Historically, a French study delineated IFALD in adult HPN patients as a value of at least 1.5-fold the upper limit of normal on two of three liver function measures for cholestasis that persists for more than 6 months [20]. This study also showed that chronic cholestasis predicts serious liver problems and is associated with the use of soybean oil-based lipids (SO) at doses >1 g/kg/day [20]. Several factors may explicate how LEs can impact on the development of IFALD:

Published surveys report that the use of a fish oil-based LEs (FO) is able to reverse IFALD [22, 23]. These surveys, nevertheless, are used at a markedly decreased dosage of FO (1 g/kg/d) if compared to that of SO in the control historic group (3 g/kg/day) [22]. That supports the hypothesis that the overall decreased fat intake rather than FO supplementation is important in reversing IFALD [21]. Interestingly a recently published paper reports two cases of reverted cholestasis by switching from SMOF lipid (Fresenius Kabi, Bad Homburg, Germany), an emulsion containing a mixture of 30 % of SO, 30 % of coconut oil, 25 % of olive oil, and 15 % of FO at 2.0–3.0 g/kg/day, to FO at 1 g/kg/day [24]. That supports the hypothesis that the reduced amount rather than the type of LEs may be hepatotoxic.

Anyway FO monotherapy has now been widely employed in clinical practice. FO alone may not be able to provide enough energy to sustain growth. A mixed LE containing soybean oil (SMOFlipid) compared with SO in a blinded randomized controlled trial in pediatric HPN patients resulted in mild changes in total bilirubin when administered four to five times per week at 2 g/kg/day and in normal growth pattern [25].

In North America, FO alone (Omegaven, Fresenius Kabi, Bad Homburg, Germany) is available on the market, whereas in Europe, it is possible to use LEs containing the mixture (SMOFlipid, Fresenius Kabi, Bad Homburg, Germany). That led to develop two different approaches to optimize LE use in the United States and Canada as compared with Europe.

Many institutions generally combine the use of novel lipid preparations and reduced rates of administration of SO to prevent the development of liver disease [21]; e.g., if bilirubin exceeds 34 μg/L, lipid intake is reduced at 1 g/k/day, while if it goes over 50 μg/L, the lipid source is changed to FO alone at 1 g/kg/day.

Table 6.1 summarizes the composition of available LEs employed in PN.

Excessive glucose intake causes increased lipogenesis and fat tissue deposition together with subsequent liver steatosis and enhanced production of triglycerides by the liver [3]. The American Society for Parenteral and Enteral Nutrition (ASPEN) [26], the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition [18], and the American Academy of Pediatrics guidelines (ESPGHAN) [27] recommend limiting the glucose infusion rate (GIR) at 12–14 mg/kg/min (18 g/kg per day) in infants and young children up to 2 years. Glucose intake should usually cover 60–75 % of nonprotein calories [3]. As reported above reduced LEs intake as strategy to prevent/treat IFALD may be required; in such cases increased glucose intake, to better satisfy the nutritional needs, resulted as well tolerated [28].

Furthermore, prophylactic cycling of PN may reduce the incidence of IFALD [21]. Cyclical PN is well tolerated and may be 3–6 months of age. In cyclical PN the maximal rate of glucose infusion may exceed the advised GIR. The maximal infusion rate should not exceed 1.2 g/kg per hour (20 mg/kg per min). A stepwise increase and decrease of glucose infusion rate at onset and at discontinuation of the infusion should be considered to avoid hyper- and hypoglycemia, respectively. A reliable method for tapering is to halve the rate for 30 minutes and then to halve this again for an additional 30 minutes. Glucose tolerance should be monitored during the first phases of the cycling PN [3].

With regard to the choice of amino acid solution, there is evidence that supplementation of TrophAmine may reduce the incidence of IFALD in certain high-risk populations such as those with NEC [19].

Furthermore, copper and manganese serum levels from PN solutions should be monitored closely in patients who have developed IFALD because they may exacerbate it [19].

There is a paucity of evidence in favoring one type of feed over the other in this setting; however, breastfeeding (BF) should be used when tolerated as it helps and promotes adaptation [30]. The full advantages of BF include the optimal macronutrient composition for human infant growth, with a full complement of macro- and micronutrients [31, 32]. In addition, it contains trophic factors such as epidermal growth factor, which likely augment the adaptive process [7]. Furthermore, BF contains immunoglobulins and natural antimicrobial properties which both enhance mucosal barrier function and prevent dangerous overgrowth of bacteria within the intestinal lumen. Finally it promotes intestinal colonization by appropriate lactobacilli and related bacteria which are important elements of healthy microbiome [33, 34]. Bovine colostrum also seems to confer beneficial effects on IF [35].

Finally BF supports physiological and psychological relationship between infant and mother. If the mother’s own milk is not available, banked breast milk, even with pasteurization, has nearly identical physiologic benefits [31]. Overall BF should be the first choice in SBS patients.

If BF is not available, formula selection should be based on:

Some HFs and AAs meet the above reported criteria. AAs have been shown effective in decreasing PN length in small and uncontrolled series of SBS patients [18, 40].

EN should be started as soon as postoperative ileus resolves [16, 41, 42], by the most physiological mode. This ideally should be in the form of oral bolus feeding via the breast or bottle. In infants unable to tolerate oral feeds, nasogastric tube feeding is needed. Continuous tube feeding is associated with increased feed tolerance by improved mucosal contact and decreased transit time within the gut [16]. Bolus tube feeding helps gut motility and adaptation and provides periods of fasting, thus reducing persistent hyperinsulinemia. After establishing an appropriate base of enteral nutrients, the general pattern is to increase the provision of enteral nutrients by a slow but steady increment, beginning at 10–20 mL/kg/day (for the average newborn). After the infant can tolerate continuous feeds of 5 mL/h, it is extremely useful to begin transition to oral feeds, providing in small quantities, three to four bolus oral feedings a day (equal or less than the volume continuously tolerated per hour). After establishing a stable feeding pattern, feeds are steadily increased on a daily basis [16]. In order to maximize overall enteral intake, it is often helpful to have continuous drips overnight. To correctly switch from PN to EN, it needs to consider that the net caloric extraction from EN is not 100 % as from PN and that macronutrient absorption from EN is superior than that of electrolytes and fluids. Therefore, PN should be decreased according to the calories provided by EN and not volume for volume [41].

In SBS infants, increasing stool output, vomiting, and irritability to the advancing EN may suggest poor tolerance to the current EN regimen. If stool output is between 30 and 40 mL/kg body weight, it needs to carefully increase EN. Doubled stool output or outputs >40 mL/kg/day are contraindications to increase enteral feeds and indications to deal with a short-term reduction in feeding volume that will be gradually reintroduced. Stool frequency greater than six times per day should induce to cautiously increase EN [16].

Carbohydrate intolerance, which determines frequent and liquid stools, is frequent in SBS patients, and it can be suggested by the presence of reducing substances on the stools and by the stool pH <6.

The rise in plasma citrulline concentration frequently accompanies the successful achieving of enteral tolerance. Citrulline is a nonessential amino acid produced by the enterocytes of the small bowel; its serum level has been shown to reflect intestinal mass in various gastrointestinal diseases. Citrulline concentration of 12–15 μmol/L or greater following EN beginning seems to predict a successful PN withdrawal [41]. In Table 6.2 we report the markers of impaired EN tolerance useful in clinical practice. The combinations of several markers are associated with evolution toward chronic IF.