New Lipid Strategies to Prevent/Treat Neonatal Cholestasis




Abstract


A growing amount of evidence suggests that specific components of parenteral nutrition (PN) are involved in the pathogenesis of intestinal failure-associated liver disease (IFALD). For a number of reasons, intravenous lipid emulsions (ILEs) are thought to play a key role in IFALD. PN without the provision of any fat source results in a higher incidence of liver dysfunction compared with PN with fat, making it difficult to draw a correlation between the role of ILE and PN-associated liver disease (PNALD) as both its presence and absence can predispose patients to developing PNALD. Moreover, excessive lipid provision is also thought to increase the incidence of IFALD. This may, in part, be caused by the widespread use of soybean oil-derived ILEs. Soybean oil-based ILEs contain high levels of proinflammatory omega-6 poly unsaturated fatty acids that result in increased production of proinflammatory products that can cause liver damage. Other components present in soybean oil-based ILEs, such as phytosterols and vitamin E content, may also contribute to the risk of IFALD. Alternative ILEs, containing fish, olive, or coconut oils, are being used to prevent or treat this potentially fatal disease. This chapter will address how the inflammatory characteristics of each oil source, the dose, and amount of phytosterols and alpha-tocopherol can either predispose patients to IFALD or be used in its prevention or treatment.




Keywords

Cholestasis, Essential fatty acid deficiency, Fish oil, Intestinal failure-associated liver disease, Intravenous lipid emulsions, Omega-3 fatty acids, Omega-6 fatty acids, Parenteral nutrition, Soybean oil

 





Summary of Key Points





  • Intestinal failure-associated liver disease (IFALD) is defined as liver disease that occurs as a result of management strategies for intestinal failure, such as prolonged courses of parenteral nutrition (PN) or repeated surgical interventions. Cholestasis associated with IFALD is typically defined as an elevated serum direct (i.e., conjugated) bilirubin ≥2 mg/dL (34.2 μmol/L).



  • For infants requiring PN for more than 30 days, current best practice recommendation is that soybean oil-based intravenous lipid emulsions (ILEs) be given at a dose of no more than 1 g/kg/day. More severe restriction of soybean oil-based ILE strategies may increase the risk of essential fatty acid deficiency (EFAD). Because of the different compositions of essential fatty acids, alternative lipid emulsions, such as those derived from fish oil or other lipid blends (e.g., olive oil), which do not need restricted lipid dosing, can be used.



  • For infants who do go on to develop cholestasis, fish oil-based ILE monotherapy rather than soybean oil-containing ILEs should be used. If fish oil is used as the exclusive source of lipids, at least 1 g/kg/day should be given, and the triene/tetraene ratio should be monitored to detect EFAD.



  • In addition to dosage, other factors that may predispose infants receiving an ILE to cholestasis include exposure of the ILE to ambient light/phototherapy or infusing/storing the ILE in di(2-ethylhexyl)phthalate (DEHP) infusion sets or containers.



  • When considering the optimal ILE for their patients, practitioners should consider the oil source, the inflammatory properties of that oil source, phytosterol content, and the amount of alpha-tocopherol present in the ILE formulation.





Introduction


Intestinal failure is a relatively rare condition and is associated with prolonged dependence on parenteral nutrition (PN). The term intestinal failure , first coined in 1981, is defined as “a reduction in the functioning gut mass below the minimal amount necessary for adequate digestion and absorption of nutrients.” In many instances, infants who are dependent on PN secondary to intestinal failure develop cholestatic liver disease, often referred to as intestinal failure–associated liver disease (IFALD). IFALD is defined as hepatobiliary dysfunction as a result of medical and surgical strategies for IF, which can either progress to end-stage liver disease or can be stabilized or reversed if intestinal adaptation can occur. IFALD had been previously been referred to as PN-associated liver disease/cholestasis (PNALD/PNAC) and PN liver disease because of the association of PN in the pathogenesis of the disease. IFALD is a broader term, which is now preferred because of the inclusion of other patient- and treatment-associated factors. It is more common in pediatric patients, particularly infants with a history of prematurity and/or bowel resection leading to short bowel syndrome and, until recently, has been a major cause of liver transplantation and death in this patient population. In children with intestinal failure (IF), the diagnosis of IFALD is usually made on the basis of long-term PN dependence and cholestasis exclusive of any other causes of hepatic injury. Cholestasis associated with IFALD is commonly defined as an elevated serum conjugated bilirubin ≥2 mg/dL (34.2 μmol/L). IFALD is seen in 40% to 60% of children who receive long-term PN (i.e., >3 months) and 15% to 40% of adults on home parenteral nutrition.


