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Parenteral nutrition (PN) and intravenous lipid emulsions (ILEs) play an important role in nutrition for premature infants and infants with intestinal failure.
Infants with intestinal failure require prolonged PN and are at high risk for intestinal failure–associated liver disease (IFALD), which is histologically hallmarked by cholestasis.
Various ILEs are available and their oil source varies.
Pure soybean oil (SO ILE) has a long-standing association with IFALD.
SO ILE’s high concentration of hepatoxic phytosterols and proinflammatory omega-6 fatty acids along with its insufficient antioxidant protection in the form of vitamin E contribute to the development and severity of IFALD.
Pure fish oil (FO ILE) is used to manage pediatric IFALD and can prevent liver failure.
FO ILE contains antiinflammatory omega-3 fatty acids and vitamin E and is devoid of phytosterols.
Multi-oil ILEs replace soybean oil with medium-chain triglycerides, olive oil–derived monounsaturated fatty acids, and eicosapentaenoic acid and docosahexaenoic acid–rich fish oil.
It remains unclear as to whether an ILE type offers any specific advantages for preterm infants without intestinal failure who require short PN courses.
When prescribing ILEs to infants with intestinal failure and preterm infants, clinicians should be mindful of the dose and fatty acid, phytosterol, and vitamin E composition.
Cholestasis affects 1 in every 2500 newborns worldwide. Because of impaired bile acid flux and bilirubin elimination, bilirubin and bile acids are retained in the liver, causing hepatocyte injury and apoptosis. The sine qua non of cholestasis in infants is a rise in serum conjugated bilirubin (CB) and bile acids. Traditionally, cholestasis has been diagnosed by an increase in serum direct bilirubin or CB, not an increase in circulating bile acids. While there is no universally agreed-upon definition for cholestasis, an arbitrary cutoff of >2 mg/dL is often used. Other commonly used diagnostic thresholds include a CB >1 mg/dL (if the total serum bilirubin is <5 mg/dL) or a CB >15% to 20% of the total serum bilirubin (if the total serum bilirubin is >5 mg/dL). Some data suggest that a lower cutoff should be used, particularly in the first two weeks of life (i.e., >0.8 mg/dL in the first 5 days or >0.5 mg/dL in the first 14 days). ,
Fig. 6.1 illustrates the hepatocellular transport and excretion of bile acids and bilirubin. Bile acids are transported into and out of the hepatocyte by organic solute transporter subunit (OST)-α and -β, organic anion-transporter polypeptide 1 (OATP1), and sodium taurocholate cotransporter peptide (NTCP). CYP7A1 is a critical, rate-limiting enzyme that endogenously synthesizes bile acids from cholesterol. The nuclear receptors farnesoid X receptor (FXR) and liver X receptor (LXR) act as intracellular sensors for bile acids and sterols. When activated by bile acids, FXR represses CYP7A1 and NTCP via the small heterodimer partner (SHP) and upregulates the bile salt exporter (BSEP, ABCB11 ), an ATP-dependent efflux transporter. BSEP excretes bile acids into the bile canaliculi, and the multidrug resistance–associated protein 2 (MRP2) and multidrug resistance protein 3 (MDR3) excrete bilirubin into the bile canaliculi. At the intestinal level, bile acids are absorbed into the enterocyte via the apical sodium–bile acid transporter (ASBPT) and bind to FXR, which activates the expression of fibroblast growth factor 19 (FGF19), a hormone that travels to the liver via the portal circulation and inhibits CYP7A1, thereby downregulating bile acid synthesis.
A common cause of cholestasis in infants cared for in the NICU is parenteral nutrition (PN)–related cholestasis. PN, specifically intravenous lipid emulsions (ILEs), has a long-standing association with cholestasis. Studies have demonstrated that phytosterols derived from ILEs with 100% soybean oil (SO ILEs) interfere with bilirubin and bile acid metabolism. , Infants at risk of PN- and ILE-induced liver injury include preterm infants and infants with underlying gastrointestinal pathology. Commonly encountered acquired and congenital gastrointestinal diseases in the NICU include necrotizing enterocolitis (NEC), intestinal perforation, gastroschisis, small bowel atresias, volvulus, meconium ileus, and Hirschsprung’s disease. Infants with intestinal failure (IF) are at the highest risk for PN- and ILE-induced liver disease. IF is defined as a reduction of gut function hallmarked by water, electrolyte, and nutrient malabsorption that leads to PN dependence.
