Intestinal Failure-Associated Liver Disease

 

Possible Mechanism of IFALD




Intestinal failure associated liver disease (IFALD) is probably the most important complication affecting children with IF on long-term PN. The prevalence of the disorder is unknown because there is no established definition of liver disease in this setting and it is unclear as to whether IFALD should be diagnosed on the basis of clinical, biological, or histological criteria. Indeed, there are insufficient data on the degree and type of liver involvement in patients with long-term PN (Goulet ; Kaufman et al. ).

The main factors contributing to liver injury in these patients are recurrent catheter-related sepsis, prematurity and low birth weight, lack of enteral feeding, disruption of entero-hepatic biliary acid cycle (proximal stoma, ileal resection), intestinal stasis, and bacterial overgrowth (obstruction, dysmotility, lack of ileo-caecal valve, over-tube feeding…).

Factors affecting the onset and the expression of IFALD that are specifically related to PN are as follows:

  • Duration of PN

  • Recurrent catheter-related sepsis

  • Altered protein energy delivery

    • Excessive or unadapted amino acid intake

    • Continuous versus cyclic infusion

    • Excessive glucose intake

    • Lipid emulsion related: phytosterols, lipoperoxidation, excess of omega-6 fatty acids, essential fatty acid deficiency

  • Potential toxic components: iron, aluminium, chromium, manganese

  • Deficiencies: taurine, choline

It should be stressed that the most important factors leading to IFALD are those related to individual patient characteristics and, importantly, the episodes of sepsis catheter or small intestinal bacterial overgrowth related (Geier et al. ; Hermans et al. ; Wagner et al. ).

IFALD develops frequently at very early ages, especially in premature infants in whom liver immaturity, frequent sepsis and necrotizing enterocolitis (NEC) facilitate liver inflammation and severe damages. At this young age, PN is most often administered continuously over 24 h and CRS is common. High risk situations for developing liver disease are as follows:

  • Premature and young infants

  • NEC or gastroschisis ± atresia

  • Protracted bowel rest/intestinal stasis

  • Small intestinal bacterial overgrowth/Gram-negative sepsis

  • Recurrent catheter-related sepsis

  • Unadapted and/or continuous (noncyclic) PN

The combination of the following factors makes cholestatic liver disease likely to occur.

An important role in this process is played by liver inflammation caused by extrahepatic infections in which microbial products brought to the liver through the blood stream, either directly or through production of cytokines, lead to alterations of bile flow. The inflammation associated with these changes may cause rapid fibrosis and eventually biliary cirrhosis with end-stage liver disease (El Kasmi et al. ).

Intravenous Lipid Emulsions and Liver Disease and IFALD

Frequently cited observational studies suggested a link between intravenous lipid emulsions ( ILE) and liver disease (Cavicchi et al. ; Colomb et al. ). Ganousse-Mazeron et al. reported that the improvement of cholestasis depends also on maintaining an appropriate protein/energy ratio in PN, achieving cyclic rather than continuous PN infusion, using medium-chain triglycerides-based lLE, and adding alpha-tocopherol in ILE (Ganousse-Mazeron et al. ).

IFALD is a multifactorial disease in which the use of soybean oil-based emulsions in PN may represent the major culprit (Koletzko and Goulet ; Goulet et al. ). Several factors should be taken into consideration when choosing an ILE for parenteral use: the content in essential fatty acids (EFAs), the ratio of ω-6/ω-3, the polyunsaturated fatty acid (PUFAs) content, the amount of medium-chain triglycerides (MCTs), and the quantity of alpha-tocopherol and phytosterols.

The probable detrimental effect of ω-6 FAs on liver function is provided by studies that showed that fat emulsions based on pure fish oil (containing ω-3 FAs) have been successful as rescue therapy in pediatric patients with SBS affected by severe liver disease (Gura et al. ). The infusion of exclusively ω-3 FAs ultimately changed the management of these patients since it allowed the reduction of intake of pro-inflammatory ω-6 and phytosterols while increasing the amounts of alpha-tocopherol, a powerful antioxidant (Lieseisen et al. ).