In neonates and infants with short bowel syndrome, IFALD tends to be more progressive and severe. In the era before lipid-sparing strategies or the use of alternative lipid emulsions came into existence, one retrospective review of all neonates at a single health system receiving PN for at least 14 days noted that IFALD occurred in 14% of infants receiving PN for 2 to 4 weeks, 43% of those receiving PN for 4 to 8 weeks, 72% of those receiving PN for 8 to 14 weeks, and 85% of those receiving PN for >14 weeks.


The mechanism of IFALD is still unknown but is probably multifactorial. Components of the PN could act as toxins, but sepsis and lack of enteral feeding are also thought to play major roles. Risk factors for IFALD include prematurity, low birth weight, and intrauterine growth restriction, suggesting that hepatic immaturity is a predisposing factor. Infants with IFALD will typically develop jaundice and elevated levels of conjugated bilirubin about 2 weeks after starting PN, but the onset may occur later. Clinical jaundice usually becomes evident when total bilirubin rises above 3 mg/dL (51.3 μmol/L). The laboratory findings are not specific; in addition to conjugated bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and gammaglutamyl transpeptidase (GGT) may be mildly elevated. As part of making a diagnosis of IFALD, other major causes of cholestasis must first be excluded. Sepsis and infection are common causes of transient conjugated hyperbilirubinemia in neonates. In those infants with sustained conjugated hyperbilirubinemia, practitioners may wish to consider having the patient evaluated for biliary obstruction (e.g., biliary atresia), infection, and metabolic and genetic liver diseases that require specific therapy.


Histologic changes in IFALD range from steatosis to cirrhosis. Steatosis is often the first histologic change seen on liver biopsy and is more frequently seen in adults on PN. With continued exposure to PN, progressive changes in hepatic histology can occur, including hepatocellular ballooning with steatosis, portal inflammation, canalicular and intracellular cholestasis (bile plugs), and bile duct proliferation that may mimic biliary obstruction. The degree of fibrosis can range from minimal portal fibrosis to cirrhosis. Despite being progressive while PN is continued, the extent of liver disease may progress more slowly if oral feeds are advanced and total PN intake is decreased. The cholestasis and abnormalities shown by liver tests tend to improve after PN is discontinued but may continue to persist for months. In one retrospective study, conjugated bilirubin normalized at a median of 13 weeks after weaning (95% confidence interval [CI] 8-14 weeks), and ALT levels normalized at a median of 35 weeks (95% CI 24-80 weeks). Furthermore, 1 year after weaning from PN, despite all patients having normal conjugated bilirubin, 42% continued to have abnormal ALT. Until recently, it was often a “race against the clock” to wean the infant from PN and have bowel adaptation occur before the infant succumbed to IFALD-associated complications.




Role of Intravenous Lipid Emulsions


Mounting evidence suggests that specific components of PN solutions, and especially intravenous lipid emulsions (ILEs), are involved in the pathogenesis of IFALD. Interestingly, PN without the provision of any fat source results in a higher incidence of liver dysfunction compared with PN with fat, making it difficult to draw a correlation between the role of ILEs and IFALD as both the presence and absence of ILEs can predispose patients to developing IFALD.