While the terms parenteral nutrition–associated cholestasis (PNAC) and intestinal failure–associated liver disease (IFALD) are often used interchangeably, they are distinctly different. PNAC generally refers to CB >2 mg/dL in the absence of other liver diseases and >14 days of PN. In uncomplicated scenarios, PNAC is transient without long-term sequelae. On the other hand, IFALD refers to hepatobiliary dysfunction secondary to the toxicities associated with the long-standing use of PN and ILE and underlying intestinal anatomic abnormalities. It remains unclear whether IFALD should be defined by clinical, laboratory, or histologic criteria. IFALD is initially characterized by cholestasis and hepatitis. Advanced IFALD is heralded by thrombocytopenia, coagulopathy, and portal hypertension. If IFALD cannot be stabilized or reversed by intestinal rehabilitation, it can progress to end-stage liver disease requiring a multivisceral, liver-inclusive transplant. While the prevalence of IFALD among children with IF is not well studied, approximately 20% to 30% of children with IF develop IFALD and 4% develop liver failure. When appropriate, the term IFALD should be used in place of PNAC since it more accurately reflects this disease’s complexity and multifactorial nature.
Well-known risk factors for PNAC and IFALD include prematurity, low birth weight, fetal growth restriction, small for gestational age, intestinal surgeries, hepatic injury secondary to infections, ischemia, medications, bacterial overgrowth, genetics, and specific PN micro- and macronutrients, including ILE. The prevalence of PNAC and IFALD varies by population and report, given the absence of standardized definitions for cholestasis, PNAC, and IFALD. In a meta-analysis of studies, the incidence of PNAC in very-low-birthweight (birth weight <1.5 kg) and extremely low-birthweight infants (birth weight <1 kg) ranged from 0% to 67%. In the same meta-analysis, the incidence of IFALD in infants and children with short bowel syndrome (SBS) or who required intestinal surgery was 23% to 63%. The incidence of PNAC or IFALD is directly proportional to PN duration. For example, infants who receive <14 to 30 days of PN have a reported incidence of 0% to 37%, while those who receive >60 days have a reported incidence of 36% to 100%.
ILEs are a standard companion to parenteral amino acids and carbohydrates when providing PN. ILEs provide nonprotein calories and fatty acids and help ensure appropriate growth and development when achieving sufficient enteral nutrition is not possible. While ILE duration and dose are associated with liver injury, specific ILE constituents, namely omega-6 fatty acids, phytosterols, and vitamin E, play a role in liver injury. , , An ILE’s fatty acid, phytosterol, and vitamin E content is determined by the ILE’s oil source ( Table 6.1 ). The first-generation ILE, which was first introduced in 1961 and approved for use in the United States in 1972, is composed of pure soybean oil (SO ILE, Intralipid Fresenius Kabi, Uppsala, Sweden). SO ILE has a skewed omega-6 to omega-3 ratio (7:1) and contains hepatotoxic phytosterols. SO ILE is also a rich source of long-chain triglycerides (LCTs) and the omega-6 polyunsaturated fatty acid (PUFA) linoleic acid (LA), which is prone to lipid peroxidation, which causes cellular injury. LA and α-linolenic acid (ALA) are considered to be essential fatty acids and are metabolized to downstream fatty acids ( Fig. 6.2 ) and bioactive eicosanoids ( Fig. 6.3 ). The eicosanoids generated from the LA pathway are considered to be proinflammatory, while the eicosanoids generated from the ALA pathway are considered to be less inflammatory and help promote the resolution of inflammation ( Fig. 6.3 ).
