile canalicular transport proteins have been identified that transport bile components out of hepatocytes. One group of these genes, multidrug resistance 1 (mdr1) and mdr2, encode P-glycoproteins. Mice lacking mdr2 expression develop liver disease that appears similar to PNALD. This study investigated the alteration in the expression of these transport proteins during the administration of total parenteral nutrition (TPN). Mice received either physiologic saline and standard chow or TPN. Mice were sacrificed on day 7, and hepatic DNA and RNA content, mRNA expression, and levels of mdr1 and mdr2 proteins were measured. TPN administration led to a significant (p < .05) decline in mdr2 mRNA expression and an increase in mdr1 mRNA expression. Mdr2 protein expression declined by 66% in the TPN-treated group, and mdr1 protein expression significantly increased by 58%. Histology and biochemical parameters showed no evidence of liver injury. Serum bile acid levels were elevated in the TPN group, suggesting the development of early cholestasis. The decline in mdr2 and rise in mdr1 mRNA and protein expression with TPN administration occurred before the development of liver injury but during an early state of cholestasis. This suggests that alterations in mdr gene expression may be a causative factor in the development of PNALD.