For more than 50 years, soybean oil-based ILE (SOLE) has been the most common form of ILE used throughout the world. This type of ILE is rich in omega-6 polyunsaturated fatty acids (PUFAs). Recent evidence, however, suggests that SOLE may be an important contributor to the pathogenesis of IFALD. Studies in animal models showed that SOLE is associated with liver injury compared with fish oil-based ILE (FOLE), which is rich in omega-3 PUFAs. Moreover, studies in adults have shown that SOLE infusion of >1 g/kg is one of several risk factors for the development of cholestatic liver disease. Excessive lipid provision is also thought to increase the incidence of IFALD. Proposed mechanisms through which SOLE’s excessive omega-6 PUFA content might cause liver injury include its proinflammatory effects and its ability to impair triglyceride export. In contrast, omega-3 PUFAs tend to have anti-inflammatory and insulin-sensitizing effects, acting through the G-protein-coupled receptor (GPR)120.


Inflammatory Characteristics of Oil Source


IFALD is considered by many to be a disease of inflammation. The presence of an underlying inflammatory source may be a key influence in the progression of PNALD in patients with IF. C-reactive protein (CRP), an acute inflammatory marker, has been shown to reflect disease progression in nonalcoholic steatohepatitis, a disease that in many ways resembles IFALD.


During episodes of acute inflammation, hepatocytes upregulate transcription and release of CRP, primarily in response to the cytokine interleukin-6 (IL-6). This response can be enhanced by a combination of IL-1β and tumor necrosis factor (TNF)-α. There is evidence from experimental animals that PN use, in comparison with enteral nutrition (EN), is associated with greater retention of TNF in the plasma compartment. As an inflammatory marker, higher TNF levels could lead to a mild chronic inflammatory state and further amplify the CRP response in the case of IFALD.


PUFAs of the omega-6 and omega-3 family serve as substrates for eicosanoid synthesis, which directly influences an immune response. Eicosanoids are involved in modulating the intensity of an inflammatory reaction ( Fig. 9.1 ). SOLE is rich in omega-6 PUFA and linoleic acid (LA), which is the precursor of arachidonic acid (ARA), the structural backbone of proinflammatory eicosanoids (see Fig. 9.1 ; Fig. 9.2 ). In contrast, the omega-3 PUFAs found in fish oils but not in plant oils, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are converted into anti-inflammatory derivatives (see Fig. 9.1 , Fig. 9.2 ). Furthermore, ARA is a precursor of prostaglandin E2 and leukotriene B4, which have proinflammatory proprieties and influence cytokine synthesis. EPA from the omega-3 family serves as an alternative progenitor for cyclooxygenase and lipo-oxygenase pathways for eicosanoid synthesis with reduced inflammatory potencies. The balance between omega-6 and omega-3 PUFAs can affect eicosanoid synthesis, inflammatory response, and cytokine synthesis. PUFAs can influence proinflammatory gene expressions, such as peroxisome proliferator-activated receptor and nuclear factor-κB. PUFAs are necessary to prevent a deficiency of EFAs. However, when present in excess, they can have negative effects, leading to an unbalanced fatty acid pattern in cell membranes and the synthesis of eicosanoids. In a cohort of infants placed on ILEs within 48 hours of birth, Gawecka et al. showed that SOLE promoted an excess of IL-6 production compared with olive oil-containing ILEs. Similarly, Raptis et al. demonstrated the anti-inflammatory role of omega-3 PUFAs via the GPR120 receptor using fish oil-based ILEs. DHA has also been shown to inhibit palmitate-induced Toll-like receptor-4 (TLR4)–activated inflammation. In addition to high omega-6 fatty acid content, SOLE also contains high levels of phytosterols, which impair bile secretion via antagonism of the nuclear receptor Farnesoid X receptor (FXR), which will be discussed in greater detail below.




Fig. 9.1


Inflammatory properties of omega-3 and omega-6 fatty acids.