The evidence gathered on the beneficial effects of fish oil in these patients has led to its use in clinical practice; however, two different approaches have been developed in North America compared to Europe. In North America, only a pure fish oil solution (Omegaven®) is available on the market, whereas in Europe, it is also possible to use an emulsion containing a mixture of soybean oil (30%), coconut oil (30%), olive oil (25%), and fish oil (15%) (SMOF-lipid®). Both ILEs contain 200 mg/L of alpha-tocopherol.

Some concerns have been raised on providing fish oil as the sole source of lipids over a long period of time. Pure fish oil provides less essential ω-6 fatty acids than that currently recommended in infants and young children. Furthermore, Omegaven® (pure fish oil) can only be given at lower infusion rates compared to SMOF-lipid®). Omegaven® may not be able to provide enough calories to sustain growth. Thus, a composite intravenous lipid emulsion b ased on the combination of several types of oil by mixing soybean oil (rich in ω-6 FAs), coconut oil (rich in MCTs), olive oil (rich in MUFAs), and fish oil (rich in ω-3 FAs) appears to promote better growth while limiting hepatic toxicity (Wanten et al. ). Phytosterols contained in soybean oil have been found to be associated with liver disease progression and their exclusion from intravenous lipid emulsions may also be beneficial in children on PN (Forchielli et al. ). Clayton compared the level of phytosterols in plasma of healthy subjects, patients with mild hepatic dysfunction and those with severe dysfunction who received soybean oil emulsion – rich in sterols – and found a link between liver damage and phytosterols plasma levels (Clayton et al. ).

Regarding the presence of tocopherol in lipid emulsions, one should emphasize that there are different preparations of tocopherol: alpha-tocopherol is the form with far greater antioxidant activity (Wanten et al. ). While soybean oil emulsions contain a high amount of gamma-tocopherol (which has 25% of the antioxidant power as compared to alpha-tocopherol), lipids based on fish oil are rich of the most powerful antioxidant vitamin E, alpha-tocopherol (Mertes et al. ). To ensure a proper antioxidant power in lipid preparations, it is advisable to add 0.5 mg of alpha-tocopherol per gram of PUFAs.

A randomized, double-blind, controlled trial on 60 preterm babies stratified by body weight has analyzed a set of parameters (clinical data, laboratory data, fatty acids in plasma and red blood cells, plasma levels of alpha-tocopherol and-phospholipids) after infusion of PN with SMOF-lipid® or soybean oil based emulsion (Tomsits et al. ). The SMOF-lipid® emulsion increased the content of eicosapentaenoic EPA and docosahexaenoic (DHA) acids and reduced the ω-6/ ω-3 ratio, improving also liver function tests.

Another study evaluated the long-term effects of the lipid mixture SMOF-lipid® versus a soybean oil-based preparation in pediatric patients on home PN (Goulet 2010). This randomized, double blind study involved 28 children who received more than four infusions of PN per week for four consecutive weeks. The infusion was administered in 12–14 h overnight. At the end of the study, no differences between biochemical and nutritional outcomes were recorded, but there was a clear association between the use of SMOF-lipid® and a significant decrease of bilirubin levels, that conversely increased in the soybean oil based group (Goulet 2010).

A confirmation of these findings comes from the study of Muhammed et al. who examined the effect of the switch from a soybean-based lipid emulsion to SMOF-lipid® in 17 children with cholestasis. The subjects were assigned to a treatment group receiving SMOF-lipid® and a group receiving soy-based lipids. Over a period of 6 months, the use of SMOF-lipid® was associated with a marked statistically significant reduction in the levels of bilirubin when compared with the soy-based lipid group (Muhammed et al. ).

It may be concluded that recent studies have emphasized the superiority of fish oil-derived lipid emulsions as a major advance for the management of patients on long-term PN. Preparations with pure fish oil are effective in improving cholestasis, but their use as the sole source of lipids may not meet essential fatty acids requirements especially in the long-term (Goulet ; Goulet and Lambe ). Nevertheless, while some randomized controlled trials have demonstrated the beneficial effect of SMOF-lipid® versus soy-based lipid emulsion, no studies have compared SMOF-lipid® to Omegaven® in these patients (Tomsits et al. ; Goulet 2010).

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