SO ILE | SO,MCT ILE | SO,OO ILE | SO,MCT,OO, FO ILE | FO ILE | |
---|---|---|---|---|---|
Oil Source (%) | |||||
Soybean oil | 100 | 50 | 20 | 30 | 0 |
MCT | 0 | 50 | 0 | 30 | 0 |
Olive oil | 0 | 0 | 80 | 20 | 0 |
Fish oil | 0 | 0 | 0 | 15 | 100 |
Fatty Acid (% by weight, mean value, or range) | |||||
Medium Chain | |||||
Caprylic | 0% | 28.5% | 0% | 17 ± 0.2% | 0% |
Capric | 0% | 20% | 0% | 12 ± 0.2% | 0% |
Long Chain | |||||
Linoleic acid (18:2n–6) | 44–62% | 27% | 13.8–22% | 14–25% | 1.5% |
α-Linolenic acid (18:3n–3) | 4–11% | 4% | 0.5–4.2% | 1.5–3.5% | 1.1% |
Arachidonic acid (20:4n–6) | 0% | 0.2% | ND | 0.5% | 0.2–2% |
Docosahexaenoic acid (22:6n–3) | 0% | 0% | 0% | 1–3.5% | 14–27% |
Eicosapentaenoic acid (20:5n–3) | 0% | 0% | 0% | 1–3.5% | 13–26% |
Oleic acid (18:1n–9) | 19–30% | 11% | 44–80% | 23–35% | 4–11% |
Omega-6 to omega-3 ratio | 7:1 | 7:1 | 9:1 | 2.5:1 | 1:8 |
Phytosterols (mcg/mL) | |||||
β-Sitosterol | 243.26 ± 4.10 | 191.6 | 197.86 ± 5.38 | 131.58 ± 7.11 | ND |
Campesterol | 37.19 ± 0.54 | 30.9 | 11.41 ± 0.33 | 20.45 ± 1.04 | 0.95 ± 0.08 |
Stigmasterol | 49.57 ± 0.62 | 46 | 11.01 ± 0.54 | 18.51 ± 0.81 | 1.37 ± 0.35 |
Vitamin E (mg/L) | |||||
α-Tocopherol | ND | 169–171 | 32 | 163–225 | 150–300 |
To reduce the provision of phytosterols, LCTs, and LA while simultaneously lowering the omega-6 to omega-3 ratio, soybean oil can be replaced by other oils (coconut, olive, and fish oils). Several ILEs are now available globally, although approval for use in the pediatric population varies by country and indication ( Table 6.1 ). Worldwide, many NICUs have transitioned from SO ILE to other ILE products. In 1984, a second-generation ILE, a 50:50 blend of soybean oil and medium-chain triglycerides (MCTs) (Lipofundin, B-Braun, Melsungen, Germany), was introduced. MCTs are derived from coconut oil. In contrast to LCTs, which are packaged into chylomicrons, MCTs are directly absorbed from the intestine into the portal circulation and transported to the liver for oxidation. MCT-based ILEs have some potential advantages when compared to LCT-based ILEs. In contrast to LCTs, MCTs are hydrolyzed more quickly and do not generate proinflammatory eicosanoids. Hence they are considered to be “immune neutral.”
In the 1990s, a third-generation ILE blend of 80% olive oil with 20% soybean oil (ClinOleic, Baxter, Deerfield, IL) became available. Olive oil is enriched with the omega-9 monounsaturated fatty acid oleic acid, which, like MCTs, is considered to be “immune neutral.” Monounsaturated fatty acids are less prone to lipid peroxidation than PUFAs. Free radicals attack double bonds, generating malondialdehyde and 4-hydroxy-2-nonenal, which are carcinogenic, mutagenic, and toxic. Furthermore, olive oil is a source of α-tocopherol, a fat-soluble antioxidant that protects against lipid peroxidation.
Lastly, in the early 2000s, fish oil–containing ILEs were marketed. Fish oil supplies the antiinflammatory omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil also contains a negligible amount of phytosterols since it is not plant based. A 100% fish oil monotherapy (FO ILE, Omegaven, Fresenius Kabi, Bad Homburg, Germany) was US Food and Drug Administration (FDA) approved for use in the United States in 2018 to manage pediatric PNAC. In addition, a composite ILE (SMOF, Fresenius Kabi, Bad Homburg, Germany) combines 30% soybean oil with 30% coconut oil, 25% olive oil, and 15% fish oil (SO,MCT,OO,FO ILE). This composite ILE provides a more balanced omega-6 to omega-3 ratio (2.5:1) and is a source of DHA, EPA, and MCTs. Because fish oil–based ILEs contain PUFAs, they are supplemented with α-tocopherol.
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