From: Lee S, Gura KM, Kim S, Arsenault DA, Bistrian BR, Puder M. Current clinical applications of omega-6 and omega-3 fatty acids. Nutr Clin Pract. 2006 Aug;21[4]:323–41.



Fig. 9.2


Synthesis of fatty acids.


Other Oil Sources


After the introduction of SOLE, a second-generation ILE was introduced in Europe, and it was a blend of 50% soybean oil and 50% medium-chain triglyceride (MCT) derived from coconut oil ( Table 9.1 ). These emulsions reduce the omega-6 PUFA content by 50%. MCTs are fatty acids that are 6 to 12 carbons long and include capric and caprylic acids. Unlike long-chain triglycerides, MCTs are easily metabolized and lack proinflammatory properties, both characteristics unique to this fat source. Furthermore, MCTs are resistant to peroxidation. MCTs also do not accumulate in the liver and consequently do not impair hepatic function. Despite these benefits, however, MCT oils are devoid of EFAs and thus cannot be used as a sole source of fat.



Table 9.1

Comparison of Lipid Emulsions (10 G Fat/100 Ml)


























































OIL Intralipid Omegaven Clinolipid SMOFlipid
Manufacturer Fresenius Kabi
(Uppsala, Sweden)
Fresenius Kabi
(Bad Homburg, Germany)
Baxter
(Deerfield, IL)
Fresenius Kabi
(Uppsala, Sweden)
Lipid Source
Soybean 100% 20% 30%
Medium-chain triglyceride 30%
Olive 80% 25%
Fish 100% 15%
Glycerol (% by weight) 2.25% 2.5% 2.5% 2.5%
Egg Phospholipid
(% by weight)
1.2% 1.2% 1.2% 1.2%


Since the 1980s, with the heightened awareness of the different inflammatory profiles of the available oil sources, there has been an evolution of ILE formulations. Emulsions have advanced from being solely made with soybean oil in the 1960s to being combined with MCTs in the 1980s, olive oil in the 1990s, and, more recently, with fish oil (see Table 9.1 ).


As previously mentioned, in the 1990s, olive oil was introduced as an oil source in ILE. Olive oil is rich in omega-9 fatty acids, primarily as oleic acid, a type of monounsaturated fatty acid (MUFA), which is not considered essential because it is not a precursor of eicosanoids. Unlike soybean oil and fish oil, olive oil is considered immune neutral. The relatively small amount of LA (approximately 5%) explains why this oil source requires blending with another oil source that contains EFA. In comparison with pure soybean oil, olive oil has a lower content of phytosterols and is naturally rich in alpha-tocopherol. Currently, the only available olive oil containing ILE is an 80% blend with 20% soybean oil (see Table 9.1 ). In this preparation, the mean concentration of LA is 35.8 mg/mL (range 27.6-44.0 mg/mL), and α-linolenic acid (ALA) is 4.7 mg/mL (range 1.0-8.4 mg/mL). This product has 30% of the PUFA content of conventional SOLE. In comparison with soybean oil, olive oil is rich in MUFAs that possess less proinflammatory properties and are more resistant to oxidative stress injuries from free radicals. In many European countries, it is the preferred lipid source. Although currently not approved in the United States for pediatric use, in a randomized controlled trial (RCT) from Australia, an olive oil-containing ILE used in preterm infants younger than 28 weeks’ gestational age was found to be safe and well tolerated.


Fish oil is the newest oil source to be used in ILE. Like olive oil, ILE containing fish oil is less proinflammatory than SOLE. In comparison with those originating from omega-6 PUFAs in SOLE, the eicosanoids produced from omega-3 PUFAs in FOLE are generally less inflammatory. Unlike SOLE, FOLE has little LA and ALA but contains their downstream metabolites, ARA, EPA, and DHA. The omega-3 PUFAs present in fish oil are also natural ligands to some receptors of the GPR family. Recent evidence demonstrates that the interaction with these receptors mediates some of the therapeutic benefits of omega-3 PUFAs in tissues, such as the liver.


Le et al. assessed lipid and fatty acid profiles of 79 pediatric patients who developed IFALD while receiving standard PN with SOLE before and after being switched to FOLE. Children who developed cholestasis while receiving PN with SOLE had their ILE administration discontinued and were treated with FOLE. FOLE was started at a dose of 1 g/kg/day infused over 12 to 24 hours. The serum fatty acid values at the end of the study were compared with baseline values that reflected the use of SOLE. The results showed a dramatic increase in omega-3 PUFAs, such as EPA and DHA. However, ALA, the precursor fatty acid to both EPA and DHA, decreased almost 60% from the baseline value. Switching from SOLE to FOLE also led to a decrease in all omega-6 PUFAs; in particular, gamma-linolenic acid, dihomo-gamma-linoleic acid, and ARA. The decrease in these fatty acids occurred concurrently with the decrease in omega-9 fatty acids (oleic acid and mead acid), which indicated that these patients did not produce extra nonessential fatty acids to compensate for the decrease in both ALA and LA concentrations. Lipid profiles of the 79 children showed decreases in low-density lipoprotein, very-low-density lipoprotein, cholesterol, and serum triglycerides. In addition to the improvement in lipid profiles, which are significant predictors of metabolic derangement, CRP also decreased significantly after treatment with FOLE.


Before being used as monotherapy, FOLE was blended with other oil sources. In a European retrospective study, the outcomes of 20 neonates with short bowel syndrome treated with an olive oil/soybean oil blend supplemented with FOLE was compared with the outcomes in a historical cohort of 18 patients with short bowel syndrome receiving SOLE alone. The rationale for the use of this blend of oils was to provide an omega-6/omega-3 fatty acid ratio of 2:1 to 1:1. This was similar to a ratio that had been reported in a previous study using a 1:1 blend of soybean and fish oils. This proportion is also within the optimal range for anti-inflammatory effects and is similar to that found in breast milk. The researchers reported that in the olive oil/soybean oil/fish oil group, the direct bilirubin levels were reversed in all 14 survivors with cholestasis (direct bilirubin >50 μmol/L) with a median time to reversal of 2.9 months; two patients died as a result of liver failure (10%). In the SOLE controls, six patients (33%) died as a result of liver failure, and only two patients had normalization of bilirubin levels.


Role of Phytosterols in the Pathogenesis of IFALD


Phytosterols are naturally occurring compounds found in plant cell membranes and are structurally similar cholesterol. In animal studies, phytosterols have been shown to interrupt hepatocyte FXR signaling and the expression of downstream bile acid transporters, thus decreasing bile flow. In animal models, phytosterols have been shown to increase the risk of sepsis by altering the migratory and phagocytic functions of neutrophils, which can also contribute to IFALD. Iyer et al. investigated the effect of intravenous plant sterols in piglets at doses equivalent to those used with commercial ILE preparations. Although they did not demonstrate any clinical or histologic changes of cholestasis within the 14-day study period, serum bile acid levels were elevated in the sterol-treated piglets, suggesting early onset of cholestasis. As part of the same investigations, using a rat hepatocyte model, Iyer et al. showed that a commercial ILE enriched with plant sterols led to significant inhibition of hepatocyte secretory function. Similarly, El Kasmi et al. used mouse models to show that in comparison with FOLE, SOLE led to accumulation of stigmasterol in serum and in the liver and that it was associated with hepatic injury and cholestasis, along with reduced expression and function of the Abcb11 and Abcc2 genes, which play a critical role in bile transport. On a molecular basis, they found that the expression of the canalicular exporter for stigmasterol, Abcg5/g8, was downregulated, resulting in hepatic accumulation of stigmasterol. This was associated with an inhibition in the expression of nuclear receptor FXR within the hepatocyte, which, in turn, reduced the expression of FXR-dependent genes, including bile salt export pumps that are responsible for driving bile flow.


In neonates, phytosterols appear to accumulate rapidly. Nghiem-Rao et al. conducted a prospective cohort study in which 45 neonates (36 SOLE recipients versus 9 controls) underwent serial blood sample measurements of sitosterol, campesterol, and stigmasterol. They reported that very preterm infants receiving SOLE had higher sitosterol exposure and concluded that the poorly developed mechanisms of eliminating phytosterols might be a contributing factor for preterm infants being at greater risk for developing IFALD.


The U.S. Food and Drug Administration (FDA), however, is concerned about the phytosterols content in ILEs. As part of the postmarketing process, manufacturers of several recently approved ILEs are now required to conduct studies in this area as a condition of the product’s approval. The requirements include developing and validating analytical methods for determining individual component phytosterol content and testing for individual component phytosterol content. On the basis of the results, data would be used to establish limits for individual phytosterol components. The FDA also requires manufacturers to develop and validate analytical methods for measuring phytosterol levels in plasma. Furthermore, FDA recommends that RCTs in pediatric patients (including neonates) be performed to compare an ILE product with a phytosterol-depleted formulation and a standard-of-care ILE to evaluate the incidence of liver injury, including IFALD. Table 9.2 compares the phytosterol content of commonly used ILEs.



Table 9.2

Phytosterol Content of Commonly Used Intravenous Lipid Emulsions




















































OIL Intralipid Omegaven Clinolipid SMOFlipid
Manufacturer Fresenius Kabi
(Uppsala, Sweden)
Fresenius Kabi
(Bad Homburg, Germany)
Baxter
(Deerfield, IL)
Fresenius Kabi
(Uppsala, Sweden)
Lipid Source
Soybean 100% 20% 30%
Medium-chain triglyceride 30%
Olive 80% 25%
Fish 100% 15%
Phytosterol Content
(mg/L)
439 + 5.7 3.66 274 + 2.6 207


Not all animal models support the role of phytosterols as a causative factor in IFALD. In one study, premature piglets fed on an exclusively PN diet with different ILEs found that it was not the phytosterol content but, rather, the vitamin E or omega-3 PUFA content that was more hepatoprotective. In fact, in subsequent studies using the same piglet model, the addition of phytosterols to 100% FOLE did not produce IFALD. There is one major difference between the piglet model of IFALD and the murine model that may be responsible for some of the observed differences in results. It is customary to treat the piglets with broad-spectrum antibiotics, which may alter the intestinal microbiota, resulting in no intestinal injury or inflammation and thus no subsequent increase in intestinal permeability leading to IFALD.


On the basis of this limited information, it would make sense to use an ILE with as little phytosterol content as possible. One means of reducing the phytosterol content in plant-based ILEs is to winterize the oil. This is a labor-intensive and somewhat expensive process and involves crystallization (or partial solidification) of the oil, followed by a separation of solids and fats.


Other Plant Toxins


Recent evidence also suggests that other plant toxins, such as isoflavonoids (i.e., biliatresone), may act to selectively destroy bile ducts outside the liver. Interestingly, SOLE is rich in both phytosterols and isoflavonoids. In animal models, biliasterone was found to destroy bile ducts outside the liver, but not inside the liver, without toxic effects on other tissues. This suggests a toxin is responsible because of its affinity to large, extrahepatic bile ducts.


Alpha-Tocopherol


Vitamin E is the major lipid-soluble antioxidant that protects unsaturated fatty acid acyl chains in the cell membranes from oxidative damage. It is added as alpha-tocopherol to ILE with high PUFA content to prevent peroxidation. Besides suppressing oxidant stress, vitamin E possesses diverse biologic functions, such as inducing bile acid activation and xenobiotic metabolism. The amount of vitamin E (as alpha-tocopherol) in ILEs may also play a role in IFALD. Alpha-tocopherol is abundant in pure fish oil and new-generation ILE blends. In humans, this form of vitamin E is preferentially absorbed and accumulated in tissues, whereas gamma-tocopherol, the principle form of vitamin E in SOLE, although easily metabolized in the liver, does not accumulate in plasma or tissues. Gamma-tocopherol also has a much lower bioactivity compared with alpha-tocopherol. Moreover, patients who have received prolonged courses of SOLE have demonstrated reduced alpha-tocopherol concentrations in their plasma lipoproteins; this may further predispose patients to IFALD. Table 9.3 summarizes the alpha-tocopherol content of representative ILEs.



Table 9.3

Alpha-Tocopherol Content of Representative Lipid Emulsions




















































OIL Intralipid Omegaven Clinolipid SMOFlipid
Manufacturer Fresenius Kabi
(Uppsala, Sweden)
Fresenius Kabi
(Bad Homburg, Germany)
Baxter
(Deerfield, IL)
Fresenius Kabi
(Uppsala, Sweden)
Lipid Source
Soybean 100% 20% 30%
Medium-chain triglyceride 30%
Olive 80% 25%
Fish 100% 15%
Vitamin E (mg/L) 38 mg 150-296 mg 32 mg 163-225 mg


In animal models, supplementation of SOLE with alpha-tocopherol has been shown to prevent hepatic damage, probably because of its antioxidant properties. The hepatoprotective effects of vitamin E are thought to be mediated by activation of the PXR and CAR target genes involved in bile acid synthesis. Others have shown, however, that in term neonatal piglets, supplemental ILE with alpha-tocopherol did not prevent cholestasis. Additional vitamin E was not associated with reduced inflammation or oxidative stress. This suggests that the benefit of supplementing SOLE with vitamin E, rather than adding additional vitamin E to FOLE, to prevent early onset of IFALD is not applicable to all animal models of IFALD and requires further investigation. Clinically, results have also been mixed. In two large RCTs, treatment with vitamin E resulted in significant improvement in steatosis, ballooning, and inflammation in adults without diabetes or cirrhosis but did not offer any sustained benefit in children with nonalcoholic fatty liver disease.


Impact of Lipid Dose on Predisposing Patients to IFALD


Regardless of type of substrate, macronutrient excess in PN has been shown to be harmful. Excessive lipid provision may be especially detrimental. To date, data on the benefits of reducing lipid intake have been conflicting. SOLE dose reduction from 2 to 3 g/kg/day to 1 g/kg/day has not been proven to decrease the incidence of IFALD. Low-dose SOLE may, however, slow the progression of hepatic disease, but when done to the extreme, it also carries the risk of predisposing patients to developing essential fatty acid deficiency (EFAD).


As part of an analysis of factors contribution to IFALD in adults receiving home parenteral nutrition, Cavicchi et al. reported that SOLE doses of >1 g/kg/day were significantly associated with chronic cholestasis and liver disease. Similarly, Cober et al. compared limiting doses of SOLE to 1 g/kg/day twice weekly in infants and compared total bilirubin levels with historical controls who received 3 g/kg/day of SOLE. A marked reduction in SOLE intake was associated with a progressive decline in bilirubin levels in infants with IFALD, without a significant effect on growth, although there was a trend toward development of EFAD.


Impact of Lipid Dispensing/Infusion Practices


Even the method used to dispense or infuse ILEs may contribute to the development of IFALD. It has been well known for many years that photodegradation of amino acids may lead to IFALD. Neuzil et al. hypothesized that ILE can be negatively affected by ambient light. This is based on the premise that alpha-tocopherol could serve as a pro-oxidant in isolated lipoprotein suspensions, such as ILEs. Neuzil et al. exposed SOLE to a single spotlight, commonly used in the treatment of neonatal jaundice, and measured the formation of triglyceride hydroperoxides by using high-performance liquid chromatography. They observed that the concentrations of these hydroperoxides in different batches of SOLE increased by 60-fold after 24 hours of exposure to phototherapy lights. Triglyceride hydroperoxides were formed during phototherapy light exposure whether the SOLE was given via plastic intravenous administration sets used routinely for infusion or via glass containers. Although to a much lesser extent than observed with phototherapy, ambient light was also shown to cause significant peroxidation of ILEs. The authors concluded that phototherapy light-induced formation of triglyceride hydroperoxides could be prevented by covering SOLE with aluminum foil or supplementing it with sodium ascorbate before light exposure.


To further complicate matters, the type of oil in the ILE may also be important factor in determining the impact of photo-oxidation. Assuming that photo-oxidation of PN may result in production of 4-hydroxynonenal, which is suspected to be involved in the pathogenesis of IFALD, Miloudi et al. attempted to find a practical means to reduce 4-hydroxynonenal in PN and assessed the in vivo impact of PN containing low concentrations of 4-hydroxynonenal. Using a newborn guinea pig model, hepatic markers of oxidative stress (glutathione, F[2α]-isoprostanes [GS-HNE]) and inflammation (messenger RNA [mRNA] of TNF-α and IL-1) were measured after the animals received infusions of PN compounded with either SOLE or FOLE over a 4-day period. Compared with SOLE, FOLE was found to reduce oxidative stress associated with PN and prevent hepatic inflammation.


Given the conflicting data and the lack of risk associated with protecting PN solutions from light, the choice remains one of risk to benefit, with many neonatal intensive care units (NICUs) opting to cover PN solutions and ILEs because this may confer some benefits and avoid the risk of undue harm.


A separate factor that has been suggested to play a role in the development of IFALD is use of tubing containing phthalates (di[2-ethylhexyl]phthalate [DEHP]) for administration of PN and ILEs. DEHP is a substance that can lead to an increase in oxidative stress and toxicity, especially in preterm infants and neonates who receive intensive care. DEHP is a phthalic acid ester and is used as a plasticizer in polyvinylchloride (PVC) and other plastics. Most PVC infusion systems are plasticized with up to 60% of DEHP. Because DEHP is not covalently bound to the plastic matrix, DEHP is easily extracted from the tubing by PN solutions and has been shown to have toxic effects on various organ systems, including the livers of animals and humans. DEHP has the potential to reduce the canalicular excretion of bilirubin and, thus, to contribute to the development of cholestasis. The extent of DEHP leaching, however, is dependent on the type of fluid being infused. Crystalloids tend not to be problematic, but blood products and ILE are. Moreover, the type of ILE can also influence the amount of DEHP that can be extracted from the container and tubing. In a study assessing the potential role of the type of ILE on the quantity of DEHP leached, it was shown after 24 hours of exposure to PVC-based tubing that DEHP migration varied significantly ( P = 0 .0000152) according to lipid type. The olive oil-based ILE leached the most DEHP (65.8 μg/mL), followed by FOLE (37.8 μg/mL). SOLE showed comparable degrees of leaching (19.6-27.8 μg/mL). Von Rettberg et al. assessed the effect of using DEHP-based tubing versus DEHP-free tubing in patients who had received PN containing ILEs for at least 14 days in pediatric intensive care units. In the preintervention period, all intravenous infusion sets, including those for administering blood products, contained PVC. After 2001, all intravenous infusion sets were switched to non-PVC sets. Of the 30 patients in the PVC group, 15 developed signs of cholestasis, whereas of the 46 patients who were treated without using PVC infusion sets, only 6 did. This was equivalent to a reduction in the incidence of cholestasis from 50% to 13%. The authors concluded that the use of infusion systems that contained PVC lead to a 5.6-fold increase in risk for the development of hepatobiliary dysfunction.

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Mar 12, 2019 | Posted by in PEDIATRICS | Comments Off on New Lipid Strategies to Prevent/Treat Neonatal Cholestasis
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